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    EudraCT Number:2017-001785-14
    Sponsor's Protocol Code Number:STRESS-L
    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:2018-08-02
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2017-001785-14
    A.3Full title of the trial
    STRESS-L: STudy into the REversal of Septic Shock with Landiolol (Beta Blockade)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    STRESS-L: STudy into the REversal of Septic Shock with Landiolol (Beta Blockade)
    A.3.2Name or abbreviated title of the trial where available
    Study into the Reversal of Septic Shock with Landiolol (Beta Blockade)
    A.4.1Sponsor's protocol code numberSTRESS-L
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN12600919
    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 Hospitals Birmingham 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.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Warwick
    B.5.2Functional name of contact pointEmma Skilton
    B.5.3 Address:
    B.5.3.1Street AddressWarwick Clinical Trials Unit, University of Warwick, Gibbet Hill Campus
    B.5.3.2Town/ cityCoventry
    B.5.3.3Post codeCV4 7AL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02476572905
    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. name Landiolol hydrochloride 300 mg lyophilised powder
    D. of the Marketing Authorisation holderAmomed Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationMalta
    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 nameLandiolol hydrochloride 300 mg lyophilised powder
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Tachycardia in Septic Shock
    E.1.1.1Medical condition in easily understood language
    Rapid heart rate in patients admitted to ICU with septic shock
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10040070
    E.1.2Term Septic shock
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10043071
    E.1.2Term Tachycardia
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this trial is to assess the efficacy, safety and mechanisms of beta-blockade in patients with septic shock and tachycardia (very fast heart rate) requiring prolonged (>24 hours continuous treatment) support with high-dose vasopressor agents (drugs that elevate arterial blood pressure).
    E.2.2Secondary objectives of the trial
    The secondary objectives of the trial are:
    • To deliver an open-label, multi-centre randomised trial to determine whether infusion of the rapid-acting, ultra-short-lived and highly specific beta-adrenergic antagonist landiolol improves mortality and length of hospital stay compared with current best clinical practice, in patients who have septic shock.
    • To investigate the pathways that are altered by beta blockade in septic shock by examining the effects of landiolol on blood markers of inflammation, metabolism and cardiomyocyte damage.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Aged 18 years or above
    • Being treated on an ICU
    • Septic shock according to internationally accepted definitions*
    • Heart rate ≥95 bpm ( at the time of randomisation)
    • Receiving vasopressor support to maintain a target blood pressure for ≥24 hours
    • Are being treated with noradrenaline at a rate ≥ 0.1mcg/kg/min

    *Sepsis -3 definitions:
    o confirmed or suspected infection requiring antibiotic therapy
    o new organ dysfunction, as evidenced by an increase in SOFA score ≥2
    o a blood lactate >2 mmol/l at any point during shock resuscitation
    o vasopressor therapy to maintain mean arterial pressure (MAP) ≥65 mmHg

    In particular the presence of a blood lactate > 2 mmol/l is only necessary for the diagnosis of septic shock and is NOT necessary for randomisation 24 hours later.
    E.4Principal exclusion criteria
    • Tachycardia as a result of pain, discomfort from medical devices (including endotracheal tubes), during interventions or other patient distress
    • Any form of vasodilatory shock that is not caused by sepsis
    • Noradrenaline infusion <0.1mcg/kg/min
    • >72 hours after start of vasopressor therapy
    • <12 hours since noradrenaline to treat a medical condition after than septic shock stopped
    • Having pre-existing severe cardiac dysfunction (NYHA grade 4 or more)
    • Having pre-existing severe pulmonary hypertension (mean PA pressures > 55mmHg)
    • Acute severe bronchospasm (due to asthma or COPD)
    • Untreated second or third degree heart block
    • Untreated phaeochromocytoma
    • Prinzmetal's angina
    • A past history of ischaemic stroke or transient ischaemic attack (TIA) or untreated severe carotid stenosis.
    • Advanced liver disease with Child-Pugh Score of ≥B.
    • Known sensitivity to beta-blockers
    • Patient / legal representative unwilling to provide written informed consent
    • Known to be pregnant
    • Terminal illness other than septic shock with a life expectancy < 28 days
    • Participants who have been administered an investigational medicinal product for another research trial in the past 30 days
    • Patients in whom the clinical team feel are about to finish their noradrenaline therapy
    • Decision of withdrawal of care is in place or imminently anticipated.
    • Receiving extracorporeal membrane oxygenation (ECMO) treatment
    E.5 End points
    E.5.1Primary end point(s)
    Our primary outcome will be the mean SOFA score over the first 14 days from entry to the trial and whilst in ICU. The mean SOFA (Vincent 1999) is a measure of the amount of organ support required by a critically ill patient and comprises six components (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems) score from 0 to 4 depending on the degree of support. We will not be using the neurological component as it has the lowest predictive power of all components and cannot be accurately scored in the sedated and intubated patient. SOFA is validated for critical illness and has similar predictive power for mortality as many other ICU scores (such as APACHE or SAPS) but has the advantage that it has been specifically used in septic patients and both the mean and highest SOFA scores predictor mortality (Ferreira 2001). In ICU, it has been shown to be closely correlated with mortality and its predictive value was similar regardless of length of stay (Ferreira 2001).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 14 days from entry to the trial and whilst in ICU.
    E.5.2Secondary end point(s)
    Secondary outcomes:
    • Mortality at day 28 and day 90
    • Length of ICU and hospital stay
    • Reduction in dose and duration of vasopressor treatment (total daily administered doses)

    Exploratory Mechanistic outcomes:
    Serial blood samples will be collected from patients. Assays will include markers of myocardial dysfunction and inflammation.

    • Measurement of Total Catecholamine. It is unknown whether beta-blockade acts through altering the effects of extraneous catecholamines administered as treatment of septic shock or by modulating those produced by the patient. Serum catecholamines will be analysed in the context of the dose of inotropes being administered.
    • Markers of myocardial dysfunction. Serum BNP has been demonstrated to be a reliable biomarker of myocardial injury, ischaemia and dysfunction in septic patients and also as a prognostic marker for a poor outcome [62, 67]. Serial measurements of Troponin-T will be made.
    • Measurement of serum Free Fatty acids and markers of Fatty Acid Metabolism.
    • Biomarkers of systemic inflammation. This will be measured using a multiplex inflammatory biomarker assay depending on the available technology at the time of analysis. A selection of cytokines will be analysed, all or some of which will include IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNF-alpha, TNF-beta, and IFN-gamma. This focused array will allow an assessment of the pro / anti-inflammatory balance over time in patients with septic shock and allow more detailed study of the other potential mechanisms of action of landiolol. Cortisol assays will measure the influence of beta blockade on the adrenal cortex
    • In addition samples will be stored for subsequent analysis (e.g. genetics / proteomics / metabolomics) as appropriate.

    The episodes of Bradycardia (HR <50 bpm), Bradycardia with haemodynamic compromise requiring intervention, Significant hypotension requiring intervention (not including temporarily stopping the infusion), Heart block, Arrhythmia, Arrhythmia with haemodynamic compromise requiring intervention should be reported.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Mortality status will be captured at days 28 and 90 following randomisation
    - Length of ICU stay (likely within first 14 days following randomisation)
    - Blood samples (serum) at trial entry, day 1, 2, 4, 6 and end of noradrenaline treatment (EONT) visit to define the pathways involved in treating sepsis with beta blockade
    - Store serum taken from blood samples at trial entry and day 1 for use in possible future research (e.g. genetics / proteomics / metabolics) as appropriate
    - Safety outcomes will evaluated up to the final follow up visit at day 90 (following randomisation)
    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. 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 Yes
    E.8.1.3Single blind No
    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 No
    E.8.2.3Other Yes
    E. description
    standard of care treatment
    E.8.2.4Number of treatment arms in the trial2
    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 concerned41
    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 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
    This study will end when the specified number of patients have been recruited, all patients have completed 90 day follow-up and the database is locked.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years0
    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. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F. of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 290
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    The majority of patients in septic shock will not have capacity to consent for themselves. A legal representative will be approached for consent in these circumstances.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state340
    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)
    Landiolol is given intravenously (IV) as an infusion and can only be administered in ICU and up to maximum of 14 days whilst a participant's heart rate is too high. Participants will be monitored by the local Research Teams during their stay in hospital at the time points mandated in the study. After discharge from ICU, or in the unlikely event the participant's heart rate remains high after 14 days, their ongoing treatment will be at the discretion of their treating clinician.
    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 Decision2017-09-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-09
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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