E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Tachycardia in Septic Shock |
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E.1.1.1 | Medical condition in easily understood language |
Rapid heart rate in patients admitted to ICU with septic shock |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040070 |
E.1.2 | Term | Septic shock |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10043071 |
E.1.2 | Term | Tachycardia |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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). |
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary 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). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 14 days from entry to the trial and whilst in ICU. |
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E.5.2 | Secondary 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.
Safety: 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.
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E.5.2.1 | Timepoint(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) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
standard of care treatment |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 41 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |