E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients requiring mechanical ventilation and sedation in ICU. |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039897 |
|
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 |
Objectives: Primary objective: The study has hierarchical co-primary objectives to demonstrate that: • Firstly: dexmedetomidine is non-inferior to current best-practice sedation with propofol/midazolam and daily sedation stops, in maintaining a target depth of sedation in long-stay (>24 hours sedation after randomisation) intensive care unit (ICU) patients • Secondly: use of dexmedetomidine, compared with current best-practice sedation with propofol/midazolam and daily sedation stops, reduces the length of ICU stay in long-stay (>24 hours sedation after randomisation) ICU patients.
|
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives: To explore the effects of dexmedetomidine compared with optimised standard care on: • nurse’s assessment of subject communication • duration of mechanical ventilation, weaning time and ventilator-free days in ICU • length of total hospital stay • functional recovery during hospitalisation • need for rescue medication to maintain sedation To describe the effects of dexmedetomidine compared with optimised standard care on: • frequency of delirium • frequency of organ failures and failure-free days • frequency of critical illness polyneuropathy (CIP) • ICU- and in-hospital survival To explore the potential differences between dexmedetomidine and optimised standard care in relation to: • costs of care in the ICU • total cost of hospitalisation To evaluate the range of blood levels seen with long-term treatment with dexmedetomidine
|
|
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Diagnosis and main criteria for inclusion and exclusion: Main criteria for inclusion: • Age 18 years • Clinical need for sedation and mechanical ventilation • Receiving full intensive care life support • Patients should have an expected stay in ICU for 48 hours from admission • Patients should have an expected requirement for sedation 24 hours from time of randomisation • Written informed consent obtained from the patient’s representative (and an independent physician where appropriate) within 36 hours of starting sedation, but not more than 72 h from the time of ICU admission
|
|
E.4 | Principal exclusion criteria |
Main criteria for exclusion: • Acute severe neurological disorder due to vascular causes, infection, intracranial expansion or injury • Uncompensated acute circulatory failure at time of randomisation [severe hypotension with mean arterial pressure (MAP) < 55 mmHg despite volume and pressors] • Severe bradycardia [heart rate (HR) < 50 beats/min] • AV-conduction block II-III (unless pacemaker installed) • Severe hepatic impairment (SOFA score>2, bilirybin>101 mcgmol/L • Positive pregnancy test or currently lactating • Need for muscle relaxation at the time of randomisation (except for intubation and initial stabilization) • Loss of hearing or vision, or any other condition that would significantly interfere with Richmond Agitation-Sedation Scale (RASS) assessment • Use of 2-agonists or antagonists at the time of randomisation (see prior and concomitant treatments, Section 5.7)
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy variables The hierarchical co-primary objectives of the study will be evaluated and analysed as follows:
1. Depth of sedation in long-stay (>24 hours sedation after randomisation) ICU patients The first of the co-primary efficacy variables is defined as the proportion of time during sedative infusion with a RASS score within the individually-prescribed target range. The comparison between the treatment groups will be done using analysis of (co-)variance [AN(C)OVA] for the outcome variables. Non-inferiority of the dexmedetomidine versus the current sedative agent will be evaluated using one-sided 97.5% confidence interval. Less that 10% (non-inferiority criteria) difference between the treatment groups is considered acceptable from clinical standpoint.
• The first of the co-primary efficacy variables is defined as the proportion of time during sedative infusion with a RASS score within the individually-prescribed target range. The comparison between the treatment groups will be done using analysis of (co-)variance [AN(C)OVA] for the outcome variables. Non-inferiority of the dexmedetomidine versus the current sedative agent will be evaluated using one-sided 97.5% confidence interval. Less that 10% (non-inferiority criteria) difference between the treatment groups is considered acceptable from clinical standpoint. 2. The length of ICU stay in long-stay (>24 hours sedation after randomisation) ICU patients will be analysed hierarchially as follows: • 1 The length of ICU stay in long-stay ICU patients, defined as time from randomisation to ‘medically fit for discharge, will be calculated and compared between the treatment groups by applying the Kaplan-Meier method and Cox’s proportional-hazards regression model. The hazard ratio between treatment groups will be estimated together with corresponding 95% confidence interval. Hazard ratio < 1 will indicate a tendency of superiority of dexmedetomidine treatment compared to current sedative agent. 2 The length of ICU stay in long-stay ICU patients, defined as time from ICU admission to ‘medically fit for discharge’, will be calculated and compared between the treatment groups by applying the Kaplan-Meier method and Cox’s proportional-hazards regression model. The hazard ratio between treatment groups will be estimated together with corresponding 95% confidence interval. Hazard ratio < 1 will indicate a tendency of superiority of dexmedetomidine treatment compared to current sedative agent.
Secondary efficacy, health economic, pharmacokinetic and safety variables • Variables with survival type of data will be applying the Kaplan-Meier method and Cox’s proportional-hazards regression model. • Variables with continuous type of data will be analysed using descriptive statistics and applicable AN(C)OVA model, if feasible. Variables with ordered or categorical data will be analysed using Fisher’s exact test or chi square’s test.
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
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 | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial 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
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |