| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Any patient requiring intensive care treatment due to critical illness. |
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| E.1.1.1 | Medical condition in easily understood language |
| Any patient requiring treatment in an intensive care unit. |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033305 |
| E.1.2 | Term | Oversedation |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 | 10039897 |
| E.1.2 | Term | Sedation |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049124 |
| E.1.2 | Term | Sedation during medical procedure |
| E.1.2 | System Organ Class | 100000004865 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039898 |
| E.1.2 | Term | Sedation excessive |
| E.1.2 | System Organ Class | 10029205 - Nervous system 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 |
Our principal objective is:
To determine whether the length of time critically ill adult patients require mechanical ventilation can be reduced when using two sedative drugs from the alpha2 agonist class, clonidine or dexmedetomidine, as compared with current usual care (sedation with the drug propofol). |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess the effects of dexmedetomidine and clonidine, compared with usual care, on other clinical, patient-centred, and economic outcomes in the ICU, hospital, and during up to 6 months follow up post-randomisation.
Clinical and Person-centred objectives
During ICU stay we will compare rates and duration of delirium, time to optimum sedation, average sedation depth, the ability of patients to communicate with staff and relatives, the quality of sedation, and duration of ICU stay. We will also compare safety based on pre-defined adverse events relevant to sedation and α2-agonist agents.
Following discharge from the ICU we will compare patient outcomes for which sedation and ICU experience may be on the causal pathway, namely patients’ memories of their ICU stay, psychological well being, and cognitive function. We will follow up patients for 6 months for survival, HRQoL, and healthcare resource use.
Economic evaluation
We will include a detailed cost-effe |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Mechanistic Sub-study - in a sub-group of participants with sepsis, who have given their consent, 2 blood samples will be collected at baseline and 60 hours. We will use several methods to explore whether there are differences in inflammation and/or immune function between the trial sub-groups with sepsis at baseline, and how these relate to trial outcomes. When consent has been provided, we will also explore whether changes in gene expression occur that are modified by alpha2-agonists, for example using whole blood transcriptomics. Where appropriate, we will also measure a panel of circulating pro- and anti-inflammatory mediators in order to explore whether alpha2-agonists have anti-inflammatory properties that might contribute to or mediate some of their beneficial effects during critical illness. |
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| E.3 | Principal inclusion criteria |
1. Patient requiring MV in an ICU
2. Aged 18 or over
3. Within 48 hours of first episode of mechanical ventilation in ICU
4. Requiring sedation with propofol
5. Expected to require a total of 48 hours of MV or more in ICU
6. Expected to require a further 24 hours of MV at the time of randomisation in the opinion of the responsible clinician
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| E.4 | Principal exclusion criteria |
1. Acute brain injury
2. Post-cardiac arrest
3. Status epilepticus
4. Continuous therapeutic neuromuscular paralysis at the time of screening or randomisation
5. Guillain-Barre Syndrome
6. Myasthenia gravis1
7. Home ventilation
8. Fulminant hepatic failure
9. Patient not expected to survive 24 hours by responsible clinician
10. Decision to provide only palliative or end-of-life care
11. Pregnancy
12. Known allergy to one of the study drugs
13. Patient known to have experienced a period with heart rate <50 beats per minute for 60 minutes or longer since commencing mechanical ventilation in the ICU
14. Untreated second or third degree heart block3
15. Transferred from another Intensive Care Unit in which MV occurred for >6 hours
16. Prisoners
17. Enrolled on another CTIMP
18. Previously enrolled on the A2B Trial
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Time to successful extubation post-randomisation (hours).
For the purpose of the trial, a successful first extubation from mechanical ventilation (MV) will be defined as follows:
a. For patients with an Endotracheal tube:
time of successful extubation will be the time of the first extubation that is followed by 48 hours of spontaneous breathing without mechanical support (i.e. the start time of the 48 hours of spontaneous breathing)
b. For patients with a tracheostomy:
time of successful extubation will be the start time of the patient’s first period of 48 hours of spontaneous breathing, where spontaneous breathing is defined as receiving support not exceeding 5 cmH2O PEEP/CPAP with ≤ 5 cmH2O pressure support above PEEP
c. For patients who are receiving non-Invasive mechanical ventilation (NIV):
time of successful extubation will be the start time of the patient’s first period of 48 hours of spontaneous breathing, where spontaneous breathing is defined as receiving support not exceeding 5 cmH2O CPAP via mask/hood (NB NIV patients receiving any pressure supported breaths will not be considered to be spontaneously breathing unassisted)
NB: The use of high flow nasal oxygen will not be counted as mechanical ventilation, so patient on high nasal flow oxygen alone will be considered to be spontaneously breathing unassisted.
The 48 hours of successful extubation is included in the definition in order to exclude patients with early failed extubations, i.e. those patients requiring reintubation within 48 hours. If a re-intubation occurs within this time window it is likely to be related to the original episode of respiratory failure requiring intubation. In this situation patients should continue to be followed for the start time at which a successful extubation occurs according to the above definitions
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Daily until successful extubation achieved |
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| E.5.2 | Secondary end point(s) |
1) Length of ICU stay
2) Delirium prior to successful extubation
3) Sedation and analgesia quality
4) Time to first optimum sedation
5) Patient's ability to communicate pain and ability to cooperate with care
6) Relative/partner/friend assessment (PerLR) of comfort and communication
7) Drug related adverse events
8) Mortality
9) Patient experience of ICU care
10) Anxiety and depression
11) Post-traumatic stress
12) Cognitive function
13) Health related quality of life |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) ICU discharge
2) Twice daily during ICU stay until primary outcome reached
3) Four hourly during ICU stay until primary outcome reached
4) Daily during the intervention period
5) Twice daily until primary outcome reached
6) Daily until primary outcome reached
7) Daily during the intervention period
8) ICU, hospital, 30, 90 and 180 days post randomisation
9) 30 and 90 days post randomisation
10) 90 and 180 days post randomisation
11) 90 and 180 days post randomisation
12) 90 and 180 days post randomisation
13) 30, 90 and 180 days post-randomisation and recalled prior to hospital admission (measured at 30 days)
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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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 50 |
| 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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| LVLS: The end of the trial will be after the final enrolled patient has completed follow up 180 days post-randomisation |
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 |
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