E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult subjects admitted to the ICU clinically indicated to require sedation with propofol and invasive ventilation
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E.1.1.1 | Medical condition in easily understood language |
ICU patient sedated and invasive ventilated |
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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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that sedation with isoflurane is non-inferior to propofol in terms of maintaining adequate sedation without rescue sedation. |
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E.2.2 | Secondary objectives of the trial |
Evaluate the safety profile of isoflurane compared to propofol in terms of experienced adverse events, biochemistry laboratory values, vital signs and organ function.
Evaluate ability to breathe spontaneous and applied ventilator mode in subjects sedated with isoflurane compared to propofol.
Efficacy objectives: Evaluate wake-up time during daily sedation stops in the ICU for subjects sedated with isoflurane compared to propofol.
Evaluate use of analgesic agent and behavioural pain scale assessments (BPS) in subjects sedated with isoflurane compared to propofol.
Evaluate time with invasive ventilation and days in ICU in the 30 days after end of study sedation for subjects sedated with isoflurane compared to propofol
Evaluate the time to extubation for subjects sedated with isoflurane compared to propofol.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects, >= 18 years
2. Continuous invasive ventilation and sedation <= 48 hours at start of study sedation
3. Clinically likely to need invasive ventilation and sedation >= 24 hours at randomisation
4. Ongoing sedation with propofol at time of randomisation
5. Prescribed target sedation depth within the RASS range -1 to -4
6. Signed informed consent or emergency situation inclusion criteria fulfilled and documented, according to procedure described in section 9.4
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E.4 | Principal exclusion criteria |
1. Has not reached prescribed target sedation depth any time within the last 8 hours at randomisation
2. History of or genetic predisposal for malignant hyperthermia
3. Uncompensated acute circulatory failure at time of randomisation (MAP < 55 mmHg despite iv fluids and vasopressors).
4. Hepatic impairment of classification C according to the Child-Pugh score (Cholongitas et al., 2005).
5. Any for the study relevant clinically significant abnormalities in clinical chemistry or haematology results at the time of screening , precluding study participation as judged by the investigator
6. Acute neuropathology without ICP monitoring, including but not limited to stroke, neurosurgery and head trauma.
7. Planned anaesthesia or surgery within 24 hours from randomisation
8. Tidal volume < 350 ml
9. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study
10. Need for continuous muscle relaxation at the time of randomisation
11. Positive pregnancy test in women
12. History of allergy/hypersensitivity to isoflurane or propofol
13. Known participation in any other clinical study that included drug treatment within three months of the first administration of investigational product
14. Documented limitation of medical treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage of time when adequate sedation depth is maintained without rescue sedation with isoflurane compared to propofol as assessed according to RASS. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 2 hrs from start of study medication is given until end of trial at max. 48hrs |
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E.5.2 | Secondary end point(s) |
Safety endpoints
Adverse events in terms of frequency and severity for subjects sedated with isoflurane compared to propofol.
Changes in vital signs, clinical chemistry and haematology values over time for subjects sedated with isoflurane compared to propofol.
Difference in ability to breathe spontaneously assessed as applied ventilator mode and spontaneous breathing trial (SBT) for subjects sedated with isoflurane compared to propofol.
Changes in organ failure measured by Sequential Organ Failure Assessment (SOFA) from baseline and over time during the study, up to one week after end of study sedation for subjects sedated with isoflurane compared to propofol.
Changes in organ functions seven and 30 days after end of study sedation for subjects sedated with isoflurane compared to propofol.
Efficacy endpoints:
Mean wake-up time for subjects sedated with isoflurane compared to propofol.
Safety Endpoint:
Dosing of opiates and BPS assessments in subjects sedated with isoflurane compared to propofol.
Ventilator time and ventilator-free days in the 30 days after end of study sedation for subjects sedated with isoflurane compared to propofol.
ICU length of stay and ICU-free days in the 30 days after end of study sedation for subjects sedated with isoflurane compared to propofol.
Time to extubation of subjects being extubated during study for subjects sedated with isoflurane compared to propofol.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From start of study sedation up to study end i.e. at the latest 48 hours. For adverse events it is up to after end of study sedation. |
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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 | No |
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) | 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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 | 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
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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 | 1 |
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 | 2 |
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 |