Clinical Trial Results:
Xenon for the prevention of postoperative delirium in cardiac surgery: A prospective randomized controlled observer-blinded trial
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Summary
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EudraCT number |
2014-005370-11 |
Trial protocol |
BE |
Global end of trial date |
12 Dec 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Dec 2019
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First version publication date |
30 Dec 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SR12/2014
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
University Hospitals Leuven
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Sponsor organisation address |
Herestraat 49, Leuven, Belgium, 3000
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Public contact |
Research Anesthesiology, University Hospitals Leuven, +32 16344270, christel.hugyens@uzleuven.be
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Scientific contact |
Research Anesthesiology, University Hospitals Leuven, +32 16344270, christel.hugyens@uzleuven.be
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Sponsor organisation name |
University Hospitals Leuven
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Sponsor organisation address |
Herestraat 49, Leuven, Belgium, 3000
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Public contact |
Anesthesia Research, University Hospitals Leuven, Mrs Cchristel Huygens, University Hospitals Leuven, 0032 16344620, christel.huygens@uzleuven.be
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Scientific contact |
Anesthesia Research, University Hospitals Leuven, Mrs Cchristel Huygens, University Hospitals Leuven, 0032 16344620, christel.huygens@uzleuven.be
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Jun 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Dec 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Dec 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Incidence of postoperative delirium (POD) as assessed by the 3D-CAM or CAM-ICU during the first 5 postoperative day
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Protection of trial subjects |
The interventional treatment was administered to patients with standard haemodynamic monitoring in the setting of a fully equipped cardiac operation room. This enabled immediate detection and treatment of adverse events. Xenon inhalation was to be immediately stopped in case that the study patient showed a life-threatening deterioration. Also after leaving the operation room, all patients were closely monitored by the study team for the occurrence of eventual (S)AE’s, first on the ICU, later on the normal ward. Moreover, the inclusion of each individual patient into the study was indicated in the electronic hospital information system and hence visible to all physicians and nurses involved in the care of this patient. This facilitates reporting of (S)AE’s to the principal investigator.
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Background therapy |
Older patients undergoing cardiac surgery have a 40–60% risk of developing postoperative delirium (POD), which is associated with increased morbidity and mortality. In animals, xenon was found to be neuroprotective. Yet, little is known about its neuroprotective effects in humans. We therefore evaluated whether xenon-anaesthesia prevents POD in patients undergoing cardiac surgery. | ||
Evidence for comparator |
The noble gas xenon has neuro- and cardio-protective effects in animal studies and maintains haemodynamics and myocardial contractility better than other anaesthetics. These neuroprotective properties have been confirmed in various in vitro and animal models of traumatic brain injury, neuronal ischaemia, cardiac arrest, intracranial bleeding, and postoperative cognitive dysfunction following cardiopulmonary bypass (CPB). Notably, in patients undergoing off-pump coronary artery bypass surgery, xenon reduced the occurrence of POD, as compared to the routinely used anaesthetic sevoflurane. This study was, however, not designed to address the prophylactic effects of xenon on POD. | ||
Actual start date of recruitment |
01 Apr 2015
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 190
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Worldwide total number of subjects |
190
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EEA total number of subjects |
190
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
177
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85 years and over |
13
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Recruitment
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Recruitment details |
From November 2015 to December 2017, 258 patients scheduled for on-pump cardiac surgery were screened. In total, 190 patients were included and randomly assigned to the xenon (n = 96) or sevoflurane (n = 94) groups . In all patients, xenon or sevoflurane was stopped and replaced with propofol infusion during the cardiopulmonary bypass period. | |||||||||
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Pre-assignment
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Screening details |
All patients received the allocated treatment and were eligible for the final analysis of the primary outcome. Screening failure occurred in 68 patients (33 not met inclusion criteria, 20 declined to participate, and 15 had other reasons that excluded them from the participation in the trial). | |||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Investigator, Subject | |||||||||
Blinding implementation details |
We applied a masked randomization procedure, using closed, sequentially numbered, opaque envelopes that were unsealed upon the patient’s arrival in the operating room. Patients were randomized by computer-generated software. Randomization was stratified by dichotomizing the European System for Cardiac Operative Risk Evaluation (EuroSCORE II) with a cut-off score of 3.Investigator I accomplished the enrollment & all postop assessment & was, similar to the patient,blinded to treatment allocation.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Xenon | |||||||||
Arm description |
General anesthesia was maintained pre- and post-cardiopulmonary bypass (CPB) with xenon 40–60% in oxygen, | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
xenon
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation vapour
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Routes of administration |
Inhalation use
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Dosage and administration details |
EEG-titrated administration via inhalation via endotracheal tube,
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Arm title
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Sevoflurane | |||||||||
Arm description |
General anesthesia was maintained pre- and post-cardiopulmonary bypass (CPB) with sevoflurane 1.0–1.4%. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Sevoflurane
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation vapour
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Routes of administration |
Inhalation use
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Dosage and administration details |
EEG-titrated administration via inhalation via endotracheal tube,
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Baseline characteristics reporting groups
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Reporting group title |
Xenon
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Reporting group description |
General anesthesia was maintained pre- and post-cardiopulmonary bypass (CPB) with xenon 40–60% in oxygen, | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sevoflurane
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Reporting group description |
General anesthesia was maintained pre- and post-cardiopulmonary bypass (CPB) with sevoflurane 1.0–1.4%. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Xenon
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Reporting group description |
General anesthesia was maintained pre- and post-cardiopulmonary bypass (CPB) with xenon 40–60% in oxygen, | ||
Reporting group title |
Sevoflurane
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Reporting group description |
General anesthesia was maintained pre- and post-cardiopulmonary bypass (CPB) with sevoflurane 1.0–1.4%. | ||
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End point title |
Incidence of postoperative delirium | |||||||||
End point description |
The primary endpoint was the POD incidence during the first 5 postoperative days, as determined using the 3D-CAM for non-ventilated patients, or the confusion assessment method adapted for ventilated patients in the ICU (CAM-ICU).Daily POD screening was performed by trained research nurses who were blinded to group allocation.
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End point type |
Primary
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End point timeframe |
The first 5 postoperative days.
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Statistical analysis title |
Primary endpoint | |||||||||
Statistical analysis description |
logistic regression analysis, adjusting for the stratification variable “EuroSCORE II ≤ 3 vs > 3
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Comparison groups |
Xenon v Sevoflurane
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Number of subjects included in analysis |
190
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
> 0.05 [1] | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Confidence interval |
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| Notes [1] - POD incidence was similar between the 2 groups. The odds ratio (95%CI for POD when comparing xenon with sevoflurane=1.18 (0.65; 2.16).After multiple imputation to address the issue of un-evaluable days, the odds ratio was 1.09 (0.59; 2.01), p=0.793. |
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Adverse events information
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Timeframe for reporting adverse events |
From enrollment until the discharge of patient.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23
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Reporting groups
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Reporting group title |
Xenon
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Reporting group description |
General anesthesia was maintained pre- and post-cardiopulmonary bypass (CPB) with xenon 40–60% in oxygen, | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sevoflurane
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Reporting group description |
General anesthesia was maintained pre- and post-cardiopulmonary bypass (CPB) with sevoflurane 1.0–1.4%. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
