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| ID | Type | Description | Link |
|---|---|---|---|
| 2019-001542-17 | EudraCT Number |
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| Name | Class |
|---|---|
| Academy of Finland | OTHER |
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An investigator-initiated clinical drug study
Main Objective:
To explore neuroprotective properties of xenon in patients after aneurysmal subarachnoid hemorrhage (SAH).
Primary endpoint: Global fractional anisotropy of white matter of diffusion tensor imaging (DTI). Hypothesis: White matter damage is less severe in xenon treated patients, i.e. global fractional anisotropy is significantly higher in the xenon group than in the control group as assessed with the 1st magnetic resonance imaging (MRI).
After confirmation of aSAH and obtaining a signed assent subjects will be randomized to the following groups:
Control group: Standard of Care (SOC) group: Air/oxygen and Normothermia 36.5-37.5°C; Xenon group: Normothermia 36.5-37.5°C +Xenon inhalation in air/oxygen for 24 hours. Brain magnetic resonance imaging techniques will be undertaken to evaluate the effects of the intervention on white and grey matter damage and neuronal loss. Neurological outcome will be evaluated at 3, 12 and 24 months after onset of aSAH symptoms Investigational drug/treatment, dose and mode of administration: 50±2 % end tidal concentration of inhaled xenon in oxygen/air.
Comparative drug(s)/placebo/treatment, dose and mode of administration: Standard of care treatment according to local and international consensus reports.
Duration of treatment: 24 hours
Assessments:
Baseline data Information that characterizes the participant's condition prior to initiation of experimental treatment is obtained as soon as is clinically reasonable. These include participant demographics, medical history, vital signs, oxygen saturation, and concentration of oxygen administered.
Acute data The collected information will contain quantitative and qualitative data of aSAH patients, as recommended by recent recommendations of the working group on subject characteristics, and including all relevant Common Data Elements (CDE) can be applied. Specific definitions, measurements tools, and references regarding each SAH CDE can be found on the weblink here: https://www.commondataelements.ninds.nih.gov/SAH.aspx#tab=Data\_Standards.
Assessments of efficacy:
Statistical methods: 1) Basic statistical tests (t-tests, Mann-Whitney, Chi square, etc); 2) Survival analysis methods; 3) An analysis of variance for repeated measurements; 4) A sample size of 100 is estimated on the basis of a recent studies in SAH patients to provide 80% power with a 2-sided α level of 0.05 to detect a mean difference of 0.02 (SD 0.035) in the global fractional anisotropy of white matter between the xenon group and the control group (98). Accordingly, this mean difference is estimated to have a predictive value for DCI and poor neurological outcome (i.e. mRS 3-6).Significance level of 0.05 and an estimation of 95 % confidence intervals will be used in the statistical analyses.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Air/Oxygen | Active Comparator | Control arm: air/oxygen with standard of care |
|
| xenon | Experimental | Xenon arm: xenon inhalation in air/oxygen with standard of care |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Xenon | Drug | Xenon arm will be treated with xenon inhalation with endtidal concentration of 50 % in air/oxygen and with standard of care |
|
| Measure | Description | Time Frame |
|---|---|---|
| Fractional anisotropy of the white matter | Global fractional anisotropy of white matter of diffusion tensor imaging (DTI). Hypothesis: White matter damage is less severe in xenon treated patients, i.e. global fractional anisotropy is significantly higher in the xenon group than in the control group as assessed with the 1st MRI. | 48-96 hours after start of aSAH symptoms |
| Measure | Description | Time Frame |
|---|---|---|
| Fractional anisotropy of white matter at cerebellum and/or at corpus callosum as assessed with the 1st MRI. | Fractional anisotropy of white matter at cerebellum and/or at corpus callosum as assessed with the 1st MRI. | 48-96 hours after start of aSAH symptoms |
| Safety and tolerability of xenon |
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Inclusion Criteria:
To be considered eligible to participate in this study, a SAH subject must meet the inclusion criteria listed below:
Exclusion Criteria:
An aSAH subject may not be enrolled in the trial if he/she meets any one of the exclusion criteria below:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Timo T Laitio, MD, PhD | Contact | +358504653201 | timo.laitio@tyks.fi |
| Name | Affiliation | Role |
|---|---|---|
| Timo T Laitio, MD, PhD | Turku University Hospital and University of Turku, Turku , Finland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Aalto University School of Science | Not yet recruiting | Helsinki | Helsinki | Finland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26978207 | Result | Laitio R, Hynninen M, Arola O, Virtanen S, Parkkola R, Saunavaara J, Roine RO, Gronlund J, Ylikoski E, Wennervirta J, Backlund M, Silvasti P, Nukarinen E, Tiainen M, Saraste A, Pietila M, Airaksinen J, Valanne L, Martola J, Silvennoinen H, Scheinin H, Harjola VP, Niiranen J, Korpi K, Varpula M, Inkinen O, Olkkola KT, Maze M, Vahlberg T, Laitio T. Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2016 Mar 15;315(11):1120-8. doi: 10.1001/jama.2016.1933. | |
| 29169472 |
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The data of this study will be available to investigators whose proposed use of the data has been approved by an independent review committee. Individual participant data that underlie the results reported in this Article will be shared (text, tables, figures, and appendices), after de-identification, along with the study protocol. These data will be available 6 months after the Article's pulication and will be available for 12 months from publication. Data can be used for individual participant data meta-analysis. Requests and proposals should be directed to timo.laitio@elisanet.fi. To gain access, data requestors will need to sign a data access agreement.
data will be available 6 months after the Article's pulication and will be available for 12 months from publication.
Requests and proposals should be directed to timo.laitio@elisanet.fi. To gain access, data requestors will need to sign a data access agreement.
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Study design is a single blind randomized two-armed parallel follow-up study.
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single blind; participants, outcomes assessors are blinded
| air/oxygen | Drug | Control group will be treated with air/oxygen |
|
Safety and tolerability of xenon as assessed with a ratio of adverse events, serious adverse events and suspected unexpected serious adverse reactions (SUSARs) during the follow-up of one year between the xenon group and the control group. |
| during the follow-up of one year |
| Composite of radiological early brain injury (EBI) and delayed cerebral ischemia (DCI) | Composite of radiological EBI (within 72 hours after start of SAH symptoms) and DCI (Criterion of DCI: 1. a new focal neurological deficit (such as hemiparesis, aphasia, apraxia, hemianopia, or neglect) /decrease in level of consciousness (i.e. decrease of at least 2 points on the Glasgow Coma Scale; either on the total score or on one of its individual components, such as eye, motor on either side, or verbal). This should last for at least 1 hour and not is due to other causes (e.g. hydrocephalus, seizures, metabolic derangement, infection, sedation) and is not apparent immediately after aneurysm occlusion, and cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies, 2. a new infarct on follow-up imaging (i.e. in any of the following: 2nd MRI, CT, CTA, DSA and perfusion CT) after 4 days post-SAH, or 3. both 1 and 2), and poor outcome at 3-months (good: mRS 0-2; poor: mRS 3-6) at 3-months and at 1 year | EBI: within first 72 hours after start of aSAH symptoms; mRS at 3 months and at 1 year and at 2 years after onset of aSAH symptoms |
| Neurogenic Stress Cardiomyopathy and Stunned Myocardium | Neurogenic Stress Cardiomyopathy and Stunned Myocardium (i.e. myocardial injury caused by sympathetic storm and autonomic dysregulation with hs-troponin elevation, left ventricular dysfunction or ECG changes) | follow-up of 1 year |
| Intracerebral pressure (ICP) | ICP level Duration of therapy for ICP control/monitoring | during ICU stay up to 14 days after onset of aSAH symptoms |
| Intracerebral pressure (ICP) | Need for ICP therapies (hypothermia, decompressive craniotomy) | during ICU stay up to 14 days after onset of aSAH symptoms |
| Intracerebral pressure (ICP) | Duration of therapy for ICP control/monitoring | during ICU stay up to 14 days after onset of aSAH symptoms |
| Plasma catecholamine level | Plasma level of noradrenaline , adrenaline, and dopamine | within 3 hours of ICU arrival, at 24h, 48h and 72 h after onset of aSAH symptoms |
| Selected biomarkers | Selected biomarkers of brain injury: neurofilament light (NF-L), glial fibrillary acidic protein (GFAP), calcium binding protein S100B (S100B), ubiquitin carboxyterminal hydrolase L1 (UCH-L1), total tau, cytokines (tumour necrosis factor alpha, interleukins 6 and 10) | within 3 hours of ICU arrival and at 24h, at 48h and at 72h after onset of aSAH symptoms |
| Development of prognostication models | Development of prognostication models with a selected combination of brain imaging, clinical data, biomarkers and metabolomics by applying artificial intelligence and machine learning for long-term outcome after aSAH | long-term outcome at 3 months, at 1 and at 2 years after onset of aSAH symptoms |
| Development of prognostication models | Development of prognostication models with a selected combination of brain imaging, clinical data, biomarkers and metabolomics by applying artificial intelligence and machine learning for DCI after aSAH | between day 4 and 6 weeks after onset of aSAH symtoms |
| Development of prognostication models | Development of prognostication models with a selected combination of brain imaging, clinical data, biomarkers and metabolomics by applying artificial intelligence and machine learning for vasospasm after aSAH | within 21 days after onset of aSAH symptoms |
| Development of prognostication models | Development of prognostication models with a selected combination of brain imaging, clinical data, biomarkers and metabolomics by applying artificial intelligence and machine learning for EBI after aSAH | within 72 hours after onset of aSAH symtoms |
| Difference of MRI parameters between xenon and control group | Difference of MRI parameters (fractional anisotropy, axial diffucivity, radial diffucivity of diffusion tensor imaging, DTI) between xenon and control group and in predicting risk for EBI | within 72 hours after onset of aSAH symptoms |
| Difference of MRI parameters between xenon and control group | Difference of MRI parameters (fractional anisotropy, axial diffucivity, radial diffucivity of DTI) between xenon and control group and in predicting risk for vasospasm | within 21 days after onset of aSAH symptoms |
| Difference of MRI parameters between xenon and control group | Difference of MRI parameters (fractional anisotropy, axial diffucivity, radial diffucivity of DTI) between xenon and control group and in predicting risk for DCI | between day 4 and 6 weeks after onset of aSAH symptoms |
| Difference of MRI parameters between xenon and control group | Difference of MRI parameters (fractional anisotropy, axial diffucivity, radial diffucivity of DTI) between xenon and control group and in predicting risk for good/poor neurological outcome at 3 moths, at 1 year and at 2 years after onset of aSAH symptoms (mRS 0-2/mRS 3-6). | at 3 months, at 1 year and at 2 years after onset of aSAH symptoms |
| Difference of CTA findings | Difference of CTA ischemic findings between xenon and control group and in predicting risk for EBI | within 72 hours after onset of aSAH symptoms |
| Difference of CTA findings | Difference of ischemic findings in CTA between xenon and control group and in predicting risk for vasospasm | within 21 days after onset of aSAH symptoms |
| Difference of CTA findings | Difference of ischemic findings in CTA between xenon and control group and in predicting risk for DCI | between day 4 and 6 weeks after onset of aSAH symptoms |
| Difference of CTA findings between xenon and control group | Difference of ischemic findings in CTA between xenon and control group and in predicting risk for good/poor neurological outcome at 3 moths, at 1 year and at 2 years after onset of aSAH symptoms (mRS 0-2/mRS 3-6). | at 3 months, at 1 year and at 2 years after onset of aSAH symptoms |
| Difference of DSA findings between xenon and control group | Difference of DSA findings indicating ischemic pattern of perfusion between xenon and control group and in predicting risk for EBI | within 72 hours after onset of aSAH symptoms |
| Difference of DSA findings between xenon and control group | Difference of DSA findings indicating ischemic pattern of perfusion between xenon and control group and in predicting risk for vasospasm | within 21 days after onset of aSAH symptoms |
| Difference of DSA findings between xenon and control group | Difference of DSA findings indicating ischemic pattern of perfusion between xenon and control group and in predicting risk for DCI | between day 4 and 6 weeks after onset of aSAH symptoms |
| Difference of DSA findings between xenon and control group | Difference of DSA findings indicating ischemic pattern of perfusion between xenon and control group and in predicting risk for good/poor neurological outcome at 3 moths, at 1 year and at 2 years after onset of aSAH symptoms (mRS 0-2/mRS 3-6). | at 3 months, at 1 year and at 2 years after onset of aSAH symptoms |
| Activity of microglia cells assessed with PET | It will be explored whether [11C](R)-PK11195 can be used to test the hypothesis of neuroprotective effect of xenon and to explore the role of inflammatory process for DCI after SAH. This could be demonstrated by showing less microglial activation in xenon group than in the reference therapy group and in the patients with good outcome, i.e. no DCI; Difference of activity of microglia cells between xenon and control group and in predicting risk for DCI | DCI between day 4 and 6 weeks after onset of aSAH symptoms; The 1st PETscan 4 ±1 weeks after onset of aSAH symptoms and the 2nd scan at 3 months after onset of SAH symptoms. |
| Activity of microglia cells assessed with PET | It will be explored whether [11C](R)-PK11195 can be used to test the hypothesis of neuroprotective effect of xenon and to explore the role of inflammatory process for neurological outcome after SAH. This could be demonstrated by showing less microglial activation in xenon group than in the reference therapy group and in the patients with good outcome, i.e. mRS 0-2; | The 1st scan at 4 ±1 weeks after and the 2nd scan at 3 months after onset of SAH symptoms. Outcome: at 3 months, at 1 year and at 2 years after onset of aSAH symptoms |
| Cerebral fluid dynamics | Predictive value of CFD simulations assessed with 3 dimensional DSA within 4 days of ICU arrival in predicting risk for EBI within 72 hours after onset of aSAH symptoms | Measures performed within 72 hours of ICU arrival |
| Cerebral fluid dynamics | Predictive value of CFD simulations assessed with 3 dimensional DSA within 21 days of ICU arrival in predicting risk for neurological outcome at 3 months, at 1 year and at 2 years after SAH (mRS 0-2) | Measures performed within 21 days of ICU arrival; outcome at 3 months, at 1 year and at 2 years after onset of aSAH symptoms |
| Cerebral fluid dynamics | Predictive value of CFD simulations assessed with 3 dimensional DSA within 21 days of ICU arrival in predicting risk for DCI within 6 weeks after onset of aSAH symptoms | Measures performed within 21 days of ICU arrival; DCI within 6 weeks after onset of aSAH symptoms |
| Kuopio University Hospital | Not yet recruiting | Kuopio | Kuopio | Finland |
|
| Tampere University Hospital | Not yet recruiting | Tampere | Pirkanmaa | Finland |
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| Turku University Hospital | Recruiting | Turku | Turku | 20521 | Finland |
|
| Elomatic | Not yet recruiting | Turku | Turku | 20810 | Finland |
|
| University of Turku, Turku Bioscience, Analysis of the metabolomics | Not yet recruiting | Turku | Turku | Finland |
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| Örebro University | Not yet recruiting | Örebro | Örebro County | Sweden |
|
| Result |
| Arola O, Saraste A, Laitio R, Airaksinen J, Hynninen M, Backlund M, Ylikoski E, Wennervirta J, Pietila M, Roine RO, Harjola VP, Niiranen J, Korpi K, Varpula M, Scheinin H, Maze M, Vahlberg T, Laitio T; Xe-HYPOTHECA Study Group. Inhaled Xenon Attenuates Myocardial Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The Xe-Hypotheca Trial. J Am Coll Cardiol. 2017 Nov 28;70(21):2652-2660. doi: 10.1016/j.jacc.2017.09.1088. |
| 37337295 | Derived | Laaksonen M, Rinne J, Rahi M, Posti JP, Laitio R, Kivelev J, Saarenpaa I, Laukka D, Frosen J, Ronkainen A, Bendel S, Langsjo J, Ala-Peijari M, Saunavaara J, Parkkola R, Nyman M, Martikainen IK, Dickens AM, Rinne J, Valtonen M, Saari TI, Koivisto T, Bendel P, Roine T, Saraste A, Vahlberg T, Tanttari J, Laitio T. Effect of xenon on brain injury, neurological outcome, and survival in patients after aneurysmal subarachnoid hemorrhage-study protocol for a randomized clinical trial. Trials. 2023 Jun 19;24(1):417. doi: 10.1186/s13063-023-07432-8. |
| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| D001930 | Brain Injuries |
| D002545 | Brain Ischemia |
| D002544 | Cerebral Infarction |
| D002318 | Cardiovascular Diseases |
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D020520 | Brain Infarction |
| D020521 | Stroke |
| D007238 | Infarction |
| D007511 | Ischemia |
| D009336 | Necrosis |
| D006331 | Heart Diseases |
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| ID | Term |
|---|---|
| D014978 | Xenon |
| ID | Term |
|---|---|
| D005741 | Noble Gases |
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D005740 | Gases |
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