Effect of Xenon on Brain Injury After Aneurysmal Subarachnoid Hemorrhage

Официальное название

Effect of Xenon on Brain Injury, Neurological Outcome and Survival in Patients After Aneurysmal Subarachnoid Hemorrhage

Обзор

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.

Подробное описание

Assessments of efficacy:

1. A brain Computer tomography angiography (CTA) and / or 3 D Digital subtraction angiography (DSA) (whenever possible instead of 2D DSA) will be performed at hospital arrival and whenever clinically indicated. 2. 1st 3 Tesla MRI 72 ± 24 hours after onset of aSAH symptoms; 2nd 3 Tesla MRI 42 ± 4 days after onset of aSAH symptoms. 3. 3D DSA: Computational fluid dynamic simulations (CFD), artificial intelligence and machine learning. 4. Brain Positron emission tomography (PET): The 1st 4 ± 1 weeks and the 2nd at 3 months after onset of aSAH symptoms. 5. Biochemical assessment: A blood samples of 20 ml for determination of plasma catecholamines, plasma metabolomics (see details of metabolomics in section 18.4.7), cardiac enzyme release (P-hs-troponin-T and heart fatty-acid binding protein), selected biomarkers will be analysed at intensive crae unit (ICU) arrival and at 24h, at 48h and at 72h after onset of SAH symptoms. In addition, a sample of spinal fluid will be collected through external ventricular drainage (EVD) at ICU arrival or as soon as it is in place and at 24h, at 48h and at 72h after onset of SAH symptoms for assessment of metabolomics 6. Electrocardiograph (ECG) at ICU arrival and at 24h, at 48h and at 72h after onset of aSAH symptoms. 7. Neurological evaluation: at 3, 12 and at 24 months after aSAH with GOSe, Modified ranking score (mRS).

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.

Вмешательства

• Препарат Xenon
  Xenon arm will be treated with xenon inhalation with endtidal concentration of 50 % in air/oxygen and with standard of care
• Препарат air/oxygen
  Control group will be treated with air/oxygen

Первичные конечные точки

• Fractional anisotropy of the white matter [Срок оценки: 48-96 hours after start of aSAH symptoms]

Вторичные конечные точки (12)

• Fractional anisotropy of white matter at cerebellum and/or at corpus callosum as assessed with the 1st MRI. [Срок оценки: 48-96 hours after start of aSAH symptoms]
• Safety and tolerability of xenon [Срок оценки: during the follow-up of one year]
• Composite of radiological early brain injury (EBI) and delayed cerebral ischemia (DCI) [Срок оценки: 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 [Срок оценки: follow-up of 1 year]
• Intracerebral pressure (ICP) [Срок оценки: during ICU stay up to 14 days after onset of aSAH symptoms]
• Intracerebral pressure (ICP) [Срок оценки: during ICU stay up to 14 days after onset of aSAH symptoms]
• Intracerebral pressure (ICP) [Срок оценки: during ICU stay up to 14 days after onset of aSAH symptoms]
• Plasma catecholamine level [Срок оценки: within 3 hours of ICU arrival, at 24h, 48h and 72 h after onset of aSAH symptoms]
• Selected biomarkers [Срок оценки: within 3 hours of ICU arrival and at 24h, at 48h and at 72h after onset of aSAH symptoms]
• Development of prognostication models [Срок оценки: long-term outcome at 3 months, at 1 and at 2 years after onset of aSAH symptoms]
• Development of prognostication models [Срок оценки: between day 4 and 6 weeks after onset of aSAH symtoms]
• Development of prognostication models [Срок оценки: within 21 days after onset of aSAH symptoms]

Критерии участия

Критерии включения

To be considered eligible to participate in this study, a SAH subject must meet the inclusion criteria listed below:

• Informed consent obtained from the next of kin or legal representative
• Aneurysmal subarachnoid hemorrhage visible on CTA or DSA.
• Deterioration of consciousness to Hunt-Hess 3-5
• Age of ≥ 18 years
• Intubated.
• GCS 3-12 obtained off neuromuscular blocking agents
• Xenon treatment can be started within 6 hours after onset of SAH symptoms

Критерии исключения

An aSAH subject may not be enrolled in the trial if he/she meets any one of the exclusion criteria below:

• Acute or chronic traumatic brain injury
• Maximum diameter of intracerebral hemorrhage > 2.5 cm
• Pneumothorax or pneumomediastinum,
• Acute lung injury requiring ≥ 60% FIO2 (fraction of inspired oxygen).
• Systolic arterial pressure < 80 mmHg or mean arterial pressure < 60 mmHg for over 30 min period
• Bilaterally fixed and dilated pupils
• Positive pregnancy test, known pregnancy, or current breast-feeding
• Neurological deficiency due to traumatic brain injury or other neurological illness
• Imminent death or current life-threatening disease
• Current enrollment in another interventional study
• The subject is known to have clinically significant laboratory abnormality, medical condition (such as decompensated liver disease or severe chronic obstructive pulmonary disease), or social circumstance that, in the investigator's opinion, makes it inappropriate for the subject to participate in this clinical trial.
• Presence of implants or foreign bodies which are not known to be MRI safe

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Финляндия · 6 центров

• Aalto University School of Science — Helsinki
• Kuopio University Hospital — Kuopio
• Tampere University Hospital — Tampere
• Turku University Hospital — Turku
• Elomatic — Turku
• University of Turku, Turku Bioscience, Analysis of the metabolomics — Turku

Швеция · 1 центр

• Örebro University — Örebro

Публикации

• 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 Da PMID 26978207
• 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. PMID 29169472
• 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 a PMID 37337295

Идентификаторы

NCT: NCT04696523 · 109/2019 Xe-SAH · 2019-001542-17

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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