Effect of xenon on brain injury, neurological outcome and survival in patients after aneurysmal subarachnoid hemorrhage

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Turku University Central Hospital

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

1 Oct 2024 → ongoing

Decision date (initial)

2022-06-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

State Research Funding, Finland · Academy of Finland

External identifiers

EU CT number

2022-500596-32-00

EudraCT number

2019-001542-17

ClinicalTrials.gov

NCT04696523

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To explore neuroprotective properties of xenon in patients after aneurysmal subarachnoid hemorrhage (SAH).

Secondary objectives 10

1. To explore the neuroprotective effect of xenon 1. On the white matter injury in cerebellum, cerebellar peduncles, corpus callosum (genu, body, splenium), anterior ventral midbrain, cingulum, hypothalamus, and centrum semiovale
2. On the incidence and severity of EBI (within 72 hours after start of SAH symptoms) and DCI (between day 4 and 6 weeks after start of aSAH symtoms)
3. On the incidence of adverse events, serious adverse events and suspected unexpected serious adverse reactions (SUSARs).
4. On the inflammatory process, i.e. microglia activation and CSF cytokine level
5. On the need and duration of intracerebral pressure (ICP) treatments
6. On the plasma catecholamine levels
7. On the release of hs troponin-T
8. On the release of neuron specific enolase (NSE), 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)
9. The exploratory objectives are as follows: 1. To explore a predictive value of the different MRI techniques (e.g. DTI, perfusion, constrained spherical deconvolution) alone and combined for clinical outcome at 3 months, at 1 and 2 years after SAH. 2. To explore pathophysiological pathways of the post-SAH period between the two treatment groups and a predictive value of selected proteomics and metabolomics on severity of EBI and DCI and neurological outcome (i.e. good outcome: mRS 0-2 vs poor outcome: 3-6) 3. To explore a role of microglia activation on the development of DCI 4. To explore a role of cytokine level on the development of DCI 5. To explore a combination of brain imaging markers, selected biomarkers (see secondary objectives # 8), plasma metabolomics, spinal fluid metabolomics and clinical examinations (e.g. motor score, pupillary light reflex with pupillometry, epileptic seizures) as a prognostication model for EBI, DCI and neurological outcome at 3 months, at 1 and 2 years after SAH (i.e. good outcome: mRS 0-2 vs poor outcome: 3-6) 6. Applicability of brain network analysis with graph theoretical analysis and anatomical connectivity of white matter tracts in prognostic models for EBI, DCI and neurological outcome at 3 months, at 1 and 2 years after SAH (i.e. good outcome: mRS 0-2 vs poor outcome: 3-6) and to investigate xenon’s effect on the connectivity. 7. Mechanisms of developing EBI and DCI by utilizing brain imaging and metabolomics (i.e. plasma and spinal fluid) 8. Clinical neurological outcome at 3-months and at 1 year and at 2 years. 9. Development of a prognostication model for EBI and DCI and neurological outcome at 3 months and at 1 year and at 2 years after SAH
10. Objectives related to the xenon delivery device Akzent X Color . Safety of the xenon delivery device Akzent X Color used in the xenon group as assessed with ventilatory parameters (tidal volume, minute volume, respiratory frequency, PEEP, plateau pressure, peak pressure, lung compliance, inspiratory O2 %, end-tidal CO2), blood gas values, frequency and type of adverse events (AE) and serious events (SAE) related to the performance of the ventilators (see details of assessing and reporting of AEs and SAEs in 22.4). Safety parameters will be compared between the control group and the xenon group in the interim analysis after 80 patients and in the final analysis with the complete population. A case by case performance of the device as well as safety are assessed by comparing ventilatory parameters (tidal volume, minute volume, respiratory frequency, PEEP, plateau pressure, peak pressure, lung compliance, inspiratory O2 %, end-tidal CO2) recorded by the device with the corresponding ventilatory parameters recorded simultaneously by the external CE-marked CARESCAPETM Respiratory Modules, GE Healthcare, https://www.gehealthcare.com/en-sg/-/jssmedia/9d671439697e47dfb2d8f69654449952.pdf (E-sCO, E-sCOV, E-sCOVX, E-sCAiO, E-sCAiOV, E-sCAiOVX, E-sCAioE, E-sCAiOVE), which are indicated for use with a host device for monitoring respiratory parameters (see details on page 78)

Conditions and MedDRA coding

Aneyrysmal subarachnoid hemorrhage needing ventilatory care in intensive care unit

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. To be considered eligible to participate in this study, a SAH subject must meet the inclusion criteria listed below: 1. Informed consent obtained from the next of kin or legal representative 2. Aneurysmal subarachnoid hemorrhage visible on CTA or DSA. 3. Deterioration of consciousness to Hunt-Hess 3-5 4. Age of ≥ 18 years 5. Intubated. 6. GCS 3–12 obtained off neuromuscular blocking agents 7. Xenon treatment can be started within 6 hours after loss of consciousness 8. The interval between the estimated onset of bleeding and the occurrence of loss of consciousness must not exceed 12 hours.

Exclusion criteria 12

1. Acute or chronic traumatic brain injury
2. Maximum diameter of intracerebral hemorrhage > 2.5 cm
3. Pneumothorax or pneumomediastinum
4. Acute lung injury requiring ≥ 60% FIO2 (fraction of inspired oxygen)
5. Systolic arterial pressure < 80 mmHg or mean arterial pressure < 60 mmHg for over 30 min period
6. Bilaterally fixed and dilated pupils
7. Positive pregnancy test, known pregnancy, or current breast-feeding
8. Neurological deficiency due to traumatic brain injury or other neurological illness
9. Imminent death or current life-threatening disease
10. Current enrollment in another interventional study
11. 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
12. Presence of implants or foreign bodies which are not known to be MRI safe

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 MRI.

Secondary endpoints 17

1. Fractional anisotropy of white matter at cerebellum, cerebellar peduncles, hypothalamus, anterior ventral midbrain, cingulum, centrum semiovale and/or at corpus callosum (genu, body, splenium) as assessed with the 1st MRI.
2. 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.
3. Composite of radiological EBI (within 72 hours after start of SAH symptoms) and DCI (Criterion of DCI
4. Neurogenic Stress Cardiomyopathy and Stunned Myocardium
5. ICP level up to 14 days after onset of aSAH symptoms
6. Need for ICP therapies up to 14 days after onset of aSAH symptoms (hypothermia, decompressive craniotomy)
7. Duration of therapy for ICP control/monitoring up to 14 days after onset of aSAH symptoms
8. Plasma catecholamine level
9. Difference of neuron specific enolase (NSE), 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) between xenon and control group and in predicting risk for EBI within first 72 hours after start of aSAH symptoms , vasospasm (within 21 days after start of SAH symptoms) and DCI (between day 4 and 6 weeks after start of SAH
10. Development of prognostication models with a selected combination of brain imaging, biomarkers, clinical data and metabolomics by applying artificial intelligence and machine learning for EBI within first 72 hours after start of aSAH symptoms , vasospasm (within 21 days after start of SAH symptoms) and DCI (between day 4 and 6 weeks after start of SAH symptoms ) and good neurological outcome at 3 moths, at 1 year and at 2 years after SAH (mRS 0-2).
11. Difference of MRI parameters between xenon and control group and in predicting risk for EBI within first 72 hours after start of aSAH symptoms , vasospasm (within 21 days after start of SAH symptoms) and DCI (between day 4 and 6 weeks after start of SAH symptoms ) and good neurological outcome at 3 moths, at 1 year and at 2 years after SAH (mRS 0-2).
12. Difference of CTA parameters between xenon and control group and in predicting risk for EBI within first 72 hours after start of aSAH symptoms , vasospasm (within 21 days after start of SAH symptoms) and DCI (between day 4 and 6 weeks after start of SAH symptoms ) and good neurological outcome at 3 moths, at 1 year and at 2 years after SAH (mRS 0-2).
13. Difference of DSA parameters between xenon and control group and in predicting risk for EBI within first 72 hours after start of aSAH symptoms , vasospasm (within 21 days after start of SAH symptoms) and DCI (between day 4 and 6 weeks after start of SAH symptoms ) and good neurological outcome at 3 moths, at 1 year and at 2 years after SAH (mRS 0-2).
14. Predictive value CFD simulations in predicting risk for EBI within first 72 hours after start of aSAH symptoms , vasospasm (within 21 days after start of SAH symptoms) and DCI (between day 4 and 6 weeks after start of SAH symptoms ) and good neurological outcome at 3 moths, at 1 year and at 2 years after SAH (mRS 0-2).
15. Difference of metabolomics of plasma and spinal fluid between xenon and control group and in predicting risk for EBI within first 72 hours after start of aSAH symptoms , vasospasm (within 21 days after start of SAH symptoms) and DCI (between day 4 and 6 weeks after start of SAH symptoms ) and good neurological outcome at 3 moths, at 1 year and at 2 years after SAH (mRS 0-2).
16. Difference of activity of microglia cells between xenon and control group and in predicting risk for DCI and good neurological outcome at 3 moths, at 1 year and at 2 years after SAH (mRS 0-2).
17. Safety of the xenon delivery device Akzent X Color used in the xenon group as assessed with ventilator parameters, blood gas values, adverse events and serious events related to the performance of the ventilators. Safety parameters will be compared between the control group and the xenon group in the interim analysis after 80 patients and in the final analysis with the complete population.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Turku University Central Hospital

Sponsor organisation

Turku University Central Hospital

Address

Savitehtaankatu 1

City

Turku

Postcode

20520

Country

Finland

Scientific contact point

Organisation

Turku University Central Hospital

Contact name

Clinical trial information desk

Public contact point

Organisation

Turku University Central Hospital

Contact name

Clinical trial information desk

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 31 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications