Trial document




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  DRKS00008981

Trial Description

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Title

The role of heme oxygenase 1 (HO-1) for hematoma resolution, neuroinflammation, circadian rhythm and clinical outcome after hemorrhagic or traumatic brain injury

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Trial Acronym

The role of heme oxygenase 1 in brain injury

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URL of the Trial

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Brief Summary in Lay Language

This clinical study will examine patients with a specific form of cerebral hemorrhage. With this special form of brain hemorrhage, rupture of an enlarged brain vessel in most cases leads to an accumulation of blood in the so-called subarachnoid space. This space surrounding the brain contains the brain fluid. The brain fluid takes on important tasks in protecting and nourishing the brain. If there is an accumulation of blood, this can on the one hand lead to a drainage obstruction with increased intracranial pressure. In addition, blood accumulation initiates a “sterile” inflammatory response in the brain (i.e. without infection). Both can lead to brain damage. The rapid breakdown of blood accumulation by the body's own hemoxygenase-1 enzyme (HO-1) is of crucial importance in this situation. In patients with this special form of cerebral hemorrhage, samples (blood, cerebral fluid) will be obtained from the drainages placed as part of the therapeutic measures at three points in time after the start of bleeding (day 1, day 7, day 14) with subsequent analysis of HO-1 and inflammatory mediators. The results of the analyses will be related to the size of the bleeding and the long-term clinical-neurological result. The primary endpoint is HO-1 enzyme activation in relation to brain function after bleeding. Secondary endpoints are HO-1 enzyme activation versus bleeding size and inflammatory response, and comparison of HO-1 enzyme activation to other prediction factors for brain function after bleeding.
Hypothesis 1: HO-1 enzyme activation is associated with better brain function after bleeding.
Hypothesis 2: The level of HO-1 activation is related to the bleeding size.
Hypothesis 3: HO-1 enzyme activation reduces the inflammatory response in the brain after bleeding.
Hypothesis 4: The level of HO-1 enzyme activation can predict brain function after bleeding.
The regulation of the circadian rhythm significantly influences the functional outcome. In polytraumatized patients with or without traumatic brain injury, blood will be obtained at three points in time (day 1, day 7, day 14) from the vascular accesses placed as part of the therapeutic measures, followed by molecular biological and laboratory chemical ex vivo analysis of period-2 gene expression, one of the genes with critical importance in circadian regulation. In addition, clinical data on the rate of renal failure (KDIGO criteria), CAM-ICU score, need for sedation, duration of ventilation, duration of ICU stay and survival after 6 months will be collected.
The primary endpoint is the rate of renal failure in patients with vs. without traumatic brain injury. Secondary endpoints are period-2 expression in blood with vs. without traumatic brain injury and with vs. without kidney failure. Correlation with CAM-ICU score, ventilation and ICU duration and survival after 6 months will be done.
Hypothesis 1: Patients with traumatic brain injury have a significantly higher rate of kidney failure.
Hypothesis 2: Polytrauma patients with traumatic brain injuries have a significantly higher period-2 expression in the blood.
In patients with severe traumatic brain injury, a small amount of cerebrospinal fluid and blood will be taken from the EVD created for therapeutic purposes (analogous to the studies in patients with SAH) at three points in time (days 1, 3 and 7 after trauma) and therein the expression of HO -1 and Per-2, the determination of inflammatory markers and the measurement of the bilirubin content. Clinical data include the initial GCS (Glasgow Coma Scale), the AIS-2005 Score, the Glasgow Outcome Score (GOS) at discharge and after 6 months, the CAM-ICU Score, the need for sedation, the duration of ventilation, the duration of the ICU stay and survival after 6 months.
The primary endpoint is the frequency of distribution of the GOS categories (GOS 1-3 vs. GOS4 & 5) in the patient population with high and low HO-1 expression in cerebrospinal fluid (HO-1 high / low patient groups). Secondary endpoints include the frequency of distribution of the GOS categories (GOS 1-3 vs. GOS4 & 5) in the patient population with high and low Per-2 expression in cerebrospinal fluid, correlation with delirium rate, ventilation and sedation duration and survival after 6 months in relation to the patient categories.
Hypothesis 1: Patients with severe traumatic brain injury and high HO-1 expression have a significantly better GOS score.
Hypothesis 2: Patients with severe traumatic brain injury and high Per2 expression have a significantly better GOS score. Changes due to amendment related to ethical approval No. 293/15, 04.06.2019.

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Brief Summary in Scientific Language

This clinical study will examine patients with non-traumatic, aneurysmal subarachnoid hemorrhage (SAH). The activity and expression of the hemoxygenase-1 enzyme (HO-1) could be of crucial importance for the hematoma degradation after SAH. In patients with SAH, samples will be taken at three times after the start of bleeding (day 1, day 7, day 14) from the CSF drainage placed as part of the therapeutic measures with subsequent molecular biological and laboratory chemical ex vivo analysis of the expression and activity of HO-1 and the expression of inflammatory mediators. The respective expression patterns in peripheral blood are to serve as intra-individual reference values ​​(control values). For this purpose, blood is taken from existing vascular accesses for molecular biological and laboratory chemical ex vivo analysis. In addition, the results of the molecular biological analyzes will be related to the radiographically determined subarachnoid hematoma volume and the clinical-neurological long-term result. In addition, the analysis of other predictive factors for the clinical-neurological long-term result should take place. The primary endpoint is HO-1 expression in relation to the clinical-neurological long-term result (modified Rankin disability scale, mRS). Secondary endpoints are HO-1 expression in relation to hematoma volume, neuroinflammation and in relation to other potential predictors of poor long-term neurological outcome (demography, medical history, laboratory values ​​on admission, SAH-dependent variables: Hunt & Hess, Fisher, aneurysm localization , Hydrocephalus, cerebral edema, intracerebral hemorrhage).
Hypothesis 1: Adequate central HO-1 induction (ratio HO-1 in cerebrospinal fluid / HO-1 in peripheral blood) has a significant influence on the clinical-neurological long-term result (mRS).
Hypothesis 2: The expression of the HO-1 in the cerebrospinal fluid correlates significantly with the hematoma volume.
Hypothesis 3: Adequate central HO-1 induction has a significant influence on the inflammatory response in the brain.
Hypothesis 4: The adequate central HO-1 induction has a predictive value comparable to the other predictors for the neurological outcome.
In polytraumatized patients with or without traumatic brain injury, blood will be obtained at three points in time (day 1, day 7, day 14) from the vascular accesses placed as part of the therapeutic measures, followed by molecular biological and laboratory chemical ex vivo analysis of period-2 gene expression, one of the genes with critical importance in the circadian regulation. In addition, clinical data on the rate of renal failure (KDIGO criteria), CAM-ICU score, need for sedation, duration of ventilation, duration of ICU stay and survival after 6 months will be collected.
The primary endpoint is the rate of renal failure in patients with vs. without traumatic brain injury. Secondary endpoints are period-2 expression in blood with vs. without traumatic brain injury and with vs. without kidney failure. Correlation with CAM-ICU score, ventilation and ICU duration and survival after 6 months will be done.
Hypothesis 1: Patients with traumatic brain injury have a significantly higher rate of kidney failure.
Hypothesis 2: Polytrauma patients with traumatic brain injuries have a significantly higher period-2 expression in the blood.
In patients with severe traumatic brain injury, a small amount of cerebrospinal fluid and blood will be taken from the EVD placed for therapeutic purposes (analogous to the studies in patients with SAH) at three time points (days 1, 3 and 7 after trauma) and therein the expression of HO -1 and Per-2, the determination of inflammatory markers and the measurement of the bilirubin content will be done. Clinical data include the initial GCS (Glasgow Coma Scale), the AIS-2005 Score, the Glasgow Outcome Score (GOS) at discharge and after 6 months, the CAM-ICU Score, the need for sedation, the duration of ventilation, the duration of the ICU stay and survival after 6 months.
The primary endpoint is the frequency of distribution of the GOS categories (GOS 1-3 vs. GOS4 & 5) in the patient population with high and low HO-1 expression in cerebrospinal fluid (HO-1 high / low patient groups). Secondary endpoints include the frequency of distribution of the GOS categories (GOS 1-3 vs. GOS4 & 5) in the patient population with high and low Per-2 expression in cerebrospinal fluid, correlation with delirium rate, ventilation and sedation duration and survival after 6 months in relation to the patient categories.
Hypothesis 1: Patients with severe traumatic brain injury and high HO-1 expression have a significantly better GOS score.
Hypothesis 2: Patients with severe traumatic brain injury and high Per2 expression have a significantly better GOS score.

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00008981
  •   2015/07/31
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  •   yes
  •   Approved
  •   293/15, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   U1111-1172-6077 
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Health Condition or Problem studied

  •   I60 -  Subarachnoid haemorrhage
  •   S06 -  Intracranial injury
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Interventions/Observational Groups

  •   In patients with subarachnoid hemorrhage we will obtain blood and cerebrospinal fluid samples from existing access tubes at different time points (day 1, day 7, day 14 after hemorrhage occurrence) to compare with diagnostic parameters obtained during treatment (CT-scans, laboratory parameters, clinical evaluation, neurological outcome by modified Rankin disability scale, mRS).
  •   In polytraumatized patients with or without traumatic brain injury, blood is to be obtained at three time points (day 1, day 7, day 14) from the vascular accesses placed as part of the therapeutic measures, followed by molecular biological and laboratory chemical ex vivo analysis of period-2 gene expression. In addition, clinical data on the rate of renal failure (KDIGO criteria), CAM-ICU score, need for sedation, duration of ventilation, duration of ICU stay and survival after 6 months will be collected.
  •   In patients with severe traumatic brain injury, a small amount of cerebrospinal fluid and blood should be taken from the EVD created for therapeutic purposes (analogous to the studies in patients with SAH) at three points in time (days 1, 3 and 7 after trauma) and therein the expression of HO -1 and Per-2, the determination of inflammatory markers and the measurement of the bilirubin content will be done. Clinical data include the initial GCS (Glasgow Coma Scale), the AIS-2005 Score, the Glasgow Outcome Score (GOS) at discharge and after 6 months, the CAM-ICU Score, the need for sedation, the duration of ventilation, the duration of the ICU stay and survival after 6 months.
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Characteristics

  •   Non-interventional
  •   Other
  •   Other
  •   Open (masking not used)
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  •   Other
  •   Basic research/physiological study
  •   Other
  •   N/A
  •   N/A
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Primary Outcome

1. Patient population: HO-1 expression (real-time PCR) in relation to the clinical-neurological long-term result (modified Rankin scale, mRS).
2. Patient population: renal failure rate in patients with vs. without traumatic brain injury.
3. Patient population: Frequency of distribution of the GOS categories (GOS 1-3 vs. GOS4 & 5) in the patient population with high and low HO-1 expression in the cerebrospinal fluid (HO-1 high / low patient groups).

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Secondary Outcome

1. HO-1 expression in relation to the hematoma volume (CT examination)
2. HO-1 expression in relation to neuroinflammation (cytokine measurement in cerebrospinal fluid)
3. HO-1 expression in relation to other potential predictors of the poor long-term neurological outcome (demography, medical history, laboratory values on admission, SAH-dependent variables: Hunt & Hess, Fisher, aneurysm localization, hydrocephalus, cerebral edema, intracerebral hemorrhage).
2. Patient population: Period-2 expression in blood with vs. without traumatic brain injury and with vs. without kidney failure. Correlation with CAM-ICU score, ventilation and ICU duration and survival after 6 months.
3. Patient population: frequency of distribution of the GOS categories (GOS 1-3 vs. GOS4 & 5) in the patient population with high and low Per-2 expression in cerebrospinal fluid, correlation with delirium rate, duration of ventilation and sedation, and survival 6 months in relation to the patient categories.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2015/09/01
  •   190
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

SAH patients:
1. Adults (> 18 years) male or female persons.
2. Detection of SAH by imaging or in the cerebrospinal fluid (lumbar puncture with blood / xanthochromia).
3. Admission to the Freiburg University Hospital within 24 hours of the onset of symptoms.
4. Surgical therapeutic intervention with placement of an EVD / lumbar drainage and a CVC / arterial catheter.
5. Ability to consent, either personally or through an authorized person.
Polytrauma +/- traumatic brain injury:
1. Adult patients with polytrauma (ISS> 16) +/- traumatic brain injury
2. Admission to the anesthetic intensive care unit within 24 hours after trauma
3. Ability to consent either in person or by proxy.
Severe traumatic brain injury:
1. Adult patients with severe traumatic brain injury (initial point value Glasgow coma scale <8)
2. Admission to the anaesthesiological intensive care unit or neurosurgical intensive care unit within 24 hours after trauma
3. Establishment of an external ventricular drainage (EVD) within 24 hours after trauma for therapeutic / diagnostic purposes
4. Ability to consent through proxy

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Exclusion Criteria

SAH patients:
1. Children <18 years.
2. Recording later than 24 hours after the onset of symptoms.
3. The patient dies within 24 hours of admission.
4. Radiographic suspicion of additional subdural or epidural bleeding.
5. Radiographic suspicion of meningitis or encephalitis.
6. pregnant patients.
7. Patients with sepsis, SIRS or other systemic inflammation symptoms.
8. Patients with pre-existing intellectual disabilities.
Polytrauma patients:
1. pre-existing kidney damage / impaired kidney function
2. Not taken within 24 hours after trauma
3. Die within 24 hours of admission
4. Traumatic or non-traumatic brain damage within the past
14 days.
Patients with severe TBI:
1. Not taken within 24 hours after trauma
2. Die within 24 hours of admission
3. Traumatic or non-traumatic brain damage within the past
14 days

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Addresses

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    • Universitätsklinik Freiburg, Klinik für Anästhesiologie und Intensivmedizin
    • Mr.  Dr.  Nils  Schallner 
    • Hugstetter Str. 55
    • 79106  Freiburg
    • Germany
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    • Universitätsklinik Freiburg, Klinik für Neurologie
    • Mr.  Dr.  Wolf  Niesen 
    • Breisacher Str. 64
    • 79106  Freiburg
    • Germany
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    • Universitätsklinik Freiburg, Klinik für Neurochirurgie
    • Mr.  Dr.  Klaus-Jürgen  Butler 
    • Breisacher Str. 64
    • 79106  Freiburg
    • Germany
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    • Universitätsklinik Freiburg, Klinik für Anästhesiologie und Intensivmedizin
    • Mr.  Dr.  Nils  Schallner 
    • Hugstetter Str. 55
    • 79106  Freiburg
    • Germany
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    • Universitätsklinik Freiburg, Klinik für Anästhesiologie und Intensivmedizin
    • Mr.  Dr.  Nils  Schallner 
    • Hugstetter Str. 55
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Deutsche Forschungsgemeinschaft e.V.
    • Kennedyallee 40
    • 53175  Bonn
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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