Brain Injuries, TraumaticNCT03900182
The Role of Hyperbaric Oxygen and Neuropsychological Therapy in Cognitive Function Following Traumatic Brain Injury
A study testing Hyperbaric Oxygen Therapy in people with Brain Injuries, Traumatic and Neuropsychology, run by Hung-Chen Wang at 1 site in Taiwan.
Trial summary
Traumatic brain injury (TBI) caused by accidents is a very important public health problem in Taiwan. There are many people with brain damage and cognitive dysfunction caused by traumatic brain injury every year. Currently, there is no effective treatment for cognitive dysfunction caused by traumatic brain injury. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Brain Injuries, Traumatic, Neuropsychology
- What is being tested?
- Hyperbaric Oxygen Therapy
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 10 participants
- Where
- 1 siteTaiwan
- Study dates
- 9 Apr 2019to 28 Feb 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Traumatic brain injury, mild and moderated.
- Age between 18 and 65 years old
Who cannot join
- Penetrating injury, including gunshot injury
- Combined with other major trauma which had unstable hemodynamics
- Major systemic disease, such ESRD, liver cirrhosis, CHF, or a malignant disease
- Evidence for alcoholism or any other addictive disorders, or known affective or other psychiatric disease or use of sedatives or neuroleptic medication
- Known neurological disorders potentially affecting the central nervous system or severe recent life events that might have interfered with neuropsychological testing.
Trial locations and contacts
1 site in 1 country.
About this study
Traumatic brain injury (TBI) caused by accidents is a very important public health problem in Taiwan. There are many people with brain damage and cognitive dysfunction caused by traumatic brain injury every year. Currently, there is no effective treatment for cognitive dysfunction caused by traumatic brain injury. Evidence from clinical studies in recent years suggests that hyperbaric oxygen therapy may be a treatment for repairing nerves after brain injury.
Many studies have shown that oxidative stress and inflammatory responses play an important role in the pathogenesis of the central nervous system. In recent years, our research team has shown that oxidative stress and inflammatory response are significantly associated with the prognosis of patients with traumatic brain injury, cerebral hemorrhage, and stroke patients. More and more evidences also show that oxidative stress and inflammatory response play an important role in the neuropathological changes of mental cognitive sequelae after traumatic brain injury. This injury may be gradual from the time of head trauma. This process begins with the generation of oxidative stress and free radicals. When the cell repair and free radical scavenging system can not effectively overcome the excessive production of free radicals, an oxidative damage reaction will occur, causing a series of inflammatory cells and cytokines to be activated. Studies have also shown that when inhibiting those free radicals that produce oxidative stress, the neurological function and cognitive function of the head after trauma can be significantly improved.
Read more
It is becoming widely acknowledged that the combined action of hyperoxia and hyperbaric pressure leads to significant improvement in tissue oxygenation while targeting both oxygenand pressure-sensitive genes, resulting in improved mitochondrial metabolism with anti-apoptotic and anti-inflammatory effects. The investigators published an article this year showing that hyperbaric oxygen therapy can improve the prognosis of patients with acute stroke and increase endothelial progenitor cells in the systemic circulation.
The investigators plan to conduct this research project through hyperbaric oxygen therapy and neuropsychological therapy, and using scientific tests and neurocognitive function assessments. The investigators hope to answer the following questions: (1) Whether the treatment of hyperbaric oxygen can improve oxidative stress and inflammatory response after brain injury, and observe changes in biomarker concentration; (2) Whether hyperbaric oxygen therapy and neuropsychological therapy can improve cognitive function after brain injury; and (3) which biomarkers are factors that influence cognitive function prognosis.
Read the detailed description
Research Methodology A prospective cohort study will be conducted. The follow-up periods are 18 weeks.
Diagnostic criteria of mild and moderate traumatic brain injury. Diagnostic criteria of traumatic brain injury will be according to (1) American Association of Neurosurgical Surgeons (AANS) Guidelines for The Management of Severe Head Injury; (2) YOUMANS Neurological Surgery Fifth Edition Guidelines for Traumatic Brain Injury.
Definitions and classifications Traumatic brain injury is defined as damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile. Consequently to the injury, brain function is temporarily or permanently impaired and structural damage may or may not be detectable with current imaging technology. TBI is usually classified based on severity, anatomical features of the injury, and the cause of the injury. The severity is assessed according to the loss of consciousness (LOC) duration, the post-traumatic amnesia (PTA), and the Glasgow coma scale (GCS) grading of the level of consciousness. Approximately (70-90%) of the TBI in the US are classified as mild TBI (mTBI) or concussion - LOC duration of 0-30 minutes, PTA duration of less than a day and GCS grade of 13-15. Post concussion syndrome (PCS) is a set of symptoms succeeding mTBI in most patients. The PCS symptoms include headache, dizziness, neuropsychiatric symptoms, and cognitive impairments. In most patients, PCS may continue for weeks or months, and up to 25% of the patients may experience prolonged PCS (PPCS) in which the symptoms last for over six months. Such individuals are at high risk for emotional and cognitive dysfunction, culminating in inability to carry out ordinary daily activities, work responsibilities and standard social relationships.
Hypotheses and Purpose:
In this study, the investigators hypothesize that the hyperbaric oxygen therapy in neurotherapeutics, in light of recent persuasive evidence for hyperbaric oxygen therapy efficacy in brain repair and of new understanding of brain energy management and response to damage. The investigators discuss the optimal timing of treatment, optimal dose-response curve (oxygenpressure levels), suitable candidates and promising future directions. The investigators speculate that these changes of biomarkers correlated with the hyperbaric oxygen therapy efficacy and the progression of neuropsychological testing during the 18 weeks follow-up.
The investigators plan to conduct this research project through hyperbaric oxygen therapy and neuropsychological therapy and using scientific tests and neurocognitive function assessments. The scientific tests including flow cytometry to evaluate the fraction of circulating activated platelets, the proportion of leukocytosis apoptosis, Erythrocyte assay of antioxidant enzymes and Enzyme-Linked Immunosorbent Assay (ELISA) for inflammatory markers.
Purpose:
- To evaluate that whether the treatment of hyperbaric oxygen can improve oxidative stress and inflammatory response after brain injury, and observe changes in biomarker concentration.
- To evaluate that whether hyperbaric oxygen therapy and neuropsychological therapy can improve cognitive function after brain injury.
- To evaluate that which biomarkers are factors that influence the prognosis of cognitive function.
- Conditions
- Brain Injuries, Traumatic, Neuropsychology
- Being tested
- Hyperbaric Oxygen Therapy
- Keywords
- Traumatic brain injury, hyperbaric oxygen therapy, neuropsychological treatment, cognitive function, biomarkers.
- Medical subject headings
- Brain Injuries, Traumatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hyperbaric Oxygen TherapyDevice
Also called Neuropsychological Therapy
The Hyperbaric Oxygen Therapy (HBOT) patients were placed in a chamber that was pressurized with air to 2.5 ATA during 15 min and were supplied 100% oxygen for 25 mins, followed by a 5-min air break. This cycle was repeated once and followed by 100% oxygen for 10 min, after which time the chamber was depressurized to 1 ATA over 15 min with 100% oxygen for a total treatment time of 100 min.
| Study group | Role | What they receive |
|---|---|---|
| HBO treated group | Active comparator | Patients in the treated group were evaluated three - at baseline, after 6 weeks of HBOT and after 6 weeks of neuropsychological treatment or no treatment. Receives: Device: Hyperbaric Oxygen Therapy |
| crossover group | Sham comparator | Patients in the crossover group were evaluated three times: baseline, after 6 weeks control period of no treatment, and after subsequent 6 weeks of HBOT Receives: Device: Hyperbaric Oxygen Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Neuropsychological testing- Wechsler Adult Intelligence scale-III (WAIS-III)
Subtests included the followings: Information with a measure of general knowledge, digit Span, vocabulary ability to define 35 words, arithmetic, comprehension, similarities, picture completion, picture arrangement, block design, digit symbol, and object assembly. The scores could further subscore into verbal comprehension, perceptual reasoning and working memory index.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Neuropsychological testing- Cognitive Ability Screening Instrument (CASI)
includes tests of nine domains of cognitive function (attention, concentration, orientation, short and long-term memory, language ability, visual construction, word list generation, abstraction, and judgment), and the score ranges from 0 (worst) to 100 (best score).
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Neuropsychological testing- mini-mental state examination (MMSE)
The Mini-Mental State Examination (MMSE) test is a 30-point questionnaire. Any score greater than or equal to 24 points (out of 30) indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Neuropsychological testing- Short Form 36 questionnaire
The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Scoring the SF-36 is a two-step process. First, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are set at 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Neuropsychological testing- The World Health Organization Quality of Life questionnaire (WHOQOL-BREF)
questionnaire is a 26-item questionnaire that evaluates 4 domains of quality of life (QoL), namely Physical, Psychological, Social Relationships and Environment
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Neuropsychological testing- Beck Depression Inventory
The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs used here differ from the original as such: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 29-63: severe depression.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Secondary outcomes (17)
oxidative damage markers: Erythrocyte superoxide dismutase (SOD) activity
by a commercially available kit (Ransod, Randox Lab., Grumlin, UK) based on the method developed by McCord and Fridovich. The SOD activity is then measured by the degree of inhibition of this reaction. The assay will be carried out on washed red blood cells, by diluting the samples to give between 30 and 60% inhibition. Together with the kit, a standard is supplied, which is diluted to provide a range of standards and a calibration curve. A standard curve will be produced by plotting % inhibition for each standard against Log 10. The result will be multiplied by the appropriate dilution factor (100) and expressed in units/litre (U/L) of whole blood.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
oxidative damage markers: Erythrocyte glutathione peroxidase (GPx) activity
Erythrocyte GPx activity will be measured using a commercially available kit (Ransel; Randox Lab, Crumlin, U.K.). The result obtained will be expressed in U/L of haemolysate and will be multiplied by the appropriate dilution factor to obtain the result in U/L of whole blood.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
oxidative damage markers: serum malondialdehyde (MDA) content
Serum MDA will be measured using the thiobarbituric acid reactive substances (TBARS) assay. TBARS reagent (1 ml) will be added to a 0.5 ml aliquot of serum and heated for 20 minutes at 100°C. The antioxidant, butylated hydroxytoluene, will be added before heating the samples. After cooling on ice, samples will be centrifuged at 840 g for 15 mins and absorbance of the supernatant will be read at 532 nm. Blanks for each sample will be prepared and assessed in the same way to correct for the contribution of A532 to the sample. TBARS results will be expressed as MDA equivalents using 1,1,3,3-tetraethoxypropane.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
oxidative damage markers: serum free thiol content
Plasma free thiols will be determined by directly reacting thiols with 5,5-dithiobis 2-nitrobenzoic acid (DTNB) to form 5-thio-2- nitrobenzoic acid (TNB). The amount of thiols in the sample will be calculated from the absorbance determined using extinction coefficient of TNB (A412 = 13,600 M-1cm-1).
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Cytokines (IL-1β) by Enzyme-linked immunosorbent assays
will be assayed in serum samples and quantified with a commercially available colorimetric ELISA.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Cytokines (IL-6) by Enzyme-linked immunosorbent assays
will be assayed in serum samples and quantified with a commercially available colorimetric ELISA.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Cytokines (IL-10) by Enzyme-linked immunosorbent assays
will be assayed in serum samples and quantified with a commercially available colorimetric ELISA.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Cytokines (TNF-α) by Enzyme-linked immunosorbent assays
will be assayed in serum samples and quantified with a commercially available colorimetric ELISA.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
endothelium-leukocyte activation (ICAM-1)
will be assayed in serum samples and quantified with a commercially available colorimetric ELISA.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
endothelium-leukocyte activation ( VCAM-1)
will be assayed in serum samples and quantified with a commercially available colorimetric ELISA.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
endothelium-leukocyte activation (E-selectin)
will be assayed in serum samples and quantified with a commercially available colorimetric ELISA.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
endothelium-leukocyte activation (L-selectin)
will be assayed in serum samples and quantified with a commercially available colorimetric ELISA.
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
neural inflammation markers (S-100)
by Enzyme-linked immunosorbent assays; The values of intra- and inter-assay coefficients were around 5%. Concentration is expressed as pg/ml
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
neural inflammation markers (tau protein)
by Enzyme-linked immunosorbent assays; The values of intra- and inter-assay coefficients were around 5%. Concentration is expressed as pg/ml
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
neural inflammation markers (MMP-2)
by Enzyme-linked immunosorbent assays; The values of intra- and inter-assay coefficients were around 5%. Concentration is expressed as ng/ml
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
neural inflammation markers (MMP-9)
by Enzyme-linked immunosorbent assays; The values of intra- and inter-assay coefficients were around 5%. Concentration is expressed as ng/ml
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
plasma cell-free DNA by Real-time quantative PCR
DNA will be extracted from 200μL plasma samples with use of a QIAamp Blood Kit (Qiagen) according to the "blood and body fluid protocol" as recommended by the manufacturer. Plasma DNA will be measured by a real-time quantitative PCR assay for the β-globin gene and ND2 gene. The β-globin gene is present in all nucleated cells of the body while ND2 gene is specific mitochondrial DNA. Expression of β-globin and mtDNA will be measured by quantitative RT-PCR based on continuous measurements of Syber green fluorescent dye that binds to double stranded DNA generated during PCR and a specific primer pair for β-globin-354F (5'-GTG CAC CTG ACT CCT GAG GAG A-3') and β-globin-455R (5'-CCT TGA TAC CAA CCT GCC CAG-3') and ND2 (forward：5'-CAC AGA AGC TGC CAT CAA GTA -3'; reverse：5'-CCG GAG AGT ATA TTG TTG AAG AG -3').
Measured: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Apr 2019
- Study start9 Apr 2019
- Primary completion28 Feb 2021
- Study completion28 Feb 2021
Why it stopped: Due to COVID-19 pandemic, patients can not receive hyperbaric oxygen therapy.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (38)Papers the sponsor has linked to this study.
- Other trials for Brain Injuries, TraumaticStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- After signing an informed consent form, the patients were invited for baseline evaluation. Included patients were randomized into two groups. The neuropsychological functions were the primary endpoints of the study. Secondary end point included quality of life evaluation. Evaluations were made by medical and neuropsychological practitioners who were blinded to patients' inclusion in the control-crossed or the treated groups. Patients in the treated group were evaluated three - at baseline, after 6 weeks of HBOT and after 6 weeks of neuropsychological treatment or no treatment. Patients in the crossover group were evaluated three times: baseline, after 6 weeks control period of no treatment, and after subsequent 6 weeks of HBOT. The post-HBOT neuropsycological evaluations were performed more than 1 week (1-2 weeks) after the end of the HBOT protocol. The following HBOT protocol was practiced: 30 daily sessions, 5 days/week, 60 minutes each, 100% oxygen at 1.5ATA.
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hung-Chen Wang
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Hung-Chen Wang, Chang Gung Memorial Hospital
- Investigators
- Tsang-Tang Hsieh, MD, Study chair, Chang Gung Medical Foundation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03900182
- Sponsor's protocol ID
- 201801854A3
- Status last verified
- Jul 2021
- First submitted
- 25 Mar 2019
- Last updated
- 2 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: We plan individual participant data sets to be shared while asking by other researchers.
Publications
Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008 Aug;7(8):728-41. doi: 10.1016/S1474-4422(08)70164-9.
PubMed 18635021Lenzlinger PM, Morganti-Kossmann MC, Laurer HL, McIntosh TK. The duality of the inflammatory response to traumatic brain injury. Mol Neurobiol. 2001 Aug-Dec;24(1-3):169-81. doi: 10.1385/MN:24:1-3:169.
PubMed 11831551Zhang X, Chen Y, Jenkins LW, Kochanek PM, Clark RS. Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care. 2005 Feb;9(1):66-75. doi: 10.1186/cc2950. Epub 2004 Sep 3.
PubMed 15693986Schmidt OI, Leinhase I, Hasenboehler E, Morgan SJ, Stahel PF. [The relevance of the inflammatory response in the injured brain]. Orthopade. 2007 Mar;36(3):248, 250-8. doi: 10.1007/s00132-007-1061-z. German.
PubMed 17333066Lu J, Goh SJ, Tng PY, Deng YY, Ling EA, Moochhala S. Systemic inflammatory response following acute traumatic brain injury. Front Biosci (Landmark Ed). 2009 Jan 1;14(10):3795-813. doi: 10.2741/3489.
PubMed 19273311Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care. 2004;1(4):479-88. doi: 10.1385/NCC:1:4:479.
PubMed 16174954Wang HC, Wang PM, Lin YJ, Kwan AL, Lin WC, Tsai NW, Cheng BC, Chang WN, Su BY, Kung CT, Lu CH. Serum adhesion molecules, outcome and neuro-psychological function in acute traumatic brain injury patients. Clin Chim Acta. 2013 Aug 23;423:122-9. doi: 10.1016/j.cca.2013.04.023. Epub 2013 Apr 30.
PubMed 23643853Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia. 2010 Feb;58(3):253-63. doi: 10.1002/glia.20928.
PubMed 19705460Rhind SG, Crnko NT, Baker AJ, Morrison LJ, Shek PN, Scarpelini S, Rizoli SB. Prehospital resuscitation with hypertonic saline-dextran modulates inflammatory, coagulation and endothelial activation marker profiles in severe traumatic brain injured patients. J Neuroinflammation. 2010 Jan 18;7:5. doi: 10.1186/1742-2094-7-5.
PubMed 20082712Carson MJ, Thrash JC, Walter B. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res. 2006 Dec;6(5):237-245. doi: 10.1016/j.cnr.2006.09.004.
PubMed 19169437Wang HC, Yang TM, Lin YJ, Chen WF, Ho JT, Lin YT, Kwan AL, Lu CH. Serial serum leukocyte apoptosis levels as predictors of outcome in acute traumatic brain injury. Biomed Res Int. 2014;2014:720870. doi: 10.1155/2014/720870. Epub 2014 Apr 17.
PubMed 24864256Kadhim HJ, Duchateau J, Sebire G. Cytokines and brain injury: invited review. J Intensive Care Med. 2008 Jul-Aug;23(4):236-49. doi: 10.1177/0885066608318458. Epub 2008 May 25.
PubMed 18504260Wang HC, Lin YJ, Shih FY, Chang HW, Su YJ, Cheng BC, Su CM, Tsai NW, Chang YT, Kwan AL, Lu CH. The Role of Serial Oxidative Stress Levels in Acute Traumatic Brain Injury and as Predictors of Outcome. World Neurosurg. 2016 Mar;87:463-70. doi: 10.1016/j.wneu.2015.10.010. Epub 2015 Oct 23.
PubMed 26481337Soriano SG, Piva S. Central nervous system inflammation. Eur J Anaesthesiol Suppl. 2008;42:154-9. doi: 10.1017/S0265021507003390.
PubMed 18289434Balabanov R, Goldman H, Murphy S, Pellizon G, Owen C, Rafols J, Dore-Duffy P. Endothelial cell activation following moderate traumatic brain injury. Neurol Res. 2001 Mar-Apr;23(2-3):175-82. doi: 10.1179/016164101101198514.
PubMed 11320596
Study at a glance
From the registry record, last updated by the sponsor on 2 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Role of Hyperbaric Oxygen and Neuropsychological Therapy in Cognitive Function Following Traumatic Brain Injury
- ClinicalTrials.gov ID
- NCT03900182
- Acronym / sponsor ID
- 201801854A3
- Conditions
- Brain Injuries, Traumatic, Neuropsychology
- Keywords
- Traumatic brain injury, hyperbaric oxygen therapy, neuropsychological treatment, cognitive function, biomarkers.
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Due to COVID-19 pandemic, patients can not receive hyperbaric oxygen therapy.
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Hung-Chen WangUniversity, hospital or other
- Study start
- 9 Apr 2019 (actual)
- Primary completion
- 28 Feb 2021 (actual)
- Study completion
- 28 Feb 2021 (actual)
- First posted
- 2 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Traumatic brain injury (TBI) caused by accidents is a very important public health problem in Taiwan. There are many people with brain damage and cognitive dysfunction caused by traumatic brain injury every year. Currently, there is no effective treatment for cognitive dysfunction caused by traumatic brain injury. Evidence from clinical studies in recent years suggests that hyperbaric oxygen therapy may be a treatment for repairing nerves after brain injury.
Many studies have shown that oxidative stress and inflammatory responses play an important role in the pathogenesis of the central nervous system. In recent years, our research team has shown that oxidative stress and inflammatory response are significantly associated with the prognosis of patients with traumatic brain injury, cerebral hemorrhage, and stroke patients. More and more evidences also show that oxidative stress and inflammatory response play an important role in the neuropathological changes of mental cognitive sequelae after traumatic brain injury. This injury may be gradual from the time of head trauma. This process begins with the generation of oxidative stress and free radicals. When the cell repair and free radical scavenging system can not effectively overcome the excessive production of free radicals, an oxidative damage reaction will occur, causing a series of inflammatory cells and cytokines to be activated. Studies have also shown that when inhibiting those free radicals that produce oxidative stress, the neurological function and cognitive function of the head after trauma can be significantly improved.
It is becoming widely acknowledged that the combined action of hyperoxia and hyperbaric pressure leads to significant improvement in tissue oxygenation while targeting both oxygenand pressure-sensitive genes, resulting in improved mitochondrial metabolism with anti-apoptotic and anti-inflammatory effects. The investigators published an article this year showing that hyperbaric oxygen therapy can improve the prognosis of patients with acute stroke and increase endothelial progenitor cells in the systemic circulation.
The investigators plan to conduct this research project through hyperbaric oxygen therapy and neuropsychological therapy, and using scientific tests and neurocognitive function assessments. The investigators hope to answer the following questions: (1) Whether the treatment of hyperbaric oxygen can improve oxidative stress and inflammatory response after brain injury, and observe changes in biomarker concentration; (2) Whether hyperbaric oxygen therapy and neuropsychological therapy can improve cognitive function after brain injury; and (3) which biomarkers are factors that influence cognitive function prognosis.
Detailed description
Research Methodology A prospective cohort study will be conducted. The follow-up periods are 18 weeks.
Diagnostic criteria of mild and moderate traumatic brain injury. Diagnostic criteria of traumatic brain injury will be according to (1) American Association of Neurosurgical Surgeons (AANS) Guidelines for The Management of Severe Head Injury; (2) YOUMANS Neurological Surgery Fifth Edition Guidelines for Traumatic Brain Injury.
Definitions and classifications Traumatic brain injury is defined as damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile. Consequently to the injury, brain function is temporarily or permanently impaired and structural damage may or may not be detectable with current imaging technology. TBI is usually classified based on severity, anatomical features of the injury, and the cause of the injury. The severity is assessed according to the loss of consciousness (LOC) duration, the post-traumatic amnesia (PTA), and the Glasgow coma scale (GCS) grading of the level of consciousness. Approximately (70-90%) of the TBI in the US are classified as mild TBI (mTBI) or concussion - LOC duration of 0-30 minutes, PTA duration of less than a day and GCS grade of 13-15. Post concussion syndrome (PCS) is a set of symptoms succeeding mTBI in most patients. The PCS symptoms include headache, dizziness, neuropsychiatric symptoms, and cognitive impairments. In most patients, PCS may continue for weeks or months, and up to 25% of the patients may experience prolonged PCS (PPCS) in which the symptoms last for over six months. Such individuals are at high risk for emotional and cognitive dysfunction, culminating in inability to carry out ordinary daily activities, work responsibilities and standard social relationships.
Hypotheses and Purpose:
In this study, the investigators hypothesize that the hyperbaric oxygen therapy in neurotherapeutics, in light of recent persuasive evidence for hyperbaric oxygen therapy efficacy in brain repair and of new understanding of brain energy management and response to damage. The investigators discuss the optimal timing of treatment, optimal dose-response curve (oxygenpressure levels), suitable candidates and promising future directions. The investigators speculate that these changes of biomarkers correlated with the hyperbaric oxygen therapy efficacy and the progression of neuropsychological testing during the 18 weeks follow-up.
The investigators plan to conduct this research project through hyperbaric oxygen therapy and neuropsychological therapy and using scientific tests and neurocognitive function assessments. The scientific tests including flow cytometry to evaluate the fraction of circulating activated platelets, the proportion of leukocytosis apoptosis, Erythrocyte assay of antioxidant enzymes and Enzyme-Linked Immunosorbent Assay (ELISA) for inflammatory markers.
Purpose:
- To evaluate that whether the treatment of hyperbaric oxygen can improve oxidative stress and inflammatory response after brain injury, and observe changes in biomarker concentration.
- To evaluate that whether hyperbaric oxygen therapy and neuropsychological therapy can improve cognitive function after brain injury.
- To evaluate that which biomarkers are factors that influence the prognosis of cognitive function.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- After signing an informed consent form, the patients were invited for baseline evaluation. Included patients were randomized into two groups. The neuropsychological functions were the primary endpoints of the study. Secondary end point included quality of life evaluation. Evaluations were made by medical and neuropsychological practitioners who were blinded to patients' inclusion in the control-crossed or the treated groups. Patients in the treated group were evaluated three - at baseline, after 6 weeks of HBOT and after 6 weeks of neuropsychological treatment or no treatment. Patients in the crossover group were evaluated three times: baseline, after 6 weeks control period of no treatment, and after subsequent 6 weeks of HBOT. The post-HBOT neuropsycological evaluations were performed more than 1 week (1-2 weeks) after the end of the HBOT protocol. The following HBOT protocol was practiced: 30 daily sessions, 5 days/week, 60 minutes each, 100% oxygen at 1.5ATA.
| Arm | Type | Receives |
|---|---|---|
| HBO treated group | Active comparator | Device: Hyperbaric Oxygen TherapyPatients in the treated group were evaluated three - at baseline, after 6 weeks of HBOT and after 6 weeks of neuropsychological treatment or no treatment. |
| crossover group | Sham comparator | Device: Hyperbaric Oxygen TherapyPatients in the crossover group were evaluated three times: baseline, after 6 weeks control period of no treatment, and after subsequent 6 weeks of HBOT |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Traumatic brain injury, mild and moderated.
- Age between 18 and 65 years old
Key exclusion criteria (5 listed)
- Penetrating injury, including gunshot injury
- Combined with other major trauma which had unstable hemodynamics
- Major systemic disease, such ESRD, liver cirrhosis, CHF, or a malignant disease
- Evidence for alcoholism or any other addictive disorders, or known affective or other psychiatric disease or use of sedatives or neuroleptic medication
- Known neurological disorders potentially affecting the central nervous system or severe recent life events that might have interfered with neuropsychological testing.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Hyperbaric Oxygen TherapyAlso: Neuropsychological TherapyThe Hyperbaric Oxygen Therapy (HBOT) patients were placed in a chamber that was pressurized with air to 2.5 ATA during 15 min and were supplied 100% oxygen for 25 mins, followed by a 5-min air break. This cycle was repeated once and followed by 100% oxygen for 10 min, after which time the chamber was depressurized to 1 ATA over 15 min with 100% oxygen for a total treatment time of 100 min. | Device | HBO treated group, crossover group |
Primary outcome
Neuropsychological testing- Wechsler Adult Intelligence scale-III (WAIS-III)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Subtests included the followings: Information with a measure of general knowledge, digit Span, vocabulary ability to define 35 words, arithmetic, comprehension, similarities, picture completion, picture arrangement, block design, digit symbol, and object assembly. The scores could further subscore into verbal comprehension, perceptual reasoning and working memory index.
Neuropsychological testing- Cognitive Ability Screening Instrument (CASI)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
includes tests of nine domains of cognitive function (attention, concentration, orientation, short and long-term memory, language ability, visual construction, word list generation, abstraction, and judgment), and the score ranges from 0 (worst) to 100 (best score).
Neuropsychological testing- mini-mental state examination (MMSE)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
The Mini-Mental State Examination (MMSE) test is a 30-point questionnaire. Any score greater than or equal to 24 points (out of 30) indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.
Neuropsychological testing- Short Form 36 questionnaire
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Scoring the SF-36 is a two-step process. First, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are set at 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores.
Neuropsychological testing- The World Health Organization Quality of Life questionnaire (WHOQOL-BREF)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
questionnaire is a 26-item questionnaire that evaluates 4 domains of quality of life (QoL), namely Physical, Psychological, Social Relationships and Environment
Neuropsychological testing- Beck Depression Inventory
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs used here differ from the original as such: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 29-63: severe depression.
17 secondary outcomes
oxidative damage markers: Erythrocyte superoxide dismutase (SOD) activity
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
oxidative damage markers: Erythrocyte glutathione peroxidase (GPx) activity
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
oxidative damage markers: serum malondialdehyde (MDA) content
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
oxidative damage markers: serum free thiol content
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Cytokines (IL-1β) by Enzyme-linked immunosorbent assays
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Cytokines (IL-6) by Enzyme-linked immunosorbent assays
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Cytokines (IL-10) by Enzyme-linked immunosorbent assays
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Cytokines (TNF-α) by Enzyme-linked immunosorbent assays
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
endothelium-leukocyte activation (ICAM-1)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
endothelium-leukocyte activation ( VCAM-1)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
endothelium-leukocyte activation (E-selectin)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
endothelium-leukocyte activation (L-selectin)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
neural inflammation markers (S-100)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
neural inflammation markers (tau protein)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
neural inflammation markers (MMP-2)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
neural inflammation markers (MMP-9)
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
plasma cell-free DNA by Real-time quantative PCR
Time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Results and safety
The study was stopped early (reason given: Due to COVID-19 pandemic, patients can not receive hyperbaric oxygen therapy.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Aug 2021.
- Background: PubMed 18635021Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008 Aug;7(8):728-41. doi: 10.1016/S1474-4422(08)70164-9.
- Background: PubMed 11831551Lenzlinger PM, Morganti-Kossmann MC, Laurer HL, McIntosh TK. The duality of the inflammatory response to traumatic brain injury. Mol Neurobiol. 2001 Aug-Dec;24(1-3):169-81. doi: 10.1385/MN:24:1-3:169.
- Background: PubMed 15693986Zhang X, Chen Y, Jenkins LW, Kochanek PM, Clark RS. Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care. 2005 Feb;9(1):66-75. doi: 10.1186/cc2950. Epub 2004 Sep 3.
- Background: PubMed 17333066Schmidt OI, Leinhase I, Hasenboehler E, Morgan SJ, Stahel PF. [The relevance of the inflammatory response in the injured brain]. Orthopade. 2007 Mar;36(3):248, 250-8. doi: 10.1007/s00132-007-1061-z. German.
- Background: PubMed 19273311Lu J, Goh SJ, Tng PY, Deng YY, Ling EA, Moochhala S. Systemic inflammatory response following acute traumatic brain injury. Front Biosci (Landmark Ed). 2009 Jan 1;14(10):3795-813. doi: 10.2741/3489.
- Background: PubMed 16174954Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care. 2004;1(4):479-88. doi: 10.1385/NCC:1:4:479.
- Background: PubMed 23643853Wang HC, Wang PM, Lin YJ, Kwan AL, Lin WC, Tsai NW, Cheng BC, Chang WN, Su BY, Kung CT, Lu CH. Serum adhesion molecules, outcome and neuro-psychological function in acute traumatic brain injury patients. Clin Chim Acta. 2013 Aug 23;423:122-9. doi: 10.1016/j.cca.2013.04.023. Epub 2013 Apr 30.
- Background: PubMed 19705460Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia. 2010 Feb;58(3):253-63. doi: 10.1002/glia.20928.
- Background: PubMed 20082712Rhind SG, Crnko NT, Baker AJ, Morrison LJ, Shek PN, Scarpelini S, Rizoli SB. Prehospital resuscitation with hypertonic saline-dextran modulates inflammatory, coagulation and endothelial activation marker profiles in severe traumatic brain injured patients. J Neuroinflammation. 2010 Jan 18;7:5. doi: 10.1186/1742-2094-7-5.
- Background: PubMed 19169437Carson MJ, Thrash JC, Walter B. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res. 2006 Dec;6(5):237-245. doi: 10.1016/j.cnr.2006.09.004.
- Background: PubMed 24864256Wang HC, Yang TM, Lin YJ, Chen WF, Ho JT, Lin YT, Kwan AL, Lu CH. Serial serum leukocyte apoptosis levels as predictors of outcome in acute traumatic brain injury. Biomed Res Int. 2014;2014:720870. doi: 10.1155/2014/720870. Epub 2014 Apr 17.
- Background: PubMed 18504260Kadhim HJ, Duchateau J, Sebire G. Cytokines and brain injury: invited review. J Intensive Care Med. 2008 Jul-Aug;23(4):236-49. doi: 10.1177/0885066608318458. Epub 2008 May 25.
- Individual participant dataSharing planned: Undecided. We plan individual participant data sets to be shared while asking by other researchers.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tsang-Tang Hsieh, MD study chair
Chang Gung Medical Foundation
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Hyperbaric Oxygen Therapy in people with Brain Injuries, Traumatic and Neuropsychology, run by Hung-Chen Wang at 1 site in Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 2 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: Due to COVID-19 pandemic, patients can not receive hyperbaric oxygen therapy.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Neuropsychological testing- Wechsler Adult Intelligence scale-III (WAIS-III) (time frame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03900182, which also lists 38 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Aug 2021.