Clinical trial NCT06927063: Long-term Recovery and Microbiota-Gut-Brain Axis Disruption After Traumatic Brain Injury
Official title: Long-term Recovery and Microbiota-Gut-Brain Axis Disruption After Traumatic Brain Injury
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Traumatic Brain Injury
Keywords: traumatic
brain
injury
traumatic brain injury
TBI
neuroinflammation
gut
microbiota
microbiota-gut-brain axis
DTI
diffusion tensor
biomarker
blood based biomarker
Lead sponsor: Turku University Hospital
Sponsor class: OTHER_GOV
Collaborators: name: Aalto University
name: University of Geneva, Switzerland
name: Göteborg University
name: University of Cambridge
name: Örebro University, Sweden
name: University of Turku
First posted: 2025-04-15
Enrollment: 160
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All those who are alive and give their consent will be included from our previous prospective studies (TBIcare or PACoS-TBI)

Brief summary: The OVERCOME-TBI project aims to collect multimodal data approximately 1-4 and 11-14 years after an earlier well-documented traumatic brain injury (TBI) and examine factors that influence disease progression in order to gain new scientific insights into the long-term pathophysiology of TBI and identify new therapeutic targets.

TBIs are among the most serious health problems worldwide and represents a significant burden for the injured, their families and society. It is estimated that more than 50 million people in the world suffer a TBI every year and half of all people will suffer a TBI in their lifetime. TBI diagnostics has lagged significantly behind that of many other diseases. The current methods for assessing severity and predicting outcomes are based only on initial stage variables, and there are no objective tools for monitoring disease progression. The current acute severity indices have shown only a modest association with outcome, particularly in patients with mTBI. However, even in patients with moderate-severe TBI, clinical predictors and imaging together explain only 35% of the variance in outcomes.

In the OVERCOME-TBI project, patients with a history of TBI sustained 1-4 and 11-14 years earlier will undergo extensive neurological, biochemical, microbiological, gastroenterological and imaging examinations. The patients have previously participated in the prospective studies of our research group, so that data on acute injuries, blood-based biomarkers and advanced imaging results are already available. The results are expected to yield objective diagnostic and treatment methods for the diagnosis of progressive brain disease after brain injury and for the identification of microbiome-gut-brain axis dysfunction associated with disease progression.

Detailed description: This detailed description outlines the scientific background, registry procedures and quality control strategies for the OVERCOME-TBI study. The study builds on previous research cohorts Evidence-based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries) and PACoS-TBI (Pathophysiological Characterization of Severe Traumatic Brain Injury) and aims to comprehensively investigate long-term outcomes and the role of the microbiome-gut-brain axis in traumatic brain injury (TBI) through multimodal and longitudinal and cross-sectional data collection.

The OVERCOME-TBI study uses a prospective observational design focusing on patients with moderate and severe TBI. It includes both recently injured TBI patients and long-term survivors to capture a broad trajectory of recovery from TBI. The study will include a broad range of modalities, including clinical assessments, neurocognitive testing, advanced neuroimaging (MRI, PET-MRI), blood biomarkers, microbiome analysis and optional endoscopic biopsies. This integrated approach is structured to provide insights into complex biological mechanisms that influence TBI outcomes.

The overall goal of the OVERCOME-TBI project is to collect multimodal data approximately 1-4 and 11-14 years after a previous, well-documented TBI and to investigate factors that influence disease progression in order to gain new scientific insights into the long-term pathophysiology of TBI and to identify new therapeutic targets. The core of the study design involves the prior collection of extensive clinical, radiological and molecular data at multiple time points: acute hospitalization (0-7 days post-injury), early follow-up (3-6 months) and long-term follow-up (≥12 months). Clinical outcomes are assessed using validated instruments such as the Glasgow Outcome Scale - Extended (GOSE) and the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). These assessments aim to capture both functional and cognitive recovery patterns. The other part of the data collection includes cross-sectional data 1-4 and 11-14 years after TBI.

In terms of registry procedures, each participant is documented in a comprehensive electronic case report form (CRF) that includes demographic information, injury details, ICU and hospital course, surgical interventions, and rehabilitation history. CRFs are created and maintained electronically via secure hospital systems. All CRFs are protected by user authentication. The registry also includes a register of study participants that is created and maintained in accordance with EU General Data Protection Regulation (GDPR) guidelines to ensure participant confidentiality and regulatory compliance.

The biological component of the study includes the collection and storage of peripheral blood, stool samples and, if possible, intestinal biopsies. The blood is collected at predefined intervals and processed into serum and plasma. These are stored at -70°C under biobank conditions with standardized protocols to ensure consistency. Stool samples are taken for microbiome analysis and biopsies, if performed, are stored at -70°C. All samples are pseudonymized and tracked using unique identifiers.

Sample analyzes are performed in several specialized laboratories, including the University of Turku (Finland), the University of Geneva (Switzerland), Sahlgrenska University Hospital (Sweden), and Örebro University (Sweden). Standard operating procedures (SOPs) were developed for blood biomarker assays, microbiome profiling and inflammatory cytokine analysis. Cross-laboratory calibration and quality control measures are instituted to ensure reproducibility and cross-site comparability.

The neuroimaging component includes MRI and PET-MRI. MRI sequences include T1-weighted, FLAIR, SWI and DTI to assess structural and microstructural changes. PET imaging is performed with radioligands that target translocator protein (TSPO) expression and provide insight into neuroinflammation. Imaging data will be analyzed centrally in Turku and Cambridge using harmonized pipelines and machine learning based segmentation methods.

Functional and cognitive assessments are an integral part of the protocol. In addition to GOSE and RPQ, the CANTAB test battery is performed. These tests aim to identify common neuropsychiatric sequelae and investigate correlations with biological and imaging markers.

Data protection and management procedures are a central part of the protocol. All data collected will be entered into a secure, GDPR-compliant data platform. Anonymization is achieved through pseudonymization and encryption strategies. A data access committee regulates data sharing and all shared datasets are derived from anonymized master files as part of data usage agreements. The central database is hosted at Turku University Hospital and is subject to strict backup and archiving protocols.

Informed consent will be obtained from all participants or their legal representatives prior to inclusion in the study. The procedure includes an oral explanation, a written information sheet and time for questions. For cognitively impaired patients, a proxy consent will be documented according to the guidelines of the local ethics committee. All consent forms will be kept in the participant's CRF.

The study has been approved by the Ethics Committee of the Wellbeing Services County of Southwest Finland and the Clinical Services of the Wellbeing Services County of Southwest Finland complies with the Declaration of Helsinki. Procedures involving radiation (PET-MRI) and invasive sampling (biopsy) will be performed within established safety limits. Risk management protocols identify potential harm and define measures for adverse events.

Quality control is embedded in every phase of the study. Standardization of data collection, harmonization of sample handling, staff training and audit trails for all data entries are emphasized.

To address potential sample size limitations or data heterogeneity, the protocol includes provisions for external collaboration. In particular, the study is aligned with the international InTBIR (International Initiative for Traumatic Brain Injury Research) framework, which facilitates data pooling and harmonization with global datasets.

Analysis strategies include logistic regression, linear mixed models and machine learning classifiers. Multimodal fusion analyzes will examine associations between neuroimaging features, cognitive outcomes and biological markers. Time series data will be used to identify trajectories and phenotypes of recovery. Missing data will be treated with multiple imputation or maximum likelihood methods with complete information, depending on the analysis.

Documentation and archiving are performed according to international standards. All physical documentation will be stored securely and electronic files will be stored on institutional servers with restricted access. Research data is retained for at least 20 years.

The study is funded by the Research Council of Finland, the Sigrid Jusélius Foundation and the Finnish State Research Funding. Insurance coverage is provided by Turku University Hospital and covers all patient-related research activities.

In summary, the OVERCOME-TBI protocol represents a comprehensive, ethically sound and scientifically rigorous study framework. It integrates high-quality registry methods, biological sample analysis, cognitive and gastrointestinal assessments, and state-of-the-art imaging. Quality assurance is enforced through robust procedures at all levels to achieve reliable, generalizable and clinically meaningful results in the field of TBI research.

Eligibility criteria: Inclusion Criteria:

* All those who are alive and give their consent will be included from our previous prospective studies (TBIcare or PACoS-TBI)

Exclusion Criteria (neurological and imaging studies):

* For patients with TBI there are no exclusion criteria, and all eligible patients who give consent will be recruited
* Those patients and controls with contraindication for head MRI (MRI-incompatible heart pacemaker, weight over 200 kg, mechanical heart valve prosthesis, first trimester of pregnancy, orbital area tattoo) will not undergo head MRI. Instead, they we will undergo the other assessments
* For controls, those who have suffered a TBI or any other brain disorder after the TBIcare or PACoS-TBI study will be excluded.

Exclusion Criteria (colonoscopy)

* Diagnosis of IBD or other diagnosis besides IBS causing severe GI symptoms, such as microscopic colitis or bile acid diarrhea
* Poorly controlled celiac disease
* Colorectal cancer diagnosed within five years
* Antibiotic or probiotic treatment, on-going or previous month.
* Unwilling or unable to undergo colonoscopy and/or standard bowel preparation.
* Significantly increased risk of heart or kidney failure or electrolyte imbalances due to bowel preparation (frailty, serious pre-existing heart or kidney insufficiency).
* Altered bowel anatomy after significant operation. Appendicectomy or cholecystectomy are considered minor operations.

Primary outcomes:
measure: Biochemical neuroinflammation burden (lipids and metabolites)
timeFrame: 1-14 years after traumatic brain injury
measure: Biochemical neuroinflammation burden (cytokines)
timeFrame: 1-14 years after traumatic brain injury
measure: Functional outcome
timeFrame: 1-14 years after traumatic brain injury
measure: Changes in microbiota
timeFrame: 1-14 years after traumatic brain injury
measure: Inflammation burden on head positron emission tomography
timeFrame: 1-14 years after traumatic brain injury
Secondary outcomes:
measure: Changes in brain white and grey matter microstructure
timeFrame: 1-14 years after traumatic brain injury
measure: Accelerated brain ageing
timeFrame: 1-14 years after traumatic brain injury
Other outcomes:
Locations:
Study officials:
affiliation: Turku University Hospital and University of Turku
name: Jussi P. Posti, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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