Impact of Multi-Disciplinary Care and Clinical Coach Coordinators on Participant Satisfaction and Retention in TBI Clinical Trials: A TEAM-TBI Study.

BACKGROUND: Targeted Evaluation Action and Monitoring of Traumatic Brain Injury (TEAM-TBI) is a monitored, multiple interventional research identifying clinical profiles and assigns individualized, evidence-based treatment program. The objective of the current study was to assess overall participant satisfaction of the multi-disciplinary care team and approach. METHODS: Between 2014 and 2017, 90 participants completed the 4-day TEAM-TBI clinical intake evaluation resulting in individualized treatment recommendations followed by a six-month intervention phase follow-up. Inclusion criteria were: age 18-60, history of chronic TBI (>6 months post-injury) with refractory clinical sequelae at screening (Post-Concussion Symptom Scale [PCSS] score >30). RESULTS: A total of 85/90 (94%) participants completed the survey at baseline focusing on intake evaluation and approach; 90% of eligible participants also completed the follow-up time-point. Hundred percent of participants had a mean score of >4 across all questions at the initial time point." CONCLUSIONS: The multi-disciplinary care approach and individualized treatment plans of the TEAM-TBI study yielded high participant retention and satisfaction scores. The Clinical Coach component of the trial was one of the highest rated aspects of the program and was associated with participant motivation and high retention rates.

Recovery Trajectories and Long-Term Outcomes in Traumatic Brain Injury: A Secondary Analysis of the Phase 3 Citicoline Brain Injury Treatment Clinical Trial.

BACKGROUND: Prospects for recovery after traumatic brain injury (TBI) are often underestimated, potentially leading to withdrawal of care in the comatose TBI patient who may ultimately have a favorable outcome with aggressive care. Outcomes and trajectories of recovery in a large series of patients with TBI were evaluated at 30, 90, and 180 days postinjury. METHODS: A secondary analysis of the phase 3 Citicoline Brain Injury Treatment (COBRIT) trial was performed analyzing recovery trajectories and long-term outcomes at 30, 90, and 180 days postinjury. A Glasgow Outcome Scale-Extended (GOS-E) score of 5 or higher was considered favorable. Pearson χ2 analysis was used, and a P value of 0.05 was considered significant. A locally weighted, polynomial regression model was used to model recovery trajectories in a nonlinear fashion. RESULTS: Subjects with TBI in the COBRIT trial had high rates of favorable outcome (57% of severe TBI, 86% of moderate TBI, and 93% of complicated mild TBI) at 6-month follow-up. These favorable outcomes often converted from high rates of unfavorable outcome at initial 1-month follow-up (85% of severe TBI, 57% of moderate TBI, and 21% of complicated mild TBI). Recovery trajectories had not plateaued at 6 months, suggesting that further improvement occurs beyond 6 months postinjury. CONCLUSIONS: In this secondary analysis of the COBRIT trial, most patients had favorable outcomes by the GOS-E at 6 months postinjury in all complicated mild and moderate TBI groups, with over half of patients with severe TBI achieving a favorable outcome as well. Of subjects in a vegetative state (GOS-E score 2) at 1 month postinjury, 18% improved to a favorable outcome by 6 months postinjury. There was substantial improvement in all groups from 1 to 6 months, and this improvement may continue beyond 6 months. Clinical trials in TBI should consider recovery curves with repeated measures to assess outcomes because arbitrary single-moment outcome determination likely underestimates treatment effect in TBI care.

Comparison of Quantitative and Qualitative Oxygen Extraction Fraction (OEF) in Acute Stroke Patients with Large Vessel Occlusion.

The superficial temporal artery-middle cerebral artery bypass (STA-MCA) bypass surgery developed by Donaghy and Yarsagil in 1967 provided relief for patients with acute stroke and large vessel occlusive vascular disease. Early reports showed low morbidity and good outcomes. However, a large clinical trial in 1985 reported a failure of extracranial-intracranial (EC/IC) bypass to show benefit in reducing the risk of stroke compared to best medical treatment. Problems with the study included cross overs to surgery from best medical treatment, patients unwilling to be randomized and chose EC/IC surgery, and loss of patients to follow-up. Most egregious is the fact that the study did not attempt to identify and select the patients at high risk for a second stroke. Based on these shortcomings of the EC/IC bypass study, a carotid occlusion surgery study (COSS) was proposed by Dr. William Powers and colleagues using qualitative hemispheric oxygen extraction fraction (OEF) by positron emission tomography (PET) between the contralateral and ipsilateral hemispheres with a ratio of 1.16 indicative of hemodynamic compromise. To increase patient enrollment, several compromises were made mid study. First. The ratio threshold was lowered to 1.12 and the level of occlusion in the carotid reduced from 70% to 60%. Despite these compromises the study was closed for futility, apparently because the stroke rate in the medically treated group was too low. Thus, the question as to the benefit of EC/IC bypass surgery remains unresolved. In our NIH funded study Quantitative Occlusive Vascular Disease Study (QUOVADIS), we used quantitative OEF to evaluate stroke risk and compared it to the qualitative count-rate ratio method used in the COSS study and found that these two methods did not identify the same patients at increased risk for stroke, which may explain the reason for the failure of the COSS study as our results show that qualitative OEF ratios do not identify the same patients as quantitative OEF.

Long-term outcome in traumatic brain injury patients with midline shift: a secondary analysis of the Phase 3 COBRIT clinical trial.

OBJECTIVE: Following traumatic brain injury (TBI), midline shift of the brain at the level of the septum pellucidum is often caused by unilateral space-occupying lesions and is associated with increased intracranial pressure and worsened morbidity and mortality. While outcome has been studied in this population, the recovery trajectory has not been reported in a large cohort of patients with TBI. The authors sought to utilize the Citicoline Brain Injury Treatment (COBRIT) trial to analyze patient recovery over time depending on degree of midline shift at presentation. METHODS: Patient data from the COBRIT trial were stratified into 4 groups of midline shift, and outcome measures were analyzed at 30, 90, and 180 days postinjury. A recovery trajectory analysis was performed identifying patients with outcome measures at all 3 time points to analyze the degree of recovery based on midline shift at presentation. RESULTS: There were 892, 1169, and 895 patients with adequate outcome data at 30, 90, and 180 days, respectively. Rates of favorable outcome (Glasgow Outcome Scale-Extended [GOS-E] scores 4-8) at 6 months postinjury were 87% for patients with no midline shift, 79% for patients with 1-5 mm of shift, 64% for patients with 6-10 mm of shift, and 47% for patients with > 10 mm of shift. The mean improvement from unfavorable outcome (GOS-E scores 2 and 3) to favorable outcome (GOS-E scores 4-8) from 1 month to 6 months in all groups was 20% (range 4%-29%). The mean GOS-E score for patients in the 6- to 10-mm group crossed from unfavorable outcome (GOS-E scores 2 and 3) into favorable outcome (GOS-E scores 4-8) at 90 days, and the mean GOS-E of patients in the > 10-mm group nearly reached the threshold of favorable outcome by 180 days postinjury. CONCLUSIONS: In this secondary analysis of the Phase 3 COBRIT trial, TBI patients with less than 10 mm of midline shift on admission head CT had significantly improved functional outcomes through 180 days after injury compared with those with greater than 10 mm of midline shift. Of note, nearly 50% of patients with > 10 mm of midline shift achieved a favorable outcome (GOS-E score 4-8) by 6 months postinjury.

Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study.

BACKGROUND AND PURPOSE: Preclinical data suggest that cell-based therapies have the potential to improve stroke outcomes. METHODS: Eighteen patients with stable, chronic stroke were enrolled in a 2-year, open-label, single-arm study to evaluate the safety and clinical outcomes of surgical transplantation of modified bone marrow-derived mesenchymal stem cells (SB623). RESULTS: All patients in the safety population (N=18) experienced at least 1 treatment-emergent adverse event. Six patients experienced 6 serious treatment-emergent adverse events; 2 were probably or definitely related to surgical procedure; none were related to cell treatment. All serious treatment-emergent adverse events resolved without sequelae. There were no dose-limiting toxicities or deaths. Sixteen patients completed 12 months of follow-up at the time of this analysis. Significant improvement from baseline (mean) was reported for: (1) European Stroke Scale: mean increase 6.88 (95% confidence interval, 3.5-10.3; P<0.001), (2) National Institutes of Health Stroke Scale: mean decrease 2.00 (95% confidence interval, -2.7 to -1.3; P<0.001), (3) Fugl-Meyer total score: mean increase 19.20 (95% confidence interval, 11.4-27.0; P<0.001), and (4) Fugl-Meyer motor function total score: mean increase 11.40 (95% confidence interval, 4.6-18.2; P<0.001). No changes were observed in modified Rankin Scale. The area of magnetic resonance T2 fluid-attenuated inversion recovery signal change in the ipsilateral cortex 1 week after implantation significantly correlated with clinical improvement at 12 months (P<0.001 for European Stroke Scale). CONCLUSIONS: In this interim report, SB623 cells were safe and associated with improvement in clinical outcome end points at 12 months. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01287936.

Increased cerebral oxygen metabolism and ischemic stress in subjects with metabolic syndrome-associated risk factors: preliminary observations.

Hypertension, diabetes, obesity, and dyslipidemia are risk factors that characterize metabolic syndrome (MetS), which increases the risk for stroke by 40%. In a preliminary study, our aim was to evaluate cerebrovascular reactivity and oxygen metabolism in subjects free of vascular disease but with one or more of these risk factors. Volunteers (n=15) 59±15 (mean±SD)years of age clear of cerebrovascular disease by magnetic resonance angiography but with one or more risk factors were studied by quantitative positron emission tomography for measure ment of cerebral blood flow, oxygen consumption, oxygen extraction fraction (OEF), and acetazolamide cerebrovascular reactivity. Eight of ten subjects with MetS risk factors had OEF >50%. None of the five without risk factors had OEF >50%. The presence of MetS risk factors was highly correlated with OEF >50% by Fisher's exact test (p<0.007). The increase in OEF was significantly (P<0.001) correlated with cerebral metabolic rate for oxygen. Increased OEF was not associated with compromised acetazolamide cerebrovascular reactivity. Subjects with one or more MetS risk factors are characterized by increased cerebral oxygen consumption and ischemic stress, which may be related to increased risk of cerebrovascular disease and stroke.