Clinical trial NCT05004389: Biomarkers of Independent Walking Post-Stroke
Official title: Investigation of Clinical, Blood, and Neuroimaging Biomarkers as Predictors of Independent Walking Post-Stroke
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Stroke, Acute
Gait, Hemiplegic
Lead sponsor: University of Vermont
Sponsor class: OTHER
Collaborators: name: National Institute of General Medical Sciences (NIGMS)
First posted: 2021-08-13
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adults (age ≥ 18 years old) with acute ischemic or intracerebral hemorrhagic stroke from the local medical center.

Brief summary: Prediction of walking recovery after stroke can inform patient-centered care and support discharge planning. The accuracy of current prediction models is limited, however, due to small study designs and narrow predictors assessed. The investigators propose a comprehensive evaluation of a novel combination of biomarkers to improve prediction of walking recovery and guide rehabilitation efforts after stroke. These include acute structural brain network disruption (utilizing MRI); blood biomarker levels (e.g., brain-derived neurotrophic factor and vascular endothelial growth factor); and clinical assessments of strength and mobility. The overall study objectives are to assess protocol feasibility and investigate relationships between select biomarkers and walking recovery to provide strong justification for a larger study on predictors of independent walking after stroke. The proposed objectives will be pursued through the following specific aims: 1) Assess feasibility of a larger study and develop methods for telehealth data collection; 2) Establish baseline levels of biomarkers and average change over time; and 3) Elucidate relationships between baseline levels of biomarkers and walking gains across time in persons after stroke. A longitudinal, observational study design will be utilized for this study. Thirty-five persons with acute (≤7 days) stroke will be recruited from the local medical center. Select inclusion criteria include presence of new lower limb weakness and assistance for walking; select exclusion criteria include cerebellar stroke or other neurological disorders such as Parkinson's Disease. Subjects will undergo clinical evaluation at week 1, 4, 9, 12, and 26 weeks post-stroke. MRI scans will occur within 12 days post-stroke and at 12 weeks post-stroke, and blood draws within 1 week, 1 to 2 weeks and at 12 weeks post-stroke. To assess feasibility the investigators will examine study processes, recruitment, resources, study management, and scientific assessment. To examine the role of acute clinical, neuroimaging, and physiological measures in predicting walking recovery, the investigators will examine relationships between these measures and walking outcome at 12-weeks post-stroke. The proposed research is expected to provide strong scientific support for future clinical trials designed to target therapies based on predicted functional potential. Such knowledge has the potential of enhancing mobility gains and patient independence following stroke.

Detailed description: The investigators will utilize a longitudinal, observational study design to investigate predictors of walking recovery post-stroke. Subjects will undergo clinical evaluation at week 1, 4, 9, 12, and 26 weeks after the initial onset of stroke symptoms; MRI scan within 12 days and at 12 weeks post-stroke; and blood draws at 1 week, 1 to 2 weeks and at 12 weeks post-stroke. Subjects will be recruited from the University of Vermont Medical Center (UVMMC), with a goal sample of 35 patients (accounts for 15% attrition). Subjects will provide written consent before participation.

Aim 1: Assess feasibility of a larger study and develop methods for telehealth data collection

Data Collection: To assess feasibility the investigators will examine study processes, recruitment, resources, study management, and scientific assessment.

Data Analyses: Feasibility questions will be examined using descriptive statistics and qualitative analyses. To ensure collection and dissemination of high quality data, the "CONSORT 2010 checklist of information to include when reporting a pilot or feasibility trial" will be used to guide data collection and analysis.

Aim 2: Establish baseline levels of biomarkers (clinical, neuroimaging, blood) and average change over time.

Experimental Protocol: Subjects will undergo baseline clinical assessment (within 1-week post-stroke), MRI scan (within 12 days post-stroke), and blood draw (within 1 week post-stroke). These same measures will be repeated 12 weeks after stroke (primary predictive outcome).

Data Analyses:

1. Establishing baseline levels of clinical measures, neuroimaging and blood biomarkers: To determine the variability in participants' walking ability/balance/strength, post-stroke preservation of sensorimotor connectivity, and acute changes in blood markers associated with immune response (IL-6, IL-10, cross-reacting protein, TNF alpha), neural function (BDNF), and blood vessel/ circulation (VEGF, matrix metalloproteinase, insulin like growth factor-1, cGP), descriptive statistics will be obtained. Results will be stratified by stroke characteristics and NIHSS score.
2. Quantifying change over time for clinical measures: defined as the average difference between 1-4-,9-,12-, and 26-week values. To examine change over time, the investigators will perform paired t-tests (or non-parametric equivalent) and effect size calculations on all outcome measures, using the 12 week post-stroke timepoint as the primary outcome. The investigators will also use the following minimal clinically important difference (MCID) or minimal detectable change (MDC) values to determine if observed statistical differences are clinically relevant: 0.16 m/s change in gait speed, 6-point change in Berg Balance Scale, and a change of three repetitions in 30 second Sit-To-Stand.
3. Quantifying change over time for neuroimaging and blood biomarkers: defined as the average difference between baseline and 12-week values. To examine change over time, the investigators will perform paired t-tests (or non-parametric equivalent) and effect size calculations.
4. Secondary analyses: will be performed with assistance and training from Core C (e.g., 5 dimensions spatial-temporal maps of walking biomechanics and/or muscle activation).

Aim 3: Elucidate relationships between baseline levels of biomarkers and walking gains across time in persons after stroke.

Experimental Protocol: Subjects will undergo the same experimental procedures as in Aims 1 and 2.

Data Analysis: To study the role of acute clinical, neuroimaging, and physiological measures in predicting recovery of independent walking post-stroke, the investigators will examine relationships between these measures and walking outcome as defined by the Functional Ambulation Category (FAC).

1. Identifying the time to regaining independent walking after stroke: defined as the time post-stroke (as measured at 1, 4, 9, 12, or 26 weeks post-stroke) at which a participant achieves a score of ≥4 on the FAC.
2. Quantifying the relationship between acute measures and walking outcome at 12 weeks post-stroke (primary predictive outcome): the relationship between clinical, MRI, and blood biomarkers and walking outcome at 12 weeks post-stroke (± independently walking) will be examined using logistic regression, correcting for potential confounders \[age, sex, stroke severity (NIHSS)\]. Secondary analyses will be performed by evaluating trends over time (repeated measures model).

Eligibility criteria: Inclusion criteria: 1) individuals with acute (≤ 7 days) ischemic or intra-cerebral hemorrhagic stroke; 2) ≥18 years of age; 3) presence of new lower limb weakness (less than 5/5 on manual muscle testing) on one side of the body or notation of weakness by MD or PT) on one side of the body; 4) unable to walk or requires supervision or assistance for walking.

Exclusion criteria: 1) cerebellar or bilateral stroke; 2) requirement for supervision or physical assistance to walk prior to admission; 3) other neurological disorders such as Parkinson's Disease or Multiple Sclerosis, 4) severe hearing impairment, 5) blindness, 6) actively receiving treatment for cancer, 7) not expected to survive for duration of the study, and 8) diagnosis of current clinical definition of active COVID-19.

Primary outcomes:
measure: Change in Functional Ambulation Category
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in diffusion tensor imaging
timeFrame: within 12 days and at 12 weeks post-stroke
measure: Change in blood markers - BDNF
timeFrame: within week 1, at 1-2 weeks and at 12 weeks post-stroke
measure: Change in blood markers - VEGF
timeFrame: within week 1, at 1-2 weeks and at 12 weeks post-stroke
Secondary outcomes:
measure: Change in National Institutes of Health Stroke Scale
timeFrame: within 72 hours and 1 week post-stroke
measure: Mini-Mental Status Exam
timeFrame: 1 week post-stroke
measure: Change in 3-meter walk test
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in Trunk Control Test
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in lower extremity muscle strength as assessed by Medical Research Council grades
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in Berg Balance Scale
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in Motricity Index (lower limb portion)
timeFrame: week 1 , week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in Modified 30 second sit to stand
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in Fatigue Severity Scale
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in Barthel Index
timeFrame: week 12 and 26 s/p stroke
measure: Change in Modified Rankin Scale
timeFrame: week 12 and 26 s/p stroke
measure: Change in physical activity levels as assessed by the Physical Activity Vital Sign questionnaire
timeFrame: week 12 and 26 post-stroke
measure: Change in Opal sensor metric - gait
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in Opal sensor metric - posture
timeFrame: week 1, week 4, week 9, week 12, and week 26 s/p stroke
measure: Change in blood markers - IL-6
timeFrame: within week 1,at 1-2 weeks and at 12 weeks post-stroke
measure: Change in blood markers - IL-10
timeFrame: within week 1,at 1-2 weeks and at 12 weeks post-stroke
measure: Change in blood markers - C reactive protein
timeFrame: within week 1 ,at 1-2 weeks and at 12 weeks post-stroke
measure: Change in blood markers - TNFalpha
timeFrame: within week 1, at 1-2 weeks and at 12 weeks post-stroke
measure: Change in blood markers - matrix metalloproteinase
timeFrame: within week 1, at 1-2 weeks and at 12 weeks post-stroke
measure: Change in blood markers - insulin-like growth factor-1
timeFrame: within 1 week, at 1-2 weeks and at 12 weeks post-stroke
measure: Change in blood markers - cGP
timeFrame: within 1 week, at 1-2 weeks and at 12 weeks post-stroke
Other outcomes:
Locations:
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
Study officials:
affiliation: University of Vermont
name: Denise Peters, DPT, PhD
role: PRINCIPAL_INVESTIGATOR
References: