Biomarkers of Independent Walking Post-Stroke

• ClinicalTrials.gov Identifier: NCT05004389
• Recruitment Status: Recruiting
• First Posted: August 13, 2021
• Last Update Posted: December 7, 2021
• Sponsor: University of Vermont
• Collaborator: National Institute of General Medical Sciences (NIGMS)
• Information provided by (Responsible Party): Denise Peters, University of Vermont

Study Description

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.

Condition or disease	Intervention/treatment
Stroke, Acute; Gait, Hemiplegic	Diagnostic Test: MRI; Diagnostic Test: blood draw; Other: Clinical assessments

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 (≤7 days 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, TNFalpha), 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 baseline and 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 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).

Study Design

• Study Type: Observational
• Estimated Enrollment: 35 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Investigation of Clinical, Blood, and Neuroimaging Biomarkers as Predictors of Independent Walking Post-Stroke
• Actual Study Start Date: December 2, 2021
• Estimated Primary Completion Date: May 2023
• Estimated Study Completion Date: May 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
Acute Stroke; Persons ≥ 18 years of age with acute (≤ 7 days) ischemic or intracerebral hemorrhagic stroke.	Diagnostic Test: MRI; white matter integrity and brain structural connectivity metrics; Diagnostic Test: blood draw; post-stroke serum/plasma levels of BDNF, VEGF, IL-6, IL-10, CRP, TNFalpha, MMPs, IGF-1, cGP; Other: Clinical assessments; measures of strength, balance, and mobility

Outcome Measures

Primary Outcome Measures :

1. Change in Functional Ambulation Category [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
   Assessment of walking assistance
2. Change in diffusion tensor imaging [ Time Frame: within 12 days and at 12 weeks post-stroke ]
   fractional anisotropy and structural connectivity metrics
3. Change in blood markers - BDNF [ Time Frame: within week 1, at 1-2 weeks and at 12 weeks post-stroke ]
   serum BDNF
4. Change in blood markers - VEGF [ Time Frame: within week 1, at 1-2 weeks and at 12 weeks post-stroke ]
   serum VEGF

Secondary Outcome Measures :

1. Change in National Institutes of Health Stroke Scale [ Time Frame: within 72 hours and 1 week post-stroke ]
   Stroke severity assessment; scores range from 0 (min) to 42 (max), with higher values indicating greater stroke severity (worse outcome)
2. Mini-Mental Status Exam [ Time Frame: 1 week post-stroke ]
   Cognition
3. Change in 3-meter walk test [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
   Assessment of gait speed
4. Change in Trunk Control Test [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
   Assessment of trunk/postural control
5. Change in lower extremity muscle strength as assessed by Medical Research Council grades [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
   Assessment of specific muscle strength; scores range from 0 (no muscle contraction) to 5 (normal power)
6. Change in Berg Balance Scale [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
   Assessment of static/dynamic sitting and standing balance; scores range from 0 (min) to 56 (max), with higher values indicating better balance/outcome
7. Change in Motricity Index (lower limb portion) [ Time Frame: week 1 , week 4, week 9, week 12, and week 26 s/p stroke ]
   assessment of motor function/strength of the lower limbs
8. Change in Modified 30 second sit to stand [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
   Assessment of lower limb power
9. Change in Fatigue Severity Scale [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
   Assessment of fatigue level; scores range from 9 (min) to 63 (max), with higher values indicating greater fatigue severity (worse outcome)
10. Change in Barthel Index [ Time Frame: week 12 and 26 s/p stroke ]
    Assessment of activities of daily living
11. Change in Modified Rankin Scale [ Time Frame: week 12 and 26 s/p stroke ]
    Assessment of level of disability; scores range from 0 (min) to 5 (max), with higher values indicating greater disability (worse outcome)
12. Change in physical activity levels as assessed by the Physical Activity Vital Sign questionnaire [ Time Frame: week 12 and 26 post-stroke ]
    Assessment of physical activity levels; self-report of average number of days and minutes engaged in physical activity per week
13. Change in Opal sensor metric - gait [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
    Assessment of spatiotemporal parameters of gait
14. Change in Opal sensor metric - posture [ Time Frame: week 1, week 4, week 9, week 12, and week 26 s/p stroke ]
    Assessment of postural sway
15. Change in blood markers - IL-6 [ Time Frame: within week 1,at 1-2 weeks and at 12 weeks post-stroke ]
    IL-6
16. Change in blood markers - IL-10 [ Time Frame: within week 1,at 1-2 weeks and at 12 weeks post-stroke ]
    IL-10
17. Change in blood markers - C reactive protein [ Time Frame: within week 1 ,at 1-2 weeks and at 12 weeks post-stroke ]
    CRP
18. Change in blood markers - TNFalpha [ Time Frame: within week 1, at 1-2 weeks and at 12 weeks post-stroke ]
    TNFalpha
19. Change in blood markers - matrix metalloproteinase [ Time Frame: within week 1, at 1-2 weeks and at 12 weeks post-stroke ]
    MMP
20. Change in blood markers - insulin-like growth factor-1 [ Time Frame: within 1 week, at 1-2 weeks and at 12 weeks post-stroke ]
    IGF-1
21. Change in blood markers - cGP [ Time Frame: within 1 week, at 1-2 weeks and at 12 weeks post-stroke ]
    cGP

Biospecimen Retention:   Samples Without DNA

serum, plasma

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

local medical center

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; 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.

Contacts and Locations

Contacts

Contact: Denise Peters, DPT, PhD; 802-656-1709; denise.peters@med.uvm.edu

Locations

United States, Vermont

University of Vermont Medical Center; Recruiting

Burlington, Vermont, United States, 05405

Contact: Research Coordinator nigel.miller@uvmhealth.org

Sponsors and Collaborators

University of Vermont

National Institute of General Medical Sciences (NIGMS)

Investigators

• Principal Investigator: Denise Peters, DPT, PhD; University of Vermont

More Information

• Responsible Party: Denise Peters, Assistant Professor, University of Vermont
• ClinicalTrials.gov Identifier: NCT05004389
• Other Study ID Numbers: 00000696; P20GM135007 ( U.S. NIH Grant/Contract )
• First Posted: August 13, 2021
• Last Update Posted: December 7, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: Data to be shared: unidentified clinical assessment and imaging data; serum/plasma samples will be stored in repository for future use.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Stroke; Gait Disorders, Neurologic; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Neurologic Manifestations