VERIFY will validate biomarkers of upper extremity (UE) motor outcome in the acute ischemic stroke window for immediate use in clinical trials, and explore these biomarkers in acute intracerebral hemorrhage. The central hypothesis is that patients have different UE outcomes depending on corticomotor system (CMS) function, measured as motor evoked potential (MEP) status with TMS, and on CMS structure, measured as acute lesion load with MRI. VERIFY will create the first multicenter, large-scale, prospective dataset of clinical, TMS, and MRI measures in the acute stroke time window.
Trial Design and Outcomes:
VERIFY is a multicenter, biomarker validation study of upper extremity motor outcome. VERIFY will validate biomarkers in the acute ischemic stroke window of upper extremity (UE) motor outcome, for immediate use in clinical trials. The central hypothesis is that patients have different UE outcomes depending on CMS function, measured as motor evoked potential (MEP) status via TMS, and on CMS structure, measured as CST lesion load via MRI. This biomarker validation study will be performed at as many as 35 acute care hospitals in the United States participating in the NIH StrokeNet. VERIFY builds on previous work showing that MEP status and MRI prognostic biomarkers distinguish between patients who will have different UE motor outcomes. However, these studies have important limitations. First, baseline measures were sometimes collected up to 2 weeks after stroke onset, which does not meet the goal of stratifying patients during the acute stroke admission. Second, most studies were performed at a single center, often with advanced TMS expertise, and with limited sample size. External validation with a large sample across a range of stroke centers is needed. Third, prior studies have used a range of TMS and MRI techniques, but a standardized protocol needs to be tested. VERIFY is designed to overcome these limitations.
Primary Aim 1: To externally validate the relationships that TMS and MRI biomarkers of CMS integrity acquired ≤ 7 days after stroke have with 90-day UE motor impairment outcome after ischemic stroke.
Primary Aim 2: To externally validate the PREP2 prediction tool used ≤ 7 days after stroke to predict 90-day UE functional outcome for individual participants with ischemic stroke.
Exploratory 1: To derive and internally validate multivariable prediction tools, using TMS and MRI CMS biomarkers as well as baseline clinical factors, to predict 90-day patient-reported UE use and global functional outcome in individual participants.
Exploratory 2: To collect outcomes in other domains of recovery to generate hypotheses that allow consideration of future ancillary studies and future directions from this rich dataset.
Exploratory Endpoints, all at 90 Days
Study Sponsor and Chair: Pooja Khatri, MD MSc (Lead), University of Cincinnati
Achala Vagal, MD MS, University of Cincinnati
Steven C. Cramer, MD MSc, University of California Los Angeles
Cathy M. Stinear, PhD, University of Auckland
NIH National Institute of Neurological Disorders and Stroke (NINDS) - 1U01NS120910-01
NIH StrokeNet National Coordinating Center at the University of Cincinnati
NIH StrokeNet National Data Management Center at Medical University of South Carolina
US FDA IDE # G200291
For More Information:
University of Cincinnati
260 Stetson St, ML 0525
Cincinnati, OH. 45219
Perinatal arterial stroke (PAS) includes infants with a diagnosis of neonatal arterial ischemic stroke or presumed prenatal arterial ischemic stroke; together these forms of early stroke have an estimated incidence of 1 in 1150 live births in the U.S. The majority of infants with PAS will develop hemiparesis in the first year of life, often resulting in lifelong impairment in neuromotor functioning as well as possible impairment in cognition, language, and quality of life. There are no evidence-based forms of rehabilitation designated as standard-of-care for these infants.
This is a Phase III multi-site randomized controlled trial comparing 2 dosages of a form of intensive pediatric rehabilitation known as Infant ACQUIRE (I-ACQUIRE) to Usual and Customary treatment (U&CT). Prior studies of this treatment show high safety, patient acceptability, and evidence of significant and enduring benefits. Briefly, I-ACQUIRE will be used to treat 8 – 24 month old children with PAS in either 3 hours/day (Moderate Dose) or 6 hours/day (High Dose) for 5 days/week for 4 weeks. Treatment will occur in a homelike or natural setting where trained therapists (certified in the I-ACQUIRE protocol) apply operant conditioning techniques to reinforce and shape new and more advanced upper extremity skills through interesting, fun, and everyday games, exploration, and self-help activities. For each child, treatment goals are set with parents who also participate in daily home practice (about 45 minutes/day) with their child. I-ACQUIRE includes all of the core features of pediatric Constraint-Induced Movement Therapy (CIMT). Fidelity of implementing the I-ACQUIRE protocol is monitored regularly via videotaped sessions. For children in the U&CT group, their community therapists will document treatment in terms of type, dosage, and child progress over the 4 weeks of active treatment.
Clinical Trial Design
In Phase 1 of I-ACQUIRE, 240 infants (N=80/group) across 12 sites will be randomly assigned to 1 of 3 groups: 1) Moderate Dose I-ACQUIRE, 2) High Dose I-ACQUIRE, or 3) U&CT. Blinded assessments occur at baseline (prior to treatment), end of 4 weeks of treatment, and 6 months post-treatment. A Parent Council will be active throughout the trial, supporting NIH’s goal of increased stakeholder engagement in clinical trials.
In Phase 2 of I-ACQUIRE, parents of the children who had been assigned to Group 3, Usual and Customary Treatment (U&CT), will have an opportunity to re-enroll so their child could be randomized to receive either the Moderate or High Dose I-ACQUIRE (provided at no cost), and then be assessed at the end of treatment and 6 months post-treatment. (Note: Data from Phase 2 will not be used to test the primary and secondary efficacy outcomes.)
Primary: Determine the efficacy of I-ACQUIRE at 2 dosage levels compared to U&CT to increase the number of new upper extremity skills on the hemiparetic side (using a minimal clinically meaningful threshold that is achieved at the end of treatment and 6 months later);
Secondary: Determine the efficacy of I-ACQUIRE at 2 dosage levels compared to U&CT to improve the use of the hemiparetic upper extremity in bimanual activities at the end of treatment and 6 months later; and,
Exploratory: Explore the association between I-ACQUIRE treatment at Moderate and/or High Doses and the infant’s gross motor development and cognition (i.e., potential cross-domain effects of treatment).
Public Health Impact
Each year, an estimated 3400+ infants in the U.S. experience PAS and have a high likelihood of lifelong impairment in neuromotor and often cognitive functioning, resulting in a high cost burden for families, the healthcare system, and society. If I-ACQUIRE proves efficacious, then the field will have the critically needed Phase III confirmatory evidence and the specific clinical protocol needed to transform rehabilitation and improve clinical outcomes and quality of life for infants with PAS.
Sharon Landesman Ramey, PhD – PRIME PI, Virginia Tech
Warren Lo, MD - Multiple PI, The Ohio State University and Nationwide Children’s Hospital
ClinicalTrials.gov Identifier: NCT03910075
TRANScranial Direct Current Stimulation for POst-stroke Motor Recovery A phase II sTudy (TRANSPORT 2)
Trial Summary: TRANSPORT 2 is a phase II multi-center transcranial direct current stimulation (tDCS) dosing selection study based on the preliminary efficacy, safety, tolerability and feasibility.
Primary Objective: To determine whether there is an overall treatment effect among 3 dosing groups (sham+mCIMT, 2 mA+mCIMT, and 4 mA+mCIMT) on day 15 (±2 days) after the start of the intervention in the Fugl-Meyer Upper-Extremity (FM-UE) scale, a measure of motor impairment. Additional outcome measures include the Wolf-Motor-Function-Test, a measure of functional motor activity, and the Stroke-Impact-Scale, a measure of quality of life. Sustained benefit will be assessed at day 45 (± 5 days) and day 105 (± 10 days).
Secondary Objectives: To confirm that the proposed intervention is safe (no significant differences in rate of adverse events), tolerable (no significant differences in discomfort as measured by Visual-Analog-Scale), and feasible to administer in a multi-site trial (>80% of subjects complete the treatment protocol and no unexplained/unresolved variability by site).
Exploratory Objectives: To examine whether wCST-LL (structural assessment of integrity of descending motor tract) or MEPs (functional assessment of integrity of descending motor tract) or combination of both are correlated with changes in FM-UE scale, and evaluate the utility of these measures as biomarkers for patient selection criteria in the future confirmatory Phase III study. We also aim to examine whether structural and functional changes within descending motor tracts and functional changes within cortical and subcortical motor network correlate with changes in motor impairment and functional motor activity.
Primary Endpoint: Fugl-Meyer Upper-Extremity (FM-UE) scale a measure of motor impairment;
Secondary Endpoints: Wolf Motor Function Test time score, a measure of functional motor activity; Stroke-Impact-Scale hand subscale as an assessment of patient-centered quality of life.
The study population is subjects who are 18-80 years of age of any gender or ethnicity, who had first-ever unihemispheric ischemic stroke in past 30-180 days resulting in unilateral limb weakness with FM-UE ≤ 54 (out of 66) that is stable across two baseline visits at the time of randomization and an mRS ≤ 2 pre-stroke. We are planning to enroll 129 subjects across three arms.
Subject recruitment will occur at up to 12 enrolling sites in the USA.
There are 3 intervention arms: sham, 2 mA, and 4 mA tDCS combined with modified Constrained-Induced Movement Therapy (mCIMT). The tDCS session is 30 minutes, and mCIMT is 60 minutes per session, 10 intervention sessions are completed over a 2-week (14 days) period.
The study duration is 48 months. Subjects will be in the trial for approximately 4 months.
TRANSPORT2 Payment Schedule
The StrokeNet Experience From a Central IRB to Local IRB Perspective Webinar (Slides)