TRANSPORT2 Study Rationale & Design Wayne Feng MD MS FANA FAHA Professor of Neurology Department of Neurology Medical University of South Carolina

Brain Stimulation Invasive Non-invasive Epidural Stimulation Deep brain stimulation Vagus nerve stimulation Transcranial Direct Current stimulation Transcranial alternating current stimulation Transcranial Magnetic Stimulation Transcranial pulsed ultrasound Scribonius Largus, physician to Emperor Claudius: To immediately remove and permanently cure a headache, however long-lasting and intolerable, a live black torpedo is put on the place which is in pain, until the pain ceases and the part grows numb

tDCS has some advantages due to his portability and ease of use. Several small sample-size proof-concept studies suggest tDCS, along with a rehabilitation therapy, can modulate brain activity and induce behavioral changes in stroke patients Hurdles and opportunities co-exist for tDCS in post-stroke motor recovery

Peripheral Rehab Therapy Constraint-induced movement therapy Effective, quantifiable, standardizable and available. Montage Bihemispheric stimulation Blinding Centrally controlled randomization process Participant, therapist, PI and tDCS technician are all blinded Timing of intervention Subacute phase : 1-6 months after stroke Outcome measure(s) Measuring motor impairment, motor function as well as quality of life Dosage

Dose of Brain Stimulation Emerges as an Important Modulator of the Effect

Phase I Study of Safety and Tolerability Stopping Rules based on adverse events 2nd degree scalp burn; seizure; new brain lesions; or discontinuation do to Aes. No dose limiting ‘toxicities’ that prevented escalation 18 subjects enrolled Treated up to 4.0 mA (3x / dose) Tolerability Issues ≤ 2 subjects observed skin redness Common across dose arms Dose escalation: 1mA> 2mA> 2.5mA> 3.0mA> 3.5mA> 4.0mA Funded by NIH: P20 GM109040 (FENG) “The study results of this study are important, because they deliver first evidence about the safety profile and tolerability of tDCS intensity relevantly higher than that used thus far in most clinical trials. Studies of this type are required to extend the parameter space for optimized clinical studies.”

TRANSPORT2 Study Design To determine whether there is an initial overall treatment effect (FM-UE) among 3 dosing groups: sham + mCIMT 2 mA + mCIMT 4 mA + mCIMT Efficacy (FM-UE change) is measured at day 15 after the initiation of the 10-day intervention. Both Intent-to-treat and per protocol analysis.

Choices of Outcomes Primary Outcome Secondary Outcomes Fugl-Meyer Upper Extremity scale: Motor Impairment Secondary Outcomes Wolf Motor Function Test: Motor Function Stroke Impact Scale (Hand Subscale): Quality of Life Secondary outcomes should have the same trend or consistent with primary outcomes Good psychometric property: reliability, validity and responsiveness

Sample Size Calculation A change of 4.25-7.25 points on the FM-UE scale is considered to be a meaningful clinically important difference (MCID). This study is powered under the assumption that mCIMT alone, will at least achieve this intervention effect (4.5) and furthermore intervention with either 2 mA or 4 mA tDCS will further increase the change in FM-UE scale from the baseline by 4.5 points (i.e., a minimum intervention effect of 9.0). Based on the meta-analysis of previous trials assessing tDCS in stroke patients, a conservative estimate of the intervention variability is defined as SD = 7. With a sample size of 31 subjects per group, a two-sided type I error rate of 10%, and standard deviation of 7, if the true pattern of mean changes is 4.5, 9.0, and 9.0 for the sham, 2 mA, and 4 mA groups respectively, we would have 83% power to reject the null hypothesis. Lost-of-follow up rates is controlled <=15% As a result, the final estimated sample size is 43 per group (129 in total).

Secondary Aims To confirm that the proposed intervention is safe, tolerable, and feasible to administer in a multi-site trial setting Endpoints Safety: Rate of Adverse Events Tolerability: Visual Analog Scale Feasibility: Treatment Completion Rate

Exploratory Aims 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 subject selection criteria in the future confirmatory Phase III study To examine whether functional or structural changes in motor tracts correlates with changes in impairment and functional motor activity induced by the intervention.

Eligibility: Inclusion Each subject must meet all of the following criteria to participate in this study: 1) 18-80 years old; and 2) First-ever unihemispheric ischemic stroke radiologically verified and occurred within the past 30-180 days; and 3) >10° of active wrist extension, >10° of thumb abduction/extension, and > 10° of extension in at least 2 additional digits; and 4) Unilateral limb weakness with a Fugl-Meyer Upper Extremity score of ≤ 54 (out of 66) to avoid ceiling effects; and 5) An absolute difference of FM-UE scores between the two baseline assessments that is ≤ 2 points indicating stable motor impairment; if subject is not stable, then he/she will be invited for a reassessment after 2 weeks (but no more than 3 reassessments); and 6) Pre-stroke mRS ≤2; and 7) Signed informed consent by the subject or Legally Authorized Representative (LAR)

Eligibility: Exclusion Each Subject who meets any of the following criteria will be excluded from the study: 1) Primary intracerebral hematoma, subarachnoid hemorrhage or bi-hemispheric or bilateral brainstem ischemic strokes; 2) Medication use at the time of study that may interfere with tDCS, including but not limited to carbamazepine, flunarizine, sulpiride, rivastigmine, dextromethorphan; 3) Other co-existent neuromuscular disorders (pre- or post-stroke) affecting upper extremity motor function; 4) Other neurological disorders (pre- or post-stroke) affecting subject’s ability to participate in the study; 5) Moderate to severe cognitive impairment defined as Montreal Cognitive Assessment (MOCA) score < 20/30; 6) History of medically uncontrolled depression or other neuro-psychiatric disorders despite medications either before or after stroke that may affect subject’s ability to participate in the study; 7) Uncontrolled hypertension despite medical treatment(s) at the time of randomization, defined as SBP≥185 mmHg or DBP≥110 mmHg (patient can be treated, reassessed and randomized later);

Eligibility: Exclusion 8) Presence of any MRI/tDCS/TMS risk factors including but not limited to: 8a) an electrically, magnetically or mechanically activated metallic or nonmetallic implant including cardiac pacemaker, intracerebral vascular clips or any other electrically sensitive support system; 8b) a non-fixed metallic part in any part of the body, including a previous metallic injury to eye; 8c) pregnancy (effects of MRI, TMS, and tDCS on the fetus are unknown); 8d) history of seizure disorder or post-stroke seizure; 8e) preexisting scalp lesion under the intended electrode placement or a bone defect or hemicraniectomy; 9) Planning to move from the local area within the next 6 months; 10) Life expectancy less than 6 months; 11) Has received Botulinum toxin injection to the affected upper extremity in the past 3 months prior to randomization or expectation that Botulinum will be given to the Upper Extremity prior to the completion of the last follow-up visit; 12) Concurrent enrollment in another investigational stroke recovery study; 13) Doesn’t speak sufficient English to comply with study procedures; 14) Expectation that subject cannot comply with study procedures and visits.

TRANSPROT2 is the FIRST stroke recovery study concept originated Acute treatment: DEFUSE3 IDEF* MISTIE3* MOST Prevention CREST2* CREST-H* ARCADIA SLEEPSMART SATURN Recovery: TELEREHAB* TRANSPORT2 IACQUIRE TRANSPROT2 is the FIRST stroke recovery study concept originated in the Stroke Trial Network

TRANSPORT2 SITES Medical University of South Carolina (Michelle Woodbury PhD & Wayne Feng MD MS) Kelly Krajeck; Emily Grattan; Scott Hutchison and Will Devries MedStar Health Research Institute (Alexander Dromerick MD) Shashwati Geed; Juby Matthews; Abigail Mitchell; Preethy Freit & Katie Larson Burke Rehabilitation Institute (Tomoko Kitago MD) Joshua Silverstein; Marissa Wuennemann ; Katherine Friel & Heather Lane. Emory University (Steve Wolf PhD PT) Michael Borich; Marsha Bidgood; Heather Stewart & Theresa McLaughlin University of Alabama Birmingham (Ling Chen MD) Tammy Davis; David Morris; Tara Pearce & Rodolphe Nenert University of Southern California (Beth Fisher PhD) Clarisa Martinez; Clare Binley; Tasha Hsu and Jorge Caro University of Kentucky (Lumy Sawaki MD PhD) Luther Pettigrew; Elizabeth Powell; Patricia Arnold & Cessandra Ginn University of Cincinnati (Oluwole Awosika MD) Emily Wasik; Emily Goodall; Emily Staggs & Kari Dunning Washington University (Catherine Lang PhD PT) Jenny Babka; Christine Gordon; Jull Newgent; Maggie Bland & Alex Carter Beth Israel Deaconess MC (Gottfried Schlaug MD PhD) Michelle Lantaigne; Andrea Norton; Anant Shinde & Sebastein Paquette Moss Rehabilitation Institute (Dylan Edwards PhD PT & Ning Cao MD) Stephaine Farm Memorial Hermann – TMC (Gerard Francisco MD & Sheng Li MD PhD) Dory Parker; Erin Edenfield; Yen-Ting Chen & Chad Tremont 4 specialists( PT=3, OT=1, vascular neurologists=6 and PMR physicians=4, non-clinician=1). Different career stages ( professors: 8; full professors=3, assistant professors=4) Represent all of regions from the US.

TRANSPORT2 TIME LINES First presentation with recovery working group (03/10/16) Budget approval by NIH Executive Scientific Committee (07/25/16) First grant submission (10/05/16) Study section meeting (04/18/2017, delayed from 02/25/17) Revised submission (07/10/2017) Study section meeting (11/02/2017) NINDs advisory council met and approved (02/01/2018) Transport2 weekly meeting started (03/14/2018) NOA released (08/15/2018) cIRB approved (10/29/2018) First investigator meeting/training workshop (02/25-02/26/2019) Expected first participant enrollment (04/30/2019) Expected last participant visit (02/28/2022)

Questions? feng@musc.edu