Phase III Multi-site Trial of I-ACQUIRE UPDATE FOR Phase III Multi-site Trial of I-ACQUIRE 20 May 2019 Sharon Landesman Ramey, Ph.D. (Lead PI) Fralin Biomedical Research Institute (FBRI), Virginia Tech (Roanoke) Warren Lo, M.D. (Co-PI) Nationwide Children’s Hospital & The Ohio State University (OSU)

Goals for today’s I-ACQUIRE call (20 May 2019) 1. Review how the national i-acquire team works and will help your local site 2. Details about recruitment and enrollment: the process of preparing to be study-certified and multiple approaches for recruitment, screening, and consenting (update about cirb) 3. The i-acquire treatment protocol: what training will cover and what all site leaders need to know about delivering i-acquire with high fidelity; also info about payments to sites for training and treatment 4. The i-acquire assessment process: review of the assessment schedule and introductory information about training of assessors and their responsibilities for scoring and data entry, IMPORTANCE of local site plan to ensure blinding of assessors 5. Parent council update and plans 6. Plans for work groups after sites start enrolling

National Team for Phase III Multi-site I-ACQUIRE (1 of 2 slides) Sharon Landesman Ramey, Ph.D. (Lead PI) Fralin Biomedical Research Institute (FBRI), Virginia Tech (Roanoke) Warren Lo, M.D. (Co-PI) Nationwide Children’s Hospital & The Ohio State University (OSU) Stephanie DeLuca, Ph.D. & Craig Ramey, Ph.D. Treatment Implementation Center Directors, FBRI, Virginia Tech (Roanoke) Amy Darragh, Ph.D., OTR/L & Jill Heathcock, Ph.D., MPT Central Assessment Center Directors, OSU Max Wintermark, M.D. Clinical MRI Center Director, Stanford University Laura Bateman National Study Coordinator, FBRI, Virginia Tech Parent Council Kim Hindery and Nicole Dodds (co-chairs)

National Team for I-ACQUIRE (2 of 2) National Coordinating Center (NCC) at U of Cincinnati Joe Broderick, M.D. Teresa Murrell-Bohn Diane Sparks Sue Roll Emily Stinson Jennifer Golan National Data Management Center (NDMC) at MUSC Yuko Palesch, Ph.D. Caitlyn Meinzer, Ph.D. Renee Martin, Ph.D. Catherine Dillon, Ph.D. Sara Butler Jessica Griffin NINDS - Scott Janis, Ph.D. Data and Safety Monitoring Board

The primary locations of the 12 I-ACQUIRE Sites (designated by lead PI location) Ann Arbor Atlanta Baltimore Boston Chicago Cincinnati Columbus Houston New Haven Philadelphia Roanoke San Diego

Purple indicates items being discussed today DESIGN FOR PHASE III I-ACQUIRE TRIAL Purple indicates items being discussed today Recruitment, Eligibility Pre-Screening and Confirmation, Consenting, and Enrollment (N=240) GOAL OF AUGUST/SEPT Perinatal Arterial Stroke (PAS) diagnosis NEW PLAN with confirmatory MRI & hemiparesis diagnosis (8–24 mos) Moderate Dose I-ACQUIRE (N=80) 3 hr/day x 20 High Dose 6 hr/day x 20   Usual & Customary Tx (U&CT) (N=80) documented Baseline (pre-treatment) Assessment Blinded Assessments (videorecorded) & Parent Ratings Implementation of Treatment Protocol (4 weeks) Active Central Monitoring, Weekly Videorecording, & Therapy Logs Post-treatment Assessment Batteries: Immediate (usually within 3 days) & 6 mos. (usually within 2 mos) Random Assignment (centralized) to I-ACQUIRE DOSAGE GROUPS or U&CT U&CT Parents offered choice of I-ACQUIRE (Delayed treatment/Crossover) will require second consent and new randomization

Inclusion/Exclusion Criteria for I-ACQUIRE Phase III Trial purple indicates discussion today Inclusion criteria TO BE RE-VERIFIED AT BASELINE ASSESSMENT 8-24 mos old at time when treatment delivered only for Phase 1 Perinatal Arterial Ischemic Stroke (PAS) diagnosed as occurring prior to 1 month PAS confirmed with clinical MRI (high-quality, standardized) will require review by Lo and Wintermark (within 7 – 10 days) Hemiparesis functional diagnosis by physician as reported by parent Parents able to participate in home-based intervention present at least 1 day/wk for therapy and 45 min/day practice at home for 5 of 7 days Exclusion Criteria TO BE RE-VERIFIED AT BASELINE ASSESSMENT Fragile medical health Prior receipt of CIMT ≥ 2 hrs/day x 10 days Botox within past 3 mos BECAUSE OF RE-VERIFICATION, WE HAVE MODIFIED STATISTICAL ANALYSIS PLAN TO BE A MODIFIED INTENT TO TREAT (ITT) ANALYSIS

CIRB and Local IRB Update; CTA Update All revisions submitted (minor, improvements) last week Now under review by CIRB (hope to hear soon) Will be able to upload final documents and let all sites know via email as well CTA documents sent to all sites # finalized is now ________ Any questions or concerns from sites?

Training will cover in detail all 8 Core Treatment Components (PAGE 1 OF 2) Constraint of the less-impaired upper extremity for first 17 days of 20 treatment days. The lightweight cast is worn continuously. REMOVED AND CHECKED WEEKLY BY THERAPIST. ALL TRAINEES WILL PRACTICE. High (intensive) dosage of treatment – either 3 or 6 hrs/day, 5 days/wk for 4 weeks – provided by protocol-trained OTs or PTs (licensed, certified) DAILY LOGS; UP TO 1 HR FOR NAPS/INTERRUPTIONS, BUT NOT NEEDED MOST DAYS. Operant conditioning techniques to shape and improve skills and abilities, combined with practice variation; emphasis on play, self-help, fun, and use of a variety of individualized reinforcers WEEKLY 1 HR VIDEOS WILL BE SCORED AND FEEDBACK PROVIDED FROM FIDELITY TOOL. ALL TRAINEES WILL LEARN ABOUT FIDELITY TOOL AND PRACTICE SCORING TAPES THEMSELVES.

Training will cover in detail all 8 Core Treatment Components (PAGE 2 OF 2) Therapy in natural settings (e.g., home, child care center) DISCUSS ACCEPTABLE ALTERNATIVES. Shaping includes total body/trunk and bimanual activities (as well as traditional arm/hand therapy activities) REPORTED DAILY AND OBSERVABLE WEEKLY. Parent-Therapist Home Program (formal module) all 4 weeks DAILY DOCUMENTING BY THERAPIST FROM PARENT SELF-REPORT – TIME, ISSUES THAT AROSE. 7. Daily therapy sessions documented CENTRAL REVIEW OF THE DAILY LOG EACH WEEK WITH FEEDBACK TO THERAPIST. 8. Transfer Package to promote future skill and motor development CENTRAL REVIEW WITH FEEDBACK.

Plans for Therapist Training in Roanoke 8 sites have signed up for their therapists (2 will be sending 3 therapists, 6 will send 2) to attend We are missing names from: Atlanta, Boston, Chicago, and Houston (important to communicate if your site needs further assistance) Arrival on afternoon/evening of Monday, June 17– full day training Tuesday through Friday, June 21 (ends 4 p.m.); both written and observed assessment of therapists’ knowledge and skills with feedback and later follow-up activities. Computers will be given to therapists and practice of casting, videotaping, recording daily log, treatment goal setting, transfer plan preparation, and practice of operant conditioning principles

Plans for Assessor Training via Webinars, review of written and videotaped materials Standardized tools by blinded assessors (primary: Bayley III, GMFM, Mini- AHA) Parent rating scales (IMAL) and report tools (stress, communication with therapist, child language) EACH SITE NEEDS WRITTEN PLAN TO ENSURE BLINDING OF ASSESSORS ALL ASSESSMENT SESSIONS ARE VIDEORECORDED IN FULL; SOME SCORING IS CENTRALIZED (Mini-AHA and EBS); Reliability monitored throughout the study with feedback provided as needed and re-coding, if needed

Permission to access and how to use Web-DCU (maintained by NDMC at MUSC) Information provided by Sara Butler

Parent Council Update In-person meeting in Roanoke on Monday, June 17 (arrival on Sunday, June 16