Trial Summary

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 livebirths 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 – 36 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, age 8 to 36 months, (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.)

Specific Aims

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. 

Principal Investigators:
Sharon Landesman Ramey, PhD – PRIME PI, Virginia Tech
Warren Lo, MD - Multiple PI, The Ohio State University and Nationwide Children’s Hospital

Other Collaborators: 

• The National Institute of Neurological Disorders and Stroke (NINDS) – 1U01NS106655-01A1
• NIH StrokeNet National Coordinating Center at the University of Cincinnati
• NIH StrokeNet National Data Management Center at Medical University of South Carolina
• I-ACQUIRE Training Implementation Center, Virginia Tech
• I-ACQUIRE Assessment Center, Ohio State University
• I-ACQUIRE Neuroimaging Center, Stanford University

ClinicalTrials.gov Identifier:  NCT3910075