Open Label Phase I hCT-MSC in Toddlers With Autism Spectrum Disorder

Study Overview
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Brief Summary
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This is a single site, prospective study of one intravenous infusion of human umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) in toddlers with autism spectrum disorder (ASD). Toddlers 18 to 48 months of age with a confirmed diagnosis of ASD will be eligible to participate. Diagnosis will be confirmed at the time of the eligibility visit at the Duke Center for Autism and Brain Development. All participants will receive a single intravenous dose of 2x106/kg hCT-MSC per kilogram at baseline. Assessments will be conducted at baseline and 6 months, with remote follow-up assessments at 12 months.

Detailed Description
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The primary purpose of this study is to evaluate safety and feasibility. Safety assessments include monitoring of acute infusion reactions, adverse events, incidence of infections, and markers of alloimmunization. Clinical outcome measures will also be described. A key clinical outcome measeure is the change in social communication abilities from baseline to 6 months based on the Joint Engagement Rating Inventory (JERI), a commonly-used and well-validated coding system for rating the quality and quantity of social communication skills in toddlers with and without ASD.91 JERI coding rates social communication abilities on a 1 to 7 scale and factors in both the quantity and quality of skills. The total joint engagement score as well as ratings on all JERI subscales that comprise the total score will be described. Other clinical endpoints will include the PDD Behavior Inventory (PDDBI) autism composite score, the mean of the Socialization Subscale Standard Score and Communication Subscale Standard Score on the Vineland Adaptive Behavior Scales (VABS-3), the Clinical Global Impression Scale (CGI) - Severity and Improvement Scales, the Communicative Development Inventories (CDI-2): Words & Sentences subscales, attention abilities via eye-tracking, and brain activity. Exploratory clinical endpoints will include autism symptoms measured by an app that elicits and records autism symptoms on an iPad (SenseToKnow), Autism Diagnostic Observation Scale (ADOS-2) Calibrated Severity Score (overall, social affect, and repetitive behavior), PDD Behavior Inventory (PDDBI) Subscales, and VABS-3 Standard Score and age equivalent for the following subscales: Socialization, Communication, and Daily Living and the Standard Score and age equivalent for the VABS-3 Adaptive Behavior Composite. Safety and VABS-3 assessments will also be conducted remotely at three and 12 months. Duration of study participation will be 12 months from the time of the baseline infusion.

Official Title
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AN OPEN LABEL PHASE I STUDY OF hCT-MSC, AN UMBILICAL CORD-DERIVED MESENCHYMAL STROMAL CELL PRODUCT IN YOUNG CHILDREN WITH AUTISM SPECTRUM DISORDER

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Biological: hCT-MSC infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 months to ≤ 48 months (48 months, 29 days) at the time of consent Confirmed clinical DSM-5 diagnosis of Autism Spectrum Disorder using the DSM-5 Checklist as informed by the Autism Diagnostic Observation Schedule - 2. Fragile X testing performed and negative; CMA and/or whole exome sequencing performed and results not linked to autism diagnosis Stable on current psychoactive medication regimen (dose and dosing schedule) for at least 2 months prior to infusion of study product Normal absolute lymphocyte count (≥1500/uL) Participant and parent/guardian are English speaking Able to travel to Duke University for two multi-day visits (baseline and six months) and parent/guardian is able to participate in interim surveys and interviews Parental consent Exclusion Criteria: General: Review of medical records indicates ASD diagnosis not likely Screening data suggests that participant would not be able to comply with the requirements of the study procedures as assessed by the study team Family is unwilling or unable to commit to participation in all study-related assessments, including protocol follow up Sibling is enrolled in this (Duke hCT-MSC) study Genetic: Records indicate that child has a known genetic syndrome such as (but not limited to) Fragile X syndrome, neurofibromatosis, Rett syndrome, tuberous sclerosis, PTEN mutation, cystic fibrosis, muscular dystrophy or a genetic mutation known to be associated with ASD Known pathogenic mutation or copy number variation (CNV) associated with ASD (e.g., 16p11.2, 15q13.2, 2q13.3) Infectious: Known active CNS infection Evidence of uncontrolled infection based on records or clinical assessment Known HIV positivity Medical: Known metabolic disorder Known mitochondrial dysfunction History of unstable epilepsy or uncontrolled seizure disorder, infantile spasms, Lennox Gastaut syndrome, Dravet syndrome, or other similar chronic seizure disorder Active malignancy or prior malignancy that was treated with chemotherapy History of a primary immunodeficiency disorder History of autoimmune cytopenias (i.e., ITP, AIHA) Coexisting medical condition that would place the child at increased risk for complications of study procedures Concurrent genetic or acquired disease or comorbidity(ies) that could require a future stem cell transplant Significant sensory (e.g., blindness, deafness, uncorrected hearing impairment) or motor (e.g., cerebral palsy) impairment Impaired renal or liver function as determined by serum creatinine >1.5mg/dL or total bilirubin >1.3mg/dL, except in patients with known Gilbert's disease Significant hematologic abnormalities defined as: Hemoglobin <10.0 g/dL, WBC < 3,000 cells/mL, ALC <1000/uL, Platelets <150 x 10e9/uL Known clinically relevant physical dysmorphology associated with neurodevelopmental conditions. Current/Prior Therapy: a. History of prior cell therapy b. Current or prior use of IVIG or other anti-inflammatory medications with the exception of NSAIDs c. Current or prior immunosuppressive therapy i. No systemic steroid therapy that has lasted >2 weeks, and no systemic steroids within 3 months prior to enrollment. Topical and inhaled steroids are permitted.

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 48 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hCT-MSC infusion<br> | Biological: hCT-MSC infusion<br>* This is a single site, phase I, open-label, prospective study of one intravenous infusion of human umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) in 12 toddlers 18 to 48 months of age with autism spectrum disorder (ASD).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of hCT-MSC infusion as measured by incidence of infusion reactions |  | 1 year | 
| Safety of hCT-MSC infusion as measured by severity of infusion reactions | CTCAE is used to measure severity | 1 year | 
| Safety of hCT-MSC infusion as measured by incidence of product-related infections |  | 1 year | 
| Safety of hCT-MSC infusion as measured by severity of product-related infections | CTCAE is used to measure severity | 1 year | 
| Safety of hCT-MSC infusion as measured by evidence of alloimmunization via anit-HLA antibodies |  | 1 year | 
| Safety of hCT-MSC infusion as measured by incidence of graft vs. host disease |  | 1 year | 
| Safety of hCT-MSC infusion as measured by severity of graft vs. host disease | CTCAE is used to measure severity | 1 year | 
| Safety of hCT-MSC infusion as measured by incidence of unexpected adverse events |  | 1 year | 
| Safety of hCT-MSC infusion as measured by severity of unexpected adverse events | CTCAE is used to measure severity | 1 year | 
| Change in PDD Behavior Inventory Autism Composite Score (PDDBI) |  | Baseline, 6 months | 
| Change in mean of the Socialization Subscale and Communication Subscale standard scores on the Vineland Adaptive Behavior Scales (VABS-3) |  | baseline, 6 months | 
| Change in Clinical Global Impression Scale (CGI) |  | baseline, 6 months | 
| Change in Communicative Development Inventories (CDI-2) |  | baseline, 6 months | 
| Change in attention abilities as assess via eye-tracking |  | baseline, 6 months | 
| Change in brain activity as measured by EEG |  | baseline, 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autism Spectrum Disorder, ASD, Autism, PDD