hCT-MSC Infusion in Adults With Autism Spectrum Disorder (AIMs)

• ClinicalTrials.gov Identifier: NCT04484077
• Recruitment Status: Not yet recruiting
• First Posted: July 23, 2020
• Last Update Posted: March 18, 2021
• Sponsor: Joanne Kurtzberg, MD
• Collaborator: The Marcus Foundation
• Information provided by (Responsible Party): Joanne Kurtzberg, MD, Duke University

Study Description

Brief Summary:

The purpose of the study is to determine the safety and tolerability of a single intravenous dose of Human Umbilical Cord Tissue Derived Mesenchymal Stromal Cells (hCT-MSC) in adults with autism spectrum disorder (ASD). hCT-MSC is a cell product isolated from umbilical cord tissue. The cells from the cord tissue are processed and expanded in the laboratory and then infused intravenously in a single dose per participant. Participants will be ages 18-35 years, with ASD and a full-scale IQ >70 without an identified genetic cause of autism. Participants will have remote follow up visits at 3 and 12 months and an in-person visit at 6 months. In addition to the primary endpoints evaluating safety, the study will include secondary and exploratory endpoints evaluating Autism Spectrum Disorder specific outcome measures to describe any changes in autism symptoms after hCT-MSC administration.

Condition or disease	Intervention/treatment	Phase
Autism Spectrum Disorder; Autism	Biological: hCT-MSC	Phase 1

Detailed Description:

This is a prospective, open label, phase one study to determine the safety and tolerability of a single intravenous dose of Human Umbilical Cord Tissue Derived Mesenchymal Stromal Cells (hCT-MSC) in adults with autism spectrum disorder (ASD). hCT-MSCs are manufactured from umbilical cord tissue donated by healthy mothers delivering full term babies via Cesarean Section. The cells are extracted from the cord tissue, expanded and cryopreserved (frozen). One dose of 2x10^6 cells/kg (maximum of 10 x 10^7) will be administered intravenously to each participant in this study.

It is hypothesized that immune dysregulation and/or abnormal neuronal connectivity that adversely affects normal brain development may cause core symptomatology observed in individuals with ASD. Mesenchymal stromal cells (MSC) have demonstrated a multitude of immunomodulatory effects which are thought to be carried out via paracrine and trophic signaling. While MSCs modulate the immune response, MSCs themselves have low immunogenicity (the body does not have a strong immune reaction against them) and they do not permanently engraft in the recipient.

Adults ages 18 to 35 years with ASD will be eligible to participate. All participants will have a screening visit that includes clinical evaluation to verify the diagnosis of ASD, cognitive abilities, ASD symptom level, and confirmation of eligibility.

One dose of 2x10^6 cells/kg (maximum of 10 x 10^7) will be administered intravenously to each participant at a baseline visit. Participants will be admitted to the infusion center on the day of their baseline visit and vital signs (heart rate, blood pressure, temperature, respiratory rate) will be measured. Participants may require some sedation prior to IV placement if they are unable to remain still or cooperate. A peripheral IV will be placed and prior to the infusion, premedications (Benadryl, Solumedrol, 0.5mg/kg each) will be administered. The hCT-MSCs product will be administered intravenously over 30-60 minutes. Pulse oximetry will be monitored continuously throughout the infusion and IV fluid maintenance will be given. Participants will be discharged after 1 hour, providing all vital signs are at their baseline and they are asymptomatic with no evidence of toxicity. Participants will be evaluated the day after the infusion to assess for any infusion-related adverse reactions or complications. A phone call or email to the participant or legally authorized representative to assess safety of the infusion will occur 7-10 days after the infusion. Remote follow up will occur 3 months and one year after infusion. Participants will return to Duke six months after infusion for repeated testing and safety follow-up. The Medical and Behavioral History Questionnaire assessing adverse events will be obtained at baseline, 3, 6 and 12-months.

The main endpoint is safety, for which acute infusion reactions, incidence of infections, and markers of alloimmunization will be assessed. Key secondary endpoints will include ASD-specific outcome measures to describe any changes in autism symptoms after product administration. Exploratory analyses will include measures obtained by EEG, eye-tracking, pupillary light reflex, computer vision analysis, and tactile stimulation.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A PHASE I STUDY OF hCT-MSC, AN UMBILICAL CORD-DERIVED MESENCHYMAL STROMAL CELL PRODUCT, IN ADULTS WITH AUTISM SPECTRUM DISORDER
• Estimated Study Start Date: May 2021
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: March 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: hCT-MSC infusion; A single, intravenous infusion of hCT-MSCs. Targeted dose is 2x10^6 cells/kg with a maximum dose of 10 x 10^7 cells/kg.	Biological: hCT-MSC; 2x10^6 hCT-MSC/kg suspended in plasmalyte-A, 5% HSA, and residual DMSO/dextran administered intravenously over 30-60 minutes via syringe pump

Outcome Measures

Primary Outcome Measures :

1. Incidence of infusion reactions [ Time Frame: Baseline through 10 days post infusion ]
   cumulative incidence as measured by clinical examination and patient interview
2. Incidence of product-related infections [ Time Frame: Baseline through 12 months ]
   cumulative incidence as measured by patient interview and questionnaire
3. Evidence of formation of anti-HLA antibodies [ Time Frame: Baseline, 6 months, 12 months ]
   change from baseline to 6 and 12 months post infusion as measured by PRA testing
4. Incidence of graft vs. host disease [ Time Frame: Baseline through 12 months ]
   cumulative incidence as measured by patient interview and questionnaire
5. Incidence of unexpected adverse events, by severity and relation to study [ Time Frame: Baseline through 12 months ]
   cumulative incidence as measured by patient questionnaire and clinical labs

Secondary Outcome Measures :

1. The Vineland Adaptive Behavior Scale Interview, 3rd Edition, Comprehensive interview form [ Time Frame: Baseline and 6 months ]
   Change from baseline to six months in the Combined Socialization Standard Score based on parent report. Scores range from 20 to 140. Higher scores indicate a higher functioning level
2. Social Responsiveness Scale, Second Edition (SRS-2) [ Time Frame: Baseline and 6 months ]
   Change from baseline to six months of the Communication Score calculated from the parent/guardian questionnaire. The SRS-2 provides a continuous measure of social ability. Scores range from 40 to >= 90, with higher scores indicating greater social impairment.
3. Social Withdrawal Subscale of the Aberrant Behavior Checklist, Community Edition (ABC-C) [ Time Frame: Baseline and 6 months ]
   Change from baseline to six months based on parent/guardian questionnaire. Scores range from 0-48. Higher scores indicate that behaviors in the subscale occur with higher frequency.
4. Repetitive Behavior Scale Revised - parent/guardian questionnaire [ Time Frame: Baseline and 6 months ]

   Change from baseline to six months based on parent report.

   • Stereotyped Behavior Subscale: 0 to 18
   • Self-Injurious behavior subscale: 0 to 24
   • Compulsive Behavior subscale: 0 to 24
   • Ritualistic behavior subscale: 0 to 19
   • Sameness Behavior subscale: 0 to 33
   • Restricted Behavior subscale: 0 to 12

   The higher the score the more the behavior occurs and the greater a problem it is.

5. Pediatric Quality of Life Inventory General Core Scales [ Time Frame: Baseline and 6 months ]
   Change from baseline to six months based on parent report. Scores range from 0 to 100 and higher scores indicate a better Health-Related Quality of Life, or better functioning.
6. Pediatric Quality of Life Inventory Family Impact Measure [ Time Frame: Baseline and 6 months ]
   Change from baseline to six months based on parent report. Scores range from 0-100 and higher scores indicate better functioning.
7. Pediatric Quality of Life Inventory General Core Scales - Adult Version [ Time Frame: Baseline and 6 months ]
   Change from baseline to six months based on self report. Scores range from 0-100 and higher scores indicate a better Health-Related Quality of Life or better functioning.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 35 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥ 18.0 years to ≤ 35.0 years at the time of consent
2. Confirmed pre-existing diagnosis of ASD in the individual's educational and/or medical record
3. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnosis of Autism Spectrum Disorder using the DSM-5 Checklist as informed by the Autism Diagnostic Observation Scale - 2 (ADOS-2)
4. Fragile X testing performed and negative; Chromosomal Microarray Analysis and/or whole exome sequencing performed and results not linked to autism diagnosis
5. Stable on current psychiatric medication regimen (dose and dosing schedule) for at least 2 months prior to infusion of study product, with no intention of changing or beginning new psychiatric medications or behavioral treatments during the duration of the study.

6. Normal absolute lymphocyte count (≥1200/uL for African American participants and

   • 1500/uL for all other participants)
7. Full Scale IQ ≥70, confirmed through cognitive testing completed by study personnel prior to consent
8. Social Responsiveness Scale, Second Edition score of ≥ 66 by parent or guardian report
9. Participant and Parent/Legally authorized representative (LAR) are English speaking
10. Able to travel to Duke University two times (baseline, six months).
11. Participant has a parent or LAR who spends four or more hours a week with the participant, who is able and willing to participate in study visits and interim surveys and interviews
12. Parent/LAR and participant consent (if participant has the capacity to provide informed consent) OR parent/LAR consent and participant assent (if participant lacks capacity to provide informed consent based on competency assessment).

Exclusion Criteria:

1. General:

   1. Review of medical records indicates ASD diagnosis and IQ > 70 unlikely.
   2. Known diagnosis of any of the following coexisting psychiatric conditions: bipolar disorder, schizophrenia, obsessive compulsive disorder associated with bipolar disorder, Tourette syndrome, or current (within the past year) evidence of suicidality as assessed by parent interview, the Columbia Suicide Severity Rating Scale, and the Symptoms Checklist-90 (SCL-90).
   3. Screening data or in-person evaluations suggest that participant would not be able to comply with the requirements of the study procedures as assessed by the study team
   4. Family is unwilling or unable to commit to participation in all study-related assessments, including protocol follow up
   5. Sibling is enrolled in this (Duke AIMs study)

2. Genetic:

   1. Records indicate that the participant 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 defect definitively known to be associated with ASD
   2. Known pathogenic mutation or copy number variation (CNV) associated with ASD (e.g., 16p11.2, 15q13.2, 2q13.3)

3. Infectious:

   1. Known active CNS infection
   2. Evidence of uncontrolled infection based on records or clinical assessment
   3. Known HIV positivity

4. Medical:

   1. Known metabolic disorder
   2. Known mitochondrial dysfunction
   3. History of unstable epilepsy or uncontrolled seizure disorder, infantile spasms, Lennox Gastaut syndrome, Dravet syndrome, or other similar chronic seizure disorder
   4. Active malignancy or prior malignancy that was treated with chemotherapy
   5. History of a primary immunodeficiency disorder
   6. History of autoimmune cytopenias (i.e., ITP, AIHA)
   7. Coexisting medical condition that would place the participant at increased risk for complications of study procedures
   8. Concurrent genetic or acquired disease or comorbidity(ies) that could require a future stem cell transplant
   9. Significant sensory (e.g., blindness, deafness, uncorrected hearing impairment) or motor (e.g., cerebral palsy) impairment
   10. Impaired renal or liver function as determined by serum creatinine >1.5mg/dL or total bilirubin >1.3mg/dL, except in participants with known Gilbert's disease
   11. Significant hematologic abnormalities defined as: Hemoglobin <10.0 g/dL, Platelets <150 x 10e9/uL, WBC <3,000 cells/mL, ALC <1200/uL for African Americans or <1500/uL for all other participants.
   12. Evidence of clinically relevant physical dysmorphology indicative of a genetic syndrome as assessed by the PIs or other investigators, including a medical geneticist and psychiatrists trained in identifying dysmorphic features associated with neurodevelopmental conditions.
   13. Current pregnancy and unwillingness to use adequate birth control for 3 months after the final study product infusion.

5. Current/Prior Therapy:

   a. Availability of a banked, qualified autologous cord blood unit or parent deferred use of qualified, autologous cord blood unit b. History of prior cell therapy c. Current or prior use of IVIG or other anti-inflammatory medications with the exception of NSAIDs d. 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.

Contacts and Locations

Contacts

Contact: Sydney Crane, RN; 9196681100; cordbloodtherapyinfo@dm.duke.edu

Contact: Lettie Moore; cordbloodtherapyinfo@dm.duke.edu

Locations

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Contact: Jessica Sun, RN 919-684-3401 jessica.sun@duke.edu

Sponsors and Collaborators

Joanne Kurtzberg, MD

The Marcus Foundation

Investigators

• Principal Investigator: Jessica Sun, MD; Duke University
• Principal Investigator: Joanne Kurtzberg, MD; Duke University
• Principal Investigator: Geraldine Dawson, PhD; Duke Health

More Information

• Responsible Party: Joanne Kurtzberg, MD, Jerome Harris Distinguished Professor of Pediatrics; Professor of Pathology; Director, Marcus Center for Cellular Cures; Director, Pediatric Blood and Marrow Transplant Program; Director, Carolinas Cord Blood Bank, Duke University
• ClinicalTrials.gov Identifier: NCT04484077
• Other Study ID Numbers: PRO00104691
• First Posted: July 23, 2020
• Last Update Posted: March 18, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Joanne Kurtzberg, MD, Duke University:

autism; MSC; hCT-MSC; mesenchymal stromal cells

Additional relevant MeSH terms:

Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders