Autism, Autism Spectrum Disorder
Conditions
Keywords
Autism, Autism Spectrum Disorder, Stem cell, Mesenchymal Stromal Cells
Brief summary
The purpose of this Phase II study is to determine the efficacy of human umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) for improving social communication abilities in children with autism spectrum disorder (ASD).
Detailed description
The purpose of this double blinded Phase II study is to determine the efficacy of human umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC), administered in two different dosing strategies, in children with autism spectrum disorder (ASD). This study will be enrolling children with ASD, aging 4-11 years of age. Qualifying subjects will undergo neuropsychological evaluation, EEG testing, eye tracking, CVA assessments, and infusion of study product. Subjects will be randomized to one of two study arms; 1) a single infusion of 6.0x106 cells/Kg at baseline, followed by a blinded placebo infusion at six months or, 2) Placebo infusion at baseline, followed by an intravenous dose of 6x106 cells/Kg at six months. The second infusion was included primarily as an incentive to ensure that all participants ultimately receive an infusion of MSC, to reduce the risk of unblinding, and to encourage study completion. Efficacy outcome measures were only evaluated 6 months before the second infusion. Safety outcomes were assessed during the entire 12 months of the study. The primary endpoint of this study is the change in social communication skill from baseline to six months. The potential risks associated with infusion of MSCs include a reaction to the product (rash, shortness of breath, wheezing, difficulty breathing, hypotension, swelling around the mouth, throat or eyes, tachycardia, diaphoresis), transmission of infection, and HLA sensitization.
Interventions
BIOLOGICALCord Tissue Mesenchymal Stromal Cells
Human Umbilical Cord Tissue Derived Mesenchymal Stromal Cells (hCT-MSC), isolated and expanded from umbilical cord tissue from allogeneic unrelated donors. One dose of 6x10e6 cells/kg administered intravenously.
OTHERPlacebo Infusion
Placebo comparative infusion
Sponsors
Joanne Kurtzberg, MD
The Marcus Foundation
Cryo-Cell International
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Blinded infusion
Intervention model description
This study is a phase II, prospective, randomized, blinded clinical trial designed to assess the efficacy of intravenous dosing of hCT-MSC for improving social communication abilities in young children with ASD. All participants will ultimately be treated with hCT-MSC. Participants randomized to arm A will each receive a single intravenous dose of 6x106 hCT-MSC per kilogram at baseline, followed by a placebo infusion at six months. Participants randomized to arm B will each receive a placebo infusion at baseline, followed by an intravenous dose of 6x106 hCT-MSC per kilogram at six months.
Eligibility
Sex/Gender
ALL
Age
4 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 4 years to \< 12 years (11 years, 364 days) at the time of consent 2. Confirmed clinical DSM-5 diagnosis of Autism Spectrum Disorder using the DSM-5 Checklist as informed by the Brief Observation of Symptoms of Autism (BOSA) and the Autism Diagnostic Interview-Revised (ADI-R) 3. Fragile X testing performed and negative; CMA and/or whole exome sequencing performed and results not linked to autism diagnosis 4. Stable on current psychiatric medication regimen (dose and dosing schedule) for at least 2 months prior to infusion of study product 5. Normal absolute lymphocyte count (≥1200/uL for African American participants and ≥1500/uL for all other participants) 6. GAI ≥ 65 via cognitive testing by study personnel 7. Participant and parent/guardian are English speaking 8. Able to travel to Duke University two times (baseline, six months), and parent/guardian is able to participate in interim surveys and interviews 9. Parental/guardian consent from at least one parent/guardian
Exclusion criteria
1. General: 1. Review of medical records and/or screening assessments indicates ASD diagnosis and/or GAI \> 65 not confident 2. Known diagnosis of any of the following coexisting psychiatric conditions: depression, bipolar disorder, schizophrenia, obsessive compulsive disorder associated with bipolar disorder, Tourette syndrome 3. Screening data suggests 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 IMPACT) study 2. Genetic: 1. 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 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. Exposure to COVID-19 in the preceding 14 days or positive COVID-19 test in the previous 28 days. Subjects with a past history of infection with COVID-19 must be symptom-free for 14 days prior to the initial visit. 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 child 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 patients 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. 5. Current/Prior Therapy: a. Availability of a banked, qualified autologous cord blood unit or parents 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change on the Average Socialization and Communication Subscale Standard Scores on the Vineland Behavior Scales (VABS-3) | Baseline, 6 months | The primary outcome measure is the mean of the Socialization and Communication Subscale Standard Scores on the Vineland Adaptive Behavior Scales (VABS-3) from the Comprehensive Interview form. The primary endpoint is the change in this outcome measure from baseline to six months before the second infusion. A positive change in the scores indicates an improvement in socialization and communication. A standard score of 100 is the mean with a standard deviation of 15 points. A score of 100 should be understood as being similar to the typical population of the same age. Scores greater than or equal to 86 are considered adequate or above adequate. Domain scores less than or equal to 85 are considered moderately low to low and indicate the patient has a significant skill deficit when compared with similarly aged peers. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in VABS-3 (Vineland Adaptive Behavior Scales) Socialization Standard Score | Baseline, 6 months | The change in the Socialization Subscale Standard Scores on the Vineland Adaptive Behavior Scales (VABS-3) from baseline to six months. Higher Socialization Standard scores indicate greater socialization. A positive change in the scores indicates an improvement in socialization. A standard score of 100 is the mean with a standard deviation of 15 points. A score of 100 should be understood as being similar to the typical population of the same age. Scores greater than or equal to 86 are considered adequate or above adequate. Domain scores less than or equal to 85 are considered moderately low to low and indicate the patient has a significant skill deficit when compared with similarly aged peers. |
| Change in VABS-3 Communication Standard Score | Baseline, 6 months | The change in the Communication Standard Scores on the Vineland Adaptive Behavior Scales (VABS-3) from the Comprehensive Interview form from baseline to six months before the second infusion. Higher scores indicate greater communication. A positive change in the scores indicates an improvement in communication. A standard score of 100 is the mean with a standard deviation of 15 points. A score of 100 should be understood as being similar to the typical population of the same age. Scores greater than or equal to 86 are considered adequate or above adequate. Domain scores less than or equal to 85 are considered moderately low to low and indicate the patient has a significant skill deficit when compared with similarly aged peers. |
| CGI-S (Clinical Global Impression - Severity of Illness) Overall Score | 6 months | The CGI-S Overall Score is a 7-point scale that requires the clinician to rate the severity of the participant's overall functioning and symptoms of autism at the time of assessment, relative to the clinician's experience with participants who have the same diagnosis. The clinician rates the severity of autism symptoms - 1, normal, no symptoms; 2, borderline level of symptoms; 3, mild symptoms; 4, moderate symptoms; 5, marked symptoms; 6, severe symptoms; or 7, extremely severe symptoms. The higher ratings indicate greater severity of overall functioning impairment. |
| CGI-I (Clinical Global Impression - Improvement) Overall Score | 6 months | The CGI-I Overall Score is a 7-point scale that requires the clinician to assess how much the participant's autism overall functioning and symptoms have improved or worsened relative to a baseline assessment. The symptoms are rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. The lower scores indicate greater improvement. |
| Change in the Pediatric Quality of Life (PedsQL) Total Scale Score | Baseline, 6 months | The PedsQL 4.0 Generic Core Scales is a 5-minute parent questionnaire that measures the child's functioning in the dimensions of physical, emotional, social, and school. The items use a Likert rating scale from 0 (Never) to 4 (Almost Always). This 0-4 scale is then transformed to 0=100, 1=75, 2=50, 3=25, and 4=0 for a reverse score. The Total Scale Score is then computed as the sum of all the items over the number of items answered on all the Scales for a total score range of 0 to 100. Higher scores indicate a better quality of life. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBeth Shaz, MD
Duke University
PRINCIPAL_INVESTIGATORLauren Franz, MBChB
Duke University
Participant flow
Pre-assignment details
The second infusion was included primarily as an incentive to ensure that all participants ultimately receive an infusion of MSC, to reduce the risk of unblinding, and to encourage study completion. Efficacy outcome measures were only evaluated 6 months before the second infusion. Safety outcomes were assessed during the entire 12 months of the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 7.6 years STANDARD_DEVIATION 2.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 69 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 94 Participants |
| Region of Enrollment United States | 137 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 69 | 0 / 65 | 0 / 3 | 0 / 68 | 0 / 1 |
| other Total, other adverse events | 53 / 68 | 40 / 69 | 39 / 65 | 1 / 3 | 48 / 68 | 0 / 1 |
| serious Total, serious adverse events | 1 / 68 | 0 / 69 | 0 / 65 | 0 / 3 | 1 / 68 | 0 / 1 |
Outcome results
None listed