Cord Blood Infusion for Children With Autism Spectrum Disorder

Study Overview
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Brief Summary
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This is a single site, prospective, randomized, double-blind study of a single intravenous autologous or allogeneic, unrelated cord blood (CB) infusion in children ages 2-7 years with Autism Spectrum Disorder (ASD). Participants will be randomly assigned to Sequence A, consisting of a single infusion of CB cells at baseline followed 6 months later by a single infusion of placebo, or Sequence B, consisting of an infusion of placebo at baseline followed 6 months later by an infusion of CB cells. All participants will ultimately be treated with CB cells at some point during the study. Participants with an available qualified autologous CB unit will receive autologous cells, and those without a suitable autologous CB unit available will receive cells from a ≥4/6 HLA-matched, ABO-matched allogeneic, unrelated donor CB unit from the Carolinas Cord Blood Bank. All infusions will be double-blinded. The primary outcomes will be assessed 6 months after the initial infusion in the sequence. Additional testing for secondary exploratory analyses will be performed at 12 months. Duration of study participation will be 12 months from the time of baseline infusion.

Official Title
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Efficacy of Intravenous Umbilical Cord Blood Infusion as Cell Therapy for Children With Autism Spectrum Disorder (ASD): Duke ACT

Conditions
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Autism, Autism Spectrum Disorder, ASD, PDD

Intervention / Treatment
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* Biological: Cord Blood Infusion
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 2 years to ≤ 7 years (7 years, 364 days) at the time of visit 1 Confirmed clinical DSM-5 diagnosis of Autism Spectrum Disorder using the DSM-5 Checklist Fragile X testing performed and negative Available and qualified umbilical cord blood unit with a minimum banked total nucleated cell dose of ≥ 2.5 x 107 cells/kg that meets criteria outlined in Section 6.0, either: Autologous umbilical cord blood unit OR ≥4/6 HLA-matched and ABO/Rh-matched allogeneic unrelated umbilical cord blood unit from the Carolinas Cord Blood Bank Stable on current psychiatric 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 two times (baseline and 6 months post-baseline), 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 Known diagnosis of any of the following coexisting psychiatric conditions: depression, bipolar disorder, schizophrenia, obsessive compulsive disorder, Tourette syndrome Screening data suggests that participant would not be able to comply with the requirements of the study procedures, including study outcome measures, as assessed by the study team Family is unwilling or unable to commit to participation in all study-related assessments, including follow up for approximately 12 months Sibling is enrolled in this (DukeACT) 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 b. Known pathogenic copy number variation (CNV) associated with ASD (e.g., 16p11.2, 15q13.2, 2q13.3) Infectious: Known active central nervous system infection Evidence of uncontrolled infection based on records or clinical assessment 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 sedation or other 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, White blood count < 3,000 cells/mL, absolute lymphocyte count <1000/uL, Platelets <150 x 10e9/uL Evidence of clinically relevant physical dysmorphology indicative of a genetic syndrome as assessed by the PIs or other investigators, including a medical geneticist or psychiatrists trained in identifying dysmorphic features associated with neurodevelopmental conditions Current/Prior Therapy: History of prior cell therapy Current or prior use of immune globulins or other anti-inflammatory medications with the exception of non steroidal anti-inflammatory medications Current or prior immunosuppressive therapy 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: 2 Years
Maximum Age: 7 Years

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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cord Blood Infusion (best source)<br>Subjects will be randomized to receive a cord blood infusion at the baseline or 6 month visit. The cord blood will be autologous (if available) or unrelated cord blood. | Biological: Cord Blood Infusion<br> <br> Biological: Placebo<br> <br> |
| Placebo Comparator: Placebo Infusion<br>Subjects will be randomized to receive a placebo infusion at the baseline or 6 month visit. The placebo is an acellular media product similar in both appearance and odor. | Biological: Cord Blood Infusion<br> <br> Biological: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Social Communication as Measured by the Vineland Adaptive Behavior Scales, Third Edition (VABS-3) | The Vineland Adaptive Behavior Scales, Third Edition (VABS-3) Socialization domain standard score has mean=100 and standard deviation=15 (range: 20-140). Higher scores indicate better developed adaptive social behavior. The change in the Socialization domain standard score was calculated for each participant from Baseline to Month 6. Changes in the Socialization standard score are indicative of skill acquisition relative to chronologically aged peers of the same sex. Thus, a zero (no change) represents change consistent with what is expected. An increase represents acquisition of more skills over time than would be expected. Participants who experience a decrease in Socialization standard score may still have acquired skills although not at the rate expected based on their age and sex. | Baseline, 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Vineland Socialization Domain Raw Score | There are 3 raw scores within the Socialization domain of the VABS-3. These are the Interpersonal Relationships Raw Score (range: 0-86), the Play and Leisure Raw Score (range: 0-72), and the Coping Skills Raw Score (range: 0-66). Higher numbers on all three scores reflect better functioning in each area. Each raw score is the sum of the item scores in the respective subdomain of Socialization skills. The items are scored as follows: 2=usually present, 1=sometimes present, 0= never present. The item scores are assigned by a trained interviewer who interviews the parent of the child participating in the study. The change in raw score was calculated for each participant from Baseline to Month 6. Positive scores indicate improvement over time whereas negative scores indicate worsening, and zero indicates no change. The scores are not norm-referenced. | Baseline, 6 months | 
| Change in Vineland Socialization Domain Age Equivalent | There are 3 age equivalent scores within the Socialization domain of the VABS-3: the Interpersonal Relationships Age Equivalent, the Play and Leisure Age Equivalent, and the Coping Sills Age Equivalent. An individual participant's age equivalent represents the chronological age (in years:months) at which their score would be considered normative. The age equivalent ranges are 0:0-22:0, 0:0-20:0, and 2:0-22:0 for the Interpersonal Relationships, Play and Leisure and Coping Skills age equivalents, respectively. The change in this age equivalent was calculated for each participant from Baseline to Month 6 and expressed as a number of months. Positive scores indicate increases in the age equivalent of the participant's social communication skills over time and are considered an improvement. Negative scores indicate decreases in the age equivalent of the participant's social communication skills and are considered worsening, and zero indicates no change. | Baseline, 6 months | 
| Change in Pervasive Developmental Disorder Behavior Inventory (PDD-BI) Composite Standard Score (Parent Questionnaire) | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The PDD-BI assesses both social impairments and development of pro-social skills that are integral to improved reciprocal social behavior. The PDD-BI renders T scores (mean=50, standard deviation=10) based on comparisons to a standardized ASD population. The Autism Composite T score ranges from 10-100. The typical child with autism scores between 40-60.Higher scores indicate more severe autism symptoms and lower scores reflect milder symptoms. Change in this score from Baseline to Month 6 was calculated for each participant. Negative change scores indicate improvement in autism symptoms over time whereas positive scores indicate worsening of symptoms, and zero indicates no change in symptoms. | Baseline, 6 months | 
| Change in Clinical Global Impressions - Severity of Illness (CGI-S) Score, Clinician Assessment | The CGI-S is a 7 point scale completed at the baseline and 6-month visits that requires the clinician to rate the severity of the participant's symptoms of autism at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. There are 3 CGI-S scores: the Social Communication Score, the Restricted and Repetitive Behaviors Score, and the Overall Score. The clinician's 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. Increases in the change score represent increases in symptom severity, decreases in the change score indicate improvement, and zero indicates no change. | Baseline, 6 months | 
| Clinical Global Impressions - Global Improvement (CGI-I) Score, Clinician Assessment | The CGI-I is a 7 point scale that requires the clinician to assess how much the participant's autism 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. There are three separate CGI-I ratings: social communicative functioning, restricted/repetitive interests and behaviors, and overall improvement. | Baseline, 6 months | 
| Change in Expressive One-Word Picture Vocabulary Test (Clinician Assessment) | This Expressive One-Word Picture Vocabulary Test is a standardized evaluation of the child's expressive one-word vocabulary by a trained clinician. It tests an individual's ability to name, with one word, objects, actions, and concepts when presented with color illustrations. Higher EOWPVT standard scores reflect a better vocabulary. The minimum score is age-dependent (years:months) as follows. For a child age 2:0 to 2:1 the minimum is 65; age 2:2-2:3 (min=62); age 2:4-2:5 (min=60); age 2:6-2:7 (min=58); age 2:8-2:9 (min=57); age 2:10-2:11 (min=56); age 3:0 and older (min=55). The maximum possible score across all ages is 145. The change in score from Baseline to Month 6 was the outcome measure. Increases reflect increases in vocabulary skills, decreasing reflect decreases in vocabulary skills, and zero reflects no change. | Baseline, 6 months | 
| Change in Vineland Adaptive Behavior Scales II (VABS-II) Communication Subscale Standard Score | The VABS-II measures adaptive functioning in socialization, communication, daily living, and motor skills. The Communication subscale standard score is derived by summing norm-referenced (by age group and sex) v-scale scores (mean=15, standard deviation=3) from the Receptive, Expressive, and Written communication subdomains and standardizing this sum to a normal distribution with mean=100 and standard deviation=15. Changes in the Communication standard score are indicative of skill acquisition relative to chronologically aged peers of the same sex. Thus, a zero (no change) represents change consistent with what is expected. An increase represents acquisition of more skills over time than would be expected. Participants who experience a decrease in Communication standard score may still have acquired skills although not at the rate expected based on their age and sex. | Baseline, 6 months | 
| Change in Vineland Adaptive Behavior Scales II (VABS-II) Daily Living Subscale Standard Score | The VABS-II measures adaptive functioning in socialization, communication, daily living, and motor skills. The Daily Living standard score is derived by summing norm-referenced (by age group and sex) v-scale scores (mean=15, standard deviation=3) from the Personal, Domestic and Community subdomains and standardizing this sum to a normal distribution with mean=100 and standard deviation=15. Changes in the Daily Living standard score are indicative of skill acquisition relative to chronologically aged peers of the same sex. Thus, a zero (no change) represents change consistent with what is expected. An increase represents acquisition of more skills over time than would be expected. Participants who experience a decrease in Daily Living standard score may still have acquired skills although not at the rate expected based on their age and sex. | Baseline, 6 months | 
| Change in Vineland Adaptive Behavior Scales II (VABS-II) Composite Score | The Vineland Adaptive Behavior Scales II (VABS-II) measures adaptive functioning in socialization, communication, daily living, and motor skills. The Adaptive Behavior Composite provides an overall summary of adaptive behavior across all of the domains. Each participant's score is standardized to a normal distribution with mean=100 and standard deviation=15. Positive scores indicate an increase in the Adaptive Behavior Composite Score over time whereas negative scores indicate decrease in the Adaptive Behavior Composite Score, and zero indicates no change in the Adaptive Behavior Composite Score. | Baseline, 6 months | 
| Change in Pervasive Developmental Disorder Behavior Inventory (PDD-BI) Repetitive, Ritualistic and Pragmatic Problems T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Repetitive, Ritualistic and Pragmatic Problems T-Score (mean=50, standard deviation=10) measures a broad range of behavioral problems associated with autism. The score ranges from 26-100 in patients aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Approach/Withdrawal Problems T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Approach/Withdrawal Problems T-Score (mean=50, standard deviation=10) measures a broad range of behavioral problems associated with autism. The score ranges from 27-100 in patients aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Sensory/Perceptual Approach Behaviors T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Sensory/Perceptual Approach Behaviors T-score (mean=50, standard deviation=10) includes behaviors that are largely non-communicative and involve approach toward asocial stimuli. The score ranges from 31 to 86 in patients aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Ritualisms/Resistance to Change T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Ritualisms/Resistance to Change T-Score (mean=50, standard deviation=10) describes behaviors that communicate the child's desires to carry out rituals or to communicate dissatisfaction with a change in the environment or routine. The score ranges from 34 to 100 for participants aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Social Pragmatic Problems T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Social Pragmatic Problems T-Score (mean=50, standard deviation=10) measures the difficulties children with autism have in either reacting to the approaches of others, understanding social conventions, or initiating social interactions with others. The score ranges from 29 to 100 for participants aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Semantic/Pragmatic Problems T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Semantic/Pragmatic Problems T-Score (mean=50, standard deviation=10) assesses the difficulties children with autism have in using spoken language to indicate comprehension, communicate meaning, respond to the interests of others, and sustain a conversation. The score ranges from 34 to 100 for participants aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Arousal Regulation Problems T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Arousal Regulation Problems T-Score (mean=50, standard deviation=10) measures behaviors that are largely non-communicative or unresponsive and reflect emotional constriction, the apparent seeking of kinesthetic sensation, and, in the parent version, difficulty with sleep regulation. The score ranges from 26 to 77 for participants aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Specific Fears T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Specific Fears T-Score (mean=50, standard deviation=10) measures behaviors that communicate the fears and anxieties associated with withdrawal from social or asocial stimuli. The score ranges from 36 to 100 for participants aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Aggressiveness T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Aggressiveness T-Score (mean=50, standard deviation=10) assesses the aggressive approach toward self or others, as well as the negative mood changes that are often associated with such behaviors. The score ranges from 36 to 100 for participants aged 2-8 years. Higher values indicate increasing levels of severity. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect worsening of problem behaviors, decreases indicate improvement, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Expressive Social Communication Abilities T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Expressive Social Communication Abilities T-Score (mean=50, standard deviation=10) measures a broad range of social communication skills affected by autism. The score ranges from 20 to 100 for participants aged 2-8 years. Higher values indicate increasing levels of competence. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect improvement, decreases indicate worsening, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Receptive/Expressive Social Communication Ability T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Receptive/Expressive Social Communication Ability T-Score (mean=50, standard deviation=10) measures a broad range of social communication skills affected by autism. The score ranges from 20 to 100 for participants aged 2-8 years. Higher values indicate increasing levels of competence. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect improvement, decreases indicate worsening, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Social Approach Behaviors T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Social Approach Behaviors T-Score (mean=50, standard deviation=10) assesses those social communication skills that are notoriously difficult for children with autism (e.g., eye contact, joint attention, effective use of gesture, imaginative skills). The score ranges from 14 to 93 for participants aged 2-8 years. Higher values indicate increasing levels of competence. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect improvement, decreases indicate worsening, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Expressive Language T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Expressive Language T-Score (mean=50, standard deviation=10) assesses the ability of the child to speak the sounds associated with the English language and to use words and sentences that indicate his or her competence with grammar, tone of voice, and the pragmatic aspects of communicating with others. The score ranges from 28 to 100 for participants aged 2-8 years. Higher values indicate increasing levels of competence. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect improvement, decreases indicate worsening, and zero indicates no change. | Baseline, Month 6 | 
| Change in PDD-BI Learning, Memory, and Receptive Language T-Score | The PDD-BI is an informant-based rating scale that assesses problem behaviors as well as appropriate social, language, and learning/memory skills. The Learning, Memory, and Receptive Language T-Score (mean=50, standard deviation=10) assesses two areas of variable competence in children with autism: (a) memory and (b) receptive language. The score ranges from 22 to 88 for participants aged 2-8 years. Higher values indicate increasing levels of competence. The change in this score from Baseline to Month 6 was calculated for each participant. Increases in the change score reflect improvement, decreases indicate worsening, and zero indicates no change. | Baseline, Month 6 | 
| Number of Participants With Infusion Reactions |  | 12 months | 
| Severity of Infusion Reactions | Grade/severity will be assessed according to CTCAE v4.0 guidelines | 12 months | 
| Number of Participants With Product-related Infections |  | 12 months | 
| Severity of Product-related Infections | Grade/severity will be assessed according to CTCAE v4.0 guidelines | 12 months | 
| Evidence of Alloimmunization Via Anti-HLA (Human Leukocyte Antigen) and Anti-RBC (Red Blood Cell) Antibodies and Nonspecific Markers of Systemic Inflammation (ESR, CRP) |  | 12 months | 
| Incidence of Graft vs. Host Disease |  | 12 months | 
| Severity of Graft vs. Host Disease | Grade/severity will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 guidelines. | 12 months | 
| Incidence of Unexpected Adverse Events, by Relation to Study Product |  | 6 months,12 months | 
| Severity of Unexpected Adverse Events, by Relation to Study Product | Grade/severity will be assessed according to CTCAE v4.0 guidelines | 6 months, 12 months |