Use of Biomarkers to Assess Outcomes in a Phase 1 Open Label Trial of Autologous Cord Blood in Young Children with Autism Spectrum Disorder
Umbilical cord blood (UCB) may facilitate neural cell protection/repair and reduce inflammation, resulting in improved social communication in children with autism spectrum disorder (ASD). We performed a phase I, open-label study of a single intravenous infusion of autologous UCB in young children with ASD and explored whether behavioral measures and neurophysiologic/imaging biomarkers could be utilized in a future Phase II, randomized trial.
To evaluate the safety of autologous UCB infusion and assess the feasibility and sensitivity to change of several validated behavioral outcome measures and eye-tracking and brain-based biomarkers in a Phase I clinical trial.
We treated 25 children with ASD, 24-72 months of age. Diagnosis was based on ADOS-2 and ADI-R, and eligibility required a qualified banked autologous UCB unit. Participants were assessed at baseline, 6, and 12 months post-infusion with the Vineland Adaptive Behavior Scales-II (VABS), Clinical Global Impression (CGI), Pervasive Developmental Disorder Behavior Inventory (PDDBI; also at 3 months), and Expressive One Word Picture Vocabulary Test (EOWPVT). The eye tracking task was a dynamic video that included an actress making joint attention bids (ET; Regions: actress, eyes, mouth and face). MRI with DTI and EEG while viewing dynamic social and nonsocial stimuli were conducted. Adverse events were monitored. Statistical significance of change on VABS, CGI, and EOWPVT was evaluated using the Wilcoxon signed-rank test. A linear spline was fit for the PDDBI, and ET was analyzed using logit-link generalized estimating equations.
We observed improvements on the VABS socialization (median=2 points; range: -8, 30; P=0.016) and communication (median=4.5; range: -8.0, 20; P=0.002) standard scores, and the CGI-I indicated improvement on 13 patients (52%) from baseline to 6-months (P = 0.001). The PDD-BI Autism Composite, reflecting ASD symptoms, declined in the first 3 months (mean=7.52, 95% CI: -12.38,-2.67; P=0.004). A median change of 4 was observed on the EOWPVT from baseline to 6 months (range: -1, 24) and 5.5 points from 6-12 months (range: -12, 16) (P < 0.01 for both). A 20% increase in odds of gazing at the eyes over time was observed (odds ratio=1.20, 95% CI: 1.00, 1.43, P=0.048). A 7 point change in socialization standard score was associated with a 14% increase in odds of gazing at the actress (OR=1.14, 95% CI: 1.07, 1.21; P < 0.001). Changes in MRI fractional anisotropy were observed but were not significantly associated with the VABS socialization standard score (P = .067). Preliminary analysis of EEG showed significant increases in occipital alpha spectral power over time but no change in other anatomical brain regions. UCB infusion was well tolerated with no serious adverse events reported. Changes in outcomes were unrelated to number of hours of behavioral therapy outside the trial.
Validated behavioral outcome measures and eye-tracking and neurophysiologic biomarkers were sensitive to change over a six-month period in an open-label study of the safety and feasibility of UCB infusion for ASD. These measures will be used in a larger, double-blind randomized trial investigating efficacy of UCB for reducing core symptoms of autism.