Methods
autistic, ICH, psychiatric, DSM-5
ADVERSE EVENTS, ADVERSE EVENT, BLIND, ADVERSE EFFECTS
We conducted a randomized double-blind, placebo-controlled crossover trial of SB-121 in fifteen 15–45 year old autistic participants. The sample size was not determined based on statistical assumptions. Evaluation of 15 total subjects was considered sufficient to allow evaluation of the study’s objectives. This was a double-blind study. The study team and subjects were blinded to the randomized study treatment assignments. In order to maintain the blind throughout the duration of the clinical study, all investigational product was affixed with a blinded label. Only the dispensing pharmacist was aware of study drug assignment. Randomization.com was utilized to generate the random allocation sequence, with two blocks of 8 patients per block. A randomization list was generated containing treatment assignments, and participants were added sequentially to the list following enrollment, and the corresponding study drug was dispensed. The study pharmacist generated the random allocation sequence, the study Principal Investigator enrolled participants, and the CCHMC Investigational Drug Service pharmacists assigned the participants. Participants were randomized in a 1:1 ratio to receive treatment with either SB-121 or placebo for 28 days. Following an approximately 14-day washout period, all participants crossed over to the other treatment (SB-121 or placebo) for 28 days.This study was conducted at the Cincinnati Children’s Hospital and in accordance with ICH GCP, the United States (US) Code of Federal Regulations (CFR) and Cincinnati Children’s Hospital IRB. The protocol was reviewed and approved by the Cincinnati Children’s Hospital Institutional Review Board and registered at clinicaltrials.gov (NCT04944901) on 30/06/2021. All participants under age 18 or over 18 with a legal guardian had a parent or legally authorized caregiver provided informed consent for their participation. Each participant provided their own additional consent or assent as possible and applicable. All participant data have been de-identified in this work. All the inclusion and exclusion criteria are listed in Supplementary Information (Supplementary Table Following consent, a screening visit was completed including administration of the ADOS-2 (which was not required if assessment was completed within the previous 36 months and results were available), clinical interview using DSM-5 criteria for ASD, a medical and psychiatric history, physical examination and laboratory tests done to confirm study eligibility. Following randomization, but before the initial dose of SB-121 or placebo, additional subject characterization measures were completed including cognitive testing using the Wechsler Abbreviated Scale of Intelligence, 2nd Edition (WASI-II) and administration of the Social Communication Questionnaire (SCQ). In each SB-121 or placebo treatment period, participants or their caregivers completed additional assessments both pre-dose and following 28 days of daily dosing (i.e., at outcome) including the Vineland Adaptive Behavior Scales, 3rd edition (Vineland-3, Comprehensive Interview)Regarding safety evaluations, participants completed safety laboratory panels (hematology and blood chemistry studies) and vital signs pre- and post-28 days of treatment during each treatment period. A full physical examination was done at screening and subsequently a limited focused physical examination was done for the evaluation of adverse events, as needed at all in person visits. Adverse events, concomitant medications and treatment compliance were assessed during all visits. All treatment emergent adverse effects (TEAEs) were recorded and tabulated for comparison across SB-121 or placebo treatment, as were the vital signs and the hematology and blood chemistry parameters.We conducted analysis of change from baseline in the Vineland-3 composite and domain scores, ABC subscale scores, and CGI-S utilizing a general linear model where the change score (i.e., the difference of post-28 days of treatment value from the pre-dosing value for each of the two periods) served as dependent variable. The difference in score was modeled as a function of treatment (SB-121 or placebo), study period (1 or 2), and the sequence of treatments (SB-121 in the first period or second). Subject was included in the model as a random effect and the sequence term measured potential crossover effect. If no crossover effect was noted for an outcome measure, then the adjusted (least squared) means for the treatments were given along with their difference and a p-value was assigned for the null hypothesis of no difference. Given the pilot nature of this analysis, p-values were not corrected for multiplicity. Given that the CGI-I is a Likert scale rating of improvement and is not administered at pre-treatment/baseline, CGI-I mean values post-treatment were compared between SB-121 and placebo.To obtain eye tracking data, participants were seated in a quiet, dark room in front of a Tobii XL300 eye tracker at a distance of 60–65 cm from the eye tracker monitor. Each participant was presented with verbal instructions to look at the screen. The eye tracker was calibrated for each participant at the beginning of the session using the Tobii Studio “five-point calibration”. Successful calibration was ascertained via Tobii Studio’s automated validation procedure. A second attempt to calibrate was conducted if the participant did not successfully calibrate initially. Following calibration, participants completed a social interest paradigm, as previously publishedRaw eye tracking data was exported from Tobii Studio and areas of interest (AOI) were created using MATLAB (version R2019a; The Mathworks, Inc., Natick, Massachusetts). The AOIs included the social scene or the geometric scene. The proportion of looking time was calculated by dividing the looking time to the AOI region by the total looking time to the geometric + social scenes. Proportion of valid looking was calculated by dividing the total looking time to anywhere on the screen divided by the total stimulus presentation time. Participants were excluded if they had less than 35% valid looking data across the videos