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Persico et al. Rare Dis Orphan Drugs J 2023;2:xx https://dx.doi.org/10.20517/rdodj.2023.08 Page 9 of 21

[50]
F. Conners' Parent Rating Scale-Revised (CPRS-R) , a 48-item parental rating scale used to evaluate the
presence and intensity of hyperactivity/inattention, impulsivity, and externalizing behaviors. Each item is
rated on a 0-3 point scale to reflect increasing symptom severity.

G. Child Behaviour Checklist (CBCL) [51,52] , which provides parental ratings for 20 and 120 items regarding
competence and behavioral problems, respectively, in youth aged 6-18 years old. Each item is scored 0-2 to
reflect symptom severity or frequency. Standard scores are scaled so that 50 is average for the youth's age
and gender, with a standard deviation of 10 points.

[53]
H. The Quality of Life in Autism Questionnaire (QOL-A) , which measures the parental quality of life
either broadly (part A, 28 items, score range 28-140) or specifically related to the ASD affecting their
offspring (part B, 20 items, score range 20-100). The total score range is 48-240, with higher scores
indicating better quality of life.

I. The World Health Organization's Quality of Life Questionnaire (WHOQOL) , which is used to assess
[54]
parental quality of life in four domains: physical, psychological, social, and environmental. The score can
range from 15 to 105, with a higher score indicating better quality of life.

Safety and Adverse Events
Adverse Events (AEs) were monitored during the study by extensive clinical evaluation at each time point,
including physical and neurological examination, routine hematology and blood chemistry. Moreover, an
investigator (A.R.) blind to treatment and not involved in patient assessments was available to interact with
families by phone throughout the study for prompt detection and management of potential adverse effects
in-between assessments. The AEs were documented for severity, duration, and management.

Statistical analyses
The statistical analysis was carried out using repeated measures mixed models. The dependent variables
were the post-treatment outcome values, whereas the independent variables were treatment (active
compound vs. active comparator), time (Period II vs. Period I), and sequence (the active compound in the
first period vs. active compound in the second period). A random intercept term was used in the model to
account for repeated measurements over the same individuals. Results for numerical variables were
reported as the mean difference (MD) from a linear mixed model, whereas for binary or ordinal categorical
variables as the odds ratio (OR) from a logistic mixed model or as the cumulative odds ratio (cOR) from an
ordinal logistic mixed model, respectively. To describe the effect of treatment in Period I and Period II,
standard linear, logistic, and ordinal logistic models were used, with post-treatment values as the dependent
variable and treatment as the independent variable. All linear models were also adjusted for pre-treatment
outcome values. Uncertainty in estimates was described using 95% confidence intervals (CI). Given the
exploratory nature of this study, nominal P-values are presented and statistical significance is set at nominal
P < 0.05 without controlling for multiple comparisons. Effect modification related to age (considering two
subgroups: < 9 and ≥ 9 years) was assessed by significance testing of the treatment x age interaction term in
a separate model for each primary outcome variable reaching nominal significance. Analyses were
[55]
performed using the R 3.6.3 statistical software .

RESULTS
The study was completed by 33 patients whose demographic, genetic, and clinical characteristics are
summarized in Table 4. The sample was randomized to receive the active compound either during the first
(n = 18, 51.4%) or during the second administration period (n = 17, 48.6%). Almost all patients displayed