Page 61 - Read Online

Persico et al. Rare Dis Orphan Drugs J 2023;2:xx https://dx.doi.org/10.20517/rdodj.2023.08 Page 17 of 21

by searching for differential effects, depending on whether the active compound is administered during the
first or the second period, rather than expecting one week of wash-out to truly bring all CNS parameters
back to baseline. Our results provide some support to this line of thought; nonetheless, a one-week wash-
out period could be applied in future studies.

(F) Our sample size was dictated by the availability of cases affected with a rare disorder, like PMS. It was
sufficient to yield nominal significance for several relevant variables but not enough for a superiority trial
design, given the small-to-moderate therapeutic effect (i.e., 0.2-0.3). Future studies should benefit from a
greater gap in efficacy between MST and a truly inactive placebo, but given these premises, a sample size of
n = 50 appears to be the minimum requirement for a cross-over study of MST. Multicenter studies may be
necessary if single rare disorders are targeted.

(G) The vast majority of patients recruited for this study were unable to swallow capsules. In these patients,
both active compound and active comparator were administered by opening capsules and dissolving their
content in a small quantity of juice or soft drink. We allowed this procedure, because we were indeed aware
that severe swallowing difficulties are frequent in PMS patients and also because, in our retrospective
[88]
[35]
study , we did not observe a loss of efficacy following this protocol. Nonetheless, we cannot entirely
exclude that differences in drug administration strategy may have contributed to the interindividual
variability in response recorded in the present trial.

In summary, this study provides further promising evidence of the positive effects of CoQ10 in PMS when
administered in association with Vitamin E and Polyvitamin B, which also appear to provide independent
synergistic contributions. Mild-to-moderate improvement was recorded in 24/31 (77.4%) PMS patients and
concerned primarily with the domains of cognition, responsiveness to environmental stimuli and adaptive
functioning, motor skills, and stereotypic behaviors. In addition, the low incidence and mildness of side
effects encourage further studies of this therapeutic approach, given the severity of PMS and the lack of
available treatments. From a different perspective, the small but tangible relief provided to parental quality
of life by the addition of CoQ10 to vitamins appears to be an important added value in a severe genetic
[90]
syndrome with a major impact on the daily living of family members and on parental stress . Defining
[89]
the most sensitive and reliable outcome measures represents a major hurdle in the experimental
[91]
psychopharmacology of neurodevelopmental disorders . This trial has been instrumental in defining the
outcome measures most sensitive to small-to-moderate clinical change in this severely-affected population,
the optimal duration, and many other methodological aspects of the experimental design, setting the stage
for confirmatory targeted RCTs for PMS, ASD, and other neurodevelopmental genetic syndromes. These
studies will also benefit from the assessment of biochemical parameters of oxidative stress to explore
whether and to what extent they predict clinical response.

DECLARATIONS
Acknowledgments
The authors wish to acknowledge all the families and patients who participated in this study, and the Italian
Association for Phelan-McDermid Syndrome (AISPHEM) for partially funding this project. The authors
also acknowledge Dr. Marilena Briguglio for contributing to the medical visits during her clinical activity.

Authors’ contributions
Conceptualization, methodology, project coordination and administration: Persico AM
Patient randomization and treatment allocation: Turriziani L, Calabrese G, Di Bella T