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Page 16 of 21 Persico et al. Rare Dis Orphan Drugs J 2023;2:xx https://dx.doi.org/10.20517/rdodj.2023.08

controlled", randomized, double-blind, cross-over trial, as it would be inaccurate to define it as "placebo-
[87]
controlled" .
(B) It is not customary to apply as many as four different primary outcome measures in an RCT. This
strategy was chosen to verify which outcome measures would display the greatest sensitivity in detecting
clinical change over time. The low sensitivity of psychodiagnostic scales and questionnaires in detecting
clinically meaningful changes not large enough to bring patients outside the ASD spectrum has been one of
the major hurdles encountered in experimental pharmacology of genetic syndromes such as Fragile X .
[39]
Based on our results, clinician-rated CGI-I and parent-rated VAS appear to be the most sensitive measures,
followed by the VABS. For example, the outcome of RBS-R and VAS for stereotypic behaviors appears
inconsistent. However, mean pre-/post-treatment changes in VAS for stereotypic behaviors were -0.79 and
-0.97 for parent- and clinician-rated scores, respectively [Table 5]. VAS ranges from 0 to 10, whereas RBS-R
is essentially a Likert scale ranging from 0 to 3. It is not surprising that the RBS-R may not be sufficiently
sensitive to change in this context. Nonetheless, care must be placed in ensuring that CGI-I and VAS be
administered by the same clinician throughout the study to ensure reliability (notice that also "parent-rated
VAS" were explained and presented to parents by the same clinician and were not self-administered). The
CARS instead failed to detect changes recorded by these other scales, likely due to difficulty in ensuring
reliability at 4-month time intervals even when administered by the same clinician. In reference to
secondary measures, we find especially promising that maternal quality of life improves by an average of
+4.72 points at the WHOQOL, reaching the highest nominal P-value recorded in this study (P = 0.0079).
This improvement with CoQ10 over vitamins alone is confirmed by the similar trend observed in fathers
(see Results). This effect size is not at all marginal, considering that a 6-point improvement in maternal
WHOQOL scores is produced by the complete normalization of child sleep patterns (Persico AM,
Cucinotta F, et al., manuscript in preparation).

(C) Placebo effects in behavioral pharmacology can be large enough to obscure the therapeutic effects
exerted by the active compound. This is another critical issue, considering that the therapeutic effect size of
MST can be realistically expected in the small-to-moderate range . Several strategies potentially able to
[35]
minimize the size of placebo effects were applied. Clinicians involved in medical visits and psychodiagnostic
testing were screened from interactions with parents outside of T0, T1, and T2. Throughout the study,
families were free to contact a dedicated investigator not involved in experimental measures whenever
necessary. Using this strategy, the number of contacts between families and experimenters was nil or limited
to extremely rare and pre-filtered major issues. Participating families were also generally compliant with our
request not to comment on the study on social media. Overall, these strategies appeared to yield satisfactory
results, although the lack of an inactive placebo here does not allow us to reliably quantify the placebo effect
size and estimate their efficacy.

(D) The duration of RCTs is often dictated more by the available budget and other practical considerations
than by preliminary efficacy and safety data. The Time x Treatment interactions depicted in Figure 4
suggest that, while 4 months represent a time interval of sufficient duration to produce therapeutic effects, a
slightly longer trial duration, if possible, may yield an even greater therapeutic effect size and/or
improvements in more areas.

(E) Cross-over studies typically include a one-week wash-out period between the "active compound" and
the "active comparator" periods [Figure 1]. This strategy was not applied here under the hypothesis that
neurodevelopmental plasticity changes, and not acute pharmacological effects, would underlie behavioral
changes. Neuroplastic effects should be expected to carry over for weeks and may be more reliably detected