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Page 4 of 21 Persico et al. Rare Dis Orphan Drugs J 2023;2:xx https://dx.doi.org/10.20517/rdodj.2023.08

METHODS
Study design
This double-blind, randomized cross-over, placebo-controlled study assessed the efficacy and safety of an
MST with CoQ10, vitamin E and complex-B vitamins in PMS. All procedures contributing to this work
comply with the ethical standards of the relevant national and institutional committees on human
experimentation and with the Helsinki Declaration. The Ethical Committee of the University of Messina
(Messina, Italy) approved the study (prot. n. 15/18, approved on May 2nd, 2018). The parents of all patients
enrolled in this study were informed about potential adverse reactions. Written informed consent was
obtained from all caregivers for their child's participation. This clinical trial adheres to CONSORT
guidelines and has been registered at https://clinicaltrials.gov/ with NCT n. 04312152.

The experimental design of this trial is displayed in Figure 1. Briefly, the total duration of the trial was 8
months. Each patient received an active compound [CoQ10 + Vit. E + polyvit. B] for 4 months and active
comparator [Vit. E + polyvit. B] for 4 months. Half of the sample received the active compound during
period I (months 1-4) and the active comparator during period II (months 5-8), while the remaining half
assumed the active comparator during period I and active compound during period II [Figure 1]. More
specifically, following a medical screening visit, enrolled patients were double-blindly randomized
according to a permuted two-block design, to receive either active compound or active comparator (Period
I) and then were switched to the other treatment condition (Period II); each treatment period lasted for 4
months. Initially eligible subjects underwent a complete clinical and psychometric assessment (T0), which
was repeated at the end of each 4-month treatment period [T1 and T2 in Figure 1]. Three investigators
(L.T., G.C., T.DB.), never involved in clinical assessments nor in direct contact with patients and caregivers,
were in charge of treatment allocation. To monitor compliance, unused capsules were retrieved and counted
at each time point. One investigator (A.R.), not involved in clinical assessments, interacted with caregivers
as needed throughout the study, for any medical need and for issues regarding the trial itself. Families were
requested to refrain from commenting on their experience and purported treatment efficacy on social
media.

Participants
Inclusion and Exclusion Criteria
Participants were required to hold a diagnosis of PMS due to a genetically documented deletion of human
chromosome 22q13.3 or a disruptive mutation in the SHANK3 gene. Other inclusion criteria were: (1) age
between 2 and 40 years old; (2) Children's Global Assessment Scale (CGAS) score between 45 and 59 at
baseline; (3) medication regimen stable for at least three months prior to enrolment and kept constant
throughout the 8-month duration of the trial; (4) behavioral intervention started at least 3 months prior to
enrolment and kept unchanged throughout the 8-month duration of the trial; (5) written informed consent
provided by both parents or a legally authorized patient representative; (6) parents and guardian able to
understand and comply with the experimental protocol.

Potential participants were excluded in the presence of any of the following: (1) known genetic syndromes
other than PMS (for example, Rett syndrome, fragile-X syndrome, etc.); (2) serious medical illnesses
(chronic renal disease, severe liver disease, cardiovascular disorders, uncontrolled hypertension with systolic
pressure values > 170 mm Hg and diastolic pressure > 100 mm Hg, malignant tumors, HIV infection); (3)
history of acute cerebrovascular disease; (4) history of stomach bleeding or active peptic ulcer; (5)
documented allergies, hypersensitivity or intolerance to one of the excipients of the experimental
compound or comparative product; (6) treatment with anticoagulants. Seizures were not a cause of
exclusion and were categorized as “frequent” if occurring more often than once every 6 months, “rare” if
occurring at a lower frequency, or otherwise “absent”.