Repurposing Mirtazapine in Rett Syndrome

ConditionRETT Syndrome With Proven MECP2 Mutation

Trial statusRecruiting

Trial phasePhase 2

Trial typeInterventional

Biological sexFemale

Age5-40

SponsorUniversity of Trieste

About this trial

Rett Syndrome (RTT) is a rare neurodevelopmental disorder caused by an MECP2 gene mutation on the X chromosome, primarily affecting females. It causes progressive motor and cognitive decline, loss of speech, repetitive hand movements, breathing issues, seizures, and sleep problems. Given RTT's association with reduced monoamine levels, antidepressants like mirtazapine (MTZ) may help.Preclinical studies in MeCP2-mutant mice and early adult RTT trials showed that MTZ improved respiratory, motor, and neurological function, sleep, and mood, prompting this pediatric and young adult study. The MirtaRett trial is a multicenter, open-label, single-arm, phase II study enrolling 54 female RTT patients (ages 5-40), divided into groups of 18 (5-10, 11-17, 18-40 years). It aims to evaluate MTZ's safety and efficacy for mood, sleep, and motor symptoms, particularly hand control. Other ares of investigation include autonomic function, behavior, caregiver burden, clinical severity, and neuronal plasticity and metabolic biomarkers. Patients will receive escalating doses of MTZ oral solution: initial low doses (3.75-15 mg/day) for two weeks, followed by optimal doses (7.5-30 mg/day) for six months. Safety, tolerability, and symptoms will be monitored over 10 months (3-month screening, 6-month treatment, 1-month follow-up). The study is conducted at four Italian RTT-specialized hospitals, led by the University of Trieste. Partner sites are in Italy, specifically at the hospitals in Milan, Genova, Siena, and Messina.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

1. Female aged 5 to 39 years inclusive, at the time of signing the informed consent.

2. Girls of childbearing age negative to pregnancy test;

3. Body weight > 10 kg. and within the expected range for RTT, based on age and height.

4. Diagnosis of RTT based on consensus clinical criteria (Neul, 2010) and a confirmed mutation in MECP2 gene.

Disqualifiers

Patient is participating to another investigational clinical trial.

Hypersensitivity to MTZ or any of the other ingredients of Mirtapil®.

Clinically significant (as determined by the investigator) cardiovascular, respiratory, gastrointestinal, renal, hepatic, haematological pathologies or other pathologies, in addition to those directly related to RTT. In particular, patients with the following parameters will be excluded: leucocyte count is < 4000/mm2; neutrophil count is < 2000/mm3; hyponatremia (< 125 mmol/L); renal dysfunction (creatinine > 2 X ULN), hepatic dysfunction (AST, ALT, bilirubin > 2 X ULN); or if severe diabetes mellitus is present.

QTcF interval on the ECG greater than 450 msec

Trial design

Design model

Single group

Treatments tested in this trial

mirtazapine
Drug
Study medication (3.75 mg, 7.5 mg, 15 mg, 30 mg of MTZ oral solution) will be given once daily at bedtime. During the first 14 days of the treatment period, the oral solution of the active drug at Dose Level 1 will be used to achieve the planned target daily dose, according to age (3.75 mg for 5-10 yrs, 7.5 mg for 11-17 yrs and 15 mg \> 18 yrs, from day 1 to 14). From Day 15 to the end of week 24, Dose Level 2 will be achieved: 7.5 mg for 5-10 yrs, 15 mg for 11-17 yrs and 30 mg for \> 18 yrs).

Treatment groups

54 Participants

are divided into 1 treatment group

Group A: Rett syndrome patients with MECP2 mutation and 5-40 years of ageExperimental treatment 1 intervention

Trial outcomes

Primary outcomes

Primary Endpoint: Improvement in the rating scale Motor-Behavior Assessment Scale (MBAS).

The drug will be considered effective if the treatment decreases the Motor-Behavior Assessment Scale (MBAS) score (maximum score=68) by at least 8.5 points (12.5%) compared to the pre-treatment value.

Time frame