NCT07430046

Repurposing Mirtazapine in Rett Syndrome

Repurposing Mirtazapine in Rett Syndrome: a Multicentric Open Label Phase II Study

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 54 (estimated)
• Sponsor: University of Trieste · Academic / Other
• Sex: Female
• Age: 5 Years – 40 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

Rett Syndrome (RTT) is a rare neurodevelopmental disease caused by a genetic mutation in the MECP2 gene located on the X chromosome and therefore particularly affects female subjects. It is characterised by an altered development of the nervous system leading to learning problems and delayed development of motor and cognitive skills. RTT is a progressive degenerative condition and there may be a worsening over time of the typical symptoms, including motor and cognitive impairments, loss of speech, repetitive hand movements, breathing abnormalities, gastrointestinal issues, mood disturbances, seizures and sleep problems. Given the reduced monoamine levels (serotonin, noradrenaline, dopamine) found in RTT, antidepressants -which modulates these neurotransmitters- may alleviate symptoms. Accordingly, mirtazapine (MTZ) was investigated, a noradrenergic and specific serotonergic antidepressant (NaSSA) for its potential benefits in RTT. Preclinical studies in MeCP2-mutant mice showed that MTZ improved respiratory, motor, and neurological function. In early human trials in RTT adults treated with MTZ for up to 5 years, reported benefits in sleep, mood, and social interactions, prompting this study in paediatric and young adult populations. Therefore, considering these preliminary results in humans, the hypothesis was put forward that MTZ could be beneficial also in RTT children. MirtaRett is a multicenter, open-label, single-arm, phase II trial that will enroll 54 female RTT patients (ages 5-40), divided into three groups of 18 patients each (5-10 years, 11-17 years and 18-40 years). The overall goal of MirtaRett is to evaluate safety and efficacy of MTZ in the treatment of mood, sleep quality, motor symptoms in particular hand control, in Rett syndrome children and adults. Other areas that will be investigated include autonomic functions, behavior, caregiver burden and overall clinical severity along with neuroplasticity and metabolism biomarkers. Antidepressant drugs are typically administered using a scalar dosing approach, starting with low doses and gradually increasing them. Thus, patients will receive escalating doses of an oral solution of mirtazapine: 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 symptom changes will be monitored over 10 months (3-month screening, 6-month treatment, 1-month follow-up). The study will be conducted across four Italian RTT-specialized hospitals, led by the University of Trieste. * Coordinating centre - Department of Life Sciences, University of Trieste. Trieste, Italy. * Partner 1. Epilepsy Center - Unit of Child Neurology, Hospital Santi Carlo Paolo and Department of Health Sciences, University of Milan, Milan, Italy. * Partner 2. Unit of Child Neurology, Giannina Gaslini Institute, Genova, Italy. * Partner 3. Pediatric Unit, Department of Woman and Child - Polyclinic Santa Maria alle Scotte. Siena, Italy. * Partner 4. Department of Human Pathology in Adults and Children "Gaetano Barresi", University Polyclinic G. Martino, University of Messina. Messina, Italy.

Conditions

• RETT Syndrome With Proven MECP2 Mutation

Interventions

Type	Name	Description
DRUG	mirtazapine	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).

Timeline

• Start date: 2025-07-09
• Primary completion: 2026-06-30
• Completion: 2026-12-31
• First posted: 2026-02-24
• Last updated: 2026-02-24

Locations

4 sites across 1 country: Italy