Repurposing Mirtazapine in Rett Syndrome (MirtaRett)

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

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.

Study Overview

• Status: Recruiting
• Conditions: RETT Syndrome With Proven MECP2 Mutation
• Intervention / Treatment: Drug: mirtazapine

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.

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Enrico Tongiorgi, PhD; Phone Number: +39 348 73477322; Email: tongi@units.it

Study Locations

• Italy
  • Genova, Italy, 16147
    • Recruiting
    • Unità di Neuropsichiatria Infantile, IRCCS, Istituto Giannina Gaslini, Genova
    • Contact: Lino Nobili, Prof, MD; Phone Number: 0039 010 5636 2432; Email: neuropsichiatria@gaslini.org
    • Contact: Giulia Prato, MD; Phone Number: 0039 010 56363760; Email: giuliaprato@gaslini.org
    • Sub-Investigator: Ramona Cordani - ramonacordani@gaslini.org, MD
  • Messina, Italy, 98125
    • Recruiting
    • UOC di Neuropsichiatria Infantile, Policlinico Universitario "Gaetano Martino" di Messina, University of Messina. Messina
    • Contact: Gabriella Di Rosa, Prof, MD; Phone Number: 0039 349 7386079; Email: neuropsichiatria.infantile@polime.it
    • Contact: Antonio G Nicotera, MD; Phone Number: 0039 090 2212911; Email: antoniogennaro.nicotera@polime.it
  • Milan, Italy, 20142
    • Recruiting
    • Centro Epilessia - Unità Neurologia Pediatrica, ASST Ospedale Santi Carlo Paolo - Dipartimento Scienze della Salute, Università di Milano
    • Contact: Maria Paola Canevini, Prof. MD; Phone Number: 0039 02 8184.4201; Email: epilessia.hsp@asst-santipaolocarlo.it
    • Contact: Ilaria Viganò, MD; Email: ilaria.vigano@asst-santipaolocarlo.it
    • Principal Investigator: Aglaia Vignoli - aglaia.vignoli@unimi.it, Prof, MD
  • Siena, Italy, 53100
    • Recruiting
    • Unità di Pediatria, Dipartimento della Donna e dei Bambini - Policlinico S. M. alle Scotte. Siena
    • Contact: Salvatore Grosso, Prof, MD; Phone Number: 0039 0577 586547; Email: salvatore.grosso@ao-siena.toscana.it
    • Contact: Claudio De Felice, MD; Phone Number: 0039 347 330.9885; Email: geniente@gmail.com
    • Sub-Investigator: Michele Minerva - michele.minerva@ao-siena.toscana.it, MD
    • Sub-Investigator: Valeria Scandurra - valeria.scandurra@ao-siena.toscana.it, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

• 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.
• 5. Breathing dysfunction (at least one of the following): period apnoea, intermittent hyperventilation, breath holding spells, air swallowing, forced expulsion of air and /or saliva.

• 6. Ten episodes or more/day of breathing dysfunction during wakefulness in the week prior to the screening visit (parents report).

  7. Stable medication regimen for 4 weeks prior to beginning the study (if receiving services - physical, occupational, or speech therapy - subjects must be on a stable regimen of these services for 3 months prior to beginning the study).

• 8. Female patients of childbearing potential must use a highly effective contraceptive method such as combined hormonal contraception (containing estrogen and progestin) associated with ovulation suppression (oral, intravaginal, transdermal); progestin-only hormonal contraception associated with ovulation suppression (oral, injectable, implantable); intrauterine device; hormone-releasing intrauterine system. Sexual abstinence is considered a highly effective contraceptive method if it aligns with the individual's usual lifestyle. Female patients of childbearing potential are to use adequate contraception as recommended by their Health Care Provider.
• 9. Written consent signed by parent/legal guardian/representative prior to screening visit
• 10. Patient is cooperative, willing to complete the study, and capable of doing so with assistance of a caregiver.
• 11. Caregiver is able to understand the instructions and fully participate.

EXCLUSION CRITERIA

Participants are excluded from the study if any of the following criteria apply:

• 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
• Surgery planned during the study.
• Severe diabetes mellitus (hyperglycaemia with values above 250/300 mg/dL);
• Pregnancy, breastfeeding.
• Evidence of clinically significant malnutrition with BMI (or BMI) (kg/m2) <
• Patients who manifested prior suicidal ideation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rett syndrome patients with MECP2 mutation and 5-40 years of age; Subjects included in the study are female patients with a diagnosis of RTT, confirmed by mutation of the MECP2 gene, and who meet the inclusion/exclusion criteria of the study. The total number of participating patients is 54, aged between 5 and 40 years, divided into three groups of 18 patients each (5-10 years, 11-17 years and 18-40 years). The study medication mirtazapine oral solution (MTZ) will be given once daily at bedtime. During the first 14 days of the treatment period, MTZ 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).

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).; Other Names: MirtaPil oral solution; Remeron oral solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From enrollment to the end of treatment at 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary endpoint 1. Reduced mood and anxiety disorder symptoms	1. The drug will be considered effective if the treatment reduces the overall Anxiety, Depression, Mood Scale (ADAMS) score (maximum score=84) by at least 10.6 points (12.5%) compared to the pre-treatment value.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 1bis: Reduced mood and anxiety disorder symptoms	1bis. The drug will be considered effective if is will reduce the overall Rett Syndrome Behaviour questionnaire (RSBQ) score by at least 11.25 points (12.5%) compared to the pre-treatment value.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 2-a. Improved Vital parameters	2-a. The drug will be considered effective if the treatment improves the measurements of Respiratory Rate (RR), obtained from the medical devices for remote sensing (Youcare Smart T-shirt) by at least 20% compared to the pre-treatment value.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 2-b. Improved Vital parameters	2-b. The drug will be considered effective if the treatment improves the measurements of Heart Rate (HR), obtained from the medical devices for remote sensing (Youcare Smart T-shirt) by at least 20% compared to the pre-treatment value.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 2-c. Improved Vital parameters	2-c. The drug will be considered effective if the treatment improves the measurements of Variation of Heart Rate (VHR), obtained from the medical devices for remote sensing (Youcare Smart T-shirt) by at least 20% compared to the pre-treatment value.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 2-d. Improved Vital parameters	2-d. The drug will be considered effective if the treatment improves the measurements of Skin Temperature (SkT) obtained from the medical devices for remote sensing (Youcare Smart T-shirt) by at least 20% compared to the pre-treatment value.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 3-a: Improved Sleep quality	3-a. The drug will be considered efficacious if the Sleep Disturbances Scale for Children (SDSC) scores will be reduced by at least 20% compared to the pre-treatment value.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 3-b: Improved Sleep Quality	3-b: The drug will be considered efficacious if the estimated time in bed (eTIB) measured by wrist actigraphy will be increasing by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 weeks.
Secondary Endpoint 3-c: Improved Sleep Quality	Description: 3-c: The drug will be considered efficacious if the estimated total sleep time (eTST), measured by wrist actigraphy, will be increasing by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 week
Secondary Endpoint 3-d: Improved Sleep Quality	Description: 3-d: The drug will be considered efficacious if the estimated sleep latency (eSOL), measured by wrist actigraphy, will be decreased by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 week
Secondary Endpoint 3-e: Improved Sleep Quality	Description: 3-e: The drug will be considered efficacious if the estimated sleep efficiency (eSE), measured by wrist actigraphy, will be increasing by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 week
Secondary Endpoint 3-f: Improved Sleep Quality	Description: 3-f: The drug will be considered efficacious if the estimated wake time after sleep onset (eWASO), measured by wrist actigraphy, will be decreasing by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 week
Secondary Endpoint 3-g: Improved Sleep Quality	Description: 3-g: The drug will be considered efficacious if the number of estimated awakenings (eAwk), measured by wrist actigraphy, will be decreasing by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 week
Secondary Endpoint 3-h: Improved Sleep Quality	Description: 3-h: The drug will be considered efficacious if the estimated sleep motor activity (eSMA), measured by wrist actigraphy, will be decreasing by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 week
Secondary Endpoint 3-i: Improved Sleep Quality	Description: 3-i: The drug will be considered efficacious if the num. ber of estimated naps (eNaps), num. ber of estimated naps (eNaps), will be decreasing by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 week
Secondary Endpoint 3-j: Improved Sleep Quality	Description: 3-j: The drug will be considered efficacious if the mean duration of the longest estimated nap (eNapD), measured by wrist actigraphy, will be increasing by 20% over the pre-treatment score.	From enrollment to the end of treatment at 24 week
Secondary Endpoint 4. Regaining of hand control	4. The drug will be considered effective if the Purposeful Hand Function scale (PHF) score increases at least 2 points above the pre-treatment score	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 5: Changes in Global severity	5. Drug efficacy will be determined using the Clinical Global Impression of Change (CGI-C) scale, which consists of a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), while 4 indicates no change. Decreased score of at least 1 point compared to the pre-treatment value is expected upon successful treatment.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 6: Reduced Rett-specific Severity	6. Drug efficacy will be determined using the Rett Syndrome Severity Scale (RCSS), which consists of 13 items providing a rating of core symptoms of RTT on a Likert scale of either 0 to 4 or 0 to 5 with a maximum total score of 58. Drug will be considered efficacious if RCSS scores will result decreased by at least 3%, i.e. 2 points compared to the pre-treatment value.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 7: Improvement in respiratory parameters	7. Drug efficacy will be determined by a reduction in the number of apnoeas-hypopnoeas by at least 5 events/hour.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 8: Decrease in caregivers burden	8. The drug will be considered beneficial if the Parenting Stress Index (PSI-SF) specifically adjusted for Italian parents of Rett Syndrome girls, will show at least a 20% reduction of the pre-treatment Parenting Stress Index (PSI-SF).	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 9-a: Increased neurotrophic factors	9-a. Drug efficacy is targeted with 20% increase compared to the pre-treatment value of the serum levels of the biomarker BDNF measured in pg/ml.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 9-b: Increased neurotrophic factors	9-b. Drug efficacy is targeted with 20% increase compared to the pre-treatment value of the serum levels of the biomarker GDNF measured in pg/ml.	From enrollment to the end of treatment at 24 weeks
Secondary Endpoint 9-c: Increased neurotrophic factors	9-c. Drug efficacy is targeted with 20% increase compared to the pre-treatment value of the serum levels of the biomarker PDGF. measured in pg/ml.	From enrollment to the end of treatment at 24 weeks

Collaborators and Investigators

• Sponsor: University of Trieste
• Collaborators: Policlinico G . Martino, Messina Italy; IRCSS Gianna Gaslini, Genova, Italy; Policlinico S.Maria alle Scotte, Siena, Italy; ASST Ospedale Santi Paolo e Carlo, Milano, Italy
• Investigators: Principal Investigator: Enrico Tongiorgi, PhD, University of Trieste, Trieste - Italy

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2025
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: July 29, 2025
• First Submitted That Met QC Criteria: February 17, 2026
• First Posted (Actual): February 24, 2026

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: mirtazapine; sleep disorder; cognitive impairment; antidepressant; parent stress; motor dysfunction; cognitive disability
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neurologic Manifestations; Cognitive Dysfunction; Sleep Wake Disorders; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Mirtazapine
• Other Study ID Numbers: CTIS ID: 28366; 2024-515411-21-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The Clinical Trial will be carried out in Italy only. Individual clinical data are therefore strictly protected by the Italian laws and regulations and cannot be shared in accordance withthe "Regolamento Generale sulla Protezione dei Dati (GDPR)" together with the "Codice Privacy" (Decreto Legislativo 196/2003), and its modifications under the "Decreto Legislativo 101/2018".

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No