Repurposing Mirtazapine in Rett Syndrome: a Multicentric Open Label Phase II Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 54
- 试验地点
- 4
- 主要终点
- Primary Endpoint: Improvement in the rating scale Motor-Behavior Assessment Scale (MBAS).
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 40 Years（Child, Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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).
干预措施: mirtazapine (Drug)
结局指标
主要结局
Primary Endpoint: Improvement in the rating scale Motor-Behavior Assessment Scale (MBAS).
时间窗: From enrollment to the end of treatment at 24 weeks
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.
次要结局
- Secondary Endpoint 7: Improvement in respiratory parameters(From enrollment to the end of treatment at 24 weeks)
- Secondary endpoint 1. Reduced mood and anxiety disorder symptoms(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 1bis: Reduced mood and anxiety disorder symptoms(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 2-a. Improved Vital parameters(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 2-b. Improved Vital parameters(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 2-c. Improved Vital parameters(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 2-d. Improved Vital parameters(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 3-a: Improved Sleep quality(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 3-b: Improved Sleep Quality(From enrollment to the end of treatment at 24 weeks.)
- Secondary Endpoint 3-c: Improved Sleep Quality(From enrollment to the end of treatment at 24 week)
- Secondary Endpoint 3-d: Improved Sleep Quality(From enrollment to the end of treatment at 24 week)
- Secondary Endpoint 3-e: Improved Sleep Quality(From enrollment to the end of treatment at 24 week)
- Secondary Endpoint 3-f: Improved Sleep Quality(From enrollment to the end of treatment at 24 week)
- Secondary Endpoint 3-g: Improved Sleep Quality(From enrollment to the end of treatment at 24 week)
- Secondary Endpoint 3-h: Improved Sleep Quality(From enrollment to the end of treatment at 24 week)
- Secondary Endpoint 3-i: Improved Sleep Quality(From enrollment to the end of treatment at 24 week)
- Secondary Endpoint 3-j: Improved Sleep Quality(From enrollment to the end of treatment at 24 week)
- Secondary Endpoint 4. Regaining of hand control(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 5: Changes in Global severity(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 6: Reduced Rett-specific Severity(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 8: Decrease in caregivers burden(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 9-a: Increased neurotrophic factors(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 9-b: Increased neurotrophic factors(From enrollment to the end of treatment at 24 weeks)
- Secondary Endpoint 9-c: Increased neurotrophic factors(From enrollment to the end of treatment at 24 weeks)
研究者
Enrico Tongiorgi, PhD
Full Professor
University of Trieste