Central Mechanisms and Treatment Response of Sodium Oxybate in Spasmodic Dysphonia and Voice Tremor
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 117
- 试验地点
- 1
- 主要终点
- Symptom Severity
研究概览
简要总结
Using a comprehensive approach of clinico-behavioral testing, neuroimaging and pharmacogenetics, the researchers will examine the clinical effects of sodium oxybate and the matched placebo on voice symptoms in spasmodic dysphonia and voice tremor.
详细描述
Spasmodic dysphonia (SD), or laryngeal dystonia, is a chronic debilitating condition that selectively affects speech production due to involuntary spasms in the laryngeal muscles. SD often extends beyond the impairment of vocal communication causing significant occupational disability and life-long social isolation. SD becomes even more incapacitating when it is associated with dystonic voice tremor (VT), which is present in about 1/3 of SD patients and is characterized by the inability to sustain a vowel for more than a few seconds. Current treatment of these disorders is limited to the temporary management of voice symptoms with repeated injections of botulinum toxin into the laryngeal muscles. These injections, however, are not fully effective in all SD patients and even less so in combined SD and VT cases. There is, therefore, a critical need to identify alternative therapeutic options that specifically target the pathophysiology of these disorders. On the other hand, the design and the use of such novel therapeutic approaches will be largely unattainable if their central mechanisms of action remain unknown. The objective of this study is to elucidate the primary determinants of clinical response to a novel oral medication, sodium oxybate (Xyrem®), in alcohol-responsive SD and VT patients. Using a comprehensive approach of clinico-behavioral testing, neuroimaging and pharmacogenetics, we aim to determine the clinical response of SD and VT symptoms to sodium oxybate and identify the primary markers of its clinical benefits. This study will use a controlled experimental design that focuses on detailed characterization of primary effects of a novel oral medication, sodium oxybate, for treatment of SD and VT symptoms.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 21 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with SD and combined SD and VT will have a clinically documented adductor or abductor form of disorder, either with or without positive effects of alcohol on their voice symptoms;
- •Healthy controls will be healthy volunteers with a negative history of laryngeal, neurological, or psychiatric problems (existing neuroimaging data will be used);
- •Age from 21 to 80 years.
- •Native English speakers.
- •Right-handedness (based on Edinburgh Handedness Inventory).
排除标准
- •Subjects who are incapable of giving an informed consent will be excluded from the study.
- •Pregnant and breastfeeding women until a time when they are no longer pregnant or breastfeeding will be excluded from the study. All patients of childbearing potential will be required to agree to use a reliable method of contraception prior to and during the study. The method of contraception will be documented in the patient's research chart. All women of childbearing potential will undergo a urine pregnancy test, which must be negative for study participation.
- •All patients with a past or present history of the following conditions will be excluded from the study;
- •Except for SD and dystonic VT, any neurological disorders, such as stroke, movement disorders, brain tumors, traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia gravis, demyelinating diseases, alcoholism, drug dependence. Patients with tremor affecting other body parts will be excluded from the study. All patients who have dystonic movements in the body regions other than the larynx will be excluded from the study. This will allow maintaining the homogenous patient population and evaluating central drug effects without confounding by the presence of other neurological conditions.
- •Any psychiatric problems, such as schizophrenia, major and/or bipolar depression, obsessive-compulsive disorder, will be excluded to maintain the homogenous patient population and allow for the evaluation of central drug effect without confounding by the presence of psychiatric conditions.
- •Any laryngeal problems, such as vocal fold paralysis, paresis, carcinoma, chronic laryngitis, will be excluded from the study.
- •Patients with a known past or present history of grade 2 or higher hepatic and renal dysfunction according to the NCI criteria will be excluded.
- •Patients with a known past or present history of moderate to severe congestive heart failure will be excluded.
- •Patients with a known past or present history of cognitive impairment and active suicidal ideations will be excluded.
- •Patients who are not symptomatic due to treatment with botulinum toxin injections into the laryngeal muscles will be excluded from the study until the time when they are fully symptomatic. The duration of positive effects of botulinum toxin vary from patient to patient, lasting on average 3-4 months. All patients will be evaluated to ensure that they are fully symptomatic prior to the entering the study.
- •To avoid the possibility of confounding effects of drugs acting upon the central nervous system, all patients will be questioned about any prescribed or over-the-counter medications as part of their initial intake screening. Those patients who receive medication(s) affecting the central nervous system (except for sodium oxybate) will be excluded from the study.
- •Patients will be asked whether they have undergone any head and neck surgeries, particularly any brain surgery and laryngeal surgeries, such as thyroplasty, laryngeal denervation, and selective laryngeal adductor denervation-reinnervation. Because both brain and laryngeal surgery may potentially lead to the brain structure and function re-organization, all subjects with a history of brain and/or laryngeal surgery will be excluded from the study.
- •Patients who have tattoos, ferromagnetic objects in their bodies (e.g., implanted stimulators, surgical clips, prosthesis, artificial heart valve, etc.) that are not MRI comparable and/or cannot be removed for the purpose of MRI study participation will be excluded from the study.
研究组 & 干预措施
Clinical response to sodium oxybate
In contrast to placebo but similar to alcohol, sodium oxybate is expected to be most effective in reducing voice symptoms in alcohol-responsive SD and VT.
干预措施: Sodium Oxybate (Drug)
Central markers of clinical response
The clinical outcome is expected to be determined by selective modulation of functional abnormalities in the brain regions controlling speech sensorimotor processing and integration in association with underlying gene variants.
干预措施: Sodium Oxybate (Drug)
结局指标
主要结局
Symptom Severity
时间窗: 40 min after drug or placebo administration
A combined clinician-objective and patient-subjective change in visual analog scale (min-max 0-100, a higher score is the worse outcome) score of symptom severity before and after drug vs. placebo intake. For analysis, patients in groups (1) Alcohol-responsive (EtOH+) Laryngeal Dystonia and (2) Alcohol-responsive (EtOH+) Laryngeal Dystonia with Dystonic Tremor of Voice were combined into the overall EtOH+ group. For analysis, patients in groups (3) Alcohol-non-responsive (EtOH-) Laryngeal Dystonia and (4) Alcohol-non-responsive (EtOH-) Laryngeal Dystonia with Dystonic Tremor of Voice were combined into the overall EtOH- group.
Minimum Treatment Efficacy
时间窗: 40 min after drug or placebo administration
Pre-specified to analysis based only on alcohol responsiveness (EtOH+). A combined clinician-objective and patient-subjective change in visual analog scale score (min-max 0-100, a higher score is the worse outcome) of symptom severity in EtOH+ patients.
次要结局
- Treatment Efficacy Dependent on LD Clinical Type(40 min after drug or placebo administration)
- Length of Treatment Efficacy(40 min to 5 hours after drug or placebo administration)
- Relationship Between Alcohol-responsiveness of Symptoms and Drug-induced Symptom Improvement(40 min after drug or placebo administration)
- Relationship Between Symptom Severity Change and Dystonia Clinical Characteristics(40 min after drug or placebo administration)
研究者
Kristina Simonyan
Professor of Otolaryngology - Head & Neck Surgery, Director of Laryngology Research
Massachusetts Eye and Ear Infirmary