<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03292458</url>
  </required_header>
  <id_info>
    <org_study_id>2019P001680</org_study_id>
    <secondary_id>R01DC012545</secondary_id>
    <nct_id>NCT03292458</nct_id>
  </id_info>
  <brief_title>Sodium Oxybate in Spasmodic Dysphonia and Voice Tremor</brief_title>
  <official_title>Central Mechanisms and Treatment Response of Sodium Oxybate in Spasmodic Dysphonia and Voice Tremor</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kristina Simonyan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Deafness and Other Communication Disorders (NIDCD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts Eye and Ear Infirmary</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Using a comprehensive approach of clinico-behavioral testing, neuroimaging and&#xD;
      pharmacogenetics, the researchers will examine the clinical effects of sodium oxybate and the&#xD;
      matched placebo on voice symptoms in spasmodic dysphonia and voice tremor.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Spasmodic dysphonia (SD), or laryngeal dystonia, is a chronic debilitating condition that&#xD;
      selectively affects speech production due to involuntary spasms in the laryngeal muscles. SD&#xD;
      often extends beyond the impairment of vocal communication causing significant occupational&#xD;
      disability and life-long social isolation. SD becomes even more incapacitating when it is&#xD;
      associated with dystonic voice tremor (VT), which is present in about 1/3 of SD patients and&#xD;
      is characterized by the inability to sustain a vowel for more than a few seconds. Current&#xD;
      treatment of these disorders is limited to the temporary management of voice symptoms with&#xD;
      repeated injections of botulinum toxin into the laryngeal muscles. These injections, however,&#xD;
      are not fully effective in all SD patients and even less so in combined SD and VT cases.&#xD;
      There is, therefore, a critical need to identify alternative therapeutic options that&#xD;
      specifically target the pathophysiology of these disorders. On the other hand, the design and&#xD;
      the use of such novel therapeutic approaches will be largely unattainable if their central&#xD;
      mechanisms of action remain unknown. The objective of this study is to elucidate the primary&#xD;
      determinants of clinical response to a novel oral medication, sodium oxybate (Xyrem®), in&#xD;
      alcohol-responsive SD and VT patients. Using a comprehensive approach of clinico-behavioral&#xD;
      testing, neuroimaging and pharmacogenetics, we aim to determine the clinical response of SD&#xD;
      and VT symptoms to sodium oxybate and identify the primary markers of its clinical benefits.&#xD;
      This study will use a controlled experimental design that focuses on detailed&#xD;
      characterization of primary effects of a novel oral medication, sodium oxybate, for treatment&#xD;
      of SD and VT symptoms.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 22, 2018</start_date>
  <completion_date type="Anticipated">August 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2023</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Symptom improvement following sodium oxybate vs. placebo intake</measure>
    <time_frame>5 years</time_frame>
    <description>Perceptual evaluation of voice symptoms before and after drug and placebo intake</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Attenuation of brain functional abnormalities following sodium oxybate vs. placebo</measure>
    <time_frame>5 years</time_frame>
    <description>Statistical examination of brain functional activity before and after drug and placebo intake</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">140</enrollment>
  <condition>Spasmodic Dysphonia</condition>
  <condition>Voice Tremor</condition>
  <arm_group>
    <arm_group_label>Clinical response to sodium oxybate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Primary markers of clinical response</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sodium Oxybate</intervention_name>
    <description>Alcohol challenge test and oral administration of a single dose of sodium oxybate and the matching placebo.</description>
    <arm_group_label>Clinical response to sodium oxybate</arm_group_label>
    <arm_group_label>Primary markers of clinical response</arm_group_label>
    <other_name>Placebo</other_name>
    <other_name>Alcohol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with SD and combined SD and VT will have a clinically documented adductor or&#xD;
             abductor form of disorder, either with or without positive effects of alcohol on their&#xD;
             voice symptoms;&#xD;
&#xD;
          2. Healthy controls will be healthy volunteers with a negative history of laryngeal,&#xD;
             neurological, or psychiatric problems (existing neuroimaging data will be used);&#xD;
&#xD;
          3. Age from 21 to 80 years.&#xD;
&#xD;
          4. Native English speakers.&#xD;
&#xD;
          5. Right-handedness (based on Edinburgh Handedness Inventory).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Subjects who are incapable of giving an informed consent will be excluded from the&#xD;
             study.&#xD;
&#xD;
          2. Pregnant and breastfeeding women until a time when they are no longer pregnant or&#xD;
             breastfeeding will be excluded from the study. All patients of childbearing potential&#xD;
             will be required to agree to use a reliable method of contraception prior to and&#xD;
             during the study. The method of contraception will be documented in the patient's&#xD;
             research chart. All women of childbearing potential will undergo a urine pregnancy&#xD;
             test, which must be negative for study participation.&#xD;
&#xD;
          3. All patients with a past or present history of the following conditions will be&#xD;
             excluded from the study;&#xD;
&#xD;
               1. Except for SD and dystonic VT, any neurological disorders, such as stroke,&#xD;
                  movement disorders, brain tumors, traumatic brain injury with loss of&#xD;
                  consciousness, ataxias, myopathies, myasthenia gravis, demyelinating diseases,&#xD;
                  alcoholism, drug dependence. Patients with tremor affecting other body parts will&#xD;
                  be excluded from the study. All patients who have dystonic movements in the body&#xD;
                  regions other than the larynx will be excluded from the study. This will allow&#xD;
                  maintaining the homogenous patient population and evaluating central drug effects&#xD;
                  without confounding by the presence of other neurological conditions.&#xD;
&#xD;
               2. Any psychiatric problems, such as schizophrenia, major and/or bipolar depression,&#xD;
                  obsessive-compulsive disorder, will be excluded to maintain the homogenous&#xD;
                  patient population and allow for the evaluation of central drug effect without&#xD;
                  confounding by the presence of psychiatric conditions.&#xD;
&#xD;
               3. Any laryngeal problems, such as vocal fold paralysis, paresis, carcinoma, chronic&#xD;
                  laryngitis, will be excluded from the study.&#xD;
&#xD;
               4. Patients with a known past or present history of grade 2 or higher hepatic and&#xD;
                  renal dysfunction according to the NCI criteria will be excluded.&#xD;
&#xD;
               5. Patients with a known past or present history of moderate to severe congestive&#xD;
                  heart failure will be excluded.&#xD;
&#xD;
               6. Patients with a known past or present history of cognitive impairment and active&#xD;
                  suicidal ideations will be excluded.&#xD;
&#xD;
          4. Patients who are not symptomatic due to treatment with botulinum toxin injections into&#xD;
             the laryngeal muscles will be excluded from the study until the time when they are&#xD;
             fully symptomatic. The duration of positive effects of botulinum toxin vary from&#xD;
             patient to patient, lasting on average 3-4 months. All patients will be evaluated to&#xD;
             ensure that they are fully symptomatic prior to the entering the study.&#xD;
&#xD;
          5. To avoid the possibility of confounding effects of drugs acting upon the central&#xD;
             nervous system, all patients will be questioned about any prescribed or&#xD;
             over-the-counter medications as part of their initial intake screening. Those patients&#xD;
             who receive medication(s) affecting the central nervous system (except for sodium&#xD;
             oxybate) will be excluded from the study.&#xD;
&#xD;
          6. Patients will be asked whether they have undergone any head and neck surgeries,&#xD;
             particularly any brain surgery and laryngeal surgeries, such as thyroplasty, laryngeal&#xD;
             denervation, and selective laryngeal adductor denervation-reinnervation. Because both&#xD;
             brain and laryngeal surgery may potentially lead to the brain structure and function&#xD;
             re-organization, all subjects with a history of brain and/or laryngeal surgery will be&#xD;
             excluded from the study.&#xD;
&#xD;
          7. Patients who have tattoos, ferromagnetic objects in their bodies (e.g., implanted&#xD;
             stimulators, surgical clips, prosthesis, artificial heart valve, etc.) that are not&#xD;
             MRI comparable and/or cannot be removed for the purpose of MRI study participation&#xD;
             will be excluded from the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kristina Simonyan, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts Eye and Ear Infirmary</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts Eye and Ear Infirmary</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://projectreporter.nih.gov/project_info_description.cfm?aid=9311894&amp;icde=36164457&amp;ddparam=&amp;ddvalue=&amp;ddsub=&amp;cr=3&amp;csb=default&amp;cs=ASC&amp;pball=</url>
    <description>NIH grant description</description>
  </link>
  <reference>
    <citation>Simonyan K, Frucht SJ. Long-term Effect of Sodium Oxybate (Xyrem(R)) in Spasmodic Dysphonia with Vocal Tremor. Tremor Other Hyperkinet Mov (N Y). 2013 Dec 9;3:tre-03-206-4731-1. doi: 10.7916/D8CJ8C5S. eCollection 2013.</citation>
    <PMID>24386608</PMID>
  </reference>
  <reference>
    <citation>Rumbach AF, Blitzer A, Frucht SJ, Simonyan K. An open-label study of sodium oxybate in Spasmodic dysphonia. Laryngoscope. 2017 Jun;127(6):1402-1407. doi: 10.1002/lary.26381. Epub 2016 Nov 3.</citation>
    <PMID>27808415</PMID>
  </reference>
  <reference>
    <citation>Battistella G, Fuertinger S, Fleysher L, Ozelius LJ, Simonyan K. Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia. Eur J Neurol. 2016 Oct;23(10):1517-27. doi: 10.1111/ene.13067. Epub 2016 Jun 27.</citation>
    <PMID>27346568</PMID>
  </reference>
  <reference>
    <citation>Kirke DN, Battistella G, Kumar V, Rubien-Thomas E, Choy M, Rumbach A, Simonyan K. Neural correlates of dystonic tremor: a multimodal study of voice tremor in spasmodic dysphonia. Brain Imaging Behav. 2017 Feb;11(1):166-175. doi: 10.1007/s11682-016-9513-x.</citation>
    <PMID>26843004</PMID>
  </reference>
  <reference>
    <citation>Kirke DN, Frucht SJ, Simonyan K. Alcohol responsiveness in laryngeal dystonia: a survey study. J Neurol. 2015 Jun;262(6):1548-56. doi: 10.1007/s00415-015-7751-2. Epub 2015 May 1.</citation>
    <PMID>25929664</PMID>
  </reference>
  <reference>
    <citation>Simonyan K, Ludlow CL. Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study. Cereb Cortex. 2010 Nov;20(11):2749-59. doi: 10.1093/cercor/bhq023. Epub 2010 Mar 1.</citation>
    <PMID>20194686</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 20, 2017</study_first_submitted>
  <study_first_submitted_qc>September 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <last_update_submitted>March 14, 2023</last_update_submitted>
  <last_update_submitted_qc>March 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts Eye and Ear Infirmary</investigator_affiliation>
    <investigator_full_name>Kristina Simonyan</investigator_full_name>
    <investigator_title>Associate Professor of Otolaryngology - Head &amp; Neck Surgery, Director of Laryngology Research</investigator_title>
  </responsible_party>
  <keyword>spasmodic dysphonia</keyword>
  <keyword>laryngeal dystonia</keyword>
  <keyword>functional MRI</keyword>
  <keyword>Xyrem</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dysphonia</mesh_term>
    <mesh_term>Hoarseness</mesh_term>
    <mesh_term>Tremor</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sodium Oxybate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03292458
org study id: 2019P001680
secondary id: R01DC012545
nct id: NCT03292458
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Symptom improvement following sodium oxybate vs. placebo intake
time frame: 5 years
description: Perceptual evaluation of voice symptoms before and after drug and placebo intake
measure: Attenuation of brain functional abnormalities following sodium oxybate vs. placebo
time frame: 5 years
description: Statistical examination of brain functional activity before and after drug and placebo intake
arm group label: Clinical response to sodium oxybate
arm group type: Experimental
description: 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.
arm group label: Primary markers of clinical response
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Sodium Oxybate
description: Alcohol challenge test and oral administration of a single dose of sodium oxybate and the matching placebo.
arm group label: Clinical response to sodium oxybate
arm group label: Primary markers of clinical response
other name: Placebo
other name: Alcohol
criteria: 
gender: All
minimum age: 21 Years
maximum age: 80 Years
healthy volunteers: No
last name: Kristina Simonyan, MD, PhD
role: Principal Investigator
affiliation: Massachusetts Eye and Ear Infirmary
facility: 
country: United States
url: https://projectreporter.nih.gov/project_info_description.cfm?aid=9311894&icde=36164457&ddparam=&ddvalue=&ddsub=&cr=3&csb=default&cs=ASC&pball=
description: NIH grant description
citation: Simonyan K, Frucht SJ. Long-term Effect of Sodium Oxybate (Xyrem(R)) in Spasmodic Dysphonia with Vocal Tremor. Tremor Other Hyperkinet Mov (N Y). 2013 Dec 9;3:tre-03-206-4731-1. doi: 10.7916/D8CJ8C5S. eCollection 2013.
PMID: 24386608
citation: Rumbach AF, Blitzer A, Frucht SJ, Simonyan K. An open-label study of sodium oxybate in Spasmodic dysphonia. Laryngoscope. 2017 Jun;127(6):1402-1407. doi: 10.1002/lary.26381. Epub 2016 Nov 3.
PMID: 27808415
citation: Battistella G, Fuertinger S, Fleysher L, Ozelius LJ, Simonyan K. Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia. Eur J Neurol. 2016 Oct;23(10):1517-27. doi: 10.1111/ene.13067. Epub 2016 Jun 27.
PMID: 27346568
citation: Kirke DN, Battistella G, Kumar V, Rubien-Thomas E, Choy M, Rumbach A, Simonyan K. Neural correlates of dystonic tremor: a multimodal study of voice tremor in spasmodic dysphonia. Brain Imaging Behav. 2017 Feb;11(1):166-175. doi: 10.1007/s11682-016-9513-x.
PMID: 26843004
citation: Kirke DN, Frucht SJ, Simonyan K. Alcohol responsiveness in laryngeal dystonia: a survey study. J Neurol. 2015 Jun;262(6):1548-56. doi: 10.1007/s00415-015-7751-2. Epub 2015 May 1.
PMID: 25929664
citation: Simonyan K, Ludlow CL. Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study. Cereb Cortex. 2010 Nov;20(11):2749-59. doi: 10.1093/cercor/bhq023. Epub 2010 Mar 1.
PMID: 20194686
responsible party type: Sponsor-Investigator
investigator affiliation: Massachusetts Eye and Ear Infirmary
investigator full name: Kristina Simonyan
investigator title: Associate Professor of Otolaryngology - Head & Neck Surgery, Director of Laryngology Research
mesh term: Dysphonia
mesh term: Hoarseness
mesh term: Tremor
mesh term: Sodium Oxybate
sharing ipd: No