<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/NCT03033355</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00010110</org_study_id>
    <nct_id>NCT03033355</nct_id>
  </id_info>
  <brief_title>Central Nervous System Changes Following BotulinumtoxinA Injection in the Bladder</brief_title>
  <official_title>A Prospective Study of Higher Neural Control Changes Following Intradetrusor Injection of BotulinumtoxinA in Patients With Multiple Sclerosis and Lower Urinary Tract Symptoms.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rose Khavari, M.D.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Methodist Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>The Methodist Hospital Research Institute</source>
  <oversight_info>
    <has_dmc>No</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>
      The purpose of this prospective research study is to evaluate higher neural changes following&#xD;
      intradetrusor injection of Botulinum toxin-A (BTX-A) in patients with Multiple Sclerosis&#xD;
      (MS). Concurrent Urodynamic and Functional Magnetic Resonance (fMRI) data will be recorded&#xD;
      pre- and post- intravesical injection of BTX-A in patients with Multiple Sclerosis (MS) and&#xD;
      neurogenic detrusor activity (NDO).&#xD;
&#xD;
      Other objectives are to evaluate the role of urinary biomarkers such as brain-derived&#xD;
      neurotropic factor (BDNF) and nerve growth factor (NGF) associated with bladder overactivity&#xD;
      and, to determine whether the common validated urgency questionnaires correlate with fMRI&#xD;
      findings and urinary biomarker concentration pre- and post- BTX-A injection in patients with&#xD;
      MS and NDO.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Multiple Sclerosis is a severe debilitating disease that affects patient's quality of life.&#xD;
      Up to 90% of patients with MS will develop lower urinary tract dysfunction within the first&#xD;
      18 years of the disease. Lower urinary tract symptoms (LUTS) can range from urgency to urge&#xD;
      urinary incontinence and/or hesitancy and incomplete bladder emptying. Urgency, frequency,&#xD;
      and neurogenic detrusor overactivity (NDO) are the most common urologic findings (34-99%)&#xD;
      during diagnostic evaluations of patients with MS. Even though anticholinergic or beta&#xD;
      agonist drugs have limited effectiveness and adverse side effects, they are the first line&#xD;
      pharmacotherapy for patients with NDO if behavioral modifications and pelvic floor physical&#xD;
      therapy are unsuccessful. Botulinum toxin-A (BTX-A) intradetrusor injection is a highly&#xD;
      effective treatment option for patients with NDO who are refractory to more conservative&#xD;
      management. BTX-A blocks the release of acetylcholine at the neuromuscular junction and leads&#xD;
      to a temporary chemodenervation of the bladder (paralysis of the muscle). Motor effects of&#xD;
      BTX-A on the bladder have been extensively studied and widely reported in the literature, and&#xD;
      the US Food and Drug Administration has approved BTX-A for the treatment of detrusor&#xD;
      overactivity in neurogenic and non-neurogenic patients. However, the sensory effects of BTX-A&#xD;
      injection correlating to central nervous system regional perception/localization of urgency,&#xD;
      frequency, and urge incontinence in humans are not well known.&#xD;
&#xD;
      Over the past decades, functional MRI (fMRI) has been used to study the activation of&#xD;
      supraspinal lower urinary tract control centers in healthy subjects during the storage and&#xD;
      voiding phases. Given these facts, the investigators are interested in evaluating the role of&#xD;
      intradetrusor injection of BTX-A in afferent response in patients with MS and NDO.&#xD;
      High-resolution neuroimaging techniques will help investigators to further understand how MS&#xD;
      affects the bladder-brain controls. This study will use fMRI and task-related blood oxygen&#xD;
      level dependent (BOLD) signal to evaluate patients with MS and NDO prior to, and 6-10 weeks&#xD;
      after intradetrusor injection of BTX-A with simultaneous urodynamic evaluation.&#xD;
&#xD;
      Clinical correlation between women with these chronic urologic problems and new discoveries&#xD;
      at level of CNS activity will give a better understanding of this disorder, leading to the&#xD;
      development of more effective diagnostic and treatment modalities.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 2014</start_date>
  <completion_date type="Actual">March 2019</completion_date>
  <primary_completion_date type="Actual">March 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Blood Oxygen Level Dependent (BOLD) Signals in brain</measure>
    <time_frame>2 months</time_frame>
    <description>During fMRI measurements BOLD signal intensity in regions of interest will be measured at baseline and will be compared to the signals 6 weeks following the injection of BotulinumtoxinA, these signals may be increased or decreased.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Urodynamic study data</measure>
    <time_frame>2 months</time_frame>
    <description>The urodynamic data will be correlated with the functional MRI data. Neurogenic Detrusor Overactivity will be correlated to BOLD signal activation at regions of interest.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">28</enrollment>
  <condition>Multiple Sclerosis</condition>
  <condition>Lower Urinary Tract Symptoms</condition>
  <condition>Neurogenic Bladder</condition>
  <condition>Detrusor, Overactive</condition>
  <condition>Urge Incontinence</condition>
  <arm_group>
    <arm_group_label>Pre- BTX-A injection</arm_group_label>
    <description>Female patients with confirmed diagnosis of Multiple Sclerosis referred to our Neurourology clinic with neurogenic lower urinary tract dysfunction prior to receiving intradetrusor injection of Botulinum Toxin-A.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Post- BTX-A injection</arm_group_label>
    <description>Female patients with confirmed diagnosis of Multiple Sclerosis referred to our Neurourology clinic with neurogenic lower urinary tract dysfunction who receive intradetrusor Botulinum Toxin-A.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intradetrusor injection of Botulinum Toxin-A</intervention_name>
    <description>Using cystoscopy, Botulinum Toxin-A is injected into the bladder.</description>
    <arm_group_label>Post- BTX-A injection</arm_group_label>
    <other_name>OnabotulinumtoxinA, Botox®</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Female subjects diagnosed with Multiple Sclerosis and lower urinary tract symptoms who are&#xD;
        refractory to conservative management for neurogenic detrusor overactivity.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with clinical diagnosis of neurogenic bladder.&#xD;
&#xD;
          -  History of any neurologic illness or injury (including but not limited to spinal cord&#xD;
             injury, Multiple Sclerosis, spina bifida, Parkinson's, major spine surgery).&#xD;
&#xD;
          -  18 years or older.&#xD;
&#xD;
          -  Female patients.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Male&#xD;
&#xD;
          -  History of any incontinence surgery (sling, MMK, Burch).&#xD;
&#xD;
          -  History of any lower urinary tract surgery or manipulation (urethral dilation).&#xD;
&#xD;
          -  Positive urine pregnancy test at enrollment .&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rose Khavari, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Methodist Hospital Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Houston Methodist Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>July 15, 2016</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 26, 2017</study_first_posted>
  <last_update_submitted>March 24, 2020</last_update_submitted>
  <last_update_submitted_qc>March 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 25, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>The Methodist Hospital Research Institute</investigator_affiliation>
    <investigator_full_name>Rose Khavari, M.D.</investigator_full_name>
    <investigator_title>Sponsor-Investigator/Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Neurogenic Bladder, Detrusor Overactivity, Botox, fMRI</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Urinary Bladder, Neurogenic</mesh_term>
    <mesh_term>Urinary Incontinence, Urge</mesh_term>
    <mesh_term>Urinary Bladder, Overactive</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
    <mesh_term>Lower Urinary Tract Symptoms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Botulinum Toxins</mesh_term>
    <mesh_term>Botulinum Toxins, Type A</mesh_term>
    <mesh_term>abobotulinumtoxinA</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>December 10, 2020</submitted>
    <returned>January 5, 2021</returned>
    <submitted>March 13, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03033355
org study id: Pro00010110
nct id: NCT03033355
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this prospective research study is to evaluate higher neural changes following
      intradetrusor injection of Botulinum toxin-A (BTX-A) in patients with Multiple Sclerosis
      (MS). Concurrent Urodynamic and Functional Magnetic Resonance (fMRI) data will be recorded
      pre- and post- intravesical injection of BTX-A in patients with Multiple Sclerosis (MS) and
      neurogenic detrusor activity (NDO).

      Other objectives are to evaluate the role of urinary biomarkers such as brain-derived
      neurotropic factor (BDNF) and nerve growth factor (NGF) associated with bladder overactivity
      and, to determine whether the common validated urgency questionnaires correlate with fMRI
      findings and urinary biomarker concentration pre- and post- BTX-A injection in patients with
      MS and NDO.
Multiple Sclerosis is a severe debilitating disease that affects patient's quality of life.
      Up to 90% of patients with MS will develop lower urinary tract dysfunction within the first
      18 years of the disease. Lower urinary tract symptoms (LUTS) can range from urgency to urge
      urinary incontinence and/or hesitancy and incomplete bladder emptying. Urgency, frequency,
      and neurogenic detrusor overactivity (NDO) are the most common urologic findings (34-99%)
      during diagnostic evaluations of patients with MS. Even though anticholinergic or beta
      agonist drugs have limited effectiveness and adverse side effects, they are the first line
      pharmacotherapy for patients with NDO if behavioral modifications and pelvic floor physical
      therapy are unsuccessful. Botulinum toxin-A (BTX-A) intradetrusor injection is a highly
      effective treatment option for patients with NDO who are refractory to more conservative
      management. BTX-A blocks the release of acetylcholine at the neuromuscular junction and leads
      to a temporary chemodenervation of the bladder (paralysis of the muscle). Motor effects of
      BTX-A on the bladder have been extensively studied and widely reported in the literature, and
      the US Food and Drug Administration has approved BTX-A for the treatment of detrusor
      overactivity in neurogenic and non-neurogenic patients. However, the sensory effects of BTX-A
      injection correlating to central nervous system regional perception/localization of urgency,
      frequency, and urge incontinence in humans are not well known.

      Over the past decades, functional MRI (fMRI) has been used to study the activation of
      supraspinal lower urinary tract control centers in healthy subjects during the storage and
      voiding phases. Given these facts, the investigators are interested in evaluating the role of
      intradetrusor injection of BTX-A in afferent response in patients with MS and NDO.
      High-resolution neuroimaging techniques will help investigators to further understand how MS
      affects the bladder-brain controls. This study will use fMRI and task-related blood oxygen
      level dependent (BOLD) signal to evaluate patients with MS and NDO prior to, and 6-10 weeks
      after intradetrusor injection of BTX-A with simultaneous urodynamic evaluation.

      Clinical correlation between women with these chronic urologic problems and new discoveries
      at level of CNS activity will give a better understanding of this disorder, leading to the
      development of more effective diagnostic and treatment modalities.
observational model: Cohort
time perspective: Prospective
measure: Blood Oxygen Level Dependent (BOLD) Signals in brain
time frame: 2 months
description: During fMRI measurements BOLD signal intensity in regions of interest will be measured at baseline and will be compared to the signals 6 weeks following the injection of BotulinumtoxinA, these signals may be increased or decreased.
measure: Urodynamic study data
time frame: 2 months
description: The urodynamic data will be correlated with the functional MRI data. Neurogenic Detrusor Overactivity will be correlated to BOLD signal activation at regions of interest.
arm group label: Pre- BTX-A injection
description: Female patients with confirmed diagnosis of Multiple Sclerosis referred to our Neurourology clinic with neurogenic lower urinary tract dysfunction prior to receiving intradetrusor injection of Botulinum Toxin-A.
arm group label: Post- BTX-A injection
description: Female patients with confirmed diagnosis of Multiple Sclerosis referred to our Neurourology clinic with neurogenic lower urinary tract dysfunction who receive intradetrusor Botulinum Toxin-A.
intervention type: Drug
intervention name: Intradetrusor injection of Botulinum Toxin-A
description: Using cystoscopy, Botulinum Toxin-A is injected into the bladder.
arm group label: Post- BTX-A injection
other name: OnabotulinumtoxinA, Botox®
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rose Khavari, MD
role: Principal Investigator
affiliation: The Methodist Hospital Research Institute
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: The Methodist Hospital Research Institute
investigator full name: Rose Khavari, M.D.
investigator title: Sponsor-Investigator/Principal Investigator
mesh term: Multiple Sclerosis
mesh term: Urinary Bladder, Neurogenic
mesh term: Urinary Incontinence, Urge
mesh term: Urinary Bladder, Overactive
mesh term: Sclerosis
mesh term: Lower Urinary Tract Symptoms
mesh term: Botulinum Toxins
mesh term: Botulinum Toxins, Type A
mesh term: abobotulinumtoxinA
sharing ipd: No
submitted: December 10, 2020
returned: January 5, 2021
submitted: March 13, 2023