<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/NCT04413344</url>
  </required_header>
  <id_info>
    <org_study_id>IACT19029</org_study_id>
    <nct_id>NCT04413344</nct_id>
  </id_info>
  <brief_title>Repurposing Bromocriptine for Abeta Metabolism in Alzheimer's Disease</brief_title>
  <acronym>REBRAnD</acronym>
  <official_title>Double-Blind Comparative Trial and Open-Label Extension Trial to Investigate the Safety and Efficacy of TW-012R in Alzheimer's Disease With Presenilin 1 (PSEN1) Mutations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kyoto University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Mie University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Osaka University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Tokushima University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Tokyo Metropolitan Geriatric Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Asakayama Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kawasaki Medical School Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Nagoya City University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Time Therapeutics, Inc.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Towa Pharmaceutical Co.,Ltd.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Kyoto University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To investigate the safety and efficacy of an orally administered dose of TW-012R in patients&#xD;
      with Alzheimer's disease bearing PSEN1 (presenilin 1) mutations (PSEN1-AD), using a placebo&#xD;
      group as a control. In addition, long-term safety will be examined in an open-label extension&#xD;
      trial.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 5, 2020</start_date>
  <completion_date type="Actual">November 15, 2021</completion_date>
  <primary_completion_date type="Actual">November 15, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>[Double-blind phase] Multicenter, randomized, placebo-controlled, double-blind, parallel-group comparison clinical trial [Extension phase] Multicenter, open-label, extension trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety (Incidence and severity of adverse events and adverse reactions)</measure>
    <time_frame>Until Week 50 (end of trial)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Severe impairment battery-Japanese version (SIB-J)</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Neuropsychiatric Inventory (NPI)</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mental Function Impairment Scale (MENFIS)</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mini-Mental State Examination-Japanese (MMSE-J)</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disability Assessment for Dementia (DAD)</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apathy Scale</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Aβ protein concentration</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma NfL protein concentration</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Total Tau, Plasma p-Tau concentration</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal fluid (CSF) Aβ concentration</measure>
    <time_frame>Until Week 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CSF Total Tau, CSF p-Tau concentration</measure>
    <time_frame>Until Week 36</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood bromocriptine concentration</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Wearable physical activity meter</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Finger tapping sensor readout</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Brain amyloid PET image</measure>
    <time_frame>Until Week 36</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Brain tau PET image</measure>
    <time_frame>Until Week 36</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Upper motor neuron burden score</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Plasma Aβ-related peptides concentration</measure>
    <time_frame>Until Week 20 and 36</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Familial Alzheimer Disease (FAD)</condition>
  <condition>PSEN1 Mutation</condition>
  <arm_group>
    <arm_group_label>Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bromocriptine</intervention_name>
    <description>TW-012R: Each tablet contains 2.87 mg of bromocriptine mesilate (JP) (2.5 mg of bromocriptine)</description>
    <arm_group_label>Active</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>Placebo: Identical tablets which contain no active ingredient</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Alzheimer's disease patients with PSEN1 mutations&#xD;
&#xD;
          -  Patients diagnosed with &quot;probable AD&quot; according to the diagnostic guideline of NIA-AA&#xD;
             or &quot;probable Alzheimer-type dementia&quot; according to the diagnostic criteria for&#xD;
             Alzheimer's disease specified in DSM-5&#xD;
&#xD;
          -  An MMSE-J score of &lt;= 25&#xD;
&#xD;
          -  Patients whose cognitive function and everyday function are obviously impaired based&#xD;
             on their medical record or information provided by a person who knows the patient well&#xD;
&#xD;
          -  Patients for whom intellectual disability and mental disorders other than dementia can&#xD;
             be ruled out based on their academic background, work history, and life history.&#xD;
&#xD;
          -  Patients with a reliable and close relationship with a partner/caregiver&#xD;
&#xD;
          -  Age&gt;=20 years at the time of giving informed consent&#xD;
&#xD;
          -  Written informed consent has been obtained from the patient or his/her legally&#xD;
             acceptable representative to participate in this trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Difficulty with the oral intake of tablets&#xD;
&#xD;
          -  Patients receiving anti-dementia drugs who have changed the dosing regimen during the&#xD;
             2 months prior to giving informed consent&#xD;
&#xD;
          -  Patients with dementia due to pathology other than Alzheimer's disease (e.g., vascular&#xD;
             dementia, frontotemporal dementia, Lewy body dementia, progressive supranuclear palsy,&#xD;
             corticobasal degeneration, Huntington's disease, and prion disease)&#xD;
&#xD;
          -  Presence of clinically relevant or unstable mental disorders. Patients with major&#xD;
             depression in remission can be enrolled.&#xD;
&#xD;
          -  Imminent risk of self-harm or harm to others&#xD;
&#xD;
          -  Body mass index (BMI) of &lt;= 17 or &gt;= 35&#xD;
&#xD;
          -  Patients with a history of alcohol dependence, drug dependence, or drug abuse within&#xD;
             the 5 years before providing informed consent&#xD;
&#xD;
          -  HBs antigen positive&#xD;
&#xD;
          -  Anti-HIV antibody positive&#xD;
&#xD;
          -  Anti-HTLV-1 antibody positive&#xD;
&#xD;
          -  Patients with an active infection, such as hepatitis C and syphilis (STS/TPHA)&#xD;
&#xD;
          -  Patients with the following liver function values on the test before enrollment&#xD;
&#xD;
          -  AST(GOT) &gt; 4.0 x Upper limit of the institutional reference range or&#xD;
&#xD;
          -  ALT (GPT) &gt; 4.0 x Upper limit of the institutional reference range&#xD;
&#xD;
          -  Patients who have uncontrolled, clinically significant medical conditions (e.g.,&#xD;
             diabetes melitus, hypertension, thyroid/endocrine disease, congestive cardiac failure,&#xD;
             angina pectoris, cardiac/gastrointestinal disease, dialysis, and abnormal renal&#xD;
             function with an estimated CLcr &lt; 30 mL/min)within 3 months prior to giving informed&#xD;
             consent in addition to the underlying disease to be investigated in the trial and for&#xD;
             whom the investigator or sub-investigator considers that there is a significant&#xD;
             medical risk in the patient's participation in the trial&#xD;
&#xD;
          -  Patients with long QT syndrome or tendency toward prolonged QTc interval (male: &gt;=470&#xD;
             msec, female: &gt;= 480 msec), or patients with a history/complication of torsades de&#xD;
             pointes&#xD;
&#xD;
          -  Patients with a history of malignancies within 5 years prior to providing informed&#xD;
             consent. However, patients with the following diseases can be enrolled if they are&#xD;
             treated appropriately:&#xD;
&#xD;
          -  Skin cancer (basal cell, squamous cell)&#xD;
&#xD;
          -  Cervical carcinoma in situ&#xD;
&#xD;
          -  Localized prostate cancer&#xD;
&#xD;
          -  Malignancies that have not recurred for at least 3 years since surgery and the&#xD;
             patient's physician has determined that the risk of recurrence is low&#xD;
&#xD;
          -  Patients with clinically significant vitamin B1/B12 deficiency or folic acid&#xD;
             deficiency within 6 months prior to giving informed consent&#xD;
&#xD;
          -  Patients who have participated in other clinical research/trials involving&#xD;
             interventions within the 3 months prior to providing informed consent&#xD;
&#xD;
          -  Patients who have previously received bromocriptine or TW-012R&#xD;
&#xD;
          -  Patients with a history of hypersensitivity to bromocriptine or ergot alkaloids&#xD;
&#xD;
          -  Patients with current or a history of thickened heart valve cusps, restricted heart&#xD;
             valve motion, and the associated heart valve lesions, such as stenosis, confirmed by&#xD;
             echocardiography&#xD;
&#xD;
          -  Pregnant females, lactating females, females who may be pregnant, and females who wish&#xD;
             to become pregnant&#xD;
&#xD;
          -  Other patients who are considered inappropriate to participate in this trial at the&#xD;
             discretion of the investigator or sub-investigator&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Haruhisa Inoue, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kyoto University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hidekazu Tomimoto, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Mie University Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Haruhiko Banno, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Kyoto University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Nagoya City University Hospital</name>
      <address>
        <city>Nagoya</city>
        <state>Aichi</state>
        <zip>467-8602</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mie University Hospital</name>
      <address>
        <city>Tsu</city>
        <state>Mie</state>
        <zip>514-8507</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kawasaki Medical School Hospital</name>
      <address>
        <city>Kurashiki</city>
        <state>Okayama</state>
        <zip>701-0192</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asakayama Hospital</name>
      <address>
        <city>Sakai</city>
        <state>Osaka</state>
        <zip>590-0018</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Osaka University</name>
      <address>
        <city>Suita</city>
        <state>Osaka</state>
        <zip>565-0871</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kyoto University Hospital</name>
      <address>
        <city>Kyoto</city>
        <zip>606-8507</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tokushima University Hospital</name>
      <address>
        <city>Tokushima</city>
        <zip>770-8503</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tokyo Metropolitan Geriatric Hospital</name>
      <address>
        <city>Tokyo</city>
        <zip>173-0015</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>May 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 2, 2020</study_first_posted>
  <last_update_submitted>March 29, 2022</last_update_submitted>
  <last_update_submitted_qc>March 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Kyoto University</investigator_affiliation>
    <investigator_full_name>Haruhisa Inoue</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bromocriptine</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/NCT04413344
org study id: IACT19029
nct id: NCT04413344
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
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has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To investigate the safety and efficacy of an orally administered dose of TW-012R in patients
      with Alzheimer's disease bearing PSEN1 (presenilin 1) mutations (PSEN1-AD), using a placebo
      group as a control. In addition, long-term safety will be examined in an open-label extension
      trial.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: [Double-blind phase] Multicenter, randomized, placebo-controlled, double-blind, parallel-group comparison clinical trial [Extension phase] Multicenter, open-label, extension trial
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Safety (Incidence and severity of adverse events and adverse reactions)
time frame: Until Week 50 (end of trial)
measure: Severe impairment battery-Japanese version (SIB-J)
time frame: Until Week 20 and 36
measure: Neuropsychiatric Inventory (NPI)
time frame: Until Week 20 and 36
measure: Mental Function Impairment Scale (MENFIS)
time frame: Until Week 20 and 36
measure: Mini-Mental State Examination-Japanese (MMSE-J)
time frame: Until Week 20 and 36
measure: Disability Assessment for Dementia (DAD)
time frame: Until Week 20 and 36
measure: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
time frame: Until Week 20 and 36
measure: Apathy Scale
time frame: Until Week 20 and 36
measure: Plasma Aβ protein concentration
time frame: Until Week 20 and 36
measure: Plasma NfL protein concentration
time frame: Until Week 20 and 36
measure: Plasma Total Tau, Plasma p-Tau concentration
time frame: Until Week 20 and 36
measure: Cerebrospinal fluid (CSF) Aβ concentration
time frame: Until Week 36
measure: CSF Total Tau, CSF p-Tau concentration
time frame: Until Week 36
measure: Blood bromocriptine concentration
time frame: Until Week 20 and 36
measure: Wearable physical activity meter
time frame: Until Week 20 and 36
measure: Finger tapping sensor readout
time frame: Until Week 20 and 36
measure: Brain amyloid PET image
time frame: Until Week 36
measure: Brain tau PET image
time frame: Until Week 36
measure: Upper motor neuron burden score
time frame: Until Week 20 and 36
measure: Plasma Aβ-related peptides concentration
time frame: Until Week 20 and 36
arm group label: Active
arm group type: Active Comparator
arm group label: Placebo
arm group type: Placebo Comparator
intervention type: Drug
intervention name: Bromocriptine
description: TW-012R: Each tablet contains 2.87 mg of bromocriptine mesilate (JP) (2.5 mg of bromocriptine)
arm group label: Active
intervention type: Drug
intervention name: Placebos
description: Placebo: Identical tablets which contain no active ingredient
arm group label: Placebo
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Haruhisa Inoue, MD, PhD
role: Principal Investigator
affiliation: Kyoto University
last name: Hidekazu Tomimoto, MD, PhD
role: Study Director
affiliation: Mie University Hospital
last name: Haruhiko Banno, MD, PhD
role: Study Director
affiliation: Kyoto University
facility: 
facility: 
facility: 
facility: 
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facility: 
facility: 
facility: 
country: Japan
responsible party type: Principal Investigator
investigator affiliation: Kyoto University
investigator full name: Haruhisa Inoue
investigator title: Professor
mesh term: Alzheimer Disease
mesh term: Bromocriptine
sharing ipd: No