<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/NCT04430959</url>
  </required_header>
  <id_info>
    <org_study_id>HSC-MS-19-1046</org_study_id>
    <nct_id>NCT04430959</nct_id>
  </id_info>
  <brief_title>Candesartan as an Adjunctive Treatment for Bipolar Depression</brief_title>
  <official_title>A Pilot, Proof of Concept, Placebo-controlled Trial of Candesartan as an Adjunctive Treatment for Bipolar Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Texas Health Science Center, Houston</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Texas Health Science Center, Houston</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will assess the safety and tolerability of Candesartan when used in patients with&#xD;
      Bipolar Disorder, in addition to their medication treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pharmacological options for the treatment of Bipolar disorder (BD) are limited and a large&#xD;
      proportion of patients does not show adequate response to treatment, especially in the case&#xD;
      of bipolar depression. It has been hypothesized that dysfunctions in the renin-angiotensin&#xD;
      system (RAS) may be involved in the pathophysiology of BD. We propose a double-blind,&#xD;
      randomized, placebo-controlled, cross-over, proof-of-concept trial to investigate the effects&#xD;
      of candesartan, an angiotensin-II receptor antagonist capable to cross the blood-brain&#xD;
      barrier, as an adjunctive agent in the treatment of bipolar depression. Bipolar patients on a&#xD;
      depressive episode will be randomly assigned to undergo two consecutive 4-week treatment&#xD;
      periods with either candesartan (4 mg daily) or placebo in a crossover study. At the&#xD;
      beginning of each treatment period, participants will complete a resting-state functional MRI&#xD;
      scan, to be performed 1.5 hours after the first dose of the study medication. Subjects will&#xD;
      be followed weekly and the Montgomery-Asberg Depression Rating Scale (MADRS) will be adopted&#xD;
      as the primary outcome measure. Response will be defined as a decrease equal or higher than&#xD;
      50% in the MADRS score from the time of study entry to the 4th week of each treatment period.&#xD;
      Possible associations between changes in brain connectivity (measured through resting state&#xD;
      functional MRI) and subsequent response to treatment will also be analyzed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    The reason the study was withdrawn was due to lack of funds. In addition, the PI is moving to a&#xD;
    different institution and it would not be feasible to proceed with the study under these&#xD;
    circumstances.&#xD;
  </why_stopped>
  <start_date type="Actual">October 1, 2020</start_date>
  <completion_date type="Anticipated">September 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2022</primary_completion_date>
  <phase>Early Phase 1</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>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Montgomery-Asberg Depression Rating Scale (MADRS) scores at the end of each treatment period.</measure>
    <time_frame>Four weeks</time_frame>
    <description>MADRS scores range from 0-60; higher scores indicate a higher level of severity of depressive symptoms. Response will be defined as a decrease equal or higher than 50% in the total MADRS score between the baseline and the 4th week of each treatment period.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hamilton Anxiety Rating Scale (HAM-A) scores at the end of each treatment period.</measure>
    <time_frame>Four weeks</time_frame>
    <description>HAM-A scores range from 0-56, with higher scores indicating more severe anxiety</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Impression - Severity scale (CGI-S) scores at the end of each treatment period.</measure>
    <time_frame>Four weeks</time_frame>
    <description>The CGI-S is a 7-point scale used to rate the severity of the patient's illness at the time of assessment, compared to the clinician's past experience regarding patients with similar diagnosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Assessment Screening Tool scores at the end of each treatment period.</measure>
    <time_frame>Four weeks</time_frame>
    <description>The Functional Assessment Screening Tool (FAST) identifies factors that may influence problem behaviors. It is a self-report checklist that contains 16 items, with each questions being marked as either &quot;yes&quot;, &quot;no&quot;, or &quot;not applicable&quot;. The checklist is designed to identify whether maladaptive behavior is maintained in four domains: attention/preferred items, escape from tasks/activities, sensory stimulation, pain attenuation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Young Mania Rating Scale (YMRS) at the end of each treatment period</measure>
    <time_frame>Four weeks</time_frame>
    <description>The YMRS is one of the most frequently utilized rating scales to assess manic symptoms. The scale has 11 items, based on the patient's subjective report and observations made during the clinical interview. Higher scores indicate a greater severity of manic symptoms. Given the cyclic nature of BD, the YMRS will be utilized to monitor patients as for the possibility of a manic switch over each four-week treatment period.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Bipolar Disorder Depression</condition>
  <arm_group>
    <arm_group_label>Candesartan first then Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 weeks of candesartan with crossover to the other.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo first then Candesartan</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>4 weeks of placebo with crossover to the other.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Candesartan</intervention_name>
    <description>Candesartan 4 mg, tablets, orally, once daily for 4 weeks</description>
    <arm_group_label>Candesartan first then Placebo</arm_group_label>
    <arm_group_label>Placebo first then Candesartan</arm_group_label>
    <other_name>Atacand</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Candesartan placebo-matching tablets, orally, once daily for 4 weeks</description>
    <arm_group_label>Candesartan first then Placebo</arm_group_label>
    <arm_group_label>Placebo first then Candesartan</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        A diagnosis of BD type I or II, and currently in a depressive episode, based on DSM-5&#xD;
        criteria.&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          1. Age 18 to 65 years.&#xD;
&#xD;
          2. A diagnosis of BD type I or II according to DSM-5 criteria, established through the&#xD;
             administration of the MINI.&#xD;
&#xD;
          3. Currently in a depressive episode, based on DSM-5 criteria.&#xD;
&#xD;
          4. MADRS &gt;20 at entry in the study.&#xD;
&#xD;
          5. No history of hypertension, diabetes, stroke, liver, kidney, heart disease, bleeding&#xD;
             disorders, cancer, hypothyroidism, auto-immune diseases, and any brain disorder&#xD;
             (seizure disorder, stroke, dementia, or neurodegenerative diseases), as well as other&#xD;
             conditions that could impact patient's safety associated with participation in the&#xD;
             study.&#xD;
&#xD;
          6. On therapeutic doses of a mood stabilizing drug (anticonvulsants or atypical&#xD;
             antipsychotics, but not lithium) or combinations of medications (including&#xD;
             antidepressants, as long as receiving at least one mood stabilizing agent) for at&#xD;
             least two weeks.&#xD;
&#xD;
          7. Allowed psychiatric comorbid conditions, such as anxiety disorders, PTSD and past&#xD;
             history of substance use (as long as do NOT meet abuse or dependence criteria&#xD;
             according to the SCID-I in the past 2 months).&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Current use of angiotensin receptor antagonists, angiotensin converting enzyme&#xD;
             inhibitors. (ACE inhibitors), or a history of allergies or poor tolerability to those&#xD;
             medications&#xD;
&#xD;
          2. Current use of lithium or any other medications that could implicate in potentially&#xD;
             dangerous. interactions with candesartan, based on available literature and the&#xD;
             investigator's judgement.&#xD;
&#xD;
          3. Pregnancy or current breastfeeding.&#xD;
&#xD;
          4. Acute systemic infections or other acute medical conditions at the time of study&#xD;
             entry.&#xD;
&#xD;
          5. Acute suicidal or homicidal ideation or other imminent concerns about safety, based on&#xD;
             the investigator's judgement and/or on a score equal or higher than 4 in the item 10&#xD;
             of the MADRS.&#xD;
&#xD;
          6. Family history of hereditary neurologic disorder.&#xD;
&#xD;
          7. Unable to give informed consent for any reason.&#xD;
&#xD;
          8. Floating metallic objects in the body.&#xD;
&#xD;
          9. Positive urine drug screening at the time of study entry.&#xD;
&#xD;
         10. Current or previous diagnosis of intellectual disability, learning disability, or&#xD;
             other severe neurodevelopmental disorders.&#xD;
&#xD;
         11. History of traumatic brain injury or head trauma with loss of consciousness for more&#xD;
             than 30 minutes.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marsal Sanches, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas, Science Center at Houston</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The University of Texas Health Science Center at Houston</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>April 2022</verification_date>
  <study_first_submitted>May 11, 2020</study_first_submitted>
  <study_first_submitted_qc>June 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>April 19, 2022</last_update_submitted>
  <last_update_submitted_qc>April 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The University of Texas Health Science Center, Houston</investigator_affiliation>
    <investigator_full_name>Marsal Sanches</investigator_full_name>
    <investigator_title>Associate Director, UT Health Center of Excellence on Mood Disorders</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Bipolar Disorder</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Candesartan</mesh_term>
    <mesh_term>Candesartan cilexetil</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04430959
org study id: HSC-MS-19-1046
nct id: NCT04430959
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study will assess the safety and tolerability of Candesartan when used in patients with
      Bipolar Disorder, in addition to their medication treatment.
Pharmacological options for the treatment of Bipolar disorder (BD) are limited and a large
      proportion of patients does not show adequate response to treatment, especially in the case
      of bipolar depression. It has been hypothesized that dysfunctions in the renin-angiotensin
      system (RAS) may be involved in the pathophysiology of BD. We propose a double-blind,
      randomized, placebo-controlled, cross-over, proof-of-concept trial to investigate the effects
      of candesartan, an angiotensin-II receptor antagonist capable to cross the blood-brain
      barrier, as an adjunctive agent in the treatment of bipolar depression. Bipolar patients on a
      depressive episode will be randomly assigned to undergo two consecutive 4-week treatment
      periods with either candesartan (4 mg daily) or placebo in a crossover study. At the
      beginning of each treatment period, participants will complete a resting-state functional MRI
      scan, to be performed 1.5 hours after the first dose of the study medication. Subjects will
      be followed weekly and the Montgomery-Asberg Depression Rating Scale (MADRS) will be adopted
      as the primary outcome measure. Response will be defined as a decrease equal or higher than
      50% in the MADRS score from the time of study entry to the 4th week of each treatment period.
      Possible associations between changes in brain connectivity (measured through resting state
      functional MRI) and subsequent response to treatment will also be analyzed.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Montgomery-Asberg Depression Rating Scale (MADRS) scores at the end of each treatment period.
time frame: Four weeks
description: MADRS scores range from 0-60; higher scores indicate a higher level of severity of depressive symptoms. Response will be defined as a decrease equal or higher than 50% in the total MADRS score between the baseline and the 4th week of each treatment period.
measure: Hamilton Anxiety Rating Scale (HAM-A) scores at the end of each treatment period.
time frame: Four weeks
description: HAM-A scores range from 0-56, with higher scores indicating more severe anxiety
measure: Clinical Global Impression - Severity scale (CGI-S) scores at the end of each treatment period.
time frame: Four weeks
description: The CGI-S is a 7-point scale used to rate the severity of the patient's illness at the time of assessment, compared to the clinician's past experience regarding patients with similar diagnosis
measure: Functional Assessment Screening Tool scores at the end of each treatment period.
time frame: Four weeks
description: The Functional Assessment Screening Tool (FAST) identifies factors that may influence problem behaviors. It is a self-report checklist that contains 16 items, with each questions being marked as either "yes", "no", or "not applicable". The checklist is designed to identify whether maladaptive behavior is maintained in four domains: attention/preferred items, escape from tasks/activities, sensory stimulation, pain attenuation.
measure: Young Mania Rating Scale (YMRS) at the end of each treatment period
time frame: Four weeks
description: The YMRS is one of the most frequently utilized rating scales to assess manic symptoms. The scale has 11 items, based on the patient's subjective report and observations made during the clinical interview. Higher scores indicate a greater severity of manic symptoms. Given the cyclic nature of BD, the YMRS will be utilized to monitor patients as for the possibility of a manic switch over each four-week treatment period.
arm group label: Candesartan first then Placebo
arm group type: Experimental
description: 4 weeks of candesartan with crossover to the other.
arm group label: Placebo first then Candesartan
arm group type: Placebo Comparator
description: 4 weeks of placebo with crossover to the other.
intervention type: Drug
intervention name: Candesartan
description: Candesartan 4 mg, tablets, orally, once daily for 4 weeks
arm group label: Candesartan first then Placebo
arm group label: Placebo first then Candesartan
other name: Atacand
intervention type: Drug
intervention name: Placebo
description: Candesartan placebo-matching tablets, orally, once daily for 4 weeks
arm group label: Candesartan first then Placebo
arm group label: Placebo first then Candesartan
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Marsal Sanches, MD PhD
role: Principal Investigator
affiliation: University of Texas, Science Center at Houston
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: The University of Texas Health Science Center, Houston
investigator full name: Marsal Sanches
investigator title: Associate Director, UT Health Center of Excellence on Mood Disorders
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Bipolar Disorder
mesh term: Candesartan
mesh term: Candesartan cilexetil