<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/NCT04417049</url>
  </required_header>
  <id_info>
    <org_study_id>20-5219</org_study_id>
    <nct_id>NCT04417049</nct_id>
  </id_info>
  <brief_title>Treatment of Bipolar Depression With Pentoxifylline</brief_title>
  <acronym>PTX-BD</acronym>
  <official_title>Pentoxifylline for Bipolar Depression: A Proof-of-Concept Feasibility Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Growing theoretical and clinical evidence has suggested that pentoxifylline may have an&#xD;
      effect in improving depressive symptoms. Herein, we aim to evaluate the effect of&#xD;
      pentoxifylline in patients with bipolar depression over an 8-week trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Growing evidence has demonstrated that inflammation and alterations in cerebral blood flow&#xD;
      (CBF) contribute to the pathophysiology of bipolar depression (BD). Pentoxifylline is a&#xD;
      phosphodiesterase inhibitor that improves CBF and has potent anti-inflammatory and&#xD;
      antioxidant effects. We therefore hypothesize that pentoxifylline may have antidepressant&#xD;
      effects in BD. We will conduct an 8-week, open-label, single-armed, feasibility study&#xD;
      assessing clinical and neurobiological effects of adjunctive pentoxifylline in the acute&#xD;
      treatment of BD. Feasibility will be determined by evaluating recruitment/retention rates,&#xD;
      target engagement (e.g., changes in biomarkers with pentoxifylline treatment) and preliminary&#xD;
      efficacy testing with 6 participants. Evaluating pentoxifylline's effects may further our&#xD;
      understanding of BD pathophysiology and help identify novel treatment targets.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 12, 2021</start_date>
  <completion_date type="Actual">November 29, 2021</completion_date>
  <primary_completion_date type="Actual">November 3, 2021</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The recruitment rate</measure>
    <time_frame>8 weeks</time_frame>
    <description>The feasibility of pentoxifylline as a treatment in bipolar disorder will be measured by recruitment rate</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The retention rate</measure>
    <time_frame>8 weeks</time_frame>
    <description>The feasibility of pentoxifylline as a treatment in bipolar disorder will be measured by retention rate of the study.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety will be assessed using patient-reported treatment emergent adverse events.</measure>
    <time_frame>8 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in depression severity using the Montgomery Asberg Depression Rating Scale (MADRS)</measure>
    <time_frame>8 weeks</time_frame>
    <description>The MADRS is a clinician-rated scale measuring depression severity. It consists of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60. A higher score is indicative of greater depressive severity Response rates are defined as ≥ 50% decrease and Remission ≤ 10 actual score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in cerebral blood flow using ASL MRI imaging</measure>
    <time_frame>8 weeks</time_frame>
    <description>Patients will complete an MRI sequence called arterial spin labelling (ASL) at baseline and week 8 to look at changes in cerebral blood flow before and after treatment. ASL does not use any contrast or radiation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in inflammatory markers using blood serum and plasma</measure>
    <time_frame>8 weeks</time_frame>
    <description>Blood will be collected in order to evaluate changes in inflammatory biomarkers associated with depressive disorders (e.g., TNF-alpha, IL-1 and IL-6).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in subjective measures of depression using 16-item Quick Inventory for Depressive Symptomology-Self Report (QIDS-SR16) Total Score</measure>
    <time_frame>8 weeks</time_frame>
    <description>Patients will complete a brief self-reported scale that measures subjective symptoms of depression. In total there are 16 items, each scored from 0 to 3. The total score ranges from 0 to 27, with higher scores indicating worse depressive severity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in subjective measures of cognition using the Perceived Deficits Questionnaire for Depression-5 item (PDQ-5-D)</measure>
    <time_frame>8 weeks</time_frame>
    <description>The PDQ-5 is a brief patient-rated scale to assess subjective cognitive dysfunction in people with depression. The PDQ originally is a 20-item questionnaire that generates a total score and 4 subscale scores in 4 cognitive domains: attention/concentration, retrospective memory, prospective memory, and planning/organization. The 5-item version (PDQ-D-5) is derived from the 20-item version and provides a validated measure of perceived cognitive deficits in depressive disorders.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in psychomotor speed, concentration and memory using the Digit Symbols Substitution Task (DSST)</measure>
    <time_frame>8 weeks</time_frame>
    <description>The DSST is used to evaluate psychomotor speed and concentration. It consists of multiple digits with unique symbols associated with each digit. Patients are asked to substitute each digit with the correct symbol in 90 seconds. Each correct symbol is counted to calculate the total score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in attention and concentration using the Trails Making Tests</measure>
    <time_frame>8 weeks</time_frame>
    <description>Trail Making Test (TMT) is a cognitive test designed to assess attention and concentration through visuomotor tracking, executive function, and cognitive flexibility. It consists of two parts, A and B. In part A, a line is drawn between consecutive numbers. In part B a line is drawn alternating between numbers and letters. Score is calculated through total time to completion of each part, with higher times indicating impairment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in verbal fluency using the FAS test</measure>
    <time_frame>8 weeks</time_frame>
    <description>Change in verbal fluency (i.e., semantic and animal naming) will be measured by using the Controlled Oral Word Association Test. Scores will be assessed through the total number of words stated in a given letter or category in a time period of one minute. Number of repetitions and intrusions will also be measured.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Bipolar Depression</condition>
  <arm_group>
    <arm_group_label>Pentoxifylline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pentoxifylline 400 MG</intervention_name>
    <description>All patients will be provided with pentoxifylline 400 mg to be orally ingested twice daily for 8 weeks.</description>
    <arm_group_label>Pentoxifylline</arm_group_label>
    <other_name>Trental</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provide written, voluntary informed consent prior to study enrollment. Substitute&#xD;
             decision makers will not be allowed to consent to study on a potential patients&#xD;
             behalf.&#xD;
&#xD;
          2. Male or female between the age of 18 to 65, inclusive.&#xD;
&#xD;
          3. Meets DSM-5 criteria for Bipolar I or II Disorder, currently experiencing a Major&#xD;
             Depressive Episode. Diagnosis will be confirmed using the Mini-International&#xD;
             Neuropsychiatric Interview (MINI) conducted by a delegated physician or trained&#xD;
             research study while assessing eligibility.&#xD;
&#xD;
          4. Patient must present with a moderate to severe depressive episode, as determined by&#xD;
             the MADRS score greater than 21.&#xD;
&#xD;
          5. Patient must be receiving guideline-concordant pharmacotherapy without changes in the&#xD;
             last month.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Currently exhibiting symptoms of mania, as determined by the Young Mania Rating Scale&#xD;
             (YMRS) score greater than 11.&#xD;
&#xD;
          2. Current symptoms of psychosis or perceptual disturbances of any kind per investigator&#xD;
             discretion&#xD;
&#xD;
          3. History of neurological disorders&#xD;
&#xD;
          4. Presence of active suicidality, as determined by the MADRS suicidality item (Item #10)&#xD;
             score greater than 4&#xD;
&#xD;
          5. Presence of a contraindication to PTX, including a drug allergy or allergy to xanthine&#xD;
             derivatives, low or labile blood pressure, acute myocardial infarction, cardiac&#xD;
             arrhythmia, peptic ulcers, coronary artery disease or coagulation disorder.&#xD;
&#xD;
          6. Renal impairment, assessed as creatinine clearance less than 80ml/min&#xD;
&#xD;
          7. Abnormal liver function, assessed as ALT or AST ≥ 3 x ULN or bilirubin ≥ 2 x ULN&#xD;
&#xD;
          8. Severe myocardial infarction&#xD;
&#xD;
          9. Patients with standard contraindications to magnetic resonance imaging (MRI), such as&#xD;
             non-MRI compatible implanted metallic devices&#xD;
&#xD;
         10. Patients with a history of cerebrovascular disease or history of intercranial&#xD;
             hemorrhage.&#xD;
&#xD;
         11. Laboratory biochemical evidence of abnormal bleeding and/or coagulopathy&#xD;
&#xD;
         12. Pregnant or breastfeeding women. Patients who are sexually active must agree to use a&#xD;
             highly effective contraceptive method&#xD;
&#xD;
         13. Use of prohibited concomitant medications&#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>Joshua D Rosenblat, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Psychiatry</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Toronto Western Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5T 2S8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>June 2, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>April 13, 2022</last_update_submitted>
  <last_update_submitted_qc>April 13, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Health Network, Toronto</investigator_affiliation>
    <investigator_full_name>Joshua Rosenblat</investigator_full_name>
    <investigator_title>Principal Investigator</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>Pentoxifylline</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/NCT04417049
org study id: 20-5219
nct id: NCT04417049
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Growing theoretical and clinical evidence has suggested that pentoxifylline may have an
      effect in improving depressive symptoms. Herein, we aim to evaluate the effect of
      pentoxifylline in patients with bipolar depression over an 8-week trial.
Growing evidence has demonstrated that inflammation and alterations in cerebral blood flow
      (CBF) contribute to the pathophysiology of bipolar depression (BD). Pentoxifylline is a
      phosphodiesterase inhibitor that improves CBF and has potent anti-inflammatory and
      antioxidant effects. We therefore hypothesize that pentoxifylline may have antidepressant
      effects in BD. We will conduct an 8-week, open-label, single-armed, feasibility study
      assessing clinical and neurobiological effects of adjunctive pentoxifylline in the acute
      treatment of BD. Feasibility will be determined by evaluating recruitment/retention rates,
      target engagement (e.g., changes in biomarkers with pentoxifylline treatment) and preliminary
      efficacy testing with 6 participants. Evaluating pentoxifylline's effects may further our
      understanding of BD pathophysiology and help identify novel treatment targets.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The recruitment rate
time frame: 8 weeks
description: The feasibility of pentoxifylline as a treatment in bipolar disorder will be measured by recruitment rate
measure: The retention rate
time frame: 8 weeks
description: The feasibility of pentoxifylline as a treatment in bipolar disorder will be measured by retention rate of the study.
measure: Safety will be assessed using patient-reported treatment emergent adverse events.
time frame: 8 weeks
measure: Change in depression severity using the Montgomery Asberg Depression Rating Scale (MADRS)
time frame: 8 weeks
description: The MADRS is a clinician-rated scale measuring depression severity. It consists of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60. A higher score is indicative of greater depressive severity Response rates are defined as ≥ 50% decrease and Remission ≤ 10 actual score.
measure: Change in cerebral blood flow using ASL MRI imaging
time frame: 8 weeks
description: Patients will complete an MRI sequence called arterial spin labelling (ASL) at baseline and week 8 to look at changes in cerebral blood flow before and after treatment. ASL does not use any contrast or radiation.
measure: Change in inflammatory markers using blood serum and plasma
time frame: 8 weeks
description: Blood will be collected in order to evaluate changes in inflammatory biomarkers associated with depressive disorders (e.g., TNF-alpha, IL-1 and IL-6).
measure: Change in subjective measures of depression using 16-item Quick Inventory for Depressive Symptomology-Self Report (QIDS-SR16) Total Score
time frame: 8 weeks
description: Patients will complete a brief self-reported scale that measures subjective symptoms of depression. In total there are 16 items, each scored from 0 to 3. The total score ranges from 0 to 27, with higher scores indicating worse depressive severity.
measure: Changes in subjective measures of cognition using the Perceived Deficits Questionnaire for Depression-5 item (PDQ-5-D)
time frame: 8 weeks
description: The PDQ-5 is a brief patient-rated scale to assess subjective cognitive dysfunction in people with depression. The PDQ originally is a 20-item questionnaire that generates a total score and 4 subscale scores in 4 cognitive domains: attention/concentration, retrospective memory, prospective memory, and planning/organization. The 5-item version (PDQ-D-5) is derived from the 20-item version and provides a validated measure of perceived cognitive deficits in depressive disorders.
measure: Changes in psychomotor speed, concentration and memory using the Digit Symbols Substitution Task (DSST)
time frame: 8 weeks
description: The DSST is used to evaluate psychomotor speed and concentration. It consists of multiple digits with unique symbols associated with each digit. Patients are asked to substitute each digit with the correct symbol in 90 seconds. Each correct symbol is counted to calculate the total score
measure: Change in attention and concentration using the Trails Making Tests
time frame: 8 weeks
description: Trail Making Test (TMT) is a cognitive test designed to assess attention and concentration through visuomotor tracking, executive function, and cognitive flexibility. It consists of two parts, A and B. In part A, a line is drawn between consecutive numbers. In part B a line is drawn alternating between numbers and letters. Score is calculated through total time to completion of each part, with higher times indicating impairment.
measure: Change in verbal fluency using the FAS test
time frame: 8 weeks
description: Change in verbal fluency (i.e., semantic and animal naming) will be measured by using the Controlled Oral Word Association Test. Scores will be assessed through the total number of words stated in a given letter or category in a time period of one minute. Number of repetitions and intrusions will also be measured.
arm group label: Pentoxifylline
arm group type: Experimental
intervention type: Drug
intervention name: Pentoxifylline 400 MG
description: All patients will be provided with pentoxifylline 400 mg to be orally ingested twice daily for 8 weeks.
arm group label: Pentoxifylline
other name: Trental
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Joshua D Rosenblat, MD, MSc
role: Principal Investigator
affiliation: Psychiatry
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University Health Network, Toronto
investigator full name: Joshua Rosenblat
investigator title: Principal Investigator
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Bipolar Disorder
mesh term: Pentoxifylline
sharing ipd: No