<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/NCT03752294</url>
  </required_header>
  <id_info>
    <org_study_id>RIN001-001</org_study_id>
    <nct_id>NCT03752294</nct_id>
  </id_info>
  <brief_title>A Novel Therapeutic Target for Alzheimer's Disease in Men and Women 50-85 Years of Age.</brief_title>
  <official_title>A 24-month, Randomized-control, Double-blind, Multi-center, Delayed-start, Pilot Study Evaluating Thrombin Inhibitions Alzheimer's Disease Using 150mg Dabigatran Daily: A Novel Therapeutic Target for Alzheimer's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Rhode Island</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Alzheimer's Drug Discovery Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Rhode Island</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      A randomized-control, double-blind, multi-center, delayed-start, pilot trial evaluating the&#xD;
      disease modifying effects of a 150mg once-a-day dose vs. placebo of dabigatran in men and&#xD;
      women, between the ages of 50-85 years, confirmed with MCI probably due to AD and mild&#xD;
      Alzheimer's Disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be conducted in 2-phases. The Phase I double-blind portion of the study&#xD;
      consists of 40-60 active participants with MCI probably due to AD and mild AD randomized to&#xD;
      150mg once-a-day dose of dabigatran or placebo. A futility analysis will be conducted based&#xD;
      on month 3 plasma biomarker changes from baseline. Excluding futility, at the end of Phase I,&#xD;
      the study continues onto the open-label phase of the study where the placebo arm will be&#xD;
      treated with 150mg once-a-day with dabigatran from months 10-21. The active treatment arm&#xD;
      will continue on dabigatran through month-21. For final analysis, a difference in intercept&#xD;
      of a generalized growth model between randomization groups during Phase 2 in the Cognitive&#xD;
      Dementia Rating Scale-Sum of Boxes (CDR-SB) will be taken as evidence of effectiveness and&#xD;
      justify further study. All patients will discontinue dabigatran after month 21 and a 3-month&#xD;
      follow-up period will confirm whether or not the proposed cognitive effects can be sustained&#xD;
      in the absence of treatment. The relationships between changes in levels of plasma biomarkers&#xD;
      over time will be tested with regards to each other and relative to MRI and cognitive testing&#xD;
      performed at scheduled intervals.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">November 2018</start_date>
  <completion_date type="Anticipated">December 2021</completion_date>
  <primary_completion_date type="Anticipated">November 2021</primary_completion_date>
  <phase>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>
    <intervention_model_description>Randomized-control, Double-blind, Multicenter, Delayed-start, Pilot</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The first phase of the study is 9-month, double-blind, randomized-control treatment. All participants participants will cross-over to phase II (open label) for an additional 12 months of treatment with a 3-month non-treatment follow-up</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluate dabigatran efficacy in MCI and mild AD population using changes in targeted plasma and CSF biomarker levels at 9 and 21 months</measure>
    <time_frame>9 and 21-months</time_frame>
    <description>Evaluate effectiveness of dabigatran (150mg daily) on disease modification measured by changes in targeted plasma and CSF biomarkers associated with the early stages of Alzheimer's disease</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Demonstrate a reduction in decline of cognitive function related to physical functioning in placebo arm after crossing over to 12-months of active treatment</measure>
    <time_frame>12 - 24 months</time_frame>
    <description>Demonstrate an observed benefit of cognitive performance/function using the ADCS ADL MCI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in cognitive performance in placebo arm after cross-over to open-label treatment phase</measure>
    <time_frame>24-months</time_frame>
    <description>Evaluate effectiveness of dabigatran (150mg daily) using the CDR-SB</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of dabigatran in experimental population (MCI and mild AD populations) based on reported serious and adverse events</measure>
    <time_frame>21-months</time_frame>
    <description>Determine the safety and tolerability of dabigatran in MCI probably due to AD and mild AD population using physician and patient reported adverse events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of cognitive performance in placebo arm after cross-over to open-label treatment phase</measure>
    <time_frame>24-months</time_frame>
    <description>Evaluate effectiveness of dabigatran (150mg daily) using the MoCA</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Mild Cognitive Impairment</condition>
  <condition>Mild Alzheimer's Disease</condition>
  <arm_group>
    <arm_group_label>Dabigatran</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive 150mg dabigatran daily for a total of 9-months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will receive placebo daily for a total of 9-months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Open Label</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>All study participants are assigned to receive 150mg dabigatran daily for a total of 12 months (study month 9 through month 21)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dabigatran</intervention_name>
    <description>At the end of a 9-month randomized-control, double-blind treatment all study participants will cross-over to the 12-month open-label phase with a 3-month non-treatment follow-up.</description>
    <arm_group_label>Dabigatran</arm_group_label>
    <arm_group_label>Open Label</arm_group_label>
    <other_name>Pradaxa</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo - Cap</intervention_name>
    <description>At the end of a 9-month randomized-control, double-blind treatment all study participants will cross-over to the 12-month open-label phase with a 3-month non-treatment follow-up</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Study Drug</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of MCI likely due to AD or mild AD based on IWG-2 criteria for typical AD (A&#xD;
             plus B at any stage) 2011 revised criteria&#xD;
&#xD;
          2. English speaking men &amp; woman age 50 -85 years (inclusive)&#xD;
&#xD;
          3. Ability to provide informed consent&#xD;
&#xD;
          4. MMSE score &gt;20 at screening&#xD;
&#xD;
          5. Informant or caregiver (e.g. family member, friend) willing to participate in&#xD;
             semi-structured interviews&#xD;
&#xD;
          6. CSF Aβ positive (MCI and AD) or a positive amyloid positron emission tomography (PET)&#xD;
             scan within 6-months prior to screening using IWG-2 criteria.&#xD;
&#xD;
          7. CDR Scale Global Score between 0.5 and 1&#xD;
&#xD;
          8. Stable dosing (prior 3-months) of standard AD medications are allowed&#xD;
&#xD;
          9. Demonstrated willingness to comply with study visit schedule, laboratory studies, and&#xD;
             other study procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pre-menopausal women (last menstruation &lt; 1 year prior to screening) who are not&#xD;
             surgically sterile.&#xD;
&#xD;
          2. Creatinine clearance &lt; 50mL/min&#xD;
&#xD;
          3. Current psychiatric or neurological disorder that would contribute to cognitive&#xD;
             impairment (focal neurological features early extrapyramidal signs, early&#xD;
             hallucinations, cognitive fluctuations, non-AD dementia, major depression)&#xD;
&#xD;
          4. Cerebrovascular disease&#xD;
&#xD;
          5. Toxic, inflammatory, and metabolic disorders, all of which may require specific&#xD;
             investigations&#xD;
&#xD;
          6. MRI Flair or T2 signal changes in the medial temporal lobe that are consistent with&#xD;
             infectious or vascular insults&#xD;
&#xD;
          7. Sudden onset or early occurrence of the following symptoms: gait disturbances,&#xD;
             seizures, major and prevalent behavioral changes&#xD;
&#xD;
          8. Inability to swallow pills&#xD;
&#xD;
          9. Current anticoagulant therapy&#xD;
&#xD;
         10. Conditions associated with an increased risk of bleeding (e.g. major surgery within&#xD;
             30-days of baseline, planned surgery or intervention during treatment period)&#xD;
&#xD;
         11. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic&#xD;
             intra-articular bleeding&#xD;
&#xD;
         12. Gastrointestinal hemorrhage within the past year&#xD;
&#xD;
         13. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous&#xD;
             30-days; hemorrhagic disorder or bleeding diathesis&#xD;
&#xD;
         14. Need for anticoagulant treatment of disorders, fibrinolytic agents within 48-hours of&#xD;
             study baseline, uncontrolled hypertension (systolic blood pressure greater than 180mm&#xD;
             Hg and/or diastolic blood pressure greater than 100 mm Hg)&#xD;
&#xD;
         15. Recent malignancy or radiation therapy (within 6-months) and a survival rate of&#xD;
             3-years,&#xD;
&#xD;
         16. Active infective endocarditis&#xD;
&#xD;
         17. Active liver disease (including but not limited to persistent ALT, AST, Alk Phos&#xD;
             greater than twice the upper limit of the normal range; active hepatitis C (positive&#xD;
             HCV RNA)&#xD;
&#xD;
         18. Active hepatitis B (HBs antigen +, anti HBc IgM +), active hepatitis A&#xD;
&#xD;
         19. HIV/AIDS diagnosis&#xD;
&#xD;
        MRI exclusionary criteria&#xD;
&#xD;
          1. Brain Aneurysm Clip&#xD;
&#xD;
          2. Implanted neural stimulator&#xD;
&#xD;
          3. Implanted cardiac pacemaker or defibrillator&#xD;
&#xD;
          4. Cochlear implant&#xD;
&#xD;
          5. Ocular foreign body (e.g. metal shavings)&#xD;
&#xD;
          6. Other implanted medical devices: (e.g. Swan Ganz catheter, mechanical prosthetic&#xD;
             heart)&#xD;
&#xD;
          7. Insulin pump&#xD;
&#xD;
          8. Metal shrapnel or bullet&#xD;
&#xD;
        Additional concomitant drug exclusionary criteria will be applied by investigator.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paula Grammas, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Executive Director of the Ryan Institute for Neuroscience</affiliation>
  </overall_official>
  <overall_official>
    <last_name>John Stoukides, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical Director, Rhode Island Mood &amp; Memory Research Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Chris Getter</last_name>
    <phone>401-874-2358</phone>
    <email>cgetter@uri.edu</email>
  </overall_contact>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>May 15, 2018</study_first_submitted>
  <study_first_submitted_qc>November 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 23, 2018</study_first_posted>
  <last_update_submitted>November 20, 2018</last_update_submitted>
  <last_update_submitted_qc>November 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 23, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MCI</keyword>
  <keyword>Mild AD</keyword>
  <keyword>Dabigatran</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dabigatran</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03752294
org study id: RIN001-001
nct id: NCT03752294
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
A randomized-control, double-blind, multi-center, delayed-start, pilot trial evaluating the
      disease modifying effects of a 150mg once-a-day dose vs. placebo of dabigatran in men and
      women, between the ages of 50-85 years, confirmed with MCI probably due to AD and mild
      Alzheimer's Disease.
The study will be conducted in 2-phases. The Phase I double-blind portion of the study
      consists of 40-60 active participants with MCI probably due to AD and mild AD randomized to
      150mg once-a-day dose of dabigatran or placebo. A futility analysis will be conducted based
      on month 3 plasma biomarker changes from baseline. Excluding futility, at the end of Phase I,
      the study continues onto the open-label phase of the study where the placebo arm will be
      treated with 150mg once-a-day with dabigatran from months 10-21. The active treatment arm
      will continue on dabigatran through month-21. For final analysis, a difference in intercept
      of a generalized growth model between randomization groups during Phase 2 in the Cognitive
      Dementia Rating Scale-Sum of Boxes (CDR-SB) will be taken as evidence of effectiveness and
      justify further study. All patients will discontinue dabigatran after month 21 and a 3-month
      follow-up period will confirm whether or not the proposed cognitive effects can be sustained
      in the absence of treatment. The relationships between changes in levels of plasma biomarkers
      over time will be tested with regards to each other and relative to MRI and cognitive testing
      performed at scheduled intervals.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Randomized-control, Double-blind, Multicenter, Delayed-start, Pilot
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The first phase of the study is 9-month, double-blind, randomized-control treatment. All participants participants will cross-over to phase II (open label) for an additional 12 months of treatment with a 3-month non-treatment follow-up
measure: Evaluate dabigatran efficacy in MCI and mild AD population using changes in targeted plasma and CSF biomarker levels at 9 and 21 months
time frame: 9 and 21-months
description: Evaluate effectiveness of dabigatran (150mg daily) on disease modification measured by changes in targeted plasma and CSF biomarkers associated with the early stages of Alzheimer's disease
measure: Demonstrate a reduction in decline of cognitive function related to physical functioning in placebo arm after crossing over to 12-months of active treatment
time frame: 12 - 24 months
description: Demonstrate an observed benefit of cognitive performance/function using the ADCS ADL MCI
measure: Changes in cognitive performance in placebo arm after cross-over to open-label treatment phase
time frame: 24-months
description: Evaluate effectiveness of dabigatran (150mg daily) using the CDR-SB
measure: Safety and tolerability of dabigatran in experimental population (MCI and mild AD populations) based on reported serious and adverse events
time frame: 21-months
description: Determine the safety and tolerability of dabigatran in MCI probably due to AD and mild AD population using physician and patient reported adverse events.
measure: Evaluation of cognitive performance in placebo arm after cross-over to open-label treatment phase
time frame: 24-months
description: Evaluate effectiveness of dabigatran (150mg daily) using the MoCA
arm group label: Dabigatran
arm group type: Active Comparator
description: Participants will receive 150mg dabigatran daily for a total of 9-months.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants will receive placebo daily for a total of 9-months.
arm group label: Open Label
arm group type: Active Comparator
description: All study participants are assigned to receive 150mg dabigatran daily for a total of 12 months (study month 9 through month 21)
intervention type: Drug
intervention name: Dabigatran
description: At the end of a 9-month randomized-control, double-blind treatment all study participants will cross-over to the 12-month open-label phase with a 3-month non-treatment follow-up.
arm group label: Dabigatran
arm group label: Open Label
other name: Pradaxa
intervention type: Drug
intervention name: Placebo - Cap
description: At the end of a 9-month randomized-control, double-blind treatment all study participants will cross-over to the 12-month open-label phase with a 3-month non-treatment follow-up
arm group label: Placebo
other name: Study Drug
criteria: 
gender: All
minimum age: 50 Years
maximum age: 85 Years
healthy volunteers: No
last name: Paula Grammas, PhD
role: Study Director
affiliation: Executive Director of the Ryan Institute for Neuroscience
last name: John Stoukides, MD
role: Principal Investigator
affiliation: Medical Director, Rhode Island Mood & Memory Research Institute
last name: Chris Getter
phone: 401-874-2358
email: cgetter@uri.edu
responsible party type: Sponsor
mesh term: Alzheimer Disease
mesh term: Cognitive Dysfunction
mesh term: Dabigatran
sharing ipd: Undecided