<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/NCT04500847</url>
  </required_header>
  <id_info>
    <org_study_id>LINE-AD</org_study_id>
    <nct_id>NCT04500847</nct_id>
  </id_info>
  <brief_title>Repurposing Nucleoside Reverse Transcriptase Inhibitors for Treatment of AD</brief_title>
  <acronym>LINE-AD</acronym>
  <official_title>Repurposing Nucleoside Reverse Transcriptase Inhibitors for Treatment of AD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Butler Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Alzheimer's Association</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Brown University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Miriam Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Butler Hospital</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This is a randomized, double-blind clinical trial of a daily oral dose of 200 mg&#xD;
      emtricitabine vs. placebo in 35 participants with biomarker-confirmed MCI or mild to moderate&#xD;
      dementia due to Alzheimer's disease. Study duration for each subject participating in the&#xD;
      placebo-controlled research study will be approximately 12 months (up to a 3 months Screening&#xD;
      Period, Baseline visit (1 month), 6 months of placebo or emtricitabine dosing, and 1 month&#xD;
      follow-up). Participants will have up to 2 months to complete all procedures for the month 6&#xD;
      study visit.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Alzheimer's disease (AD) is a devastating and increasingly frequent neurological disorder&#xD;
      whose onset is strongly correlated with advanced age. Between 2000 and 2017 deaths from AD&#xD;
      have increased 145%, and AD has become the 6th leading cause of death in the USA.&#xD;
      Unfortunately, in spite of immense research and clinical efforts spanning several decades,&#xD;
      cures have been elusive. This has prompted searches for new mechanisms of disease and new&#xD;
      targets of therapy. One such direction is inflammation: aging and many age-associated&#xD;
      diseases are believed to be causally linked with a chronic inflammatory state. The brain is&#xD;
      no exception, and the presence of inflammation in the AD brain establishes an environment&#xD;
      that is hostile for the function and survival of neurons. While it is not yet clear whether&#xD;
      inflammation is the root cause of AD, it is increasingly believed that alleviating these&#xD;
      inflammatory processes might slow down the progression of the disease. This research study&#xD;
      will test to determine if the inflammatory state can be alleviated with a class of drugs&#xD;
      known as nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs were developed to treat&#xD;
      Acquired Immune Deficiency Syndrome (AIDS) caused by infection with Human Immunodeficiency&#xD;
      Virus (HIV). Investigators hypothesize that NRTI drugs, by inhibiting neuroinflammation, may&#xD;
      be effective in the treatment of AD. The primary goal of this trial will be to assess safety&#xD;
      and tolerability of Emtriva in a geriatric population of individuals diagnosed with mild&#xD;
      cognitive impairment or early AD.&#xD;
&#xD;
      This study will be conducted in subjects with mild to moderate Alzheimer's disease (AD),&#xD;
      including subjects with mild cognitive impairment (MCI). Subjects must be positive for&#xD;
      amyloid pathology. Subjects must be 50 to 85 years old, and apart from the clinical diagnosis&#xD;
      of early AD, in good health as determined by the Investigator based on their medical history.&#xD;
      Participants must be HIV/HBV negative and pass all the screening assessments based on the&#xD;
      inclusion/exclusion criteria.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 17, 2021</start_date>
  <completion_date type="Anticipated">March 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2024</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The pharmacist will not be masked. All investigators will be masked until the end of the study.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with treatment emergent adverse events (TEAE's) in the treatment group will be compared to the placebo group</measure>
    <time_frame>Baseline to the follow up study visit (7-8 months after first treatment)</time_frame>
    <description>Number of participants with treatment emergent adverse events and serious adverse events as assessed by CTCAE (Version 4.03).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in key inflammatory biomarkers; Tumor necrosis factor-alpha (TNF-α), Interleukin 1-beta (IL-1β), and Interferon-alpha (IFN-α)</measure>
    <time_frame>Baseline to the follow up study visit (7-8 months after first treatment)</time_frame>
    <description>Blood draws will be taken from baseline to the follow up study visit. Inflammation and discovery research assays to detect levels of TNF-α, IL-1β, and IFN-α will be performed at Brown University.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mini Mental State Examination (MMSE) Total Scores</measure>
    <time_frame>Screening phase, month 3 and month 6 after first treatment</time_frame>
    <description>To determine changes of the MMSE scores from the screening phase to 6 months after first treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in Clinical Dementia Rating (CDR)</measure>
    <time_frame>Screening phase, month 3 and 6 months after first treatment</time_frame>
    <description>To determine changes of CDR scores from screening phase to 6 months after first treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in Alzheimer's Disease Assessment Scale-cognitive (ADAS-Cog -13)</measure>
    <time_frame>Screening phase, month 3 and month 6 after first treatment</time_frame>
    <description>To determine changes in ADAS-Cog scores from screening phase to 6 months after first treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)</measure>
    <time_frame>Screening phase, month 3 and month 6 after first treatment</time_frame>
    <description>To determine changes in ADCS-ADL scores from screening phase to 6 months after first treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in Free and Cued Selective Reminding Test (FCSRT+IR) with delayed recall</measure>
    <time_frame>Screening phase, month 3 and month 6 after first treatment</time_frame>
    <description>To determine changes in FCSRT+IR with delayed recall from screening phase to 6 months after first treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in cerebrospinal fluid (CSF) phosphorylated tau/amyloid beta 42 (pTau/Aβ42) ratios</measure>
    <time_frame>Screening phase to month 6-7 after first treatment</time_frame>
    <description>To determine changes in pTau/Aβ42 ratios from the screening phase to 6 months after first treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">35</enrollment>
  <condition>Alzheimer Disease, Early Onset</condition>
  <condition>Mild Cognitive Impairment</condition>
  <condition>Moderate Dementia</condition>
  <arm_group>
    <arm_group_label>Group 1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>25 MCI and mild to moderate AD subjects</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>10 MCI and mild to moderate AD subjects</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Emtriva Capsule</intervention_name>
    <description>200mg daily oral dose</description>
    <arm_group_label>Group 1</arm_group_label>
    <other_name>Emtricitabine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>200mg daily oral dose</description>
    <arm_group_label>Group 2</arm_group_label>
    <other_name>Capsule manufactured to mimic Emtriva</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female, ages 50-85 years inclusive&#xD;
&#xD;
          -  Intellectually, visually and auditory capable, fluent in, and able to read, the&#xD;
             language in which study assessments are administered (e.g. completion of at least six&#xD;
             years of regular schooling or sustained employment or equivalent local level of&#xD;
             knowledge).&#xD;
&#xD;
          -  Must meet NIA-AA research criteria for MCI and mild dementia due to AD&#xD;
&#xD;
          -  Mini Mental State Exam (MMSE) 15-30 inclusive&#xD;
&#xD;
          -  Clinical Dementia Rating (CDR) 0.5 - 2&#xD;
&#xD;
          -  Must meet a cerebrospinal fluid (CSF) pTau/Aβ42 ratio of &gt; 0.024&#xD;
&#xD;
          -  Participants must have an appropriate study partner who agrees to participate in the&#xD;
             study and who is intellectually, visually, and auditory capable, and fluent in, and&#xD;
             able to read, the language in which study assessments are administered. Additionally,&#xD;
             the study partner must be capable of and willing to: Accompany the participant to&#xD;
             visits that requires the input of the study partner&#xD;
&#xD;
          -  Concurrent treatment with cholinesterase inhibitors and memantine are permitted on a&#xD;
             stable dose for at least 60 days prior to baseline.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current medical or neurological condition that might impact cognition or performance&#xD;
             on cognitive assessments, e.g., Huntington's disease, Parkinson's disease, syphilis,&#xD;
             schizophrenia, bipolar disorder, active major depression, attention deficit/&#xD;
             hyperactivity disorder (ADD/ADHD), multiple sclerosis (MS), amyotrophic lateral&#xD;
             sclerosis (ALS), active seizure disorder, current alcohol/drug abuse or dependence, or&#xD;
             dependence within the last two years, or history of traumatic brain injury associated&#xD;
             with loss of consciousness and ongoing residual transient or permanent neurological&#xD;
             signs/symptoms including cognitive deficits, and/or associated with skull fracture&#xD;
&#xD;
          -  Brain MRI results showing findings unrelated to AD that, in the opinion of the&#xD;
             investigator might be a leading cause of future cognitive decline, might pose a risk&#xD;
             to the participant, or might confound MRI assessment for safety monitoring&#xD;
&#xD;
          -  Score &quot;yes&quot; on item four or item five of the Suicidal Ideation section of the Columbia&#xD;
             Suicide Severity Rating Scale (eC-SSRS patient-reported outcome), if this ideation&#xD;
             occurred in the past six months, or &quot;yes&quot; on any item of the Suicidal Behavior&#xD;
             section, except for the &quot;Non-Suicidal Self-Injurious Behavior&quot; (item is included in&#xD;
             the Suicidal Behavior section), if this behavior occurred in the past 2 years prior to&#xD;
             screening&#xD;
&#xD;
          -  Use of other investigational drugs prior to screening until:&#xD;
&#xD;
               -  Small molecules: after five half-lives, or within 30 days until the expected&#xD;
                  pharmacodynamic effect has returned to baseline, whichever is longer&#xD;
&#xD;
               -  Biologicals: blood concentration has returned to baseline (or below serological&#xD;
                  responder threshold) for antibodies induced by active immunotherapy; or five&#xD;
                  half- lives for monoclonal antibodies or other biologicals&#xD;
&#xD;
          -  Approximately four weeks prior to randomization, the use of any drug or treatment&#xD;
             known for the potential to cause major organ system toxicity, i.e. drugs that may&#xD;
             require periodic safety monitoring of a specific organ or body fluid. Examples&#xD;
             include, but are not limited to clozapine, cancer medical treatment like tamoxifen,&#xD;
             systemic immunosuppressive drugs like methotrexate or interferon, or other&#xD;
             immunosuppressive biological medicines for rheumatic diseases or multiple sclerosis&#xD;
&#xD;
          -  A positive drug screen, if, in the investigator's opinion, this is due to drug abuse&#xD;
             or dependence.&#xD;
&#xD;
          -  Significant ECG findings that are assessed as clinically significant by the&#xD;
             investigator (e.g. sustained ventricular tachycardia, significant second or third&#xD;
             degree atrioventricular block without a pacemaker, long QT syndrome or clinically&#xD;
             meaningful prolonged QT interval).&#xD;
&#xD;
          -  Contraindication to lumbar puncture including use of anti-coagulants, low platelet&#xD;
             count, history of back surgery (with the exception of microdiscectomy or laminectomy&#xD;
             over one level), signs or symptoms of intracranial pressure, spinal deformities or&#xD;
             other spinal conditions that in the judgment of the investigator would preclude a&#xD;
             lumbar puncture&#xD;
&#xD;
          -  History of or active hepatitis or HIV infection (based on a positive lab result for&#xD;
             HBV and/or HIV, to be performed during screening&#xD;
&#xD;
          -  Severe renal impairment&#xD;
&#xD;
          -  Severe hepatic impairment&#xD;
&#xD;
          -  Significant cardiac disease including recent (within six months) myocardial&#xD;
             infarction, congestive heart failure or unstable angina&#xD;
&#xD;
          -  Female subjects who are pregnant or currently breastfeeding.&#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>Meghan Riddle, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Butler Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>John Sedivy, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brown University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Meghan Riddle, MD</last_name>
    <phone>(401) 455-6403</phone>
    <email>MRiddle@butler.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Joslynn Faustino, PhD</last_name>
    <phone>(401) 455-6403</phone>
    <email>JFaustino@butler.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Memory and Aging Program, Butler Hospital</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02906</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Meghan Riddle, MD</last_name>
      <phone>401-455-6403</phone>
      <email>MRiddle@butler.org</email>
    </contact>
    <contact_backup>
      <last_name>Denise Jerue, RN</last_name>
      <phone>401 455-6403</phone>
      <email>DJerue@butler.org</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 15, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>June 5, 2023</last_update_submitted>
  <last_update_submitted_qc>June 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Butler Hospital</investigator_affiliation>
    <investigator_full_name>Meghan Riddle</investigator_full_name>
    <investigator_title>Director of Neurology and the Memory and Aging Program</investigator_title>
  </responsible_party>
  <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>Emtricitabine</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/NCT04500847
org study id: LINE-AD
nct id: NCT04500847
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a randomized, double-blind clinical trial of a daily oral dose of 200 mg
      emtricitabine vs. placebo in 35 participants with biomarker-confirmed MCI or mild to moderate
      dementia due to Alzheimer's disease. Study duration for each subject participating in the
      placebo-controlled research study will be approximately 12 months (up to a 3 months Screening
      Period, Baseline visit (1 month), 6 months of placebo or emtricitabine dosing, and 1 month
      follow-up). Participants will have up to 2 months to complete all procedures for the month 6
      study visit.
Alzheimer's disease (AD) is a devastating and increasingly frequent neurological disorder
      whose onset is strongly correlated with advanced age. Between 2000 and 2017 deaths from AD
      have increased 145%, and AD has become the 6th leading cause of death in the USA.
      Unfortunately, in spite of immense research and clinical efforts spanning several decades,
      cures have been elusive. This has prompted searches for new mechanisms of disease and new
      targets of therapy. One such direction is inflammation: aging and many age-associated
      diseases are believed to be causally linked with a chronic inflammatory state. The brain is
      no exception, and the presence of inflammation in the AD brain establishes an environment
      that is hostile for the function and survival of neurons. While it is not yet clear whether
      inflammation is the root cause of AD, it is increasingly believed that alleviating these
      inflammatory processes might slow down the progression of the disease. This research study
      will test to determine if the inflammatory state can be alleviated with a class of drugs
      known as nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs were developed to treat
      Acquired Immune Deficiency Syndrome (AIDS) caused by infection with Human Immunodeficiency
      Virus (HIV). Investigators hypothesize that NRTI drugs, by inhibiting neuroinflammation, may
      be effective in the treatment of AD. The primary goal of this trial will be to assess safety
      and tolerability of Emtriva in a geriatric population of individuals diagnosed with mild
      cognitive impairment or early AD.

      This study will be conducted in subjects with mild to moderate Alzheimer's disease (AD),
      including subjects with mild cognitive impairment (MCI). Subjects must be positive for
      amyloid pathology. Subjects must be 50 to 85 years old, and apart from the clinical diagnosis
      of early AD, in good health as determined by the Investigator based on their medical history.
      Participants must be HIV/HBV negative and pass all the screening assessments based on the
      inclusion/exclusion criteria.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The pharmacist will not be masked. All investigators will be masked until the end of the study.
measure: Number of participants with treatment emergent adverse events (TEAE's) in the treatment group will be compared to the placebo group
time frame: Baseline to the follow up study visit (7-8 months after first treatment)
description: Number of participants with treatment emergent adverse events and serious adverse events as assessed by CTCAE (Version 4.03).
measure: Change from baseline in key inflammatory biomarkers; Tumor necrosis factor-alpha (TNF-α), Interleukin 1-beta (IL-1β), and Interferon-alpha (IFN-α)
time frame: Baseline to the follow up study visit (7-8 months after first treatment)
description: Blood draws will be taken from baseline to the follow up study visit. Inflammation and discovery research assays to detect levels of TNF-α, IL-1β, and IFN-α will be performed at Brown University.
measure: Change in Mini Mental State Examination (MMSE) Total Scores
time frame: Screening phase, month 3 and month 6 after first treatment
description: To determine changes of the MMSE scores from the screening phase to 6 months after first treatment.
measure: Change from baseline in Clinical Dementia Rating (CDR)
time frame: Screening phase, month 3 and 6 months after first treatment
description: To determine changes of CDR scores from screening phase to 6 months after first treatment.
measure: Change from baseline in Alzheimer's Disease Assessment Scale-cognitive (ADAS-Cog -13)
time frame: Screening phase, month 3 and month 6 after first treatment
description: To determine changes in ADAS-Cog scores from screening phase to 6 months after first treatment.
measure: Change from baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)
time frame: Screening phase, month 3 and month 6 after first treatment
description: To determine changes in ADCS-ADL scores from screening phase to 6 months after first treatment.
measure: Change from baseline in Free and Cued Selective Reminding Test (FCSRT+IR) with delayed recall
time frame: Screening phase, month 3 and month 6 after first treatment
description: To determine changes in FCSRT+IR with delayed recall from screening phase to 6 months after first treatment.
measure: Change from baseline in cerebrospinal fluid (CSF) phosphorylated tau/amyloid beta 42 (pTau/Aβ42) ratios
time frame: Screening phase to month 6-7 after first treatment
description: To determine changes in pTau/Aβ42 ratios from the screening phase to 6 months after first treatment.
arm group label: Group 1
arm group type: Active Comparator
description: 25 MCI and mild to moderate AD subjects
arm group label: Group 2
arm group type: Placebo Comparator
description: 10 MCI and mild to moderate AD subjects
intervention type: Drug
intervention name: Emtriva Capsule
description: 200mg daily oral dose
arm group label: Group 1
other name: Emtricitabine
intervention type: Drug
intervention name: Placebo
description: 200mg daily oral dose
arm group label: Group 2
other name: Capsule manufactured to mimic Emtriva
criteria: 
gender: All
minimum age: 50 Years
maximum age: 85 Years
healthy volunteers: No
last name: Meghan Riddle, MD
role: Principal Investigator
affiliation: Butler Hospital
last name: John Sedivy, PhD
role: Principal Investigator
affiliation: Brown University
last name: Meghan Riddle, MD
phone: (401) 455-6403
email: MRiddle@butler.org
last name: Joslynn Faustino, PhD
phone: (401) 455-6403
email: JFaustino@butler.org
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Butler Hospital
investigator full name: Meghan Riddle
investigator title: Director of Neurology and the Memory and Aging Program
mesh term: Alzheimer Disease
mesh term: Cognitive Dysfunction
mesh term: Emtricitabine
sharing ipd: No