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Trial record 1 of 1 for:    sedivy | Alzheimer Disease
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Repurposing Nucleoside Reverse Transcriptase Inhibitors for Treatment of AD (LINE-AD)

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ClinicalTrials.gov Identifier: NCT04500847
Recruitment Status : Recruiting
First Posted : August 5, 2020
Last Update Posted : December 22, 2021
Sponsor:
Collaborators:
Alzheimer's Association
Brown University
The Miriam Hospital
Information provided by (Responsible Party):
Stephen Salloway, Butler Hospital

Brief Summary:
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 dementia due to Alzheimer's disease. Study duration for each subject participating in the placebo-controlled research study will be approximately 9 months (up to a 1 month Screening Period, Baseline visit (1 month), 6 months of placebo or emtricitabine dosing, and 1 month follow-up).

Condition or disease Intervention/treatment Phase
Alzheimer Disease, Early Onset Mild Cognitive Impairment Drug: Emtriva Capsule Drug: Placebo Phase 1

Detailed Description:

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 early Alzheimer's disease (AD), including subjects with mild cognitive impairment (MCI) due to AD. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Primary Purpose: Treatment
Official Title: Repurposing Nucleoside Reverse Transcriptase Inhibitors for Treatment of AD
Actual Study Start Date : December 17, 2021
Estimated Primary Completion Date : March 31, 2023
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Group 1
25 MCI and early AD subjects
Drug: Emtriva Capsule
200mg daily oral dose
Other Name: Emtricitabine

Placebo Comparator: Group 2
10 MCI and early AD subjects
Drug: Placebo
200mg daily oral dose
Other Name: Capsule manufactured to mimic Emtriva




Primary Outcome Measures :
  1. 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 months after first treatment) ]
    Number of participants with treatment emergent adverse events and serious adverse events as assessed by CTCAE (Version 4.03).


Secondary Outcome Measures :
  1. 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 months after first treatment) ]
    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.

  2. Change in Mini Mental State Examination (MMSE) Total Scores [ Time Frame: Screening phase, month 3 and month 6 after first treatment ]
    To determine changes of the MMSE scores from the screening phase to 6 months after first treatment.

  3. Change from baseline in Clinical Dementia Rating (CDR) [ Time Frame: Screening phase, month 3 and 6 months after first treatment ]
    To determine changes of CDR scores from screening phase to 6 months after first treatment.

  4. 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 ]
    To determine changes in ADAS-Cog scores from screening phase to 6 months after first treatment.

  5. 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 ]
    To determine changes in ADCS-ADL scores from screening phase to 6 months after first treatment.

  6. 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 ]
    To determine changes in FCSRT+IR with delayed recall from screening phase to 6 months after first treatment.

  7. Change from baseline in cerebrospinal fluid (CSF) phosphorylated tau/amyloid beta 42 (pTau/Aβ42) ratios [ Time Frame: Screening phase to month 6 after first treatment ]
    To determine changes in pTau/Aβ42 ratios from the screening phase to 6 months after first treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female, ages 50-85 years inclusive
  • Intellectually, visually and auditory capable, fluent in, and able to read, the language in which study assessments are administered (e.g. completion of at least six years of regular schooling or sustained employment or equivalent local level of knowledge).
  • Must meet NIA-AA research criteria for MCI and mild dementia due to AD
  • Mini Mental State Exam (MMSE) 20-30 inclusive
  • Clinical Dementia Rating (CDR) 0.5 or 1
  • Must meet a cerebrospinal fluid (CSF) pTau/Aβ42 ratio of > 0.024
  • Participants must have an appropriate study partner who agrees to participate in the study and who is intellectually, visually, and auditory capable, and fluent in, and able to read, the language in which study assessments are administered. Additionally, the study partner must be capable of and willing to: Accompany the participant to visits that requires the input of the study partner
  • Concurrent treatment with cholinesterase inhibitors and memantine are permitted on a stable dose for at least 60 days prior to baseline.

Exclusion Criteria:

  • Current medical or neurological condition that might impact cognition or performance on cognitive assessments, e.g., Huntington's disease, Parkinson's disease, syphilis, schizophrenia, bipolar disorder, active major depression, attention deficit/ hyperactivity disorder (ADD/ADHD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), active seizure disorder, current alcohol/drug abuse or dependence, or dependence within the last two years, or history of traumatic brain injury associated with loss of consciousness and ongoing residual transient or permanent neurological signs/symptoms including cognitive deficits, and/or associated with skull fracture
  • Brain MRI results showing findings unrelated to AD that, in the opinion of the investigator might be a leading cause of future cognitive decline, might pose a risk to the participant, or might confound MRI assessment for safety monitoring
  • Score "yes" on item four or item five of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale (eC-SSRS patient-reported outcome), if this ideation occurred in the past six months, or "yes" on any item of the Suicidal Behavior section, except for the "Non-Suicidal Self-Injurious Behavior" (item is included in the Suicidal Behavior section), if this behavior occurred in the past 2 years prior to screening
  • Use of other investigational drugs prior to screening until:

    • Small molecules: after five half-lives, or within 30 days until the expected pharmacodynamic effect has returned to baseline, whichever is longer
    • Biologicals: blood concentration has returned to baseline (or below serological responder threshold) for antibodies induced by active immunotherapy; or five half- lives for monoclonal antibodies or other biologicals
  • Approximately four weeks prior to randomization, the use of any drug or treatment known for the potential to cause major organ system toxicity, i.e. drugs that may require periodic safety monitoring of a specific organ or body fluid. Examples include, but are not limited to clozapine, cancer medical treatment like tamoxifen, systemic immunosuppressive drugs like methotrexate or interferon, or other immunosuppressive biological medicines for rheumatic diseases or multiple sclerosis
  • Chronic treatment (> three months) of strong CYP3A4 inducers or strong CYP3A4 inhibitors
  • A positive drug screen, if, in the investigator's opinion, this is due to drug abuse or dependence.
  • Significant ECG findings that are assessed as clinically significant by the investigator (e.g. sustained ventricular tachycardia, significant second or third degree atrioventricular block without a pacemaker, long QT syndrome or clinically meaningful prolonged QT interval).
  • Contraindication to lumbar puncture including use of anti-coagulants, low platelet count, history of back surgery (with the exception of microdiscectomy or laminectomy over one level), signs or symptoms of intracranial pressure, spinal deformities or other spinal conditions that in the judgment of the investigator would preclude a lumbar puncture
  • History of or active hepatitis or HIV infection (based on a positive lab result for HBV and/or HIV, to be performed during screening
  • Severe renal impairment
  • Severe hepatic impairment
  • Significant cardiac disease including recent (within six months) myocardial infarction, congestive heart failure or unstable angina
  • Female subjects who are pregnant or currently breastfeeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04500847


Contacts
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Contact: Stephen Salloway, MD (401) 455-6403 SSalloway@butler.org
Contact: Joslynn Faustino, PhD (401) 455-6403 JFaustino@butler.org

Locations
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United States, Rhode Island
Memory and Aging Program, Butler Hospital Recruiting
Providence, Rhode Island, United States, 02906
Contact: Stephen Salloway, MD    401-455-6403    SSalloway@butler.org   
Contact: Denise Jerue, RN    401 455-6403    DJerue@butler.org   
Sponsors and Collaborators
Butler Hospital
Alzheimer's Association
Brown University
The Miriam Hospital
Investigators
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Principal Investigator: Stephen Salloway, MD Butler Hospital
Principal Investigator: John Sedivy, PhD Brown University
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Responsible Party: Stephen Salloway, Director of Neurology and the Memory and Aging Program, Butler Hospital
ClinicalTrials.gov Identifier: NCT04500847    
Other Study ID Numbers: LINE-AD
First Posted: August 5, 2020    Key Record Dates
Last Update Posted: December 22, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Cognitive Dysfunction
Dementia
Tauopathies
Emtricitabine
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents