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Pilot Study to Investigate the Safety and Feasibility of AntiRetroviral Therapy for Alzheimer's Disease (ART-AD)

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ClinicalTrials.gov Identifier: NCT04552795
Recruitment Status : Recruiting
First Posted : September 17, 2020
Last Update Posted : March 19, 2021
Sponsor:
Collaborator:
Owens Medical Research Foundation
Information provided by (Responsible Party):
Bess Frost, PhD, The University of Texas Health Science Center at San Antonio

Brief Summary:
The objective of the study is to evaluate the ability of (-)-L-2',3'-dideoxy-3'-thiacytidine (3TC) to engage its intended target, penetrate the central nervous system (CNS), suppress neurodegeneration, and assess safety and tolerability in patients with early stage Alzheimer's disease. This study will provide the initial data on target engagement and Alzheimer's disease-relevant outcomes for future trials.

Condition or disease Intervention/treatment Phase
Alzheimer Disease, Early Onset Drug: 3TC Phase 1 Phase 2

Detailed Description:
This open label study of 3TC will collect initial proof-of-concept data on 3TC target engagement, CNS penetration, efficacy and safety in older adults with early stage Alzheimer's disease. If successful, data will be used to design a larger phase 2 clinical trial. The investigators aim to I) Quantify 3TC target engagement and CNS penetration, II) Determine if 3TC suppresses Alzheimer's disease-relevant outcomes, and III) Assess the safety and tolerability of 3TC in older individuals with early Alzheimer's disease. The study will consist of a screening/baseline period of 30 days pre-treatment, a 24-week open label treatment period, and a follow up visit one month following treatment. Visits to the clinic include a pre-treatment screening visit that includes a comprehensive neuropsychological exam, a tablet-based neuropsychological exam, and a blood draw. For eligible participants, a lumbar puncture will be performed on day one of treatment. Participants will visit the clinic on day one of treatment and at weeks 8, 16, and 24 of treatment to complete medication checks, physical examinations, tablet-based cognitive screening, and blood draw. At week 24 of treatment, patients will undergo a post-treatment comprehensive neuropsychological exam, a lumbar puncture to collect cerebrospinal fluid, and a blood draw. One month after the final dose of medication, participants will return to the clinic for a final safety assessment and disenrollment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, one arm study.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study to Investigate the Safety and Feasibility of AntiRetroviral Therapy for Alzheimer's Disease (ART-AD)
Actual Study Start Date : February 15, 2021
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : June 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Lamivudine

Arm Intervention/treatment
Experimental: Open-Label 3TC
12 subjects will receive 3TC, 300-mg, daily for 24 weeks.
Drug: 3TC
12 subjects will be administered 3TC, 300mg once daily, via an oral tablet for 24 weeks.
Other Names:
  • Epivir
  • lamivudine




Primary Outcome Measures :
  1. Change in reverse transcriptase activity from baseline to 24 weeks in blood and cerebrospinal fluid (CSF) of study participants [ Time Frame: Baseline to 24 weeks ]
    The extent of 3TC target engagement will be measured by calculating the change in reverse transcriptase activity in plasma and CSF of participants at baseline compared to week 24 using a modified version of the EnzCheck Reverse Transcriptase Assay.

  2. 3TC CNS penetration in participants [ Time Frame: 24 weeks ]
    The extent of 3TC CNS penetration will be calculated based on the ratio of plasma to CSF levels of 3TC 5'-triphosphate using High Performance Liquid Chromatography with tandem Mass Spectrometry (HPLC/MS/MS).


Secondary Outcome Measures :
  1. Change in dementia severity from baseline to week 24 of treatment based on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) [ Time Frame: Baseline to 24 weeks ]
    The CDR-SOB is a semi-structured interview with both subjects and caregivers, scored on six domains of cognitive functioning: memory, orientation, judgment, community affairs, home and hobbies, and personal scale. The CDR-SOB is obtained by summing each of the domains, with scores ranging from 0-18. Higher scores denote greater dementia severity.

  2. Incidence of treatment-emergent adverse events [ Time Frame: Baseline, Week 8, Week 16, Week 24 ]
    Incidence of adverse and serious adverse events likely due to study drug will be recorded.

  3. Incidence of treatment-emergent abnormal vital signs [ Time Frame: Baseline, Week 8, Week 16, Week 24 ]
    Vital signs including blood pressure, heart rate, temperature, and respiration will be measured.

  4. Incidence of treatment-emergent abnormal laboratory test results [ Time Frame: Baseline, Week 8, Week 16, Week 24 ]
    A complete blood count (CBC) and comprehensive metabolic panel (CMP) will be measured.



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 50-80 years
  2. Clinical diagnosis of early Alzheimer's disease (Clinical Dementia Rating (CDR) = 0.5, Mini-Mental State Exam (MMSE) = 24-30)
  3. If using drugs to treat symptoms related to Alzheimer's disease, doses must be stable for at least eight weeks prior to screening visit 1
  4. Labs: Adequate blood cell counts (white blood cells: 4,000-111,000 cells per microliter (cells/mcL); absolute neutrophil count: 1,800-8,700 cells/mcL; platelets: 120-500 K/µL; hemoglobin 12.0-17.5 grams/dL); LFT's within 2x normal value; creatinine clearance test (CrCl) ≥ 50 mL/min; cholesterol (≤260 mg/dl), triglycerides≤ 400 mg/dl), and glucose control (HbA1c ≤ 8%). Prothrombin time/partial thromboplastin time/international normalized ratio (PT/PTT/INR) within normal limits
  5. Body mass index (BMI) within range of 19 - 35 kg/m2
  6. Must have a reliable informant or caregiver
  7. Participants must have no plans to travel that interfere with study visits

Exclusion Criteria:

  1. Any medical or neurologic condition (other than Alzheimer's Disease) that might be a contributing cause of the subject's cognitive impairment
  2. Clinically significant unstable psychiatric illness in the past six months
  3. Significant hearing, vision, or motor deficits that interfere with participation
  4. Alcohol or drug abuse/dependence in the past six months
  5. Stroke, transient ischemic attack, or unexplained loss of consciousness in the past six months
  6. Unstable angina, myocardial infarction, advanced chronic heart failure, or clinically significant conduction abnormalities within the past six months
  7. Relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities
  8. Diagnosis of HIV infection or AIDS (CD4 count < 200), HIV/Hepatitis B Virus (HBV) co-infection, HBV or human T-cell leukemia virus infection
  9. History of impaired renal or liver function
  10. Current use of memantine or sorbitol-containing products
  11. Individuals with HIV, HBV, or who have current/previous use of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) or non-NRTIs.
  12. Poorly controlled blood pressure (BP) (systolic BP > 160, diastolic BP > 90 mmHg)
  13. Uncontrolled diabetes (HbA1c > 8%, or the current use of insulin)
  14. Significant systematic illness or infection in the past 30 days
  15. Pregnant women

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): NCT04552795


Contacts
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Contact: Bess Frost, PhD (210) 562-5037 bfrost@uthscsa.edu
Contact: Antoinette Lewis, MPA (210) 450-8023 lewisa7@uthscsa.edu

Locations
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United States, Texas
Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases Recruiting
San Antonio, Texas, United States, 78229
Contact: Bess Frost, PhD    210-562-5037    bfrost@uthscsa.edu   
Principal Investigator: Bess Frost, PhD         
Principal Investigator: Campbell Sullivan, PsyD         
Sam and Ann Barshop Institute for Longevity & Aging Studies Recruiting
San Antonio, Texas, United States, 78229
Contact: Bess Frost, PhD    210-562-5037    bfrost@uthscsa.edu   
Contact: Antoinette Lewis, MPA    210-450-8023    lewisa7@uthscsa.edu   
Principal Investigator: Bess Frost, PhD         
Principal Investigator: Nicolas Musi, MD         
University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Bess Frost, PhD    210-562-5037    bfrost@uthscsa.edu   
Contact: Antoinette Lewis, MPA    210-450-8023    lewisa7@uthscsa.edu   
Principal Investigator: Bess Frost, PhD         
Principal Investigator: Campbell Sullivan, PsyD         
Principal Investigator: Nicolas Musi, MD         
Sponsors and Collaborators
Bess Frost, PhD
Owens Medical Research Foundation
Investigators
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Principal Investigator: Bess Frost, PhD Univ of Texas Health Science Center at San Antonio
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Responsible Party: Bess Frost, PhD, Associate Professor, Sam and Ann Barshop Instititute for Aging and Longevity Studies, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Disorders, Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT04552795    
Other Study ID Numbers: HSC20200396H
First Posted: September 17, 2020    Key Record Dates
Last Update Posted: March 19, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Protocol, Published Data
Supporting Materials: Study Protocol
Time Frame: After study completion, upon publication of data and on ClinicalTrials.gov 1 year after primary completion date of study.
Access Criteria: Data will be analyzed by the study investigators.

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