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

Primary Purpose

Alzheimer Disease, Early Onset

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
3TC
Sponsored by
Bess Frost, PhD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alzheimer Disease, Early Onset

Eligibility Criteria

50 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Aged 50-99 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

Sites / Locations

  • Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases
  • Sam and Ann Barshop Institute for Longevity & Aging Studies
  • University of Texas Health Science Center at San Antonio

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open-Label 3TC

Arm Description

12 subjects will receive 3TC, 300-mg, daily for 24 weeks.

Outcomes

Primary Outcome Measures

Change in reverse transcriptase activity from baseline to 24 weeks in blood and cerebrospinal fluid (CSF) of study participants
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.
3TC CNS penetration in participants
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

Change in dementia severity from baseline to week 24 of treatment based on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)
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.
Incidence of treatment-emergent adverse events
Incidence of adverse and serious adverse events likely due to study drug will be recorded.
Incidence of treatment-emergent abnormal vital signs
Vital signs including blood pressure, heart rate, temperature, and respiration will be measured.
Incidence of treatment-emergent abnormal laboratory test results
A complete blood count (CBC) and comprehensive metabolic panel (CMP) will be measured.

Full Information

First Posted
August 11, 2020
Last Updated
May 12, 2023
Sponsor
Bess Frost, PhD
Collaborators
Owens Medical Research Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT04552795
Brief Title
Pilot Study to Investigate the Safety and Feasibility of AntiRetroviral Therapy for Alzheimer's Disease
Acronym
ART-AD
Official Title
Pilot Study to Investigate the Safety and Feasibility of AntiRetroviral Therapy for Alzheimer's Disease (ART-AD)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 15, 2021 (Actual)
Primary Completion Date
May 4, 2023 (Actual)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Bess Frost, PhD
Collaborators
Owens Medical Research Foundation

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease, Early Onset

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Open-label, one arm study.
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Open-Label 3TC
Arm Type
Experimental
Arm Description
12 subjects will receive 3TC, 300-mg, daily for 24 weeks.
Intervention Type
Drug
Intervention Name(s)
3TC
Other Intervention Name(s)
Epivir, lamivudine
Intervention Description
12 subjects will be administered 3TC, 300mg once daily, via an oral tablet for 24 weeks.
Primary Outcome Measure Information:
Title
Change in reverse transcriptase activity from baseline to 24 weeks in blood and cerebrospinal fluid (CSF) of study participants
Description
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.
Time Frame
Baseline to 24 weeks
Title
3TC CNS penetration in participants
Description
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).
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Change in dementia severity from baseline to week 24 of treatment based on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)
Description
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.
Time Frame
Baseline to 24 weeks
Title
Incidence of treatment-emergent adverse events
Description
Incidence of adverse and serious adverse events likely due to study drug will be recorded.
Time Frame
Baseline, Week 8, Week 16, Week 24
Title
Incidence of treatment-emergent abnormal vital signs
Description
Vital signs including blood pressure, heart rate, temperature, and respiration will be measured.
Time Frame
Baseline, Week 8, Week 16, Week 24
Title
Incidence of treatment-emergent abnormal laboratory test results
Description
A complete blood count (CBC) and comprehensive metabolic panel (CMP) will be measured.
Time Frame
Baseline, Week 8, Week 16, Week 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Aged 50-99 years Clinical diagnosis of early Alzheimer's disease (Clinical Dementia Rating (CDR) = 0.5, Mini-Mental State Exam (MMSE) = 24-30) 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 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 Body mass index (BMI) within range of 19 - 35 kg/m2 Must have a reliable informant or caregiver Participants must have no plans to travel that interfere with study visits Exclusion Criteria: Any medical or neurologic condition (other than Alzheimer's Disease) that might be a contributing cause of the subject's cognitive impairment Clinically significant unstable psychiatric illness in the past six months Significant hearing, vision, or motor deficits that interfere with participation Alcohol or drug abuse/dependence in the past six months Stroke, transient ischemic attack, or unexplained loss of consciousness in the past six months Unstable angina, myocardial infarction, advanced chronic heart failure, or clinically significant conduction abnormalities within the past six months Relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities Diagnosis of HIV infection or AIDS (CD4 count < 200), HIV/Hepatitis B Virus (HBV) co-infection, HBV or human T-cell leukemia virus infection History of impaired renal or liver function Current use of memantine or sorbitol-containing products Individuals with HIV, HBV, or who have current/previous use of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) or non-NRTIs. Poorly controlled blood pressure (BP) (systolic BP > 160, diastolic BP > 90 mmHg) Uncontrolled diabetes (HbA1c > 8%, or the current use of insulin) Significant systematic illness or infection in the past 30 days Pregnant women
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bess Frost, PhD
Organizational Affiliation
Univ of Texas Health Science Center at San Antonio
Official's Role
Principal Investigator
Facility Information:
Facility Name
Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Sam and Ann Barshop Institute for Longevity & Aging Studies
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University of Texas Health Science Center at San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Protocol, Published Data
IPD Sharing Time Frame
After study completion, upon publication of data and on ClinicalTrials.gov 1 year after primary completion date of study.
IPD Sharing Access Criteria
Data will be analyzed by the study investigators.

Learn more about this trial

Pilot Study to Investigate the Safety and Feasibility of AntiRetroviral Therapy for Alzheimer's Disease

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