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

The University of Texas Health Science Center at San Antonio12 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Alzheimer Disease, Early Onset

Interventions

3TCDRUG

12 subjects will be administered 3TC, 300mg once daily, via an oral tablet for 24 weeks.

Eligibility

Sex: ALLMin age: 50 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Locations (3)

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases

San Antonio, Texas, United States

Sam and Ann Barshop Institute for Longevity & Aging Studies

San Antonio, Texas, United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Outcomes

Primary Outcomes

Change in Reverse Transcriptase Activity From Baseline to 24 Weeks in Plasma of Study Participants

The extent of 3TC target engagement was measured by calculating the change in reverse transcriptase activity in plasma of participants at baseline compared to week 24 using a modified version of the EnzCheck Reverse Transcriptase (RT) Assay.

Time frame: Baseline to 24 weeks

3TC CNS Penetration

CNS penetration was calculated based on the ratio of CSF to plasma levels of 3TC after 24 weeks of 3TC using High Performance Liquid Chromatography with tandem Mass Spectrometry (HPLC/MS/MS).

Time frame: 24 weeks

Secondary Outcomes

Change in Dementia Severity From Baseline to Week 24 of Treatment Based on the PACC-5 Z-score

The Preclinical Alzheimer Cognitive Composite (PACC-5) score is calculated as a mean normative Z-score across five measures, including MMSE (0-30), Logical Memory Delayed Recall (0-25), Digit-Symbol Coding Test (0-93), Category Fluency, and Free and Cued Selective Reminding Test (0-96). Although typically relegated to individuals with prodromal and asymptomatic disease, the PACC-5 was included given its sensitivity to Alzheimer's disease-specific cognitive change.To calculate the Z score for each patient; the formula is Z = (x - M)/SD, where x is the patient's verbal memory raw score and M and SD are the estimates from the previous step. Positive Z values indicate scores that are greater than the mean of the pooled sample, and negative values indicate scores that are less than the pooled mean.A Z-score of zero represents the mean for this study population. Negative values mean a worse outcome than the standard population.

Time frame: Baseline to 24 weeks

Incidence of Treatment-Emergent Adverse Events

Incidence of adverse and serious adverse events potentially due to study drug

Time frame: Baseline to Week 24

Incidence of Treatment-Emergent Abnormal Vital Signs

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.