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

Phase 1

Completed

• Conditions: Alzheimer Disease, Early Onset
• Interventions: Drug: 3TC

• Registration Number: NCT04552795
• Lead Sponsor: 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.

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.

Study Timeline

• Study First Submitted: 2020-08-11
• Study First Submitted QC: 2020-09-10
• Study First Posted: 2020-09-17
• Study Start: 2021-02-15
• Primary Completion: 2023-05-04
• Study Completion: 2023-11-04
• Results First Submitted: 2024-05-03
• Status Verified: 2024-07
• Results First Submitted QC: 2024-08-07
• Last Update Submitted: 2024-08-07
• Results First Posted: 2024-08-09
• Last Update Posted: 2024-08-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-Label 3TC	3TC	12 subjects will receive 3TC, 300-mg, daily for 24 weeks.

Primary Outcome Measures

Name	Time	Method
3TC CNS Penetration	24 weeks	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).
Change in Reverse Transcriptase Activity From Baseline to 24 Weeks in Plasma of Study Participants	Baseline to 24 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Incidence of Treatment-Emergent Adverse Events	Baseline to Week 24	Incidence of adverse and serious adverse events potentially due to study drug
Change in Dementia Severity From Baseline to Week 24 of Treatment Based on the PACC-5 Z-score	Baseline to 24 weeks	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.
Incidence of Treatment-Emergent Abnormal Vital Signs	Baseline to Week 24	Blood pressure, heart rate, temperature, and respiration, are measured and any significant change of any of these vital signs that show a significant change from the baseline value are reported as an event.

Trial Locations

Locations (3)

Sam and Ann Barshop Institute for Longevity & Aging Studies; 🇺🇸 San Antonio, Texas, United States

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases; 🇺🇸 San Antonio, Texas, United States

University of Texas Health Science Center at San Antonio; 🇺🇸 San Antonio, Texas, United States