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

Study Overview
=================
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.

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

Conditions
-----------------
Alzheimer Disease, Early Onset

Intervention / Treatment
-----------------
* Drug: 3TC


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, one arm study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label 3TC<br>12 subjects will receive 3TC, 300-mg, daily for 24 weeks. | Drug: 3TC<br>* 12 subjects will be administered 3TC, 300mg once daily, via an oral tablet for 24 weeks.<br>* Other names: lamivudine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to 24 weeks | 
| 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). | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to 24 weeks | 
| Incidence of treatment-emergent adverse events | Incidence of adverse and serious adverse events likely due to study drug will be recorded. | Baseline, Week 8, Week 16, Week 24 | 
| Incidence of treatment-emergent abnormal vital signs | Vital signs including blood pressure, heart rate, temperature, and respiration will be measured. | Baseline, Week 8, Week 16, Week 24 | 
| Incidence of treatment-emergent abnormal laboratory test results | A complete blood count (CBC) and comprehensive metabolic panel (CMP) will be measured. | Baseline, Week 8, Week 16, Week 24 |