Alzheimer Disease, Early Onset
Conditions
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.
Interventions
DRUG3TC
12 subjects will be administered 3TC, 300mg once daily, via an oral tablet for 24 weeks.
Sponsors
Owens Medical Research Foundation
The University of Texas Health Science Center at San Antonio
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, one arm study.
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 Adverse Events | Baseline to Week 24 | Incidence of adverse and serious adverse events potentially due to study drug |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from University of Texas Health San Antonio outpatient clinics and through local flier/newspaper advertisements.
Participants by arm
| Arm | Count |
|---|---|
| Open-Label 3TC 12 subjects will receive 3TC, 300-mg, daily for 24 weeks.
3TC: 12 subjects will be administered 3TC, 300mg once daily, via an oral tablet for 24 weeks. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Open-Label 3TC |
|---|---|
| Age, Customized Age group 65 - 74 years of age | 5 Participants |
| Age, Customized Age group <= 65 years of age | 3 Participants |
| Age, Customized Age group 75 - 84 years of age | 4 Participants |
| Age, Customized Average age (min, max) | 69.4 years |
| Average BMI | 25.2 kg/m^2 STANDARD_DEVIATION 4.6 |
| Concurrent Treatment with Donepezil | 7 Participants |
| Duration of Symptoms Prior to Trial 1-2 years | 2 Participants |
| Duration of Symptoms Prior to Trial <= 1 year | 1 Participants |
| Duration of Symptoms Prior to Trial 3+ years | 2 Participants |
| Duration of Symptoms Prior to Trial Unknown | 7 Participants |
| Education Level | 15.3 years STANDARD_DEVIATION 2.4 |
| Past Medical History <= 1 Comorbidities | 2 Participants |
| Past Medical History 2+ Comorbidities | 10 Participants |
| Race/Ethnicity, Customized Race African American | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants |
| Race/Ethnicity, Customized Race White, Hispanic | 1 Participants |
| Race/Ethnicity, Customized Race White, non-Hispanic | 9 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 2 / 12 |
| serious Total, serious adverse events | 1 / 12 |
Outcome results
Primary
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
Population: Three subjects removed due to missed blood or CSF draw; one subject removed based on the ROUT method of outlier analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Open-Label 3TC | 3TC CNS Penetration | 0.502 ng/mL |
Primary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open-Label 3TC | Change in Reverse Transcriptase Activity From Baseline to 24 Weeks in Plasma of Study Participants | -0.0074 Enzyme units | Standard Error 0.03 |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open-Label 3TC | Change in Dementia Severity From Baseline to Week 24 of Treatment Based on the PACC-5 Z-score | -1.59 Z-score |
| POST-Treatment | Change in Dementia Severity From Baseline to Week 24 of Treatment Based on the PACC-5 Z-score | -1.59 Z-score |
Secondary
Incidence of Treatment-Emergent Abnormal Vital Signs
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.
Time frame: Baseline to Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-Label 3TC | Incidence of Treatment-Emergent Abnormal Vital Signs | 0 Events |
Secondary
Incidence of Treatment-Emergent Adverse Events
Incidence of adverse and serious adverse events potentially due to study drug
Time frame: Baseline to Week 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open-Label 3TC | Incidence of Treatment-Emergent Adverse Events | Gastrointestinal bleeding due to peptic ulcer | 1 Participants |
| Open-Label 3TC | Incidence of Treatment-Emergent Adverse Events | No adverse events | 11 Participants |