Phase II Clinical Trial to Evaluate the Safety and Feasibility of Senolytic Therapy in Alzheimer's Disease
Overview
- Phase
- Phase 2
- Intervention
- Dasatinib + Quercetin
- Conditions
- Alzheimer Disease, Early Onset
- Sponsor
- Washington University School of Medicine
- Enrollment
- 48
- Locations
- 5
- Primary Endpoint
- Serious Adverse Events (SAEs) and Adverse Events (AEs) in treatment group as compared to placebo group
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
The objective of the study is to determine the safety, feasibility, and efficacy of senolytics in older adults with amnestic mild cognitive impairment (MCI) or early-stage AD (Clinical Dementia Rating (CDR)=0.5 or 1) who are tau PET positive
Detailed Description
This study is a Phase II multi-site, randomized, double-blind placebo controlled trial to determine safety, feasibility, and efficacy of senolytics in older adults with amnestic mild cognitive impairment (MCI) or early-stage AD (Clinical Dementia Rating (CDR)=0.5 or 1) who are tau PET positive.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Ages 60 years and older at study entry
- •All ethnicities
- •Diagnosis of amnestic mild cognitive impairment (aMCI) or early Alzheimer's disease (AD)
- •Elevated tau protein as determined by CSF performed during screening. Evidence of elevated tau from previously available CSF samples will also be allowed for eligibility determination.
- •FDA-approved medications for AD (e.g. donepezil, rivastigmine, galantamine) are permitted as long as the participant has been maintained on a stable dose for at least three months prior to study entry.
- •Labs: Normal blood cell counts, normal liver and renal function without clinically significant excursions as determined by coordinating center Medical Monitor. Total cholesterol \<240 mg/dl, HbA1c ≤ 7%.
- •Prothrombin Time (PT)/Partial Thromboplastin Time (PTT)/International Normalized Ratio (INR) within normal limits.
- •Participants must have the ability to provide written consent or be accompanied by a Legally Authorized Representative designated to sign informed consent (if determined not to have decision capacity).
- •Participants must have a study partner who agrees to participate throughout the duration of the study. The study partner must have frequent and sufficient contact (approximately 10 hours per week) with the participant and be able to provide accurate information regarding the participant's cognitive and functional abilities.
- •Participants must have no travel plans that would interfere with scheduling visits following consent over the 12 months of study duration.
Exclusion Criteria
- •Body mass index (BMI)\>40 kg/m
- •Average QTcF (from 3 ECGs obtained at least one minute apart) at screening of ≥450msec in males and ≥460msec in females.
- •MRI contraindications including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker.
- •Pregnancy or possible pregnancy.
- •Any significant neurologic disease other than prodromal or early AD including Parkinson's disease, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities.
- •Current or history of alcohol or substance abuse or dependence within the past 2 years per Diagnostic and Statistical Manual of Mental Disorders (DSM V criteria).
- •Endorsement of current suicidality or suicidal ideation on the screening C-SSRS.
- •Uncontrolled diabetes (HbA1c \> 7% or the current use of insulin or sulfonylureas).
- •Poorly controlled blood pressure (systolic BP\>160, diastolic BP\>90 mmHg) based on two or more readings and as determined by the PI/study clinician.
- •eGFR \< 10 ml/ min/ 1.73 m
Arms & Interventions
Treatment
Dasatinib (D) is given as (1) 100mg capsule daily for 2 consecutive days (Sprycel®, Bristol Myers Squibb). Quercetin (Q) will be given as (4) 250 mg capsules daily (total 1000 mg daily) for the same 2 consecutive days (Thorne Research). Both are administered orally.
Intervention: Dasatinib + Quercetin
Placebo
Matching placebo capsules following the same administration protocol as the experimental treatment - administered once daily (1st dose of each cycle will be given, supervised, at the clinic visit; the 2nd dose will be taken at home) for 2 consecutive days followed by a 13-day (+/- 2 day) no-drug period for 12 consecutive weeks for 6 rounds of administration.
Intervention: Placebo Capsules
Outcomes
Primary Outcomes
Serious Adverse Events (SAEs) and Adverse Events (AEs) in treatment group as compared to placebo group
Time Frame: Baseline to Week 48
Adverse Events (AEs) and SAEs will be collected at each in-person visit and at scheduled telephone visits from baseline to week 48. Incidence of SAEs between groups (treatment vs. placebo) will be reviewed by the Data Safety Monitoring Board (DSMB) for clinical significance.
Secondary Outcomes
- Change in cellular senescence blood marker Cluster of Differentiation 3 (CD3) in blood(Baseline to Week 12)
- Change in cellular senescence blood marker cyclin-dependent kinase inhibitor 2A (p16INK4A+) in blood(Baseline to Week 12)
- Change in cellular senescence blood marker T cells in blood(Baseline to Week 12)
- Change in cellular senescence blood marker Senescence-Associated Secretory Phenotype (SASP) composite score(Baseline to Week 12)
- Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) slope(Baseline to Week 48)
- Change in Positron Emission Tomography (PET) - Computed Tomography (CT) - brain tau pathology(Baseline to Week 48)
- Change in the 14 - item Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog 14) slope(Baseline to Week 48)