Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD) Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Clinical Trial to Evaluate the Safety and Feasibility of Senolytic Therapy in Alzheimer's Disease

Conditions
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Alzheimer Disease, Early Onset, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Dasatinib + Quercetin
* Other: Placebo Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 65 years and older at screening Both sexes All ethnicities Diagnosis of amnestic mild cognitive impairment (aMCI) or early Alzheimer's disease (AD) Elevated tau protein as determined by CSF Aβ:tau ratio 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 by Site PI). 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 Must speak English fluently and have at least six years of formal education Exclusion Criteria: Body mass index (BMI)>40 kg/m2 corrected QT interval (QTc) >450 msec MRI contraindications including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker. 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 Diagnostic and Statistical Manual of Mental Disorders (DSM V criteria) Uncontrolled diabetes (HbA1c > 7% or the current use of insulin or sulfonylureas) Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg) eGFR < 10 ml/ min/ 1.73 m2. Myocardial infarction, angina, stroke, or transient ischemic attack in the past 6 months. Chronic heart failure. Presence of significant liver disease with total bilirubin >2X upper limit. Inability to tolerate oral medication. Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus, or sirolimus). Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy. Subjects on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.) other than low-dose aspirin Subjects taking H2 antagonists or proton pump inhibitors who are unable or unwilling to reduce or hold therapy for at least 2 days prior to and during each of the 2-day courses of Dasatinib plus quercetin dosing. Instead, subjects may use antacids prior to and during each of the 2-day courses of Dasatinib plus quercetin dosing. Subjects taking the following other drugs if they cannot be held for at least 2 days before and during administration of study drug or placebo: digoxin, lithium, all statins, repaglidine, bosentan, gemfibrozil, olmesartan, enalapril, valsartan, methotrexate, corticosteroids, thyroid hormones, eluxadoline, eltrombopag, nitroglycerin, pioglitazone, glyburide, enzalutamide, ezetimibe, colchicine, imatinib, cyclosporine, tacrolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, heparin, full dose ASA, clopidogrel, celecoxib, desipramine, thioridazine, venlafaxine, tizanidine, atomoxetine, voriconazole, citalopram, diazepam, escitalopram, propranolol, clozapine, cyclobenzaprine, mexiletine, olanzapine, ondansetron, riluzole. Presence of any condition that the Investigator believes would put the subject at risk or would preclude the patient from successfully completing all aspects of the trial.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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. | Drug: Dasatinib + Quercetin<br>* D+Q will be 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.<br>|
| Placebo Comparator: Placebo<br>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. | Other: Placebo Capsules<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Events (SAEs) and Adverse Events (AEs) in treatment group as compared to placebo group | 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. | Baseline to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cellular senescence blood marker Senescence-Associated Secretory Phenotype (SASP) composite score | Composite score (average z-score of log-transformed values) of ten primary SASP factors measured in blood. | Baseline to Week 12 | 
| Change in cellular senescence blood marker Cluster of Differentiation 3 (CD3) in blood | Primary markers of cellular senescence CD3 measured in blood. | Baseline to Week 12 | 
| Change in cellular senescence blood marker cyclin-dependent kinase inhibitor 2A (p16INK4A+) in blood | Primary markers of cellular senescence p16INK4A+ measured in blood. | Baseline to Week 12 | 
| Change in cellular senescence blood marker T cells in blood | Primary markers of cellular senescence T cells measured in blood. | Baseline to Week 12 | 
| Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) slope | CDR is calculated on the basis of testing six different cognitive and behavioral domains such as memory, orientation, judgment and problem solving, community affairs, home and hobbies performance, and personal care. The CDR is based on a scale of 0-3: no dementia (CDR = 0), questionable dementia (CDR = 0.5), MCI (CDR = 1), moderate cognitive impairment (CDR = 2), and severe cognitive impairment (CDR = 3). The six domains are often summed to create a 0 - 18 sum of the boxes score. CDR-SB has been shown to demonstrate sensitivity to cognitive changes associated with progression of amnestic mild cognitive impairment (aMCI) and early Alzheimer's Disease (AD). | Baseline to Week 48 | 
| Change in the 14 - item Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog 14) slope | A psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment. Scores from the original portion of the test range from 0 (best) to 65 (worse), and are added to the mean of the words not immediately recalled (max of 10) and the number of items not recalled after a delay (ranging from 0-10) all total the maximum score of 85. A positive change indicates cognitive worsening. | Baseline to Week 48 | 
| Change in Positron Emission Tomography (PET) - Computed Tomography (CT) - brain tau pathology | Tau levels in the brain will measured by 18F AV1451 PET imaging to assess target engagement of dasatinib and quercetin (D+Q) and impact on brain tau as a relevant Alzheimer's Disease (AD) biomarker. | Baseline to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer Disease, amnestic mild cognitive impairment