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

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

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

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment; Alzheimer Disease, Early Onset
• Intervention / Treatment: Drug: Dasatinib + Quercetin; Other: Placebo Capsules

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.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Miranda Orr, PhD; Phone Number: 336-713-8830; Email: morr@wakehealth.edu
• Study Contact Backup: Name: Sarah B Bohlman, MSL; Phone Number: 336-716-7354; Email: sarabrow@wakehealth.edu

Study Locations

• Spain
  • Barcelona, Spain
    • Not yet recruiting
    • Fundación ACE Clinical Site
    • Principal Investigator: Merce Boada Rovira
    • Contact: Mercé Boada Rovira
  • Barcelona, Spain
    • Not yet recruiting
    • Hospital Clínic de Barcelona Site
    • Contact: Raquel Sánchez del Valle; Email: rsanchez@clinic.cat
    • Principal Investigator: Raquel Sánchez del Valle
  • Barcelona, Spain
    • Not yet recruiting
    • Sant Pau Clinical Site
    • Contact: Rafael Blesa González; Email: rblesa@santpau.cat
    • Principal Investigator: Rafael Blesa González
  • Sevilla, Spain
    • Not yet recruiting
    • FISEVI Clinical Site
    • Contact: Emilio Franco Macías; Email: efranco17@gmail.com
    • Principal Investigator: Emilio Franco Macías
• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Wake Forest Health Sciences
      • Contact: Miranda Orr, PhD; Phone Number: 336-713-8830; Email: morr@wakehealth.edu
      • Contact: Sarah B Bohlman, MSL; Phone Number: 336-716-7354; Email: sarabrow@wakehealth.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 63 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ages 65 years and older at screening
2. Both sexes
3. All ethnicities
4. Diagnosis of amnestic mild cognitive impairment (aMCI) or early Alzheimer's disease (AD)
5. Elevated tau protein as determined by CSF Aβ:tau ratio
6. 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.
7. 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%.
8. prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR) within normal limits
9. 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).
10. 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.
11. Participants must have no travel plans that would interfere with scheduling visits following consent over the 12 months of study duration
12. Must speak English fluently and have at least six years of formal education

Exclusion Criteria:

1. Body mass index (BMI)>40 kg/m2
2. corrected QT interval (QTc) >450 msec
3. MRI contraindications including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker.
4. Pregnancy
5. 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.
6. 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)
7. Uncontrolled diabetes (HbA1c > 7% or the current use of insulin or sulfonylureas)
8. Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg)
9. eGFR < 10 ml/ min/ 1.73 m2.
10. Myocardial infarction, angina, stroke, or transient ischemic attack in the past 6 months.
11. Chronic heart failure.
12. Presence of significant liver disease with total bilirubin >2X upper limit.
13. Inability to tolerate oral medication.
14. 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).
15. Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy.
16. Subjects on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.) other than low-dose aspirin
17. 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.
18. 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.
19. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Dasatinib + Quercetin; 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.
Placebo Comparator: 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.	Other: Placebo Capsules; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: The University of Texas Health Science Center at San Antonio
• Investigators: Principal Investigator: Miranda Orr, PhD, Wake Forest University Health Sciences; Principal Investigator: Suzanne Craft, PhD, Wake Forest University Health Sciences

Publications and helpful links

General Publications

• Gonzales MM, Krishnamurthy S, Garbarino V, Daeihagh AS, Gillispie GJ, Deep G, Craft S, Orr ME. A geroscience motivated approach to treat Alzheimer's disease: Senolytics move to clinical trials. Mech Ageing Dev. 2021 Dec;200:111589. doi: 10.1016/j.mad.2021.111589. Epub 2021 Oct 21.
• Guerrero A, De Strooper B, Arancibia-Carcamo IL. Cellular senescence at the crossroads of inflammation and Alzheimer's disease. Trends Neurosci. 2021 Sep;44(9):714-727. doi: 10.1016/j.tins.2021.06.007. Epub 2021 Aug 5.

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2021
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: December 22, 2020
• First Submitted That Met QC Criteria: December 22, 2020
• First Posted (Actual): December 28, 2020

Study Record Updates

• Last Update Posted (Estimated): December 14, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Alzheimer Disease; amnestic mild cognitive impairment
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Protein Kinase Inhibitors; Antioxidants; Dasatinib; Quercetin
• Other Study ID Numbers: IRB00067429

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No