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

• ClinicalTrials.gov Identifier: NCT04685590
• Recruitment Status: Recruiting
• First Posted: December 28, 2020
• Last Update Posted: December 23, 2022
• Sponsor: Wake Forest University Health Sciences
• Collaborator: The University of Texas Health Science Center at San Antonio
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

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

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease, Early Onset; Mild Cognitive Impairment	Drug: Dasatinib + Quercetin; Other: Placebo Capsules	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase II Clinical Trial to Evaluate the Safety and Feasibility of Senolytic Therapy in Alzheimer's Disease
• Actual Study Start Date: December 22, 2021
• Estimated Primary Completion Date: January 2027
• Estimated Study Completion Date: January 2032

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. Change in cellular senescence blood marker Senescence-Associated Secretory Phenotype (SASP) composite score [ Time Frame: Baseline to Week 12 ]
   Composite score (average z-score of log-transformed values) of ten primary SASP factors measured in blood.
2. Change in cellular senescence blood marker Cluster of Differentiation 3 (CD3) in blood [ Time Frame: Baseline to Week 12 ]
   Primary markers of cellular senescence CD3 measured in blood.
3. Change in cellular senescence blood marker cyclin-dependent kinase inhibitor 2A (p16INK4A+) in blood [ Time Frame: Baseline to Week 12 ]
   Primary markers of cellular senescence p16INK4A+ measured in blood.
4. Change in cellular senescence blood marker T cells in blood [ Time Frame: Baseline to Week 12 ]
   Primary markers of cellular senescence T cells measured in blood.
5. Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) slope [ Time Frame: Baseline to Week 48 ]
   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).
6. Change in the 14 - item Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog 14) slope [ Time Frame: Baseline to Week 48 ]
   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.
7. Change in Positron Emission Tomography (PET) - Computed Tomography (CT) - brain tau pathology [ Time Frame: Baseline to Week 48 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Miranda Orr, PhD; 336-713-8830; morr@wakehealth.edu

Contact: Sarah B Bohlman, MSL; 336-716-7354; sarabrow@wakehealth.edu

Locations

United States, North Carolina

Wake Forest Health Sciences; Recruiting

Winston-Salem, North Carolina, United States, 27157

Contact: Miranda Orr, PhD 336-713-8830 morr@wakehealth.edu

Contact: Sarah B Bohlman, MSL 336-716-7354 sarabrow@wakehealth.edu

Sponsors and Collaborators

Wake Forest University Health Sciences

The University of Texas Health Science Center at San Antonio

Investigators

• Principal Investigator: Suzanne Craft, PhD; Wake Forest University Health Sciences
• Principal Investigator: Miranda Orr, PhD; Wake Forest University Health Sciences

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT04685590
• Other Study ID Numbers: IRB00067429
• First Posted: December 28, 2020
• Last Update Posted: December 23, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Wake Forest University Health Sciences:

amnestic mild cognitive impairment; Alzheimer Disease

Additional relevant MeSH terms:

Dasatinib; Quercetin; Alzheimer Disease; Cognitive Dysfunction; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antioxidants; Protective Agents; Physiological Effects of Drugs