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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Wake Forest University Health Sciences

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2024-12-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Alzheimer's Drug Discovery Foundation (ADDF)

External identifiers

EU CT number

2024-514411-95-00

ClinicalTrials.gov

NCT04685590

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Assess the safety and feasibility of 12 weeks of treatment with senolytics (dasatinib plus quercetin) compared with placebo in adults with aMCI or early-stage AD with elevated tau per CSF and determine effects on key blood markers of cellular senescence.

Secondary objectives 2

1. To test the hypothesis that 12 weeks of treatment with senolytics as compared to placebo in adults with aMCI/early AD will improve functional performance measured by the CDR Sum of Boxes (CDR-SB).
2. To test the hypothesis that 12 weeks of treatment with senolytics as compared to placebo in adults with aMCI/early AD will improve cognitive performance measured by the ADAS-Cog14.

Conditions and MedDRA coding

Amnestic mild cognitive impairment (aMCI, single or multi-domain) or early stage Alzheimer's Disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Ages 60 years and older at study entry
2. Both sexes
3. All ethnicities
4. Diagnosis of aMCI or early AD per the following criteria: a. aMCI, i. CDR 0.5, Memory Box score ≥ 0.5, ii. MMSE 24-30, iii. WMS-IV Logical Memory II < 11 for ≥16 years education, ≤ 9 for 8-15 years education, ≤ 6 for 0-7 years education (exceptions to cutoffs may be allowed on a case-by-case basis upon review and adjudication by the study investigators), b. Early AD, i. CDR 0.5 or 1.0, ii. MMSE 20-30, iii. WMS-IV Logical Memory II ≤ 8 for ≥16 years education, ≤ 4 for 8-15 years education, ≤ 2 for 0-7 years education (exceptions to cutoffs may be allowed on a case-by-case basis upon review and adjudication by the study investigators)
5. 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.
6. 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 baseline visit.
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. PT/PTT/INR within normal limits
9. Participants must have the ability to provide written consent
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. The study partner must provide written consent for their own participation.
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 Spanish fluently and have at least six years of formal education
13. Participants must be fully vaccinated against COVID-19 (2 doses) with the primary vaccine series with any dose of the vaccine received at least 30 days prior to initiation of the study drug. COVID boosters are allowed during study intervention period when scheduled at least four days before or after administration of the investigational product.

Exclusion criteria 22

1. Body mass index (BMI)>40 kg/m2
2. Average QTcF (from 3 ECGs obtained at least one minute apart) at screening of ≥450msec in males and ≥460msec in females
3. MRI contraindications including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker.
4. Pregnancy or possible 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 (DSM V criteria)
7. Endorsement of current suicidality or suicidal ideation on the screening C-SSRS
8. Uncontrolled diabetes (HbA1c >7% or the current use of insulin or sulfonylureas)
9. 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
10. eGFR < 10 ml/ min/ 1.73 m2.
11. Myocardial infarction, angina, stroke, or transient ischemic attack in the past 6 months.
12. Chronic heart failure.
13. Presence of significant liver disease with total bilirubin >2X upper limit.
14. Inability to tolerate oral medication.
15. 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).
16. Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, or other chemotherapy.
17. Subjects on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.) other than low dose aspirin unless able to be held for 2 days prior to LP and with the documented approval of the prescribing clinician.
18. 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.
19. Concomitant use of strong CYP3A4 inhibitors (see list in section 5.5).
20. Co-enrollment in another ADRD research study with a potentially disease-modifying intervention or study drug that may impact senescent cells. Participants previously enrolled in a study meeting these criteria are eligible to screen after a washout period of ≥6 months from date of last dose to date of screening.
21. 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.
22. Use of anti-amyloid therapies (e.g. aducanumab, lecanamab)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Safety of 12 weeks of treatment with dasatinib and quercetin as compared to placebo, as measured by incidence of AEs and SAEs from baseline to week 48. Treatment with Dasatinib + Quercetin is expected to be as safe as placebo when comparing incidence of SAEs between groups. AEs and SAEs will be collected at each in-person visit and at scheduled telephone visits.

Secondary endpoints 4

1. Change in blood senescence marker SASP composite score from baseline to week 12. Biomarker analysis will include a composite score generated from ten core SASP factors (i.e., IL-9, IL-1a, IL-6, IL-2, MMP-9, MMP-12, MMP-2, FGF-2, IL-1RA, and GM-CSF). Blood collections will be obtained at baseline, after 12 weeks treatment of D+Q (or placebo), and every 12 weeks during follow up visits under fasted conditions.
2. Change in p16INK4a+/CD3+ T cells in blood from baseline to week 12. The biomarker analyses will include quantifying senescent cells in blood (p16INK4a+/CD3+ T cells). Blood collections will be obtained at baseline, after 12 weeks treatment of D+Q (or placebo), and every 12 weeks during follow up visits under fasted conditions.
3. Change in CDR Sum of Boxes (CDR-SB) slope from screening to week 48. The CDR will be performed at screening, at week 12 of treatment and end of study at week 48.
4. Change in ADAS-Cog slope from baseline to week 48.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Wake Forest University Health Sciences

Sponsor organisation

Wake Forest University Health Sciences

Address

Medical Center Boulevard

City

Winston Salem

Postcode

27157-0001

Country

United States

Scientific contact point

Organisation

Wake Forest University Health Sciences

Contact name

Ryan Bodamer

Public contact point

Organisation

Wake Forest University Health Sciences

Contact name

Ryan Bodamer

Third parties 4

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications