DASATINIB for Amnestic mild cognitive impairment | Alzheimer's disease (early stage)

Inclusion criteria

• {"criterion_text":"- Ages 60 years and older at study entry\n- 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.\n- Participants must have no travel plans that would interfere with scheduling visits following consent over the 12 months of study duration\n- Must speak Spanish fluently and have at least six years of formal education\n- 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.\n- Both sexes\n- All ethnicities\n- 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)\n- 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.\n- 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.\n- 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%.\n- PT/PTT/INR within normal limits\n- Participants must have the ability to provide written consent"}

Exclusion criteria

• {"criterion_text":"- Body mass index (BMI)>40 kg/m2\n- eGFR < 10 ml/ min/ 1.73 m2.\n- Myocardial infarction, angina, stroke, or transient ischemic attack in the past 6 months.\n- Chronic heart failure.\n- Presence of significant liver disease with total bilirubin >2X upper limit.\n- Inability to tolerate oral medication.\n- 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).\n- Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, or other chemotherapy.\n- 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.\n- 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.\n- Concomitant use of strong CYP3A4 inhibitors (see list in section 5.5).\n- Average QTcF (from 3 ECGs obtained at least one minute apart) at screening of ≥450msec in males and ≥460msec in females\n- 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.\n- 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.\n- Use of anti-amyloid therapies (e.g. aducanumab, lecanamab)\n- MRI contraindications including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker.\n- Pregnancy or possible pregnancy\n- 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.\n- Current or history of alcohol or substance abuse or dependence within the past 2 years (DSM V criteria)\n- Endorsement of current suicidality or suicidal ideation on the screening C-SSRS\n- Uncontrolled diabetes (HbA1c >7% or the current use of insulin or sulfonylureas)\n- 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"}

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Measured by incidence of adverse events (AEs) and serious adverse events (SAEs) from baseline to week 48. AEs and SAEs will be collected at each in-person visit and at scheduled telephone visits."}

Secondary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Composite SASP score generated from ten core SASP factors measured in blood. Blood collected at baseline, after 12 weeks of treatment, and every 12 weeks during follow-up under fasted conditions."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Quantification of p16INK4a+/CD3+ T cells in blood at baseline, week 12, and every 12 weeks during follow-up under fasted conditions."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"CDR-SB measured at screening, week 12, and week 48; analysis of change in slope from screening to week 48."}
• {"endpoint_text":"- Change in ADAS-Cog slope from baseline to week 48.","definition_or_measurement_approach":"ADAS-Cog assessments at baseline and during follow-up to determine change in slope to week 48."}

Spain

Earliest CTIS Part Ii Submission Date

18-11-2024

Latest Decision Or Authorization Date

02-12-2024

Processing Time Days

14

Number Of Sites

1

Number Of Participants

24

Primary sponsor

Full Name

Wake Forest University Health Sciences

Organisation Type

Educational Institution

Country Of Registered Address

United States

Contract research organisations

Name

Datamedrix GmbH

Responsibilities

sponsorDuties codes: 6,7

Name

Anapath Research S.A.

Responsibilities

sponsorDuties codes: 4

Third parties

• {"country":"Austria","full_name":"Neuroscios GmbH","duties_or_roles":"sponsorDuties codes: 1,12,2,5,8,9","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Wake Forest University Health Sciences","duties_or_roles":"sponsorDuties codes: 10,11,4","organisation_type":"Educational Institution"}
• {"country":"Austria","full_name":"Datamedrix GmbH","duties_or_roles":"sponsorDuties codes: 6,7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Spain","full_name":"Anapath Research S.A.","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}