Clinical trial NCT04063124: Senolytic Therapy to Modulate Progression of Alzheimer's Disease
Official title: Pilot Study to Investigate the Safety and Feasibility of Senolytic Therapy to Modulate Progression of Alzheimer's Disease (SToMP-AD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Alzheimer Disease
Keywords: Dementia
Alzheimer
Cognitive decline
dasatinib
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
First posted: 2019-08-21
Enrollment: 5
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This study is an open-label pilot study of intermittent D+Q to measure its target engagement in CSF and blood, and to establish the feasibility and safety of D+Q treatment in older adults with early stage AD as initial proof-of-concept for a larger Phase 2 clinical trial.
Primary purpose: TREATMENT

Brief summary: The purpose of this pilot study is to evaluate whether a combination of two drugs, dasatinib (D) and quercetin (Q) \[D+Q\], penetrate the brain using cerebrospinal fluid (CSF) in older adults with early Alzheimer's disease (AD). This combination of drug therapy has been shown to affect dying cells in humans with other chronic illnesses and in Alzheimer's mice models. The study team want to know if this combination of medications will reach the brain in order to evaluate if this intervention may be effective for treating AD symptoms in future studies. This is also known as a "proof of concept" study.

Detailed description: Up to 40 potential candidates will be pre-screened to identify eligible men and women ages 65 years and over with a clinical diagnosis of early AD on a stable dose of cholinesterase inhibitors for at least 3 months (for example, Aricept).

Eligible participants will undergo laboratory assessments of blood and urine, receive study medications over a twelve week period, and complete pre- and post-treatment testing including: an MRI for digital imaging of the brain; lumbar puncture to obtain cerebrospinal fluid; memory and thinking assessments; quality of life questionnaires; and tests of walking, balance and strength, all of which will be done for research purposes only.

Participants must be accompanied by a Legally Authorized Representative and have no travel plans for 4-5 months that would interfere with study visits.

Eligibility criteria: Inclusion Criteria:

1. Age 65 years or above.
2. Clinical diagnosis of AD (MoCA 10-20 and Clinical Dementia Rating Scale/CDR = 1) on a stable dose of cholinesterase inhibitors for at least three months
3. Body Mass Index (BMI) within range of 19 - 35 kg/ m2
4. Labs: Normal blood cell counts without clinically significant excursions (WBCs: 4,500-10,500 cells/mcL; absolute neutrophil count: 1,800-8,700 cells/mcL; platelets: 140-450 K/uL; hemoglobin 12.0-17.5 grams/dL); liver and renal function (AST 10-40 IU/L, total bilirubin 0.1-1.4 mg/dl); cholesterol (\<240 mg/dl), triglycerides (\<300 mg/dl), and glucose control (HbA1c \< 7%). PT/PTT/INR within normal limits
5. Participants must be accompanied by a Legally Authorized Representative designated to sign informed consent and to provide study partner reported outcomes at all remaining visits
6. Participants must have no plans to travel over the next 4-5 months that interfere with study visits following consent

Exclusion Criteria:

1. Hearing, vision, or motor deficits despite corrective devices;
2. Alcohol or drug abuse;
3. MRI contraindications;
4. Myocardial infarction, angina, stroke or transient ischemic attack in the past 6 months; QT interval \>440 on ECG will not be enrolled. Chronic heart failure will be exclusionary;
5. Participants with coagulation disorders;
6. Neurologic, musculoskeletal, or other condition that limits subject's ability to complete study physical assessments;
7. Uncontrolled diabetes (HbA1c \> 7% or the current use of insulin);
8. Current or chronic history of liver disease, or known hepatic or biliary abnormalities;
9. Use of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or anti-coagulant medication;
10. Current use of quinolone antibiotics.
11. Poorly controlled blood pressure (systolic BP\>160, diastolic BP\>90 mmHg).
12. Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and psychiatric disease.
13. History of or MRI-positive for any space occupying lesion, including mass effect or abnormal intracranial pressure, which would indicate contraindication to lumbar puncture

Primary outcomes:
measure: Brain Penetrance of Dasatinib (D)
timeFrame: Change from 0 to 12 weeks
measure: Brain Penetrance of Quercetin (Q)
timeFrame: Change from 0 to 12 weeks
Secondary outcomes:
measure: Alzheimer's Disease Marker - CSF Tau
timeFrame: Change from 0 to 12 weeks
measure: Alzheimer's Disease Marker - CSF Amyloid Beta
timeFrame: Change from 0 to 12 weeks
measure: Senescence Marker IL-6 in CSF
timeFrame: Change from 0 to 12 weeks
measure: Senescence Marker P16 in CSF
timeFrame: Change from 0 to 12 weeks
measure: Electronic Gait Mapping Under Single and Dual-task Conditions
timeFrame: Change from 0 to 12 weeks
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: Change from 0 to 12 weeks
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases
state: Texas
Study officials:
affiliation: UT Health San Antonio
name: Nicolas Musi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gonzales MM, Garbarino VR, Marques Zilli E, Petersen RC, Kirkland JL, Tchkonia T, Musi N, Seshadri S, Craft S, Orr ME. Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial. J Prev Alzheimers Dis. 2022;9(1):22-29. doi: 10.14283/jpad.2021.62.
citation: 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.