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

Pilot Study to Investigate the Safety and Feasibility of Senolytic Therapy to Modulate Progression of Alzheimer's Disease (SToMP-AD)

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Dasatinib + Quercetin

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intermittent D+Q; Senolytic treatment in 5 individuals with early AD to determine levels of drug that reach the central nervous system (CNS) by collecting cerebral spinal fluid (CSF), and begin collecting initial data on target engagement of senescent cells, AD-related markers, and AD-relevant outcomes for future trials.	Drug: Dasatinib + Quercetin; Intermittent D+Q administered for 2 days on/14 days off for 12 weeks (6 cycles); Other Names: D+Q

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain Penetrance of Dasatinib (D)	Cerebrospinal Fluid (CSF) collected by lumbar puncture before and after 12 weeks of treatment to determine levels of drug that reach the central nervous system will be measured by high performance liquid chromatography/mass spectrometry (HPLC/MS)	Change from 0 to 12 weeks
Brain Penetrance of Quercetin (Q)	CSF collected by lumbar puncture before and after 12 weeks of treatment to determine levels of drug that reach the central nervous system using HPLC/MS	Change from 0 to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montreal Cognitive Assessment (MoCA)	A test which scores the participant with score ranges between 0 and 30. A score of 26 or over is considered normal. Individuals with mild cognitive impairment score lower and individuals with Alzheimer's disease score even lower.	Change from 0 to 12 weeks
Alzheimer's Disease Marker - CSF Tau	Cerebrospinal Fluid collected by lumbar puncture analyzed for level of tau proteins present in CSF	Change from 0 to 12 weeks
Alzheimer's Disease Marker - CSF Amyloid Beta	Cerebrospinal Fluid collected by lumbar puncture analyzed for level of amyloid beta proteins present in CSF	Change from 0 to 12 weeks
Senescence Marker IL-6 in CSF	Laboratory measure of level of IL-6 found in CSF collected pre and post treatment	Change from 0 to 12 weeks
Senescence Marker P16 in CSF	Laboratory measure of level of P16 found in CSF collected pre and post treatment	Change from 0 to 12 weeks
Electronic Gait Mapping Under Single and Dual-task Conditions	Participants walk on a pressure-sensitive walkway to capture data on gait speed	Change from 0 to 12 weeks

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: Mayo Clinic
• Investigators: Principal Investigator: Nicolas Musi, MD, UT Health San Antonio

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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2020
• Primary Completion (Actual): December 10, 2021
• Study Completion (Actual): January 30, 2023

Study Registration Dates

• First Submitted: August 1, 2019
• First Submitted That Met QC Criteria: August 16, 2019
• First Posted (Actual): August 21, 2019

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: February 3, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Cognitive decline; Dementia; Alzheimer; dasatinib
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; 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: HSC20190222H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: At study completion
• IPD Sharing Access Criteria: Through journal publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No