Senolytic Therapy to Modulate Progression of Alzheimer's Disease

NCT04063124 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: HSC20190222H
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Alzheimer Disease

Keywords

Dementia; Alzheimer; Cognitive decline; dasatinib

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Alzheimer's Disease Marker - CSF Tau

  Change from 0 to 12 weeks

• Alzheimer's Disease Marker - CSF Amyloid Beta

  Change from 0 to 12 weeks

• Senescence Marker IL-6 in CSF

  Change from 0 to 12 weeks

• Senescence Marker P16 in CSF

  Change from 0 to 12 weeks

• Electronic Gait Mapping Under Single and Dual-task Conditions

  Change from 0 to 12 weeks

Study Arms (1)

Intermittent D+Q

EXPERIMENTAL

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

Interventions

Dasatinib + Quercetin DRUG

Intermittent D+Q administered for 2 days on/14 days off for 12 weeks (6 cycles)

Also known as: D+Q

Intermittent D+Q

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Age 65 years or above.
• 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
• Body Mass Index (BMI) within range of 19 - 35 kg/ m2
• 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
• 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
• Participants must have no plans to travel over the next 4-5 months that interfere with study visits following consent

You may not qualify if:

• Hearing, vision, or motor deficits despite corrective devices;
• Alcohol or drug abuse;
• MRI contraindications;
• Participants with coagulation disorders;
• Neurologic, musculoskeletal, or other condition that limits subject's ability to complete study physical assessments;
• Uncontrolled diabetes (HbA1c \> 7% or the current use of insulin);
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities;
• Use of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or anti-coagulant medication;
• Current use of quinolone antibiotics.
• Poorly controlled blood pressure (systolic BP\>160, diastolic BP\>90 mmHg).
• Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and psychiatric disease.
• History of or MRI-positive for any space occupying lesion, including mass effect or abnormal intracranial pressure, which would indicate contraindication to lumbar puncture

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead
• Mayo Clinic: collaborator

Study Sites (1)

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases

San Antonio, Texas, 78229, United States

Location

Related Publications (7)

• Garbarino VR, Palavicini JP, Melendez J, Barthelemy NR, He Y, Kautz TF, Lopez-Cruzan M, Mathews JJ, Xu P, Zhang B, Saliba A, Ragi N, Sharma K, Mason D, Johnson S, Hendrix S, Craft S, Petersen RC, Espindola-Netto JM, Xue A, Tchkonia T, Kirkland JL, Salardini A, Musi N, Bateman RJ, Gonzales MM, Orr ME. Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease. Neurotherapeutics. 2025 Jul;22(4):e00591. doi: 10.1016/j.neurot.2025.e00591. Epub 2025 Apr 23.

  PMID: 40274471 DERIVED

• Andrews TD, Day GS, Irani SR, Kanekiyo T, Hickson LJ. Uremic Toxins, CKD, and Cognitive Dysfunction. J Am Soc Nephrol. 2025 Jun 1;36(6):1208-1226. doi: 10.1681/ASN.0000000675. Epub 2025 Feb 26.

  PMID: 40009460 DERIVED

• Garbarino VR, Palavicini JP, Melendez J, Barthelemy N, He Y, Kautz TF, Lopez-Cruzan M, Mathews JJ, Xu P, Zhan B, Saliba A, Ragi N, Sharma K, Craft S, Petersen RC, Espindola-Netto JM, Xue A, Tchkonia T, Kirkland JL, Seshadri S, Salardini A, Musi N, Bateman RJ, Gonzales MM, Orr ME. Evaluation of Exploratory Fluid Biomarker Results from a Phase 1 Senolytic Trial in Mild Alzheimer's Disease. Res Sq [Preprint]. 2024 Mar 8:rs.3.rs-3994894. doi: 10.21203/rs.3.rs-3994894/v1.

  PMID: 38496619 DERIVED

• Gonzales MM, Garbarino VR, Kautz TF, Palavicini JP, Lopez-Cruzan M, Dehkordi SK, Mathews JJ, Zare H, Xu P, Zhang B, Franklin C, Habes M, Craft S, Petersen RC, Tchkonia T, Kirkland JL, Salardini A, Seshadri S, Musi N, Orr ME. Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. Nat Med. 2023 Oct;29(10):2481-2488. doi: 10.1038/s41591-023-02543-w. Epub 2023 Sep 7.

  PMID: 37679434 DERIVED

• Sarkar P, Kumar A, Behera PS, Thirumurugan K. Phytotherapeutic targeting of the mitochondria in neurodegenerative disorders. Adv Protein Chem Struct Biol. 2023;136:415-455. doi: 10.1016/bs.apcsb.2023.02.013. Epub 2023 Mar 24.

  PMID: 37437986 DERIVED

• 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.

  PMID: 35098970 DERIVED

• 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.

  PMID: 34687726 DERIVED

MeSH Terms

Conditions

Alzheimer Disease; Dementia; Cognitive Dysfunction

Interventions

Dasatinib; Quercetin

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Flavonols; Flavonoids; Chromones; Benzopyrans; Pyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Mitzi Gonzales, PhD
• Organization: UT Health San Antonio

Gonzalesm20@uthscsa.edu

210-450-9047

Study Officials

• Nicolas Musi, MD

  UT Health San Antonio

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: 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.

Study Record Dates

• First Submitted: August 1, 2019
• First Posted: August 21, 2019
• Study Start: February 14, 2020
• Primary Completion: December 10, 2021
• Study Completion: January 30, 2023
• Last Updated: March 6, 2023
• Results First Posted: March 6, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: At study completion
• Access Criteria: Through journal publication

Locations

US (1)