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

• ClinicalTrials.gov Identifier: NCT04063124
• Recruitment Status: Completed
• First Posted: August 21, 2019
• Results First Posted: March 6, 2023
• Last Update Posted: March 6, 2023
• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborator: Mayo Clinic
• Information provided by (Responsible Party): Mitzi Gonzales, PhD, The University of Texas Health Science Center at San Antonio

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease	Drug: Dasatinib + Quercetin	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• 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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study to Investigate the Safety and Feasibility of Senolytic Therapy to Modulate Progression of Alzheimer's Disease (SToMP-AD)
• Actual Study Start Date: February 14, 2020
• Actual Primary Completion Date: December 10, 2021
• Actual Study Completion Date: January 30, 2023

Arms and Interventions

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 Name: D+Q

Outcome Measures

Primary Outcome Measures :

1. Brain Penetrance of Dasatinib (D) [ Time Frame: Change from 0 to 12 weeks ]
   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)
2. Brain Penetrance of Quercetin (Q) [ Time Frame: Change from 0 to 12 weeks ]
   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

Secondary Outcome Measures :

1. Alzheimer's Disease Marker - CSF Tau [ Time Frame: Change from 0 to 12 weeks ]
   Cerebrospinal Fluid collected by lumbar puncture analyzed for level of tau proteins present in CSF
2. Alzheimer's Disease Marker - CSF Amyloid Beta [ Time Frame: Change from 0 to 12 weeks ]
   Cerebrospinal Fluid collected by lumbar puncture analyzed for level of amyloid beta proteins present in CSF
3. Senescence Marker IL-6 in CSF [ Time Frame: Change from 0 to 12 weeks ]
   Laboratory measure of level of IL-6 found in CSF collected pre and post treatment
4. Senescence Marker P16 in CSF [ Time Frame: Change from 0 to 12 weeks ]
   Laboratory measure of level of P16 found in CSF collected pre and post treatment
5. Electronic Gait Mapping Under Single and Dual-task Conditions [ Time Frame: Change from 0 to 12 weeks ]
   Participants walk on a pressure-sensitive walkway to capture data on gait speed
6. Montreal Cognitive Assessment (MoCA) [ Time Frame: Change from 0 to 12 weeks ]
   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.

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Texas

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

The University of Texas Health Science Center at San Antonio

Mayo Clinic

Investigators

• Principal Investigator: Nicolas Musi, MD; UT Health San Antonio

  Study Documents (Full-Text)

Documents provided by Mitzi Gonzales, PhD, The University of Texas Health Science Center at San Antonio:

Study Protocol and Statistical Analysis Plan  [PDF] August 12, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Mitzi Gonzales, PhD, Associate Professor, The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT04063124
• Other Study ID Numbers: HSC20190222H
• First Posted: August 21, 2019
• Results First Posted: March 6, 2023
• Last Update Posted: March 6, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All IPD that underlie results in a publication
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: At study completion
• Access Criteria: Through journal publication

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mitzi Gonzales, PhD, The University of Texas Health Science Center at San Antonio:

Dementia; Alzheimer; Cognitive decline; dasatinib

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Dasatinib; Quercetin; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antioxidants; Protective Agents; Physiological Effects of Drugs