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

Primary Purpose

Alzheimer Disease

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Dasatinib + Quercetin

About this trial

This is an interventional treatment trial for Alzheimer Disease focused on measuring Dementia, Alzheimer, Cognitive decline, dasatinib

Eligibility Criteria

65 Years - undefined (Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

Hearing, vision, or motor deficits despite corrective devices;
Alcohol or drug abuse;
MRI contraindications;
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;
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

Sites / Locations

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intermittent D+Q

Arm Description

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.

Outcomes

Primary Outcome Measures

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)

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

Secondary Outcome Measures

Alzheimer's Disease Marker - CSF Tau

Cerebrospinal Fluid collected by lumbar puncture analyzed for level of tau proteins present in CSF

Alzheimer's Disease Marker - CSF Amyloid Beta

Cerebrospinal Fluid collected by lumbar puncture analyzed for level of amyloid beta proteins present in CSF

Senescence Marker IL-6 in CSF

Laboratory measure of level of IL-6 found in CSF collected pre and post treatment

Senescence Marker P16 in CSF

Laboratory measure of level of P16 found in CSF collected pre and post treatment

Electronic Gait Mapping Under Single and Dual-task Conditions

Participants walk on a pressure-sensitive walkway to capture data on gait speed

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.

Full Information

NCT ID

NCT04063124

First Posted

August 1, 2019

Last Updated

February 3, 2023

Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

Mayo Clinic

1. Study Identification

Unique Protocol Identification Number

NCT04063124

Brief Title

Senolytic Therapy to Modulate Progression of Alzheimer's Disease

Acronym

SToMP-AD

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

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Completed

Study Start Date

February 14, 2020 (Actual)

Primary Completion Date

December 10, 2021 (Actual)

Study Completion Date

January 30, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

Mayo Clinic

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer Disease

Keywords

Dementia, Alzheimer, Cognitive decline, dasatinib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

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)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Intermittent D+Q

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Dasatinib + Quercetin

Other Intervention Name(s)

D+Q

Intervention Description

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

Primary Outcome Measure Information:

Title

Brain Penetrance of Dasatinib (D)

Description

Time Frame

Change from 0 to 12 weeks

Title

Brain Penetrance of Quercetin (Q)

Description

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

Time Frame

Change from 0 to 12 weeks

Secondary Outcome Measure Information:

Title

Alzheimer's Disease Marker - CSF Tau

Description

Cerebrospinal Fluid collected by lumbar puncture analyzed for level of tau proteins present in CSF

Time Frame

Change from 0 to 12 weeks

Title

Alzheimer's Disease Marker - CSF Amyloid Beta

Description

Cerebrospinal Fluid collected by lumbar puncture analyzed for level of amyloid beta proteins present in CSF

Time Frame

Change from 0 to 12 weeks

Title

Senescence Marker IL-6 in CSF

Description

Laboratory measure of level of IL-6 found in CSF collected pre and post treatment

Time Frame

Change from 0 to 12 weeks

Title

Senescence Marker P16 in CSF

Description

Laboratory measure of level of P16 found in CSF collected pre and post treatment

Time Frame

Change from 0 to 12 weeks

Title

Electronic Gait Mapping Under Single and Dual-task Conditions

Description

Participants walk on a pressure-sensitive walkway to capture data on gait speed

Time Frame

Change from 0 to 12 weeks

Title

Montreal Cognitive Assessment (MoCA)

Description

Time Frame

Change from 0 to 12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: Hearing, vision, or motor deficits despite corrective devices; Alcohol or drug abuse; MRI contraindications; 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; 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Nicolas Musi, MD

Organizational Affiliation

UT Health San Antonio

Official's Role

Principal Investigator

Facility Information:

Facility Name

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78229

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

All IPD that underlie results in a publication

IPD Sharing Time Frame

At study completion

IPD Sharing Access Criteria

Through journal publication

Citations:

PubMed Identifier

35098970

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.

Results Reference

derived

PubMed Identifier

34687726

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.

Results Reference

derived

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Senolytic Therapy to Modulate Progression of Alzheimer's Disease

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