Senolytic Therapy to Modulate Progression of Alzheimer's Disease

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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04063124

Acronym

SToMP-AD

Enrollment

Registered

2019-08-21

Start date

2020-02-14

Completion date

2023-01-30

Last updated

2023-03-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alzheimer Disease

Keywords

Dementia, Alzheimer, Cognitive decline, dasatinib

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.

Interventions

DRUGDasatinib + Quercetin

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

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

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.

Eligibility

Sex/Gender

ALL

Age

65 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Brain Penetrance of Dasatinib (D)	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)
Brain Penetrance of Quercetin (Q)	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

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

Countries

United States

Participant flow

Recruitment details

Subjects that were consented and passed screening

Participants by arm

Arm	Count
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. Dasatinib + Quercetin: Intermittent D+Q administered for 2 days on/14 days off for 12 weeks (6 cycles)	5
Total	5

Arm

Count

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

Total

Baseline characteristics

Characteristic	Intermittent D+Q
Age, Continuous	76 years STANDARD_DEVIATION 5
Educational level College degree or higher	2 Participants
Educational level High school graduate	2 Participants
Educational level Some college	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	5 Participants
Region of Enrollment United States	5 participants
Sex: Female, Male Female	2 Participants
Sex: Female, Male Male	3 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 5
other Total, other adverse events	4 / 5
serious Total, serious adverse events	0 / 5

Outcome results

Primary

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)