Clinical trial NCT05422885
Conditions: Aging
Keywords: Alzheimer's disease Senescence
Sponsor: Lewis Lipsitz
Start date: 2022-05-20; Completion date: 2024-01-24
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this pilot study is to demonstrate the safety and feasibility of administering intermittent doses of Dasatinib and Quercetin (D+Q) in older adults at risk of Alzheimer's disease (AD). The study will evaluate whether giving D+Q may improve cerebral blood flow regulation, mobility, and cognition in older adults, and thus may prevent progression to Alzheimer's disease.

Detailed description:
The investigators will conduct a 12-week single arm, open label, pre-post pilot study in 12 adults aged 65 or older with slow gait speed (\<1.0 m/sec) and Mild Cognitive Impairment (MCI, defined as a Telephone Montreal Cognitive Assessment Score (MoCA) \<19). Participants will be asked to take 100mg of Dasatinib and 1,250mg of Quercetin for 2 consecutive days, every two weeks over a period of 12 weeks (12 doses in total, given over 6 cycles).

At baseline, enrolled participants will undergo gait speed and neurocognitive testing, and provide blood and urine to evaluate biomarkers of senescence. At visits 3,4, 6, and 7, participants will have safety labs drawn, and the study team will assess medication adherence and adverse events. At visits 2, 5, and 8, participants will undergo cognitive assessments, gait speed testing, cerebral blood flow and neurovascular coupling testing. At the final study visit, participants will again provide blood and urine to assess biomarkers of senescence.

Arms: arm 1: Dasatinib and Quercetin
Interventions: intervention 1: Dasatinib intervention 2: Quercetin
Intervention descriptions: intervention 1: Dasatinib 100 mg for 2 consecutive days, every two weeks for 12 weeks intervention 2: Quercetin 1,250 mg for 2 consecutive days, every two weeks for 12 weeks

Protocol documents:
Prot_ICF_000.pdf: 
 
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Appendix AA. 
 
 
 
 
 
Senolytics to Alleviate Mobility Issues and 
Neurological Impairment in Aging 
“STAMINA” 
 
Study Protocol 
 
IRB Pro00053594 
ClinicalTrials.gov identifier: NCT ###### 
 
 
 
 
 
 
 


 
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CHAPTER 1:  INTRODUCTION 
 
Abnormalities in cognition and mobility are common accompaniments of aging that often precede the 
development of Alzheimer’s disease. Among their many etiologies, these abnormalities are associated with 
alterations in the regulation of cerebral blood flow to frontal regions of the brain that subserve executive 
functions and gait speed. We have previously shown that treatment with cocoa flavanols can improve blood 
flow in response to a cognitive task (neurovascular coupling [NVC]), as well as executive function in older 
people with impaired NVC. These compounds can also reduce the number of senescent cells and their toxic 
secretory products (SASP) in a variety of tissues. 
 
In mice, “senolytic” compounds such as flavanols and tyrosine kinase inhibitors, have been shown to reduce 
neurofibrillary tangle density, neuron loss, and ventricular enlargement, and in humans with idiopathic 
pulmonary fibrosis, improve gait speed and other functional abilities. Based on these findings, we hypothesize 
that the flavanol, Quercetin, and tyrosine kinase inhibitor, Dasatinib, (D+Q) will improve NVC in response to an 
executive task, reduce circulating SASP components, and in so doing, improve cognition and mobility in older 
adults who are at risk of Alzheimer’s disease. 
 
Our long-term goal of this study is to prevent common age-related impairments in cognition and mobility that 
lead to the development of Alzheimer’s disease by interrupting one of the fundamental mechanisms of aging, 
namely the accumulation of senescent cells and their damaging products. As a first step, this study will 
determine the feasibility and safety of administering Quercetin and Dasatinib to eliminate these cells from the 
body, and test whether their elimination can improve brain blood flow, cognition, and mobility in older adults at 
risk of developing Alzheimer’s disease.  
 
The overall aim of this study is to demonstrate the feasibility and safety of administering intermittent 
doses of Dasatinib and Quercetin in older adults at risk of Alzheimer’s disease. We will conduct a 12-
week single arm, open label, pre-post pilot study in 12 older adults aged ≥65 years with slow gait speed (<1.0 
m/sec) and Mild Cognitive Impairment (MCI, defined as a Telephone Montreal Cognitive Assessment Score 
(tMoCA) <19 points). Participants will be asked to take 100 mg of Dasatinib and 1,250 mg of Quercetin for 2 
consecutive days, every two weeks over a period of 12 weeks (i.e., 12 doses in total). During this study we will 
evaluate measures of feasibility, safety, physical function and cognitive function. Our overall hypothesis is that 
co-administration of Dasatinib and Quercetin in older adults will be feasible and safe, without serious adverse 
effects.  
 
Innovation and Impact: The results from this study will obtain preliminary evidence on the feasibility of a novel 
approach that may improve cerebral blood flow regulation, mobility, and cognition in older adults, and prevent 
their progression to Alzheimer’s disease. The study may also help establish proof-of-concept that the cognitive 
and functional disabilities of older age arise, in part, from the secretory products of senescent cells and can be 
alleviated by senolytic agents. 
 
 


 
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CHAPTER 2:  BACKGROUND 
 
Abnormalities in cognition and mobility are common accompaniments of aging and predictors for the 
development of Alzheimer’s disease.1-3 They are associated with vascular risk factors and microvascular 
damage to critical neural circuits in the brain, 4-6 especially those in periventricular and frontal lobe regions 
nourished by the middle cerebral artery (MCA). We have previously identified abnormalities in cerebral blood 
flow regulation in this territory that are associated with slow gait, falls, and cognitive dysfunction.7,8 We also 
demonstrated improvements in MCA cerebral blood flow with 1 and 2 weeks of treatment with flavanol-rich 
cocoa.9 Our group showed that 4 weeks’ consumption of cocoa flavanols can improve blood flow in response 
to a cognitive task (neurovascular coupling, NVC), as well as Trail Making Test scores in older adults with 
impaired NVC.10 Other investigators have shown that cocoa flavanols can improve Trail Making and Verbal 
Fluency in older people with mild cognitive impairment 11 (MCI). Flavanols can interrupt amyloidogenic 
processes, prevent tau phosphorylation, inhibit the development of Alzheimer’s disease, and reverse cognitive 
deficits in rodents.12 Therefore, they have been touted as possible therapeutic agents to prevent the 
development or progression of Alzheimer’s disease.12-14 However, to our knowledge, flavanols have not been 
rigorously studied for their effect on cognition and mobility in humans at risk of Alzheimer’s disease. 
 
The accumulation of senescent cells and their products, which are components of the senescence-associated 
secretory phenotype (SASP), are associated with age-related deficits in cognition and mobility, including 
Alzheimer’s Disease.15 In mice and humans, “senolytic” compounds such as the plant-derived flavanols and 
tyrosine kinase inhibitors can reduce the number of senescent cells in a variety of tissues.15,16 They have also 
been shown to reduce neurofibrillary tangle density, neuron loss, and ventricular enlargement.17,18 Senolytics 
improve carotid vascular reactivity and exercise capacity; delay, prevent, or alleviate a range of age-related 
disorders and chronic diseases; enhance health span, decrease frailty, and increase survival.15,16,19-21 
Moreover, these compounds have been found to be safe and well-tolerated in humans.22 Many of these 
biologic effects, including the improvement in cerebral blood flow regulation that we previously observed, could 
improve gait and cognition, declines in which are both predecessors of Alzheimer’s disease. To date there are 
no randomized controlled trials (RCT) examining these important outcomes.  
 
Based on our previous work with cocoa flavanols, and that of our collaborators Dr. James Kirkland and 
colleagues at Mayo Clinic with other senolytics, we hypothesize that the joint administration of the flavanol, 
Quercetin, and tyrosine kinase inhibitor, Dasatinib, (D+Q) will be feasible and safe. Prior studies suggest that 
D+Q is an excellent candidate for intervention, but human data supporting its testing in older adults with 
mobility impairment or MCI are lacking. This study will provide preliminary evidence on mobility and cognitive 
measures to design future studies with the ultimate goal of improving cerebral blood flow to watershed regions 
of the brain that subserve executive functions and gait speed, and reducing circulating SASP components, 
thereby improving cognition and mobility. The pilot project described in this application will develop these data, 
and will provide the experience necessary to design an RCT measuring the effects of these two compounds on 
gait and cognition in larger numbers of older adults.  
 
Together, these discoveries will enable us to appropriately design future, large-scale efficacy trials to 
determine if D+Q has potential to alleviate age-related impairments in cognition and mobility in older adults at 
risk of Alzheimer’s disease.  
 


 
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CHAPTER 3:  RESEARCH DESIGN AND METHODS 
 
3.1 Study Objectives 
The overall aim of this study is to demonstrate the feasibility and safety of administering intermittent doses of 
Dasatinib and Quercetin in older adults at risk of Alzheimer’s disease. We will conduct a 12-week single arm, 
open label, pre-post pilot study in 12 older adults aged ≥65 years with slow gait speed (<1.0 m/sec) and Mild 
Cognitive Impairment. Participants will be asked to take 100 mg of Dasatinib and 1,250 mg of Quercetin for 2 
consecutive days, every two weeks over a period of 12 weeks (i.e., 12 doses in total). During this study we will 
evaluate measures of feasibility, safety, physical function, and cognitive function. Our specific aims are:  
1) Determine the feasibility, safety, and recruitment challenges of studying intermittent doses of 
Quercetin and Dasatinib (D+Q) in older adults at risk of Alzheimer’s disease. We will evaluate the 
number of volunteers needed to be screened to identify eligible participants, the number of protocol 
deviations that are necessary to ensure safe and scientifically rigorous human subject participation 
(reported to the FDA and IRB), the frequency of any adverse drug effects, and compliance with 
medication administration. 
2) To obtain preliminary data on the effect of this D+Q regimen on: a) sitting and standing 
cerebral blood flow (CBF), and neurovascular coupling (NVC) during an executive task, b) gait 
speed, c) and executive function. We will measure CBF during sitting and standing, NVC during an N-
Back cognitive task, 4 meter gait speed, and executive function via the Trail Making Test (TMT) pre- and 
post-intervention to estimate the average changes and variability of these measures. Such information 
will be used to design future, large-scale efficacy trials.  
3) To develop preliminary evidence concerning whether D+Q is associated with a) a reduction in 
biomarkers of senescence in serum and urine and senescent cells in blood, and b) whether 
reductions in these biomarkers are associated with improvements in NVC, gait speed, and 
executive function. We will measure biomarkers of senescence in urine and plasma and senescent 
cells in blood pre- and post-intervention to obtain preliminary evidence of potential mechanisms. 
Our overall hypothesis is that a 12 week co-administration of intermittent doses of Dasatinib and Quercetin in 
older adults at risk of Alzheimer’s disease will be feasible and safe. 
 
3.2 Overview 
 
We will conduct a single-site, single-arm, open label pilot study of D+Q in older adults at risk of Alzheimer’s 
disease. Screened and eligible participants will perform baseline physical and cognitive assessments, as well 
as provide a blood and urine sample. They will then be asked to take 100 mg of Dasatinib and 1,250 mg of 
Quercetin for two consecutive days. Every two weeks, the same cycle will be repeated where participants are 
asked to take the same dose of study medications for 2 consecutive days. A total of six, 2-day administrations 
of study medications will take place over a total of 12 weeks. Two weeks after their last dose, participants will 
complete a follow-up assessment of physical and cognitive function, as well as provide a blood and urine 
sample. Safety and possible adverse events will be monitored throughout the entire duration of the study as 
described below. 
 
3.3 Organizational Structure of the Team 
 
The trial will be conducted under the leadership of Dr. Lewis A. Lipsitz, Principal Investigator, and administered 
at the Hebrew Rehabilitation Center (HRC). Dr. Lipsitz will be responsible for leadership of all aspects of the 
design, conduct, analysis and interpretation, and reporting of this pilot study. 
 
The trial’s Steering Committee will include Dr. Lipsitz and co-Investigators Drs. Thomas Travison (clinical 
trialist and biostatistician) and Courtney Millar (postdoctoral fellow). Additionally, our collaborators Drs. James 
Kirkland and Tamar Tchkonia at the Mayo Clinic, who will be measuring biomarkers of senescence, will serve 
as members of the Steering Committee. 
 
The Steering Committee will meet at least monthly, or more frequently as needed. Functions of the Committee 
will include monitoring the progress of the trial, overseeing the scientific direction of the study, assuring quality 


 
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control of data collection and statistical analyses, reviewing scientific and safety reports from the study, and 
approving publications and presentations of study results.  
 
The trial’s Oversight/Operations Committee will be the day-to-day working group of the study, and will include 
Drs. Lipsitz, Travison, and Millar; the project directors, Margaret Gagnon, RN, and Ikechukwu Iloputaife; and 
research associate and/or other study staff. The Oversight Committee will meet weekly or more as needed to 
monitor ongoing study progress, review safety data, resolve problems, and plan for the next stages of the trial. 
 
3.4 Overall Timeline 
 
Months 
3 
6 
9 
12 
15 
18 
21 
24 
Start-up 
X 
 
 
 
 
 
 
 
Recruit, Treat & Assess Subjects 
 
X 
X 
X 
X 
X 
 
 
Operations Committee Weekly 
Meetings 
X 
X 
X 
X 
X 
X 
X 
X 
Steering Committee Monthly 
Meetings 
X 
X 
X 
X 
X 
X 
X 
X 
DSMB Meetings 
 
X 
 
X 
 
X 
 
 
Biomarker Assays 
 
 
 
 
 
X 
X 
 
Data Analysis 
 
 
 
 
 
 
X 
X 
Final Publication 
 
 
 
 
 
 
 
X 
 
We propose a 2-year timeline for this pilot study, with a 3-month startup period, 15 month clinical intervention, 
and 6 month final period for biomarker assays, analyses, and publication. 
 
The first 3 months will be dedicated to study start up activities and the study infrastructure will be developed. 
During this time, the IND and IRB applications will be submitted, the Clinical Trials.gov application will be 
completed, and the Safety Monitoring Board members will be determined and convened to review and approve 
the final intervention, data gathering, and safety monitoring protocols. Study staff will be trained during all-team 
Study Initiation Visits.  
 
Following study start-up, recruitment and enrollment activities will begin and are anticipated to be completed by 
month 18. The study intervention, subject assessments, and data processing will proceed simultaneously.   
 
Biomarker analyses and data cleaning and analysis will begin in month 18 and will be completed by month 24, 
with the preparation of a final study report for publication.  
 
The Operations study team will meet weekly throughout the study to review and record the study progress and 
human subject safety. The Steering Committee will meet monthly throughout the study. The DSMB will meet 
every 6 months.  
 
3.4 Inclusion/Exclusion Criteria 
 
Individuals expressing an interest in participating after recruitment out-reach will be screened over the 
telephone. Those eligible and interested will be scheduled for the in-person screening visit (Visit 1).  
 
Participants will complete several in-person screening procedures at Visit 1 to confirm that they meet the 
following inclusion criteria. 
 
Inclusion Criteria 
• Men and women ≥65 years 
• Ambulatory 
• Community-dwelling 


 
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• Slow gait speed (<1 m/sec) 
• Mild Cognitive Impairment (Telephone MoCA score <19 points, which is indicative of cognitive impairment23) 
 
Exclusion criteria have been selected to ensure safety and optimize compliance, while minimizing confounds 
due to overt disease or conditions that may significantly influence study outcomes. Exclusions may be 
identified during the initial telephone screening, or during the in-person screening as described below. 
 
Pre-screen Telephone Exclusion Criteria - Potential participants will be assessed over the phone for the 
following:  
• Age <65 years 
• Telephone MoCA score < 10 points, which corresponds to a full MoCA score of 14 points24 and indicates 
dementia25 
• Unwilling to take study medications or follow study protocol  
• Non-ambulatory 
• Inability to independently perform Katz Activities of Daily Living (ADLs)26  
• Allergies to Quercetin and/or Dasatinib 
• Hospitalization within 6 months 
• Unstable coronary artery disease (myocardial infarction within 6 months or angina), stroke or transient 
ischemic attack in the past 6 months, chronic heart failure, current or chronic history of liver disease, 
neurodegenerative disease including Parkinson’s Disease, anemia, or chronic renal disease, or drug or 
alcohol abuse in the previous 5 years 
 
In-person Screening Exclusion Criteria - Potential participants will be assessed in-person for the following (See 
Appendix A for clinical safety exclusion thresholds/definitions):  
• Those allergies to Quercetin and/or Dasatinib 
• Unstable coronary artery disease (myocardial infarction within 6 months or angina), or as per clinical 
judgement 
• Hospitalization within 6 months, or as per clinical judgement 
• Stroke or transient ischemic attack in the past 6 months, or as per clinical judgement 
• Chronic heart failure, or as per clinical judgement 
• Current or chronic history of liver disease, neurodegenerative disease including Parkinson’s Disease, or as 
per clinical judgement 
• Drug or alcohol abuse in the previous 5 years, or as per clinical judgement 
• QTc prolongation (>450 ms), or as per clinical judgement 
• Anemia (Hgb<9), or as per clinical judgement 
• Thrombocyopenia (Platelets <150 x 103/mcL), or as per clinical judgement 
• Neutropenia (Absolute Neutrophil Count ,<1,500 cells/mcL), or as per clinical judgement 
• Prolongation of prothrombin time (>13 seconds) or International Normalized Ratio (>1.1), or as per clinical 
judgement 
• Indications of current fluid retention, including pulmonary rales or >+1 ankle edema, or as per clinical 
judgement 
• History or current diagnosis of pulmonary hypertension by self-report, previous echocardiogram, right 
ventricular or right atrial enlargement or strain on EKG, examination findings of right-sided heart failure 
(JVD, HJR, peripheral edema), or as per clinical judgement. 
• Chronic renal disease (Glomerular Filtration Rate [GFR< 30 mL/min/1.73 m2]), or as per clinical judgement 
• Chronic use of the following medications: anti-arrhythmic medications, antipsychotics and anxiolytics, anti-
platelet or anti-coagulant medications other than aspirin, quinolone antibiotics, or drugs metabolized by the 
same liver enzymes as Quercetin or Dasatinib (See Appendix B for a complete list of contraindications, 
cautions, and interactions of study medications).  


 
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• If we are unable to insonate the middle cerebral artery through a temporal bone window on at least one side 
using transcranial Doppler ultrasound (TCD) 
 
3.5 Number of Subjects and Study Duration  
 
We will recruit a total of 12 individuals (both men and women), in proportion to the gender and racial 
distribution of the greater Boston population, through local newspaper and internet advertisements, physician 
referrals, our registry of research volunteers, Hebrew SeniorLife (HSL) senior housing sites, and patient 
registries at Beth Israel Deaconess Medical Center and the Harvard CTSA. Participants will remain in the study 
for a total of 14 weeks.  
 
3.6 Study Endpoints 
 
Primary Study Endpoints 
The primary feasibility and safety outcomes for Aim 1 will be: 
1. The number of volunteers needed to be screened to identify eligible participants 
2. The number of protocol deviations necessary to enable subjects to participate comfortably and safely 
while maintaining scientific rigor (reported to the FDA and IRB) 
3. The frequency of any adverse drug effects 
4. Compliance with medication administration  
 
For Aims 2 and 3, the primary outcome variables will be:  
1. Cerebral blood flow (CBF) during an N-Back cognitive task (NVC)  
2. Executive function (Trails B minus A score; TMT)  
3. The 4 meter gait speed  
 
Secondary Study Endpoints 
The secondary outcomes for this study will be:  
1. The Short Physical Performance Battery score (SPPB)27 
2. The Timed Up and Go (TUG) test28 
3. Grip strength 
4. Slowing of gait speed during a subtraction task (dual task cost),29 
5. Circulating and urinary inflammatory markers, senescent cells, and SASP factors.22 
 
3.7 Study Medications 
 
Each participant will be given a planned maximum daily dosage of 1,250 mg of Quercetin (the contents of five 
250 mg capsules) and 100 mg of Dasatinib orally once a day for 2 days (one will be taken at the study clinic, 
one will be taken at home), every 2 weeks for 6 cycles, over 12 consecutive weeks. Our proposed dose was 
determined based on the dose provided in the first reported clinical trial of D+Q. In patients aged 55-84 years 
with Idiopathic Pulmonary Fibrosis - a fatal, relentlessly progressive, cellular senescence-related disease - a 3 
week course of intermittent D+Q (9 doses) was found to be safe and well-tolerated by the subjects in that 
clinical trial, and enhanced physical function within a month of initiating treatment.22 Furthermore, there were no 
changes in body weight, vital signs, or clinical chemistries following the intervention.22 Only one serious adverse 
event was reported following completion of the intervention. This was a possible bacterial multifocal pneumonia 
and pulmonary edema superimposed on IPF, which resulted in temporary hospitalization with subsequent 
complete resolution. Since our subjects will not have underlying pulmonary disease, this is highly unlikely to occur. 
 
CHAPTER 4:  RECRUITMENT AND DATA COLLECTION 
 
4.1 Recruitment Overview and Target Population 
 


 
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Participants will be recruited from the Boston area community, senior housing facilities in urban and suburban 
areas, and research recruitment repositories. We will utilize a multi-pronged approach to meet our recruitment 
goals: 
• 
We will recruit from the research repository that resides at HRC, which currently contains approximately 
200 individuals with known demographics and health history who were screened with cognitive and gait 
assessments for previous research studies within our laboratory and have expressed interest in future 
research participation. 
• 
We will perform medical record reviews to identify potentially eligible individuals at the Hebrew 
SeniorLife (HSL) geriatric medicine practices.  
• 
We will advertise through direct mailings to all residents of HRC’s seven supportive housing facilities 
(over 3,000 residents).  
• 
We will give presentations at each Hebrew SeniorLife (HSL) facility.  
• 
We will use the Harvard Catalyst (CTSA) Shared Health Research Information Network (SHRINE) to 
identify volunteers from Harvard-affiliated hospitals and clinics. 
• 
We will advertise our study within numerous local media outlets, on HRC’s Hinda and Arthur Marcus 
Institute for Aging Research and other websites (e.g., Craig’s List), and at www.clinicaltrials.gov. 
 
We will enroll individuals in this study on a rolling basis until 12 participants have enrolled and completed the 
intervention. Our target population is adults ≥65 years, who have a gait speed <1.0 m/sec and have Mild 
Cognitive Impairment (Telephone MoCA <1923). To maintain adequate participant retention, we will develop 
personal relationships between participants and study staff, schedule appointments at convenient times, give 
reminders for each visit, and provide food and beverages during visits. The Marcus Institute has on-site 
parking for study participants. Based upon our previous experience, we have also budgeted for round-trip 
transportation by Uber or Lyft for all study visits. We will use precautions to prevent COVID-19 infection, 
including frequent handwashing, masks, limitation of personal contacts, social distancing when possible, and 
sanitation of all surfaces and equipment in our facilities. We will compensate our participants for their time. 
 
4.2 Participant Visit Schedule 
Once eligibility has been determined at the in-person screening visit, participants will be asked to complete 7 
additional in-person visits and 12 brief telephone calls. All study visits will take place at the Clinical Research 
Laboratory at HRC, Roslindale, MA or at an HRC-affiliated housing site. Free parking or transportation will be 
provided for all study visits. 
 
Eligible participants who would like participate in our study will be provided with a schedule of all future study 
visits, including dates and times. A copy of the individualized study visit calendars will be pre-populated within 
the REDCap Calendar of events. The table below lists the assessments that will be performed at each study 
visit. 
 
Visits 
Assessments and Medication Administration at Each Visit 
Telephone screener  
We will ask information about: 
1. 
Age 
2. 
Activities of daily living (ADL)  
3. 
Cognitive status (Telephone MoCA) 
4.    Contraindications or allergies to Quercetin and/or Dasatinib 
5. 
Unstable coronary artery disease (myocardial infarction within 6 months or angina), stroke or 
transient ischemic attack in the past 6 months, chronic heart failure, current or chronic history 
of liver disease, neurodegenerative disease including Parkinson’s Disease, anemia, or chronic 
renal disease, or drug or alcohol abuse in the previous 5 years.  
6.    Hospitalization within 6 months 
7.    Current medications 
Visit 1, Week 0: In-
person eligibility, 
baseline safety labs  
[10 +/- 3 days from 
Telephone 
screening] 
• Assessments/Activities 
1. 
ICF 
2. 
Physical Exam by study physician, Dr. Lipstiz, or trained medical professional 
3. 
Vital signs and EKG  
4. 
Assessment of gait 
5. 
Health history and current/past medications 


 
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6. 
Height and weight 
7. 
Blood sample: clinical safety labs and serum senescent biomarkers 
8. 
Urine sample: urinary senescent biomarkers  
9. 
Identify a proxy 
10. CBF/NVC protocol 
Visit 2, Week 2:  
Baseline 
assessment and 
dosage visit [14 +/- 
3 days from first in-
person visit] 
• Assessments/Activities 
1. 
Adverse event baseline assessment (before med administration) 
2. 
Vital signs  
3. 
Gait trials (DT gait protocol– Normal and DT walks), SPPB, TUG, Hand grip strength 
4. 
Full MoCA, TMT, CES-D 
5. 
Suicidal ideation screener 
6. 
Instrumental activities of daily living (IADL) 
• Medication Administration 
1. 
D+Q administration (first dosage) 
2. 
Provide Home dosage (second day dosage and instructions) 
Post –Visit 
Telephone Calls  
1. 
At-home dosage reminder call and post-visit survey (1 day after visit) 
2. 
Telephone check-in for AE (3-5 days after visit) 
Visit 3,  Week 4: 
Dosage visit  [14 +/- 
3 days from 
Baseline Visit] 
 
 
• Assessments/Activities 
1. 
Adverse event assessment 
2. 
Vital signs and EKG 
3. 
Blood sample: clinical safety labs 
4. 
Medication Compliance/pill count 
5. 
Suicidal ideation 
• Medication Administration 
1. 
D+Q administration (third dosage) 
2. 
Provide Home dosage (fourth day dosage and instructions) 
Post –Visit 
Telephone Calls  
1. 
At-home dosage reminder call and post-visit survey (1 day after visit) 
2. 
Telephone check-in for AE (3-5 days after visit) 
Visit 4,  Week 6: 
Dosage visit [14 +/- 
3 days from Visit 3] 
 
• Assessments/Activities 
1. 
Repeat of Visit 3 assessments and activities 
• Medication Administration 
1. 
D+Q administration (fifth dosage) 
2. 
Provide Home dosage (sixth day dosage and instructions) 
Post –Visit 
Telephone Calls  
1. 
At-home dosage reminder call and post-visit survey (1 day after visit) 
2. 
Telephone check-in for AE (3-5 days after visit) 
Visit 5,  Week 8:  
Midpoint 
assessment and 
dosage visit [14 +/- 
3 days Visit 4] 
 
• Assessments/Activities 
1. 
A repeat of Visit 2 assessments and activities 
2. 
Physical Exam by study physician, Dr. Lipstiz, or trained medical professional 
3. 
Blood sample: clinical safety labs  
4. 
EKG 
5. 
CBF/NVC 
• Medication Administration 
1. 
D+Q administration (seventh dosage) 
2. 
Provide Home dosage (eighth day dosage and instructions) 
Post –Visit 
Telephone Calls  
1. 
At-home dosage reminder call and post-visit survey (1 day after visit) 
2. 
Telephone check-in for AE (3-5 days after visit) 
Visit 6, Week 10:  
Dosage visit [14 +/- 
3 days Visit 5] 
 
• Assessments/Activities 
1. 
Repeat of Visit 3 assessments and activities 
• Medication Administration 
1. 
D+Q administration (ninth dosage) 
2. 
Provide Home dosage (tenth day dosage and instructions) 
Post –Visit 
Telephone Calls  
1. 
At-home dosage reminder call and post-visit survey (1 day after visit) 
2. 
Telephone check-in for AE (3-5 days after visit) 
Visit 7, Week 12:  
Final dosage visit 
[14 +/- 3 days Visit 
6] 
• Assessments/Activities 
1. 
Repeat of Visit 3 assessments and activities 
• Medication Administration 
1. 
D+Q administration (eleventh dosage) 
2. 
Provide Home dosage (twelfth day dosage and instructions) 
Post –Visit 
Telephone Calls  
1. 
At-home dosage reminder call and post-visit survey (1 day after visit) 
2. 
Telephone check-in for AE (3-5 days after visit) 
Visit 8, Week 14:  
Final follow-up visit 
• Assessments/Activities 
1. 
Repeat of Visit 2 assessments and activities 


 
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[14 +/- 3 days Visit 
7] 
2. 
Physical Exam by study physician, Dr. Lipstiz, or trained medical professional 
3. 
EKG 
4. 
CBF/NVC 
5. 
Blood sample: clinical safety labs and serum senescent biomarkers 
6. 
Urine sample: urinary senescent biomarkers  
 
4.3 Participant Study Timeline 
Including the telephone screening, participants will spend a total of 14 weeks in the study. The participant 
timeline is shown below:  
 
 
 
4.4 Compliance and Attrition 
 
At the start of an individual’s study participation, he/she will will be given a schedule of their study visits. Visits 
will be scheduled at a time of day that the participant determines is most convenient for them, and will repeated 
at the same time for each visit. Transportation will be provided for each visit as needed, snacks will be 
available, and stipends will be provided for each study milestone. A reminder card will be sent a week before a 
scheduled visitand/or a reminder call will be made to participants on the day prior to each study visit. 
 
Participants will be tracked throughout their enrollment. Each study visit will be documented. Each study visit 
will be followed with a brief telephone check-in to ask the participant questions about medication compliance, 
adverse effects, and their experience during the most recent visit. All calls to the participant and their feedback 
will be carefully tracked. Notes that may facilitate compliance, such as “call before 10 am”, etc, will be kept in 
participant files. 
 
We will employ specific strategies to maximize participation and compliance: 
• 
Positive Framing about Benefits: Information will be presented in terms of the possible gains rather 
than the avoidance of losses as this is a more effective motivational approach.  
• 
Feedback and Recognition of Progress: Participants will be acknowledged throughout their 
participation with thank you notes, and will be recognized for their contributions to the study through 


 
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regular brief flyers/newsletters such as “Partners in Progress – Mobility and Falls updates”.  We will 
remain in close contact with individuals throughout their participation with follow-up calls each month.  
• 
Incentives and Rewards: Participants will receive snacks at each visit, cards for achieving milestones, 
such as birthdays, holidays, etc.; and certificates of completion.   
 
4.5 Study Visits and Assessments 
 
All study visits will take place at the Clinical Research Laboratory at HRC, Roslindale MA or at an HRC-
affiliated housing site. Free parking or transportation will be provided for all study visits. A summary of study 
visits and assessments is provided in the table below. Given that a primary goal of this pilot study is feasibility, 
we will allow for flexibility for the administration of some assessments at visits, as long as these changes do 
not impede the scientific interpretation. For example, if the participant is not able to provide a urine sample at 
the screening visit, they will be allowed to provide a urine sample at visit 2, as long as it is taken before any 
treatment is administered.  
 
 
Table. Study Visits and Assessments Timeline 
Visits 
0 
Telephone 
Screen 
1 
2 
3 
4 
5 
6 
7 
8 
Weeks 
 
0 
2 
4 
6 
8 
10 
12 
14 
Procedures: 
 
 
 
 
 
 
 
 
 
Telephone pre-screen script 
X 
 
 
 
 
 
 
 
 
Telephone MoCA 
X 
 
 
 
 
 
 
 
 
Katz Activities of Daily Living 
X 
 
 
 
 
 
 
 
 
Screening/Consent  
 
X 
 
 
 
 
 
 
 
Medical History  
 
X 
 
 
 
 
 
 
 
Gait Speed 
 
X 
 
 
 
X 
 
 
X 
Comorbidity Score 
 
X 
 
 
 
 
 
 
 
Height and Weight 
 
X 
 
 
 
 
 
 
 
Blood Senescent Cells 
 
X 
 
 
 
 
 
 
X 
Inflammatory Markers 
 
X 
 
 
 
 
 
 
X 
Urinary SASP Factors 
 
X 
 
 
 
 
 
 
X 
CBF, NVC 
 
X 
 
 
 
X 
 
 
X 
Safety Blood Tests1,2 
 
X 
 
X 
X 
X 
X 
X 
X 
Full Physical Exam  
 
X 
 
 
 
X 
 
 
X 
Vital Signs3 
 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
 
X 
 
X 
X 
X 
X 
X 
X 
Suicidal Ideation Screener 
 
 
X 
X 
X 
X 
X 
X 
X 
Treatment Administration  
 
 
X 
X 
X 
X 
X 
X 
 
Treatment Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
Acute Post-Treatment BP4 
 
 
X 
X 
X 
X 
X 
X 
 
Symptoms and AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
Cognitive Assessments5  
 
 
X 
 
 
X 
 
 
X 
Dual Task Gait Speed 
 
 
X 
 
 
X 
 
 
X 
SPPB, TUG, Grip  
 
 
X 
 
 
X 
 
 
X 
CESD-R 
 
 
X 
 
 
X 
 
 
X 
IADL’s6 
 
 
X 
 
 
X 
 
 
X 
1Includes complete blood count with differential, prothrombin time/International Normalized Ratio, a 
comprehensive metabolic panel (including glucose, calcium, sodium, potassium, bicarbonate, 
chloride, blood urea nitrogen, creatinine, albumin, total protein, alkaline phosphatase, alanine 
aminotransferase, aspartate aminotransferase, total and direct bilirubin, glomerular filtration rate, and 
cystatin C) 


 
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2As per clinical judgement, additional safety blood tests will be done if warning symptoms are positive 
on the symptom questionnaire (Appendix J) that are administered during the telephone visits after 
the treatment administration. 
3Includes seated blood pressure, postural blood pressure, body temperature, heart rate, respiratory 
rate, and oxygen saturation 
4Measure of seated blood pressure 30- and 60-minutes following the treatment administration to 
detect acute vasodilatory effects of the drugs.  
5Includes the full 30-point MoCA and the Trail Making Test 
AE, adverse events; BP, blood pressure; CBF, cerebral blood flow; CESD-R, Center for 
Epidemiological Studies Depression Scale- Revised; NVC, neurovascular coupling; SASP, 
senescence-associated secretory phenotype; SPPB, Short Physical Performance Battery; TCD, 
Transcranial Doppler ultrasound; TUG, Timed Up-and-Go. 
6Instrumental activities of daily living (IADL) 
 
Detailed information on study procedures at each visit is outlined below.  
 
Visit 0- Telephone screening (approximately 45 minutes): Volunteers will be asked about cognitive 
complaints, slowing of gait-speed, impairments in ADL’s, current medical conditions, sociodemographics, 
current medications, and exclusion criteria (see §3.4). Participants will also be asked to complete the 
Telephone MoCA to evaluate cognitive status. A Telephone MoCA score <19, which is indicative of cognitive 
impairment,23 is an inclusion criteria of this study. 
 
Telephone Montreal Cognitive Assessment (tMoCA) will be administered by a trained research assistant to 
determine if the potential participant has Mild Cognitive Impairment (defined as a Telephone MoCA score 
<19).23 Individuals with a tMoCA score <10 will be excluded, since it corresponds to a full MoCA score of 14 
points,24 which is indicative of dementia.25 The assessor will be trained and certified in the conduct of this test.  
 
Visit 1 – In-person screening (approximately 3 hours): 
Individuals deemed potentially eligible via the phone screen will complete an in-person screen. All screening 
assessments, other than the physical exam, will be administered by trained research assistants. Prospective 
participants will read and sign an informed consent form approved by HRC’s IRB, Advarra. A medical history 
questionnaire will be completed which will ask about current/past conditions, medications, years of education, 
etc. A 4-meter gait speed will be assessed with a stop-watch over a 4-meter track. Dr. Lipsitz or a trained 
clinician will conduct a physical exam to determine eligibility. Vital signs and an EKG (See Appendix A for 
clinical safety exclusion thresholds) will also be assessed. Height and weight will be measured. We will do a 
bilateral Transcranial Doppler insonation of the MCA to be sure there is a suitable temporal bone window to 
perform CBF and NVC measurements. If a suitable window is found, the participant will perform the CBF/NVC 
assessment. Additionally, we will collect up to 60 mL blood sample to check clinical safety measures (~15 mL) 
and biomarkers of senescence (~45 mL). Urine (~10-15 mL) will also be collected to measure biomarkers of 
senescence. Eligible participants will identify a proxy for study staff to call if study staff cannot get in contact 
with the participant. Subjects who meet inclusion criteria will then will be scheduled to return for a baseline 
assessment, 6 cycles of treatment, and a follow-up assessment.  
 
Medical History: Additional measures to characterize the participants will include age, sex, existing or previous 
medical conditions, and the Charlson comorbidity score.30 
 
Height/Weight will be measured at the screening visit.  
1. Height will be measured using a stadiometer.  
2. Weight will be measured using a Detecto balance beam scale. 
 
Physical Exam will include a chest, cardiac, and a brief neurological assessment and be performed by the 
study clinician (or a trained medical professional) at the screening visit to determine eligibility.  
 
Vital Signs (See Appendix A for clinical safety exclusion thresholds) will be performed at each in-person visit. 


 
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1. Body temperature, pulse, heart rate, breathing rate, oxygen saturation, seated blood pressure, postural 
change of blood pressure, and postural change of heart rate) will be assessed by the study doctor or 
trained personnel. 
2. An EKG will be administered by trained personnel and reviewed by the PI and study clinician (Dr. 
Lipsitz) to evaluate the QTc interval.  
 
CBF and NVC Dual Task: We will assess the CBF response to cognitive activation (N-back) (NVC) while 
seated and standing from a seated position using protocols previously developed in our laboratory.31 Subjects 
will practice the N-Back task prior to initiating recording. Participants will first be instrumented with EKG 
electrodes, a finometer (to continuously record finger blood pressure), an automatic blood pressure cuff, and 
the TCD probe affixed on the temporal window to insonate the MCA.   
While subjects are sitting comfortably, they will be asked to watch a computer display and complete the 
following tasks as part of the N-back protocol: 
1. Identify X (IDX) task. This is the control condition from which absolute and relative changes in MCA 
blood flow during the 2-back task are calculated. A series of single letters appears in succession on the 
projection screen. Subjects are asked to click the right button of a mouse each time they see the letter 
X. Each letter is displayed for 3 seconds. A 5 second delay between flashing letters, indicated by a 
blank screen, reduces “tracers.” 
2. 2-Back: A series of single letters will appear in succession and subjects will be asked to click the right 
button each time they see a letter that occurred 2 back. 
The sequence of testing for each task (IDX and 2-back) is as follows: 55 seconds of blank screen, 95 seconds 
of IDX followed by 55 seconds of blank screen, followed by 95 seconds of 2-Back, with a 5 second instruction 
in between each task to indicate which task they should be doing. This sequence will be repeated 2 times for a 
total of about 6.5 minutes. Each individual’s performance during the N-back task is recorded and scored as the 
percent correct of the total. 
 
Participants will also be asked to complete the following sit-to-stand protocol while instrumented with EKG 
electrodes etc.: 
1. First participants will be asked to sit quietly for 3 minutes while CBF and continuous BP are being 
recorded.  
2. Next participants will be asked to stand for 1 minute while recordings continue.  
3. The same procedure will be repeated a second time.   
 
 
Blood (60 mL) will be collected via serum separator, EDTA, or heparinized tubes by a trained phlebotomist 
using sterile procedures either at HRC or one of the facilities affiliated with HRC. 
1. Approximately 15 mL (~4 mL of blood in EDTA, ~3 mL of blood in a sodium citrate tube, and ~ 8mL of 
blood in serum separator tubes) portion of the collected blood sample from participants will be used to 
measure CBC, glucose, liver enzymes, bilirubin, BUN, creatinine, cystatin C, calcium, albumin, 
prothrombin and international normalized ratio. Samples will be processed, labeled with confidential 
participant numbers, and measured by HRC clinical laboratory vendor or a reliable clinical laboratory 
(e.g., Quest Diagnostics) (See Appendix A for clinical safety exclusion thresholds). 
2. Approximately ~45 mL (30 mL of blood in EDTA, 5 mL of blood in heparinized tube, and 10 mL of blood 
in serum separator tube) portion of blood will be collected, processed, aliquoted, and temporarily stored 
in a -70 degree centigrade freezer. A portion of the 45 mL of blood will be used to isolate cells (e.g., 
CD3+ T lymphocytes and peripheral blood mononuclear cells) by HRC study staff or a reliable clinical 
laboratory (e.g., laboratories affiliated with collegiate universities or hospitals). Processed blood 
samples will be shipped on dry ice to Mayo in batches to measure biomarkers of senescence and aging 
(e.g., CD3+ T lymphocytes, mitochondrial/nuclear [mt/N] DNA, key microRNA’s, cytokines, etc.) in 
serum and in plasma.  
 
Urine (10-15 mL) will be collected in a sterile container at the screening and final follow-up visits.  
1. Urine will be centrifuged and the supernatant will be collected, aliquoted into 0.5 mL tubes, labeled with 
confidential participant numbers, and temporarily stored at -70 degrees Centigrade; then shipped on 


 
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dry ice in bulk to Mayo Clinic for batch analyses of urinary SASP factors (e.g., IL-6, MCP-1, MMPs, 
etc.) 
 
Visit 2 – Baseline assessments (approximately 2.5 hours): 
Approximately 2 weeks later, eligible participants will have a baseline assessment and receive their first dose 
of D+Q. First, evaluation of symptoms and adverse events (pre-medication administration) will be performed.  
Vital signs will be measured. A questionnaire on mood (Center of Epidemiology Studies-Depression Scale 
Revised; CESD-R), instrumental activities on daily living (IADLS), physical function assessments (SBBP, TUG, 
hand grip strength, and gait speed) and cognitive assessments (the full 30-point MoCA and TMT) will be 
completed. Participants will under-go a familiarization of the serial subtraction assessment to determine which 
cognitive task will be implemented in the walking/dual task assessment. Next, the walking/dual task protocols 
will be completed. Given that newly taking pharmaceuticals has results in increased suicidal ideation, 
participants will also be screened for suicidal ideation with the P4 suicidality screener.32 The last activity of the 
visit will be related to D+Q administration. Participants will be asked to take 100 mg of Dasatinib (1 pill) and 
1,250 mg of Quercetin (5 pills) with a glass of water. Research study staff will monitor the participants up to the 
next hour to evaluate any immediate adverse effects. During this hour, post-treatment seated blood pressure 
will be measured at 30- and 60- minutes after treatment administration. Finally, participants will be provided the 
at-home dosage and instructions for consumption of D+Q that will be taken the following day. Breaks and 
snacks will be provided throughout the visit.  
 
 
Physical Function will be assessed with three tests: TUG,152 hand grip strength (via dynamometer) and 
SPPB.149  
1. Hand grip strength will be measured with a hand-held dynamometer and we will record the result of 
each trial to the nearest pound and kilogram. If the difference between any two measures exceeds 6.6 
lbs. (3 kg), we will repeat the test once more after a rest period and average the 3 best measurements. 
2. The SPPB includes measures of balance (timing of tandem, semi-tandem, and side-by-side stands, 
test-re-test (T-R-T) correlation=0.97), 4-meter walking speed (T-R-T correlation = 0.89), and ability and 
time to rise from a chair 5 times (T-R-T correlation = 0.73).27,33 SPPB validity has been demonstrated by 
showing a gradient of risk for admission to a nursing home and mortality along the full range of the 
scale from 0-12.27 In the EPESE population, summary scores less than 9 independently predicted 
disabilities in ADL and mobility at 1-6 years of follow-up.33,34 
3. The TUG152 requires the participant to stand up from a chair, walk three meters, turn around, walk back 
and sit down. The average time to complete two separate trials will be recorded. This test has high test-
retest reliability and discriminant validity in older adults.153, 154 
 
Familiarization will happen just prior to implementation of the walking dual task assessment. Participants will 
complete a 30-second familiarization of the walking/dual task paradigm. This procedure will 1) determine the 
cognitive task to be used in the assessment, thereby ensuring that it is not too difficult and/or anxiety provoking 
to the participant, and 2) minimize the potential for procedural-related learning to influence outcomes. First, we 
will determine the cognitive task to be used for each participant using a modified procedure30, 50, 135-137 in which 
participants are seated in a chair and asked to count backwards from 200 by 3’s for 30 seconds. If the 
participant is successfully able to produce 3-5 correct answers within the 30 seconds they will be instructed to 
count back by 3’s for the walking/dual task assessments for the rest of the study. If the participant is unable to 
produce 3-5 correct answers within 30 sections, then the participant will be instructed to count back by 1’s for 
the walking/dual task assessment. To maintain consistency at future visits that evaluate the walking/dual task 
assessment (e.g., Visit 5 and 8), participants will be instructed to count backwards from 200 by 3’s or 1’s 
(whichever task was chosen at baseline visit) for 30 seconds in a seated position just prior to the walking tasks.  
 
A Gait Speed and Walking/Dual Task protocol will be completed. Procedures will follow published 
recommendations 24,139,140 that produce excellent test-retest reliability.45, 141-145 We have used this paradigm in 
our laboratory for over ten years. Participants will complete two, 20 meter walks in each of the following 
conditions: 
1. Single task (ST): walking without a cognitive distraction 


 
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2. Dual task (DT): walking while counting backwards from a random 3-digit number (either by 3’s or 1’s; 
whichever was deemed appropriate during familiarization). 
Trial order will be randomized for each assessment and at least 1 min of rest will be provided between trials. 
The walking trials will be a 20 m distance. Prior to testing, participants will be outfitted with wireless 
biosensors—each containing a triaxial accelerometer, goniometer and magnetometer—on the sternum, low 
back, wrists and ankles to record gait kinematics (Mobility Lab™, APDM Inc). Participants will be reminded to 
walk at their preferred, comfortable pace prior to each walking trial.  
 
The cognitive task will be verbalized serial subtractions from a random three-digit number between 200 and 
300, to be provided to the participant prior to each trail. The type of serial subtractions (3’s or 1’s) will be 
determined in a familiarization session just prior. Participant responses during each trial will be recorded. We 
have chosen serial subtractions as the cognitive dual task because: 1) it activates a distributed cortical network 
including the left dlPFC that is fed by the MCA,146 2) it is the most widely used dual task paradigm 24,147 and 
induces significant and meaningful dual task costs to both postural sway when standing and gait kinematics 
when walking in older adults with and without a history of recurrent falls, 30,37,38,148 3) it has been used by our 
team and will thus enable comparison of current results to those from past studies, and 4) it is reliable and 
minimally influenced by learning after familiarization.145 No instructions will be given regarding task 
prioritization. This approach has been chosen to most closely mimic real-life situations.24,140,147  
 
Cognitive assessments will include: 
1. Montreal Cognitive Assessment (MoCA, Full 30-point version) will be administered by a trained research 
assistant. A different, validated version of the MoCA will be used at each assessment to minimize 
practice effects.35 Version order will be randomized across participants. The assessor will be trained 
and certified in the conduct of this test.  
2. Executive function using the Trail Making Test (TMT parts A and B, and B minus A to correct for 
performance speed).36,37  
 
Mood and Suicidal Ideation will be assessed. Mood will be measured because it influences performance on 
clinical tests of physical and cognitive function.38,39 Suicidal ideation will be assessed throughout the study. 
1. We will use the CESD-R,40 which consists of 20 questions regarding feelings of depression, 
worthlessness, loneliness, energy level, and fear. The CESD-R has high internal consistency (r=0.90) 
and a test-retest reliability of 0.51.41 
2. Suicidal ideation will be assessed using the validated 4-item questionnaire, P4 Suicidality Screener.32 
 
Acute Post-Treatment Blood Pressure will be assessed after each administration of study medications. 
Quercetin is known to have vasodilatory effects. To determine whether Quercetin is acutely acting as a 
vasodilator, we will measure seated blood pressure before and 30- and 60-minutes after the treatment 
administration.  
 
Visit 3 – 3rd and 4th Dosages (approximately 2 hours): 
Approximately 14 +/- 3 days later, the participant will have their next visit. An evaluation of symptoms and 
adverse events will be performed using open-ended questions about any events since the last dose, and a 
questionnaire that asks about previously reported potential side effects. A 15 mL blood sample will be taken to 
assess clinical safety measures (same as screening). Vital signs and EKG will be measured. We will also 
assess medication compliance of the previous at-home dose, by asking whether the medications were taken 
and examining the pill bottles that participants are asked to return. Finally, participants will be asked to take 
100 mg of Dasatinib (1 pill) and 1,250 mg of Quercetin (5 pills) with a glass of water. Research study staff will 
monitor the participants for approximately 1 hour to evaluate any immediate adverse effects. Finally, 
participants will be provided the at-home dosage and instructions for consumption of D+Q that will be taken the 
following day.  
  
Visit 4 – 5th and 6th Dosages (approximately 2 hours): 
Approximately 14 +/- 3 days later, the participant will have their next visit. An evaluation of symptoms and 
adverse events will be performed as described above. A 15 mL blood sample will be taken to assess clinical 


 
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safety measures (same as screening). Vital signs and EKG will be measured. We will also assess compliance 
with the previous at-home dose as described above. Finally, participants will be asked to take 100 mg of 
Dasatinib (1 pill) and 1,250 mg of Quercetin (5 pills) with a glass of water. Research study staff will monitor the 
participants for the next 1 hour to evaluate any immediate adverse effects. Finally, participants will be provided 
the at-home dosage and instructions for consumption of D+Q that will be taken the following day.  
 
Visit 5 – 7th and 8th Dosages (approximately 3 hours): 
Approximately 14 +/- 3 days later, participants will have a mid-point assessment. An evaluation of symptoms 
and adverse events will be performed. A 15 mL blood sample will be taken to assess clinical safety measures 
(same as screening). Dr. Lipsitz or a trained clinician will conduct a physical exam. Vital signs and EKG will be 
measured. CBF and NVC measurements will be taken. We will also evaluate measures of physical function 
(SBBP, TUG, hand grip strength, and gait speed), IADLS, and cognitive assessments (MoCA, TMT, and CES-
D). Participants will then be asked to take 100 mg of Dasatinib (1 pill) and 1,250 mg of Quercetin (5 pills) with a 
glass of water. Research study staff will monitor the participants for the next 1 hour to evaluate any immediate 
adverse effects. Finally, participants will be provided the at-home dosage and instructions for consumption of 
D+Q that will be taken the following day. Breaks and snacks will be provided throughout the visit. 
 
Visit 6 – 9th and 10th Dosages (approximately 2 hours) 
Approximately 14 +/- 3 days later, the participant will have their next visit. An evaluation of symptoms and 
adverse events will be performed. A 15 mL blood sample will be taken to assess clinical safety measures 
(same as screening). Vital signs and EKG will be measured. We will also assess medication compliance of the 
previous at-home dose. Participants will then be asked to take 100 mg of Dasatinib (1 pill) and 1,250 mg of 
Quercetin (5 pills) with a glass of water. Research study staff will monitor the participants for the next 1 hour to 
evaluate any immediate adverse effects. Finally, participants will be provided the at-home dosage and 
instructions for consumption of D+Q that will be taken the following day.  
 
Visit 7 – 11th and 12th Dosages (approximately 2 hours) 
Approximately 14 +/- 3 days later, the participant will have their next visit. An evaluation of symptoms and 
adverse events will be performed. A 15 mL blood sample will be taken to assess clinical safety measures 
(same as screening). Vital signs and EKG will be measured. We will also assess medication compliance of the 
previous at-home dose. Participants will then be asked to take 100 mg of Dasatinib (1 pill) and 1,250 mg of 
Quercetin (5 pills) with a glass of water. Research study staff will monitor the participants for the next 1 hour to 
evaluate any immediate adverse effects. Finally, participants will be provided the at-home dosage and 
instructions for consumption of D+Q that will be taken the following day.  
 
Visit 8 – Final Follow-up (approximately 2.5 hours): 
Approximately 14 +/- 3 days later, participants will have a final follow-up assessment. An evaluation of 
symptoms and adverse events will be performed. A urine sample will be collected to measure urinary markers 
of cellular senescence. A 60 mL blood sample will be taken to assess clinical safety measures (same as 
screening) and serum biomarkers of cellular senescence. Dr. Lipsitz or a trained clinician will conduct a 
physical exam. Vital signs and EKG will be performed measured. CBF and NVC measurements will be 
assessed. We will evaluate IADL’s, measures of physical function (SBBP, TUG, hand grip strength, and gait 
speed) and cognitive assessments (30-point MoCA, TMT, and CESD-R). Breaks and snacks will be provided 
throughout the visit.  
 
Telephone Reminders and Follow-ups (takes approximately 5-10 minutes each, 1-2 hours total) 
Participants will be called prior to each in-person visit to remind the participant of the scheduled visit, provide 
brief instructions for the visit, and perform a telephone COVID screen if necessary. The participant will also be 
called the day of each at-home dosage administration (i.e., the day after Visits 2 -7), and approximately 3 +/-2 
days after each in-person dosage visit (i.e., Visit 2-7). During these calls participants will be asked about 
medication compliance with at-home dose, visit satisfaction, side effects, and/or symptoms.  
 
4.6 Drug Intervention 
 


 
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Dasatinib (D) is a chemotherapeutic agent primarily used for the treatment of Chronic Myeloid Leukemia 
(CML). It is a tyrosine kinase inhibitor that has been shown to reduce the abundance of senescent cells in 
animals and humans.  
 
Quercetin (Q) is a safe, over-the-counter health promotion product with anti-inflammatory and antioxidant 
properties that is commonly used in doses similar to ours for the prevention of cancer, cardiovascular disease, 
diabetes, and infections. It is a flavonoid that has also been shown to reduce the abundance of senescent cells 
in animals and humans.  
 
Treatment Regimen 
 
Eligible participants will be asked to take D+Q for 2 consecutive days every two weeks. This cycle will be 
repeated 6 times during the 12 week study duration. As a result, participants will consume a total of 12 doses 
of D+Q. Each daily dose consists of 100 mg of Dasatinib and 1,250 mg of Quercetin. The Dasatinib comes in a 
100 mg tablet, while the Quercetin comes in 250 mg tablets. Thus, there will be 1 pill of Dasatinib and 5 pills of 
Quercetin for each daily dose.  
 
Preparation and Packaging 
 
The preparation and packaging will be carried out by the research pharmacy Johnson Compounding in 
Waltham MA (approximately 14 miles from HRC). Johnson Compounding will purchase 100 mg tablets of 
Dasatinib that is manufactured by Bristol Myers Squibb and 250 mg tablets of Quercetin manufactured by 
Thorne Research. The investigational products for this study will be delivered to and managed by Johnson 
Compounding Pharmacy according to FDA-approved procedures. When an eligible participant is enrolled in 
our study, Dr. Lipsitz and/or study staff will notify Johnson Compounding with the subject name, confidential 
subject ID number, date of birth, as well as information on allergies and current medications (disclosure of 
participants’ PHI to Johnson Compounding is allowed pursuant to the HIPAA authorization language in the 
informed consent document) and Dr. Lipsitz will write a prescription for that individual. The subject’s name and 
date of birth will be placed on the bottle to assure that the medication is dispensed to the correct participants’ 
confidentiality. Dr. Lipsitz is certified by the Massachusetts Controlled Substances Registration (MCSR) Board 
to Use Controlled Substances and Investigational New Drugs in Research. Each cycle, a participant’s two-day 
dose will be bottled by Johnson Compounding (e.g., 1 bottle will contain two, 100 mg tablets of Dasatinib and 1 
bottle will contain ten, 250 mg capsules of Quercetin, labeled with the participants’ name and date of birth, and 
instructions). Every label will include a statement that these products are for investigational use only. The filled 
prescription bottles will be either picked up by study staff or delivered to our laboratory via FedEx or other 
courier prior to the scheduled in-person visits. 
 
Receiving, Storage, and Dispensing of Study Medications at HSL 
 
Throughout the study, all study drug disposition and accountability will be tracked using a tracker modeled after 
the Study Drug/Investigational Product Tracker (See Appendix C for sample form) provided by the NIA Clinical 
Research Toolbox which will require date, time, and signature of study staff. All of the study medications will be 
stored at room temperature 68° to 77°F (20° to 25°C) in a locked laboratory cabinet at HRC.  
 
At the end of each study dosage visit (Visits 2-7) a trained study staff member will dispense 1, 100 mg tablet of 
Dasatinib from the participant’s corresponding pill bottle and 5, 250 mg tablets of Quercetin from the 
participant’s other corresponding bottle. The Study Drug/Investigational Product Tracker will be filled out 
accordingly by study staff (See Appendix C for sample form provided by the NIA Clinical Research Toolbox) to 
evaluate study drug disposition and accountability. The participant will be asked to take the study medications 
(100 mg Dasatinib and 1,250 mg of Quercetin) with a glass of water. Participants will be monitored for an hour 
by a study staff member, to evaluate any possible acute adverse effects. Any adverse or serious adverse 
events will be logged on forms that will be modeled after those provided by the NIA Clinical Research Toolbox 
(See Appendix E&F for sample forms). The monitoring period and any adverse effects will also be recorded in 
a study monitoring log. Study staff will also fill out a Compliance Log (See Appendix D for sample form), 


 
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modeled after the Compliance Log provided by the NIA Clinical Research Toolbox, throughout the study to 
measure compliance with the study medications.   
 
The remaining pills in the two bottles (one, 100 mg tablet of Dasatinib in one bottle and five, 250 mg tablets of 
Quercetin in another bottle) are the participant’s next day dose. The bottles will be given to participants to take 
at home with appropriate instructions for storage and administration. All participants will be asked about 
compliance via telephone calls and study staff will fill out the Compliance Log (See Appendix D) to monitor 
compliance with study drugs. Participants will be asked to also indicate the time of each dose. Any unexpected 
mishaps with study medications (e.g., dropped or lost pill) will also be logged.  
 
Return or Destruction of Study Drug 
 
Participants will be asked to bring back the pill bottles (empty or with any remaining study medications tablets if 
they did not take them). The amount of drug returned and drug remaining will be logged and stored in a locked 
cabinet in the laboratory at HSL until disposal. 
 
At the completion of the study, there will be a final reconciliation of drugs shipped, drugs dispensed, drug 
returns, drugs lost, and drugs remaining. This reconciliation will be logged in the Study Drug/Investigational 
Product Tracker (modeled after Appendix C) and will be signed and dated. Any discrepancies noted will be 
documented and investigated, prior to return or destruction of unused study drug. Any returned or unused 
drugs will be destroyed on-site by research staff by placing pills in commercially available drug deactivation 
and disposal pouches or returned to Johnson Compounding for proper disposal. Drugs destroyed will be 
documented in the study log files accordingly. 
 
Participant Compliance Monitoring 
 
Participant compliance with the study medications will be monitored in three ways:  
1. During the in-person study visit and follow-up telephone calls, study staff will monitor and log 
compliance of study medications on a Compliance Log (See Appendix D for sample form). 
2. Participants will be asked to return their pill bottles with any remaining tablets they did not take on their 
next visit. 
3. The Advarra CRO will monitor this process and its documentation to help assure compliance with good 
clinical practice and FDA regulations.  
 
4.7 Informed Consent 
 
All interested individuals will be asked to provide verbal consent to complete an initial eligibility screen during a 
phone conversation with study personnel.  Potentially eligible participants will then schedule an in-person 
screening visit.  Potential participants may be sent by email or conventional post (per request, and according to 
their preference) a copy of the informed consent form for them to review at their own pace prior to the in-
person screening. Written informed consent will be obtained by study personnel at the beginning of the in-
person screening visit.   
 
4.8 Participant Withdrawal  
 
Any participant who expresses a desire to discontinue participation in the study will be withdrawn at their 
request immediately. If during the course of their study enrollment, a participant develops a new medical 
condition that would contraindicate further participation in the study, as determined by a study physician (Dr. 
Lipsitz), the participant will be informed of this and withdrawn from the study. All data collected prior to 
withdrawal will be maintained in the study data set. 
 
A subject may be withdrawn from the study prior to completing all of the study related procedures due to the 
following conditions: 
• Subject safety issues 


 
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• Failure of subject to adhere to protocol requirements 
• Disease progression 
• Subject decision to withdraw from the study (withdrawal of consent) 
Withdrawn subjects may not reenter the study unless there are extenuating circumstances (e.g. family 
emergency or required travel out of town) that interfere with the start of the study before any medications are 
administered. In this case, they may be scheduled to start over again. 
 
Throughout the study, participants will undergo routine physical exams that includes an evaluation of the 
participant’s vital signs and the electrical conductivity of the heart (i.e., EKG). Participants will also have their 
blood evaluated for relevant safety markers. Thresholds for the safety measures (vital signs, EKG, and blood 
values) are outlined in Appendix A. If participants meet any of the safety thresholds outlined in Appendix A, the 
study doctor will determine if the participant will be allowed to continue with the study based on their clinical 
judgment, as well as input from the Data Safety Monitoring Board.   
 
4.9 Methods to Protect Participant Privacy   
 
The following are the planned procedures for effectively protecting against and minimizing loss of participant 
privacy: 
1. Phone screening will be conducted in a private office space. 
2. Study visits will be conducted in private rooms located within the laboratory. 
3. Each participant will be given a unique study identification number and data will not include any of the 
participant’s PHI. 
4. All participant-identifying information will be stored and managed on a secured database server. The 
information will be password protected.  
5. Participant confidentiality will be maintained in accordance with Health Insurance Portability and 
Accountability Act (HIPAA) regulations. 
6. Only the PI, study personnel, and laboratory personnel approved by the IRB and authorized to view PHI 
will have access to the information. 
7. PHI will not be used during discussion, presentation or publication of any research data. 
8. Files containing PHI data collected for recruitment and screening purposes will be kept in locked, 
secured filing cabinets accessible only to designated study personnel (research assistants and 
investigators) 
 
4.10 Minimization of Bias 
 
Since participants will serve as their own controls, there is no inter-subject bias. Moreover, some of the data 
will be gathered using instruments (e.g., Transcranial Doppler) that cannot be influenced by preconceived 
assumptions. Additionally, to minimize analyst bias, biomarkers will be de-identified and analyzed by 
technicians unfamiliar with the participants or study phase. Finally, data will be analyzed by investigators who 
are blinded to participant identity.  
 
 
CHAPTER 5:  TRAINING 
 
Procedures to ensure scientific rigor: A manual of operations will be created with standard participant instructions 
for each question and assessment. All research staff will review and sign the Site Signature Log – Delegation of 
Authority Log (See Appendix G) provided by the NIA Clinical Research Toolbox to confirm their responsibilities 
related to the study. During startup, staff will undergo intensive training, and all training sessions will be logged 
and signed accordingly. They will conduct all study procedures on 4-5 older adult volunteers (more if necessary) 
with oversight from the PI to ensure consistency of raters and equipment setup. Quality checks will be done 
every six months throughout the data collection period. 
 
Training will be based on standardized materials developed for the study, and coordinated by the Project 
Director. Well-established tests of cognitive function will be administered to characterize critical functions 


 
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relevant to several hypotheses being tested in this project. Every six months, the staff will undergo training review 
and quality checks on all assessments and drug distribution protocols. Additionally, any time there is an 
amendment to the study protocol, the change will be logged on the Protocol Log (See Appendix H). All study 
staff will be provided a summary of the protocol modifications (See example in Appendix I) and under-go re-
training for the new protocol. The date, duration, and certification of all training will be documented and signed 
by the Principal Investigator on the appropriate training logs.  
 
CHAPTER 6:  DATA MANAGEMENT AND QUALITY 
 
6.1 Data Management  
 
All data collected for analysis will be de-identified and assigned a unique study number. Data collection forms 
will also be kept in a locked file cabinet in the office of the Dr. Lipsitz (PI) at Hebrew SeniorLife. Data will be 
entered and stored on a password-protected secure server at HRC. 
 
The Institute for Aging Research primarily employs the REDCap system to facilitate data management 
operations. REDCap is a full-featured clinical trials data management system (DMS) accessible to data entry 
and data analysis workstations using secure Web technologies. The REDCap product is developed and 
maintained by Vanderbilt University in cooperation with REDCap Consortium members, including HRC. HSL 
hosts and maintains a dedicated instance of REDCap for use across our research enterprise. Each research 
study is provided separate project workspace in which all of the study data are stored in a MySQL relational 
database on the private corporate network behind several firewalls and located physically within the HSL data 
center. 
 
6.2 Participant Tracking  
 
Each recruited participant will be tracked closely throughout study enrollment. A study events calendar will be 
created within the REDCap database and interfaced with a “Study Hub” developed by the Marcus Institute data 
management team.  Any outstanding or incomplete visits will be accessible in real time to the project director 
and study team. The study team will maintain regular communications with each study participant throughout 
enrollment, through regularly scheduled follow up calls, and established retention strategies will be used as 
discussed in section 4.4. 
 
6.3 Outcome measures 
 
Name 
Type 
Timeframe 
Brief description 
Feasibility and Safety 
Primary 
Throughout the entire 
study 
a) the number of volunteers needed to 
be screened to identify eligible 
participants, b) the number and type of 
protocol deviations necessary to assure 
participant comfort and safety (reported 
to the IRB), c) the frequency of possible 
adverse drug effects, and d) compliance 
with medication administration.  
Cerebral blood flow and 
Neurovascular coupling 
Primary 
Screening, 8, and 14 
weeks 
This metric assesses the ability of the 
brain to increase blood flow in response 
to posture change and a cognitive task. 
Executive Function 
(Trails B minus A) 
Primary 
Baseline, 8, and 14 
weeks 
This metric assesses executive cognitive 
function and is corrected for response 
time. 
Gait speed 
Primary 
Screening, 8, and 14 
weeks 
This metric assesses the ability to 
control gait. It is performed without a 
distracting cognitive task.  


 
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SPPB: Short Portable 
Performance Battery 
Secondary 
Baseline, 8, and 14 
weeks 
This test assesses physical 
performance, including gait, balance, 
and strength to perform a chair stand. 
TUG: Timed Up and Go 
Secondary 
Baseline, 8, and 14 
weeks 
This is a timed test of mobility, including 
standing from a chair, walking 20 feet, 
and turning.  
Grip strength 
Secondary 
Baseline, 8, and 14 
weeks 
This test measures grip strength using a 
hand dynamometer. 
Gait speed during 
cognitive task 
Secondary 
Baseline, 8, and 14 
weeks 
This test measures gait speed in 
response to a cognitive task.  
Senescent CD3 cells 
expressing p16INK4A 
Secondary 
Screening  and 14 
weeks 
This measures the number of senescent 
CD3 lymphocytes in blood.  
SASP factors in blood 
and urine 
Secondary 
Screening and 14 
weeks 
These assays measure senescence 
associated biomarkers in blood and 
urine, including IL-1α, IL-6, and MMP-9 
and MMP-12. 
 
6.4 Statistical Design and Power 
 
Sample Size Considerations 
This project will enroll 12 individuals who will be assessed before, during, and following the 12-week D+Q 
intervention. The proposed sample size is motivated by the need to make resource assessments in the design 
of a subsequent RCT of D+Q. We anticipate screening at least two and possibly many more individuals for 
every potential participant who is eligible and advances to enrollment. Under conservative assumptions we will 
be able to estimate the proportion of participants screened who are eligible and advance to enrollment to within 
0.20 using an 80% exact binomial confidence interval, the upper bound of which will be used in planning the 
subsequent trial. We will additionally utilize data obtained in this pilot to similarly estimate the variability of 
outcomes measures and differences attributable to administration of D+Q; again using an 80% confidence 
interval, we will be able to estimate the standard deviation of continuous measures including CBF and gait 
speed to within 0.3 standardized units. The design is not intended to provide sufficient data to test the efficacy 
or effectiveness of D+Q on endpoints relevant for Aims 2 and 3. However, prior small human studies have 
demonstrated surprisingly robust relationships. For instance, a recent human study of only 9 subjects by the 
Kirkland group42 successfully demonstrated that D+Q reduced adipose tissue senescent cell burden within 11 
days after a single 3 day course of treatment. Furthermore, circulating SASP factors were reduced in these 9 
subjects. We therefore anticipate that we will see suggestive evidence of an association with SASP factors and 
inflammatory biomarkers in serum and urine, and senescent cells in blood, sufficient to motivate moving 
forward to a larger clinical trial.  
 
Analytic plan 
We will assess distributional characteristics of the primary and secondary outcomes. In addition to analyzing 
the data from all participants enrolled, we will also explore subgroup analysis based on visit attendance and 
medication compliance. Feasibility endpoints for Aim 1 will be summarized using sample statistics and 
confidence intervals. For Aim 2, comparison of functional variables from before to during or after D+Q 
treatment will be performed using plots and summary tables. Paired differences will be obtained for each 
endpoint and summarized using sample means, standard deviations, and confidence intervals. For Aim 3 
correlations between changes in biomarkers of senescence and changes in functional outcomes will be 
assessed using scatterplot smoothing and summarized using linear or nonlinear regression analyses as 
appropriate. Though we will be unable to adjust for covariates, the influence of age and sex will be explored 
through the use of stratification and added variable plotting. 
 
CHAPTER 7:  DATA SAFETY MONITORING PLAN 
 
7.1 Participant Risks 


 
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The potential risks to study participants include:  
 
Risks Associated with Quercetin: The most common side effects are headache and tingling of the arms and 
legs. Serious interactions may occur with everolimus and topotecan. Volunteers taking these drugs will be 
excluded. Interactions that may increase or decrease other drug metabolism may also occur with cyclosporin 
and drugs metabolized by P450 enzymes CYP2C8, CYP2C9, CYP2D6, and CYP3A4. The potential for 
interactions and their clinical implications will be carefully reviewed by the PI and Pharmacy before anyone 
taking these drugs is enrolled in the study. 
 
Risks Associated with Dasatinib: There are several potentially serious side effects with prolonged daily use, but 
these are largely avoided with intermittent administration over only 2 days. Long-term daily treatment for CML 
may result in myelosuppression, bleeding (usually associated with thrombocytopenia and serious in <1% of 
patients), fluid retention (5% after 5 years of follow-up), cardiac dysfunction (<8.5% after 5 years), reversible 
pulmonary arterial hypertension, QTc prolongation, and dermatologic reactions. Commonly reported adverse 
reactions in older patients treated daily over a long term for CML include fatigue, pleural effusion, diarrhea, 
dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. Less frequently reported 
adverse reactions include abdominal distention, dizziness, pericardial effusion, congestive heart failure, 
hypertension, pulmonary edema, and weight decrease. Since participants will receive only 2 doses at a time 
with 2 weeks’ washout between cycles, adverse effects are unlikely to occur, but we will monitor them closely 
for any potential effects. 
 
Potential drug interactions reported to affect Dasatinib concentrations include strong inhibitors and inducers of 
CYP3A4, St. John’s Wort, and gastric acid reducing agents such as H2 antagonists or proton pump inhibitors. 
These medications are not likely to interact significantly with only 2 doses of Dasatinib at 2 week intervals, but 
participants who need to continue taking them will be excluded. Any side-effects will be closely monitored and 
reviewed by the study P.I. If needed, research staff will coordinate appropriate care for individuals with adverse 
effects as per clinical judgment. 
 
Furthermore, Dasatinib has been associated with fetal toxicity. Thus, all participants will be advised of the fetal 
risks associated with use of Dasatinib. Females of child-bearing potential or males having sex with women of 
child-bearing potential are required to use an effective method of contraception (e.g., condoms) throughout the 
duration of the study and for 90 days after the last study dose. Participants who become pregnant, or 
impregnate someone else while engaged in the study will be asked to notify study staff and their study doctor 
immediately.    
 
Risks Associated with Quercetin and Dasatinib: Thus far, 3 clinical interventions administering D+Q have been 
completed. In 14 adults aged 55-84 years with Idiopathic Pulmonary Fibrosis, 3 weeks of 9 intermittent doses of 
D+Q (NCT02874989) yielded a retention rate of 100% and there were no serious events. There were no changes 
in body weight, vital signs, or clinical chemistries.22  The non-serious events reported during this intervention 
included respiratory symptoms, skin irritation/bruising, and gastrointestinal discomfort. Of note, the dosing 
strategy we are employing is less frequent (2 out of every 15 days instead of 3 out of every 7 days), to reduce 
toxicity2. In a second clinical intervention, adults with diabetic kidney disease reported that all participants 
completed intended doses and no serious adverse events occurred.42 A third and final completed intervention 
found no complications after 5 consecutive days of administration of D+Q in 64 health middle-aged adults.43 
 
Risks Associated with CBF/NVC measurements: The risks associated with CBF/NVC measurements are 
minimal. There is no known risk associated with the TCD used to measure CBF. The probes used to measure 
CBF are held in place by a headband, which may cause minor discomfort from its pressure placed around the 
head. The electrode patches that will be placed on the participant to measure the EKG could cause stickiness, 
skin irritability, and slight discomfort. As with the other cognitive assessments, participants may experience 
mental fatigue and/or anxiety. Participants will be advised that they can refuse to answer any of the questions. 
It is also possible that some participants may become dizzy or lightheaded when standing from a seated 
position. 


 
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Risks Associated with Assessments of Walking and Physical Function: The proposed walking tests have been 
adapted from the large-scale, population-based MOBILIZE Boston study (PI: L. Lipsitz) and multiple completed 
and ongoing clinical studies within the Clinical Research Laboratory at the Hinda and Arthur Marcus Institute 
for Aging Research. They have been designed to be safe for individuals of varying risk and conditioning levels 
including older adult fallers. The physical activity associated with these tests is of low to moderate intensity. 
Potential risks include strains, sprains, muscle soreness, and light-headedness. In rare instances, more 
serious side effects such as an injurious fall may occur. For all functional tests, a trained "spotter" will stand 
behind or close to the subject to provide stabilizing assistance if necessary. 
 
Risks Associated with Mood and Cognition: Risks associated with answering these questions are minimal, but 
participants may experience mental fatigue and/or anxiety. Participants will be advised that they can refuse to 
answer any of the questions.  
 
Risks Associated with Blood Draw: Risks associated with a blood draw include discomfort, bruising, and/or 
bleeding where the needle is inserted. It is also possible that some participants may become dizzy or lightheaded. 
There is a very small risk of infection at the phlebotomy site. Participants will also be advised to refrain from 
donating blood at least 8 weeks after the last study visit. 
 
Risks Associated with EKG: The risks associated with an EKG are minimal. The patches that will be placed on 
the participant to measure the EKG could cause stickiness, skin irritability, and slight discomfort.  
 
7.2 Risk Minimization  
 
General Risk Minimization: The proposed protocol requires 8 visits over 14 weeks and therefore imposes a 
relatively high participant burden with respect to time and effort. Our study team has a strong track record of 
successful clinical research requiring similar participation, and retention has been high in these projects. The 
Clinical Research Laboratory at the Marcus Institute is located near a cafeteria and rest room, and is equipped 
with comfortable seating, a TV, movies, books, and magazines to keep individuals occupied during rest 
periods. Several additional strategies will be employed to minimize participant burden and maximize 
adherence to the protocol. We will: 
- Develop a personal relationship between participants and members of the staff. 
- Schedule appointments at convenient times with familiar staff. 
- Explain to participants all aspects of their participation and follow up. We will demonstrate and practice 
study procedures before beginning data collection. 
- Provide reminders of all appointments and follow-up phone calls. 
- Include personal notes in the participant’s data file to remember events in the life of the participant; these 
can be commented on at the next visit (e.g., birthday, birth of a grandchild). 
- Provide snacks and lunch during all visits. 
- Provide transportation for all visits, if required. 
- Provide valet or dedicated on-site parking spaces. 
- Compensate participants for visits. 
 
Informed Consent Process: All potential participants will be advised that joining the study is completely 
voluntary and that they may withdraw from the study at any time. The Informed Consent document will be 
reviewed with the participant at the start of the first Study Visit, either having them read it or asking them to 
follow along as the staff reads it. When the staff is confident that the participant is completely familiar with the 
document and understands all the aspects of the informed consent form, it should be signed by the participant 
in the presence of the staff member, and should then be signed by the staff member. All consent forms will be 
double checked to make sure they are properly signed and dated. Copies of completed consent forms will be 
given to the participant and the original signed document will be kept on file at the Hinda and Arthur Marcus 
Institute for Aging Research. 
 


 
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Risk Minimization for Older Adults with Cognitive Impairment: To ensure all individuals are of cognitive capacity 
to provide informed consent and participate safely in the study, we will exclude individuals who have scores on 
the telephone MoCA that indicate they may be beyond Mild Cognitive Impairment and may have dementia. 
Unfortunately, the telephone MoCA has only been validated to identify Mild Cognitive Impairment, but not 
dementia. However, the telephone MoCA scoring has been correlated with the full MoCA score. A score of14 
points on the full 30 point MoCA is consistent with a diagnosis of dementia25 and correlates with a telephone 
MoCA score of 10 points.24 Therefore, we plan to use a lower limit of 10 points on the telephone MOCA to 
exclude people with probable dementia  
 
Risk Minimization Related to Dasatinib and Quercetin: Before each drug administration the following will be 
done: vital signs, review of study drug compliance and other medication use, adverse event screening, and 
functional assessment (Gait speed, SPPB, TUG, and grip strength). Safety blood tests will be obtained during 
each visit and sooner if adverse effects occur prior to these times. See Appendix A for clinical safety 
thresholds.  A research assistant will call each participant the day after drug administration and 3 +/-2 days 
after each drug administration cycle to question them about symptoms and potential adverse effects. If a 
participant reports they experienced any new or severe symptoms  that have been associated with Dasatinib 
and Quercetin (Appendix J), an additional safety blood test will be obtained as soon as possible, if appropriate 
and/or as per clinical judgment.  
 
We will minimize the risk to subjects from this study by excluding those with conditions listed in the exclusion 
criteria. We will also monitor subjects carefully for adverse effects and abnormalities in blood tests or EKGs 
that may indicate a safety risk. As noted in the research plan and timeline above, participants will be 
questioned about side effects 1 day and 3+/-2 days after each two-day treatment cycle. Blood studies and an 
EKG will also be performed after each dosage visit to detect any adverse hematologic, hepatic, renal, or 
cardiac effects. 
 
The elimination half-life for Quercetin is 11 hours and for Dasatinib it is 4 hours, so after a few days the drugs 
are gone, but their effects on senescent cells persist. Although continuous daily doses Dasatinib can cause 
endothelial dysfunction and edema, this is prevented by the antioxidant effects of Quercetin and is not likely to 
occur with such short-term administration. 
  
CBF/NVC Risk Minimization: Participants will be permitted to rest between studies to prevent fatigue. Only a 
trained research staff member will administer the TCD, finometer, EKG and automatic blood pressure cuff. The 
participants will be informed they can refuse the procedure at any time. 
 
Walking and Physical Function Risk Minimization: For all physical tests, a trained “spotter” will stand behind or 
close to the participant to provide stabilizing assistance if necessary. Participants will be instructed to stop 
performing or skip any test that makes them feel uncomfortable. Adequate rest will be given in between each 
test, and any reusable equipment will be cleaned with disinfectant after each use. 
 
Assessments of Mood and Cognition Risk Minimization: Participants will be advised that they can refuse to 
answer any of the questions. Participants will be permitted to rest between studies to prevent fatigue. 
 
Blood Draw Risk Minimization: Only a trained phlebotomist will be drawing blood using standard, sterile safety 
procedures. 
 
EKG Risk Minimization: Only a trained research staff member will administer the EKG. The participants will be 
informed they can refuse the procedure at any time.  
 
Protection of Personal Health Information: All primary study data will be recorded with computer tablets on 
electronic case report forms (CRF) or as digital files generated from laboratory equipment. All data recording 
will be in accordance with procedures and guidelines outlined in the study’s Manual of Operations (MOO) 
authored by the study team. Participant confidentiality will be maintained by recording subject data using a 
unique subject identifier. Identifiable data, such as contact information and medical record numbers, will be 


 
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recorded and stored separately from the clinical study data. Any paper-based study material and any 
identifiable data will be kept separate in a locked file cabinet accessible by authorized study staff only. Only the 
study staff directly responsible for the data collection and the safety of the participant will have access to 
identifiable information. All electronic CRF data will be stored securely in an electronic data capture and 
management system. Raw electronic instrumentation data will be organized and saved on a private network 
file dedicated to the research project. Only those listed on the approved IRB protocol will have access to 
subject data. Subject data will be coded and locked in a file cabinet in a locked office. Identifying information 
will not be used during discussion, presentation or research publication. All documents and electronic data will 
be archived for a minimum of three years, or as required by the IRB and federal regulations, after the 
completion of the clinical trial. The study will be registered at clinicaltrials.gov. The Principal Investigator will 
obtain a Massachusetts Controlled Substance Registration (MCSR) from the Department of Public Health to be 
certified to dispense the study medications. 
 
The Hinda and Arthur Marcus Institute for Aging Research employs the Research Electronic Data Capture 
(REDCap) system for data capture and data management operations. REDCap is a full-featured clinical trials 
data management system (DMS) accessible to data entry and data analysis workstations using secure Web 
technologies. While REDCap can be used to collect virtually any type of data (including 21 CFR Part 11, 
FISMA, and HIPAA-compliant environments), it is specifically geared to support online or offline data capture 
for research studies and operations. REDCap is developed and maintained by Vanderbilt University in 
cooperation with REDCap Consortium members, including HRC. HSL hosts and maintains a dedicated 
instance of REDCap for use across our research enterprise. Each research project is provided separate 
workspace in which all of the study data are stored in a MySQL relational database on the private corporate 
network behind several firewalls and located physically within the HSL data center. 
 
7.3 Adverse Events Collection and Reporting 
 
Any adverse or serious adverse events will be logged using forms either provided by or modeled after the form  
that are provided by the NIA Clinical Research Toolbox (See Appendix E&F).  
 
Definition of an Adverse Event  
An adverse event is any untoward medical occurrence in a participant, whether or not it is causally related to 
the study. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the study. Adverse events will 
be recorded on the appropriate case report forms and source documents. The investigator and/or trained staff 
member will evaluate all adverse events as to their severity and relation to the test article. The severity of 
adverse events will be graded as follows: 
Mild: Awareness of a sign or symptom but easily tolerated. 
Moderate: Discomfort sufficient to cause interference with usual activity or to affect clinical status. 
Severe: Incapacitating with inability to do usual activity or to significantly affect clinical status. 
Life Threatening: The participant was at immediate risk of death from the adverse event as it occurred. 
The Investigator will also assess the relationship of any adverse event to the study, based upon available 
information, using the following guidelines: 
0 = Unlikely: No temporal association, or the cause of the event has been identified 
1 = Possible: Temporal association, but other etiologies are likely to be the cause; however, 
involvement of the study procedures cannot be excluded. 
2 = Probable: Temporal association, other etiologies are possible, but not likely. 
 
To determine the attribution and temporal association of an adverse event we will consider the following: 
1) Whether the symptom has been previously associated with the study medications as 
listed in Appendix J. 
2) Whether the participant reports they have experienced the same symptom prior to the 
study intervention.  
3) Whether the symptom occurred and resolved within 24 hours of taking the study 
medication.  


 
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The PI and study doctor, Dr. Lewis Lipsitz, will consider the symptom according to the conditions stated above 
and determine temporality as per clinical judgment. The PI will consult the DSMB members as needed.  
 
Definition of a Serious Adverse Event  
A serious adverse event is any experience that results in any of the following outcomes:  
• Death 
• Is life-threatening 
• Inpatient hospitalization or prolongation of hospitalization 
A persistent or significant disability/incapacity. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
Adverse and Serious Adverse Event Reporting 
There is a potential for adverse events and incidental findings during this study. A structured questionnaire 
asking about adverse events will be assessed during and within 3 days following all visits. However, when any 
adverse has been identified, the study team will take appropriate action necessary to protect the study subject 
and then complete an Adverse Event form that is modeled after the adverse event tracking form from the NIA 
Clinical Research Toolbox (See Appendix E for sample form). This form requires Principal Investigator review 
and signature. After review by the Principal Investigator any adverse event will be reported to the IRB, DSMB, 
and FDA as appropriate.  
 
If a serious event occurs, it will be brought immediately to the attention of the Principal Investigator who will 
examine the participant, decide if immediate treatment is necessary, initiate such treatment at the Beth Israel 
Deaconess Medical Center Emergency Room or appropriate hospital or urgent care setting, contact the 
primary care physician, and notify the IRB, DSMB, and FDA as appropriate. The Serious Adverse Event form 
(See Appendix F) that is provided by the NIA Clinical Research Toolbox will be completed, which requires 
Principal Investigator review and signature 
 
Unanticipated problems or adverse events will be reported according to Advarra’s IRB written guidelines for 
interventional studies. Unanticipated problems and serious adverse events that are probably, possibly, or 
definitely related to the study will be reported as soon as possible from the time of learning of the event, but 
reported within 10 days to Advarra’s IRB per Advarra IRB guidelines. Advarra will be provided a written report 
submitted and a submission of the incident via the eIRB system. This form will record any adverse symptoms 
and/or study protocol deviations. Study staff will reference Appendix K (Subject Safety Event Reporting 
Decision Chart) provided and updated regularly by Advarra to determine whether an event needs to be 
reported to the Advarra IRB.  
 
All other adverse events/study incidents will be logged on an Adverse Event log and reported to the FDA every 
quarter.  
 
For less serious or incidental findings the Principal Investigator will speak with the participant about the 
finding, suggest appropriate follow-up, and if necessary, provide a letter describing the findings and need for 
follow-up.The Principal Investigator will also speak with the participant’s primary care provider if the participant 
gives permission to do so. If at any time the participant cannot be reached, the PI will contact the proxy the 
participant identified at Visit 1. Similarly, if the participant has a MoCA score or physical findings that are of 
concern as per clinical judgment, the PI will review the result, determine if the participant is in need of clinical 
follow-up, and if so, inform the participants about whom to contact. 
 
Safety and emergency procedures 
Situation 
Immediate 
Notification 
Process 
Event Follow up Plan, 
Documentation of 
Event, and Event 
Reporting 
Data Management 
and Storage 


 
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Adverse Event occurs 
at a Study Visit  
Implement 
Safety/Emergency 
Procedures as 
indicated 
Project 
Director/Study 
nurse or  PI 
Notified 
 
PD -TBD 
 
PI– Dr. Lew Lipsitz 
Medical coverage 
Office: 617-971-
5318, Cell: 617-
470-5323; 
Covering MD 
within the Marcus 
Institute  (when Dr. 
Lipsitz is not 
available) 
Project Director/PI will 
follow-up  with 
Participant 
Any adverse event or 
unanticipated problem 
that occurs at any time 
will be reported to the 
HSL IRB, the DSMB, 
the FDA, and the NIA 
in compliance with 
established guidelines. 
MedDRA coding: 
System Organ Class 
(SOC) and Preferred 
Term (PT) will be used 
for coding of all 
reported events 
All Adverse Event 
Tracking data and 
Adverse Event data 
will be entered into 
the Redcap data 
base. 
Adverse event paper 
forms will be stored 
in a locked file 
cabinet 
Adverse Event 
reported at the Visit 
Follow up Survey  
Adverse Event 
reported at the 
telephone follow-up 
visits 
 
Any adverse events that take place during testing will be reported by the PI, Dr. Lewis Lipsitz, Director of the 
Marcus Institute for Aging Research, Professor of Medicine at HMS and Chief of Gerontology at BIDMC and 
recorded in the database. Dr. Lipsitz will have ultimate responsibility for monitoring participant safety in the 
trial. The investigators will be responsible for reviewing each adverse event in a timely fashion, and reporting 
all incidents to the DSMB in accordance with the established DSMB charter, and preparing a summary report. 
Any adverse events will be reported to the HRC IRB according to written guidelines. 
 
7.4 Participant and Study Stopping Rules  
 
Participant Stopping Rules: As outlined in section 4.8 Participant Withdrawal, participants that meet the 
identified clinical safety thresholds, will be evaluated by the study doctor to determine continuation of the study. 
Similarly, if a participant experiences any adverse event that is deemed “severe” as outlined in section 7.3 
(Adverse Events Collection and Reporting) their continuation in the study will be determined by the study 
doctor, with guided input from the DSMB. Additionally, if a serious adverse event (SAE) occurs, it will be 
carefully reviewed by the study doctor and the DSMB, and appropriately reported to the FDA. Any report of a 
serious adverse event (SAE) that is thought to be directly related to the study drugs or study procedures, will 
result in the participant’s discontinuation from the study.  
 
Study Stopping Rules: Similar to the participant stopping rules, all serious adverse events (SAE) will be 
carefully reviewed by the study doctor and the DSMB, and appropriately reported to the FDA. The DSMB will 
review each SAE and determine if study termination is warranted. 
 
7.5 Sponsor–Investigator Reporting: Notifying the FDA 
 
The sponsor-investigator (Dr. Lipsitz) will report to the FDA all unexpected, serious suspected adverse 
reactions according to the required IND Safety Reporting timelines, formats, and requirements. 
 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event will be reported as a serious suspected 
adverse reaction. This will be reported to the FDA on FDA Form 3500A no later than 7 calendar days after the 
sponsor-investigator’s initial receipt of the information about the event. 
 
Other unexpected serious suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event, will be reported as a serious suspected 


 
Version 9  
5/9/2022 
adverse reaction. This will be reported to the FDA on FDA Form 3500A no later than 15 calendar days after the 
sponsor-investigator’s initial receipt of the information about the event. 
 
Any clinically important increase in the rate of serious suspected adverse reactions over those listed in the 
protocol or product insert will be reported as a serious suspected adverse reaction. This will be reported to the 
FDA on FDA Form 3500A no later than 15 calendar days after the sponsor-investigator’s initial receipt of the 
information about the event. 
 
Findings from other studies in human or animals that suggest a significant risk in humans exposed to the drug 
will be reported. This will be reported to the FDA on FDA Form 3500A, no later than 15 calendar days after the 
sponsor-investigator’s initial receipt of the information about the event. 
 
7.6 Potential Benefits 
 
Participants may not receive any significant health benefit from participation, although some may benefit from 
knowledge of their health status, as well as potential therapeutic effects of D+Q.  We believe that the potential 
benefits of determining the feasibility of D+Q as a therapeutic intervention to improve mobility and cognitive 
function as well as mitigate the risk of Alzheimer’s disease development in older adults outweigh the above-
outlined potential risks to participants, which are expected to be minor, transient, and relatively rare.  
The data from this study are expected to provide critical preliminary information regarding the feasibility of 
using senolytics to improve both physical and cognitive function in older adults at risk of Alzheimer’s disease. 
Results from this study will directly inform the design of future, large-scale efficacy trials.  
 
7.7 Participant Compensation 
 
Participants will be provided a $300 stipend to compensate them for their time spent completing study 
procedures. 
 
7.8 Data and Safety Monitoring 
 
The Principal Investigator (PI) will be responsible for ensuring each participant’s safety on a daily basis. Safety 
monitoring procedures will be implemented and reviewed by a Data Safety Monitoring Board (DSMB), in 
accordance with NIA safety policies for human intervention studies. The criteria for discontinuing a participant's 
participation include the participant's request, as well as any Iife-threatening or potentially disabling event, 
including syncope, seizures, an injurious non-accidental fall, hemodynamic collapse, stroke, transient ischemic 
attack, dysrhythmia, renal insufficiency, angina, myocardial infarction, anaphylaxis, acute hemorrhage, 
hospitalization for acute illness, or as per clinical judgment. These adverse events will be recorded and 
included in the database. If a determination about continued participation cannot be made according to these 
criteria, the adverse event report will be faxed to the chair of the Data Safety Monitoring Board (DSMB) who 
will make a decision with members of the Board.  
 
A DSMB will be established for this project. The Data and Safety Monitoring Board (DSMB) will act in an 
advisory capacity to the NIA Director to monitor participant safety, evaluate the progress of the study, review 
procedures for maintaining the confidentiality of data, the quality of data collection, management, and 
analyses. This will consist of nationally recognized experts in geriatric medicine, biostatistics, clinical research, 
geroscience, and/or clinical trials. The chairperson will be an individual who is readily accessible for 
consultation. At the first meeting of the DSMB, members will review the study protocol and safety-monitoring 
plan. 
 
Prior to the start of the study the DSMB will review the IRB approved protocol, procedure manual, and 
informed consent documents, with regard to participant safety, recruitment, randomization, intervention, data 
management, quality control, and confidentiality. The Board will recommend any necessary changes of the 
protocol to the PI and will review and approve revisions.  The Board will identify relevant data parameters and 
the format of the information to be regularly reported. 


 
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The Board will then decide how often they will meet to review standardized reports over the course of the two 
year project. They will review the progress of recruitment and retention of participants, compliance with the 
protocol, and operating procedures. If they raise concerns about safety issues, they may request additional 
data and propose specific analyses. They will make recommendations to the PIs regarding recruitment, 
retention, compliance, and safety issues, and will send a written report to the Program Administrator following 
each meeting. The DSMB will be sent reports of research activity and summaries of safety monitoring 
information before each meeting. 
 
The DSMB Charter will be reviewed and approved by the Board and the NIA and provides a detailed list of the 
DSMB responsibilities. 
CHAPTER 8:  REFERENCES  
1. 
Verghese, J., et al., Motoric cognitive risk syndrome and the risk of dementia. J Gerontol A Biol Sci Med 
Sci, 2013. 68(4): p. 412-8. 
2. 
Verghese, J., et al., Motoric cognitive risk syndrome and predictors of transition to dementia: A 
multicenter study. Alzheimers Dement, 2019. 15(7): p. 870-877. 
3. 
Ayers, E. and J. Verghese, Gait Dysfunction in Motoric Cognitive Risk Syndrome. J Alzheimers Dis, 
2019. 71(s1): p. S95-S103. 
4. 
Verghese, J., Microvascular disease and motoric dysfunction. Neurology, 2013. 80(8): p. 717. 
5. 
Benedictus, M.R., et al., White Matter Hyperintensities Relate to Clinical Progression in Subjective 
Cognitive Decline. Stroke, 2015. 46(9): p. 2661-4. 
6. 
Montero-Odasso, M., et al., Vascular burden predicts gait, mood, and executive function disturbances 
in older adults with mild cognitive impairment: results from the gait and brain study. J Am Geriatr Soc, 
2012. 60(10): p. 1988-90. 
7. 
Sorond, F.A., et al., Cerebrovascular hemodynamics, gait, and falls in an elderly population: MOBILIZE 
Boston Study. Neurology, 2010. 74(20): p. 1627-33. 
8. 
Sorond, F.A., et al., Neurovascular coupling is impaired in slow walkers: the MOBILIZE Boston Study. 
Ann Neurol, 2011. 70(2): p. 213-20. 
9. 
Sorond, F.A., et al., Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. 
Neuropsychiatr Dis Treat, 2008. 4(2): p. 433-40. 
10. 
Sorond, F.A., et al., Neurovascular coupling, cerebral white matter integrity, and response to cocoa in 
older people. Neurology, 2013. 81(10): p. 904-9. 
11. 
Desideri, G., et al., Benefits in cognitive function, blood pressure, and insulin resistance through cocoa 
flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and 
Aging (CoCoA) study. Hypertension, 2012. 60(3): p. 794-801. 
12. 
Aggarwal, A., et al., Quercetin alleviates cognitive decline in ovariectomized mice by potentially 
modulating histone acetylation homeostasis. J Nutr Biochem, 2020. 84: p. 108439. 
13. 
Baptista, F.I., et al., Flavonoids as therapeutic compounds targeting key proteins involved in 
Alzheimer's disease. ACS Chem Neurosci, 2014. 5(2): p. 83-92. 
14. 
Uddin, M.S., et al., Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer's 
Disease. Molecules, 2020. 25(6). 
15. 
Tchkonia, T. and J.L. Kirkland, Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic 
Strategies. JAMA, 2018. 320(13): p. 1319-1320. 
16. 
Kirkland, J.L. and T. Tchkonia, Cellular Senescence: A Translational Perspective. EBioMedicine, 2017. 
21: p. 21-28. 
17. 
Musi, N., et al., Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell, 
2018. 17(6): p. e12840. 
18. 
Zhang, P., et al., Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell 
senescence and cognitive deficits in an Alzheimer's disease model. Nat Neurosci, 2019. 22(5): p. 719-
728. 
19. 
Kirkland, J.L., et al., The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc, 2017. 65(10): p. 2297-
2301. 


 
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5/9/2022 
20. 
Xu, M., et al., Senolytics improve physical function and increase lifespan in old age. Nat Med, 2018. 
24(8): p. 1246-1256. 
21. 
Zhu, Y., et al., The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 
2015. 14(4): p. 644-58. 
22. 
Justice, J.N., et al., Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-
label, pilot study. EBioMedicine, 2019. 40: p. 554-563. 
23. 
Pendlebury, S.T., et al., Telephone assessment of cognition after transient ischemic attack and stroke: 
modified telephone interview of cognitive status and telephone Montreal Cognitive Assessment versus 
face-to-face Montreal Cognitive Assessment and neuropsychological battery. Stroke, 2013. 44(1): p. 
227-9. 
24. 
Katz, M.J., et al., T-MoCA: A valid phone screen for cognitive impairment in diverse community 
samples. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2021. 13(1): p. 
e12144. 
25. 
Dautzenberg, G., J. Lijmer, and A. Beekman, Diagnostic accuracy of the Montreal Cognitive 
Assessment (MoCA) for cognitive screening in old age psychiatry: Determining cutoff scores in clinical 
practice. Avoiding spectrum bias caused by healthy controls. International journal of geriatric 
psychiatry, 2020. 35(3): p. 261-269. 
26. 
Katz, S., et al., Progress in development of the index of ADL. Gerontologist, 1970. 10(1): p. 20-30. 
27. 
Guralnik, J.M., et al., A short physical performance battery assessing lower extremity function: 
association with self-reported disability and prediction of mortality and nursing home admission. J 
Gerontol, 1994. 49(2): p. M85-94. 
28. 
Podsiadlo, D. and S. Richardson, The timed "Up & Go": a test of basic functional mobility for frail elderly 
persons. J Am Geriatr Soc, 1991. 39(2): p. 142-8. 
29. 
Beurskens, R. and O. Bock, Age-related deficits of dual-task walking: a review. Neural Plast, 2012. 
2012: p. 131608. 
30. 
Charlson, M.E., et al., A new method of classifying prognostic comorbidity in longitudinal studies: 
development and validation. J Chronic Dis, 1987. 40(5): p. 373-83. 
31. 
Sorond, F., Kiely, DK, Galica, A, Moscufo, N, Serrador, JM, Iloputaife, I, Egorova, S, Dell'Oglio, E, 
Meier, D, Newton, E, Milberg, WP, Guttmann, C, Lipsitz, LA., Neurovascular Coupling is Impaired in 
Slow Walkers: The MOBILIZE Boston Study. Annals of Neurology, 2011. 70(2): p. 213-20. 
32. 
Dube, P., et al., The p4 screener: evaluation of a brief measure for assessing potential suicide risk in 2 
randomized effectiveness trials of primary care and oncology patients. Primary care companion to the 
Journal of clinical psychiatry, 2010. 12(6): p. PCC.10m00978. 
33. 
Guralnik, J.M., et al., Lower-extremity function in persons over the age of 70 years as a predictor of 
subsequent disability. N Engl J Med, 1995. 332(9): p. 556-61. 
34. 
Guralnik, J.M., et al., Lower extremity function and subsequent disability: consistency across studies, 
predictive models, and value of gait speed alone compared with the short physical performance battery. 
J Gerontol A Biol Sci Med Sci, 2000. 55(4): p. M221-31. 
35. 
Costa, A.S., et al., Alternate-form reliability of the Montreal cognitive assessment screening test in a 
clinical setting. Dement Geriatr Cogn Disord, 2012. 33(6): p. 379-84. 
36. 
Trailmaking Tests A and B, D.W.D.A.G.s.O. Washington, Editor. 1944. 
37. 
Tombaugh, T.N., Trail Making Test A and B: normative data stratified by age and education. Arch Clin 
Neuropsychol, 2004. 19(2): p. 203-14. 
38. 
Best, J.R., J.C. Davis, and T. Liu-Ambrose, Longitudinal Analysis of Physical Performance, Functional 
Status, Physical Activity, and Mood in Relation to Executive Function in Older Adults Who Fall. J Am 
Geriatr Soc, 2015. 63(6): p. 1112-20. 
39. 
Boggio, P.S., et al., A randomized, double-blind clinical trial on the efficacy of cortical direct current 
stimulation for the treatment of major depression. Int J Neuropsychopharmacol, 2008. 11(2): p. 249-54. 
40. 
Eaton, W., et al., Center for Epidemiologic Studies Depression Scale: review and revision (CESD and 
CESD-R). , in The Use of Psychological Testing for Treatment Planning and Outcomes Assessment 
(3rd Ed.), Volume 3: Instruments for Adults, , M. Maruish, Editor. 2004, Lawrence Erlbaum: Mahway, 
NJ. 
41. 
Himmelfarb, S. and S.A. Murrell, Reliability and validity of five mental health scales in older persons. J 
Gerontol, 1983. 38(3): p. 333-9. 


 
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5/9/2022 
42. 
Hickson, L.J., et al., Senolytics decrease senescent cells in humans: Preliminary report from a clinical 
trial of dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine, 2019. in 
press. 
43. 
Jaba, T. and A. David, Dasatinib and Quercetin: Short-Term Simultaneous Administration Improves 
Physical Capacity in Human. Journal of Biomedical Sciences, 2019. 8(3.3). 
 


Appendix A. 
 
Clinical Safety Laboratory Test Thresholds, From 
Merckmanuals.com/professional/resources/normal-laboratory-values/  
American Board of Internal Medicine Laboratory Test Reference Ranges – January 
2018 
 
Test 
Parameter 
Threshold* (Or >20% different than 
baseline, or as per clinical 
judgement.) 
EKG 
QTc Prolongation 
>450 ms (Also evidence of right ventricular 
enlargement, right atrial enlargement, or 
right heart strain.) 
Blood Measures 
Glomerular Filtration Rate 
GFR <30 mL/min/1.73 m2 
Complete Blood Count 
WBC <4,000 or >11,000 cells/mcL 
Neutrophils <1,500 cells/mcL 
Hbg <9 g/dL 
Hematocrit <34% 
Platelets <150 x 103/mcL 
Alanine Aminotransferase 
>70 U/L (2 x normal) 
Aspartate Aminotransferase 
>70 U/L (2 x normal) 
Glucose 
>200 mg/dl 
Total Bilirubin 
>1.5 mg/dL 
Direct Bilirubin 
>0.3 mg/dL 
Blood Urea Nitrogen 
>25 mg/dL 
Creatinine 
>1.3 mg/dL 
Cystatin C 
>1.15 mg/dL 
Calcium 
>11, corrected for albumin 
Albumin 
<3.5 g/dL, also used to correct calcium 
level: Corrected Ca = measured Ca + 0.8 
(4.0 – serum albumin in g/dL). 
Sodium 
>147 meq/L 
Potassium 
>5.4 meq/L 
Bicarbonate 
>32 meq/L 
Chloride 
>108 meq/L 
Total Protein 
>7.8 g/dL 
Alkaline Phosphatase 
>150 U/L 
Prothrombin Time 
>13 seconds 
International Normalized Ratio (INR) 
>1.1 
Vitals 
Temperature 
>100.3 ºF 
Seated Blood Pressure 
>180/100 
Seated Heart Rate 
>100 
Postural Change in Blood Pressure 
Systolic blood pressure <100 mmHg or 
a 20 mmHg decline in blood pressure 
with symptoms of dizziness, 
lightheadedness, or near syncope at 
one minute or three minutes of standing 
Postural Change in Heart Rate 
Increase of >25 bpm 
Respiration Rate 
>20 
Oxygen Saturation 
<92% 


 


Appendix B.  
Dasatinib Contraindications, Interactions, or Cautions 
All contraindications, interactions, and/or cautions will be evaluated by the PI, Lewis A. Lipsitz, MD, as 
per clinical judgment 
•
anti-arrhythmic medications
•
antipsychotic medications
•
anxiolytic medications
•
anti-platelet medications
•
anti-coagulant medications other than aspirin
•
quinolone antibiotics
•
CYP3A4 inhibitors or CYP3A4 inducers
•
other drugs metabolized by the same liver enzymes as Quercetin or Dasatinib
•
antacids
•
H2 antagonists
•
proton pump inhibitors
•
frequent consumption of grapefruit juice
•
frequent consumption/use of St. John’s wort
•
hypersensitivity to drug/class/component
•
pregnancy
•
breastfeeding during tx and x2wk after D/C
•
pulmonary HTN
•
electrolyte abnormalities, uncorrected
•
caution in female pts of reproductive potential
•
caution in elderly pts
•
caution if hepatic impairment
•
caution if myelosuppression
•
caution if thrombocytopenia
•
caution if fluid retention
•
caution if cardiopulmonary dz
•
caution if congenital long QT syndrome
•
caution if QT prolongation
•
caution if QT prolongation family hx
•
caution if torsades de pointes hx
•
caution if ventricular arrhythmias
•
caution if bradycardia
•
caution if recent MI
Protocol


• 
caution if CHF 
• 
caution if cumulative high dose anthracycline tx 
• 
caution if thyroid disorder 
 
Quercetin Contraindications, Interactions, or Cautions  
All contraindications, interactions, and/or cautions will be evaluated by the PI, Lewis A. Lipsitz, MD, as 
per clinical judgment 
 
• 
quinolone antibiotics 
• 
cyclosporine 
• 
medications changed by the liver (e.g., CYP2C8, CYP2C9, CYP2D6, or CYP3A5)  
• 
medications moved by pumps in cells (P-glycoprotein substrates) 
• 
antihypertensive drugs 
• 
warfarin 
• 
caution if pregnant and/or breastfeeding 
• 
caution if kidney problems 
 
 


  Study Drug (IP) Tracker
Use this form as template to track study drug dispense.  All items are required to complete each row.
Date Received/
Dispensed
Received By
Dispensed To
Amount Dispensed
Dispensed By
Amount Remaining
Amount Returned
Protocol 
Appendix C


Study Drug Compliance Log 
Protocol: [Protocol name] 
Principal Investigator: [Principal Investigator's name] 
Site ID: [Site ID] 
To be updated at every study contact when the participant receives or returns study drug. 
* Examples of units dispensed: tablets, pills, bottles, vials, etc.
Date Dispensed 
Amount 
Dispensed 
Units* 
Dispensed 
Date Returned 
Actual 
Amount 
Returned 
Expected 
Amount 
Returned 
[Date Drug Dispensed] 
(dd/mmm/yyyy) 
[Amount 
Dispensed] 
[Units 
Dispensed] 
[Date Drug Returned] 
(dd/mmm/yyyy) 
[Actual 
Amount 
Returned] 
[Expected 
Amount 
Returned] 
[Date Drug Dispensed] 
(dd/mmm/yyyy) 
[Amount 
Dispensed] 
[Units 
Dispensed] 
[Date Drug Returned] 
(dd/mmm/yyyy) 
[Actual 
Amount 
Returned] 
[Expected 
Amount 
Returned] 
[Date Drug Dispensed] 
(dd/mmm/yyyy) 
[Amount 
Dispensed] 
[Units 
Dispensed] 
[Date Drug Returned] 
(dd/mmm/yyyy) 
[Actual 
Amount 
Returned] 
[Expected 
Amount 
Returned] 
[Date Drug Dispensed] 
(dd/mmm/yyyy) 
[Amount 
Dispensed] 
[Units 
Dispensed] 
[Date Drug Returned] 
(dd/mmm/yyyy) 
[Actual 
Amount 
Returned] 
[Expected 
Amount 
Returned] 
[Date Drug Dispensed] 
(dd/mmm/yyyy) 
[Amount 
Dispensed] 
[Units 
Dispensed] 
[Date Drug Returned] 
(dd/mmm/yyyy) 
[Actual 
Amount 
Returned] 
[Expected 
Amount 
Returned] 
[Date Drug Dispensed] 
(dd/mmm/yyyy) 
[Amount 
Dispensed] 
[Units 
Dispensed] 
[Date Drug Returned] 
(dd/mmm/yyyy) 
[Actual 
Amount 
Returned] 
[Expected 
Amount 
Returned] 
[Date Drug Dispensed] 
(dd/mmm/yyyy) 
[Amount 
Dispensed] 
[Units 
Dispensed] 
[Date Drug Returned] 
(dd/mmm/yyyy) 
[Actual 
Amount 
Returned] 
[Expected 
Amount 
Returned] 
Protocol 
Appendix D


Adverse Event Form 
Adverse Event 
Last updated 14JUN2019 
Has the participant had any Adverse Events during this study? 
Yes 
 No (If yes, please list all Adverse Events below) 
STUDY NAME 
Site Number: 
Pt_ID: 
______________________ 
______________________ 
Severity 
Study Intervention 
Relationship 
Action Taken Regarding Study 
Intervention 
Outcome of AE 
Expected 
Serious 
1 = Mild 
2 = Moderate 
3 = Severe 
1 = Definitely related 
2 = Possibly related 
3 = Not related 
1 = None 
2 = Treatment Stopped 
3 = Treatment Interrupted 
4 = Reduced Dose 
5 = Increased Dose 
6 = Delayed Dose 
1 = Resolved, No Sequel 
2 = AE still present- no treatment 
3 = AE still present-being treated 
4 = Residual effects present-not treated 
5 = Residual effects present- treated 
6 = Death 
7 = Unknown 
1 = Yes 
2 = No 
1 = Yes 
2 = No 
(If yes, 
complete SAE 
form) 
Adverse Event 
Start Date 
Stop Date 
Severity 
Relationship to 
Study Treatment 
Action 
Taken 
Outcome 
of AE 
Expected? 
Serious 
Adverse 
Event? 
PI 
Initials
& Date 
1. 
2. 
3.
Protocol 
Appendix E


Serious Adverse Event (SAE) Report Form 
Serious Adverse Event Report Form 
1 of 2 
Last Updated 14JUN2019 
1.
SAE Onset Date:
2.
SAE Stop Date:
3.
Location of serious adverse event (e.g. at study site or elsewhere):
4.
Was this an unexpected adverse event?
 Yes 
 No 
5.
Brief description of participant with no personal identifiers:
Sex: 
 Female 
 Male 
Age:
6.
Adverse Event Term:
7.
Brief description of the nature of the serious adverse event (attach description if more space needed):
8.
Category of the serious adverse event:
 death – date ____________ 
 congenital anomaly / birth defect 
 life-threatening 
 required intervention to prevent 
 hospitalization - initial or prolonged 
 permanent impairment (Devices Only) 
Protocol Title: 
Protocol Number:
Site Number:  
Pt_ID: 
Protocol 
Appendix F


Serious Adverse Event (SAE) Report Form 
Serious Adverse Event Report Form 
2 of 2  
Last Updated 14JUN2019 
 
 death – date ____________ 
 congenital anomaly / birth defect 
 disability / incapacity 
 important medical event  
9. Intervention type: 
 Medication (Drug, Biological, Vaccine) or Nutritional Supplement: specify ____________ 
 Device: Specify: ____________ 
 Procedure/Surgery: Specify: ____________ 
 Behavioral/Life Style: Specify: ____________ 
 Radiation: Specify: ____________ 
 Genetic (gene transfer, stem cell, recombinant DNA): Specify: ____________ 
10. Relationship of event to intervention: 
 Not Related (clearly not related to the intervention) 
 Possible (may be related to intervention) 
 Definite (clearly related to intervention) 
11. Was study intervention discontinued due to event? 
12. What medications or other steps were taken to treat serious adverse event?  
 
13. List any relevant tests, laboratory data, history, including preexisting medical conditions 
 
14. Type of report: 
 Initial 
 Follow-up 
 Final 
Signature of Principal Investigator:       
 
Date:  
 Yes 
 No 


Site Signature Log/Delegation of Autority Log
Version 1.0
The purpose of this form is to: a.) serve as the ‘Site Signature Log" and b.) assure that the individuals performing study related tasks/procedures are appropriately trained and authorized by the Investigator to perform the task/procedure.  
This form should be completed prior to the initiation of any study-related tasks/procedures.  The original form should be maintained at your site in the study regulatory/study binder.  This form should be updated during the course of the 
study as needed.  
Site Signature Log/Delegation of Authority Log
STUDY NAME
Site Number: _____________
Obtain Informed Consent 
Source Document Completion
Case Report Form (CRF) 
Completion
Assess Inclusion and Exclusion 
Criteria 
Physical Examination
Medical History
Medication History / 
Concomitant Medication
Collect Vital Signs
Review Vital Signs and Labs for 
Clinical Significance
Laboratory Specimen 
Collection/Shipping
AE Inquiry and Reporting
AE/SAE interpretation 
(severity/relationship to IP)
Administration of 
Investigational Product (IP) 
IP Accountability 
Regulatory Document 
Maintenance
Administrative
Please Print
v
v
v
I certify that the above individuals are appropriately trained, have read the Protocol and pertinent sections of 21CFR 50 and 56 and ICH GCPs, and are authorized to perform the above study related tasks/procedures.  Although I have 
delegated significant trial-related duties, as the Principal Investigator, I still maintain full responsibility for this trial.
Investigator 
Date:
NAME:
Other: (please specify)
STUDY ROLE:
SIGNATURE:
INITIALS:
DATES OF STUDY INVOLVEMENT:
NAME:
Other: (please specify)
STUDY ROLE:
SIGNATURE:
INITIALS:
DATES OF STUDY INVOLVEMENT:
NAME:
Other: (please specify)
STUDY ROLE:
SIGNATURE:
INITIALS:
DATES OF STUDY INVOLVEMENT:
NAME:
Other: (please specify)
STUDY ROLE:
SIGNATURE:
INITIALS:
DATES OF STUDY INVOLVEMENT:
NAME:
Other: (please specify)
STUDY ROLE:
SIGNATURE:
INITIALS:
DATES OF STUDY INVOLVEMENT:
NAME:
Other: (please specify)
STUDY ROLE:
SIGNATURE:
INITIALS:
DATES OF STUDY INVOLVEMENT:
Protocol 
Appendix G


Summary of Changes (Version # to Version #) 
Location of Change 
Change/Modification in Version # 
Protocol 
Appendix H


Protocol Amendment Summary of Changes Template 
Version 1.0 
1 of 3 
Version Date: 29Mar2012 
Protocol Amendment Summary of Changes 
Template 
Purpose:  
To support the documentation of changes from one 
institutional review board (IRB)-approved version of a 
protocol to the next 
Audience/User: 
The protocol amendment author, who will use the tool to 
create the summary of changes  
Best Practice 
Recommendations: 
Administrative details of template 
•
Review this template and customize to the specific needs
and requirements of the study. Sample text may be
updated as needed.
•
In the template, the instructions and explanatory text are
indicated by {blue italics}. Instructional text will also be
enclosed in braces to signify this text for screen-readers
used by the visually impaired.
•
Text enclosed with <> is a placeholder for a specific
detail (e.g., <protocol title>); replace as appropriate.
•
Remove <> and instructional text before finalizing the
document.
Pre-amendment 
•
It is useful to maintain an ongoing list of potential protocol
changes—both administrative changes as well as
substantive changes—that are being considered for
inclusion in a protocol amendment. Some maintain a
working version of a protocol amendment in which the
POTENTIAL changes have been tracked in a version of
the protocol that is maintained separately from the active
version.
•
To reduce paperwork and confusion, it is helpful to batch
protocol changes together into one amendment when
possible.
•
The list of potential changes should be vetted through the
protocol team, prior to inclusion in the draft protocol
amendment that is submitted to the IRB.
Preparing and reviewing the protocol amendment summary 
document 
•
Consider IRB-specific guidelines/preferences when
preparing the protocol amendment summary document.
Protocol 
Appendix I


Protocol Amendment Summary of Changes Template 
Version 1.0 
 
2 of 3  
Version Date: 29Mar2012 
• The structure of the protocol amendment summary 
document may depend on the contents of the 
amendment. In some cases, it may be most appropriate 
to list the changes one by one as they appear in the 
protocol. In other cases, an ordering by conceptual 
change [e.g., DSMB-requested changes or administrative 
changes] may be best.   
• When possible, protocol section numbers should be 
referenced. It is also helpful to reference page numbers. 
• Include a rationale for each set of protocol changes. 
Document as “administrative change” when appropriate. 
• The protocol amendment summary document should be 
carefully reviewed and confirmed against the actual 
protocol amendment immediately before submission. 
Remember that page numbers change as things are 
updated in the protocol. It is therefore important to do a 
quality control check of the section and page numbers. 
 
 
It is best to submit a pdf of the protocol if you are referencing 
page numbers. This is because page numbers for pdfs are 
constant across all computer software and systems, 
whereas the pagination in MS Word documents is 
system/printer dependent. 
 
 
The protocol amendment summary document will be 
submitted to the IRB, stored in the study files, and accessed 
by the study team. 
 
 
It is preferable to maintain both a track-changes and a clean 
version of the protocol version that is submitted to the IRB. 
Tool Revision History 
Version Number       
Version Date       
Summary of Revisions Made:       
Version Number       
Version Date       
Summary of Revisions Made:       
Version Number       
Version Date       
Summary of Revisions Made:       
Version Number       
Version Date       
Summary of Revisions Made:       
 
 


Protocol Amendment Summary of Changes Template 
Version 1.0 
 
3 of 3  
Version Date: 29Mar2012 
Detailed Summary of Protocol Changes 
Protocol Number:       
Protocol Title:       
 
Version Number 
Version Date 
Current Approved Protocol <Version # of most 
recently approved 
protocol> 
<Date of most recently 
approved protocol> 
Amended Protocol <Version # of amended 
protocol being 
submitted to the IRB> 
<Date of amended 
protocol being 
submitted to the IRB> 
 
Section and page numbers are references to the {indicate track-changes version, if that is 
what you are using} amended protocol. 
1. <Section Number, Section Title, Page Number(s)>  
Old Text:       
New Text: {Include new text, preferably with track changes on to reveal the differences 
from the previous version of the document.} 
Rationale for Change:       
2. <Section Number, Section Title, Page Number(s)>  
Old Text:       
New Text: {Include new text, preferably with track changes on to reveal the differences 
from the previous version of the document.} 
Rationale for Change:       
{Replicate above structure as needed for additional changes, ensuring that the numbering is 
continuous.} 
{The item below is a suggested final item that covers all remaining administrative updates that 
have not otherwise been detailed above.} 
3. Administrative changes: Minor changes involving grammar, wordsmithing, 
punctuation, and other editorial changes have been made throughout the 
document. All are clearly identified in the track-changes version of the amendment. 


STAMINA SYMPTOMS QUESTIONNAIRE 
STUDY ID 
                 
ASSESSOR ID: 
            
DATE 
        /         /             
     
 
 
Cycle 
and 
Visit 
   
            
1B– 1st Cycle Baseline 
1M- 1st Cycle Meds Call 
1C- 1st Cycle Check-in 
 
2B– 2nd Cycle Baseline 
2M- 2nd Cycle Meds Call 
2C- 2nd Cycle Check-in 
 
3B– 3rd Cycle Baseline 
3M- 3rd Cycle Meds Call 
3C- 3rd Cycle Check-in 
 
4B– 4th Cycle Baseline 
4M- 4th Cycle Meds Call 
4C- 4th Cycle Check-in 
 
5B– 5th Cycle Baseline 
5M- 5th Cycle Meds Call 
5C- 5th Cycle Check-in 
 
6B– 6th Cycle Baseline 
6M- 6th Cycle Meds Call 
6C- 6th Cycle Check-in 
 
Next is a set of questions about symptoms that you may have experienced.  Please answer yes 
if you have experienced any of the following NEW symptoms after taking the study drugs or they 
are more severe than usual: 
 
 
0 
No 
1 
Yes 
8  
Refused 
9 
DK/ 
NVR 
Fatigue (tiredness) 
 
 
 
 
Fainting 
 
 
 
 
Dizziness 
 
 
 
 
Difficulty Breathing 
 
 
 
 
Bruising in places other than where blood was drawn 
 
 
 
 
Coughing 
 
 
 
 
Skin Rash 
 
 
 
 
Fluttering Chest Sensation 
 
 
 
 


Diarrhea 
 
 
 
 
Blood in Stool 
 
 
 
 
Loss of Appetite 
 
 
 
 
Severe Headache 
 
 
 
 
Tingling/numbness of arms or legs 
 
 
 
 
Something else I haven’t mentioned?  
 
 
 
 
 
 
 
 
 
[IF SOMETHING ELSE IS YES] Please specify 
 
 


The IRB does not  
require the eventbe  
reported to the IRB
The IRB does not require  
the event to bereported
Submit a noncompliance  
report at www.cirbi.net
Submit an unanticipated problem/UADE  
report at www.cirbi.net
Report the event asan  
SAE at www.cirbi.net
Submit an unanticipated  
problem report at  
www.cirbi.net
Yes
Did the event occur in a clinical trial  
regulated by the FDA?
No
Did the event occur in a device trial?
No
Yes
Was the effect, problem, or death  
previously identified in nature, severity, or  
degree of incidence in the investigational  
plan or application?
Yes
No
Did the event represent any other  
unanticipated serious problem associated  
with a device that relates to the rights,  
safety, or welfare of subjects?
Yes
No
No
Does the event suggest that the  
research places subjects or others at  
a greater risk of harm than was  
previously known or recognized?
Yes
Was the event serious?
Yes
Does the event have implications for  
the conduct of the study (e.g.,  
requiring a significant change)?
Yes
No
Was the event related or possibly  
related to participation in the research?
Yes
Did the noncompliance issue affect a  
subject's rights, safety, or well-being  
and/or the completeness, accuracy  
and reliability of the study?
Yes
Did the SAE occur at the research site  
that would be reporting?
Yes
No
Was the event a serious adverse
event (SAE) as defined by the study  
protocol?
Yes
No
No
Yes
Was the event unexpected in nature,  
severity, or frequency?
?
Yes
No
Did the event involve noncompliance  
with the protocol, IRB requirements  
or regulations?
?
Yes
Was the event unexpected in nature,  
severity, or frequency?
?
No
Yes
Did the event result in any serious  
adverse effect on health or safety or any  
life-threatening problem or death caused  
by, or associated with, the device?
?
Subject Safety Event Reporting Decision Chart
Start
No
Version 2 2/25/2021


National Institute of Aging 
Page 1 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
 
INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
Sponsor / Study Title: 
 
National Institute of Aging / “Senolytics to Alleviate Mobility 
Issues and Neurological Impairment in Aging (STAMINA)” 
 
Principal Investigator: 
 
Lewis Lipsitz, MD 
 
Telephone: 
 
617-971-5688  
617-470-5323 (24 Hours, emergency only) 
 
Address: 
Hebrew Senior Life 
1200 Centre St. 
Boston, MA    02131 
 
 
Concise Summary of Key Information 
The purpose of this research study is to test the use of an FDA approved chemotherapeutic (used 
to treat cancer) agent (called Dasatinib or Sprycel) and a dietary supplement (called Quercetin) in 
older adults using low, every-other-week doses for 12 weeks. We want to test if we can re-
purpose these drugs to help people with concerns about their memory and mobility. We will 
include 12 people with mild memory and walking problems who may be at risk of developing 
Alzheimer’s disease in the future.  
 
Other studies have already tested these drugs in people with a severe lung disease, people with 
chronic kidney disease, and in healthy adults. During this study, the number of times you will be 
asked to take the drugs is very small compared to the daily doses of Dasatinib used for many 
months to treat cancer, or the daily doses of Quercetin when used as a dietary supplement for 
health promotion. These study drugs have been found to be safe in adults with a severe lung 
disease called pulmonary fibrosis and chronic kidney disease. We now want to test them in older 
adults with slow walking speed and mild cognitive impairment. Because we will be providing a 
low dose that you take only 2 days every other week, we do not anticipate major risks. 
 
Participation in this study will take a total of 14 weeks and will require 8 in-person visits. You 
will be asked to take 100 mg of Dasatinib and 1,250 mg of Quercetin for 2 days every other 
week for a total of 12 weeks. During the study we will ask you about any symptoms you’ve had, 
and to provide blood and urine samples. And finally, we will measure your physical ability (for 
example your walking) and cognition (for example your memory).  
 
About this Consent Form 
Please read this form carefully. This form provides important information about participating in a 
research study. As a research participant, you have the right to take your time in making 
decisions about participating in this research and you are encouraged to discuss your decision 
with your family and your doctor. If you have any questions about the research or any part of this 
form, please ask us. If you decide to take part in this research, you will be asked to sign and date 


National Institute of Aging 
Page 2 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
this form, and a copy will be provided for you. Please take your time in making your decision as 
to whether you wish to participate or not. Ask the study staff to explain any words or information 
contained in this informed consent document that you do not understand or are unsure about. 
You may also discuss this study with your friends, family, and primary care doctor. 
 
What you should know about a Research Study 
Participation in research is voluntary, which means that it is something for which you volunteer. 
It is your choice to participate in the study, or to decline participation. If you choose to 
participate now, you may change your mind and stop participating at a later date. Refusal to 
participate or withdrawal of participation will not result in any penalty or loss of benefits to 
which you are otherwise entitled such as care by your healthcare provider or negative 
consequences to your living arrangements. 
 
Purpose of the Research 
As people grow older they accumulate old cells in their bodies that stop dividing and produce 
harmful toxins that can damage organs and cause a variety of diseases. These cells, called 
senescent cells, cause inflammation, tissue damage, and degenerative processes that can lead to 
memory loss, mobility problems and even Alzheimer’s disease. You are being asked to take part 
in this study because you are older than 65, you have memory and mobility concerns, and may 
be at risk of developing Alzheimer’s disease. Therefore, you may have these old cells (senescent 
cells) in your body.  
 
Scientist are developing and testing drugs that can eliminate these senescent cells from the body 
to prevent diseases like Alzheimer’s disease. One of these is a dietary supplement called 
Quercetin that comes from fruits and vegetables. Another is called Dasatinib (also called 
Sprycel), which is used to treat certain cancers if taken every day for long periods of time. 
Dasatinib and Quercetin has been taken by patients with idiopathic pulmonary fibrosis (a severe 
lung disease) and chronic kidney disease without causing serious adverse events. Dasatinib and 
Quercetin have improved signs of Alzheimer’s disease in animal studies, but these drugs have 
not been tested in people with memory and mobility problems. Therefore, we want to see if we 
can re-purpose these drugs in people with memory and mobility problems who may be at risk of 
Alzheimer’s disease so we can test their effects on symptoms, memory, walking speed, mood, 
and blood flow to the brain. In our study, the use of Dasatinib and Quercetin is investigational. 
This means that the study drugs have not yet been approved by the FDA for the purpose we are 
studying, namely, treatment of the pre-stages of Alzheimer’s disease. That is why we are 
conducting this pilot study. A pilot research study is a small study conducted in order to evaluate 
how practical it is to conduct certain procedures, and to refine the study design for future larger-
scale studies. The FDA, which monitors all investigational studies with drugs has given us 
approval to do this study. 
 
Key Information 
1. How many people will be in the study? 
 
A total of 12 people will be in this pilot study. In order to find the 12 people that are able 
to be in our study, we may need to screen many more because some won’t qualify for the 
study.  


National Institute of Aging 
Page 3 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
2. How long is the study and how many visits? 
 
Each person will be enrolled for 14 weeks, and requires 8 in-person and 12 short 
telephone calls (10 minutes each) with a study staff member. You can stop participating 
at any time.  
3. Where are the study visits?  
Most study visits will take place in our research center located at Hebrew Rehabilitation 
Center (HRC; 1200 Centre Street, Roslindale, MA 02131). It may be possible to have 
some of the study visits at one of the HRC-affiliated housing sites. 
4.   How often do I take the study drugs? 
At visit 2, you will be asked to take the first dose of 100 mg of Dasatinib and 1,250 mg of 
Quercetin (D&Q). You will take another dose of these study drugs the next day at home. 
The following week you will not have to take any. You will then return to the research 
center and repeat the two week cycle 5 more times, which will equal a total of 12 weeks. 
This means you will take 12 doses of D&Q during this study.  
5. How many pills do I take during the study? 
 
You will be asked to take 1 pill of Dasatinib and 5 pills of Quercetin 12 times during this 
study over a total of 12 weeks. You will take the same dose each time you take the study 
drugs. 
 
Research Procedures 
Involvement in this study will require 8 in-person study visits at our research center over 14 
weeks. Transportation will be provided if needed. Below outlines each study visit in detail. There 
are visits that require blood draws. It is okay for you to eat before the blood draw (you don’t 
need to come to the study laboratory fasted). If at any time you feel uncomfortable answering a 
question or do not want to perform one of the study assessments, you can say so and the 
assessment will be stopped immediately.  
 
Visit 1 (takes roughly 3 hours): Hebrew Rehabilitation Center, Roslindale 
At this first visit, you will learn all the details of the study and you will be given time to ask any 
questions you might have. If you decide to participate then you will be asked to sign and date the 
consent form and you will receive a copy to take home with you.  
 
You will be asked some questions about your medical history, your daily activities and 
medications including dietary supplements you take. You’ll have a brief physical exam of your 
heart and lungs conducted by our study clinician. Vital signs, such as blood pressure, pulse, 
temperature, respirations, electrocardiogram (EKG), height, and weight will be measured. You 
will also do a short walking task at your usual walking speed. You’ll be asked to have a blood 
test (about 4 tablespoons will be drawn) to determine if it is safe for you to take the study drugs 
and determine if you have any old (senescent) cells in your blood. You will also be asked to 
provide a urine sample to check for old (senescent) cells in your urine. The blood and urine 
samples will be taken at either HRC or an HRC-affiliated site.  
 
During Visit 1, we will use a Doppler microphone, called a transcranial Doppler, to see if we can 
measure your brain blood flow. To do this, we will place the microphone at your temple just in 
front of your ear.  In some people, the bone at the temple is so thick that the ultrasound cannot 
detect the blood flow. This is normal. However, if this happens, we will not be able to enroll you 


National Institute of Aging 
Page 4 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
in the study. If we can detect blood flow, we will measure the blood flow to the brain while you 
perform a memory task and when you stand up from a seated position. 
 
If you don’t qualify for the study, we will send you a letter with the results of your lab work so 
you can share them with your doctor. 
 
Visit 2:  Baseline visit (before any study drugs; takes roughly 3 hours):   
Approximately 2 weeks later, you will come back Hebrew Rehabilitation Center for a second 
study visit. At this visit we will ask you some questions about your health, mood, and if you are 
currently experiencing any health symptoms. We will measure your vital signs (blood pressure 
and heart rate) as we did at Visit 1. You’ll complete some tests of memory and thinking such as 
connecting numbers and letters, drawing things, remembering specific words and answering 
various questions. You will be asked to do some physical assessments, such as walking and 
balance measures. Your handgrip strength will be measured by asking you to squeeze a handgrip 
several times. At the end of the visit, we will give you your 1st dose of Dasatinib and Quercetin 
with a glass of water. We will also give you your 2nd dose to take home and instructions on how 
to take the study drugs the next day.  
 
Visits 3 and 4 (takes roughly 2 hours each): 
Approximately 2 weeks later, you will have a third visit. Approximately 2 weeks after the third 
visit you have a fourth visit. At both visits we will evaluate any symptoms (same as Visit 2), 
perform an assessment of vital signs and EKG (same as Visit 1), and provide study drugs 
(same as Visit 2). We will also draw approximately 1 tablespoon of blood to see if it is safe for 
you to continue to take the study drugs.  
 
Visit 5 (takes roughly 3 hours): 
Approximately 2 weeks later, you will have a fifth visit where we will evaluate any symptoms 
(same as Visit 2), perform a brief physical exam by our study clinician (same as Visit 1), perform 
an assessment of your vital signs and EKG (same as Visit 1), provide study drugs (same as 
Visit 2), and draw approximately 1 tablespoon of blood (same as Visit 3). Additionally we will 
perform memory/thinking assessments (same as Visit 2), physical assessments (same as Visit 
2), and we will measure your blood-flow to the brain (same as Visit 1). 
 
Visits 6 and 7 (takes roughly 2 hours each): 
Approximately 2 weeks later, you will have a sixth visit. Approximately 2 weeks after the sixth 
visit you will have a seventh visit. At both visits we will evaluate any symptoms (same as Visit 
2), perform an assessment of vital signs and EKG (same as Visit 1), provide study drugs (same 
as Visit 2) and draw approximately 1 tablespoon of blood (same as Visit 3). 
 
Visit 8 (takes roughly 2.5 hours): 
Approximately 2 weeks later, you will have a final visit where we will evaluate any symptoms 
(same as Visit 2), perform a brief physical exam by our study clinician (same as Visit 1), perform 
an assessment of vital signs and EKG (same as Visit 1), and draw approximately 4 tablespoons 
of blood (same as Visit 1). Additionally we will perform memory/thinking assessments (same 
as Visit 2), physical assessments (same as Visit 2), and we will measure your blood-flow to the 
brain (same as Visit 1). 


National Institute of Aging 
Page 5 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
 
Telephone Reminders and Check-ins (takes 5-10 minutes each, approximately 60 minutes 
total): 
Prior to each in-person visit, study staff will call you to remind you of your scheduled visit and 
we may ask you about recent symptoms. Approximately 1 and 3-5 days after each in-person 
visit, a study staff member will call you to ask you if you took the most-recent at-home dose of 
Dasatinib and Quercetin and if you have had any symptoms or side effects that might be related 
to the drugs. 
 
Visit 
Purpose 
Procedures 
Time 
Place* 
Visit 1 
Screening 
visit  
Blood test, urine sample, brain blood flow 
with memory test, physical assessments, 
physical exam, medical history, height and 
weight, vitals/EKG 
~3  
hours 
HRC 
Visit 2, 
Baseline 
Start study 
drug: 1st & 
2nd dosage 
Memory/thinking and physical assessments, 
symptoms questionnaire, vitals and receive 
study drugs  
~2 ½ 
hours 
HRC 
Visit 3, Week 
2 
3rd & 4th 
Dosage 
Blood test, symptoms questionnaire, 
vitals/EKG, and receive study drugs 
~2  
hours 
HRC 
Visit 4, Week 
4 
5th & 6th 
Dosage 
Blood test,  symptoms questionnaire, 
vitals/EKG, and receive study drugs 
~2  
hours 
HRC 
Visit 5, Week 
6 
Mid-point 
visit, 7th 
&8th 
Dosage 
Blood test,  memory/thinking assessments, 
physical exam, physical assessments, 
symptoms questionnaire, brain blood flow, 
vitals/EKG, and receive study drugs 
~3  
hours 
HRC 
Visit 6, Week 
8 
9th & 10th 
Dosage 
Blood test, symptoms questionnaire, 
vitals/EKG, and receive study drugs 
~2 
hours 
HRC 
Visit 7, Week 
10 
Final 11th 
& 12th 
Dosage 
Blood test, symptoms questionnaire, 
vitals/EKG, and receive study drugs 
~2  
hours 
HRC 
Visit 8, Week 
12 
Follow-up 
Visit 
Blood test, urine sample, memory/thinking 
assessments, physical exam, physical 
assessments, brain blood flow, vitals/EKG, 
and symptoms questionnaire 
~2 ½ 
hours 
HRC 
*It is possible some study visits could occur at HRC or an HRC-affiliated facility 
 
Possible Future Use of Biological Specimens or Data 
In order to further increase scientific knowledge and enable future research of other age-related 
conditions, the identifiable samples and/or identifiable private information collected from you 
during this study may be used for future studies or shared with other researchers. If the study 
doctor distributes your samples and/or information to other researchers or institutions, your 
samples and/or information will be labeled with a research code and any personal identifiers will 
be removed so that no-one will know that they came from you. No additional consent will be 
requested for the future use of your samples or information. 
 


National Institute of Aging 
Page 6 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
If you have questions about storing samples or would like to request that samples be removed 
from storage, please let us know.  It is not always possible to remove samples from storage or to 
retrieve samples from which identifiers have been removed and/or that have already been sent to 
other investigators. Data and specimens collected before you decide to withdraw your permission 
for their use, will not be able to be withdrawn because they have not been saved with your name 
or identifying information attached to them.   
 
If you agree to participate in this study, we will draw at most 4 tablespoons of blood at each visit. 
Some of your blood will be sent to Mayo Clinic in Rochester, Minnesota to measure the old cells 
and products of the old cells in your blood. The left over blood (approximately 1 tablespoon) and 
urine (approximately 1 tablespoon) will continue to be stored in a freezer at Mayo Clinic. The 
left over blood/urine will not be labeled with your name. It is possible that we will measure other 
things in the blood/urine in the future. An Institutional Review Board (IRB) must also approve 
any future research using your blood/urine.  
 
The research that is performed with your blood/urine is not designed to help you specifically. 
There is no personal benefit to you for agreeing to this part of the research, but it might help 
people who have diseases at some point in the future. The results of the research performed with 
your blood/urine will not be given to your study doctor or put in your medical record. The 
research using your blood/urine will not affect your care. Your blood/urine will only be used for 
research and will not be sold.  
 
Return of Research Results 
During this research we may learn information from the study results that could be important for 
your health or your treatment; however, we will not share this information with you. We will tell 
you about anything we discover that could impact your immediate health or decision to stay in 
the study. 
 
Risks and Discomforts of Participating in the Research 
Being a part of any research study comes with some risk. You should discuss the risks below 
with the study staff. Risks and side effects related to the study visits, study drugs, and study 
involvement include: 
1. Study Drugs 
• All drugs can have side effects. You will be asked to take Dasatinib only two days every 
two weeks. Each week your body will have a chance to clear Dasatinib before you take 
the next dose. Long-term daily intake of Dasatinib has been shown to cause adverse 
effects that include:  
o Low blood cell counts 
o Bleeding problems 
o Fluid retention 
o Heart problems 
o Pulmonary arterial hypertension (high blood pressure in the vessels of your lungs) 
o Skin reactions 
o Fatigue (tiredness) 
o Diarrhea 
o Cough 


National Institute of Aging 
Page 7 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
o Bleeding in the digestive tract 
o Appetite disturbance 
o Bloating 
o Dizziness 
o Weight loss 
o Tumor Lysis Syndrome, which is caused by the fast breakdown of cancer cells. 
Tumor Lysis Syndrome can further cause kidney failure and an abnormal heart 
beat.  
 
Dasatinib can cause other side effects if taken while you are taking certain other 
medications. If you need to take any of the following medications, and cannot stop them 
temporarily, you will not be able to be in the study: anti-arrhythmic medications, 
antipsychotics and anxiolytics, anti-platelet or anti-coagulant medications other than 
aspirin, quinolone antibiotics, or drugs metabolized by the same liver enzymes as 
Dasatinib. The study staff will carefully review your medications to check if you are 
taking any of these. You will not be taking the Dasatinib daily. You will only receive 2 
doses every 14 days. Thus, adverse effects are not likely to occur. A study doctor will 
review all safety measures (symptoms, blood tests and EKG).  
• Quercetin may cause headaches and tingling of the arms and legs. There are serious 
interactions that occur with some other medications. To avoid this risk, you will not be 
eligible if you are taking medications that interact with Quercetin. 
2. Blood Sampling 
• You may experience discomfort, bruising and/or bleeding where the needle is inserted to 
get a blood sample. Occasionally some people become dizzy, lightheaded or feel faint. 
Infection could occur, but it is rare and therefore unlikely. Frequent donation of blood can 
result in low iron in your blood (iron deficient anemia). You should not donate blood for 
at least 8 weeks after completing this study.  
3. EKG (electrical activity of the heart) 
• When we measure the electrical activity of the heart, we will place patches (similar to 
stickers) on your arms and legs that are connected to the heart monitoring machine. When 
we remove the patches you may experience stickiness, skin irritability, and slight 
discomfort.  
4. Physical Tests 
• Your ability to perform certain physical activities will be measured before and after you 
take the study drugs. 
• There is a small risk of a fall during the walking and balance tests. A trained “spotter” 
will be at your side at all times. 
5. Brain Blood Flow 
• There is no known risk associated with the machine used to measure blood flow to the 
brain (Transcranial Doppler ultrasound). This device is similar to a Doppler a doctor 
would use to listen to a baby’s heartbeats in the womb. The probes used to measure blood 
flow in the brain are held in place by a headband, which may cause minor discomfort 
from its pressure placed around the head.  
6. Questionnaires and Memory/Thinking Tests 
• During the clinic visits we will ask you a variety of questions that you may feel are 
boring or wonder why we need this information. Please know that we only collect 


National Institute of Aging 
Page 8 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
information that we feel may be useful to know when studying the effects of Dasatinib 
and Quercetin. You may become tired during the questionnaires and if this occurs we can 
take a break until you are ready to continue.  
 
There may also be other side effects that we cannot predict. The study doctor does not know all 
the side effects that you may experience. Like all investigational drugs, all side effects may not 
have been identified at this time; some may be mild or others very serious. Everyone taking part 
in the study will be watched closely for any side effects. It is important that you tell your study 
doctor when you feel or seem different compared to your usual self while taking part in the 
study. You should tell the research staff about all the medication, vitamins and supplements you 
take and any medical conditions you have. This may help avoid side effects and/or other risks.  
 
Reproductive and Other Risks 
Females: Taking the study drug may involve risks to a pregnant woman, an embryo, fetus 
(unborn baby) or nursing infant. If you are of child-bearing potential, you are required to use an 
effective method of birth control while you are participating in this study and for 90 days after 
your last dose of the study drug. 
 
Males: If you have sex with a woman of child-bearing potential, you are required to use an 
effective method of birth control while you are participating in this study and for 90 days after 
your last dose of the study drug. Acceptable methods of birth control for use in this study are a 
condom. A condom is required to be used also by vasectomized men with a partner of child-
bearing potential to prevent delivery of the study drug through seminal fluid. The study doctor or 
study staff will discuss this with you. If your female partner becomes pregnant while you are 
participating in this study or within 90 days after you have stopped taking the study drug, tell 
your study doctor or study staff immediately. 
 
All records associated with your participation in this study will be confidential.  However, 
because the use of this drug is regulated by the Food and Drug Administration (FDA) and 
the National Institute of Aging (NIA), agents of the FDA and the National Institute of 
Aging may have access to these records during the course of their duties.  Representatives 
of Hebrew Rehabilitation Center and the institutional review board, Advarra, reviewing 
this study will also have access to your file to monitor that the study is conducted properly. 
 
In Case of Injury while Participating in the Research 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study. If we cannot provide the care directly, we will arrange for the care to be provided 
to you at a nearby institution.  We (and/or the treating provider, as appropriate) reserve the right 
to bill your insurance company or other third parties, if appropriate, for the care you get for the 
injury. We will try to have these costs paid for, but you may be responsible for some of them. 
For example, if the care is billed to your insurer, you will be responsible for payment of any 
deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault. There are no plans to pay 
you or give you other compensation for an injury beyond what is described above, should one 
occur. However, you are not giving up any of your legal rights by signing and dating this form. 


National Institute of Aging 
Page 9 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of the study as soon as possible. The 
researcher's name and phone number are listed on the first page of this consent form. 
 
Benefits to Participating in the Research 
You may not directly benefit from this study, but others may benefit from the knowledge gained 
in connection with your participation. 
 
Alternative Treatments or Procedures to those Conducted in the Research 
This research study is for research purposes only. The only alternative is to not participate in this 
study. 
 
Confidentiality of Information Collected as Part of the Research 
With any research study, there is a risk of a breach in confidentially. This would mean that 
someone who should not have access to your information may try to find a way to get it. We will 
do our best to protect your confidential information by giving you a special study identification 
number that we will include instead of your name, on the research records. Taking part in this 
research study may involve providing information that you consider confidential or private. 
Efforts, such as coding research records, keeping the records secure, and allowing only 
authorized people to have access to research records will be made to keep your information safe.  
 
A Data Safety Monitoring Board, which is an independent group of experts overseeing the 
study’s safety, will be reviewing the data from this study while it is being conducted.  This group 
of experts will not see your name or be able to determine your identity when reviewing your 
records. All personal information obtained in the study will be kept confidential, and this 
information will only be available to the research staff and the Advarra Institutional Review 
Board (IRB). The records identifying your name will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly available. The 
results of the study will only be published or presented as group data.  No individual participants 
will be identified. Forms to collect data will be labeled with a unique study number and kept 
locked in the study office. 
 
Your records may be reviewed in order to meet federal or state regulations. Reviewers may 
include representatives from the Food and Drug Administration, the National Institutes of Health 
and its agencies, Hebrew Senior Life representatives and Advarra Institutional Review Board 
members with oversight responsibility for this study, or others in order to meet regulatory 
requirements. 
 
Certificate of Confidentiality 
The National Institutes of Health (NIH) has issued a Certificate of Confidentiality to further 
protect your privacy. With this Certificate, the study doctors may not disclose research 
information that may identify you in any Federal, State, or local civil, criminal, administrative, 
legislative, or other proceedings, unless you have consented for this use. Research information 
protected by this Certificate cannot be disclosed to anyone else who is not connected with the 
research unless: there is a law that requires disclosure (such as to report child abuse or 


National Institute of Aging 
Page 10 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
communicable diseases, but not for legal proceedings); you have consented to the disclosure, 
including for your medical treatment; or the research information is used for other scientific 
research, as allowed by federal regulations protecting research participants.  
 
Disclosure is required, however, for audits or program evaluations requested by the agency that 
is funding this project (the NIH, the study sponsor)  or for information that may be required by 
the Food and Drug Administration (FDA). Any research information that is placed in your 
medical record would not be covered under this Certificate.  
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If others obtain your written consent to receive research information, then the 
researchers may not use the Certificate to withhold that information. Finally, you should 
understand that the study doctor is not prevented from taking steps, including reporting to 
authorities, to prevent serious harm to yourself or others. 
 
Compensation for Participating in the Research 
You will be paid up to a total of $300 if you complete all the study visits discussed above. You 
will be paid for the visits that you complete according to the following schedule:  
• $30.00 for the completion of Visit 1 
• $50.00 for the completion of Visit 2 
• $30.00 for the completion of Visit 3 
• $30.00 for the completion of Visit 4 
• $50.00 for the completion of Visit 5 
• $30.00 for the completion of Visit 6 
• $30.00 for the completion of Visit 7 
• $50.00 for the completion of Visit 8 
 
If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete. You will be paid by check upon the completion of your enrollment in the study. It may 
take up to 8 weeks to receive your stipend check. If you have any questions regarding your 
compensation for participation, please contact study staff. The findings from this research may 
result in the future development of products that are of commercial value. There are no plans to 
provide you with financial compensation of for you to share in any profits if this should occur.  
 
Costs to Participating in the Research 
All study costs include any study mediations and procedures directly related to this study will be 
paid for by the study. Costs for your regular medical care, which are not related to this study, 
will be your own responsibility. There are no costs to you for participating in this study. 
 
Withdrawal from the Research  
Your participation in this research is completely voluntary. If you chose not to participate or 
withdraw from the study, you will incur no penalty or loss of usual benefits. You may withdraw 
your consent and discontinue participation at any time without affecting your employment, job 
evaluations, health care or other services you may be receiving. If you choose to take part in the 
study, you have the right to stop at any time.  


National Institute of Aging 
Page 11 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
 
You will be informed of any significant new findings developed during the course of this 
research which may affect your willingness to continue participation. If you decide to stop 
participating in the study we encourage you to have a consultation with our study doctor.  
 
Your participation in this research project may be terminated if any procedure is determined to 
be inappropriate or potentially harmful for you. The study doctors also have the right to stop 
your participation in the study at any time. This could be because:  
1. It’s in your best medical interest 
2. Your condition worsened 
3. New information becomes available  
4. You had an unexpected reaction 
5. You failed to follow study instructions 
6. Or because the entire study was stopped 
 
If you decide to leave the study or you are asked to stop participating, any data that has already 
been collected will be kept by the study doctors.  
 
Authorization for Use and Disclosure of Your Protected Health Information 
As part of this study, we will be collecting and sharing information about you with others.  Please 
review this section carefully as it contains information about the federal privacy rules and the use 
of your information. 
 
Protected Health Information (PHI) 
By signing and dating this informed consent document, you are allowing the study doctors and 
other authorized personnel to use and disclose health information about you. This may include 
information about you that already exists such as: such as medical records, demographic 
information, laboratory results, etc. as well as any new information generated as part of this study 
through questionnaires, tests, and procedures that we may ask you to undergo.  This is your 
Protected Health Information, or PHI. 
 
People/Groups at HSL Who Will Use Your Protected Health Information 
Your Protected Health Information, PHI, may be shared with the study listed on this consent form 
as well as the supporting research team (for example research assistants, statisticians, data 
managers, laboratory personnel, administrative assistants). Your PHI may also be shared with the 
Advarra IRB as it is responsible for reviewing studies for the protection of the research subjects. 
 
People/Groups Outside of HSL with Whom Your Protected Health Information Will Be 
Shared 
We will take care to maintain confidentiality and privacy about you and your Protected Health 
Information, PHI. We may share your PHI with the following groups so that they may carry out 
their duties related to this study: 
 
• The sponsor of this study National Institute of Health/National Institute of Aging (for 
inspection and copying of records pertaining to this research) and their clinical research 
organizations 


National Institute of Aging 
Page 12 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
• Other researchers and centers that are part of this study at Marcus Institute for Aging 
Research 
• Other collaborative organizations (e.g., the research pharmacy, clinical laboratories, etc) that 
are involved with this study 
• Other hospitals and medical centers taking part in this study at Marcus Institute for Aging 
Research and research collaborators at those institutions 
• Your health insurance company, for portions of the research and related care that are 
considered billable.  
• Federal and state agencies that oversee or review research information, such as the Food and 
Drug Administration, the Department of Health and Human Services, the National 
Institutes of Health, and public health and safety authorities  
• Data and Safety Monitoring Board(s) that oversee this study 
 
Those who receive your PHI may make further disclosures to others. If they do, your information 
may no longer be covered by the federal privacy regulations. 
 
Why We Are Using and Sharing Your Protected Health Information 
The main reason for using and sharing your Protected Health Information is to conduct and oversee 
the research as described in this Informed Consent Document.   
 
No Expiration Date - Right to Withdraw Authorization 
Your authorization for the use and disclosure of your Protected Health Information, PHI, in this 
Study shall never expire.  However, you may withdraw your authorization for the use and 
disclosure of your PHI at any time by notifying the Principal Investigator in writing. If you do this, 
you will not be able to stay in this study. If you would like to withdraw your authorization, please 
send a letter notifying the Principal Investigator at the address listed on the first page of this form. 
Please be aware that the investigators in this study will not be required to destroy or retrieve any of 
your PHI that has already been used or disclosed before the Principal Investigator receives your 
letter. 
 
Right to Access and Copy Your PHI 
If you wish to review or copy your Protected Health Information, PHI, as it is made part of your 
medical record, you may do so after the completion or termination of the study by sending a letter 
to the Principal Investigator. You may not be allowed to inspect or copy your PHI until this study 
is completed or terminated. 
 
Notice of Privacy Practices 
In addition to signing and dating this document, you may also be asked to sign an HSL 
Acknowledgement Received Notice of Privacy Practices form to acknowledge that you have 
received the HSL Notice of Privacy Practices.  
 
ClinicalTrials.Gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 


National Institute of Aging 
Page 13 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
Whom to Contact About This Study 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the principal investigator 
at the telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00053594. 
 
If you agree, at the completion of this study, we would like to store the data we collect from you 
for possible use in future research studies. The data may be stored and used indefinitely and may 
be used for future studies to understand and improve function in those who fall with balance, 
walking or memory problems. Your data will be given a unique identification number and stored 
without your name or other information that could identify you. Only the investigator (or a 
specific person on the study staff) will have a list to know which study data are linked to which 
study participant, and this list will be kept confidential in a secure location. If the study doctor 
distributes data to other researchers, those data will be released with a unique identifier and 
without any way to identify you. If at any time you would like to have the data removed or 
deleted from storage, please let us know and the data will be transferred or destroyed according 
to your wishes. 
 
(1) I agree to allow the following information and materials collected from me for this research 
study to be stored and used for future studies to understand age-related disease: Data from 
physical and mental assessments.   
___Yes ___ No 
 
(2) I agree to allow Dr. Lewis Lipsitz to keep my contact information and contact me in the 
future with information about new research opportunities.  I understand that I am not 
obligated to participate in the future and can request to not be contacted at any time.  
___Yes ___ No 
 


National Institute of Aging 
Page 14 of 14  
 
Lewis Lipsitz, MD 
Advarra IRB Approved Version 23 Apr 2022 
 
 
 
Documentation of Informed Consent and Authorization: 
 
• I have read this consent form and was given enough time to consider the decision to 
participate in this research. 
• This research has been satisfactorily explained to me, including possible risks and 
benefits. 
• All my questions were satisfactorily answered.  
• I understand that participation in this research is voluntary and that I can withdraw at any 
time. 
• I am signing and dating this consent form prior to participation in any research activities. 
• I give permission for participation in this research and for the use of associated protected 
health information as described above (HIPAA).  
 
Research Participant 
 
 
__________________ 
_______________________________________________ 
Date (MM/DD/YEAR) 
Signature of Research Participant 
 
Study Doctor or Associate’s Statement,  Signature & Date: 
 
• I have fully explained the research described above, including the possible risks and 
benefits, to all involved parties (participant /legal guardian as applicable).  
• I have answered and will answer all questions to the best of my ability.  
• I will inform all involved parties of any changes (if applicable) to the research procedures 
or the risks and benefits during or after the course of the research.  
• I have provided a copy of the consent form signed by the participant /guardian and a copy 
of the hospital’s privacy notification (if requested). 
 
 
__________________ 
_______________________________________________ 
Date (MM/DD/YEAR) 
Signature of Study Doctor or Associate 
 
 
 

SAP_001.pdf: 
 
 
 
 
1 of 8
 
 
 
 
 
SAFETY AND FEASIBILITY OF DASATINIB AND 
QUERCETIN IN ADULTS AT RISK FOR ALZHEIMER’S 
DISEASE (STAMINA) 
 
STATISTICAL ANALYSIS PLAN 
 
NCT Number: 05422885 
January 23, 2024 
 


 
 
 
 
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Statistical Analysis Plan 
 
Advarra Protocol Number: Pro00053594 
 
Principal Investigator 
 
Lewis Lipsitz MD 
 
Director 
 
Marcus Institute for Aging Research 
 
lipsitz@hsl.harvard.edu 
 
Trial Statistician 
 
 
Thomas Travison PhD 
 
Senior Scientist 
 
Marcus Institute for Aging Research 
 
tgt@hsl.harvard.edu 
 
 
Synopsis. This document provides the statistical analysis plan (SAP) for the Senolytics to Improve Cognition and Mobility 
in Older Adults at Risk of Alzheimer’s Disease (STAMINA) trial (NIA AG073886). This is an open-label single arm trial 
intended to develop evidence of feasibility of delivery of combination Dasatinib and Quercetin (D+Q) for preservation of 
cognitive function among older adults at risk of Alzheimer’s disease.  
 


 
 
 
 
3 of 8
 
Contents 
 
Introduction 4 
Design, Objectives, and Hypotheses 4 
Administration of Intervention 5 
Outcomes Measures 5 
Analytic plan 5 
Overall approach 5 
Aim-specific Analyses 5 
Sensitivity Studies 5 
Sample size considerations 6 
Statistical Programming 6 
Appendix. Tables: Detailed Description of Outcomes Measures 7 
 
 
 
 


 
 
 
 
4 of 8
Introduction  
 
 
Abnormalities in cognition and mobility are common accompaniments of aging that often precede the development of 
Alzheimer's disease. Among their many etiologies, these abnormalities are associated with alterations in the regulation of 
cerebral blood flow to frontal regions of the brain that subserve executive functions and gait speed. We have previously 
shown that treatment with cocoa flavanols can improve blood flow in response to a cognitive task (neurovascular coupling 
[NVC]), as well as executive function in older people with impaired NVC. These compounds can also reduce the number 
of senescent cells and their toxic secretory products (SASP) in a variety of tissues. In mice, “senolytic” compounds such as 
flavanols and tyrosine kinase inhibitors, have been shown to reduce neurofibrillary tangle density, neuron loss, and 
ventricular enlargement, and in humans with idiopathic pulmonary fibrosis, improve gait speed and other functional 
abilities. Based on these findings, we hypothesize that the flavanol, Quercetin, and tyrosine kinase inhibitor, Dasatinib, 
(Q+D) will improve NVC in response to an executive task, reduce circulating SASP components, and in so doing, improve 
cognition and mobility in older adults who are at risk of Alzheimer's disease. 
 
This single-arm, open label study will be used to demonstrate the feasibility of administration of Q+D among older adults 
at risk of Alzheimer’s Disease, and to develop preliminary evidence of the combination’s ability to preserve cognitive 
function among such individuals.  
Design, Objectives, and Hypotheses 
 
This is a single-site, single-arm, open label, 12 week pilot study conducted in 12 older adults aged ≥65 years with slow gait 
speed (<1.0 m/sec) and Mild Cognitive Impairment. The overall objective is to demonstrate the feasibility and safety of 
administering intermittent doses of two senolytic compounds Dasatinib and Quercetin (D+Q) in older adults at risk of 
Alzheimer’s disease. Screened and eligible participants will perform baseline physical and cognitive assessments, as well 
as provide a blood and urine sample. Two weeks after their last dose, participants will complete a follow-up assessment 
of physical and cognitive function, as well as provide a blood and urine sample. Safety and possible adverse events will be 
monitored throughout the entire duration of the study as described below. The specific aims are:  
 
1) To determine the feasibility, safety, and recruitment challenges of studying intermittent doses of D+Q in older 
adults at risk of Alzheimer’s disease. We will evaluate the number of volunteers needed to be screened to identify 
eligible participants, the number of protocol deviations that are necessary to ensure safe and scientifically rigorous 
human subject participation (reported to the FDA and IRB), the frequency of any adverse drug effects, and compliance 
with medication administration. 
 
2) To obtain preliminary data on the effect of this D+Q regimen on: a) sitting and standing cerebral blood flow (CBF), 
and neurovascular coupling (NVC) during an executive task, b) gait speed, c) and executive function. We will measure 
CBF during sitting and standing, NVC during an N-Back cognitive task, 4 meter gait speed, and executive function via the 
Trail Making Test (TMT) pre- and post-intervention to estimate the average changes and variability of these measures. 
Such information will be used to design future, large-scale efficacy trials.  
 
3) To develop preliminary evidence concerning whether D+Q is associated with a) a reduction in biomarkers of 
senescence in serum and urine and senescent cells in blood, and b) whether reductions in these biomarkers are 
associated with improvements in NVC, gait speed, and executive function. We will measure biomarkers of senescence 
in urine and plasma and senescent cells in blood pre- and post-intervention to obtain preliminary evidence of potential 
mechanisms. 
 
We hypothesize that 12 week co-administration of intermittent doses of D+Q in older adults at risk of Alzheimer’s disease 
will be feasible and safe. 
 
 


 
 
 
 
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Administration of Intervention 
 
Participants will ingest 100 mg of Dasatinib and 1,250 mg of Quercetin for two consecutive days. Every two weeks, the 
same cycle will be repeated where participants are asked to take the same dose of study medications for 2 consecutive 
days. A total of six, 2-day administrations of study medications will take place over a total of 12 weeks. 
Outcomes Measures  
 
The primary outcome measure will be the proportion of individuals screened who advance to full enrollment in the trial, 
defined as ‘recruitment rate’ in Appendix; Table 1. Outcomes related to safety will include incidence of adverse events 
(AE) and serious adverse events (SAE; Table 1.)  Other endpoints will include measures of physical and executive function 
(Tables 2 and 3 respectively) and biomarkers of senescence (Table 4).  
Analytic plan 
Overall approach 
 
Outcomes measures will be computed as detailed in Tables 1-4. We will assess distributional characteristics of each 
outcome measure, and develop descriptions of each endpoint using tabular and graphical summaries. Following this, 
descriptive comparisons of pre- and post- intervention measures will be developed as appropriate.  
Aim-specific Analyses 
 
Aim 1 is concerned with feasibility and safety of administration of the combination intervention. Recruitment rate will 
be computed with reference to the number of potential enrollees approached for screening (Table 1) and coupled with 
an 80% confidence interval to assist with planning of future trials.  
 
Total incidence of each AE and SAE will be computed and reported.  
 
Medication compliance will be estimated with a participant-level mean and corresponding 80% confidence interval.  
 
Aim 2 is concerned with physical and executive function, which are measured at three timepoints (Tables 2 and 3). 
Descriptive assessments will be developed at each timepoint. A mixed-effects regression model incorporating random 
intercepts will be used to develop estimates, using regression contrasts, of within-individual change in each measure 
at weeks 8 and 14. Estimates of changed will be accompanied by model-based 80% confidence intervals.  
 
Aim 3 is concerned with biomarkers of senescence, which are measured at baseline and 14 weeks (Table 4). Descriptive 
assessments will be developed at each timepoint, and within-participant change scores computed. Point and 80% 
confidence interval estimates of mean change will be computed for each marker. Correlations between changes in 
biomarkers of senescence and changes in functional outcomes will be assessed using scatterplot smoothing and 
summarized using mixed-effects linear or nonlinear regression analyses as appropriate. 
 
Sensitivity Studies  
 
The potential influence of age and sex will be explored via stratification and added variable plotting as appropriate. 
Participant compliance with intervention will be summarized, and association with other outcomes examined with 
descriptive analyses as appropriate.  
 
 


 
 
 
 
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Sample size considerations  
 
This project will enroll 12 individuals who will be assessed before, during, and following the 12-week D+Q intervention. 
The proposed sample size is motivated by the need to make resource assessments in the design of a subsequent RCT of  
D+Q. We anticipate screening at least two and possibly many more individuals for every potential participant who is 
eligible and advances to enrollment. Under conservative assumptions we will be able to estimate the proportion of 
participants screened who are eligible and advance to enrollment to within 0.20 using an 80% exact binomial confidence 
interval, the upper bound of which will be used in planning the subsequent trial. We will additionally utilize data obtained 
in this pilot to similarly estimate the variability of outcomes measures and differences attributable to administration of 
D+Q; again using an 80% confidence interval, we will be able to estimate the standard deviation of continuous measures 
including CBF and gait speed to within 0.3 standardized units. The design is not intended to provide sufficient data to test 
the efficacy or effectiveness of D+Q on endpoints relevant for Aims 2 and 3. However, prior small human studies have 
demonstrated surprisingly robust relationships. For instance, a recent human study of only 9 subjects by the Kirkland 
group successfully demonstrated that D+Q reduced adipose tissue senescent cell burden within 11 days after a single 3 
day course of treatment. Furthermore, circulating SASP factors were reduced in these 9 subjects. We therefore anticipate 
that we will see suggestive evidence of an association with SASP factors and inflammatory biomarkers in serum and urine, 
and senescent cells in blood, sufficient to motivate moving forward to a larger clinical trial.  
Statistical Programming  
 
Analyses will be performed using R version 4.2.2 or later (R Foundation for Statistical Computing, Vienna) or SAS version 
9.3 or later (SAS Institute, Cary, NC.)  
 
 


 
 
 
 
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Appendix. Tables: Detailed Description of Outcomes Measures 
 
Table 1: Feasibility- and Safety-Related Outcomes  
Outcome 
Unit
Type
Timeframe
Brief description
Recruitment Rate 
#of participants 
completed 
study/# 
of 
screened 
participant 
Primary
Throughout the entire 
study 
The number of volunteers 
needed to be screened to 
identify eligible participants. 
Adverse Events
N of AE’s
Primary
Throughout the entire 
study 
The frequency of adverse 
events – related or possibly 
related 
to 
the 
study 
medications. 
Serious
Adverse 
Events 
N of SAE’s
Primary
Throughout the entire 
study 
The 
frequency 
of 
serious 
adverse drug events. 
Medication 
Compliance 
% of intended 
doses 
consumed 
Primary
Week 
2 
(Baseline), 
Week 4, Week 6, Week 
8, Week 10, Week 12, 
Week 14 
Compliance with medication 
administration. Assessed via 
self-reported intake of the at-
home dosage as well as 
returned pill containers/pills. 
 
Table 2: Physical Function-Related Outcomes  
Outcome 
Unit
Type 
Timeframe
Brief description
Gait Speed
Meters/sec
Primary
Screening, 8, and 14 
weeks 
This metric assesses the ability 
to control gait. It is performed 
without a distracting cognitive 
task. The faster of two trials 
will be used. 
SPPB: Short Portable 
Performance 
Battery 
Points
Secondary
Week 2 (Baseline), 8, 
and 14 weeks 
Physical
performance, 
including gait, balance, and 
strength to perform a chair 
stand. The total score will be 
used. 
TUG: Timed Up and 
Go 
Meters/sec
Secondary
Week 2 (Baseline), 8, 
and 14 weeks 
This is a timed test of mobility, 
including standing from a chair, 
walking 20 feet, and turning. 
The faster of the two trials will 
be used. 
Grip strength
kg
Secondary
Week 2 (Baseline), 8, 
and 14 weeks 
This 
test 
measures 
grip 
strength 
using 
a 
hand 
dynamometer. The maximum 
of the 3 trials will be used.  
 
 
 


 
 
 
 
8 of 8
Table 3: Executive Function Related Outcomes  
Outcome 
Unit
Type 
Timeframe
Brief description
Full MoCA score
Points
Primary
Week 2 (Baseline), 8, 
and 14 weeks 
An evaluation of global 
cognitive function  
2 Trial Avg of Left 
MCA cerebral blood 
flow 
during 
cognitive task (2BK -  
BL2BK) – (IDX – BL 
IDX) 
Cm/sec 
Primary
Screening, 8, and 14 
weeks 
Speed of blood flow on the 
Left MCA to the brain to 
increase 
blood 
flow 
in 
response to a cognitive task. 
Two trials averaged. 
2 Trial Avg of Right 
MCA cerebral blood 
flow 
during 
cognitive task (2BK -  
BL2BK) – (IDX – BL 
IDX) 
Cm/sec 
Primary
Screening, 8, and 14 
weeks 
Speed of blood flow on the 
Right MCA to the brain to 
increase 
blood 
flow 
in 
response to a cognitive task. 
Two trials averaged. 
1st Trial of Left MCA 
cerebral blood flow 
during cognitive task 
(2BK -  BL2BK) – (IDX 
– BL IDX) 
Cm/sec 
Primary
Screening, 8, and 14 
weeks 
Speed of blood flow on the 
Left MCA to the brain to 
increase 
blood 
flow 
in 
response to a cognitive task. 
1st trial only. 
1st Trial of Right MCA 
cerebral blood flow 
during cognitive task 
(2BK -  BL2BK) – (IDX 
– BL IDX) 
Cm/sec 
Primary
Screening, 8, and 14 
weeks 
Speed of blood flow on the 
Right MCA to the brain to 
increase 
blood 
flow 
in 
response to a cognitive task. 
1st trial only. 
Avg of Left and Right 
MCA cerebral blood 
flow 
during 
cognitive task (2BK -  
BL2BK) – (IDX – BL 
IDX) 
Cm/sec 
Primary
Screening, 8, and 14 
weeks 
Speed of blood flow on the 
Right MCA to the brain to 
increase 
blood 
flow 
in 
response to a cognitive task. 
Two trials on each side (left 
vs right) averaged. 
1st Trial only Avg of 
Left and Right MCA 
cerebral blood flow 
during cognitive task 
(2BK -  BL2BK) – (IDX 
– BL IDX) 
Cm/sec 
Primary
Screening, 8, and 14 
weeks 
Speed of blood flow on the 
Right MCA to the brain to 
increase 
blood 
flow 
in 
response to a cognitive task. 
1st trial only on each side 
(left vs right)  
Executive Function 
(Trails B minus A) 
Percentile
Primary
Week 2 (Baseline), 8, 
and 14 weeks 
Executive
function 
corrected for response time
Dual-task cost in gait 
speed ([VelocityST - 
VelocityDT] 
/ 
VelocityST x 100%) 
% difference
Secondary
Week 2 (Baseline), 8, 
and 14 weeks 
Gait speed in response to a 
cognitive 
task 
(DT). 
Compared to a gait speed 
without (ST).  
Dual-task 
cost 
in 
accuracy([AccuracyS
T - AccuracyDT] / 
AccuracyST x 100%) 
% difference
Secondary
Week 2 (Baseline), 8, 
and 14 weeks 
This test measures accuracy 
of a cognitive task while 
walking (DT), compared to 
accuracy while completing 
the cognitive task while 
sitting (ST).  
 


 
 
 
 
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Table 4: Biomarkers of Senescence 
Outcome 
Unit
Type 
Timeframe
Brief description
Senescent CD3 cells 
expressing p16INK4A 
Secondary
Screening and 14 weeks
This measures the number 
of 
senescent 
CD3 
lymphocytes in blood.  
Urinary interleukin-
1- alpha 
picogram/mL
Secondary
Screening and 14 weeks
Assay will measure the 
senescence 
associated 
biomarkers, interleukin-1- 
alpha 
(picogram/mL), 
in 
urine. 
Serum interleukin-1-
alpha 
picogram/mL
Secondary
Screening and 14 weeks
Assay will measure the 
senescence 
associated 
biomarkers, interleukin-1- 
alpha 
(picogram/mL), 
in 
serum. 
Urinary interleukin-
6 
picogram/mL
Secondary
Screening and 14 weeks
Assay will measure the 
senescence 
associated 
biomarkers, 
interleukin-6 
(picogram/mL), in urine. 
Serum interleukin-6
picogram/mL
Secondary
Screening and 14 weeks
Assay will measure the 
senescence 
associated 
biomarkers, 
interleukin-6  
(picogram/mL), in serum. 
Urinary MMP-9
nanogram/mL
Secondary
Screening and 14 weeks
Assay will measure the 
senescence 
associated 
biomarkers, 
MMP-9 
(nanogram/mL), in urine. 
Serum MMP-9
nanogram/mL
Secondary
Screening and 14 weeks
Assay will measure the 
senescence 
associated 
biomarkers, 
MMP-9 
(nanogram/mL), in serum. 
Urinary MMP-12
nanogram/mL
Secondary
Screening and 14 weeks
Assay will measure the 
senescence 
associated 
biomarkers, 
MMP-12 
(nanogram/mL), in urine. 
Serum MMP-12
nanogram/mL
Secondary
Screening and 14 weeks
Assay will measure the 
senescence 
associated 
biomarkers, 
MMP-12 
(nanogram/mL), in serum.