Conditions: Alzheimer Disease
Keywords: Dementia Alzheimer Cognitive decline dasatinib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purpose of this pilot study is to evaluate whether a combination of two drugs, dasatinib (D) and quercetin (Q) \[D+Q\], penetrate the brain using cerebrospinal fluid (CSF) in older adults with early Alzheimer's disease (AD). This combination of drug therapy has been shown to affect dying cells in humans with other chronic illnesses and in Alzheimer's mice models. The study team want to know if this combination of medications will reach the brain in order to evaluate if this intervention may be effective for treating AD symptoms in future studies. This is also known as a "proof of concept" study.

Detailed description:
Up to 40 potential candidates will be pre-screened to identify eligible men and women ages 65 years and over with a clinical diagnosis of early AD on a stable dose of cholinesterase inhibitors for at least 3 months (for example, Aricept).

Eligible participants will undergo laboratory assessments of blood and urine, receive study medications over a twelve week period, and complete pre- and post-treatment testing including: an MRI for digital imaging of the brain; lumbar puncture to obtain cerebrospinal fluid; memory and thinking assessments; quality of life questionnaires; and tests of walking, balance and strength, all of which will be done for research purposes only.

Participants must be accompanied by a Legally Authorized Representative and have no travel plans for 4-5 months that would interfere with study visits.

Arms:
arm 1: Senolytic treatment in 5 individuals with early AD to determine levels of drug that reach the central nervous system (CNS) by collecting cerebral spinal fluid (CSF), and begin collecting initial data on target engagement of senescent cells, AD-related markers, and AD-relevant outcomes for future trials.

Interventions: intervention 1: Dasatinib + Quercetin
Intervention descriptions: intervention 1: Intermittent D+Q administered for 2 days on/14 days off for 12 weeks (6 cycles)

Protocol document:
Prot_SAP_000.pdf: 
 
19-222H, Gonzales, Form BB, 08-12-21, AMD.docx  
Revised version: 
v2.2_08-12-21 
CONFIDENTIAL 
 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL 
ANALYSIS PLAN 
 
 
 
 
 
Official Study Title: Pilot Study to investigate the safety and 
feasibility of Senolytic Therapy to Modulate the Progression 
of Alzheimer’s Disease (SToMP-AD) 
 
 
NCT number: NCT04063124 
 
IRB Approval Date: 08/12/2021 
 
Unique Protocol ID: HSC20190222H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SToMP-AD 
 
 
 
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CONFIDENTIAL 
CLINICAL RESEARCH PROTOCOL 
 
IRB#: HSC20190222H 
 
Pilot Study to investigate the safety and feasibility of 
Senolytic Therapy to Modulate the Progression 
of Alzheimer’s Disease (SToMP-AD) 
 
Principal Investigator: 
Mitzi Gonzales, PhD 
Assistant Professor, Neurology 
Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases  
 
Mailing Address: 
     UT Health San Antonio 
     7703 Floyd Curl Drive, Mail Code 8070 
     San Antonio, TX 78229-3900 
 
Clinical Sites:     
     McDermott Clinical Sciences Building 
     8403 Floyd Curl Drive, Room 5.110, San Antonio, TX 78229 
     210-567-8229 
 
Co-PI and IND Sponsor: 
Nicolas Musi, MD 
UT Health San Antonio 
Professor of Medicine and Director 
Sam and Ann Barshop Institute for Longevity and Aging Studies 
7703 Floyd Curl Drive, Mail Code 7755 
San Antonio, TX 78229-3900 
210-617-5197 
 
Funding Sponsor: 
Institutional Grant from the Center for Biomedical Neuroscience in 
partnership with Institute for Integration of Medicine and Science 
 
Partially funded by UTHealth San Antonio Dept of Medicine Clinical and 
Innovative Therapeutics Pilot Program Award [for CSF analysis and 
lipidomics only] and Older Americans Independence Center/Claude D. 
Pepper Center Scholar Award Program 
 
Study Product: 
Dasatinib (SPRYCEL®, Bristol Myers Squibb) and Quercetin (Thorne 
Research) in combination 
Protocol #: 
HSC20190222H  
IND Number: 
143945 
NCT#: 
04063124 
 
 
                                                           TABLE OF CONTENTS 
 
 
 


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STUDY SUMMARY ............................................................................................................................................. 1 
1. INTRODUCTION ............................................................................................................................................. 3 
1.1. 
BACKGROUND ...................................................................................................................................... 3 
1.2. 
INNOVATION ......................................................................................................................................... 3 
1.3. 
PRELIMINARY DATA .............................................................................................................................. 3 
1.4. 
DOSE RATIONALE AND RISK/BENEFITS .................................................................................................. 4 
2. 
STUDY OBJECTIVE .................................................................................................................................. 5 
3. 
STUDY DESIGN ......................................................................................................................................... 5 
3.2. 
GENERAL DESIGN ................................................................................................................................ 5 
3.3. 
STUDY ENDPOINTS .............................................................................................................................. 6 
3.4. 
POTENTIAL RISKS TO SUBJECT SAFETY ................................................................................................ 6 
4. 
SUBJECT SELECTION AND WITHDRAWAL .......................................................................................... 8 
4.1. 
INCLUSION CRITERIA ............................................................................................................................ 8 
4.2. 
EXCLUSION CRITERIA ........................................................................................................................... 9 
4.3. 
SUBJECT RECRUITMENT AND RETENTION .............................................................................................. 9 
4.4. 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 10 
4.4.1. 
When and How to Withdraw Subjects ..................................................................................... 10 
4.4.2. 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 10 
5. 
STUDY DRUG .......................................................................................................................................... 10 
5.1. 
DESCRIPTION ..................................................................................................................................... 10 
5.2. 
TREATMENT REGIMEN ........................................................................................................................ 11 
5.3. 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 11 
5.4. 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 11 
5.5. 
PRIOR AND CONCOMITANT THERAPY ................................................................................................... 11 
5.6. 
PACKAGING AND PRODUCT INVENTORY ............................................................................................... 12 
5.6.1. 
Receipt of Drug Supplies ......................................................................................................... 12 
5.6.2. 
Storage .................................................................................................................................... 12 
5.6.3. 
Dispensing of Study Drug ........................................................................................................ 12 
5.6.4. 
Return or Destruction of Study Drug ....................................................................................... 12 
6. 
STUDY VISITS AND PROCEDURES ...................................................................................................... 13 
6.1. 
VISIT -1 (MINUS 1), CONSENT AND SCREENING VISIT ........................................................................... 13 
6.2. 
VISIT 1 – BASELINE MEASUREMENTS “A” (1-4 WEEKS AFTER SCREENING). ............................................ 14 
6.3. 
VISIT 2 – BASELINE MEASUREMENTS “B” (WITHIN 30 DAYS OF VISIT 1). ................................................ 15 
6.4. 
VISIT 3 – BASELINE MEASUREMENTS “C” - DRUG ADMINISTRATION (+3-10 DAYS AFTER VISIT 2”B”) ....... 16 
6.5. 
VISIT 4 – CYCLE 2 (14 (± 2) DAYS AFTER VISIT 3) ................................................................................ 16 
6.6. 
VISIT 5 – CYCLE 3 (14 (± 2) DAYS AFTER VISIT 4) ................................................................................ 16 
6.7. 
VISIT 6 – CYCLE 4 (14 (± 2) DAYS AFTER VISIT 5) ................................................................................ 16 
6.8. 
VISIT 7 – CYCLE 5 (14 (± 2) DAYS AFTER VISIT 6) ................................................................................ 17 
6.9. 
VISIT 8 – CYCLE 6 (14 (± 2) DAYS AFTER VISIT 7) ................................................................................ 17 
6.10. 
VISIT 9 – CYCLE 6 (WITHIN 4 HOURS OF DOSE #12) ............................................................................. 17 
6.11. 
VISIT 10 – END OF STUDY MEASURES AND DISENROLLMENT (3-10 DAYS AFTER VISIT 9) ....................... 17 
6.12. 
SUMMARY VISIT SCHEDULE TABLE ........................................................................................................ 1 
7. 
STATISTICAL PLAN .................................................................................................................................. 3 
7.1. 
SAMPLE SIZE DETERMINATION .............................................................................................................. 1 
7.2. 
STATISTICAL METHODS ........................................................................................................................ 1 
8. 
SAFETY AND ADVERSE EVENTS ........................................................................................................... 1 
8.1. 
DEFINITIONS ........................................................................................................................................ 1 
8.3. 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ......................................... 3 
8.3.1. 
Investigator responsibilities - The PI is responsible for: ............................................................ 3 
8.4. 
REPORTING PROCESS .......................................................................................................................... 4 


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CONFIDENTIAL 
8.5. 
MEDICAL MONITORING ......................................................................................................................... 4 
8.5.1. 
Investigator reporting of Protocol Deviations/Violations ............................................................ 4 
8.5.2. 
Definitions of Protocol Deviations/Violations ............................................................................. 4 
8.6. 
STOPPING RULES................................................................................................................................. 5 
9. 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 5 
9.1. 
CONFIDENTIALITY ................................................................................................................................. 5 
9.2. 
SOURCE DOCUMENTS .......................................................................................................................... 5 
9.2.1. 
Research Electronic Data Capture (REDCap) and origination of electronic source data ......... 5 
9.2.2. 
Paper source data ..................................................................................................................... 5 
9.2.3. 
Handwritten entries .................................................................................................................... 6 
9.3. 
DATA MANAGEMENT ............................................................................................................................. 6 
9.4. 
RECORDS RETENTION .......................................................................................................................... 6 
10. 
STUDY MONITORING, AUDITING, AND INSPECTING....................................................................... 6 
10.1. 
DATA AND SAFETY MONITORING PLAN (DSMP) .................................................................................... 6 
10.2. 
AUDITING AND INSPECTING ................................................................................................................... 7 
11. 
ETHICAL CONSIDERATIONS .............................................................................................................. 7 
12. 
STUDY FINANCES ................................................................................................................................ 7 
12.1. 
FUNDING SOURCE ................................................................................................................................ 7 
12.2. 
CONFLICT OF INTEREST ........................................................................................................................ 7 
12.3. 
SUBJECT STIPENDS OR PAYMENTS ....................................................................................................... 7 
13. 
PUBLICATION PLAN ............................................................................................................................ 8 
14. 
REFERENCES ....................................................................................................................................... 9 
15. 
ATTACHMENTS .................................................................................................................................. 10 
SUMMARY OF PROTOCOL CHANGES.......................................................................................................... 11 
 
 
 


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CONFIDENTIAL 
 
List of Abbreviations 
 
CSF – cerebrospinal fluid 
AD – Alzheimer’s disease 
D – dasatinib 
Q – quercetin 
D+Q or DQ, combination therapy with D and Q 
HPLC/MS/MS – High Performance Liquid Chromatography-Mass Spectrometry 
MoCA – Montreal Cognitive Assessment 
CDR – Clinical Dementia Rating 
WMS-IV – Wechsler Memory Scale 
CNS – Central nervous system 
NFT – neurofibrillary tangles 
 
 
 


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CONFIDENTIAL 
       Study Summary 
Title 
Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD) 
Protocol Number 
HSC20190222H 
Phase 
2 
Methodology 
Open label pilot 
Study Duration 
Between 20-24 weeks  
Study Center(s) 
Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases and UT Health San 
Antonio Medical Arts and Research Center (MARC) 
Objective 
To evaluate dasatinib and quercetin (D+Q) brain penetrance in older adults with early 
Alzheimer’s disease (AD) and investigate changes in senescent and AD-related markers as 
initial proof-of-concept for a larger phase 2 clinical trial 
Number of 
Subjects 
Screen up to 40 with intent for 5 completers. Additional subjects may be enrolled if attrition 
exceeds the anticipated rate (~25%). 
Inclusion Criteria 
1) Both genders and all ethnic groups 
2) Age 65 years and above 
3) Clinical diagnosis of AD (MoCA 7-23 and Clinical Dementia Rating [CDR global] = 1 and 
memory domain ≥1) on a stable dose of cholinesterase inhibitors for at least three months 
4) Labs: Normal blood cell counts without clinically significant excursions; liver and renal 
function; total cholesterol (<240 mg/dl),), and glucose control (HbA1c ≤ 7%). PT/PTT/INR 
within normal limits 
5) A Legally Authorized Representative (LAR) designated to sign informed consent and to 
provide study partner reported outcomes at all remaining visits must accompany 
participants. 
6) Participants must have no travel plans that would interfere with scheduling visits following 
consent over the 4-5 months of study duration  
Exclusion Criteria 
1) Hearing, vision, or motor deficits despite corrective devices 
2) Alcohol or drug abuse 
3) MRI contraindications 
4) Myocardial infarction, angina, stroke or transient ischemic attack in the past 6 months; 
QT interval >440 on screening ECG will be excluded. Chronic heart failure is 
exclusionary. 
5) Coagulation disorders are exclusionary. 
6) Neurologic, musculoskeletal, or other condition that limits subject’s ability to complete 
study physical assessments 
7) Uncontrolled diabetes  (HbA1c  >  7%  or  the current use of insulin) 
8) Current or chronic history of liver disease, or known hepatic or biliary abnormalities (>2x 
normal values) 
9) Use of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or 
anti-coagulant medication 
10) Current use of quinolone antibiotics, hydroxychloroquine or chloroquine 
11) Use of systemic steroids within 6 months prior to screening and throughout the study 
duration 
12) Poorly controlled blood pressure (2 or more readings of systolic BP>160, diastolic BP>90 
mmHg) 
13) Active inflammatory, COVID-19, autoimmune, infectious, hepatic, gastrointestinal, 
malignant, and psychiatric disease 
14) History of, or positive CT or MRI image with any space occupying lesion, including mass 
effect or abnormal intracranial pressure, which would indicate contraindication to lumbar 
puncture.  


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CONFIDENTIAL 
Study Product, 
Dose, Route, 
Regimen 
D is given as (1) 100mg capsule daily for 2 consecutive days (Sprycel®, Bristol Myers 
Squibb). Q will be given as (4) 250 mg capsules daily (total 1000 mg daily) for the same 2 
consecutive days (Thorne Research). Both are administered orally.  
Duration of 
administration 
D+Q will be administered once daily (1st dose of each cycle will be given, supervised, at the 
clinic visit; the 2nd dose will be taken at home) for 2 consecutive days followed by a 13-day 
(+/- 2 day) no-drug period for 12 consecutive weeks for 6 rounds of administration. 
Statistical 
Methodology 
Similar to an early phase 2 trial, we are seeking preliminary evidence of safety and tolerability 
and the objective is to estimate the pre/post differences in pertinent laboratory values and 
adverse event reporting. We will report the change in post intervention laboratory values 
relative to baseline with the 95% confidence interval. Experimental results will be expressed 
as means ± SE.  


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CONFIDENTIAL 
1. Introduction 
 
This document is a protocol for a human research study. This study will be conducted according to Good 
Clinical Practice guidelines as adopted by FDA, applicable government regulations, and within Institutional 
research policies and procedures.  
1.1. 
Background 
 
The underlying processes driving chronic neurodegeneration in Alzheimer’s disease (AD) and related 
neurodegenerative disorders are largely unknown. Moreover, individuals with AD suffer from significantly 
more co-morbid conditions than demographically matched older adults. Treatments that target systemic 
pathologies associated with advanced aging may provide benefit to the AD patient demographic. Toward this 
end, we have identified cellular senescence as a relevant target for intervention. Cellular senescence is a 
complex stress response involving aberrant cell cycle activity, adaptations to maintain survival, cellular 
remodeling, and metabolic dysfunction. Simultaneously, senescent cells secrete toxic molecules that induce 
chronic cell death. Senescent cells accumulate in many tissues with aging, and their clearance improves 
tissue from individuals with AD. With the use of AD transgenic mouse models and postmortem human brain 
tissue, we identified tau protein accumulation as the cause of senescence in the brain. Preclinical studies 
using dasatinib and quercetin (D+Q) cleared senescent cells, and decreased tau accumulation, ventricle 
enlargement, white matter hyperintensities and rescued aberrant cerebral blood flow(1). Clinical studies with 
this drug combination are underway in individuals with a separate chronic age-associated health conditions, 
idiopathic pulmonary fibrosis (IPF); the study retention rate is 100% with no DQ discontinuation(2). In the 14 
completed study participants, non-serious events were primarily mild-moderate in severity and reversible 
including respiratory symptoms, skin irritation/bruising, and gastrointestinal discomfort. One serious event 
was reported following completion of the intervention – possible bacterial pneumonia and pulmonary edema 
superimposed on IPF (the study trial disease condition). The subject was temporarily hospitalized and 
subsequently released with complete resolution. 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), reducing toxicity. We are well positioned 
to test intermittent senolytic treatment in individuals with AD to evaluate blood brain barrier penetrance of D 
and Q, and begin collecting initial data on target engagement and AD-relevant outcomes for future trials.  
1.2. 
Innovation 
 
Treatment with senolytics to measure the concentration of D+Q that reaches the cerebrospinal fluid and 
crosses the blood-brain barrier is a novel approach to help identify targeted therapy and dosing for clearing 
cellular senescence and tau accumulation known to be present in Alzheimer’s disease. 
1.3. 
Preliminary data 
 
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects over 5.6 million 
Americans and has no curative treatment. Recent evidence suggests that AD pathophysiology begins 
decades prior to 
symptoms(3). A poor understanding of mediators that drive disease onset and 
progression during the long prodromal, asymptomatic stages presents a large barrier for developing 
effective therapeutic strategies. 
The cellular senescence stress response is the quintessence of latent, chronic tissue destruction. Effects 
of a toxic insult may lay dormant for years or decades. Using gene expression derived from postmortem 
human brain tissue from individuals with AD, we found neurons with NFTs (neurofibrillary tangles) 
upregulate signaling pathways consistent 
with cellular senescence (Fig. 1a)(1). These include 
upregulation of pro-survival and inflammatory pathways and down regulation of cell death pathways. 
Predicted upstream regulators of these gene expression profiles were also consistent with senescence 
in human AD and transgenic AD mouse models recapitulated these gene expression patterns (Fig. 


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CONFIDENTIAL 
1b, c). 
 
 
Pharmacological agents targeting senescent cells, termed senolytics, have successfully decreased a 
variety of age-associated pathologies in model organisms(4-6). The intervention consists of brief and 
intermittent  dosing,  which  allows  for  the  clearance  of 
senescent cells thereby eliminating a source of 
inflammation and toxicity. One of the best-characterized 
senolytic treatments is dasatinib and quercetin (D+Q or 
DQ). D, a tyrosine kinase inhibitor with blood brain barrier 
penetrance, decreased microgliosis and exerted 
neuroprotective effects in AD pre-clinical models(7-9). Q, a 
naturally occurring  flavonoid,  reduced  AD-associated 
protein accumulation and inflammation in transgenic AD 
mice(10). Recently we treated AD mice with DQ 
combination therapy  and  found  a  significant  
improvement  in  multiple AD-relevant phenotypes 
including reduced  ventricle volume, aberrant cerebral 
blood flow, and white matter hyperintensity (WMH) 
pathology (Fig. 2a, b)(1). These significant differences 
occurred concomitant with  clearing 35 percent of pro-
inflammatory senescent NFT-containing neurons (Fig. 2c). 
In these old mice, clinically relevant outcomes were 
improved after only 6 single oral doses of DQ spanning 12 
weeks. The dose, 5 mg/kg D  and  50 mg/kg Q, are similar 
to dosages used in humans. These results demonstrate 
the feasibility of selectively ablating senescent cells in vivo 
and the efficacy of these drugs for alleviating AD-
associated deficits in brain structure and function. Since D 
and Q have been used in patients for other indications, 
and improve AD-relevant outcomes in pre-clinical studies, 
we propose to pilot this drug combination in older adults 
with early stage AD. 
1.4. 
Dose Rationale and Risk/Benefits 
 
Eligible participants will be treated with 100 mg of dasatinib (D) daily for 2 consecutive days plus quercetin 
(Q) for the same 2 consecutive days with (4) 250 mg capsules daily (total 1000 mg daily: 2 in AM and 2 in 
PM), followed by a 13-day (+/- 2 day) no-drug period to complete a single cycle. We will repeat until 
completing 6 cycles in approximately 12 consecutive weeks to achieve a time period in which cognitive 


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CONFIDENTIAL 
changes may be detectable. The small sample and objectives would be consistent with a Phase II study (i.e., 
we need to know what the D and Q drug levels would be in the CSF during this same duration). The risk 
profile is described in detail in Section 3.4. 
 
The study will consist of a screening/baseline period of up to 30 days pre-medication, with an 84-day 
treatment period, and a post-intervention visit for study outcomes on day 85 (up to +10 days). The study 
duration is not expected to exceed 24 weeks for subjects. 
 
2. Study Objective 
 
The objective of the study is to test intermittent senolytic treatment in 5 individuals with early AD to determine 
levels of drug that reach the central nervous system (CNS) by collecting cerebral spinal fluid (CSF), and 
begin collecting initial data on target engagement of senescent cells, AD-related markers, and AD-relevant 
outcomes for future trials. 
3. Study Design 
 
3.1. 
General Design 
This study is an open-label pilot study of intermittent D+Q to measure its target engagement in CSF and 
blood, and to establish the feasibility and safety of D+Q treatment in older adults with early stage AD as initial 
proof-of-concept for a larger Phase 2 clinical trial. 
 
Aim 1: To assess the degree of drug brain penetration by assessing cerebrospinal fluid 
(CSF). D and Q are rapidly metabolized and cleared from the systemic circulation; however, less 
information is known on brain penetration and metabolism. Lumbar punctures will be performed pre-
treatment and after the final D+Q dose to assess CSF D and Q levels after a 12-week intermittent 
treatment regimen. D and Q and their metabolites will be measured by HPLC/MS chromatography. 
Aim 2: To investigate target engagement of D+Q treatment in early Alzheimer’s disease 
with CSF and blood markers and MRI measures. Pre- and post- measures will include brain 
MRI-derived traditional markers of white matter damage (primary: white matter hyperintensities; 
secondary: covert brain infarcts, cerebral microbleeds, enlarged perivascular spaces) as well as 
novel indices (functional connectivity, peak skeletonized mean diffusivity, cerebral blood flow, free-
water  fractional  anisotropy).  We will also analyze levels of relevant AD markers (i.e., total tau, 
phosphorylated tau, Aβ40 and Aβ42, neurofilament light, and glial fibrillary acidic protein), 
senescence (i.e., p16, IL-6, PAI-1, ICAM-1) and lipid (through shotgun lipidomics) markers in the 
CSF and/or plasma.  
Aim 3: To evaluate change from baseline in cognition and functional status after  12 weeks 
of D+Q treatment. Cognitive changes will be evaluated with a detailed neuropsychological 
battery with measures of global cognition, verbal and visual memory, attention, processing speed, 
executive function,  visuospatial function, language, and mood/behavioral symptoms. Functional 
status will be evaluated with questionnaires, interview, grip strength and electronic gait mapping.  
Aim 4: To establish the safety and tolerability of 12-week D+Q treatment in older adults with 
early symptomatic Alzheimer’s disease. At three, five, s e v e n ,  nine, and twelve weeks, 
safety evaluations will be conducted including assessment for adverse events, compliance to study 
drug regimen, physical examination, vital signs, and laboratory assessment (CBC, CMP, plasma 
D+Q levels). 
 


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CONFIDENTIAL 
3.2. 
Study Endpoints  
a) Primary outcome: To determine blood brain barrier penetrance of D and Q in older adults with 
early symptomatic Alzheimer’s disease. Lumbar punctures will be performed before and after the 
final D+Q dose, to assess CSF D and Q levels after a 12-week intermittent treatment regimen. D and 
Q and their metabolites will be measured by HPLC/MS chromatography. 
Secondary outcomes:   
b) To assess target engagement of D+Q. Target engagement of D+Q will be assessed by pre- and post- 
measurements of blood and/or CSF by analyzing plasma and/or CSF levels of relevant AD markers (i.e., 
t-tau, p-tau, Aβ40, Aβ42, NFL, GFAP), senescence markers (i.e., p16, IL-6, PAI-1, ICAM-1), and 
lipid species prior to beginning D+Q treatment and after the final D+Q dose 12 weeks later.  
c) To establish the safety and tolerability of 12-week D+Q treatment in older adults with early 
symptomatic Alzheimer’s disease. At three, six, nine, and twelve weeks, safety evaluations will 
be conducted including assessment for adverse events, study compliance, physical examination, 
vital signs, and laboratory assessment (CBC, CMP, plasma D+Q levels). 
d) To assess changes in cognition, functional status, and physical performance - Change from 
baseline in gait, grip, cognitive exams (MoCA, WMS-IV Logical Memory, Benson Figure, 
California Verbal Learning Test II Short Form, Trail Making Test Parts A&B, Number Span Test, 
Category Fluency, Phonemic Fluency, Boston Naming Test, Digit Symbol Substitution Test), and 
questionnaires (Lawton ADL/IADL, Neuropsychiatric Inventory) 
e) To assess changes in MRI-derived markers of brain structure and function - Change from baseline 
in brain MRI measures including WMH, covert brain infarcts, cerebral microbleeds, enlarged 
perivascular spaces, functional connectivity, peak skeletonized mean diffusivity, cerebral blood flow, 
free-water fractional anisotropy. 
 
3.3. 
 Potential Risks to Subject Safety 
a) Drug Administration. 
 
Dasatinib (SPRYCEL®) is indicated for use in chronic myeloid leukemia and acute lymphoblastic 
leukemia. In cancer trials the most frequently reported adverse event is fluid retention(11). Also common 
are rash and gastrointestinal effects (Please refer to Attachment D, Full Prescribing Information). 
Dasatinib treatment may result in mild hypoglycemia, especially in uncontrolled type II diabetics(12, 13).  
QTc prolongation  may  occur. Dasatinib may increase the risk of prolongation of QTc in patients including 
those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking 
antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose 
anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to and during dasatinib administration. 
The  most  serious  side  effects  are  cardiac  adverse  events  including  rare  fatal myocardial 
infarction(14). Many side-effects are alleviated in intermittent D administration(15).  
For more detail, please refer to Attachment D, Full Prescribing Information, including: 
• 
Most common adverse reactions (≥15%) in patients receiving SPRYCEL® (dasatinib) as single-
agent therapy: 
o Myelosuppression 
o Fluid retention events 


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o Diarrhea 
o Headache 
o Skin rash 
o Hemorrhage 
o Dyspnea 
o Fatigue 
o Nausea 
o Musculoskeletal pain.  
• 
Drug Interactions: 
o Strong CYP3A4 Inhibitors: Dose reduction may be necessary.  
o Strong CYP3A4 Inducers: Dose increase may be necessary.  
o Antacids: Avoid simultaneous administration.  
o H2 Antagonists and Proton Pump Inhibitors: Avoid co-administration.  
 
Quercetin is a flavonoid present in many fruits, vegetables, and grains and is also used as an 
ingredient in supplements, beverages, or various types of foods. Q administered as an oral supplement 
at doses similar to those described in the present trial is used as an anti-inflammatory and 
antineoplastic, and is indicated for cancer, cardiovascular disease, inflammation, lipid effects, platelet 
aggregation, prostatitis, and viral infection, though data is inconclusive for several of these conditions. 
Quercetin is generally safe and well-tolerated. However, mild and temporary side effects such as headaches, 
extremity tingling, and stomach discomfort have been reported, along with kidney toxicity. It is also possible 
that quercetin may interact with antihypertensive drugs to lower blood pressure.  
  
D+Q: In a recent open label pilot of 14 subjects with idiopathic pulmonary fibrosis, a multi-site study used 
this combination intermittently for 3 days on, 4 days off over 3 consecutive weeks to total 9 doses (Justice et 
al., 2019, EbioMedicine, https://doi.org/10.1016/j.ebiom.2018.12.052). In their pilot, the most common 
adverse experiences were respiratory symptoms (16 reports), skin irritation/bruising (14 reports), and 
gastrointestinal discomfort (12 reports). Two severe headache events occurred. One serious adverse event 
was reported following completion of DQ intervention (possible pneumonia and pulmonary edema with 
underlying idiopathic pulmonary fibrosis), which resulted in temporary hospitalization with subsequent 
complete resolution. 
 
a) Blood withdrawal.  (To minimize these risks a qualified phlebotomist will perform venipunctures.) 
 
• 
Pain, bleeding, bruising, or swelling at the site of the needle stick 
• 
Hematoma 
• 
Nerve damage 
• 
Infection 
• 
Fainting or light-headedness 
 
b) Cognitive Assessment.   
 
• 
Psychosocial - embarrassment, discomfort or anxiety upon testing memory and thinking 
• 
Patient or Study Partner-Reported Outcomes include questionnaires related to AD symptoms, 
cognition, and mood scales.  
 


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c) Brain Imaging.   
 
• 
No known harmful side effects associated with temporary exposure to the strong magnetic field used 
by MRI scanners.  
• 
Anxiety and claustrophobia inside the MRI tube - severe claustrophobia is exclusionary for this study. 
 
d) Lumbar Puncture. (To minimize these risks, a qualified provider specifically trained in the procedure will 
perform the lumbar puncture, and, if clinically indicated may use fluoroscopy.) 
 
• 
Temporary pain and discomfort in the back.  
• 
Headache.  
• 
Persistent low-pressure headache due to leakage of CSF. If this headache persists, it may require 
additional treatment.  Uncommonly, a blood patch (injection of some of participant blood into the 
lumbar puncture site to patch the CSF leak) may be required. 
• 
Infection 
• 
Damage to nerves in the back  
• 
Bleeding into the CSF space 
• 
Allergic reaction to the local anesthetic (lidocaine) used for the lumbar puncture, such as swelling or 
rash at the puncture site. 
 
The lumbar puncture will be completed with fluoroscopy if clinically indicated and at the discretion of the 
provider or investigator. Fluoroscopy involves exposure to radiation. The amount of radiation exposure 
received from the procedure is equivalent to a uniform whole-body dose of 300 mrem (a unit of 
radiation exposure) which is approximately 0.5 times the amount of environmental radiation exposure 
(620 mrem dose) that each member of the general public receives per year. There is no known 
minimum level of radiation exposure that is recognized as being totally free of the risk of causing 
genetic defects (abnormal cells) or cancer. However, the probability of harm from such risk associated 
with the amount of radiation exposure received from fluoroscopy is considered to be low when 
compared to other everyday risks each member of the general public receives each year, depending 
on the amount of radiation each participant has personally been exposed to in the past, particularly in 
the previous year.  
 
 
e) Physical Function Assessment. 
• 
Brief, temporary fatigue with electronic gait mapping repeating tasks and/or using handheld 
dynamometer to measure grip strength 
• 
Psychosocial - heightened awareness of physical limitations may cause anxiety or embarrassment 
during testing, which will be mitigated by ensuring privacy 
4. Subject Selection and Withdrawal 
4.1. 
Subjects 
Up to 40 potential candidates will be pre-screened to identify eligible men and women ages 65 years and 
over with a clinical diagnosis of early AD.  Additional subjects may be enrolled if attrition exceeds the 
anticipated rate (~25%). 
4.2. 
Inclusion Criteria 
1) Age 65 years or above. 
2) Clinical diagnosis of AD (MoCA 7-23 and Clinical Dementia Rating Scale/global CDR = 1 and memory 
domain ≥1) on a stable dose of cholinesterase inhibitors for at least three months 
3) Labs: Normal blood cell counts without clinically significant excursions (WBCs: 4,500-10,500 


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cells/mcL; absolute neutrophil count: 1,800-8,700 cells/mcL; platelets: 140-450 K/uL; hemoglobin 12.0-
17.5 grams/dL); liver and renal function (AST 10-40 IU/L, total bilirubin 0.1-1.4 mg/dl); cholesterol (<240 
mg/dl), , and glucose control (HbA1c < 7%). PT/PTT/INR within normal limits 
4) Participants must be accompanied by a Legally Authorized Representative designated to sign informed 
consent and to provide study partner reported outcomes at all remaining visits 
5) Participants must have no plans to travel over the next 4-5 months that interfere with study visits following 
consent 
4.3. 
    Exclusion Criteria 
Subjects will be excluded if they exhibit: 
1) Hearing, vision, or motor deficits despite corrective devices; 
2) Alcohol or drug abuse; 
3) MRI contraindications; 
4) Myocardial infarction, angina, stroke or transient ischemic attack in the past 6 months; QT interval >440 on 
ECG will not be enrolled. Chronic heart failure will be exclusionary; 
5) Participants with coagulation disorders; 
6) Neurologic, musculoskeletal, or other condition that limits subject’s ability to complete study physical 
assessments; 
7) Uncontrolled diabetes (HbA1c  >  7%  or  the current use of insulin); 
8) Current or chronic history of liver disease, or known hepatic or biliary abnormalities >2x normal values; 
9) Use of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or anti-coagulant 
medication; 
10) Current use of quinolone antibiotics, hydroxychloroquine or chloroquine. 
11) Use of systemic steroids within 6 months prior to screening and throughout the study duration 
12) Poorly controlled blood pressure (2 or more readings of systolic BP>160, diastolic BP>90 mmHg). 
13) Active inflammatory, COVID-19, autoimmune, infectious, hepatic, gastrointestinal, malignant, and 
psychiatric disease. 
14) History of, or current positive CT or MRI with any space occupying lesion, including mass effect or 
abnormal intracranial pressure, which would indicate contraindication to lumbar puncture 
4.4. 
Subject Recruitment and Retention 
Participants with early AD will be enrolled from the UT Health San Antonio outpatient clinics, adjunct private 
practice offices and or University Hospital System clinics and hospitals. Recruitment methods may include 
electronic medical record queries, posting study fliers in medical offices or senior centers, community 
engagement activities, and/or newspaper or web-based advertisements including social media. A UT Health 
website to present the project to the public will be published online and could be referenced by other 
institutional websites. The study will be published on clinicaltrials.gov. All these strategies will be considered, 
made available and implemented/adapted according to the local policies and regulations. 
 
Telephone pre-screening prior to the clinic screening visit may be employed to ensure potential candidates 
will meet inclusion and exclusion criteria for enrollment. 
 
Transportation, parking and/or meal vouchers may be provided to participants according to local policies. 
 
 


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4.5. 
Early Withdrawal of Subjects 
4.5.1. When and How to Withdraw Subjects 
Subjects have the right to withdraw fully or partially from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution. 
 
Withdrawal of full consent for a study means that the subject does not wish to receive further investigational 
treatment and does not wish to or is unable to continue further study participation including any follow-up in 
person, by phone, through third parties including relatives or friends, via discussion with other treating 
physicians, and by use of medical records; subject data up to withdrawal of full consent will be included in the 
analysis of the study. Any subject may withdraw full consent to participate in the study at any time during the 
study. The Principal Investigator or sub-investigator will discuss with the subject appropriate procedures for 
withdrawal from the study. 
4.5.2. Data Collection and Follow-up for Withdrawn Subjects 
If subjects are withdrawn prematurely from the study, appropriately designated research staff will make efforts 
to collect at least survival data upon last contact that subject.  
 
Investigator will consult with Study Statistician with regard to any incomplete data set as compared to the full 
data set that fully supports the analysis.  If a subject withdraws consent to participate in the study, attempts 
will be made to obtain permission to record survival data up to the protocol-described end of subject follow-
up period.  
 
Investigator and designated research staff make it a high priority to obtain survival data on all subjects lost to 
follow up. Lost to follow up will be defined as a subject missing 2 or more consecutive visits, not answering or 
responding to 3 follow up phone calls to subject or emergency contacts or returned receipt of 1 certified letter. 
5. Study Drug  
5.1. 
Description  
Dasatinib. SPRYCEL®  is a potent inhibitor of multiple oncogenic kinases, cellular enzymes involved in the 
transmission of growth signals from the cell membrane to the nucleus. The CAS number for dasatinib 
monohydrate is 863127-77-9. The molecular formula is C22H26C1N7O2S • H2O, which corresponds to a 
formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01.  
Dasatinib is a white to off-white powder and has a melting point of 280°–286°C. The drug substance is 
insoluble in water (0.008 mg/mL) at 24 ± 4°C. The pH of a saturated solution of dasatinib in water is about 
6.0. Two basic ionisation constants (pKa) were determined to be 6.8 and 3.1, and one weakly acidic pKa 
was determined to be 10.8. The solubilities of dasatinib in various solvents at 24 ± 4°C are as follows: slightly 
soluble in ethanol (USP), methanol, polyethylene glycol 400 and propylene glycol; very slightly soluble in 
acetone and acetonitrile; and practically insoluble in corn oil. SPRYCEL® film-coated tablets contain the 
following inactive ingredients: lactose, microcrystalline cellulose, croscarmellose sodium, hydroxpropyl 
cellulose and magnesium stearate. The tablet coating contains: hypromellose, titanium dioxide and 
polyethylene glycol. 
Mechanism of Action 
Dasatinib inhibits the activity of the BCR-ABL kinase and SRC-family kinases at low nanomolar or 
subnanomolar concentrations. Dasatinib also inhibits a number of other kinases including c-KIT, the EPHA2 
receptor and the PDGFβ receptor. Unlike imatinib, it binds not only to the inactive but also to the active 
conformation of the BCR-ABL kinase. This suggests a reduced propensity for acquired drug resistance due 
to the emergence of mutations that promote the adoption of the kinase’s active conformation. 
Quercetin. 


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Widely found in the plant kingdom, quercetin is the most abundant of the flavonoid molecules. It is found in 
numerous foods, including apples, onions, teas, and berries, vegetables of the cabbage family, seeds, and 
nuts. 
Quercetin is most commonly taken by mouth.  
Mechanism of Action 
Quercetin’s best-known mechanism of action involves its ability to stabilize mast cell membranes, which in 
turn can decrease the release of histamine. In this way, it provides nutritional support for individuals who 
occasionally suffer from allergies. Other benefits include its cardiovascular support and protection of the 
gastrointestinal tract. A number of quercetin’s beneficial effects appear to be due to its antioxidant activity. 
Quercetin can scavenge free radicals and inhibit the oxidation of LDL cholesterol. By itself, and when paired 
with vitamin C, quercetin can reduce the incidence of oxidative damage to skin and nerves caused by 
glutathione depletion. 
For more detailed information, see Protocol Attachment D. 
5.2. 
Treatment Regimen 
Administration Protocol.  
Study subjects will come to the clinic on the first day of each drug schedule (i.e., day 1 of each drug cycle). At this 
visit subjects will be given D and Q by study staff. The subjects will be sent home with the PM dose of Q and the 
day 2 medication (D+Q). This will be followed by the 13-day (+/- 2 day) no-drug holiday, and then repeated 
(subjects to clinic for day 1 D+Q, home day 2 D+Q, 13-day no drug, etc., etc.,) for 12 weeks totaling 6 rounds of 
D+Q.   
Assigning Subjects 
In this pilot, all subjects receive the same treatment, dose and frequency.  
 
5.3. 
Preparation and Administration of Study Drug 
The initial intake of dasatinib and quercetin will be through the Biggs Institute of UT Health San Antonio 
located in the McDermott Building. They will receive the drugs packaged for individual subject use from the 
Research Pharmacy. Once appropriately labeled, the study drugs will be dispensed to the designated study 
staff for administration to the study participant. The study subjects will have the 2-day quantity of D+Q 
dispensed to them at each cycle on day 1 of study visits (week 1, 3, 5, 7, 9, and 12). 
5.4. 
Subject Compliance Monitoring 
Participants and/or their study partner will be encouraged to bring empty pill bottles and adherence logs to 
each visit for review by the study team. Study coordinator will complete medication reconciliation at each 
visit. 
5.5. 
Prior and Concomitant Therapy 
Exclusionary medications:  
Drugs that affect coagulation (i.e., anti-platelet or anti-coagulant medications) and current use of 
quinolone antibiotics are exclusionary.  
Low dose aspirin (81mg) may not be considered exclusionary if used for stroke prevention or other 
cardiovascular treatment and participant is on stable therapy without adverse reaction for at least 6 months 
(consult with sponsor before enrolling). 
 
COVID-19 Vaccinations:  


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In the event study participants are given the opportunity to receive a vaccination (injection) for COVID-19 prophylaxis 
(either Tozinameran® or mRNA-1273®),  Subjects will be asked to not get the COVID-19 Vaccine injection within 4 
days after the second day of a treatment cycle (Day 1 and Day 2 of taking the study medication).  Subjects will also be 
asked to not get the COVID-19 vaccine injection within 3 days prior to beginning a new treatment cycle.      
 
Prior to the patient resuming therapy with the IP, they will be contacted by the study staff to confirm no changes in status 
have occurred that would contraindicate resumption of therapy with the IP. A delegated study clinician will have a 
documented conversation with the participant and/or their LAR regarding scheduling their COVID-19 vaccination in the 
context of the study dosing schedule.   
 
5.6. 
Packaging and Product Inventory  
 
Nature and Contents of the Container 
Drugs for individual subject use will be clearly labeled and identified as “For Investigational Use only—Not 
for Resale”.  
 
The Research Pharmacy will: 
• 
Inventory receipt of initial shipment and ensure appropriate temperature control 
• 
Distribute D and Q by labeling each individual subject packet(s) with Subject ID from list provided by 
PI or Co-PI to the Biggs Institute prior to receipt of inventory 
5.6.1. Receipt of Drug Supplies 
 
Any damaged or unusable study drug in a given shipment will be documented by the Research Pharmacy.  
The Research Pharmacist will notify the Principal Investigator and the Material Supplier of any damaged 
study drug. 
 
Special instructions upon receipt 
The Research Pharmacy reconciles inventory received per local standard operating procedure and makes 
copies of any accompanying shipping documentation enclosed provides and copies to IND sponsor. 
5.6.2. Storage 
SPRYCEL® (dasatinib) tablets should be stored at 25° C (77° F); excursions permitted between 15°– 30° C 
(59°–86° F) [see USP Controlled Room Temperature]. For more details, please see also SPRYCEL® 
(dasatinib) Full Prescribing Information 12-2018, Attachment D, Pharmacy Manual. 
5.6.3. Dispensing of Study Drug 
Designated staff from the Biggs Institute maintains the Drug Inventory and Dispensing Logs to track how, 
when and to whom the investigational drug was dispensed and assigned to subjects. Study clinical staff will 
document administration in research records regarding dosing, unused drug, drug damaged, or wasted. 
Study subjects are instructed to swallow dasatinib whole, and not to chew or crush medication when 
administered. 
5.6.4. Return or Destruction of Study Drug 
The procedures for final reconciliation of the site’s drug supply at the end of the study will be in accordance 
with local site Pharmacy standard operating procedures.  
 
Procedures for proper handling and disposal of anticancer drugs should be considered. There is no general 
agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 
SPRYCEL (dasatinib) tablets consist of a core tablet (containing the active drug substance), surrounded by 
a film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. However, 


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if tablets are crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy 
gloves. Note: personnel who are pregnant should avoid exposure to crushed and/or broken tablets. 
6. Study Visits and Procedures  
 
Special Considerations related to COVID-19 
 
1) 
Potential participants will be screened by telephone 1-2 business days in advance of study visits to 
assess for signs or symptoms of COVID-19 and for reports of recent exposure to people known to be infected 
with the virus. Upon arrival to the visit and before entering the research unit building, participants will be 
surveyed again, body temperature documented, and receive a mask if they need one. 
 
2)  
For added safety, approximately 1-2 business days before starting the drug intervention, enrolled 
participants will be tested for SARS CoV-2 with a nasopharyngeal swab for rRT-PCR (Real-time reverse 
transcriptase–polymerase chain reaction) analysis. Research funds will pay for the testing. If a participant 
tests positive, the investigator will refer the subject to their primary care physician for medical care and may 
withdraw the subject from participation in the trial. If a participant provides the researchers documentation of 
completed vaccination for COVID-19 (e.g.   vaccination card) that took place at least one week prior to their 
first dosing, the rRT-PCR test may be waived with study physician approval.  Phone pre-screening(s) and 
temperature checks will be done on all participants regardless of vaccination status.  
 
 
3) 
If a participant develops COVID-19 signs or symptoms at any time during the study, the investigators will 
arrange for testing and if indicated, will refer the participant to their PCP for medical care. During the 6-month study 
drug treatment, participants testing positive for COVID-19 will be withdrawn from treatment and their study participation 
will stop. Participants testing positive for COVID-19 during the pre- or post-treatment study periods will be required to 
wait until their symptoms resolve and they receive a negative COVID-19 test before continuing their study participation.  
5.7. 
Visit -1 (minus 1), Consent and Screening Visit 
5.7.1. Consent Process 
The participant is scheduled to come to the designated research area and will be accompanied by a Legally 
Authorized Representative (LAR) for the consenting process.  
In line with recommendations put forth by the Global Alliance for Genomics and Health, Aging, and Dementia 
Task Team, researchers will first attempt to seek consent from the study participant with AD. In order to have 
appropriate safeguards, decision-making capacity specific to participation in the research study (i.e., 
understanding the purpose, procedures, risks and benefits of study participation) will be evaluated using a 
standardized instrument for assessing capacity to consent developed by Jeste et al, 2007  and tailored to the 
study (see Attachment E.).In the event of questions regarding capacity, the research coordinator and/or 
research nurse practitioner will consult with the PI or other qualified study team members. If the study 
participant is found to lack capacity to consent, researchers will obtain consent from a legally authorized 
representative (LAR) who will be instructed to respect the will and preferences of the study participant. When 
a LAR is necessary, the researchers will still include the study participant in the consent process and will seek 
to obtain assent for study participation.  
5.7.2. Screening and eligibility 
After the informed consent process is completed, subjects will be screened for eligibility.  
Screening will include vital signs and physical examination with anthropomorphic measurements (height, 
weight, BMI), medical history, concomitant medication review (participants will be encouraged to bring their 
medications to the appointment), electrocardiogram (ECG), non-fasting blood measures for safety, including: 
complete blood count (CBC), comprehensive metabolic panel (CMP) including liver function tests, and lipid 


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panel, hemoglobin A1c (A1c), urinalysis (UA), and coagulation panel (PT/PTT/INR). Screening cognitive 
assessments will include Montreal Cognitive Assessment (MoCA) score and Clinical Dementia Rating scale 
(CDR).  
If clinical bloodwork has been obtained within 60 days of the screening visit, and results are available to the 
investigator through medical records, the values may be recorded for research and not require repeat blood 
specimen collection. Clinical urinalysis results obtained within 10 days of screening may be recorded for 
research and not require repeating, unless investigator deems the new specimen collection is clinically 
indicated. Since bacteriuria is common in the older population, a positive specimen may be sent for culture 
and sensitivity or the specimen collection may be repeated if investigator deems appropriate. 
The screening visit is estimated to require 2.5 hours. 
 
For participants scheduled for Visit 1, research staff will call the study participant and/or LAR/study partner 
within one business day of Visit 1 to confirm the appointment and provide a reminder about fasting. 
 
5.8. 
Visit 1 – Baseline Measurements “A” (1-4 weeks after screening).  
Within 4 weeks of the Screening visit, enrolled subjects will return to the research site in a fasting state for 
vital signs, concomitant medication review, adverse event review, research marker urine sample and blood 
draw, and lumbar puncture to acquire CSF baseline measures of senescence, aging and Alzheimer’s disease. 
A snack will be offered. Researchers will assess study participants’ willingness to continue their study 
participation with direct inquiry to the study participant and LAR. If there is any indication of diminished capacity 
or significant cognitive changes (i.e. observed by research staff or reported by family members), the 
researchers will evaluate the participant’s current capacity to consent using a standardized instrument as 
described under question 2 (if the participant originally was deemed to have capacity to consent) or evaluate 
assent and surrogate consent (if the participant originally was deemed to lack capacity to consent). 
The LP Baseline A Visit is estimated to require 1 hour, including processing of specimens shown below and 
30 minutes rest following the procedure. Refer to Manual of Operating Procedures for details of the LP 
procedure. 
 
(i) Lumbar puncture (LP) to acquire CSF (5mL volume, 30 minutes). 
• 
CSF: CSF will be separated into 0.5-1mL aliquots and frozen at -80C. See Analyses below. 
 
(ii) Blood draw 30-40mL volume for inflammatory and senescent markers.  
• 
Blood: Blood will be separated into aliquots for analysis by UTHealth/Biggs Institute and stored, in 
part, for confirmation by Mayo and/or Wake Forest  
• 
Separated from 20-30mL drawn, will be plasma volume of 10-15mL for inflammatory and senescent 
markers 
• 
Whole blood volume of 5-10mL for senescent markers 
 
(iii) Urine 
• 
Urine will be separated into aliquots and stored by UTHealth/Biggs Institute until analysis phase. 
 
Analyses.  
 
CSF: 
  
CSF will be separated into 1mL aliquots and frozen at -80C. (i) Aliquots will be analyzed by the Pharmacology 
Core facility (Dr. Marty Javors) using HPLC/MS chromatography; (ii) ELISA or Simoa HD-1 Analyzer for tau 
and Abeta to be performed by UT Health/Biggs Institute; (iii) lipidomics by the UT Health Lipidomics Core, 


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Director Dr. Xianlin Han; (iv) metabolomics by UT Health Dr. Kumar Sharma; (v) senescence measures to 
be confirmed by Mayo Clinic and/or Wake Forest. 
 
Blood/plasma:  
 
Whole Blood: Whole blood will be processed with Magnetic-activated cell sorting (MACS); CD3+T 
lymphocytes (blood) will be analyzed for senescence-associated markers (such as p16, IL-6 and IL-6R, 
plasminogen activator inhibitor (PAI) -1 and 2, intracellular adhesion molecule (ICAM)-1 and 2). 
Plasma and urine will be separated into 1mL aliquots and frozen at -80C.  i) Aliquots of plasma will be 
analyzed by the Pharmacology Core facility (Dr. Marty Javors) using HPLC/MS chromatography; (ii) ELISA 
or Simoa HD-1 Analyzer for tau and Abeta to be performed by UT Health/Biggs Institute; (iii) lipidomics by 
the UT Health Lipidomics Core, Director Dr. Xianlin Han; (iv) metabolomics by UT Health Dr. Kumar Sharma 
(plasma and urine); (v) senescence measures (plasma and urine) to be confirmed by Mayo and/or Wake 
Forest Clinic. 
 
Confirm scheduling of Visit 2, Baseline B. Within one to two business days of Visit 2, research staff may call 
the study participant and/or LAR/study partner to confirm the appointment. 
 
 
5.9. 
Visit 2 – Baseline Measurements “B” (within 30 days of Visit 1). 
 
Within 30 days of the Visit 1, enrolled subjects will be asked to return to the research unit with LAR for Visit 2. 
Examination and activities during this visit include reassessment of willingness to participate in the study (as 
described under Visit 1), vital signs, weight, concomitant medication, and adverse event review, with the 
following measures: 
 
(i) Cognitive examination (90 minutes) - note all measures may not be administered depending on researcher 
discretion):  
• 
Hopkins Verbal Learning Test – Revised (HVLT-R) 
• 
WMS Logical Memory 
• 
Benson Figure 
• 
Number Span Test 
• 
Trail Making Test Parts A&B 
• 
Phonemic Fluency 
• 
Semantic Fluency 
• 
Geriatric Depression Scale – 15-item 
• 
Questionnaires (Lawton ADL/IADL, Neuropsychiatric Inventory) 
(ii) Functional and physical performance measure (30 minutes):  
• 
Electronic gait mapping under single and dual-task conditions 
• 
Grip strength 
(iii) To establish feasibility of MRI brain imaging for a larger study, we will encourage, but not require, study 
participants to receive brain imaging including: (45 minutes) 
• 
WMH, covert brain infarcts, cerebral microbleeds, enlarged perivascular spaces, functional 
connectivity, peak skeletonized mean diffusivity, cerebral blood flow, free-water fractional anisotropy.  
 
Visit 2 is estimated to require 3.0 hours. Confirm scheduling of Visit 3. Within one to two business days of Visit 
3, research staff may call the study participant and/or LAR/study partner to confirm the appointment. 
 
 


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5.10. Visit 3 – Cycle 1 - Drug Administration (+3-10 days after Visit 2”B”) 
The participant and LAR will be asked to come to the research unit for drug dispensing and safety monitoring 
at Visits 3-8. Participant will undergo reassessment of willingness to participate in the study (as described 
under Visit 1), vital signs, concomitant medication review, ECG, and: 
 
• 
AE assessment 
• 
Blood draw (non-fasting) for safety labs: CBC, CMP, plus uric acid and phosphorus levels, prior to 
drug administration  
• 
Administer, dispense study medication, and schedule further follow up safety monitoring Visits 4-8. 
Administration of the 1st dose of medication and dispensing of PM dose of Q and the 2nd dose of D+Q 
medication (to be taken at home, 24 hours after dose #1). A study staff member calls the subject and/or LAR 
to verify that the subject has taken the second dose at the designated time.  
 
Visit 3 is estimated to require 2 hour or less. Scheduling of Visit 4: to occur 14 days (± 2 days) after Visit 3. 
Within one to two business days of Visit 4, research staff may call the study participant and/or LAR/study 
partner to confirm the appointment. 
 
5.11. Visit 4 – Cycle 2 (14 (± 2) days after Visit 3)  
Study subjects will return to the research unit for reassessment of willingness to participate in the study, vital 
signs, weight/BMI, concomitant medication and adverse event review, non-fasting CBC, D+Q 
compliance/tolerability, administration of the 3rd dose of study medication (to be taken in the clinic during this 
visit) and dispensing the PM dose of Q with the 4th dose of D+Q to take at home the following day. A study 
coordinator calls the subject and/or LAR to verify that the subject has taken the second dose at the designated 
time. 
 
The estimated duration of this visit is 30-60 minutes. Confirm scheduling of Visit 5. Within one to two business 
days of Visit 5, research staff may call the study participant and/or LAR/study partner to confirm the 
appointment. 
 
5.12. Visit 5 – Cycle 3 (14 (± 2) days after Visit 4) 
Subjects will return to the research unit for reassessment of willingness to participate in the study, safety labs 
[complete blood cell count (CBC), comprehensive metabolic panel (CMP)] plus uric acid and phosphorus 
levels, ECG, vital signs, concomitant medication and adverse event review, D+Q compliance/tolerability, and 
administration of the 5th dose of study medication (to be taken in the clinic during this visit). Study staff 
dispenses the PM dose of Q with the 6th dose of D+Q to take at home the following day, and performs a 
telephone follow up call to verify that the subject has taken the second dose at the designated time. 
 
The estimated duration of this visit is 30-60 minutes. Confirm scheduling of Visit 6. Within one to two business 
days of Visit 6, research staff may call the study participant and/or LAR/study partner to confirm the 
appointment. 
 
5.13. Visit 6 – Cycle 4 (14 (± 2) days after Visit 5) 
Subjects will return to the research unit for reassessment of willingness to participate in the study, vital signs, 
weight/BMI, concomitant medication and adverse event review, D+Q compliance/tolerability, and 
administration of the 7th dose of study medication (to be taken in the clinic during this visit). Study staff 
dispenses the PM dose of Q with the 8th dose of D+Q to take at home the following day, and performs a 


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telephone follow up call to verify that the subject has taken the second dose at the designated time. 
 
The estimated duration of this visit is 30-60 minutes. Confirm scheduling of Visit 7. Within one to two business 
days of Visit 7, research staff may call the study participant and/or LAR/study partner to confirm the 
appointment. 
 
5.14. Visit 7 – Cycle 5 (14 (± 2) days after Visit 6) 
Subjects will return to the research unit for reassessment of willingness to participate in the study, safety labs 
(CBC. CMP plus uric acid and phosphorus levels, PT/PTT/INR), vital signs and ECG, concomitant medication 
and adverse event review, D+Q compliance/tolerability, and administration of the 9th dose of study 
medication (to be taken in the clinic during this visit). Study staff dispenses the PM dose of Q with the 10th 
dose of D+Q to take at home the following day, and performs a telephone follow up call to verify that the 
subject has taken the second dose at the designated time. 
The estimated duration of this visit is 30-60 minutes. Confirm scheduling of Visit 8. 
 
5.15. Visit 8 – Cycle 6 (14 (± 2) days after Visit 7)  
Subjects will return to the research unit for final assessment of D+Q compliance/tolerability, reassessment of 
willingness to participate in the study, safety labs (CBC, CMP plus uric acid and phosphorus levels, A1c), vital 
signs, weight/BMI, concomitant medication and adverse event review, and physical exam. Study staff 
administers the 11th dose of medication and dispenses the PM dose of Q with the 12th dose of D+Q 
medication (to take at home, 24 hours after dose #11). 
Schedule Visit 9 post-treatment LP for the following day (within 4 hours after participant takes dose DQ#12) 
and provides detailed instructions to the participant and LAR.  
The estimated duration of this visit is 30-60 minutes. Confirm scheduling of Visit 9. Research staff will call the 
study participant and/or LAR/study partner within one business day of Visit 9 to confirm the appointment and 
provide a reminder about fasting. 
 
5.16. Visit 9 – Cycle 6 (within 4 hours of Dose #12) 
A study coordinator calls the subject and/or LAR for D+Q compliance/tolerability, and to confirm that the 
subject took the second dose at the designated time or plans to bring their second dose to the appointment. 
Timing of the LP appointment may be adjusted according to the actual timing of morning Dose #12. The 
participant returns to the designated research unit at the confirmed time. 
 
Examination and activities during this visit include: arrive in the fasting state, reassessment of willingness to 
participate in the study, vital signs, weight, concomitant medication and adverse event review, and (i) urine 
sample and blood draw for research labs with (ii) lumbar puncture to acquire CSF. A snack will be offered.  
Study staff dispenses the final dose of Q for PM home administration. 
 
The estimated duration of this visit is 1.5 hours. Scheduling of Visit 10 for further post-treatment measures 
and final follow up with disenrollment. 
 
Analyses. (repeat as shown in Visits 1 and 2) 
 
5.17. Visit 10 – End of Study Measures and Disenrollment (3-10 days after Visit 9)  
The participant returns to the research unit 3-10 days after the LP to undergo reassessment of willingness to 
participate in the study and 12-week post-treatment measures, including vitals, weight, ECG,, concomitant 


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medication and adverse event review as well as: 
• 
Cognitive test battery, including MoCA and CDR plus all assessments shown in Visit 2 
 
• 
Brain MRI (repeat as shown in Baseline “B” and “C”) 
• 
AE review, instructions for future AD follow up and study staff enters disenrollment note. 
The estimated duration of this visit is 3.5 hours.  
5.18. Follow Up Visit-Conducted at least 3 Months after the date of Visit 10  
The participants will be contacted at least 3 months after they have completed visit 10 regarding a follow up 
visit to be done either in person or remotely. The process of this follow up will be as follows:  
i. Consent  
1) The participant and/or their LAR will be contacted and the in-person follow up visit (including risks 
and discomforts) will be described to them in order to determine if they are willing to return to the 
Biggs for these measures.  If the participant/LAR agrees a visit will be scheduled.  They will also be 
asked to fast for least 8 hours prior to labs being drawn.     
2) If the participant/LAR declines to come back to the Biggs Institute for the purpose of the follow up 
visit or it is not feasible due to health state/relocation, the study staff will ask if they would be agreeable 
to conducting a visit remotely by phone.  IF the participant/LAR declines, no follow up information will 
be collected.   
3) In both situations 1 or 2, the study staff will first get consent from the LAR and, if possible, obtain 
assent from the participant.  Given the situation, assent may be obtained at the time of the visit.   
3) If, at the time of follow up it is discovered the participant has passed away, no decedent information 
will be collected from their LAR/Next of Kin.   
ii. Study Follow up Visit-In person.  
If a participant and their LAR return to clinic, the visit procedures conducted will be as follows:  
1) Obtaining verbal assent from the participant (if not conducted during the initial phone call)  
2) Collection of Vital Signs (BP/HR) and Weight.  
3) Fasting blood draw for Disease Biomarkers (~35 mL total)  
4) Provision of a Snack  
5) Update of medical history, concomitant medications, and serious adverse events incurred since 
visit 10.    
6) Neuro-cognitive tests: MoCA, CDR, and the cognitive battery as described in visit 2.  
7) Completion of the ADCS-CGIC, GDS-15, Lawton IADL, and the NPI.   
iii.  Study Follow up Remote Visit  
If a participant elects to provide follow up information remotely (i.e. via phone) the visit procedures conducted 
will be as follows:  
1) Obtaining verbal assent from the participant (if not conducted during initial phone call)  
2) Update of Medical History, concomitant medications, and serious adverse events incurred since 
visit 10.   
3) Conducting the CDR  
4) Completion of the ADCS-CGIC, GDS-15, Lawton IADL, and the NPI.  This can be done either over 
the phone or the assessments can be mailed to the participant/LAR and they can be returned.   
5) The participant/LAR will be asked if they've been examined by their PCP or other provider in the 


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past 2-3 months or if they have any upcoming doctors appoints in the next 2-3 months.  If so, they 
will be asked if they are agreeable to signing a release of information form to allow us to request 
records in order to obtain a more recent recording of vitals and weight.  
A Summary Visit Schedule Table is shown on the following page(s). 
 
 
 


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5.18. Summary Visit Schedule Table 
 
Visit Number 
Visit (-) 1  
Consent 
& Screen 
Visit 1  
Baseline 
"A" 
Visit 2 
Baseline   
"B" 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Follow 
Up Visit  
Visit Window 
1- 4wks 
ā V1"A" 
Wk 1,    
Day 1 
 V1 +     
up to 
30d 
V2 +     
3-10d 
V3 +14   
±2d 
V4 +14   
±2d   
V5 +14   
±2d   
V6 +14   
±2d 
V7 +14   
±2d 
V8   
+1d 
V9     
+3-10d 
V10+90 
days or 
more 
 
Cycle# (dose#) 
--- 
--- 
--- 
Cycle 1 
(DQ1-
2) 
Cycle 2 
(DQ3-
4) 
Cycle  3   
(DQ 5-
6) 
Cycle  4   
(DQ 7-
8) 
Cycle 5 
(DQ9-
10) 
Cycle 6 
(DQ11) 
Cycle 6 
(DQ12) 
Post tx 
testing 
and 
EOS 
 
 
 
Consent with LAR 
X 
  
  
  
  
  
  
  
  
  
  
x 
Reassess willingness 
to participate   
with LAR 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MoCA, CDR 
X 
  
  
  
  
  
  
  
  
  
X 
x 
Vitals: BP,HR,T,RR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X*** 
Height (V1 only),   
Weight (BMI) 
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
 
ECG 
X 
  
  
X 
 
 X 
  
X 
 
 
 X 
 
H & P 
X 
  
  
  
  
  
  
  
X 
  
  
 
ConMeds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
Safety Labs (not fasting) 
  
 
CBC w diff 
X 
  
  
X 
X 
X 
 
X 
X 
  
  
 
CMP w/ liver panel, 
lipids, 
(add uric acid, 
phosphorus 
V3,5,7,8) 
X 
  
  
X 
 
X 
 
X 
X 
  
  
 
 Hemoglobin A1c  
X 
 
 
 
 
 
 
 
X 
 
 
 
PT/PTT/INR 
X 
  
  
 
 
 
 
X 
 
  
  
 


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COVID-19 RT-PCR** 
 
 
 
X** 
 
 
 
 
 
 
 
 
Clinical Procedures 
 
MRI 
  
  
X 
  
  
  
  
  
  
  
X 
 
LP for CSF* 
  
X 
  
  
  
  
  
  
  
X 
  
 
Blood draw and 
urine specimen- 
Research Labs 
  
X 
  
  
  
  
  
  
  
X 
  
X*** 
HVLT-R 
  
  
X 
  
  
  
  
  
  
  
X 
X*** 
WMS Logical Mem 
  
  
X 
  
  
  
  
  
  
  
X 
X*** 
Benson Figure 
  
  
X 
  
  
  
  
  
  
  
X 
X*** 
Number Span Test 
  
  
X 
  
  
  
  
  
  
  
X 
X*** 
Trail Making Test 
A&B 
  
  
X 
  
  
  
  
  
  
  
X 
X*** 
Phonemic and 
Semantic Fluency 
  
  
X 
  
  
  
  
  
  
  
X 
X*** 
Geriatric Depression 
Scale-15 
  
  
X 
  
  
  
  
  
  
  
X 
X 
 Lawton IADL 
  
  
X 
  
  
  
  
  
  
  
X 
X 
CGIS 
  
  
X 
  
  
  
  
  
  
  
X 
X 
Neuropsych 
inventory 
  
  
X 
  
  
  
  
  
  
  
X 
X 
Physical Function Testing 
  
 
Electronic gait 
mapping 
  
  
X 
  
  
  
  
  
  
  
X 
 
Grip strength 
  
  
X 
 
  
  
  
  
  
  
X 
 
Study Medication  
  
 
Administer in clinic 
  
  
  
X 
X 
X 
X 
X 
 -- 
 -- 
  
 
Dispense next dose 
to home 
  
  
  
X 
X 
X 
X 
X 
X 
 -- 
  
 
Schedule Next Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
Phone Follow up 
Dose & Tolerability 
  
  
  
X  
X 
X 
X 
X 
X 
X 
  
 
End of Study 
  
 
Final AE review 
  
  
  
  
  
  
  
  
  
  
X 
 
Final Forms Review 
  
  
  
  
  
  
  
  
  
  
X 
 


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Follow up 
instruction 
  
  
  
  
  
  
  
  
  
  
X 
 
Disenrollment Note 
  
  
  
  
  
  
  
  
  
  
X 
 
*may include fluoroscopy, if indicated         **May require COVID-19 RT-PCR testing 24-48 hours prior to drug dispensing visit or procedure 
***TO be done at the in-person follow up visit only.   
 


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6. Statistical Plan 
6.1. 
Sample Size Determination 
This is a pilot study to collect data on brain penetrance of a study medication. The sample size was 
determined as what would be feasible given the time and budget constraints of the pilot (i.e., one-year and 
$50K).  
6.2. 
Statistical Methods 
Analytical Approach. 
Similar to an early phase 2 trial, we are seeking preliminary evidence of blood brain barrier penetrance, 
changes in senescence, with secondary evaluation of safety and tolerability to estimate the pre/post 
differences in pertinent laboratory values and adverse event reporting. We will report the change in post 
intervention laboratory values relative to baseline with the 95% confidence interval. Experimental results will 
be expressed as means ± SE.  
 
7. Safety and Adverse Events 
7.1. 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRSO) 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
Adverse Event (AE) 
In general, AE is used very broadly and encompasses physical and psychological harms and includes:   
 
Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated 
with the subject’s participation in the research, whether or not it is considered related to the subject’s 
participation in the research. 
 
Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that:  
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
• results in inpatient hospitalization or prolongation of existing hospitalization; 


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• results in a persistent or significant disability/incapacity; 
• results in a congenital anomaly/birth defect; or 
• based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition (examples 
of such events include allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse). 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as up to 2 weeks following the last administration of study treatment or 
procedures.  
 
Pre-existing Condition 
A preexisting condition is one that is present at the start of the study.  A pre-existing condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during the 
study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the end 
of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse event 
must also be recorded and documented as an adverse event.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation 
of the drug, more frequent follow-up assessments, further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a SAE unless specifically instructed otherwise in this protocol.  Any condition responsible for 
surgery should be documented as an AE if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an AE in the 
following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  
• Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery was 
elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is 
a worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 
 
7.2. 
Recording of Adverse Events 
At each contact with the subject, the investigator or study staff will seek information about adverse events by 
specific questioning and, if appropriate, by examination.  Information on all AEs will be recorded immediately 
in the source document, and in the appropriate AE section of the case report form (CRF).  AEs will be tracked 
using the HSC IRB AE tracking form or REDCap data management tool (See Section 9.3) to be reviewed by 


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Site Investigator and IND Sponsor on a monthly and ad hoc basis, depending on severity and 
expected/unexpected nature of the event. 
 
All AEs occurring during the study period will be recorded. The clinical course of each event will be followed 
until resolution, stabilization, or until it has been determined that the study treatment or participation is not 
the cause.  SAEs that are still ongoing at the end of the study period will be followed up to determine the final 
outcome.  Any SAE that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation will be recorded and reported per Institutional policy and according to FDA 
requirements. 
 
7.3. 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
Any incidents, experiences, and outcomes reported or discovered during clinic or telephone assessment that 
meet AE criteria will be documented.  Any AE reported as serious (SAE) requires submitting a Prompt Report 
Form to the IRB with a copy of the SAE or UPIRSO prompt report submitted to the Pepper DSMB for review 
as well as the funding agency Program Officer within 24 hours of notification to PI. All AE that are not serious 
nor UPIRSO will be summarized annually and submitted at continuing review to the IRB, FDA (if applicable) 
or other pertinent research committees with oversight of the study. 
 
SAE and or UPIRSO will be reported per IRB policy and procedure. Events that do not involve AE or SAE 
(non-AE UPIRSO), and which are a result of study participation may also require prompt reporting to the IRB 
per local policy. The report will include a description of the event, when and how it was reported, as well as 
any official chart records or documentation to corroborate the event or the reporting of the event. All AE will 
be graded as mild, moderate, or severe. Any action resulting in a temporary or permanent suspension of this 
study (e.g. local site IRB actions) will be reported per funding agency, DSMB, and IRB stipulations. 
 
Serious adverse events (SAE) still ongoing at the end of the study period will be followed up to determine 
the final outcome and or referred to participant’s primary care provider.  Any SAE that occurs after the study 
period that is considered to be possibly related to the study treatment or study participation will be recorded 
and reported per Institutional policy and according to FDA requirements. 
 
7.3.1. Investigator responsibilities - The PI or Co-PI (MD) is responsible for: 
• 
Reviewing all incidents, experiences, and outcomes that may represent UPIRSO. 
• 
Determining whether event represents a possible UPIRSO 
• 
Promptly reporting to IRB per local policy 
• 
Contacting institutions involved 
• 
Implementing actions necessary to eliminate immediate hazard 
• 
Submitting follow up reports to IRB 
• 
Submitting amendments to IRB, if applicable or stipulated 
 
Report SAE and UPIRSO immediately by phone and or secure email to: 
 
PI: Mitzi Gonzales, PhD 
AND 
Co-PI/IND Sponsor: Nicolas Musi, MD 
Assistant Professor, Biggs Institute 
 
UT Health Barshop Institute  
323-273-2107 
 
210-630-5001 
Gonzalesm20@uthscsa.edu 
 
musi@uthscsa.edu 
 
Within the following 48 hours, the PI provides further information on the SAE or UPIRSO in the form of a 
written narrative.  This should include a copy of the completed Prompt Report Form, and any other diagnostic 


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information that will assist the IRB to understand of the event.  A copy of the SAE or UPIRSO prompt report 
is submitted to the Pepper DSMB for review as well as the funding agency or Program Officer. 
 
For further special reporting requirements, please refer to the DSMP document approved by the funding 
agency or Program Officer. 
Additional reporting requirements 
 
The site investigator reports to the regulatory sponsor of the study. The IND sponsor (or sponsor-investigator 
if investigator initiated) is responsible for reporting to FDA when applicable, according to 21 CFR 312 
regulations. Contact FDA for guidance 
8.4. 
Reporting Process 
SAE may be submitted on FDA Form 3500A or in a narrative format. The contact information for submitting 
safety reports is noted below: 
 
Food and Drug Administration, Center for Drug Evaluation and Research 
Division of Metabolism and Endocrinology Products 
5901-B Ammendale Road, Beltsville, MD 20705-1266 
Phone: (301) 796-2290   Fax: (301) 796-9712  
8.5. 
Medical Monitoring 
The PI and Co-PI initiating the study will review the safety and progress of this study on a frequent basis 
or when needed if protocol deviations/violations, SAE or SAE-UPIRSO occurs.  The Pepper Center 
DSMB shall serve in a monitoring capacity and receive notification of SAE or SAE-UPIRSO. (See Section 
10.1) 
 
The PI and or Co-PI will review source documentation in the research record and or medical record when 
study coordinator provides an electronic alert or secure email to review.   
8.5.1. Investigator reporting of Protocol Deviations/Violations 
Departures during the conduct of a research study constitute a protocol deviation, violation or exception 
and as such must be reported to the UTHSCSA IRB. 
 
Tracking and reporting of protocol deviations and violations to the IRB is the responsibility of the PI. To 
determine whether deviations or violations require prompt reporting or other action, refer to the IRB 
document entitled “Decision Tree – Evaluating Departures” on the IRB website. Failure to report departures 
from the protocol according to IRB policy may constitute possible non-compliance, which will require a 
Prompt Report Form and possible FDA reporting by IRB. 
 
Deviations and violations may be identified in a number of ways including:  
• 
A report by an individual can be made directly to the IRB Office.  
• 
The IRB may learn of event through its continuing review of ongoing research.  
• 
Compliance reviews (audits) conducted by the Office of Regulatory Affairs and Compliance or one 
of the HSC affiliated institutional compliance offices.  
• 
A report by an individual can be made directly to the Office of Regulatory Affairs and Compliance 
(Hotline) or one of the HSC affiliated institutional compliance offices.  
• 
A report by another committee, department, institution, or official.  
• 
An audit or report from the study sponsor or sponsor’s monitoring entity. 
8.5.2. Definitions of Protocol Deviations/Violations  
• 
Protocol deviations 
• 
Protocol violations  


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• 
Emergency violations  
• 
For more information , refer to UTHSCSA IRB Policy website: 
https://research.uthscsa.edu/irb/policy/deviations  
8.6. 
Stopping Rules  
 
In the unlikely event that a study-related death or SAE occurs, the decision to stop the trial, either 
temporarily or permanently, will be the responsibility of the MSM or Pepper Center DSMB in collaboration 
with the Sponsor Investigator. 
9. Data Handling and Record Keeping 
9.1. 
Confidentiality 
Information learned about all subjects will be kept confidential.  All data and protected health information 
in paper form will be kept confidential by assigned anonymous identifier and kept secured (password 
protected and/or double locked). Subjects will not be identified in any way in any publication.   
9.2. 
Source Documents 
Source data will be originated both electronically and on paper. Electronic data may be originated in either 
the medical record, IDEAS (subject registration with identifiers), or in REDCap (questionnaires answered 
verbally). The study team will maintain a list of forms to identify where source data are generated for this 
protocol. 
 
Print all entries legibly in black ink.  Erasures and white-out material are prohibited. If any entry error has 
been made on paper, to correct such an error, draw a single straight line through the incorrect entry and 
enter the correct data above it.  All such changes must be initialed and dated.  For clarification of illegible 
or uncertain entries, print the clarification above the item, then initial and date it. 
9.2.1. Research Electronic Data Capture (REDCap) and origination of electronic source data 
Contemporaneous medical histories, physical exams, concomitant medications, checklists of consent 
processing, and documentation of eligibility criteria may be originated electronically in REDCap with date 
and time stamp and e-signed by the study team member obtaining the data. Then REDCap forms will be 
downloaded in PDF format containing saved source data, and printed to file in the paper participant record 
at the research site. Other electronically originated data in REDCap include: adverse event (AE) 
assessments and AE logs, enrollment logs, protocol deviation logs, and other study management 
checklists. Other electronic medical record data (UT Health EPIC, UHS Sunrise) including pre-existing 
history, exams, medication lists, and such may be accepted as source data. 
 
NOTE: Identifiers will not be entered into REDCap, except for the unique study number assigned to 
each subject. The electronic enrollment key with identifiable information will be created in IDEAS 
where the unique study number is assigned and stored. 
 
All missing data will be routinely queried, corrected, and or explained.  If a space on the Case Report Form 
(CRF) is left blank because the procedure was not done or the question was not asked, write “N/D”.  If the 
item is not applicable to the individual case, write “N/A”.   
9.2.2. Paper source data 
Paper source data will be collected from handwritten subject diaries, pharmacy logs, then entered into the 
REDCap database. All missing data will be routinely queried, corrected, and or explained.  If a space is left 
blank on paper because the procedure was not done or the question was not asked, write “N/D”, initialed 
and dated by the staff member.  If the item is not applicable to the individual case, write “N/A”.   
• 
Lab reports originating from medical records will be printed and filed in paper participant files to 


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facilitate investigator review.  Lab data will be entered into REDCap to facilitate analysis. 
• 
Questionnaires and assessments (e.g., cognitive assessments verbally administered according to 
purchased test booklets and copyrighted material) may be originated electronically in REDCap. 
Otherwise, it may be necessary to originate survey data on a paper source and transfer the data 
elements to REDCap for calculation, data management and analysis. Paper sources will be filed in 
paper subject records. 
• 
Supervising physician investigators will sign and date paper records upon review. 
9.2.3. Handwritten entries 
All handwritten entries will be created contemporaneously to the visit or phone call, and legibly in blue or 
black ink. Erasures and white-out material are prohibited. If any entry error has been made on paper, to 
correct such an error, draw a single straight line through the incorrect entry and enter the correct data 
above it.  All such changes must be initialed and dated.  For clarification of illegible or uncertain entries, 
print the clarification above the item, then initial and date it. 
9.3. 
Data Management 
Database Management Software: All data collection for this project will be maintained using the UT Health 
San Antonio REDCap platform which is managed by the Department of Epidemiology and Biostatistics.  
Data System: REDCap is a computing environment developed by Vanderbilt University consisting of a 
collection of instruments, under the management of UT Health San Antonio’s Information Management 
systems, policies, and procedures that govern its informatics operations. Data projects are designed to be 
end-user oriented and constructed to optimize workflow and minimize errors. The electronic enrollment 
key with identifiable information will be created in IDEAS where the unique study number is assigned 
and stored. 
 
All data will be input using a web front-end interface. All users are individually assigned authorization for 
access to specific components of the database application. Information that is input is checked for logical 
and range consistency and mandatory data fields must be entered in order to input a record.  
 
9.4. 
Records Retention 
 
The Sponsor-investigator and Principal Investigator are responsible for maintaining study essential 
documents for at least 3 years after the funding grant period ends or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product, whichever is longer.  
 
These documents should be retained for a longer period if required by a funding agency, the FDA or other 
institutional retention policy.  In such an instance, it is the responsibility of the sponsor or Principal 
Investigator to inform the institution as to when these documents no longer need to be retained.  
10.   Study Monitoring, Auditing, and Inspecting 
10.1. Data and Safety Monitoring Plan (DSMP) 
The Principal Investigator (PI) and Co-PI (MD) will be responsible for ensuring the timely monitoring of the 
data integrity and safety of study participants. The PI and/or Co-PI will communicate on a per visit basis 
with other members of the study staff to review adverse events and protocol compliance within 5-7 calendar 
days of the most recent study visit or phone encounter.  
 
The  (PI) and Co-PI (MD)  assign a staff member to conduct periodic quality assessments on consent 
processes and on collected data to ensure data integrity, security and control for quality assurance, which 
is also reviewed on an annual basis by the regulatory coordinator and PI when preparing continuing review 


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documentation for IRB submission. 
 
This study may choose to utilize one of two options for objective monitoring: 1) appointment of a Medical 
Safety Monitor to review the study after the first subject is completed and again before the last subject is 
completed; or 2) the OAIC Pepper Center Data and Safety Monitoring Board (Pepper DSMB) at appropriate 
intervals determined by the Board following initial protocol review and based on relative risk. The Pepper 
Center DSMB meets 2-3 times a year, by teleconference call, to review study progress of designated 
studies and assesses participants’ safety. 
10.2. Auditing and Inspecting 
The Principal Investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
funding sponsor, the Pepper DSMB, government regulatory bodies, and University compliance groups of 
all study related documents (e.g. source documents, regulatory documents, data collection instruments, 
study data etc.).  The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
The Principal Investigator will ensure that the designated regulatory coordinator or other quality assurance 
reviewer is given access to all the above noted study-related documents and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct study monitoring visits as 
assigned. 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11.    Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312) applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to the Institutional Review Board (IRB), in agreement 
with local legal prescriptions, for formal approval of the study conduct.  Refer to funding agency policies as 
to whether or not submitting amendments may be required. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  
12.  Study Finances 
12.1. Funding Source 
This study is financed through an institutional grant from the Center for Biomedical Neuroscience in 
partnership with Institute for Integration of Medicine and Science. Additional funds have been awarded for 
analysis of CSF and lipidomics. An RL5 Scholar Award from the Pepper Center will also supplement the 
funding for this pilot. 
12.2. Conflict of Interest 
UT Investigators are required to submit Conflict of Interest disclosures with every new study submitted for 
review by UTHealth San Antonio IRB.  
12.3. Subject Stipends or Payments 
This study will reimburse subjects for time and transportation.  A schedule of payments is shown below. 
The total potential reimbursement to a subject is $625, including the additional $150 if opting in for MRIs, 
for the study for all visits, or payments may be prorated to include the last visit completed if study 
participation is terminated early. Manual payments for additional visits, if necessary, will be handled on an 


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ad-hoc basis with prior approval from the funding sponsor. 
 
Table 2. Participant Compensation 
Study Visit 
Compensation Amount 
Visit -1: Screening and Consent 
$25 
Visit 1 
$100 
Visit 2 
$50 + (opt in MRI $75) 
Visit 3, 4, 5, 6, 7, 8 
$25 each 
Visit 9 
$100 
Visit 10 
$50 + (opt in MRI $75) 
Manual Payment (unscheduled visit, lab visit, or AE) 
$25 
 
13.    Publication Plan 
The Institution, IND Sponsor or respective designees may present or publish the results of a scientific 
investigation involving this Study in accordance with ICJME guidelines and institutional requirements. 
 
 
 
 
 


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14.   References 
 
1. 
Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Tau protein aggregation is 
associated with cellular senescence in the brain. Aging Cell. 2018:e12840. doi: 10.1111/acel.12840. PubMed PMID: 
30126037. 
2. 
Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, 
Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-
label, pilot study. EBioMedicine. 2019;(In press). 
3. 
Cummings J, Aisen PS, DuBois B, Frölich L, Jack CR, Jones RW, Morris JC, Raskin J, Dowsett SA, 
Scheltens PJAsr, therapy. Drug development in Alzheimer’s disease: the path to 20252016;8(1):39. 
4. 
Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PDJJotAGS. The clinical potential of senolytic 
drugs2017;65(10):2297-301. 
5. 
Tchkonia T, Kirkland JLJJ. Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic 
Strategies2018;320(13):1319-20. 
6. 
Zhu Y, Doornebal EJ, Pirtskhalava T, Giorgadze N, Wentworth M, Fuhrmann-Stroissnigg H, Niedernhofer LJ, 
Robbins PD, Tchkonia T, Kirkland JLJA. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL 
inhibitors, A1331852 and A11554632017;9(3):955. 
7. 
Gagalo I, Rusiecka I, Kocic I. Tyrosine Kinase Inhibitor as a new Therapy for Ischemic Stroke and other 
Neurologic Diseases: is there any Hope for a Better Outcome? Curr Neuropharmacol. 2015;13(6):836-44. PubMed 
PMID: 26630962; PMCID: PMC4759323. 
8. 
Dhawan G, Floden AM, Combs CK. Amyloid-beta oligomers stimulate microglia through a tyrosine kinase 
dependent mechanism. Neurobiol Aging. 2012;33(10):2247-61. doi: 10.1016/j.neurobiolaging.2011.10.027. PubMed 
PMID: 22133278; PMCID: PMC3294077. 
9. 
Sabogal-Guaqueta AM, Munoz-Manco JI, Ramirez-Pineda JR, Lamprea-Rodriguez M, Osorio E, Cardona-
Gomez GP. The flavonoid quercetin ameliorates Alzheimer's disease pathology and protects cognitive and emotional 
function in aged triple transgenic Alzheimer's disease model mice. Neuropharmacology. 2015;93:134-45. doi: 
10.1016/j.neuropharm.2015.01.027. PubMed PMID: 25666032; PMCID: PMC4387064. 
10. 
Sabogal-Guáqueta AM, Munoz-Manco JI, Ramírez-Pineda JR, Lamprea-Rodriguez M, Osorio E, Cardona-
Gómez GPJN. The flavonoid quercetin ameliorates Alzheimer's disease pathology and protects cognitive and 
emotional function in aged triple transgenic Alzheimer's disease model mice2015;93:134-45. 
11. 
Masiello D, Gorospe G, 3rd, Yang AS. The occurrence and management of fluid retention associated with TKI 
therapy in CML, with a focus on dasatinib. J Hematol Oncol. 2009;2:46. doi: 10.1186/1756-8722-2-46. PubMed PMID: 
19909541; PMCID: PMC2785832. 
12. 
Agostino NM, Chinchilli VM, Lynch CJ, Koszyk-Szewczyk A, Gingrich R, Sivik J, Drabick JJ. Effect of the 
tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and 
nondiabetic patients in general clinical practice. J Oncol Pharm Pract. 2011;17(3):197-202. doi: 
10.1177/1078155210378913. PubMed PMID: 20685771. 
13. 
Breccia M, Muscaritoli M, Cannella L, Stefanizzi C, Frustaci A, Alimena G. Fasting glucose improvement 
under dasatinib treatment in an accelerated phase chronic myeloid leukemia patient unresponsive to imatinib and 
nilotinib. Leuk Res. 2008;32(10):1626-8. doi: 10.1016/j.leukres.2008.01.015. PubMed PMID: 18321570. 
14. 
Cortes J, Mauro M, Steegmann JL, Saglio G, Malhotra R, Ukropec JA, Wallis NT. Cardiovascular and 
pulmonary adverse events in patients treated with BCR-ABL inhibitors: Data from the FDA Adverse Event Reporting 
System. Am J Hematol. 2015;90(4):E66-72. doi: 10.1002/ajh.23938. PubMed PMID: 25580915. 
15. 
La Rosee P, Martiat P, Leitner A, Klag T, Muller MC, Erben P, Schenk T, Saussele S, Hochhaus A. Improved 
tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia 
resistant or intolerant to imatinib. Ann Hematol. 2013;92(10):1345-50. doi: 10.1007/s00277-013-1769-2. PubMed 
PMID: 23625298. 
16.  
Jeste DV, Palmer BW, Appelbaum PS, et al. A New Brief Instrument for Assessing Decisional Capacity for 
Clinical Research. Arch Gen Psychiatry. 2007;64(8):966–974. doi:10.1001/archpsyc.64.8.966 
 
 
 
 
 
 


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15. Attachments 
A. Agreements 
B. Visit schedule 
C. Lab protocol 
D. Pharmacy and Drug Information 
E. Capacity to Consent (Jeste et al, 2007) 
 
 


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SUMMARY OF PROTOCOL CHANGES 
 
Date of 
Change 
Version 
Section Modified 
Before Change 
After Change 
03-13-19 
1.0 initial to IRB 
all 
NA 
NA 
03-25-19 
1.0 updated to FDA 
5. Study Drug 
-- 
Added quercetin 
04-16-19 
1.1 admin changes 
after VPRCTO 
review 
6.9, pg 18 (14) 
 
 
 
Visit Schedule 
 
 
 
 
 
Summary Table 
 
Cover page 
Scheduling Visits 
10 and 11, missing 
visit duration for 
Visits 8 and 9 
Missing elements 
in visit table that 
are written in the 
narrative protocol, 
ie, telephone calls 
per  
 
Font size 11 
 
IND,IRB# pending 
Remove Visit 11, added 
visit duration 
 
 
Added telephone calls 
to Visit  Schedule at 
Visit 3  
 
 
 
Font size 9 
 
Numbers updated 
04-17-19 
1.1 repeat admin 
changes 
Visits and Visit 
Schedule 
Inconsistencies 
identified between 
narrative and table 
Consistency check and 
update 
04-18-19 
1.1 repeat admin 
changes 
Visit 10 and footer 
version date 
Cycle 6 
 
Drug Compliance & 
Tolerability 
Replaced with new visit 
title 
Replaced as Phone FU 
Dose and Tolerability 
04-30-19 
1.1 repeat admin 
changes 
Visit table, footer 
version date 
Table missing flexible 
window @V3-8 
Added ±2d window   @ 
V3-8 to be consistent with 
protocol narrative, ICF 
06-19-19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cover page 
 
 
 
Summary Table 
 
 
 
 
 
 
 
Study Design 
 
 
 
 
 
 
 
 
Regulatory 
Sponsor 
 
 
 
Objectives 
 
 
 
Inclusion/Exclusion 
 
 
 
Objectives and 
Inclusion/Exclusion 
 
 
 
 
 
 
Changed to “Co-PI and 
IND Sponsor” for Dr. 
Musi 
 
Add “to investigate 
senescent and AD-
related markers’ 
 
Add contraindication 
language for to LP as 
an exclusion 
 
Add “to investigate 
senescent and AD-
related markers’ 
 
Add contraindication 
language for to LP as 
an exclusion 
 
 


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06-30-19 cont’d 
1.2 cont’d 
Study Design cont’d 
 
Visit Schedule  
 
 
 
 
Section 5.4 
 
 
Section 5.6 
 
 
 
 
Section 6.1 
 
 
 
 
 
Section 8.3 
 
 
Section 8.5 
 
 
 
Section 9.3 
 
 
Section 10.1 
 
 
 
General document 
cleanup 
 
 
Subjects, section 3 
 
 
Visits 3, 5, 7, 9 
 
 
 
 
“…bring empty pill 
bottles….” 
 
--drug 
responsibiltlies 
 
 
 
Consent process 
and screening 
separated 
 
 
 
PI phone number 
 
 
Re: medical 
monitoring 
 
 
Data management 
 
 
Data safety 
 
 
 
Entire document 
 
Moved Subjects to 
Section 4.1 
 
Added ECG testing 
upon recommendation 
by Pepper Center 
DSMB review of 
protocol 
 
Added “adherence logs” 
 
 
Added Co-PI (MD) to 
pharmacy information 
since PhD PI cannot 
prescribe 
 
Added Section 6.1.1. to 
show consent process 
details and 
reassessment at each 
visit 
 
Changed to correct 
phone number 
 
Added Co-PI(MD) to 
medical monitoring 
since PI is PhD 
 
Added information 
about IDEAS for 
identifiers 
 
Added Co-PI 
responsibility for data 
safety and monitoring 
 
Grammatical and 
formatting edits to 
clarify and polish 
 
 
1.2.1 
Section 3.3.a) 
 
Potential risks – 
paragraph on D+Q, 
Page 11 
 
Revised paragraph to 
include reference to 
JJustice article on the 
D+Q pilot, consistent 
with consent form 
 
08-30-19 
1.3 
Section 3.3, Drug 
 
 
 
Section 3.3, LP 
Risks related to 
Quercetin 
 
 
Risks related to 
Modified per IRB 
request in response to 
stipulations  
 
Added optional use of 


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Lumbar Puncture 
 
fluoroscopy and 
radiation exposure 
11-27-19 
1.4 
Cover 
page, 
versioning 
 
Inclusion/Exclusion 
Criteria 
 
Visits/Procedures 
 
Summary 
of 
Protocol Changes, 
version 1.4 herein 
 
 
 
Add 
uric 
acid 
and 
phosphorus to Safety 
Labs at visits 3,5,7,8 
Change 
PT/PTT/INR 
labs to visit 7 (rather 
than 8) 
Remove Clinical Global 
Impressions of Change 
scale – add general 
statement that not all 
tests (visits 2 and 10) 
may 
be 
given 
depending on research 
discretion  
Change 
inclusion 
criteria: Moca 10-20, 
CDR global of 1, CDR 
memory domain >1 
Exclusion 
criteria: 
remove TRGs, add two 
BP readings, add CT or 
MRI, specify values for 
abnormal 
hepatic 
or 
biliary abnormalities  
Make visits 1 and 9 (LP 
visits) fasting 
Move the final ECG 
from visit 9 to visit 10 
Remove 
SPPB 
and 
TUG (visits 2 and 10)  
Add 
metabolomics 
analyzed by Dr. Sharma 
Add urine to be frozen 
for research  
 
01-14-2020 
1.5 
Cover page 
 
 
Study 
Design, 
Aims 
 
Exclusion 
criteria 
and 
Concomitant 
Meds prohibited 
 
Change 
fluoroscopy at Visit 
1 and 9 to be the 
default 
 
Throughout 
document 
IND# 143495 
NCT# pending 
 
SPPB in Aims 
 
 
 
 
 
 
Section 3.3.d. 
Risk of LP, 
fluoroscopy "if 
indicated" 
 
Administrative 
errors 
IND# 
143945 
NCT#04063124 
 
Remove SPPB, TUG, 
from Aims 
 
Added systemic steroid 
use as exclusionary 6 
months prior and during 
study 
 
The lumbar punctures 
will be performed under 
fluoroscropy (default). 
 
 
Remove extra spaces, 
commas 
06-05-2020 
1.6 
Cover page 
 
Versioning 
 
Versioning updated 
 


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Sect 6, Study Visits 
& Procedures 
 
Visit 
2 
and 
9, 
Lumbar Puncture 
Exclusion criteria 
 
 
Visit 4 
 
 
Required 
update 
 
Updated 
 
 
 
Fluoroscopy as 
default 
Added Barshop Inst. as 
clinical site 
 
 
Added 
special 
considerations related 
to COVID-19 
 
Fluoroscopy 
only 
if 
clinically indicated 
Exclude 
if 
taking 
hydroxychloroquine or 
chloroquine 
 
 
Add non-fasting CBC 
08-03-2020 
1.7 
Section 6, ,Study 
Visits 
& 
Procedures 
Updates 
Added 
update 
for 
COVID testing 
09-15-20 
1.8 
Throughout 
document 
Study site 
update 
Removed 
FORU, 
MARC and BICRC as 
study sites. 
11-19-20 
1.9 
Inclusion Criteria 
MoCA score 
10-20 
Expanded MoCA score 
to 7-23  
1-15-2021 
2.0 
Concomitant 
Therapy 
COVID 19 
Vaccination 
Added 
dosing 
guidelines for patient 
who 
may 
undergo 
COVID-19 vaccination.  
1-26-2021 
2.1 
COVID 
19 
Considerations  
COVID testing  
Added that the initial 
COVID 19 test could be 
waived if participants 
have been vaccinated 
at least one week prior 
to first dosing.   
8-12-2021 
2.2 
Add 5.18 Follow 
Up Visit Conducted 
at least 3 months 
after the date of 
Visit 10 
Final Follow up 
data 
Added to look at longer 
term 
outcomes 
in 
patients who completed 
the study at least 3 
months prior.  Verbal 
consent will be obtained 
for either a fasting in-
person 
visit 
or 
to 
complete assessments 
over the phone without 
the 
additional 
blood 
draw.