Clinical trial NCT04200911
Conditions: Cognitive Impairment, Mild Alzheimer Disease
Sponsor: The University of Texas Health Science Center at San Antonio
Start date: 2020-06-01; Completion date: 2022-01-13
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Evaluation of central nervous system penetration of orally administered Rapamune (RAPA) in older adults with Mild Cognitive Impairment (MCI) or early Alzheimer's disease (AD) and investigate associated safety, tolerability, target engagement, cognition, and functional status as initial proof-of-concept study

Detailed description:
This study is an open-label pilot study of orally administered RAPA to measure its target engagement in Cerebrospinal Fluid (CSF) and blood, and to establish the feasibility and safety of RAPA treatment in older adults with MCI and early stage AD as initial proof-of-concept for a larger Phase 2 clinical trial.

Arms: arm 1: Sirolimus 1mg orally once a day for 8 weeks
Interventions: intervention 1: Rapamune
Intervention descriptions: intervention 1: Sirolimus 1mg capsules

Protocol documents:
Prot_SAP_000.pdf: 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
Revised version:2-05-2021 v1.7.4 
CONFIDENTIAL 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS 
PLAN 
 
 
 
 
 
Official Study Title: Cognition, Age, and RaPamycin Effectiveness –              
DownregulatIon of thE mTor pathway  (CARPE DIEM)  
 
 
NCT number: NCT04200911 
 
IRB Approval Date: 06.18.2021 
 
Unique Protocol ID: HSC20190850H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CLINICAL RESEARCH PROTOCOL 
 
IRB#: HSC20190850H  
 
 
 
Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor pathway 
 (CARPE DIEM)  
 
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, San Antonio, TX 78229 
     210-567-8229 
 
  
 
      
Co-PI: 
Dean Kellogg, MD, PhD 
UT Health San Antonio 
Professor of Medicine  
 7703 Floyd Curl Drive, Mail Code 7755 
San Antonio, TX 78229-3900 
210-617-5197 
 
Funding Sponsor: 
Institutional Grant from the Institute for Integration of Medicine and 
Science/Clinical and Translational Science Award (IIMS/CTSA) 
 
Study Product: 
Sirolimus (Rapamune®, Greenstone LLC) 
Protocol #:   
HSC20190850H 
IND Number:  
Exempt 
NCT#: 
 
NCT04200911 
 
 
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 ................................................................................................................. 4 
3. 
STUDY DESIGN ......................................................................................................................... 4 
3.2. 
GENERAL DESIGN .................................................................................................................. 5 
3.3. 
STUDY ENDPOINTS ................................................................................................................ 5 
3.4. 
POTENTIAL RISKS TO SUBJECT SAFETY ................................................................................. 6 
4. 
SUBJECT SELECTION AND WITHDRAWAL .................................................................... 8 
4.1. 
INCLUSION CRITERIA ............................................................................................................. 8 
4.2. 
EXCLUSION CRITERIA ............................................................................................................ 8 
4.3. 
SUBJECT RECRUITMENT AND RETENTION.............................................................................. 9 
4.4. 
EARLY WITHDRAWAL OF SUBJECTS ...................................................................................... 9 
4.4.1. 
When and How to Withdraw Subjects ........................................................................... 9 
4.4.2. 
Data Collection and Follow-up for Withdrawn Subjects ........................................... 10 
5. 
STUDY DRUG .......................................................................................................................... 10 
5.1. 
DESCRIPTION ....................................................................................................................... 10 
5.2. 
TREATMENT REGIMEN ......................................................................................................... 10 
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 .............................................................................. 11 
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 ................................................................................... 12 
6.1. 
VISIT  1 - CONSENT AND SCREENING VISIT ......................................................................... 13 
6.2. 
VISIT 2 – BASELINE MEASUREMENTS PART I. ..................................................................... 13 
6.3. 
VISIT 3 – BASELINE MEASUREMENTS PART II ..................................................................... 15 
6.4. 
VISIT 4 – DRUG ADMINISTRATION & MONINTORING .......................................................... 15 
6.5. 
VISIT 5– DRUG ADMINISTRATION & MONINTORING ........................................................... 16 
6.6. 
VISIT 6 – DRUG ADMINISTRATION & MONINTORING .... ERROR! BOOKMARK NOT DEFINED. 
6.7. 
VISIT 7 – LUMBAR PUNCTURE, BLOOD DRAW, & MONITORINGERROR! BOOKMARK 
NOT 
DEFINED. 
6.8. 
VISIT 8 – END OF STUDY MEASURES AND DISENROLLMENT ............................................... 17 
6.9. 
SUMMARY VISIT SCHEDULE TABLE .............................. ERROR! BOOKMARK NOT DEFINED. 
7. 
STATISTICAL PLAN .............................................................................................................. 20 


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7.1. 
SAMPLE SIZE DETERMINATION............................................................................................ 20 
7.2. 
STATISTICAL METHODS ....................................................................................................... 20 
8. 
SAFETY AND ADVERSE EVENTS ...................................................................................... 20 
8.1. 
DEFINITIONS ........................................................................................................................ 20 
8.3. 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .................... 22 
8.3.1. 
Investigator responsibilities - The PI is responsible for: ............................................ 23 
8.4. 
REPORTING PROCESS ........................................................................................................... 23 
8.5. 
MEDICAL MONITORING ....................................................................................................... 24 
8.5.1. 
Investigator reporting of Protocol Deviations/Violations .......................................... 24 
8.5.2. 
Definitions of Protocol Deviations/Violations ............................................................ 24 
8.6. 
STOPPING RULES ................................................................................................................. 24 
9. 
DATA HANDLING AND RECORD KEEPING ................................................................... 25 
9.1. 
CONFIDENTIALITY ............................................................................................................... 25 
9.2. 
SOURCE DOCUMENTS .......................................................................................................... 25 
9.2.1. 
Research Electronic Data Capture (REDCap)  
9.2.2. 
Paper source data ....................................................................................................... 25 
9.2.3. 
Handwritten entries .................................................................................................... 26 
9.3. 
DATA MANAGEMENT .......................................................................................................... 26 
9.4. 
RECORDS RETENTION .......................................................................................................... 26 
10. 
STUDY MONITORING, AUDITING, AND INSPECTING ........................................... 26 
10.1. 
DATA AND SAFETY MONITORING PLAN (DSMP) ................................................................ 26 
10.2. 
AUDITING AND INSPECTING ................................................................................................. 27 
11. 
ETHICAL CONSIDERATIONS ......................................................................................... 27 
12. 
STUDY FINANCES.............................................................................................................. 27 
12.1. 
FUNDING SOURCE................................................................................................................ 27 
12.2. 
CONFLICT OF INTEREST ....................................................................................................... 27 
12.3. 
SUBJECT STIPENDS OR PAYMENTS ....................................................................................... 27 
13. 
PUBLICATION PLAN ........................................................................................................ 28 
14. 
REFERENCES ...................................................................................................................... 28 
 
 
 


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List of Abbreviations 
 
AD – Alzheimer’s disease 
MCI – Mild Cognitive Impairment  
CSF – Cerebrospinal Fluid 
RAPA – Sirolimus (Rapamune®) 
S6K1-P - Ribosomal protein S6 Kinase Beta-1 
HPLC/MS/MS – High Performance Liquid Chromatography-Mass Spectrometry 
MMSE– Mini Mental State Examination (MMSE) 
MoCA - Montreal Cognitive Assessment  
CDR – Clinical Dementia Rating 
MINT - Multilingual Naming Test  
HVLT-R – Hopkins Verbal Learning Test-Revised 
CVLT-III – California Verbal Learning Test III   
NPI – Neuropsychiatric Inventory  
FAQ – Functional Activities Questionnaire  
GDS – Geriatric Depression Scale 
 
 
 


CARPE-DIEM 
 
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CONFIDENTIAL 
       Study Summary 
Title 
Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
pathway (CARPE DIEM)  
 
Protocol 
Number 
20190850H 
Phase 
2 
Methodology 
Open label  
Study Duration 
Between 12-18 weeks  
Study Center(s) 
UTHSA McDermott (Biggs, RII) 
Objective 
To evaluate central nervous system penetration of orally administered RAPA in older 
adults with Mild Cognitive Impairment (MCI) or early Alzheimer’s disease (AD) and 
investigate associated safety, tolerability, target engagement, cognition, and functional 
status as initial proof-of-concept for a larger phase 2 clinical trial 
Number of 
Subjects 
Screen up to 60 with intent for 10 completers. Additional subjects may be enrolled if 
attrition exceeds the anticipated rate (~25%). 
Inclusion 
Criteria 
1) Both genders and all ethnic groups 
2) Ages 55 to 85 years 
3) Diagnosis of MCI or AD  with a Clinical Dementia Rating Scale (CDR) score = 0.5 – 
1;  
4) Labs: Normal blood cell counts without clinically significant excursions; normal liver 
and renal function; and glucose control (HbA1c < 6.5%). Lipid panel and 
PT/PTT/INR within normal limits 
5) A Legally Authorized Representative (LAR) designated to sign informed consent (if 
necessary) for Visit 1 
6)  An available LAR or other study partner for reported outcomes must accompany 
participants to all study visits. 
7) Participants must have no travel plans over the three to four months following 
enrollment that would interfere with scheduling visits following consent  
8) Stable dose of AD medications (Donepezil, rivastigmine, Memantine, galantamine) 
for at least three months prior to baseline (visit 2) is allowed 
 


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Exclusion 
Criteria 
1) Diabetes (HBA1c≥6.5% or antidiabetic medications) 
2) History of skin ulcers or poor wound healing 
3) Current tobacco or illicit drug use or alcohol abuse 
4) Use of anti-platelet or anti-coagulant medications other than aspirin 
5) Current medications that affect cytochrome P450 3A4 (see section 4.3); current or 
recent medications for hypertriglyceridemia (eg, Gemfibrozil) 
6) Hypersensitivity or history of allergy to Rapamycin 
7) Immunosuppressant therapy within the last year; 
current 
treatment 
with 
hydroxychloroquine and chloroquine (requires "washout period" of 14 days) 
8) Chemotherapy or radiation treatment within the last year 
9) Current or chronic history of liver disease or known hepatic or biliary abnormalities 
10) History of primary hypertriglyceridemia. Abnormal triglycerides >200 or LDL 
cholesterol >193, or other abnormal labs deemed clinically significant upon 
investigator review 
11) Current or chronic history of pulmonary disease or abnormal pulse oximetry (<90%) 
12) Chronic heart failure 
13) Pregnancy 
14) Recent history (past six months) of myocardial infarction, active coronary artery 
disease, intestinal disorders, stroke, or transient ischemic attack 
15) Significant neurological conditions other than AD 
16) Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHG - two 
readings) 
17) Active inflammatory, COVID-19, autoimmune, infectious, hepatic, gastrointestinal, 
malignant, and/or psychiatric disease 
18) History of, or MRI, or CT positive for, any space occupying lesion, including mass 
effect or abnormal intracranial pressure, which would indicate contraindications to 
lumbar puncture 
19) Organ transplant recipients 
 
Study Product, 
Dose, Route, 
Regimen 
RAPA (Sirolimus, Rapamune®) will be administered orally as (1) 1mg capsule daily 
Duration of 
administration 
RAPA will be administered once daily for 8 consecutive weeks. 
Statistical 
Methodology 
Similar to an early phase 2 trial, we are seeking preliminary evidence of the degree of 
central nervous system penetration of orally administered RAPA in older adults with 
MCI and early AD and investigate associated safety, tolerability, target engagement, 
cognition, and functional status as initial proof-of-concept for a larger phase 2 clinical 
trial. 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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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 mechanistic (formerly mammalian) target of rapamycin (mTOR) signaling pathway is crucial for cell 
metabolism and its dysregulation contributes to age-related chronic medical conditions. RAPA (rapamycin, 
sirolimus), an FDA-approved immunosuppressant, effectively inhibits the mTOR pathway and thus manifests a 
wide variety of effects. In preclinical trials, orally administered RAPA extends longevity and mitigates the 
development of chronic diseases1,2. Moreover, growing research suggests that RAPA can alter the cellular and 
biological processes underlying the development of Alzheimer’s disease (AD), including abnormal protein 
accumulation, diminished autophagy, and attenuated cerebral blood flow3-6. Specifically, the mTOR pathway 
exerts a strong influence on amyloid beta (aβ) and tau deposition consistent with upregulated mTOR signaling 
as observed in postmortem brain tissue from individuals with AD7. In multiple mouse models, orally 
administered RAPA dampens mTOR signaling, reduces cerebral aβ levels by approximately 40-50%, and 
diminishes tau aggregation5,6, remediating cognitive deficits4. Suppression of the mTOR gene similarly 
diminishes aβ deposition8, directly implicating mTOR inhibition as the mechanism mediating RAPA’s effect on 
neuropathological protein accumulation. In addition to exerting direct influence on aβ and tau accumulation, 
mTOR activity has been shown to accelerate abnormal protein accumulation by suppressing autophagy5,6. In 
contrast, RAPA-treated mice with pharmacologically increased autophagy demonstrate a three-fold increase in 
lysosomal aβ levels9, implicating the drug’s ability to upregulate autophagy in neuropathological protein 
clearance.  
RAPA has also been shown to restore cerebrovascular function4, which evidences early alterations in AD 
including chronic reductions in cerebral perfusion10, impaired endothelium-dependent vasodilation11, and 
increased blood-brain barrier permeability12. RAPA increases nitric oxide production through the 
phosphorylation of endothelial nitric oxide synthase, inducing cortical vasodilation4. In mice, RAPA treatment 
restored cerebral blood flow levels and increased cerebral blood vessel density4. These changes were coupled 
with diminished aβ deposition in the blood vessels, reduced aβ plaques, and lower incidence of cerebral 
microbleeds4. Finally, RAPA dramatically dampened microglial activation,3 a hallmark pathological feature of 
AD13. Activated microglial cells release pro-inflammatory cytokines and reactive oxygen species14, inducing 
neuronal damage. In transgenic AD mouse models, RAPA diminished microglial activation, subsequently 
reducing interleukin 1-β, enhancing N-methyl-D-aspartate (NDMA) activity, and facilitating memory3.  
1.2. 
Innovation 
Treatment with RAPA to measure the concentration of the drug that reaches the cerebrospinal fluid and crosses 
the blood-brain barrier is a novel approach to help identify targeted therapy for MCI and Alzheimer’s disease. 
1.3. 
Preliminary data 
While human clinical trials of RAPA in AD have not yet been conducted, trials for other conditions have 
provided preliminary support for the cognitive benefits of RAPA treatment. In a sample of heart transplant 
recipients, four-week RAPA treatment (everolimus) improved performance on measures of memory, attention, 
and executive function, as well as enhanced mood15. To evaluate safety and tolerability in older adults, we 
recently conducted a randomized, placebo-controlled trial of eight-week RAPA treatment (1 mg/day) in 
individuals ages 70-95 years old16. No serious adverse events occurred. The reported adverse events were 
limited to facial rash (N=1), stomatitis (N=2, 1 placebo and 1 RAPA treated), and gastrointestinal distress 


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(N=2). Statistically, but not clinically significant, decrements were observed in multiple erythrocyte parameters 
(i.e. hemoglobin, hematocrit, red blood cell count).  
 
 
PLACEBO (n=14) 
RAPA (n=11) 
Group Difference 
 
Pre 
Post 
P 
value 
Difference 
(95% CI) 
Pre 
Post 
P 
value 
Difference 
(95% CI) 
P value 
Differenc
e (95% 
CI) 
HgB 
13.81±
1.53 
13.98±
1.63 
0.33 
0.16 [-0.19, 
0.51] 
13.94 ± 
1.35 
13.12 ± 
1.22 
0.003 -0.82 [-1.29, 
-0.35] 
0.001 
0.98 
[0.43, 
1.54] 
HCT 
41.29 ± 
4.13 
41.96 ± 
4.54 
0.21 
0.67 [-0.42, 
1.76] 
41.57 ± 
3.79 
39.24 ± 
3.75 
0.002 -2.34 [-3.57, 
-1.1] 
<0.001 
3.01 
[1.45, 
4.56] 
HgB=hemoglobin 
HCT=hematocrit 
16 Ellen Kraig, et al. Table 4 
Measures of cognition and physical functioning were unchanged, although several informants reported 
anecdotal observations of improved cognition. A subset of individuals underwent assessment of cutaneous 
vasodilation, a measure of nitric oxide-dependent endothelial function, and displayed a strong trend towards 
post-treatment improvement (p=0.052). In light of the compelling preclinical data demonstrating that RAPA 
restores cognition in AD by exerting influence on multiple pathophysiological pathways4-6,9, coupled with data 
on safety and possible cognitive benefits derived from human trials, we are now well-positioned to conduct the 
first clinical trial of RAPA in individuals with symptomatic MCI and AD.  
1.4. 
Dose Rationale and Risk/Benefits 
Eligible participants will be treated with 1 mg of RAPA daily for 8 consecutive weeks. The most common 
adverse events include mucositis, stomatitis, diarrhea, nausea, and acneiform rash. Pneumonitis, the most 
serious potential adverse event, occurs in <1-5% of cases, typically after prolonged drug exposure (>six 
months). In our recent clinical trial of elderly adults receiving 1mg RAPA daily, the same dosage to be used in 
this proposal, no serious adverse events occurred16. The reported adverse events were limited to facial rash 
(N=1), stomatitis (N=1; 1 on placebo and 1 on RAPA), and gastrointestinal distress (N=2).  
 
The study will consist of a screening/baseline period of up to 30 days pre-study drug, with a 56-day (+3 day) 
treatment period, and a post-intervention visit for study outcomes on final day of dosing and up to +14 days. 
The study duration is not expected to exceed 18 weeks for participants. 
2. Study Objective 
The objective of the study is to assess the degree of central nervous system penetration of orally administered 
RAPA treatment using collecting cerebral spinal fluid (CSF), and begin collecting initial data on safety, 
tolerability, target engagement, AD-related markers, and AD-relevant outcomes for future trials. 
3. Study Design 
 


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3.1. 
General Design 
This study is an open-label pilot study of orally administered RAPA to measure its target engagement in CSF 
and blood, and to establish the feasibility and safety of RAPA treatment in older adults with MCI and early 
stage AD as initial proof-of-concept for a larger Phase 2 clinical trial. 
Aim 1: To assess the degree of central nervous system penetration and drug clearance with 8-week RAPA 
treatment. Lumbar punctures will be performed before treatment and after the final RAPA dose 8 weeks later 
to assess CSF levels of the drug. Quantification will be completed with HPLC/MS/MS chromatography.  
Aim 2: To assess the safety and tolerability of 8-week RAPA treatment in older adults with MCI and AD. 
At three timepoints across the 8-week intervention, safety evaluations will be conducted including monitoring 
for adverse events, study compliance, vital signs, and laboratory assessment (CBC, comprehensive metabolic 
panel (CMP) 
Aim 3: To investigate target engagement of RAPA treatment for AD pathology. We will evaluate levels of 
relevant AD biomarkers (e.g., total tau, phosphorylated tau, Aβ40 and Aβ42, neurofilament light, and glial 
fibrillary acidic protein), inflammatory (e.g., IL-6, PAI-1, soluble ICAM-1) and other relevant analytes in the 
CSF and/or blood at time points prior to RAPA treatment and after 8 weeks on the drug.  
Aim 4: To evaluate changes from baseline in cognition, functional status, and physical functioning after 8 
weeks of RAPA treatment. Pre- and post-treatment changes in cognition, disease severity, functional status, 
mood, and physical functioning will be assessed using a battery of tests appropriate for use with AD 
populations.  
3.2. 
Study Endpoints  
a) Primary outcome: To determine blood brain barrier penetrance of RAPA in older adults with mild 
cognitive impairment or early symptomatic Alzheimer’s disease. Lumbar punctures will be performed 
at baseline and after the final RAPA dose, to assess CSF levels of the drug. Quantification will be 
completed with HPLC/MS/MS chromatography.   
Secondary outcomes:   
b) To assess the safety and tolerability of 8-week RAPA treatment in older adults with AD. At three 
timepoints across the 8-week intervention, safety evaluations will be conducted including monitoring for 
adverse events, study compliance, vital signs, and laboratory assessment (CBC, comprehensive metabolic 
panel (CMP), blood RAPA levels). 
c) To investigate target engagement of RAPA treatment in AD. We will evaluate levels of relevant AD 
biomarkers (e.g., total tau, phosphorylated tau, Aβ40 and Aβ42, neurofilament light, and glial fibrillary 
acidic protein), inflammatory (e.g., IL-6, PAI-1, soluble ICAM-1) and other relevant analytes in the CSF 
and/or blood at time points prior to RAPA treatment and after 8 weeks on the drug. 
d) To evaluate changes from baseline in cognition, functional status, and physical functioning after 8 
weeks of RAPA treatment Pre-intervention to post-intervention change in cognitive tests (MoCA, 
HVLT-R, Craft Stories, Benson Figure Copy and Delayed Recall, Trail Making Test Parts A&B, 
Number Span Test, Semantic Fluency, Phonemic Fluency, MINT, Hayling), physical functioning 
assessment (electronic gait mapping under single and dual-task conditions, grip strength), and 
questionnaires/semi-structured interviews (CDR, GDS, NPI, FAQ,). 


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3.3. 
Potential Risks to Subject Safety 
a) Drug Administration. 
RAPA and its functional homologs (i.e. everolimus (Afinitor, Novartis)) are FDA-approved drugs with well-
established pharmacology and safety profiles17. Clinical trials are ongoing for several neurological conditions 
including amyotrophic lateral sclerosis18, recurrent glioblastoma19, and tuberous sclerosis complex20.  The most 
common adverse events include mucositis, stomatitis, diarrhea, nausea, and acneiform rash. Pneumonitis, the 
most serious potential adverse event, occurs in <1-5% of cases, typically after prolonged drug exposure (>six 
months), and blood levels ≥ 10ng/ml. Many side effects are alleviated with lower dosing and shorter durations 
of exposure. In our recent clinical trial of elderly adults receiving 1mg RAPA daily, the same dosage to be used 
in this proposal, no serious adverse events occurred16. The reported adverse events were limited to facial rash 
(N=1), stomatitis (N=1; 1 on placebo and 1 on RAPA), and gastrointestinal distress (N=2).  
Rapamycin and rapalogs "exhibit little or minimal nephrotoxicity" (Ma, 2018). In rare cases involving 
transplant patients changed from calcinuria inhibitors to rapamycin, decreased creatinine clearance and 
increased proteinuria have been reported. We will monitor creatinine clearance and proteinuria by safety labs 
including urinalysis. 
For more detail, please refer to the package insert included in this submission, Full Prescribing Information, 
including: 
• Most common adverse reactions (≥15%)  
o Mucositis and stomatitis (inflammation of the mouth and tongue) 
o Mouth scores 
o Acne like rash 
o Hyperlipidemia (increased triglycerides and fat in the blood) 
o Increased blood sugar 
o Peripheral edema (swelling in the arms, legs, hands, feet) 
o Hypertension (high blood pressure) 
o Constipation 
o Diarrhea  
o Headache 
o Fever 
o Anemia (low red blood cell count or hemoglobin) 
o Nausea  
o Arthralgias (pain in the joints) 
o Pain 
• Drug Interactions: 
o Strong CYP3A4 and/or P-gp Inhibitors: Avoid co-administration.  
 Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, 
protease inhibitors (e.g. HIV and hepatitis C that include drugs such as ritonavir, 
indinavir, boceprevir, and telaprevir), metoclopramide, nicardipine, verapamil 
o Strong CYP3A4 Inducers: Avoid co-administration 


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 Carbamazepine, phenobarbital, phenytoin, rifapentine, St. John’s Wort (Hypericum 
perforatum) 
o Live vaccinations: Avoid co-administration 
 
b) 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 
 
This study may include genetic testing. Genetic information is unique to each individual and could potentially 
be used to discover possible changes in a person’s future health status or life expectancy, or that of his/her 
children and family members. Even though the results of genetic testing cannot be linked to an individual, it is 
possible that people of specific ethnic backgrounds may be found to be at more risk for certain diseases based 
on future genetic research and this information might harm the individual in the future as a member of the 
group.   
 
c) Cognitive Assessment and Semi-structured Interviews/Questionnaires 
 
• Psychosocial - embarrassment, discomfort or anxiety upon testing memory and thinking 
• Patient or Study Partner-Reported Outcomes include questionnaires related to AD symptoms, cognition, 
sleep, and mood scales.  
 
d) Lumbar Puncture. (To minimize these risks, a qualified provider specifically trained in the procedure 
will perform the lumbar puncture.) 
 
• 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. 
 
If clinically indicated due to obesity, arthritis, scoliosis or any other condition that makes it difficult to identify 
the correct insertion point on the lumbar spine, the lumbar puncture will be completed with fluoroscopy. 
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 
50% of the average 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 


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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 timed short distance walking 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 
 
Subject Selection and Withdrawal 
4.1. 
Subjects 
Up to 60 potential candidates will be pre-screened to identify eligible men and women, ages 55 to 85 years old, 
with a clinical diagnosis of MCI or early AD.  Additional subjects may be enrolled if attrition exceeds the 
anticipated rate (~25%). 
4.2. 
Inclusion Criteria 
1) Both genders and all ethnic groups 
2) Age 55 to 85 years old 
3) Diagnosis of MCI or AD with a  Clinical Dementia Rating Scale score (CDR) = 0.5 – 1;   
4) Labs: Normal blood cell counts without clinically significant excursions (WBCs: 3500-10,500 cells/ uL; 
absolute neutrophil count: 1,800-8,700 cells/ uL; platelets: 140-450 K/uL; hemoglobin 11.0-17.5 grams/dL); 
liver and renal function (AST 10-40 IU/L, total bilirubin 0.1-1.4 mg/dl, creatinine clearance within normal 
limits);  and glucose control (HbA1c < 6.5%). Lipid panel and PT/PTT/INR within normal limits 
5) A Legally Authorized Representative (LAR) designated to sign informed consent (if necessary) must 
provide accompaniment at Visit 1 
6) An available LAR or other study partner for reported outcomes must accompany participants to all 
study visits. 
7) Participants must have no travel plans over the three to four months following enrollment that would 
interfere with scheduling visits following consent 
8) Stable dose of AD medications (Donepezil, rivastigmine, Memantine, galantamine) for at least three 
months prior to baseline (visit 2) is allowed 
4.3. 
    Exclusion Criteria 
Subjects will be excluded if they exhibit: 
1) Diabetes (hbA1c>6.5% or antidiabetic medications) 
2) History of skin ulcers or poor wound healing 
3) Current tobacco or illicit drug use or alcohol abuse  
4) Use of anti-platelet or anti-coagulant medications other than aspirin 
5) Current medications that affect cytochrome P450 3A4); current or recent medications for 
hypertriglyceridemia (eg, Gemfibrozil)  
6) Hypersensitivity or history of allergy to Rapamycin 


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7) Immunosuppressant therapy within the last year; current treatment with hydroxychloroquine or 
chloroquine (requires "washout period" of 2 weeks) 
8) Chemotherapy or radiation treatment within the last year 
9) Current or chronic history of liver disease or known hepatic or biliary abnormalities 
10) History of primary hypertriglyceridemia. Abnormal triglycerides >200 or LDL cholesterol >193, or other 
abnormal labs deemed clinically significant upon investigator  
11) Current or chronic history of pulmonary disease or abnormal pulse oximetry (<90%) 
12) Chronic heart failure 
13) Pregnancy 
14) Recent history (past six months) of myocardial infarction, active coronary artery disease, intestinal 
disorders, stroke, or transient ischemic attack 
15) Significant neurological conditions other than AD. 
16) Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg with two readings) 
17) Active inflammatory, COVID-19, autoimmune, infectious, hepatic, gastrointestinal, malignant, and/or 
psychiatric disease 
18) History of, or MRI or CT positive for, any space occupying lesion, including mass effect and/or abnormal 
intracranial pressure, which would indicate contraindication to lumbar puncture. 
19) Organ transplant Recipients  
4.4. 
Subject Recruitment and Retention 
Participants with MCI and early AD will be enrolled from UT Health San Antonio, local clinics, and the 
community. 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. 
 
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 


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Investigator, co-Principal Investigator, or other trained study staff 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.  
 
Investigators 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.  
 
Investigators and/or 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. 
4. Study Drug  
The study drug is the FDA approved formulation of Rapamune® 1mg oral tablets. 
5.1. 
Description  
Rapamune® (sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by 
Streptomyces hygroscopicus. Its molecular formula is C51H79NO13 and its molecular weight is 914.2.  
Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, 
chloroform, acetone, and acetonitrile. The inactive ingredients in Rapamune® Tablets include sucrose, lactose, 
polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium 
dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, 
carnauba wax, dl-alpha tocopherol, and other ingredients.  
Mechanism of Action 
Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine 
(Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other 
immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, 
FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 
complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the 
mechanistic Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven 
T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.  
Detailed information is supplied on the Rapamune® package insert. 
 
5.2. 
Treatment Regimen 
Administration Protocol.  
Study subjects will come to the clinic on the first day of study drug administration (Visit 4) and will receive enough 
study medications for consecutive daily administration (+two extra pills) until the next scheduled clinic visit (Visit 5). 
At Visit 5, subjects will receive enough study medications for consecutive daily administration (+two extra pills) until 


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the next scheduled clinic visit (Visit 6). At Visit 6, subjects will receive enough study medications for consecutive daily 
administration (+two extra pills) until the next scheduled clinic visit (Visit 7). 
Assigning Subjects 
In this open label early phase 2 study, all subjects receive the same treatment dose of 1mg of RAPA once a day.  
 
5.3. 
Preparation and Administration of Study Drug 
RAPA will be dispensed through the Biggs Institute at 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. At study Visits 4, 5, and 6, study subjects will receive enough study medications for consecutive 
daily administration (+two extra pills) until their next scheduled clinic visit. 
5.4. 
Subject Compliance Monitoring 
Participants and/or their study partner will be encouraged to bring pill bottles and adherence logs to each visit 
for review by the study team. The study coordinator will complete medication reconciliation at each visit. 
5.5. 
Prior and Concomitant Therapy 
COVID-19 Vaccinations:  
In the event study participants are given the opportunity to receive a vaccination (injection) for COVID-19 
prophylaxis (either Tozinameran® or mRNA-1273®), they will be instructed to cease therapy with the IP 
(RAPA/Placebo) for a period of four days prior to each injection of the vaccine and three days afterwards. 
Subjects will be asked to notify study staff of their plans to be vaccinated so they can be re-educated on this 
requirement.    
 
5.5. 
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 immunosuppressive therapy (e.g. active infection).  
Any subject who experiences a treatment interruption due to COVID-19 vaccination may have their time in the 
double blind portion of the study extended by the investigators depending on the number of days the IP was not 
taken.   
 
Exclusionary medications:  
• Anti-platelet or anti-coagulant medications other than aspirin are exclusionary.  
• Medications that affect cytochrome P450 3A4  
• Additionally, immunotherapy, chemotherapy, and/or radiation therapy within one year of study 
enrollment.   
• Current treatment with hydroxychloroquine or chloroquine (requires "washout period" of 2 weeks) 
5.6. 
Packaging and Product Inventory  
 
Nature and Contents of the Container 
Drugs for individual subject use will be clearly labeled and identified as “Caution: New Drug –Limited by Federal 
(or United States) law to investigational use” per 21CFR312.6.  
 
Designated staff at the Biggs Institute will: 


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• Inventory receipt of initial shipment and ensure appropriate temperature control 
• Distribute RAPA by labeling each individual subject packet(s) with Subject ID from list provided by PI 
or Co-PI to pharmacy 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 designated staff and 
investigators at the Biggs Institute .  They will notify the Principal Investigator and the Material Supplier of any 
damaged study drug. 
 
Special instructions upon receipt 
Designated staff at the Biggs Institute 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 
Rapamune® Tablets should be stored at 20° to 25°C (USP Controlled Room Temperature) (68° to 77°F). Use 
cartons to protect blister cards and strips from light. Dispense in a tight, light-resistant container.  
5.6.3. Dispensing of Study Drug 
Designated staff from the Biggs Institute maintain 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 RAPA 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. Since Rapamune is not absorbed through the skin, there 
are no special precautions for destruction. However, if direct contact with the skin or mucous membranes 
occurs, wash thoroughly with soap and water; rinse eyes with plain water.  
5. 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.  
3)  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 


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with study physician approval.  Phone pre-screening(s) and temperature checks will be done on all participants 
regardless of vaccination status.  
 
4) 
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.  
 
6.1. 
Visit 1, Consent and Screening Visit 
6.1.1. Consent Process 
The participant is scheduled to come to the designated research area in a non-fasting state, 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 cognitive impairment. 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, 200721  and tailored to the study. 
In the event of questions regarding capacity, the research study 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.  
6.1.2. 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), 
medical history, concomitant medication review, non-fasting blood measures for safety, including: complete blood 
count (CBC), comprehensive metabolic panel (CMP), hemoglobin A1c (A1c), routine urinalysis, and coagulation 
panel (PT/PTT/INR). Screening cognitive assessments will include the MMSE, CDR, and CVLT-II.   
The screening visit is estimated to require 2.5 hours.   
After receiving all test results (including laboratory data), the study investigators will make a determination 
regarding eligibility.  
Investigators may repeat any labs found to be outside the normal ranges to confirm reliability of results and 
eligibility throughout the duration of the study. 
Investigators or research staff will call the study participant and/or LAR/study partner to inform of eligibility 
status and schedule Visit 2 (if applicable). For participants scheduled for Visit 2, research staff will call the 
study participant and/or LAR/study partner within one business day of Visit 2 to confirm the appointment and 
provide a reminder about fasting and complete COVID-19 symptom and exposure telephone assessment. 
6.2. 
Visit 2 – Baseline Measurements Part I (within 30 days after Visit 1).  
Within 4 weeks of the Screening visit, enrolled subjects will return to the research site in a fasting state (nothing 
to eat/drink, except water, for at least eight (8) hours before visit) for vital signs, concomitant medication review, 


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adverse event review, fasting safety (CMP, lipid panel) and research labs, and lumbar puncture to acquire CSF 
baseline measures of RAPA, as well as markers of AD (e.g. total tau, phosphorylated tau, Aβ40 and Aβ42, NFL, 
and GFAP),  pro-inflammatory markers (e.g. IL-6, PAI-1, soluble ICAM-1), and other relevant analytes. A snack 
will be offered immediately following the lumbar puncture.  
Research labs (blood and CSF) will also be banked for future analyses, including possible genetic analyses. Before 
all study procedures, researchers will assess study participants’ willingness to continue their study participation 
with direct inquiry to the study participant and LAR (if applicable). 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 Visit 
1 (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). 
 
Visit 2 is estimated to require up to 3 hours, including at least 30 minutes rest following the procedure. If 
indicated due to obesity, arthritis, scoliosis or any other condition that makes it difficult to identify the correct 
insertion point on the lumbar spine, the lumbar puncture will be completed with fluoroscopy. This procedure 
will occur in room RII 1.326 using a c-arm machine that has been inspected by the UT Radiation Safety Office. 
This room is shielded, and the procedure will be conducted by a board certified neuroradiologist who has 
received extensive training in the use of fluoroscopy for LPs. Refer to Standard Operating Procedures for more 
details about the lumbar puncture procedure. 
 
(i) Lumbar puncture (LP) to acquire CSF (up to 30m volume) 
• CSF: CSF will be separated into aliquots and frozen. See Analyses below. 
 
(ii) 
Blood draw 60mL volume for RAPA/S6k1-P levels, AD markers, proinflammatory and other relevant 
analytes.  
• Blood: Blood will be separated into aliquots for analysis by UTHealth Biggs Institute and Department of 
Cell Systems and Anatomy as follows: 
o 40ml volume of whole blood, separated into 8 vials 
o 2ml volume of whole blood, separated into three aliquots  
o Separated from 18 of whole blood, 8-12ml of serum (0.2-0.5ml aliquots) and 6-8ml of plasma (0.2-
.0.5ml aliquots) 
 
 
 
 
Analyses.  
 
CSF: 
  
CSF will be separated into aliquots and frozen. (i) Aliquots will be analyzed by the Pharmacology Core facility 
using HPLC/MS chromatography; (ii) ELISA or Simoa HD-1 Analyzer for AD and pro-inflammatory markers 
to be performed by UT Health (Biggs Institute and Department of Cell Systems and Anatomy). 
 
Blood:  
 
Blood, apportioned as described above, will separated into aliquots and frozen.  i) Aliquots will be analyzed by 
the Pharmacology Core facility using HPLC/MS chromatography; (ii) ELISA, Luminex-based assays, and/or 


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Simoa HD-1 Analyzer for AD and pro-inflammatory markers performed by UT Health (Biggs Institute and 
Department of Cell Systems and Anatomy). 
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 and complete COVID-19 symptom and 
exposure telephone assessment. 
6.3. 
Visit 3a – Baseline Measurements Part II (within 30 days of Visit 2) and Visit 3b - COVID-19 testing 
(within 72 hrs of Visit 4). 
 
Within 30 days of the Visit 2, enrolled subjects will be asked to return to the research unit with LAR for Visit 3a. 
Examination and activities during this visit include reassessment of willingness to participate in the study (as 
described under Visit 1), vital signs, concomitant medication, and adverse event review, with the following 
measures: 
 
(i) Cognitive examination (1.5 hours):  
• 
Montreal Cognitive Assessment (MoCA) 
• 
Hopkins Verbal Learning Test Revised (HVLT-R) 
• Craft Stories 
• Benson Figure Copy and Delayed Recall 
• Number Span Test 
• Trail Making Test Parts A&B 
• Phonemic Fluency 
• Semantic Fluency 
• 
Multilingual Naming Test (MINT) 
• 
Hayling 
 
(ii) Participant-Reported (GDS) and Informant-Reported (FAQ, NPI) 
 
(iii) Functional and physical performance measure (1 hour):  
• Electronic gait mapping under single and dual-task conditions 
• grip strength 
 
For added safety, approximately 1-2 business days before starting the drug intervention (Visit 4), participants 
will be asked to return for Visit 3b and 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. Visit 3b is estimated to require 30 minutes. 
 
Visit 3a is estimated to require 3 hours. Confirm scheduling of Visit 4. 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. The 
COVID-19 symptom and exposure telephone assessment may be completed either at Visit 3a or at time of Visit 
4 scheduling confirmation, within one-two business days of Visit 4. 
 
6.4. 
Visit 4 – Study Drug Dispensing & Monitoring (within 15 days of Visit 3) 
The participant and LAR/study partner will visit the research unit for drug dispensing and safety monitoring. 
Participant will arrive in a fasting state (nothing to eat/drink, except water, for at least eight (8) hours before 
visit), undergo reassessment of willingness to participate in the study (as described under Visit 2), vital signs, 


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weight, concomitant medication review, and: 
 
• Administration of the CDR (If Visit 1 was conducted more than 60 days prior to visit 4)  
• AE assessment 
• Blood draw (fasting) for safety labs: CBC, CMP, lipid panel, HbA1c, and urinalysis 
• Dispense study medication and schedule further follow up safety monitoring (Visits 5 - 8). 
Dispensing of enough study medications for consecutive daily administration (+2 extra pills) until the next scheduled 
clinic visit (Visit 5). 
Visit 4 is estimated to require 1.5 hours or less. Scheduling of Visit 5: to occur four weeks (± 2 days) after Visit 
4. 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 and complete COVID-19 symptom and exposure telephone assessment. 
 
6.5. 
Visit 5 – Study Drug Dispensing & Monitoring (4 weeks( + 2 days) of Visit 4) 
The participant and LAR/study partner return to the research unit for drug dispensing and safety monitoring. 
Participant will arrive fasting (nothing to eat/drink, except water, for at least eight (8) hours before visit), 
undergo reassessment of willingness to participate in the study (as described under Visit 2), vital signs, weight, 
concomitant medication review, and: 
 
• AE assessment 
• Compliance review 
• Blood draw (fasting) for safety labs: CBC, CMP, and lipid panel   
• Dispense study medication and confirm further follow up safety monitoring (Visit 6). 
Dispensing of enough study medications for consecutive daily administration (+two extra pills) until the next 
scheduled clinic visit (Visit 6). 
Visit 5 is estimated to require 1 hour or less. Scheduling of Visit 6: to occur three weeks (± 2 days) after Visit 5. 
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 and complete COVID-19 symptom and exposure telephone assessment. 
6.6. 
Visit 6 – Study Drug Accountability & Monitoring (3 weeks( + 2 days) of Visit 5) 
The participant and LAR/study partner return to the research unit for drug accountability and safety monitoring. 
Participant will arrive fasting (nothing to eat/drink, except water, for at least eight (8) hours before visit), 
undergo reassessment of willingness to participate in the study (as described under Visit 2), vital signs, weight, 
concomitant medication review, and: 
 
• AE assessment 
• Compliance review 
• Blood draw (fasting) for safety labs: CBC, CMP, lipid panel, urinalysis and coagulation panel 
(PT/PTT/INR)  
• Re-dispense study medication and confirm further follow up safety monitoring (Visit 7). 
Confirm participant has enough study medications for consecutive daily administration (+two extra pills) until the 
next scheduled clinic visit (Visit 7). 
 
Visit 6 is estimated to require 1 hour or less. Scheduling of Visit 7: to occur one week (± 2 days) after Visit 6. 
Within 24 hours of Visit 7, research staff will call the study participant and/or LAR/study partner to confirm the 


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appointment, complete COVID-19 symptom and exposure telephone assessment, and provide a reminder about 
fasting and provision of the final study medication dose in clinic. 
 
6.7. 
Visit 7 – Lumbar Puncture, Blood Draw, Final Drug Accountability & Monitoring (1 week ( + 2 
days) of Visit 6) 
 
The participant will be asked to arrive fasting (nothing to eat/drink, except water, for at least eight (8) hours 
before visit), accompanied by LAR/study partner, to return to the research unit in the morning before taking 
his/her final dose of RAPA. Examination and activities during this visit include: reassessment of willingness to 
participate in the study, administration of the final dose of RAPA, vital signs, concomitant medication, 
compliance and adverse event review, fasting blood draw for safety and research labs with lumbar puncture to 
acquire CSF (as described under Visit 2), followed by provision of a snack (optional). 
At Visit 7 study staff should collect all remaining supply of RAPA from the participant for a final drug 
accountability check.   
 
Visit 7 is estimated to require 3 hours or less. Scheduling of Visit 8: to occur 7-14 after Visit 8. Within one to 
two business days of Visit 8, research staff will call the study participant and/or LAR/study partner to confirm 
the appointment and complete COVID-19 symptom and exposure telephone assessment. 
6.8. 
+69+ – End of Study Measures and Disenrollment (7 to 14 days after Visit 7) 
 
The participant and LAR/study partner returns to the research unit, in a fasting state (nothing to eat/drink, except 
water, for at least eight (8) hours before visit), 7-14 days after the LP to undergo reassessment of willingness to 
participate in the study and 12-week post-treatment measures, including vitals, weight, concomitant medication, 
history and physical, fasting safety labs (CBC, CMP, lipid panel, HbA1c, and urinalysis)) as well as: 
 
• Provision of a snack 
• Cognitive test battery & Questionnaires, including CDR plus all assessments listed in Visit 3 
• Physical functional performance (same as Visit 3) 
• Final AE review, instructions for future AD follow up and study staff enters disenrollment note. 
The estimated duration of this visit is 3.5 hours.  
A Summary Visit Schedule Table is shown on the following page(s). 
6.9. 
Summary Visit Schedule Table 
 
 
Visit Number 
Visit 1  
MCD  
Visit 2 
MCD 
Visit 
3a 
MCD 
Visit 3b 
MCD 
Visit 4 
MCD 
Visit 5 
MCD 
Visit 6 
MCD 
Visit 7 
MCD 
Visit 8 
MCD 
Visit Window 
 
V1 +    
up to 
30d  
 V2 +   
up to 
30d 
w/in 24-
72 hrs 
of Visit 
4 
V3 +    
up to 
15d 
V4 
+4w  
±2d 
V5 +3w  
±2d 
V6 +1w  
±2d 
V7+7-
14d 


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Consent 
X 
 
Reassess 
willingness to 
participate  
 
X 
X 
 
X 
X 
X 
X 
X 
CDR 
X 
 
X*** 
X 
 
 
 
 
 
 
 
 
 
 
Vitals: 
BP,HR,T,RR, 
Pulse Oximetry 
X 
X 
X 
 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
X 
 
X 
Has & P 
X 
 
X 
ConMeds 
X 
X 
X 
 
X 
X 
X 
X 
X 
AE Review 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Blood Draws, Labs, and Lumbar Punctures 
COVID-19 RT-
PCR swab** 
 
 
 
X 
 
 
 
 
 
Fasting Blood 
Draw 
 
X 
 
 
X 
X 
X 
X 
X 
Non-fasting Blood 
Draw 
X  
 
 
 
 
 
 
 
 
CBC w diff 
X 
 
X 
X 
X 
 
X 
CMP with lipid 
panel  
X 
X 
 
X 
X 
X 
X 
X 
 Hemoglobin A1c  
X 
 
 
 
X 
 
 
 
X 
PT/PTT/INR 
X 
 
 
 
X 
 
 
Routine Urinalysis 
X 
 
 
 
X 
 
X 
 
X 
Research Labs 
 
X 
 
 
 
 
 
X 
 
Lumbar Puncture 
(potentially with 
Fluoroscopy) 
 
X 
 
 
 
 
 
X 
 


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Cognitive, Physical, and Sensory Assessments  
Snack Provision 
(optional) 
 
X 
 
 
 
 
 
X 
X 
MoCA 
 
 
X 
 
 
 
 
 
X 
HVLT-R 
 
 
X 
 
 
 
 
 
X 
Craft Stories 
X 
 
X 
Benson Figure 
X 
 
X 
Number Span Test 
X 
 
X 
Trail Making Test 
A&B 
X 
 
X 
Phonemic and 
Semantic Fluency 
X 
 
X 
MINT 
 
 
X 
 
 
 
 
 
X 
Hayling 
 
 
X 
 
 
 
 
 
X 
GDS 
X 
 
X 
FAQ  
X 
 
X 
NPI 
X 
 
X 
Electronic Gait 
Mapping 
X 
 
X 
Grip strength 
X 
 
 
X 
 
Study Medication 
Compliance 
Review 
 
 
 
 
 
X 
X 
X 
 
Administer in 
clinic 
 
 
 
 
 
X* 
 
Dispense Study 
Drug 
 
 
X 
X 
  
 
 


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Schedule/Confirm 
Next Visit 
X 
X 
X 
 
X 
X 
X 
X 
 
**COVID-19 
symptom and 
exposure telephone 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
End of Study 
Final AE review 
 
X 
Final Forms 
Review 
 
X 
Follow up 
instruction 
 
X 
Disenrollment 
Note 
 
X 
**COVID testing 24-72 hours prior to drug dispensing visit; COVID symptom and exposure assessment 24-72 
hours prior to study visits; COVID testing may be repeated in event participant shows signs or symptoms of 
COVID-19 or, if positive, until a negative test is achieved 
*At visit 7, all remaining supply of RAPA should be returned to the study staff for a final drug accountability 
check.   
***CDR will only be repeated at visit 4 if visit 1 was conducted more than 60 days prior.  
7. Statistical Plan 
7.1. 
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).  
7.2. 
Statistical Methods 
Analytical Approach. 
Similar to an early phase 2 trial, we seek preliminary evidence of drug safety and tolerability with estimation of 
pre/post differences in a pertinent laboratory values and adverse event occurrences. We will report changes in 
post-intervention laboratory values relative baseline with the 95% confidence interval. Experimental results will 
be expressed as means ± SE. Comparisons of means between pre/post evaluations will be done by regression 
using the intent to treat principle defined above. Given the small sample size, there are no plans for interim 
analyses.  
8. Safety and Adverse Events 
8.1. 
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) 


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• 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; 
• 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 


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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. 
 
8.2. 
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 
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. 
 
8.3. 
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 an institutional Prompt 
Response 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. 
 


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SAE and or UPIRSO will be reported per institutional 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. 
 
8.3.1. 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: Dean Kellogg, 
MD, PhD 
Assistant Professor, Biggs Institute 
 
Barshop Institute & VA Hospital 
323-273-2107 
 
210-617-5197 
Gonzalesm20@uthscsa.edu 
 
kelloggd@uthscsa.edu 
 
Within the following 48 hours, the PI or co-PI provides further information on the SAE or UPIRSO in the form 
of a written narrative.  This should include a copy of the completed Institutional Prompt Response Form and 
any other diagnostic 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: 


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Food and Drug Administration, Center for Drug Evaluation and Research 
Division of Neurology Products 
10903 New Hampshire Avenue, Silver Spring, MD 20993 
Building 22, Suite 4346 
Phone: (301) 796-2250 
Fax: (301) 796-9842 
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. 
Determination of whether deviations or violations require prompt reporting or other action will be made 
according to IRB and institutional policies Failure to report departures from the protocol according to IRB 
policy may constitute possible non-compliance, which will require a prompt response 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  
• Emergency violations  
• Refer to UT Health San Antonio IRB Policy website for more information 
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. 
 
There are several reasons why the researchers may need to end the subject’s participation in the study.  
 
Some reasons are: 
• The researcher believes that it is not in the subject’s best interest to stay in the study 


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• Adverse drug reaction that does not resolve by dosing titration or if reaction is severe 
• Subject becomes ineligible to participate due to concomitant use of an exclusionary medication 
• Subject’s health condition changes and needs treatment that is not allowed while participating in the 
study 
• Subject does not follow instructions from the research team. 
• The study is stopped 
 
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 Designated Safety Officer in collaboration with the Sponsor 
Investigator. 
 
The research team will discuss options for medical care with the subject when participation in the study ends. 
 
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 or in REDCap (. 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. 
 
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 
facilitate investigator review.  Lab data will be entered into REDCap to facilitate analysis. 


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• 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.  
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 Principal Investigator and co-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 and Co-PI when preparing continuing review 
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 Older Americans Independence Center (OAIC) Pepper Center Data and Safety Monitoring 


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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.  Funding agency policies will be 
referenced regarding the potential requirement of an amendment submission. 
 
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. 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 cognitive impairment. 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 
. In the event of questions regarding capacity, the research study 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 
12.   Study Finances 
12.1. Funding Source 
This study is financed through an institutional grant from the Institute for Integration of Medicine and 
Science/Clinical Translational Science Award.  
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 $435 for the study for all visits. Payments may be prorated to 


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include the last visit completed if study participation is terminated early. Manual payments for additional visits, 
if necessary, will be handled on an ad-hoc basis with prior approval from the funding sponsor. 
 
Table 2. Participant Compensation 
Study Visit 
Compensation Amount 
Visit 1: Screening and Consent 
$35 
Visit 2 
$75 
Visit 3 
$75 
Visit 4, 5, 6 
$25 each 
Visit 7 
$100 
Visit 8 
$75 
Manual Payment (unscheduled visit, lab visit, or AE) 
$25 
 
13.     Publication Plan 
The Institution, Sponsor or respective designees may review results prior to presenting or publishing the results 
of a scientific investigation involving this Study in accordance with ICJME guidelines and institutional 
requirements. 
 
14.    References 
 
1. 
Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically 
heterogeneous mice. nature. 2009;460(7253):392. 
2. 
Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK. The TOR pathway comes of age. Biochimica et 
Biophysica Acta (BBA)-General Subjects. 2009;1790(10):1067-1074. 
3. 
Majumder S, Caccamo A, Medina DX, et al. Lifelong rapamycin administration ameliorates age‐
dependent cognitive deficits by reducing IL‐1β and enhancing NMDA signaling. Aging cell. 
2012;11(2):326-335. 
4. 
Lin A-L, Zheng W, Halloran JJ, et al. Chronic rapamycin restores brain vascular integrity and function 
through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s 
disease. Journal of Cerebral Blood Flow & Metabolism. 2013;33(9):1412-1421. 
5. 
Spilman P, Podlutskaya N, Hart MJ, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits 
and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PloS one. 2010;5(4):e9979. 
6. 
Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mTOR, Aβ 
and tau: effects on cognitive impairments. Journal of Biological Chemistry. 2010:jbc. M110. 100420. 
7. 
Perluigi M, Pupo G, Tramutola A, et al. Neuropathological role of PI3K/Akt/mTOR axis in Down 
syndrome brain. 2014;1842(7):1144-1153. 
8. 
Caccamo A, De Pinto V, Messina A, Branca C, Oddo S. Genetic reduction of mammalian target of 
rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring 
hippocampal gene expression signature. Journal of Neuroscience. 2014;34(23):7988-7998. 
9. 
Caccamo A, Magrì A, Medina DX, et al. mTOR regulates tau phosphorylation and degradation: 
implications for Alzheimer's disease and other tauopathies. Aging cell. 2013;12(3):370-380. 
10. 
Benedictus MR, Leeuwis AE, Binnewijzend MA, et al. Lower cerebral blood flow is associated with 
faster cognitive decline in Alzheimer’s disease. European radiology. 2017;27(3):1169-1175. 
11. 
Kisler K, Nelson AR, Montagne A, Zlokovic BV. Cerebral blood flow regulation and neurovascular 
dysfunction in Alzheimer disease. Nature Reviews Neuroscience. 2017;18(7):419. 
12. 
Halliday MR, Rege SV, Ma Q, et al. Accelerated pericyte degeneration and blood–brain barrier 
breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. Journal of Cerebral Blood Flow & 
Metabolism. 2016;36(1):216-227. 


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Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
13. 
Jun G, Naj AC, Beecham GW, et al. Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer 
disease risk loci and reveals interactions with APOE genotypes. Archives of neurology. 
2010;67(12):1473-1484. 
14. 
Wang W-Y, Tan M-S, Yu J-T, Tan L. Role of pro-inflammatory cytokines released from microglia in 
Alzheimer’s disease. Annals of translational medicine. 2015;3(10). 
15. 
Lang U, Heger J, Willbring M, Domula M, Matschke K, Tugtekin S. Immunosuppression using the 
mammalian target of rapamycin (mTOR) inhibitor everolimus: pilot study shows significant cognitive 
and affective improvement. Paper presented at: Transplantation proceedings2009. 
16. 
Kraig E, Linehan LA, Liang H, et al. A randomized control trial to establish the feasibility and safety of 
rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive 
effects. Experimental gerontology. 2018;105:53-69. 
17. 
Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita MJTO. The emerging safety profile of 
mTOR inhibitors, a novel class of anticancer agents. 2009;4(2):135-142. 
18. 
Mandrioli J, D’Amico R, Zucchi E, et al. Rapamycin treatment for amyotrophic lateral sclerosis: 
Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-
ALS trial). 2018;97(24):e11119. 
19. 
Cloughesy TF, Yoshimoto K, Nghiemphu P, et al. Antitumor activity of rapamycin in a Phase I trial for 
patients with recurrent PTEN-deficient glioblastoma. 2008;5(1):e8. 
20. 
Curatolo P, Moavero RJCn. mTOR inhibitors in tuberous sclerosis complex. 2012;10(4):404-415. 
21.  
Dilip V. Jeste, MD; Barton W. Palmer, PhD; Paul S. Appelbaum, MD; et al. A New Brief Instrument for 
Assessing Decisional Capacity for Clinical Research 
22. 
Ma KM, Yung S, Chan TM. mTOR Inhibition and Kidney Diseases. 
 
 


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CONFIDENTIAL 
SUMMARY OF PROTOCOL CHANGES TABLE 
 
Date of 
Change 
Version 
Section Modified 
Before Change 
After Change 
10-22-19 
IND (should have 
been 1.0) 
N/A 
Clinical Protocol 
for FDA by OCR 
Submitted 11-05-19 
11-25-19 
Updated to 1.1 
Cover Page 
 
Clinical Site 
 
 
Summary of Protocol 
Changes Table 
IND Number: 
 
VA Clinical 
Research Unit 
 
None 
Exempt 
 
UT MARC 
 
 
Added table on Page 
29 to track future 
changes 
02-10-20 
Updated to v1.2 
Multiple 
From v1.1 
Changed to v1.2 
during IRB review 
process 
04-30-20 
Updated to v1.3 
Cover page and 
headers 
 
Inclusion criteria, 
Study Summary and 
Section 4.2 
 
Section 6, Visits  
 
 
 
Section 8.6, Stopping 
Rules 
 
v1.2    2-20-20 
 
 
Cholesterol >240 
 
 
 
Safety labs 
 
 
 
Fundamental 
statement 
 
Recruitment- at 
phone screening 
and 
Exclusion criteria 
Section 4.3 
Versioning updated  
v1.3 04-09-20 
 
Removed cholesterol 
as an inclusion 
criterion 
 
Added lipid panel to 
safety labs at Visit 
2,4,5,6,7,8 
 
Clarified stopping 
rules 
 
Added exclusion 
language about history 
of triglyceridemia 
06-05-20 
Updated to v1.4 
Cover page and 
headers 
 
Section 6, Visits 
V1.3 or 1.3.1 
 
 
No introductory 
statement about 
COVID screening 
and testing 
 
Visit window and 
Drug dispensing 
…weeks +3days 
Versioning updated to 
v1.4 05-26-20 
 
Added paragraphs 
about COVID 
screening and testing 
pre-drug intervention  
 
Changed to +2 days to 
= monthly dispensed 
amount to 30/bottle 


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06-30-20 
Updated to v1.5 
Exclusion criteria 
See v1.4** 
Added 
“Hypersensitivity or 
history of allergy to 
Rapamycin” 
08-03-20 
Updated to v1.6 
Multiple 
List of Abbrev. 
 
Inclusion Criteria 
 
 
Secondary 
Outcomes 
 
Fitbit Monitoring 
 
 
Optional 
OCT/OCTA 
 
 
Study Visits & 
Procedures 
 
Summary Visit 
Schedule Table 
 
Source 
Documentation 
Updated 
 
Updated lab info for 
Dx of MCI or AD 
 
Revised lab info and 
testing batteries 
 
Removed from 
protocol 
 
Removed from 
protocol 
 
Revised COVID info 
and cognitive exams 
 
Required updates 
 
 
Removed IDEAS  
09-15-20 
Updated to v1.7 
Multiple 
Study Site Update 
Removed MARC, 
FORU & BICRC as 
study sites. 
10-16-20 
1.7.1 
6.3 
 
 
 
6.6, Visit 6 
 
 
6.8, Visit 8 
 
 
 
6.9, Summary Visit 
Schedule Table 
Removed Geneus 
Lab for COVID 
testing 
 
Corrected safety 
labs to fasting 
 
specified tests to be 
performed, added 
optional snack 
 
Added optional 
snack at Visit 8 
Require update 
 
 
 
Required correction 
 
 
Added for clarity 
 
 
 
Required correction 
12-21-20 
 
 
 
 
 
1.7.2 
5.5 
 
 
 
 
 
Added guidance for 
dosing 
interruption(s) in 
the event a 
participant may 
Per internal discussion 
of changing medical 
situation(s)  
 


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CONFIDENTIAL 
 
 
01-21-2021 
 
 
5-special 
considerations for 
COVID  
receive a COVID-
19 Vaccination. 
 
 
Criteria by which 
COVID-19 PCR 
test can be waived  
2-5-2021 
 
4.2 inclusion criteria  
Change CVLT-III 
cut off ≤ 
Per PI to develop 
more consistent set of 
IC/EC with the other 
alzheimers association 
funded trials.   
2-5-2021 
 
6.6 and 6.7 
Language 
clarification of drug 
dispensing.  
Clarifying that no new 
drug will be dispensed 
at visit 6 and all study 
drug should be 
returned at visit 7.   
4-12-2021 
 
4.2 
Modification of 
inclusion criteria 3  
Change of inclusion 
criteria to make the 
diagnosis of AD/MCI 
based on the CDR 
Rating exclusively.  
After further review of 
literature removal of 
the other two 
assessments will not 
make a significant 
difference in 
population.  
4-12-2021 
 
6.4 
Adding CDR 
assessment to Visit 
4 
Repeat of the CDR 
prior to drug 
dispensation for 
confirmation 
purposes.  
21-May-
2021 
 
4.2 
Modification of 
Inclusion Criteria # 
8.  
Clarification that 
participants must be 
on stable dosage(s) of 
Alzheimer’s 
medications for 3 
months prior to 
baseline (visit 2) 
18-JUN-
2021 
 
6.4 and 6.9  
Change to Schedule 
of procedures  
Clarify that CDR will 
only be done at visit 4 
if the visit is done 60 
or more days after 
Visit 1.  
 


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CONFIDENTIAL 
**v1.4 changes included with v1.5 changes and submitted together for IRB approval (amendment dated 7-01-
2020) 
 

ICF_001.pdf: 
Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor pathway 
(CARPE DIEM) 
 
19-850H, Gonzales, Form D, 06-18-21, AMD.doc 
 
 
Page 1 of 23 
UTHSCSA Research Consent (v March 5 2019) 
 
 
 
Protocol #: HSC20190850H 
 
 
NCT # 04200911 
 
 
Date Approved: 06.18.2021


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
pathway (CARPE DIEM) 
 
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Page 2 of 23 
UTHSCSA Research Consent (v March 5 2019) 
 
 
Consent to be part of a Research Study 
To be conducted at  
UT Health Science Center San Antonio  
 
Concise Summary 
 
Important Information  
This information gives you an overview of the research.  More information about these topics may be found in 
the pages that follow.  You may choose not to take part in the study or may choose to leave the study at any 
time.  Deciding not to participate, or deciding to leave the study later, will not result in any penalty or loss of 
benefits to which you are entitled and will not affect your relationship with us. 
 
1. What problem is this study trying to solve? 
You are being asked to participate in a research study.  Scientists do research to answer important questions 
which might help change or improve the way we do things in the future.  
 
The purpose of this pilot study is to evaluate whether a study drug, Rapamycin (“RAPA”, Sirolimus, 
Rapamune®) reaches the brain using cerebrospinal fluid (CSF) in older adults with mild cognitive impairment 
(MCI) and early stage Alzheimer’s disease (AD). This drug has been shown to improve cerebral blood flow, 
decrease neuroinflammation, and enhance memory in Alzheimer’s mice models. We want to know if this 
medication reaches the brain in order to evaluation if this intervention may be effective for treating MCI and AD 
symptoms in future studies. This is also known as a “proof of concept” study. 
 
For more information, please see the Why is this Study being Done section below.   
 
2. What will happen to me during the study and how is this different from continuing with usual care? 
What are all my options for treatment, including the pros and cons? 
 
Eligible participants will have 8 clinic visits to undergo laboratory assessments of blood, receive the study 
medication over an 8-week period and complete pre- and post-treatment testing including: 2 visits with lumbar 
punctures to obtain cerebrospinal fluid; blood draw (7 out of 8 visits); memory and thinking assessments; mood 
and sleep questionnaires, and tests of physical functioning, all of which will be done for research purposes 
only. The possible benefit of participating is contributing to science, which may improve treatments for MCI and 
AD in the future. The cons of participating may include medication side effects, pain or bleeding from blood 
draws and lumbar puncture, emotional distress from assessments of memory and thinking, or fatigue from 
physical performance measures. 
 
Other available treatments for early stage AD include cholinesterase inhibitors (Aricept [donepezil], Exelon 
[rivastigmine], Razadyne [galantamine]) and Namenda [memantine]. If you are prescribed these medications, 
you can continue taking them throughout the study assuming that you have been on a stable dose for at least 
three months. Treatment pros include established benefits for slowing the progression of the disease. The con 
is that these medications do not cure AD and the disease will gradually get worse over time.  
 
For more information, please see the What will be done if you decide to be in the research section below.   
 
3. How much time will I spend on the study? 
This study involves 8 visits over the course of approximately 12-18 weeks. Visits are scheduled 1 to 4 weeks 
apart. Visits last anywhere from 45-minutes to 3.5-hours. The total hours of participation may range from 15-18 
hours. 
 
4. Could taking part in the study help me and are there risks?  


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UTHSCSA Research Consent (v March 5 2019) 
 
We cannot guarantee that you will benefit from participating in this study other than to receive study medication 
and study related clinical care at no cost to you, and a small amount of reimbursement for your time and travel 
to the clinic. 
 
The risks associated with your participation may include medication side effects, pain or bleeding from blood 
draws and lumbar puncture, emotional distress from assessments of memory and thinking, or fatigue from 
physical performance measures. 
 
For more information, please see How could you or others benefit from your taking part in this study 
section below.  For details and a list of risks you should know about, please see the What are the risks of 
participation in the research section below. 
 
5. What else should I consider before I make my decision? 
Another important factor to consider before participating is the need for you to be accompanied to visit 1 by 
someone who is legally authorized to represent you such as your husband/wife or child, as well as study 
partner (husband/wife, child) for all other study visits. 
 
Please review the rest of this document for additional details about these topics and other information 
you should know before making a decision about participating in this research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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UTHSCSA Research Consent (v March 5 2019) 
 
 
 
 
 
Information about this form 
If you are providing consent for someone else, for example your child, your next-of-kin or someone for whom 
you are the legal guardian or are designated as a surrogate decision maker on a medical power of attorney, 
please note that in the sections that follow the word “you” refers to the person you are providing consent for.  
 
You may be eligible to take part in a research study.  This form gives you important information about the 
study.   
 
Please take time to review this information carefully.  You should talk to the researchers about the study and 
ask them any questions you have.  You may also wish to talk to others (for example, your friends, family, or a 
doctor) about your participation in this study.  If you decide to take part in the study, you will be asked to sign 
this form.  Before you sign this form, be sure you understand what the study is about, including the risks and 
possible benefits to you. 
 
Please tell the researchers or study staff if you are taking part in another research study. 
 
Voluntary Participation - You do not have to participate if you don't want to.  You may also leave the study at 
any time.  If you leave the study before it is finished, there will be no penalty to you, and you will not lose any 
benefits to which you are entitled.   
 
General Information – “Who is conducting this research?” 
Principal Investigator 
The Principal Investigator (PI) is the researcher directing this study; the PI is responsible for protecting your 
rights, safety and welfare as a participant in the research.  The PI for this study is Mitzi Gonzales, PhD of the 
University of Texas Health Science Center San Antonio (UTHealth San Antonio or UTHSA), at the Glenn Biggs 
Institute for Alzheimer’s and Neurodegenerative Diseases. The Co-PI for this study is Dean Kellogg, MD of The 
University of Texas Health Science Center San Antonio (UT Health San Antonio or UTHSA) and Sam and Ann 
Barshop Institute for Longevity and Aging Studies. The Co-Principal Investigator shares the principal 
investigator’s responsibilities for this study. 
 
Non-Profit Funding. 
This study is funded by an institutional grant awarded by the Institute for Integration of Medicine & 
Science/Clinical and Translational Science (IIMS/CTSA) at UTHSA. This organization receives and distributes 
funding from state and federal sources so that the researchers can conduct the study. 
 
Purpose of this study – “Why is this study being done?” 
The purpose of this pilot study is to evaluate whether a study drug, Rapamycin (“RAPA”, Sirolimus, 
Rapamune®) reaches the brain using cerebrospinal fluid (CSF) in older adults with mild cognitive impairment 
(MCI) and early stage Alzheimer’s disease (AD). 
 
You are asked to participate in this clinical trial, which evaluates inflammatory and AD-related markers in the 
blood and cerebrospinal fluid, possible medication side effects, memory/thinking, sleep/activity, physical 
functioning in individuals with MCI and early stage AD. 
 
The researchers hope to learn if this drug reaches the brain in order to evaluate if this intervention may be 
effective for treating MCI and AD symptoms in future studies 
 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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UTHSCSA Research Consent (v March 5 2019) 
 
This study involves the use of an FDA-approved drug called Rapamycin (“RAPA”, Sirolimus, Rapamune®), 
that has not yet been approved by the U.S. Food & Drug Administration (FDA) for treating MCI or Alzheimer’s 
disease. 
 
This study will help find out what effects, good and/or bad, this drug has on people who take it and its effect on 
the condition/disease. The safety of this drug in humans has been tested in prior research studies; however, 
some side effects may not yet be known.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.  
 
Information about Study Participants – “Who is participating in this research?” 
You are being asked to be a participant in this study because you have been diagnosed with MCI or early 
stage Alzheimer’s disease. 
 
How many people are expected to take part in this study?  
This study will screen approximately 60 individuals to enroll and complete all procedures and interventions on 
10 people.  
 
Information about Study Procedures – “What will be done if you decide to be in the research?” 
While you are taking part in this study, you will be asked to attend 8 visits with the researchers or study staff. 
Your Legally Authorized Representative (LAR or legal representative) must accompany you to the first visit and 
your LAR/study partner must accompany you to all remaining visits. 
  
It will be necessary for you to return to the research clinic 8 times across a period of up to 18 weeks. 
 
Special Considerations related to COVID-19 
 
1) 
You will be phone screened 1 to 2 business days before all 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, you will be screened again, have your temperature 
taken, and will receive a mask if you need one. 
 
2)  
For added safety, participants enrolled in the study will be tested for the coronavirus also known as 
SARS CoV-2. Approximately 24-72 hours before starting the study drug intervention you will be tested with a 
nasopharyngeal swab (inserted in the nose to the back of the mouth) for rRT-PCR (Real-time reverse 
transcriptase–polymerase chain reaction) COVID-19 analysis.  Research funds will pay for the testing. If you 
test positive, the investigator will refer you to your primary care physician for medical care and may withdraw 
you from participation in the trial.  If you have completed your vaccination to COVID-19 at least one-week prior 
to your first dose of study drug, the rRT-PCR test may be waived with the authorization of the study doctor.  It 
will be necessary for you to provide proof of your completed vaccination such as the card issued to you by the 
place where you got the vaccine or a similar record from your doctor. 
 
3) 
If you develop COVID-19 signs or symptoms at any time during the study, the investigators will arrange 
for testing and if indicated, will refer you to your PCP for medical care. Research funds will pay for the testing. 
If you test positive for COVID-19 during the 8-week study drug treatment, you will be withdrawn from treatment 
and your study participation will stop. If you test positive for COVID-19 during the pre- or post-treatment study 
periods, you will be required to wait until your symptoms resolve and you receive a negative COVID-19 test 
before continuing your study participation.  
 
4) COVID-19 Vaccination: If you decide to be vaccinated for COVID-19, at any point during the study, please 
notify the research team. If your vaccination occurs during the study treatment period, the research team will 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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Page 6 of 23 
UTHSCSA Research Consent (v March 5 2019) 
 
advise that you stop taking the study medication for four days before and at least three days after each vaccine 
dose. Prior to resuming the study drug, the research team will contact you to evaluate for any new symptoms 
and advise you on when to resume the study drug. The temporary stop in taking the study medications will not 
change the total number of days that you take the study drug during the course of the research study. Your 
end of study treatment date will simply be extended by the number of days that the drug was withheld.  
Visit 1 – Screening  
 
Consent - Researchers will first attempt to seek consent from you. In order to have appropriate safeguards, 
we will assess your capacity to understand the purpose, procedures, risks and benefits of study participation 
using a standardized instrument (questionnaire) for assessing capacity to consent. If your capacity to consent 
is diminished, the researchers will obtain consent through your representative who is legally allowed to speak 
for you (LAR). When a LAR is necessary, the researchers will instruct your LAR to respect your will and 
preferences relevant to this study and we will still include you in the consent process and seek to obtain your 
assent (approval) for study participation 
 
Screening – After you sign this consent to participate, exams, tests, and/or procedures may be done as 
described below to find out if you can continue in the study; this is called screening. We may be able to use the 
results of exams, tests, and/or procedures you completed before enrolling in this study.  You will be told which 
results we will obtain and which procedures will not have to be repeated.  Most of the procedures are for 
“research only” and if any are performed for standard of care (soc), we will inform you accordingly. 
 
Screening Procedures 
We will ask you to come in a non-fasting state to the Biggs Institute at the McDermott Clinical Sciences 
Building (Biggs-McDermott) located at 8403 Floyd Curl Drive on the 5th floor in Room 5.110. The following 
procedures will take place: 
 
• 
Physical examination – we will measure vital signs (blood pressure, heart rate, respiratory rate and 
temperature, pulse oximetry), height , weight , and calculate Body Mass Index (BMI). We will perform a 
physical examination similar to what you would have when visiting your family doctor. 
 
• 
Medical history and medications – we will ask you questions about your health history and a list of current 
and recent medications you have taken or are taking. 
 
• 
Cognitive screening assessment – Using a brief assessment scale, we will evaluate your memory and 
thinking. 
 
• 
Non-fasting blood draw to measure safety indicators, including complete blood count (CBC), 
comprehensive metabolic panel (CMP), hemoglobin A1c (A1c to check for diabetes), and coagulation 
panel (PT/PTT/INR). A urine specimen will also be collected to check your kidneys.  
 
This visit is expected to require 2.5 hours. 
 
The results of the screening exams, tests, and/or procedures will be reviewed to determine whether you will be 
allowed to continue in the study.  After receiving all test results (including laboratory data), the study 
investigators or research staff will call you to let you know if you quality for the study. If you are not allowed to 
continue in the study, the researcher will discuss the reasons with you. If there are abnormal lab results that 
are interpreted to be clinically significant, investigators may ask to repeat the testing or advise you to consult 
with your primary care provider before enrolling you in the study. If you do qualify for the study and remain 
interested in participating, Visit 2 will be scheduled. Within one business day of Visit 2, research staff will call 
you and/or your LAR/study partner to confirm the appointment and provide a reminder about fasting.  
 
 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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UTHSCSA Research Consent (v March 5 2019) 
 
Visit 2 – Baseline Measurements Part I (within 30 days of Visit 1 [Biggs-MCD or RII-MCD]) 
 
You will be asked to return with your legal representative/study partner to the McDermott location (RII – First 
Floor) to undergo the first of 2 visits to collect pre-treatment (also called Baseline) measurements. You must 
arrive to this appointment after an 8-hour fast (nothing to eat/drink at least 8 hours before your visit, except 
water, as instructed).  
• 
Vital signs – heart rate, blood pressure, respiratory rate, temperature, pulse oximetry  
• 
Review of current medications 
• 
Fasting Blood draw – comprehensive metabolic panel (CMP, lipid panel) and research lab work for 
inflammatory and AD markers 
• 
Lumbar puncture – also known as a ‘spinal tap’ from which fluid is obtained.  
This procedure involves placing a needle in the lower back to obtain fluid that bathes the brain and spinal 
cord (this fluid is called cerebrospinal fluid or CSF). The correctly placed needle enters a sac below the 
actual spinal cord. The lower back is generally considered the safest site to obtain this fluid for laboratory 
testing.  
 
The physician will tell you which position they want you in for this test. It is important to be as still as you 
can during the procedure. There is not usually a lot of pain because a local anesthetic is used to numb the 
area but some patients feel a slight pressure and soreness when the needle goes in. If clinically indicated 
for subject safety during the procedure, the physician performing the spinal tap may opt to use fluoroscopy, 
an imaging technique using X-ray, to identify the correct insertion point on the spine. 
 
This procedure is performed for research purposes so that investigators may learn whether the study 
medication crosses from the bloodstream into the brain (also called the blood-brain barrier) and at what 
concentration the medication reaches the CSF. 
• 
Provision of a snack (optional) 
 
This visit is expected to require 3 hours. An appointment for the next visit will be scheduled. Within one to two 
business days of Visit 3, research staff may call you and/or your LAR/study partner to confirm the appointment.  
 
Visit 3 – Baseline Measurements Part II (up to 30 days after Visit 2 [Biggs-MCD]) 
 
You will be asked to return with your legal representative/study partner to the Biggs-McDermott location within 
30 days after Visit 2 for Visit 3 that will include: 
• 
Medication review 
• 
Adverse event (AE) review – a list of questions concerning any medical experiences related or unrelated to 
the research since the last visit 
• 
Cognitive examination – we will administer a set of detailed cognitive assessments to score your memory, 
mental status, comprehension and thinking. Physical functioning and sensory performance measures  
□ We will provide instruction and ask you to perform some physical performance tests that include 
walking on a pressure sensitive walkway to capture data on steps, balance and gait. We will 
measure your hand grip strength.  
 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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UTHSCSA Research Consent (v March 5 2019) 
 
Visit 3 is estimated to require 3.0 hours, and at the end of Visit 3 we will confirm the scheduling of Visit 4. 
Within one to two business days of Visit 4, research staff may call you and/or your LAR/study partner to 
confirm the appointment. 
 
COVID-19 Testing: Within one to three days of your Visit 4 appointment, you will be asked to complete COVID-
19 testing with a nasopharyngeal swab (inserted in the nose to the back of the mouth) for rRT-PCR (Real-time 
reverse transcriptase–polymerase chain reaction) analysis. Please complete the test at the location provided to 
you by the study staff. Research funds will pay for your test and study staff will access your results 
electronically from the laboratory’s secure portal. If your test is positive, research staff will call to inform you of 
the results. Research staff may also call you to ensure that you complete the COVID-19 test prior to study Visit 
4. 
 
Visit 4 – Study Drug Dispensing and Monitoring (within 15 days of Visit 3 – [Biggs-MCD]) 
 
You will be asked to return with your legal representative/study partner to the Biggs-McDermott location after 
an 8-hour fast (nothing to eat/drink, except water, at least 8 hours before your visit) within 15 days after Visit 3 
for Visit 4 that will include: 
• 
Vital signs 
• 
Medication and records review 
• 
Fasting blood draw for safety labs (CBC, CMP, lipid panel, HbA1c); a urine specimen will be collected to 
monitor kidney function 
• 
Adverse event review – a list of questions concerning any medical experiences related or unrelated to the 
research since the last visit 
• 
Cognitive Screening Assessment may be repeated if this visit is done more than 60 days after visit 1.  
• 
Dispense study medications to take at home with written instructions 
• 
Scheduling Visit 5 to occur 
 
Visit 4 is estimated to require 1.5 hours or less. Scheduling of Visit 5 to occur 4 weeks (± 2 days) after Visit 4. 
Within one to two business days of Visit 5, research staff may call you and/or your LAR/study partner to 
confirm the appointment. 
 
Visit 5 – Study Drug Dispensing and Monitoring (4 weeks ± 2 days after Visit 4 – [Biggs-MCD]) 
 
We will ask you to return to the Biggs-McDermott location with your LAR/study partner after an 8-hour fast 
(nothing to eat/drink, except water, at least 8 hours before your visit) for:  
• 
Vital signs 
• 
Weight  
• 
Medication and adverse event review 
• 
Fasting blood draw for safety labs (CBC, CMP, lipid panel) 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
pathway (CARPE DIEM) 
 
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• 
Study medication compliance/tolerability - questions regarding how often you took the study medication 
and any side effects 
• 
Dispense study medications to take at home with written instructions 
 
The estimated duration of this visit is 1 hour or less. We will also confirm scheduling of Visit 6. Within one to 
two business days of Visit 6, research staff may call you and/or your LAR/study partner to confirm the 
appointment. 
 
Visit 6 – Study Drug Dispensing and Monitoring (3 weeks ± 2 days after Visit 5 – [Biggs-MCD]) 
 
We will ask you to return to the Biggs-McDermott location with your LAR/study partner after an 8-hour fast 
(nothing to eat/drink, except water, at least 8 hours before your visit) for:  
• 
Vital signs 
• 
Weight  
• 
Medication and adverse event review 
• 
Fasting blood draw for safety labs (CBC, CMP, lipid panel, PT/PTT/INR) ; a urine specimen will be 
collected to monitor kidney function 
• 
Study medication compliance/tolerability (able to tolerate medication)  
• 
Study Staff will return study medications to take at home with written instructions 
The estimated duration of this visit one hour or less. We will also confirm scheduling of Visit 7 for return to the 
Biggs-MCD location. Within one business day of Visit 7, research staff will call you and/or your LAR/study 
partner to confirm the appointment and provide a reminder about fasting. 
 
Visit 7 – Lumbar Puncture, Blood Draw, and Monitoring (1 week ± 2 days after Visit 6 – [Biggs-MCD or  
RII-MCD]) 
 
We will ask you and your LAR/study partner to return to the first floor of the McDermott location after at least 
an 8-hour fast (nothing to eat/drink, except water, at least 8 hours before your visit) and before taking your final 
dose of the study medication. At this visit, please plan to bring all remaining study medication with you to return 
to the study staff.  Please make note of any study medication that may have been lost or damaged during the 
course of the study.   
 
During this visit, research activities include:  
• 
Vital signs  
• 
Medication and adverse event review 
• 
Fasting blood draw –CMP, lipid panel, and research lab work for inflammatory and AD markers 
• 
Lumbar puncture to acquire CSF.  
• 
Provision of a snack (optional) 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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The estimated duration of this visit is 3 hours or less. We will confirm scheduling of Visit 8 for further post-
treatment measures and final follow up with disenrollment. Within one to two business days of Visit 8, research 
staff may call you and/or your LAR/study partner to confirm the appointment. 
 
Visit 8 – Post treatment testing and End of Study (7-14 days after Visit 7 – [Biggs-MCD]) 
 
We will ask you and your LAR/study partner to return to the Biggs-McDermott research unitafter an 8-hour fast 
(nothing to eat/drink, except water, at least 8 hours before your visit) to undergo final post-treatment measures, 
including: 
• 
Vitals, weight , medication review, history and physical examination  
• 
Cognitive test battery, including all assessments from Visit 3 and one of the screening visit measures 
(CDR) 
• 
Physical performance testing like in Visit 3 
• 
 fasting blood draw for safety labs (CBC, CMP, lipid panel, hbA1c) and urinalysis to evaluate your kidneys 
• 
Provision of a snack  
• 
Final AE review and disenrollment processing  
The estimated duration of this visit is 3.5 hours. A Summary Table of all visits is shown below. 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
pathway (CARPE DIEM) 
 
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UTHSCSA Research Consent (v March 5 2019) 
 
 
Visit Number 
Visit 
1  
Biggs
-MCD  
Visit 2 
Biggs/
RII-
MCD 
Visit 3 
Biggs-
MCD 
Visit 4 
Biggs-
MCD 
Visit 5 
Biggs-
MCD 
Visit 6 
Biggs-
MCD 
Visit 7 
Biggs/
RII-
MCD 
Visit 8 
Biggs-
MCD 
Visit Window 
 
V1 +    
up to 
30d  
 V2 +    
up to 
30d 
V3 +    
up to 
15d 
V4 
+4w  
±3d 
V5 +3w  
±3d 
V6 +1w  
±3d 
V7+7-
14d 
Consent 
X 
Reassess 
willingness to 
participate  
 
X 
X 
X 
X 
X 
X 
X 
 CDR 
X 
X* 
X 
Vitals: 
BP,HR,T,RR, 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
 
X 
H & P 
X 
X 
ConMeds 
X 
X 
X 
X 
X 
X 
X 
X 
AE Review 
 
X 
X 
X 
X 
X 
X 
X 
Blood Draws, Labs, and Lumbar Punctures 
COVID-19 RT-
PCR nasal swab** 
 
 
 
X 
 
 
 
 
Non-Fasting Blood 
Draw  
X 
 
 
 
 
 
 
 
Fasting Blood 
Draw 
 
X 
 
X 
X 
X 
X 
X 
CBC w diff 
X 
X 
X 
X 
 
X 
CMP and lipids  
X 
X 
X 
X 
X 
X 
x 
 Hemoglobin A1c  
X 
 
 
X 
 
 
 
X 
PT/PTT/INR 
X 
 
 
X 
 
 
Urinalysis, routine 
X 
 
 
X 
 
X 
 
X 
Research Labs 
 
X 
 
 
 
 
X 
 
Lumbar Puncture 
(potentially with 
Fluoroscopy) 
 
X 
 
 
 
 
X 
 
Cognitive, Physical, and Sensory Assessments  
Snack Provision 
(optional) 
 
X 
 
 
 
 
X 
X 
Montreal Cognitive 
Assessment  
 
 
X 
 
 
 
 
X 
HVLT-R 
 
 
X 
 
 
 
 
X 
Craft Stories 
X 
X 
Benson Figure 
X 
X 


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Number Span Test 
X 
X 
Trail Making Test 
A&B 
X 
X 
Phonemic and 
Semantic Fluency 
X 
X 
Multilingual 
Naming Test 
 
 
X 
 
 
 
 
X 
Hayling 
 
 
x 
 
 
 
 
x 
GDS-15 
X 
X 
FAQ  
X 
X 
NPI 
X 
X 
Electronic Gait  
Mapping 
X 
X 
Grip strength 
X 
 
X 
Study Medication 
Compliance 
Review 
 
 
 
 
X 
X 
X 
 
Administer in clinic 
 
 
 
 
X 
 
Dispense next 
dose to home 
 
X 
X 
X 
 
 
Schedule/Confirm 
Next Visit 
X 
X 
X 
X 
X 
X 
X 
 
End of Study 
Final AE review 
X 
Final Forms 
Review 
X 
Follow up 
instruction 
X 
Disenrollment Note 
X 
 
**COVID-19 RT-PCR swab performed 24-72 hours prior to drug dispensing visit 
 
*CDR will only be done if visit 4 is conducted more than 60 days after visit 1.  
 
Assignment to Study Medication 
 
When it is determined that you are eligible for the study, you will be prescribed and provided with the study 
medication. Everyone enrolled in the study takes the same prescribed treatment, which will be 1 mg of 
Rapamycin (“RAPA”, Sirolimus, Rapamune®) daily for 8-weeks.  
 
Future Use of Your Information or Biospecimens Collected as Part of Your Participation 
Future studies: Identifiers may be removed and the de-identified information or biospecimens could be used 
for future research studies or distributed to another investigator for future research studies without additional 
informed consent from you or your legally authorized representative. Your biospecimens, even if identifiers are 
removed, may be used for commercial profit and you would not share in this commercial profit. 
 
Human Genetics: Research involving your biospecimens will, or in the future, might include whole genome 
sequencing. Whole genome sequencing is the process of determining the complete DNA sequence of a 
person or other organism’s genome at a single time.  DNA is short for deoxyribonucleic acid. DNA contains 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
pathway (CARPE DIEM) 
 
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UTHSCSA Research Consent (v March 5 2019) 
 
information that determines in part the traits, such as eye color, height, or disease risk, that are passed on from 
parent to child 
 
Return of Research Test Results for Genetic Tests to Subjects 
It is possible that this study will identify information about you that was previously unknown, such as disease 
status or risk.   
 
There are no plans to provide this information to you or your physician unless the information indicates that you 
may be at risk for a serious illness known at the time of testing to be treatable and it can be confirmed by a 
clinical laboratory.  In that case, we will attempt to notify you using the contact information you have provided.  
 
If you do not want to be notified of any of these incidental findings, please initial below.   
 
_____ Please do not notify me of any incidental findings obtained from this research. 
 
The Genetic Information Nondiscrimination Act (GINA) is a Federal law that will protect you in the following 
ways: 
• 
Health insurance companies and group plans may not request genetic information from this research; 
• 
Health insurance companies and group plans may not use your genetic information when making 
decisions regarding your eligibility or premiums; 
• 
Employers with 15 or more employees may not use your genetic information when making a decision to 
hire, promote, or fire you or when setting the terms of your employment. 
 
GINA does not protect you against genetic discrimination by companies that sell life insurance, disability 
insurance, or long-term care insurance.  GINA also does not protect you against discrimination based on an 
already-diagnosed genetic condition or disease. 
 
Could your participation end early? There are several reasons why the researchers may need to end your 
participation in the study (early withdrawal).  Some reasons are: 
• 
The researcher believes that it is not in your best interest to stay in the study. 
• 
You become ineligible to participate. 
• 
Your condition changes and you need treatment that is not allowed while you are taking part in the study. 
• 
You do not follow instructions from the researchers. 
• 
The study is stopped. 
 
The researchers will discuss your options for medical care when your participation in this study ends. 
 
Risks – “What are the risks of participation in the research?” 
Risks associated with participation in this research may be related to: a) drug administration side effects and 
potential drug-drug interactions, b) blood draw, c) genetic informational risks, d) cognitive assessment and 
semi-structured interviews/questionnaires, e) lumbar puncture, f) risks of radiation exposure, g). physical and 
sensory functioning assessments, h) COVID-19 swab test.  
 
Side effects from this study will usually go away soon after you stop taking the medication or a reasonable time 
after a procedure. In some cases, side effects can be long lasting or may never go away. 
 
Everyone taking part in the study will be watched carefully for any side effects.  However, the study doctors 
don’t know all the side effects that may happen.  Be sure to tell your study doctor immediately, about any side 
effect that you have while taking part in the study. 
 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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UTHSCSA Research Consent (v March 5 2019) 
 
The following section will describe the risks related to each your participation in this research study.  You 
should talk to your study doctor about any side effects or other problems that you have while taking part in the 
study.   
 
Side effects can range from mild to serious.  Serious side effects are those that may require hospitalization, are 
life threatening or fatal (could cause death).  The frequency that people experience a certain side effect can 
range from many (likely), few (less likely) or only one or two (rarely).   
a) Drug Administration 
Rapamycin (RAPA) (Sirolimus, Rapamune®) is FDA-approved and indicated for use as an 
immunosuppressant. The most common adverse events include mucositis, stomatitis, diarrhea, nausea, and 
acneiform rash. Many side effects are alleviated with lower dosing and shorter durations of exposure. In a 
recent clinical trial of elderly adults receiving 1mg RAPA daily, the same dosage to be used in this proposal, no 
serious adverse events occurred. The reported adverse events were limited to facial rash (N=1), stomatitis 
(N=1; 1 on placebo and 1 on RAPA), and gastrointestinal distress (N=2).  
o Likely, and may be serious (more than or 15 out of 100 people): 
o Mucositis and stomatitis (inflammation of the mouth and tongue) 
o Mouth scores 
o Acne like rash 
o Hyperlipidemia (increased cholesterol and fat in the blood) 
o Increased blood sugar 
o Peripheral edema (swelling in the arms, legs, hands, feet) 
o Hypertension (high blood pressure) 
o Constipation 
o Diarrhea  
o Headache 
o Fever 
o Anemia (low red blood cell count or hemoglobin) 
o Nausea  
o Arthralgias (pain in the joints) 
o Pain  
o Urinary urgency (the feeling that you have to go to the restroom right away)  
o Insomnia 
o Oral paresthesia (numbness) 
o Transient numbness in mouth or other parts of the body 
o Rare, and may be serious (1 to 5 people out of 100) : 
• 
Pneumonitis – inflammation of lung tissue, may be fatal 
• 
A hypersensitivity response (allergic reaction), though rare, may develop. Some signs of allergic 
reactions are rash, itching, hives, and shortness of breath. 
• 
Low platelets (increases the risk of bruising and bleeding) 
• 
Low white blood cells (increases the risk of developing infections) 
• 
Infections 
• 
Certain types of cancer (i.e. lymphoma and skin cancer)  


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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UTHSCSA Research Consent (v March 5 2019) 
 
• 
Protein in the urine which may signal a decrease in kidney function 
Drug-Drug Interactions may include: 
• 
Strong CYP3A4 Inhibitors – clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, 
atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, such that dose 
reduction may be necessary.  
• 
Strong CYP3A4 Inducers – carbamazepine, dexamethasone, ethosuximide, glucocorticoids, 
griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, 
oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib (mild), St John’s wort, sulfadimidine, 
sulfinpyrazone, troglitazone, such that dose increase may be necessary.  
• 
Live vaccinations - measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, TY21s typhoid 
 
b) Blood withdrawal  (To minimize these risks a qualified phlebotomist will perform venipunctures.) 
 
o Likely, and may not be serious (5 to 10 out of 100 people): 
• 
Pain, bleeding, bruising, or swelling at the site of the needle stick 
• 
Fainting or light-headedness 
o Less likely, and may or may not be serious (1 to 5 out of 100 people): 
• 
Hematoma (bleeding outside of the blood vessels 
o Rare risks and complications (less than 1 in 100 people) 
• 
Nerve damage 
• 
Infection 
 
c) Genetic Information 
 
This study may include genetic testing.  Human tissue contains genes that determine many of a person’s 
physical characteristics, such as the color of eyes and hair.  In some cases, genetic testing of tissues can be 
used to indicate a risk for the development of certain diseases.  Genetic information is unique to each 
individual and could potentially be used to discover possible changes in a person’s future health status or life 
expectancy, or that of his/her children and family members. Even though the results of genetic testing cannot 
be linked to you, it is possible that people of your ethnic background may be found to be at more risk for certain 
diseases based on future genetic research and this information might harm you in the future as a member of 
the group.  Releasing this information to others, such as including it in your medical record, may pose a 
possible risk of discrimination, or increase difficulty in obtaining or maintaining disability, long-term care, or life 
insurance.   
 
These risks would occur if your information is released by mistake.  The measures being taken to protect your 
privacy are discussed below and make this possibility unlikely. 
 
Even though the results of genetic testing may not be linked to you, it is possible that people of your ethnic 
background may be found to be at more risk for certain diseases based on future genetic research and this 
information might harm you in the future as a member of the group. Also, there may be unknown risks of 
genetic testing in the future. 
 
d) Cognitive Assessment  (Patient or Study Partner-Reported Outcomes include questionnaires related to 
cognitive symptoms, memory and thinking, functional status, sleep, and mood scales.) 
o Likely, and may not be serious (less than 5-20 subjects out of 100) 
 
 


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• 
Psychosocial – you may experience embarrassment, discomfort or anxiety during memory and 
thinking tests 
 
o Less likely (less than 5-20 subjects out of 100) and Not Serious: 
• 
Uncomfortable answering questions –If you feel uncomfortable answering questions, one of the 
investigators will speak with you to help clarify your doubts. Your responses will be kept confidential. 
You do not have to respond to any question that you do not feel comfortable answering.  
 
o Rare (less than 5 subject out of 100) and Serious: 
• 
Breach of confidentiality- It is possible in a rare occurrence there may be a breach of confidentiality.  
However, the researchers have taken steps to minimize this risk such as keeping focus group audio 
recordings and materials in a secure, locked location. 
 
e) Physical Functioning Assessment 
 
o Likely, and may not be serious (approximately 5-20 out of 100 people): 
• 
Psychosocial - heightened awareness of physical limitations may cause anxiety or embarrassment 
during testing, which will be mitigated by ensuring privacy 
• 
Brief, temporary fatigue with timed short distance walking and/or using handheld dynamometer to 
measure grip strength 
 
f) Lumbar Puncture  (To minimize these risks, a qualified provider specifically trained in the procedure will 
perform the lumbar puncture; if clinically indicated, an xray called fluoroscopy may be used) 
 
o Likely, and may not be serious (more than 5 out of 100 people): 
• 
Temporary pain and discomfort in the back – affects up to two thirds of people having LP and rarely is 
it permanent 
• 
Shooting pain down the legs at the time of the procedure is common, affecting about 10% of people 
having LP and it usually stops as or shortly after the needle is removed 
• 
Bleeding – is more common if you have been taking blood thinning drugs such as Warfarin, Aspirin, 
Clopidogrel (Plavix, Iscover. Coplavix), Prasugrel (Effient), Dipyridamole (Persantin or Asasantin), 
Ticagrelor (Brilinta), Apixaban (Eliquis), Dabigatran (Pradaxa), Rivaroxaban (Xarelto). 
o Less likely (1 to 5 out of 100 people), and may  be serious: 
• 
Allergic reaction to the local anesthetic (lidocaine) used for the lumbar puncture, such as swelling or 
rash at the puncture site 
• 
Headache – may be severe and last up to several days and could require further treatment 
• 
Persistent low-pressure headache due to leakage of CSF. If this type of “spinal headache” persists, it 
may require additional treatment.  The chances of having a spinal headache depend on many factors 
including age, weight, and size of needle used for the LP. A spinal headache may occur up to 5 days 
after the LP procedure. This type of headache usually is described as more severe when upright and 
gets better when lying down.  
Conservative management includes adequate hydration and or drinking things high in caffeine like 
Mountain Dew, or strict bedrest for 24-48 hours.  
Uncommonly, if conservative treatment fails, a blood patch (injection of some of participant blood into 


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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the lumbar puncture site to patch the CSF leak) may be required. 
o Rare risks and complications (less than 1 in 100 people) 
• 
Bleeding at the site of the needle insertion or into the spinal canal can be immediate or delayed. Often 
harmless but may cause leg problems. Lower limb weakness or numbness is an exceedingly 
uncommon complication. It may vary from mild to severe. It usually lasts only a short time but rarely 
can be permanent. 
• 
Infection may occur at the needle site and affect the bones of the back or the spinal fluid. It is very 
rare but death from meningitis can occur. 
• 
Needle injury problems are uncommon and include occasional implantation of skin cells that can 
cause local lumps or tumors (dermoids). They are harmless and may need surgical removal, which is 
extremely rare. 
• 
Brain Herniation or Coning (Movement of the brain) is an exceedingly rare condition that can lead to 
death or severe disability. Death as a result of this procedure is ultra-rare. 
 
g) Risks from Radiation Exposure (Lumbar Puncture with Fluoroscopy):  
o If clinically indicated due to obesity, arthritis, scoliosis or any other condition that makes it difficult to 
identify the correct insertion point on the lumbar spine, the lumbar puncture will be completed with 
fluoroscopy, an imaging technique using X-ray. Fluoroscopy involves exposure to radiation. The amount 
of radiation exposure that you will receive from this procedure is equivalent to a uniform whole-body dose 
of 300 mrem (a unit of radiation exposure) which is approximately 0.5 times the average 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 that you will receive from this study is considered to be 
low when compared to other everyday risks each member of the general public receives per year, 
depending on the amount of radiation you personally have been exposed to in the past, particularly in the 
previous year. 
If you have had radiation (like x-rays) before, please tell us now. We want to make sure that the 
probability of harm from the amount of radiation you will be exposed to in this study continues to be low 
when combined with the radiation you have received within the past year. If you are pregnant, you cannot 
take part in this research study. If you are able to have a baby, are not pregnant and wish to take part in 
this study, we will give you a urine test to be sure that you are not pregnant now. This test will be free. If 
you get pregnant while taking part in this study, or you think you are pregnant, please tell Dr. Gonzales 
right away. 
 
h) COVID-19 Swab Test: 
During the COVID-19 nasopharyngeal swab test you will have a 6-inch swab (similar to a long Q-tip) 
inserted into your nose into the passageway that connects the base of the nose to the back of the throat. 
The swab will be rotated to collect fluids. The procedure will be performed on both nostrils. This may cause 
discomfort, cause you to experience a “gagging” reflex, or have a lachrymal reflex “cause your eyes to 
become teary.” 
 
It is possible that the COVID-19 test could produce an incorrect test result “false-negative.”  If you have 
symptoms of COVID-19 and your test result is negative, the study doctor may stop your study treatment 
until your symptoms resolve and a repeat COVID-19 test is performed 
 
For more information about risks and side effects, ask one of the researchers or study staff. 
 
We will tell you about any significant new findings which develop during the course of this research which may 
relate to your willingness to continue taking part.   


Title of Study: Title of Study: Cognition, Age, and RaPamycin Effectiveness – DownregulatIon of thE mTor 
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Are there Risks related to withdrawing from the study?  
If you decide to withdraw from this study early, please discuss your decision with the principal investigator 
and/or co-principal investigator.  The researchers may ask you to complete study withdrawal procedures at a 
final study visit.  This visit includes lumbar puncture, blood draw, cognitive assessment, and physical 
functioning and sensory assessment. There is no risk to you if you do not complete the final withdrawal 
procedures and you can choose not to participate in them. 
 
Are there risks if you also participate in other research studies? 
Being in more than one research study at the same time may increase the risk to you.  It may also affect the 
results of the studies.  You should not take part in more than one study without approval from the researchers.   
 
What if a research-related injury occurs?  
The researchers have taken steps to minimize the known or expected risks.  However, you may still 
experience problems or side effects, even though the researchers are careful to avoid them.  In the event of a 
research-related injury or if you experience an adverse reaction, please immediately contact your study doctor.  
See the section “Contact Information” for phone numbers and additional information.  You may also need to tell 
your regular doctors. 
 
If you are injured or made sick from taking part in this research study, medical care will be provided. This care 
may be billed to you or your insurance. Depending on the circumstances, this care may be provided at no cost 
to you. We have no plans to give you money if you are injured. The investigator can provide you with more 
information.  
 
If you sign this form, you do not give up your right to seek additional compensation if you are harmed as a 
result of being in this study. 
 
Benefits – “How could you or others benefit from your taking part in this study?” 
There is no guarantee or promise that you will receive any benefit from this study.  
 
We hope the information learned from this study will benefit other people with similar conditions in the future. 
 
Alternative procedures or course of treatment – “What other options are there to participation in this 
study?” 
There are other options available to you.  Your other choices may include: 
 
The standard of care for early stage AD that does not involve research is treatment with cholinesterase 
inhibitors (Aricept [donepezil], Exelon [rivastigmine], Razadyne [galantamine]) and /or Namenda [memantine].  
There are no standard of care medications for MCI. Cholinesterase inhibitors and Namenda cannot stop the 
damage Alzheimer’s disease causes to brain cells, but may stabilize symptoms for a limited time or slow the 
progression of the disease in some cases. For the current study, participants can continue treatment as usual 
and remain on cholinesterase medications and/or Namenda, if they have maintained a stable dose for at least 
three months.  
 
Many clinical trials for MCI and AD are ongoing. A list of available trials can be found at this link after creating a 
secure account: https://trialmatch.alz.org/find-clinical-trials#createaccount 
 
As no disease-modifying treatments for AD are available, the progression of the disease is similar for no 
treatment and treatment as usual. AD gradually progresses over time and cognitive and functional abilities 
become more impaired. In the severe stages, AD is associated with complications that ultimately lead to death. 
Individuals with MCI convert to dementia at a rate of 10-15% per year, but not all individuals will convert.  
 
Payments – Will there be any payments for participation? 


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The researchers will provide you with a MasterCard®.  Compensation will be automatically credited after 
completion of each study visit Your name, address and date of birth will be shared with a third-party solely for 
the purposes of compensation processing.  This information will only be used for the administration of the 
compensation (ClinCard) and will be kept strictly confidential.   
 
A schedule of payments is shown below. The total potential reimbursement to a subject is $435 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 ad-hoc basis with prior 
approval from the funding sponsor. 
 
Table 2. Participant Compensation 
Study Visit 
Compensation Amount 
Visit 1: Screening and Consent 
$35 
Visit 2 
$75 
Visit 3 
$75 
Visit 4, 5, 6 
$25 each 
Visit 7 
$100 
Visit 8 
$75 
Manual Payment (unscheduled visit, lab visit, or AE) 
$25 
 
If you are paid, the money you receive may be taxable.  When the total payment is $600 or more in one 
calendar year, the institution must report the amount to the IRS.  The IRS considers it earned income and 
treats it like any other income.  
 
Costs – Will taking part in this study cost anything? 
While being seen at the study sites for this study, you or your health insurance company will be responsible for 
the cost of treatments and procedures that are not part of this study. It is important to understand that some 
insurance companies do not cover some costs (for example, approved drugs used in a way different from the 
package instructions). If your insurance company does not cover these treatments or procedures, you will be 
required to pay for them. 
 
Ask the researchers if you have any questions about what it will cost you to take part in this study (for example 
bills, fees, or other costs related to the research). 
 
The sponsor will provide the study drug free of charge during this study.  At the end of your participation, you 
must return all unused study drug to the researcher.   
 
Confidentiality – How will your records be kept confidential? 
Information we learn about you in this study will be handled in a confidential manner, within the limits of the 
law.  If we publish the results of the study in a scientific journal or book, we will not identify you.  The 
Institutional Review Board and other groups that have the responsibility of monitoring research may want to 
see study records which identify you as a subject in this study.    
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the Federal Government. 
With this Certificate, the researchers cannot be forced to disclose information that may identify you, even by a 
court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings.  
The researchers will use the Certificate to resist any demands for information that would identify you, except as 
explained below.  The Certificate cannot be used to resist a demand for information from personnel of the 
United States Government that is used for auditing or evaluation of federally funded projects or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA).  
You should understand that a Certificate of Confidentiality does not prevent you or a member of your family 
from voluntarily releasing information about yourself or your involvement in this research.  If an insurer, 


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employer, or other person obtains your written consent to receive research information, then the researchers 
may not use the Certificate to withhold that information. 
 
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, without your 
consent, information that would identify you as a participant in the research project under certain 
circumstances.  Circumstances that warrant the release of your information without your permission include: 
abuse and/or neglect, intention to harm yourself or others, or certain communicable diseases. 
 
Limits of Confidentiality 
Even without your consent, suspected or known abuse or neglect of a child, disabled, or elder abuse, 
threatened violence to self or others or other local health reporting requirements will be reported to appropriate 
authorities. 
 
Research policies require that private information about you be protected and this is especially true for your 
health information.  However, the law sometimes allows or requires others to see your information.  The 
information given below describes how your privacy and the confidentiality of your research records will be 
protected in this study. 
 
What is Protected Health Information (PHI)?   
Protected Health Information is information about a person’s health that includes information that would make it 
possible to figure out whose it is.  According to the law, you have the right to decide who can see your 
protected health information.  If you choose to take part in this study, you will be giving your permission to the 
investigators and the research study staff (individuals carrying out the study) to see and use your health 
information for this research study.  In carrying out this research, the health information we will see and use 
about you will include: 
• 
your medical history and blood work,  
• 
information that we get from your medical record,  
• 
information contained in your underlying medical records related to your medical history and treatments 
prior to the study,  
• 
information that is created or collected during your participation in the study including medical and 
treatment history,   
• 
information you give us during your participation in the study such as during interviews or from 
questionnaires, results of blood tests; demographic information like your age, marital status, the type of 
work you do and the years of education you have completed. 
 
We will get this information by asking you, asking your doctor, by looking at your chart at the UT Medicine 
clinics at UT Health San Antonio or University Hospital. 
 
How will your PHI be shared?   
Because this is a research study, we will be unable keep your PHI completely confidential.  We may share your 
health information with people and groups involved in overseeing this research study including: 
• 
the company funding the study 
• 
the company (Pfizer, Inc) that makes the study drug/device.  
• 
the following collaborators at other institutions that are involved with the study and not affiliated with the UT 
IRB: Mayo Clinic and Wake Forest University Medical Center 
• 
the Barshop Institute’s Claude D. Pepper Center Data and Safety Monitoring Board (DSMB) - the 
committee that checks the study data on an ongoing basis, to determine if the study should be stopped for 
any reason. 
• 
the members of the local research team 
• 
the Institutional Review Board and the Compliance Office of the University of Texas Health Science Center 
at San Antonio, and other groups that oversee how research studies are carried out.  


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• 
The Research offices at [the University of Texas Health Science Center at San Antonio, University Health 
System (UHS).   
• 
the Food and Drug Administration (FDA) and other U.S. and international governmental regulatory 
agencies involved in overseeing drug or device research 
 
If you decide to participate in this study, you will be giving your permission for the groups named above, to 
collect, use and share your health information.  If you choose not to let these groups collect, use and share 
your health information as explained above, you will not be able to participate in the research study. 
 
Parts of your PHI may be photocopied and sent to a central location or it may be transmitted electronically, 
such as by e-mail or fax. The groups receiving your health information may not be obligated to keep it private.  
They may pass information on to other groups or individuals not named here.   
 
The Genetic Information Nondiscrimination Act (GINA) is a Federal law that will protect you in the following 
ways: 
• 
Health insurance companies and group plans may not request genetic information from this research; 
• 
Health insurance companies and group plans may not use your genetic information when making 
decisions regarding your eligibility or premiums; 
• 
Employers with 15 or more employees may not use your genetic information when making a decision to 
hire, promote, or fire you or when setting the terms of your employment. 
 
GINA does not protect you against genetic discrimination by companies that sell life insurance, disability 
insurance, or long-term care insurance.  GINA also does not protect you against discrimination based on an 
already-diagnosed genetic condition or disease. 
 
How will your PHI be protected?   
In an effort to protect your privacy, the study staff will use code numbers instead of your name, to identify your 
health information.  Initials and numbers will be used on any photocopies of your study records, and other 
study materials containing health information that are sent outside of the UT Health San Antonio for review or 
testing.  If the results of this study are reported in medical journals or at meetings, you will not be identified. 
 
Do you have to allow the use of your health information? 
You do not have to allow (authorize) the researchers and other groups to see and share your health 
information.  If you choose not to let the researchers and other groups use your health information, there will 
be no penalties but you will not be allowed to participate in the study.   
 
After you enroll in this study, you may ask the researchers to stop using your health information at any time .  
However, you need to say this in writing and send your letter to Mitzi Gonzales, PhD or Dean L. Kellogg, Jr, 
MD, PhD, UT Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229.  If you tell the 
researchers to stop using your health information, your participation in the study will end and the study staff will 
stop collecting new health information from you and about you for this study.  However, the study staff will 
continue to use the health information collected up to the time they receive your letter asking them to stop. 
 
Can you ask to see the PHI that is collected about you for this study?   
The federal rules say that you can see the health information that we collect about you and use in this study.  
Contact the study staff if you have a need to review your PHI collected for this study. 
Because of the type of research, you can only access your PHI when the study is done.  At that time, you have 
the right to see and copy the medical information we collect about you during the study, for as long as that 
information is kept by the study staff and other groups involved.   
How long will your PHI be used?   
 
By signing this form, you agree to let us use and disclose your health information for purposes of the study until 
02-28-2030.  This permission to use your personal health information expires on the date noted above. 


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Contact Information – Who can you contact if you have questions, concerns, comments or 
complaints? 
 
If you have questions now, feel free to ask us.  If you have additional questions, concerns, comments or 
complaints later or you wish to report a problem which may be related to this study please contact: 
 
Primary contacts: 
Haritha Katragadda can be reached at 210-450-3167 during normal work hours. 
 
 . For medical concerns after hours please contact the research doctor on call at 210-258-4605. 
 
  
The University of Texas Health Science Center committee that reviews research on human subjects 
(Institutional Review Board) will answer any questions about your rights as a research subject, and take any 
concerns, comments or complaints you may wish to offer.  You can contact the IRB by calling 210-567-8250, 
or by mail to IRB, UTHSCSA, Mail Code 7830, 7703 Floyd Curl Drive, San Antonio, TX  78229-3900. 


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Research Consent & HIPAA Authorization Signature Section 
If you agree to participate in this research and agree to the use of your protected health information in this 
research sign this section. You will be given a signed copy of this form to keep.  You do not waive any of your 
legal rights by signing this form.   
 
SIGN THIS FORM ONLY IF THE STATEMENTS LISTED BELOW ARE TRUE 
• 
You have read the above information. 
• 
Your questions have been answered to your satisfaction about the research and about the collection, use 
and sharing of your protected health information.    
 
Adult Signature Section 
• 
You have voluntarily decided to take part in this research study. 
• 
You authorize the collection, use and sharing of your protected health information as described in this form. 
 
 
 
 
 
 
 
AM 
PM 
Printed Name of Subject 
 
 
 
Signature of Subject 
 
 
Date 
 
Time 
 
AM 
PM 
Printed Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
Time 
 
  Check if consent and authorization obtained from an individual who is unable to read and/or write but can otherwise communicate and/or comprehend English. Have witness initial below. 
Declaration of witness:  I was present for the entire consent process.  ________ ←(initials of witness) 
 
 
 
 
 
 
AM 
PM 
Printed Name of Person Obtaining 
Consent & Authorization 
 
Signature of Person Obtaining Consent & 
Authorization  
 
 
Date 
 
Time 
Consent and authorization was obtained from this individual who is unable to read and/or write but can otherwise communicate and/or comprehend English.   The method used 
for communication with the subject was: ______________________.   
The specific means by which the subject communicated agreement to participate was: ____________________________________ 
 
Surrogate Signature Section   
• 
You are voluntarily giving your consent for another person to participate in this study because you believe 
this person would want to take part if able to make the decision and you believe it is in this person’s best 
interest.   
• 
You also authorize the collection, use and sharing of another person’s protected health information as 
described in this form. 
 
AM 
PM 
Printed Name of Subject 
 
 
 
Signature of Subject, indicating Assent  
(If incapable of signing, person obtaining consent 
should initial here) 
 
 
Date 
 
Time 
 
 
AM 
PM 
Printed Name of Person Giving 
Consent & Authorization for Subject    
 
 Signature of Person Giving Consent & Authorization 
Family Member/Guardian/Legally Authorized 
Representative 
 
 
Date 
 
Time 
 
 
AM 
PM 
Printed Name of Witness  
 
Witness Signature 
 
 
 
Date 
 
Time 
 
 
AM 
PM 
Printed Name of Person Obtaining 
Consent & Authorization 
 
Signature of Person Obtaining Consent & 
Authorization 
 
Date 
 
Time