Cognition, Age, and RaPamycin Effectiveness - DownregulatIon of thE mTor Pathway (CARPE DIEM)
Phase: EARLY_PHASE1
Conditions: Cognitive Impairment, Mild, Alzheimer Disease
Sponsor: The University of Texas Health Science Center at San Antonio

 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Title: CARPE DIEM Study  
 
Page ii 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page iii 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
 
 
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 

Title: CARPE DIEM Study  
 
Page iv 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 
 
 
 

Title: CARPE DIEM Study  
 
Page v 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
 
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 
 
page 1 
Version: 10-16-20 v1.7.1 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
Revised version:2-05-2021 v1.7.4 
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 
 

Title: CARPE DIEM Study  
 
Page 2 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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.  

Title: CARPE DIEM Study  
 
Page 3 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
1. Introduction 
 
This document is a protocol for a human research study. This study will be conducted according to Good 
Clinical Practice guidelines as adopted by FDA, applicable government regulations, and within Institutional 
research policies and procedures.  
1.1. 
Background 
The 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 

Title: CARPE DIEM Study  
 
Page 4 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
(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 
 

Title: CARPE DIEM Study  
 
Page 5 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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,). 

Title: CARPE DIEM Study  
 
Page 6 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page 7 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
 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 

Title: CARPE DIEM Study  
 
Page 8 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page 9 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page 10 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page 11 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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: 

Title: CARPE DIEM Study  
 
Page 12 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
• 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 

Title: CARPE DIEM Study  
 
Page 13 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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, 

Title: CARPE DIEM Study  
 
Page 14 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page 15 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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, 

Title: CARPE DIEM Study  
 
Page 16 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page 17 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page 18 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 
 

Title: CARPE DIEM Study  
 
Page 19 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
 
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 
  
 
 

Title: CARPE DIEM Study  
 
Page 20 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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) 

Title: CARPE DIEM Study  
 
Page 21 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
• 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 

Title: CARPE DIEM Study  
 
Page 22 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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. 
 

Title: CARPE DIEM Study  
 
Page 23 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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: 

Title: CARPE DIEM Study  
 
Page 24 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
 
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 

Title: CARPE DIEM Study  
 
Page 25 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
• 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. 

Title: CARPE DIEM Study  
 
Page 26 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
• 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 

Title: CARPE DIEM Study  
 
Page 27 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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 

Title: CARPE DIEM Study  
 
Page 28 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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. 

Title: CARPE DIEM Study  
 
Page 29 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
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. 
 
 

Title: CARPE DIEM Study  
 
Page 30 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
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 

Title: CARPE DIEM Study  
 
Page 31 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
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)  
 

Title: CARPE DIEM Study  
 
Page 32 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
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.  
 

Title: CARPE DIEM Study  
 
Page 33 
Version 12-21-20 v1.7.2 
 
19-850H, Gonzales, Form BB, 06-18-21, AMD.docx 
 
 
 
19-850H, 
Gonzales, Form BB, 06-18-21, AMD.docx 
CONFIDENTIAL 
**v1.4 changes included with v1.5 changes and submitted together for IRB approval (amendment dated 7-01-
2020)