Conditions: Alzheimer's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
This is a Phase II, randomized, double blind, placebo controlled, parallel group, proof of concept three-site study, to evaluate the effect of Rasagiline in the regional brain metabolism on 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG-PET).

Detailed description:
The study consists of two phases: a 24 week double blind placebo controlled treatment period and a 4 week follow up period. Patients will be randomized in a 1: 1 ratio at baseline to receive either Rasagiline or matching placebo

The study drug will be given as 0.5 mg dose once daily for the 4 weeks, then increases to 1 mg daily for the next 20 weeks. A total of 50 subjects will be enrolled: 25 will receive Rasagiline and 25 will receive matching placebo for the 24-week treatment period.

Primary objective is to determine if exposure to 1 mg of Rasagiline daily is associated with improved regional brain metabolism in the treatment group compared to the placebo group in Alzheimer's Disease patients

Arms:
arm 1: Subjects will be randomized in 1:1 ratio to receive Rasagiline or the matching placebo 24-week double blind treatment.

Subjects will take one 0.5 mg Rasagiline tablet or the matching placebo once a day on Baseline (Day 1) through Week 4. The dose will be titrated up to one 1 mg tablet or the matching placebo once a day starting on Week 5 until the Week 28 (end of treatment visit). arm 2: Subjects will be randomized in 1:1 ratio to receive Rasagiline or the matching placebo 24-week double blind treatment.

Subjects will take one 0.5 mg Rasagiline tablet or the matching placebo once a day on Baseline (Day 1) through Week 4. The dose will be titrated up to one 1 mg tablet or the matching placebo once a day starting on Week 5 until the Week 28 (end of treatment visit).

Interventions: intervention 1: Rasagiline intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
1 of 54
A 24-week, Three-site, Randomized, Double Blind, Placebo 
Controlled, Parallel Group, Proof-of-concept Study to evaluate the 
effect of Rasagiline in the regional brain metabolism on FDG PET in 
Patients with Mild to Moderate Alzheimer’s Disease 
 
(Rasagiline Rescue in Alzheimer’s Disease Clinical Trial) 
 
 
Amendment #5 
 
Compound: Rasagiline 
Protocol number: R2-001  
Phase: II  
 
Sponsor Investigator: Jeffrey L. Cummings, MD, ScD 
Director, Cleveland Clinic Lou Ruvo Center for Brain Health 
 
888 West Bonneville Avenue 
Las Vegas, NV  89106 
702-483-6031 (phone) 
702-483-6028 (fax)  
cumminj@ccf.org 
 
 
Co-Investigators: 
James Leverenz, MD, Director, Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Site 
Babak Tousi, MD, Director, Geriatrics Program, Cleveland Clinic, Lakewood Site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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PROTOCOL SYNOPSIS 
TITLE 
A 24-week, Three-site, Randomized, Double Blind, Placebo Controlled, 
Parallel Group, Proof-of-concept Study to evaluate the effect of Rasagiline in 
the regional brain metabolism on FDG PET in Patients with Mild to Moderate 
Alzheimer’s Disease 
(Rasagiline Rescue in Alzheimer’s Disease Clinical Trial) 
 
STUDY NAME 
R2 Trial 
NAME OF ACTIVE 
INGREDIENT 
Rasagiline mesylate 
NAME OF INVESTIGATIONAL 
PRODUCT 
Azilect® (rasagiline) 
STUDY PHASE 
Phase II 
INDICATION 
Mild to Moderate Alzheimer’s Disease 
PRIMARY OBJECTIVE  
To determine if exposure to 1 mg of Rasagiline daily  is associated with 
improved regional brain metabolism in the treatment group compared to the 
placebo group in Alzheimer’s Disease patients  
 
SECONDARY OBJECTIVES 
 
To evaluate the efficacy of Rasagiline 1 mg once daily compared to 
placebo after a 24-week treatment on cognition (ADAS-Cog 11), 
activities of daily living (ADCS-ADL), global function (CGIC), and 
neuropsychiatric symptoms (NPI)  
 
To evaluate the efficacy of Rasagiline 1 mg once daily compared to 
placebo after 24 week treatment on measures of executive function 
(mazes and cancellation of the ADAS-Cog, Digit Span test, and 
Controlled Oral Word Association Test [COWAT] for verbal 
fluency)To evaluate the safety and tolerability of rasagiline as 
measured by incidence of adverse events/serious adverse events 
(AEs/SAEs), clinical laboratory test data, vital signs, 12 lead EKG 
data, brain MRI findings 
 
To correlate the relationship of changes in 18F-AV-1451 Tau imaging 
to clinical measures 
 
STUDY DESIGN 
This is a Phase II, randomized, double blind, placebo controlled, parallel 
group, proof-of-concept three-site study, to evaluate the effect of rasagiline in 
the regional brain metabolism on FDG PET.   
The study consists of two phases: a 24-week double blind placebo controlled 
treatment period and a 4-week follow-up period. Patients will be randomized 
to a 1:1 ratio at Baseline to receive either rasagiline or matching placebo.  


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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The study drug will be given as 0.5 mg dose once daily for the first 4 weeks; 
it will be increased to 1 mg daily for the next 20 weeks. A total of 50 subjects 
will be enrolled: 25 will receive rasagiline and 25 will receive matching 
placebo for the 24-week treatment period.   
STUDY ENDPOINTS  
Primary Endpoint  
The primary study endpoint is the change from Baseline to Week 24 in 
regional glucose metabolism as measured by standard uptake units regional 
(SUVr) obtained through the FDG-PET. 
Secondary Endpoints  
 Change from Baseline to Week 24 in18F-AV-1451  Tau PET imaging SUVr  
 Change from Baseline to Week 24 on the scores of MMSE, ADAS-Cog 11 
and CGIC 
 Change from Baseline to Week 24 on the scores of NPI and ADCS-ADL 
 Change from Baseline to Week 24 on the scores of Digit Span test, 
COWAT and QoL–AD/Study Partner 
 Correlation between changes in clinical measures (rasagiline vs. placebo 
change from baseline) and SUVr for FDG PET and SUVr for18F-AV-1451  
Tau PET 
 Correlation between SUVr for FDG PET and SUVr for18F-AV-1451  Tau 
PET 
 Safety and tolerability as measured by incidence of adverse events/serious 
adverse events (AEs/SAEs), clinical laboratory test data, vital signs, 12-
lead EKG data 
 Proportion of subjects with adverse events, serious adverse events and 
adverse events leading to discontinuation over the 24-week double blind 
treatment period  
 Proportion of subjects with laboratory abnormalities  
 Proportion of subjects with EKG abnormalities 
SAMPLE SIZE 
Target enrollment is 50 subjects and will be recruited from three sites of the 
Cleveland Clinic Lou Ruvo Center for Brain Health – Las Vegas, Cleveland 
Main Campus and Lakewood sites 
KEY INCLUSION CRITERIA  
 Males or females 50 to 90 of age inclusive 
 Diagnosis of probable AD (NINCDS-ADRDA criteria) 
 Positive fluorodeoxyglucose PET ([18F]-FDG PET) scan compatible with 
AD as determined by the ADM Diagnostics LLC (ADMdx) criteria at 
screening  
 Must be willing to undergo18F-AV-1451  Tau PET scan at Baseline and 
Week 24 visits 
 MMSE = 12-26 (inclusive) 
 Must have a study partner who is able and willing to comply with all required 
study procedures 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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 Have at least eight years of education and should have previously (in pre-
AD condition) been capable of reading, writing, and communicating 
effectively with others in English 
 If receiving therapy with a cholinesterase inhibitor and/or memantine, the 
dose of these agents has been stable for at least 60 days prior to screening 
 KEY EXCLUSION CRITERIA  
 Any non-AD neurological disease 
 MRI findings indication of a non-AD diagnosis 
 Screening laboratory studies that are 1.5 times above or below the highest 
and lowest range of normal for each test, respectively 
 History of melanoma; history of malignancy within the past five years 
with the exception of basal cell or squamous cell carcinoma, in-situ 
cervical carcinoma, or localized prostate cancer  
DISALLOWED MEDICATIONS 
 Meperidine (Demerol) 
 Ciprofloxacin 
 MAO inhibitors such as but not limited to the following: Isocarboxazid, 
Phenelzine, Selegiline, and Tranylcypromine. 
 Dextromethorphan and Nuedexta 
 Hydroxyzine  
 Diphenhydramine  
 Scopolamine  
 Cyproheptadine 
 Oxybutynin  
 Fesoterodine 
 Solifenacin  
 Darifenacin  
 Dicyclomine  
 Glycopyrrolate 
 Antipsychotics such as but not limited to the following most commonly used 
antipsychotic medications: Haloperidol, Quetiapine, Ziprasidone, and 
Risperidone 
 
MEDICATIONS WITH LIMITED 
DOSES 
Antidepressants are excluded with the following exceptions: 
 
Amitriptyline < 50 md/d 
 
Trazodone < 100 mg/d 
 
Citalopram < 20 mg/d 
 
Escitalopram < 10mg/d 
 
Sertraline < 100 mg/d 
 
Paroxetine < 30 mg/d 
 
Mirtazapine < 30 mg/d 
 
Buspirone < 30mg/d 
 
Fluoxetine <40 mg/d 
 
Bupropion <150 mg/d 
 
Duloxetine <60 mg/d 
 
Venlafaxine <125 mg/d 
 
No hypnotic the night prior to or day of PET scan preceding the scan 
 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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DIETARY ADJUSTMENT 
High tyramine-containing foods will be avoided: 
 
Sausages, salami, pickled herring 
 
Fava beans 
 
Tap beers, non-pasteurized beers 
 
Sauerkraut, yeast extract, soybean products including soy sauce 
 
Aged cheeses 
 
DRUG DOSAGE AND 
FORMULATION 
Subjects will take one 0.5 mg dosage Rasagiline tablet or the matching placebo 
once a day orally from Baseline visit to Week 4 visit. The dose will be titrated 
to one 1 mg dosage tablet or the matching placebo once a day starting on Week 
5 through Week 24. 
 
DURATION OF PARTICIPATION 
This is a 34-week study comprised of 7 in-clinic visits 
PLACEBO 
A matching oral placebo will be used 
ROUTE OF ADMINISTRATION 
Oral 
PROCEDURES 
Physical and neurological exam, MRI, [18F]-FDG PET,  18F-AV—1451 
Tau PET, ECG, vitals, clinical laboratory tests, MMSE, ADAS-Cog 11, 
CGIC, NPI, ADCS-ADL, Digit Span, COWAT, QoL–AD/Study Partner 
 
STATISTICAL CONSIDERATION 
Intent-to-Treat (ITT) - The primary FDG analysis will include all patients who 
received both a screening and end of study scan of acceptable quality.  
Modified Intent-to-Treat (mITT) – All randomized subjects who have been 
dispensed study medication and have one post-baseline visit during the 
blinded phase of the study. 
Per-protocol (PP) population – All ITT subjects who complete the study 
(Week 24) and have ingested between 80%to 120% of the prescribed study 
medication as measured by pill count. 
Observed case – An observed case analysis of all patients completing the study 
will be conducted. 
Last Observation Carried Forward (LOCF) – Clinical data imputation will use 
the LOCF approach for missing patients. 
Responder analysis – Responders will be defined as those that have a 
significant improvement on brain metabolism on FDG for the whole brain or 
for any of the pre-specified regions. 
A secondary analysis will compare the changes in FDG at 24 weeks compared 
to the projected expected metabolism based on the Baseline FDG findings. 
ADVERSE EVENTS  
SAFETY 
Orthostatic vital signs, ECG, hematology, chemistry, TSH, B12 and urinalysis 
(UA) collected at Screening and at end of study 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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TOLERABILITY 
Side effects data will be collected and converted to systems data using a data 
dictionary. 
DSMB   No Independent DSMB is required. 
 
1. PROTOCOL AMENDMENT #5 SUMMARY OF CHANGESChange made to inclusion criteria: MMSE 12-
26 (inclusive); previously 12-22 (inclusive)  
PROTOCOL AMENDMENT #4 SUMMARY OF CHANGES 
1. 
Addition of other allowed medications 
2. 
Change made to inclusion criteria #8 stable dose changed from 3 months to 60 days. 
 
PROTOCOL AMENDMENT # 3 SUMMARY OF CHANGES  
1. Clarification on allowed antidepressants 
2. Cyclobenzaprine changed from disallowed medications to allowed medications  
3. Addition of other allowed medications 
4. Addition of other disallowed medications 
 
PROTOCOL AMENDMENT # 2 SUMMARY OF CHANGES  
Addition of the language “T1 sequencing” at Section 7.1 Screening Visit bullet MRI part  
PROTOCOL AMENDMENT # 1 SUMMARY OF CHANGES  
1. Addition of 18F-AV-1451 Tau imaging in Screening visit as a non-optional sub-study 
2. Addition of 18F-AV-1451 Tau imaging Companion Protocol 
3. Change from the use of the CIBIS+ and CIBIC+ to CGIC for the visit assessments 
4. Change from QoL–Treatment/Patient to QoL–AD/Caregiver 
5. Change from ADAS-Cog 13 to ADAS-Cog 11 rating scale 
6. Addition of OSU-TBI-ID 
7. Change in Brain MRI Sequence 
 
 
 
 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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TABLE OF CONTENTS 
 
Title Page …………………………………………………………………………………………...  
1 
Protocol Synopsis...............................................................................................................................  
2 
Protocol Amendment # 1 Summary of Changes ................................................................................  
6 
Table of Contents ...............................................................................................................................  
7 
Abbreviations …………………………………………………………………………………..…… 
11 
1. Novelty and Relevance ..................................................................................................................  
12 
1.1 Introduction .....................................................................................................................  
12 
1.2 Preclinical Data ...............................................................................................................  
12 
1.3 Pharmacology of Rasagiline ...........................................................................................  
13 
1.4 Clinical Data … ..............................................................................................................  
13 
1.5 Application to Alzheimer’s Disease ...............................................................................  
14 
2. Supporting Data .............................................................................................................................  
14 
2.1 Glucose Metabolism as a Biomarker of Neuronal Function ...........................................  
14 
2.2 Dementia Classifier .........................................................................................................  
15 
2.3 AD Progression Classifier ...............................................................................................  
15 
2.4 Predicting Cognitive Trajectories … ..............................................................................  
16 
2.5 Glucose Metabolism as a Measure of Drug Effect .........................................................  
17 
2.6 Tau Imaging as a Measure of Drug Effect……………………………………………..          17 
3. Study Objectives and Endpoints  ...................................................................................................  
18 
3.1 Primary Objective ……………………………………………………………………… 
18 
3.2 Secondary Objectives ………………………………………………………………….. 
18 
3.3 Primary Endpoint ………………………………………………………………………  
18 
3.4 Secondary Endpoints …………………………………………………………………… 
18 
4. Study Design ..................................................................................................................................  
18 
5. Subject Selection and Withdrawal .................................................................................................  
20 
5.1 Inclusion Criteria ............................................................................................................  
20 
5.2 Exclusion Criteria ...........................................................................................................  
20 
5.3 Subject Recruitment  .......................................................................................................  
21 
5.4 Subjects Withdrawal .......................................................................................................  
22 
5.5 Data Collection and Follow-up for Withdrawn Subjects ................................................  
22 
6. Study Treatment  ............................................................................................................................  
22 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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6.1 Study Drug  .....................................................................................................................          22 
6.2 Treatment Regimen .........................................................................................................  
23 
6.3 Administration of Treatment  ..........................................................................................  
23 
6.4 Subject Compliance Monitoring .....................................................................................  
23 
6.5 Prior and Concomitant Therapy ......................................................................................  
23 
6.6 Blinding of Study Drug ………………………………………………………………..  
25 
6.7 Receiving, Storage, Dispensing and Return ....................................................................  
25 
6.7.1 Receipt of Drug Supplies ................................................................................  
25 
6.7.2 Storage ............................................................................................................  
25 
6.7.3 Packaging of Study Drug …………………………………………………… 
25 
6.7.4 Dispensing of Study Drug ...............................................................................  
25 
6.7.5 Return or Destruction of Study Drug ..............................................................  
25 
7. Description of Study Visits ............................................................................................................  
26 
7.1 Visit 1 – Screening (Days -60 to -1) ...............................................................................   
26 
7.2 Visit 2 – Baseline (Day 1) …………………………………………………………… ..  
26 
7.3 Visit 3 – Week 4 …………………………………………………………….. ...............  
27 
7.4 Visit 4 – Week 8 ……………………………………………………………. ................  
28 
7.5 Visit 5 – Week 24 …………………………………………………………… ...............  
28 
7.6 Visit 6 – Follow-up Visit/End of Study/Early Discontinuation (Week 28) ....................  
29 
7.7 Unscheduled Visits .........................................................................................................  
29 
7.8 Study Calendar of Procedures .........................................................................................  
29 
8. Study Specific Procedures ……………………………………………………………………….          31 
8.1 Cognitive Evaluations …………………………………………………………………          31 
8.1.1 Mini-Mental State Examination (MMSE) …………………………...……..          31 
8.1.2 Alzheimer’s Disease Assessment Scale-Cognitive 11 (ADAS-Cog 11) ….            31 
8.2 Clinical and Functional Evaluations …………………………………………………..          31 
8.2.1 Clinician Global Impression of Change (CGIC) ………………………...…          31 
8.2.2 Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)....      31 
8.2.3 Neuropsychiatric Inventory (NPI) ………………………………………….          31 
      8.2.4 Controlled Oral Word Association Test (COWAT)………………………….         32 
      8.2.5 Digit Span…………………………………………………………………….         32 
      8.2.6 QoL-AD/Study Partner ………………………………………………………         32 
      8.2.7 Ohio State University Traumatic Brain Injury Identification Method  
                (OSU TBI-ID) Questionnaire ………………………………………………          32 


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THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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9.  Study Methods….………………………………………………………………………………..         33 
 
9.1 
Safety Assessments ………………………………………………………………….         33 
 
9.2  Concomitant Medications ……….………………..…………………………………         33 
 
9.3 
Physical Examination ………………………………………………………………..        33 
 
9.4 
Neurological Examination …………………………………………………………...        33 
 
9.5 
Electrocardiogram (ECG) ……………………………………………………………        34 
 
9.6  Orthostatic Vital Signs………. ………………………………………………………        34 
 
9.7  Clinical Laboratory Evaluation ………………………………………………………        34 
9.8  Biomarker Studies and ApoE Genotyping .………………………………………..…        34 
 
9.9 
MRI ………………………………………………………………………………….         35 
 
9.10   [18F]-FDG-PET Imaging .…..………………………………………………………         35 
 
9.11   18F-AV-1451 Tau PET Imaging ………………………………………………....……         36 
10.  Potential Risks……………………………………….………………………………………….         37 
 
10.1    Rasagiline Treatment Risk…………..………………………………………………         37 
 
10.2    MRI Risk …………………………………………………………………………….        37 
 
10.3    [18F]-FDG-PET Scan Risk ...………………………………………………………..        37 
10.4  CT Scan Risk …………………………………………………………………………       38 
 
10.5    18F-AV-1451 Tau PET Scan Risk……………………………………….……………         38 
             10.6   Radiation Risk …………………………………………………………..……………        38 
10.7  Placebo Risk …………………………………………………………………………        39 
10.8  Blood Draw Risk……………………………………………………………………..         39 
11. Statistical Plan ..............................................................................................................................          38 
11.1 Sample Size Determination ...........................................................................................  
38 
11.2 Statistical Methods ........................................................................................................  
39 
11.3 Subject Populations for Analysis ..................................................................................  
39 
11.4 FDG PET Imaging Analysis .........................................................................................  
40 
11.4.1 Screening Classification ……………………………………..……………         40 
11.4.2 Screening Characterization …………………………………….……….…         40 
11.4.3 Longitudinal Voxel-based Evaluation……………………….….……….…        40 
11.4.4 Longitudinal Region of Interest Evaluation………………….….…………        41 
11.4.5 Correlation to Cognitive Change…………………………….….…………         41 
              11.5 18F-AV-1451 Tau Imaging Analysis ……………………….………………….………          42 
12. Safety and Adverse Events ..........................................................................................................          42 


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R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
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12.1 Definitions ....................................................................................................................  
42 
12.2 Recording of Adverse Events .......................................................................................  
42 
12.3 Reporting of Serious Adverse Events ...........................................................................  
43 
12.3.1 Study Sponsor-Investigator Notification by Investigator .............................  
43 
12.3.2 IRB Notification by Investigator ..................................................................  
43 
12.3.3 FDA Notification by Sponsor-Investigator ...................................................          44 
12.4 Unblinding Procedures..................................................................................................  
44 
12.5 Stopping Rules ..............................................................................................................  
44 
12.6 Medical Monitoring ......................................................................................................  
44 
12.6.1 Internal Data Safety Monitoring Board (DSMB) .........................................  
44 
13. Data Handling and Record Keeping ............................................................................................  
44 
             13.1 Confidentiality and Privacy ..........................................................................................  
44 
13.2 Source Documents ........................................................................................................  
45 
13.3 Case Report Forms ........................................................................................................  
45 
13.4 Records Retention .........................................................................................................  
45 
13.5 Database ........................................................................................................................  
45 
14. Study Monitoring, Auditing, and Inspecting ...............................................................................  
45 
14.1 Study Monitoring Plan ..................................................................................................  
45 
14.2 Audit and Inspection .....................................................................................................  
45 
15. Ethical Considerations .................................................................................................................  
45 
16. Study Finances .............................................................................................................................  
46 
16.1 Funding Source .............................................................................................................  
46 
16.2 Conflict of Interest (COI) ..............................................................................................  
46 
16.3 Subject Stipends or Payments .......................................................................................  
46 
17. Publication Plan ...........................................................................................................................  
46 
18. Literature Cited ............................................................................................................................  
47 
19. Appendix A. Technical Description of FDG PET Acquisition and Analysis ..............................  
50 
20. Appendix B. Study Procedure Table ............................................................................................  
55 


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R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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ABBREVIATIONS 
 
AD  
 
Alzheimer’s disease 
ADAGIO 
 
Attenuation of Disease Progression with Azilect® Given Once Daily 
ADAS-cog 11   
Alzheimer’s Disease Assessment Scale, 11 item version 
ADCS-ADL  
 
Alzheimer’s Disease Cooperative Study, Activities of Daily Living  
ADDF   
 
Alzheimer’s Drug Discovery Foundation 
ADMdx   
 
ADM Diagnostics LLC 
ADNI    
 
Alzheimer’s Disease Neuroimaging Initiative 
CBC    
 
Complete blood count 
CC   
 
 
Cleveland Clinic 
CDR 
 
 
Clinical Dementia Rating 
CGIC    
 
Clinician Global Impression of Change 
COWAT   
 
Controlled oral word association test 
CRF 
 
 
Case Report Form 
CT 
 
 
Computed tomography 
DBS 
 
 
Deep Brain Stimulation 
DICOM 
 
Digital Imaging and Communications in Medicine 
ECG    
 
Electrocardiogram 
FDA    
 
Food and Drug Administration 
FDG PET   
 
Fluorodeoxyglucose positron emission tomography 
FTD    
 
Frontotemporal dementia 
GCP 
 
 
Good Clinical Practice 
ICH 
 
 
International Conference on Harmonisation 
IRB   
 
 
Institutional Review Board 
ITT 
 
 
Intent-to-Treat 
LBD 
 
 
Lewy Body Dementia 
LOCF  
 
Last Observation Carried Forward 
LOO    
 
Leave-one-out independent testing approach 
LRCBH   
 
Lou Ruvo Center for Brain Health 
MAO-A 
 
Selective monoamine oxidase A  
MAO-B 
 
Selective monoamine oxidase B 
MAPK  
 
Mitogen-activated protein kinase 
MCI 
 
 
Mild cognitive impairment 
mITT  
 
Modified Intent-To-Treat 
MMSE  
 
Mini Mental State Examination  
MRI    
 
Magnetic Resonance Imaging 
NINCDS-ADRDA 
National Institute of Neurological and Communicative Disorders and Stroke and  
 
 
 
Alzheimer’s Disease and Related Disorders Association 
NPI   
 
 
Neuropsychiatric Inventory 
OSU TBI-ID 
 
Ohio State University Traumatic Brain Injury Identification Method 
QoL  
 
 
Quality of life 
PKC 
 
 
Protein kinase C 
PP 
 
 
Per-protocol 
SUVr    
 
Standardized Uptake Ratio 
 
    
                                                                  


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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A 24-WEEK, THREE-SITE, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, 
PARALLEL GROUP, PROOF-OF-CONCEPT STUDY TO EVALUATE THE EFFECT OF 
RASAGILINE IN THE REGIONAL BRAIN METABOLISM ON FDG PET IN PATIENTS WITH 
MILD TO MODERATE ALZHEIMER’S DISEASE 
 
Rasagiline Rescue in Alzheimer’s Disease Clinical Trial (R2 Trial) 
 
1.  Novelty and Relevance 
1.1 Introduction 
Rasagiline is a selective monoamine oxidase B (MAO-B) inhibitor.  Rasagiline has been used 
extensively for the treatment of Parkinson’s disease (PD) where it is approved for signs and symptoms 
of idiopathic PD as initial monotherapy and as adjunct therapy to levodopa (package insert).  Rasagiline 
is currently being studied in a 24-week, multi-center, randomized, double-blind, placebo-controlled, 
add-on parallel group study to assess the efficacy of rasagiline on cognition in patients with Parkinson’s 
disease (Study TBT-1012-PM106).  Pre-clinical observations (summarized below) document 
neuroprotective activities of rasagiline beyond those of MAO-B inhibition.  The pre-clinical evidence, 
utility in PD, and the history of benefit of selegiline---a related MAO-B inhibitor---in Alzheimer’s 
disease (AD), provide the rational for a clinical trial of rasagiline in AD.  This proposal outlines a 
clinical trial based on a partnership between the Alzheimer’s Drug Discovery Foundation (ADDF), 
Cleveland Clinic Lou Ruvo Center for Brain Health and ADM Diagnostics LLC (ADMdx) to conduct 
a clinical trial in mild to moderate AD.   
 
Several novel aspects are incorporated in the clinical trial design presented.  Rasagiline is a repurposed 
agent and repurposing has many benefits in terms of accelerating development of AD therapies (1,2).   
The use of a biomarker as a primary outcome --- fluorodeoxyglucose positron emission tomography 
(FDG PET) --- is also a novel approach and allows a smaller number of patients to be recruited into the 
trial.  The incorporation of Tau imaging with the novel ligand T807 (Avid Radiopharmaceuticals) is 
also innovative and has the opportunity to advance understanding of neuroprotection, neurofibrillary 
tangles, and tau imaging. This is the first clinical trial in which positive tau imaging will be required at 
baseline.  Tau imaging will be secondary outcome of the trial, and there will be opportunities to 
understand the information provided by tau imaging as a complement to FDG imaging. The use of the 
Cleveland Clinic Lou Ruvo Center for Brain Health’s distributed clinical trial infrastructure is also a 
trial innovation.  Recruitment sites will include the Lou Ruvo Center for Brain Health in Las Vegas, 
Nevada (led by Jeffrey Cummings, MD, ScD and Kate Zhong, MD) and the Lou Ruvo Center for Brain 
Health in Cleveland, Ohio (led by James Leverenz, MD with referrals from the Lakewood Campus site 
led by Babak Tousi, MD).  In addition, we will add novel, clinical trial outcomes sensitive to executive 
function and relevant to dopamine D1 receptor activation anticipated with MAO-B inhibition.  
Together, these novel trial design aspects promise to advance an understanding of rasagiline as well as 
to enhance clinical trial methodologies for AD drug development. 
 
1.2. Preclinical Data 
Rasagiline is a selective MAO-B inhibitor (3).  Rasagiline has been shown to have neuroprotective, 
antiapoptotic action dependent on BCL-2, protein kinase C (PKC), and the proteasome-ubiquitin 
complex (4).  Importantly, the S-Isomer of rasagiline (TBT1022) is more than 1,000 times less potent 
as a MAO inhibitor and exhibits comparable neuroprotective activity.  In pre-clinical experiments, 
TBT1022 protects mitochondrial viability by activating BCL-2 and PKC and by down- regulating the 
proapopotic FAS Bax protein families (5).  Importantly, from an AD therapeutic perspective, 


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propargylamine-containing compounds such as rasagiline modulate proteolytic cleavage of the amyloid 
beta precursor protein (APP), decreasing beta amyloid production by activation of the non-amyloid 
genic alpha-secretase pathway.  This effect involves activation of mitogen-activated protein kinase 
(MAPK) and PKC (6, 7).   
 
These kinases are deregulated in AD and they contribute to tau hyperphosphorylation and the formation 
of neurofibrillary tangles (31, 32). These observations link rasagiline to tau hyperphosphorylation, 
neurofibrillary tangle formation, and possibly detectable effects on tau imaging (33, 34)  
 
1.3. Pharmacology of Rasagiline 
Rasagiline is a selective, potent and irreversible MAO-B inhibitor.  It is well absorbed from the 
gastrointestinal tract and is highly blood-brain barrier penetrant.  Unlike selegiline, it is not metabolized 
to amphetamine-like derivatives (8).  Rasagiline has a molecular weight of 267.34 Daltons.  It has a 
100-fold selectivity for MAO-B compared to MAO-A.  Rasagiline is metabolized through the CYP1A2 
cytochrome P450 enzyme system and 1A2 inhibitors should be avoided in patients receiving treatment 
with rasagiline (3).  The major metabolite of rasagiline is 1(R)-aminoindan which at doses used in 
humans is unlikely to function as a MAO inhibitor.  The T-max of Rasagiline is 1 hour.  High fat meals 
impair the absorption of the drug reducing the Cmax and area under the curve (AUC) by 60% and 20% 
respectively.  The Tmax of rasagiline is not affected by food and the reduction in AUC is not statistically 
significant.  Plasma protein binding ranges from 88% - 94% and the mean volume of distribution at 
steady state is 87 liters.  There is virtually complete biotransformation before excretion with 
dealkylation and hydroxylation followed by glucuronidation and conjugation (3).  The principal side 
effects observed in clinical trials in patients with PD include dyskinesia, nausea, falls, weight loss, 
constipation, postural hypertension, arthralgia, vomiting, abdominal pain, anorexia, and abnormal 
dreams.   
 
Drug-drug interactions are historically a concern with MAO inhibitors, particularly tyramine-rich foods 
and beverages.  Although such interactions have not been problematic in patients with selective MAO-
B inhibitors, foods with particularly high concentrations of tyramine (aged cheese, sauerkraut, sausage, 
pickled herring) will be avoided in the course of the study.  Similarly, sympathomimetic agents will 
also be avoided in trial participants.   
 
As a repurposed agent, rasagiline has substantial advantages since there is extensive study of the 
pharmacokinetics and pharmacodynamics of the compound in both healthy volunteers and patients with 
PD.   
 
1.4. Clinical Data 
Rasagiline has been extensively studied in the treatment of PD (9).  Among the most important studies 
was the Attenuation of Disease Progression with Azilect® Given Once Daily (ADAGIO) study (10, 
11).  A secondary analysis of the ADAGIO study (12) provided additional insight into the trial 
outcomes.  Of particular importance is the attention to non-motor outcomes including cognition 
presented in the secondary analysis.  Both the 1mg and 2mg doses were associated with an improvement 
in the activities of daily living subscore as well as the UPDRS mentation subscore and the Parkinson 
Fatigue Scale (12).  The ADAGIO study suggests that cognitive impairment in PD was improved 
through treatment with rasagiline.  Many of the mechanisms of rasagiline relevant to its activity in PD 
are also relevant to the treatment of AD.   
 
Further support for pursuing a clinical trial of rasagiline in AD is provided by the double-blind, placebo 
controlled trial of selegiline, alpha-tocopherol and a combination of both of these agents compared to 
placebo in treatments with AD (13).  In this study of patients with moderate AD, there were significant 


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delays in the time to primary outcome for treatment with selegiline, alpha-tocopherol or combination 
therapy.  Primary outcomes included death, institutionalization, and loss of the ability to perform 
activities of daily living or severe dementia (defined as a Clinical Dementia Rating score of 3).   
 
1.5. Application to Alzheimer’s disease 
The data available for PD and for AD suggest a pharmacologic profile of rasagiline compatible with 
either disease modification or symptomatic improvement or both.  Enhanced mitochondrial function 
and improved dopamine neurotransmitter function would be anticipated to provide symptomatic benefit 
whereas the antiapoptotic neuroprotective activity of Rasagiline would be expected to provide disease 
modification.  The proposed clinical trial will not resolve whether one or both of these important 
therapeutic modalities are predominant.  The clinical trial is designed to demonstrate if there is 
enhanced metabolism in a treatment group compared to a placebo-control. The mechanism of rasagiline 
is highly supportive of an effect on AD with aspects such as modulation of APP metabolism uniquely 
relevant to AD. 
 
2. Supporting Data 
 
FDG PET analyses and interpretation as well as site qualification will be done by ADMdx.  This section 
provides background information on the analytic methodology to be used in this study.  Technical 
aspects of site qualification, scanner variables, and PET and magnetic resonance imaging (MRI) 
acquisition are presented in the appendix. 
 
18F-AV-1451 Tau imaging data will be analyzed by ADMdx. 
 
All clinical and imaging data will be integrated through a database constructed by the Alzheimer’s 
Disease Cooperative Study (ADCS) and clinical-imaging integration analyses will be conducted in 
conjunction with ADCS statisticians (http://ADCS.org). 
 
 
 
2.1. Glucose Metabolism as a Biomarker of Neuronal Function  
The loss of synaptic activity and neuronal function is closely associated with reductions in glucose 
metabolism, a primary energy source that is measurable using FDG PET (14, 15). AD is characterized 
by a specific, progressive pattern of hypometabolism that begins in medial temporal and posterior 
cingulate cortices, extends to temporo-parietal cortices and eventually affects most cortical regions. 
Different types of dementia are characterized by distinctive patterns of decline (16), which in turn 
correlate with the domains of cognition and function that become impaired (17).  Representative 
patterns from two different types of dementia are shown in Figure 1 below, where blue represents 
significant declines in glucose metabolism relative to normal controls.   
 
ADMdx has focused on the use of FDG PET, amyloid PET, and other markers to differentiate dementia 
types, predict cognitive trajectory, measure longitudinal change, and assess pharmacologic effects on 
brain glucose metabolism.  This has included the application of advanced machine learning approaches, 
optimized image quality control and processing, and collection of extensive reference data for the 
detection of disease, longitudinal change, and drug effect.  


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 Figure 1.  Metabolic patterns on FDG PET distinguishing AD and FTD 
 
2.2 Dementia Classifier 
The ADMdx Dementia Classifier is a machine learning-based software tool that has been trained to 
differentiate different forms of dementia using the FDG PET scans of 133 subjects with clinical 
diagnoses including Normal, AD, Frontotemporal Dementia (FTD), and Lewy Body Disease (LBD) 
(with pathology or autopsy confirmation where available). The classifier compares the voxels of an 
independent test subject scan to a series of image patterns (canonical variables) that uniquely combine 
to characterize each type of dementia. The probability of a match with each dementia is determined. 
Validation was performed using a Leave-One-Out (LOO) approach and with completely independent 
test subjects.  Accuracies achieved in the LOO analysis were: AD vs. FTD 96%, AD vs. Semantic 
Dementia 97%, and AD vs. LBD 100%. The classifier was subsequently applied to other scans 
including those of subjects participating in studies of bapineuzumab.  It was found that subjects with 
amyloid plaque were more likely to show hypometabolic FDG patterns as identified using ADMdx’s 
dementia classification software, and that patients without AD pathology were less likely to show an 
AD pattern (18). ADMdx is continuing to refine its classification approaches. 
 
2.3. AD Progression Classifier 
ADMdx has also developed a classifier trained on subjects from the Alzheimer’s Disease Neuroimaging 
Initiative (ADNI) database with clinical diagnoses of Normal (negative for AD), Normal-declined, mild 
cognitive impairment (MCI), MCI who converted to AD, and AD.  This classifier assigns a numeric 
score to each independent test subject that reflects the degree to which the subject expresses a pattern 
of decline within regions including those shown in Figure 2 (19). 
 
 
 
 
 
 
 
 
Figure 2.  A portion of the 
pattern of glucose metabolism 
decline characterizing 
progression from NL to AD 
dementia 


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As a further illustration of the AD Progression Classifier, Figure 3 shows the mean (and S.E.M.) 
progression scores for Normal (NL), Early MCI (EMCI), Late MCI (LMCI), and AD subjects from  
ADNI, all amyloid positive as measured using amyloid PET scans (20).  For each diagnostic class, the 
score at baseline and at 24 months post-baseline are shown.  It can be seen that the score captures the 
progression of hypometabolism across diagnostic classes, as well as the 24-month progression within 
those classes.  Rate of decline is greatest in AD subjects. 
 
 
 
2.4. Predicting Cognitive Trajectories 
We have applied the AD Progression Classifier to 72 NL (40 with amyloid data available), 173 MCI 
(87 with amyloid data available), and 50 AD subjects from the ADNI database, comparing the classifier 
score as a predictor of decline in MMSE, CDR-sum of boxes (CDR-sb), and ADAS-Cog 11 to other 
predictors (baseline MMSE, baseline CDR-sb, baseline ADAS-Cog 11, and amyloid cortical average 
Standardized Uptake Value Ratio (SUVr)). Results indicated that the AD Progression score was a 
significant predictor of decline in these measures and a better predictor than the other variables tested6. 
The classifier was also applied to patients in a trial of bapineuzumab, with the result that more severe 
hypometabolism at baseline as identified by ADMdx’s AD Progression Classifier was a strong 
predictor of subsequent clinical decline over the course of the trials (18). 
 
 
 
 
 
Figure 3.  AD Progression scores of 
amyloid positive NL, EMCI, (L)MCI, 
and AD subjects at baseline and 24 
months (same subjects) (mean, 
S.E.M. bars) 


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2.5 Glucose Metabolism as a Measure of Drug Effects 
 
In addition to measuring disease-related changes in neuronal activity, FDG PET can capture drug-related 
effects, even in small group sizes and at acute doses, depending upon effect.  Figure 4 shows the acute 
effects of a lower and higher dose of an NK1 antagonist compound as measured in a double-blinded 
randomized crossover study of 10 normal healthy volunteers.  Acute changes observed in glucose 
metabolism were consistent with clinical effects observed in a separate chronic dosing study. The graph in 
Figure 4 shows each subject’s expression of the primary pattern of change for placebo and each treatment 
dose.  These results were obtained using ADMdx’s multivariate pattern analysis software (NPAIRS), which 
uses Principal Component Analysis (PCA) and Canonical Variate Analysis (CVA) to segregate signal from 
noise, identify the component patterns contributing to overall effect, determine the relative contribution of 
each pattern, measure each subject’s relative expression of the pattern, and provide metrics regarding the 
reproducibility and predictive power of the group results, and identify patterns of effect. It provides a 
powerful tool to gain insight into treatment effects (21, 22).  
 
 
2.6 Tau Imaging as a Measure of Drug Effect 
Several kinases (e.g., MAPK PCK) are deregulated in AD and they contribute to tau hyperphosphorylation 
and the formation of neurofibrillary tangles (31, 32). These observations link rasagiline to tau 
hyperphosphorylation, neurofibrillary tangle formation, and possibly detectable effects on tau imaging (33, 
34)  
The incorporation of Tau imaging with the novel ligand18F-AV-1451 (Avid Radiopharmaceuticals)  provides 
the opportunity to advance understanding of neuroprotection, neurofibrillary tangles, and tau imaging. This 
is the first clinical trial in which tau imaging will be required at baseline.  Tau imaging will be secondary 
outcome of the trial, and there will be opportunities to understand the information provided by tau imaging 
as a complement to FDG imaging. 
 
 
 
 
Figure 4.  Increases (red) and decreases (blue) in glucose metabolism relative to placebo at a lower and higher dose of an NK1 
antagonist.  Eigenplot at right shows individual subject expression of the primary pattern of change relative to placebo, and 
relative to one another, for each treatment dose. 


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3. STUDY OBJECTIVES and ENDPOINTS 
3.1 Primary Objective 
To determine if exposure to 1 mg of rasagiline once daily is associated with improved regional 
brain metabolism in the treatment group compared to the placebo group after a 24-week double 
blind study treatment in Patients with Mild to Moderate Alzheimer’s Disease 
3.2  Secondary Objectives 
 
To evaluate the efficacy of rasagiline 1 mg once daily compared to placebo after a 24-week 
treatment on cognition (ADAS-Cog 11), activities of daily living (ADCS-ADL), global function 
(CGIC), and neuropsychiatric symptoms (NPI)  
 
To evaluate the efficacy of rasagiline 1 mg once daily compared to placebo after a 24-week 
treatment on measures of executive function (Digit Span test, and Controlled Oral Word 
Association Test [COWAT] for verbal fluency) 
 
To evaluate the safety and tolerability of rasagiline as measured by incidence of adverse 
events/serious adverse events (AEs/SAEs) clinical laboratory test data, vital signs, 12-lead EKG 
data,  
 
To evaluate the correlation of FDG-PET results to 18F-AV-1451 (T807) Tau PET results 
 
To correlate the relationship of 18F-AV-1451 (T807) Tau imaging to clinical measures 
 
     3.3 Primary Endpoint  
The primary study endpoint is the change from screening visit (baseline FDG) to Week 24 in regional 
glucose metabolism as measured by standardized uptake value ratio (SUVr) obtained through the FDG-
PET. 
3.4 Secondary Endpoints 
 
Change from Baseline18F-AV-1451 Tau PET imaging SUVr results to Week 24 results 
 
Change from Baseline to Week 24 on the scores of MMSE, ADAS-Cog 11, CGIC 
 
Change from Baseline to Week 24 on the scores of NPI and ADCS-ADL 
 
Change from Baseline to Week 24 on the scores of Digit Span test, COWAT and QoL–AD/Study 
Partner 
 
Safety and tolerability as measured by incidence of adverse events/serious adverse events 
(AEs/SAEs) clinical lab test data, vital signs, 12-lead EKG data 
 
Proportion of subjects with adverse events, serious adverse events and adverse events leading to 
discontinuation over the 24-week double blind treatment period  
 
Proportion of subjects with laboratory abnormalities  
 
Proportion of subjects with ECG abnormalities 
 
4. STUDY DESIGN 
 
This is a 24 week, Phase II, randomized, double blind, placebo controlled, parallel group, proof-of-concept 
three-site study, to evaluate the effect of rasagiline in the regional brain metabolism on FDG PET in patients 
with mild to moderate Alzheimer’s disease. 
The study consists of two phases: a 24-week double blind placebo controlled treatment period with a 4-
week follow-up period. Patients will be randomized to a 1:1 ratio at Baseline to receive rasagiline or 
matching placebo treatment.  


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The study drug will be given as 0.5 mg dose once daily for the first 4 weeks then increased to 1 mg dose 
daily tablet for the next 20 weeks. A total of 50 subjects will be enrolled and will be randomized to a 1:1 
ratio. Twenty-five participants will receive rasagiline and the other 25 will receive matching placebo for 
the 24-week treatment period.   
 
Figure 5.  Research Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1 – Screening visit (within a 60-day period); MRI, FDG PET and 18F-AV-1451 Tau imaging 
Visit 2 – Baseline (Week 1) 
Visit 3 Week 4; increase dose from 0.5 mg QD to 1 mg QD 
Visit 4 Week 8 
Visit 5 –Week 24; blood draws, FDG PET & 18F-AV-1451 Tau imaging, end of treatment 
Visit 6 – Follow-up Visit/ Week 28; end of study/early discontinuation 
 
 
 
 
 
Study Visits 
End of 
Treatment 
Safety FU/EOS 
Screening 
Visit 
(V1) 
Screening period 
   Randomization 
0.5 mg dose rasagiline 
or placebo 
1 mg dose rasagiline or placebo 
≤ 60 days 
Baseline 
(V2) 
Week 4 
(V3) 
Week 8 
(V4) 
Week 24 
(V5) 
Week 28 
(V6) 
N = 50 subjects total 
Randomized to a 1:1 ratio  at V2 to receive 4 weeks of 
double blind treatment of either 0.5 mg dose rasagiline or 
placebo 
Titration at V3 to receive 20 weeks of double blind 
treatment of either 1 mg dose of rasagiline or placebo  


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5. SUBJECT SELECTION AND WITHDRAWAL 
 
5.1 Inclusion Criteria 
1. Males or females 50 to 90 years of age inclusive 
2. Diagnosis of probable AD according to National Institute of Neurological and 
Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders 
Association (NINCDS-ADRDA) criteria 
3. Positive fluorodeoxyglucose PET ([18F]-FDG PET) scan compatible with AD as 
determined by the ADM Diagnostics LLC (ADMdx) criteria 
4. Must be willing to undergo 18F-AV-1451 Tau imaging at Screening and Week 24 visits 
5. Mini-Mental State Examination (MMSE) score between 12-26 inclusive 
6. Must have a study partner who is able and willing to comply with all required study 
procedures 
7. Have at least eight years of education and should have previously (in pre-AD condition) 
been capable of reading, writing, and communicating effectively with others in English 
8. If receiving therapy with a cholinesterase inhibitor and/or memantine, the dose of these 
agents has been stable for at least 60 days prior to screening 
9. Willing and able to provide informed consent by either the subject or subject’s legal 
representative 
10. Willing and able to comply with study visits, treatment plan, laboratory tests, brain 
imaging and other procedures 
11. Females must be postmenopausal 
 
5.2 Exclusion Criteria 
1. Any clinically relevant neurological disorder capable of producing a dementia syndrome 
including Parkinson’s disease, stroke, vascular dementia, dementia with Lewy bodies, 
frontotemporal dementia and others 
2. Psychosis or is receiving antipsychotic treatment 
3. MRI findings indication of a non-Alzheimer’s disease diagnosis 
4. History of melanoma; history of malignancy within the past five years with the exception 
of basal cell or squamous cell cancer, in-situ cervical cancer, or localized prostate cancer 
5. History of Deep Brain Stimulation (DBS) 
6. History of seizure in the past three years prior to randomization 
7. Any contraindication of having brain MRI 
8. Any contraindication of having PET (inability to lie flat and still for the duration of the 
scan, intolerance to previous PET such as hypersensitivity reaction to PET ligand or 
imaging agent) 
9. The subject has any unstable medical illness including hypertension, congestive heart 
failure, chronic obstructive pulmonary disease, renal failure, liver failure or other organ 
compromise 


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10. Uncontrolled hypertension (systolic blood pressure [BP] ≥ 160 mmHg, or diastolic BP ≥ 
100 mmHg; US National Institutes of Health [NIH] Seventh Report of the Joint National 
Committee [JNC 7] criteria). Hypertensive patients whose BP is controlled with 
medication to systolic BP < 160 mmHg and diastolic BP < 100 mmHg are eligible. 
 
11. Baseline laboratory studies that are 1.5 times above or below the highest and lowest range 
of normal values 
12. Other clinically important abnormality on vital signs, physical examination, neurological 
examination or laboratory results, that could compromise the study or be detrimental to 
the subject 
13. Have either: 1) Screening ECG with QTc > 450 msec if male or QTc > 470 msec if female; 
or 2) A history of additional risk factors for Torsades de Pointes (TdP) (e.g., hypokalemia, 
family history of Long QT Syndrome) or are taking drugs that are known to cause QT-
prolongation; Patients with a prolonged QTc interval in the setting of intraventricular 
conduction block (e.g. right bundle branch block [RBBB] or left bundle branch block 
[LBBB], may be enrolled with sponsor approval; or 3) History of atrial fibrillation 
 
14. The patient has taken rasagiline or any other MAOIs within 90 days prior to the 
Screening/Baseline Visit 
 
15. The subject has an allergy to rasagiline 
 
16. Other disallowed medications (taken within 30 days before the Screening/Baseline Visit 
and during the study) include anticholinergics, meperidine, dextromethorphan, tramadol, 
St. John’s wort, methadone, cocaine, ciprofloxacin, or other CYP1A2 inhibitors 
 
17. Has had a PET scan or radiotherapy within 6 months prior to the Screening visit 
18. Has participated in an investigational drug or device study within 30 days prior to 
Screening 
19. Unable to swallow uncrushed oral medication in tablet form 
20. Has any condition or reason that, in the opinion of the investigator, could interfere with 
the ability of the patient to participate or complete the trial, or places the patient at undue 
risk or complicates the interpretation of safety or efficacy data 
 
5.3 Subject Recruitment 
Subjects will be recruited from three sites of the Cleveland Clinic, Lou Ruvo Center for Brain 
Health -- Las Vegas, Cleveland Main Campus and Lakewood site. Subjects may be referred directly 
to the clinical trial from community physicians.   Advertising materials used for the trial will be 
approved by the Cleveland Clinic Institutional Review Board (IRB) prior to implementation.  
 
 
 
 
 


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5.4 Subject Withdrawal 
Patients and caregivers are informed that they have the right to withdraw from the study at any time 
without prejudice or loss of benefit to which they are otherwise entitled. 
The investigator or sponsor may withdraw a patient from the study in the event of an inter-current 
illness, adverse event, non-compliance, protocol violation and other reasons concerning the health 
or wellbeing of the patient.  
 
Following are specific circumstances justifying withdrawal: 
 
Development of an inter-current medical condition or need for concomitant treatment that          
precludes further participation in the trial 
 
Unacceptable toxicity or any adverse event that precludes further participation in the trial 
 
The investigator removes the patient from the trial in the best interests of the patient 
 
Non-adherence to study regimen as determined by pill count 
 
Patient withdraws consent to continued participation in the trial 
 
Patients who withdraw prior to study completion will be asked to return to the clinic to complete 
visit 6 (end of study) assessments. 
 
5.5 Data Collection and Follow-up for Withdrawn Subjects 
 
All subjects who discontinue the trial prematurely will be followed.  
 
Every effort will be made to maintain contact with patients discontinuing treatment during the 
course of the trial. 
 
Reasons for withdrawal will be investigated and documented. 
 
All efforts should be made to document the outcome following the withdrawal. 
 
Patients who withdrew from the study will not be replaced. 
6. STUDY TREATMENT  
6.1 Study Drug 
Azilect® tablets contain rasagiline (as the mesylate), a propargylamine-based drug indicated for 
the treatment of idiopathic Parkinson's disease. It is designated chemically as: 1H-Inden-1-amine, 
2, 3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate. The empirical formula of rasagiline 
mesylate is (C12H13N) CH4SO3 and its molecular weight is 267.34. 
Its structural formula is: 
                                                       
 
Rasagiline mesylate is a white to off-white powder, freely soluble in water or ethanol and sparingly 
soluble in isopropanol. Each Azilect tablet for oral administration contains rasagiline mesylate 
equivalent to 0.5 mg or 1 mg of rasagiline base. 


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Each Azilect tablet also contains the following inactive ingredients mannitol, starch, pregelatinized 
starch, colloidal silicon dioxide, stearic acid and talc.The matching placebo will look exactly like 
the study medication to maintain the double blind design of the study. 
 
6.2  Treatment Regimen 
Subjects will be randomized to a 1:1 ratio to receive Rasagiline or the matching placebo 24-week 
double blind treatment.  
Subjects will take one 0.5 mg rasagiline tablet or the matching placebo once a day on Baseline (Day 
1) through Week 4. The dose will be titrated up to one 1 mg tablet or the matching placebo once a 
day starting on Week 5 until the Week 28 (end of treatment visit). 
6.3 Administration of Treatment 
Study medication should be administered once daily, with or without food.  Subjects will swallow 
all orally administered study medication as a whole and will not chew the medication before 
swallowing. 
Patients will be given 1 month supply of 0.5 mg rasagiline or matching placebo tablets to take home 
on the day of randomization (Visit 2) with detailed instruction of taking one capsule once a day for 
4 weeks. Patient is to return to clinic for Visit 3 (Week 4), when the dose will be increased to 1 
tablet of 1 mg rasagiline or matching placebo once a day. Patients are to continue taking 1 tablet of 
1 mg rasagiline or matching placebo once a day for the next 20 weeks of treatment. 
Table 1 Group and Treatment Phases 
Groups 
Treatment Phases 
Baseline to Week 4 
Week 5 to Week 24 
Active  
1 x 0.5 mg rasagiline QD 
1 x 1 mg rasagiline QD 
Placebo 
1 x matching placebo QD 
1 x matching placebo QD 
 
6.4 Subject Compliance Monitoring 
Adherence to the study protocol will be judged by pill counts. Non-adherence of less than 80% of 
the anticipated dose will result in study discontinuation. Accepted drug compliance is compliance 
rate of 80% to 120%.   
6.5 Prior and Concomitant Therapy 
Concomitant treatment is any drug or substances administered between screening and end of study 
(Week 24).  
Allowed Concomitant Therapy: 
 
Medications for chronic medical conditions are allowed at a stable dose during the study 
provided the subject has been on a stable dose for at least 3 months prior to randomization.  
 
Cholinesterase inhibitors and memantine are allowed provided the therapy has been stable 
for at least 3 months prior to screening and that the patient stays on a stable dose during 
the study. 


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 
Anticholinergic medications allowed include the following: Ranitidine, Loratadine, 
fexofenadine, cetirizine, cyclobenzaprine 
Disallowed Concomitant Therapy: 
 
Meperidine (Demerol), Propoxyphene and Tramadol 
 
Ciprofloxacin and other CYP1A2 Inhibitors 
 
MAO inhibitors such as but not limited to the following: Isocarboxazid, Phenelzine, 
Selegiline, and Tranylcypromine 
 
Dextromethorphan and Nuedexta 
 
St. John’s wort 
 
Levodopa/Carbidopa 
 
Theophylline 
 
Sympathomimetic medications 
 
Hydroxyzine  
 
Diphenhydramine  
 
Scopolamine  
 
Cyproheptadine 
 
Oxybutynin  
 
Fesoterodine 
 
Solifenacin  
 
Darifenacin  
 
Dicyclomine  
 
Glycopyrrolate 
 
Antipsychotics such as but not limited to the following most commonly used 
antipsychotic medications: Haloperidol, Quetiapine, Ziprasidone, and Risperidone 
 
Antidepressants are excluded with the following exceptions: 
 
Amitriptyline ≤ 25 mg/d 
 
Nortriptyline ≤ 50 mg/d 
 
Trazodone ≤ 50 mg/d 
 
Citalopram ≤ 20 mg/d 
 
Escitalopram < 10mg/d 
 
Sertraline ≤ 100 mg/d 
 
Paroxetine ≤ 20 mg/d 
 
Mirtazapine ≤ 30 mg/d 
 
Buspirone < 30mg/d 
 
Fluoxetine ≤ 40 mg/d 
 
Bupropion ≤ 150 mg/d 
 
Duloxetine ≤ 60 mg/d 
 
Venlafaxine ≤ 125 mg/d 
 
No hypnotics the night prior to or day of PET scan preceding the scan 
 
High tyramine-containing foods will be avoided: 
 
Sausages, salami, pickled herring 
 
Fava beans 
 
Tap beers, non-pasteurized beers 
 
Sauerkraut, yeast extract, soybean products including soy sauce 


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R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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 
Aged cheeses 
 
 
6.6  Blinding of Study Drug  
An unblinded pharmacist or unblinded study personnel will administer and dispense the trial 
medication to the subjects to maintain the double-blinding of the study.  
 
 
6.7 Receiving, Storage, Dispensing and Return 
6.7.1 
Receipt of Drug Supplies 
All drugs for the study will be shipped to each of the three sites of the Cleveland Clinic 
Lou Ruvo Center for Brain Health. Upon receipt of the study treatment supplies, an 
inventory will be performed and a drug receipt log filled out and signed by the person 
accepting the shipment.   The unblinded pharmacist or unblinded study staff will count and 
verify that the shipment contains all the items noted in the shipment inventory. Any 
damaged or unusable study treatment product in a given shipment will be documented in 
the study files. Active drug and the matching placebo soft capsules will be provided by 
Teva Pharmaceuticals. 
6.7.2 
Storage 
Rasagiline can be stored at room temperature. High temperatures will be avoided. The drug 
will be protected from light. No special temperature controls are necessary beyond those 
of room temperature. 
6.7.3 
Packaging of Study Drug 
Study active medication and placebo will be packaged in 1-month supply bottles. There 
will be a total of 40 capsules in a bottle of either the rasagiline drug or the placebo. Each 
participant will return study medication bottles (including any unused study medication) at 
each visit for drug accountability purposes. 
6.7.4 
Dispensing of Study Drug  
Participants will receive study drug or placebo in one-month supply bottles. At Baseline 
(Visit 2), the randomized subject will be given one (1) bottle containing either the active 
drug or the placebo. All subjects will be instructed to take one 0.5 mg tablet once a day for 
the first 4 weeks. A dosing instructions sheet will also be provided to all subjects as a 
dosing guide. At Visit 3 (Week 4), subjects will be seen at the clinic and, if there is no 
reason to discontinue therapy, will be advanced and instructed to take one 1 mg tablet once 
daily for 4 weeks. Patients will then be seen at Visit 4 (Week 8) at which time they will 
receive a 4-month supply of the study medication. Regular study drug reconciliation will 
be performed to document drug dispensed; drug consumed, and drug remaining. This 
reconciliation will be logged on the drug reconciliation form, signed and dated by the study 
coordinator. 
6.7.5 
Return or Destruction of Study Drug 
There will be a final reconciliation of the study drug at the conclusion of the study. The 
reconciliation will be logged onto the drug reconciliation form, signed and dated. Any 
discrepancies noted will be investigated, resolved and documented prior to return of unused 
study drug.  


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Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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7.  DESCRIPTION OF STUDY VISITS 
7.1  Visit 1 – Screening (Days -60 to -1) 
Subjects will undergo all screening procedures within 60 days prior to baseline visit to confirm the 
study eligibility. 
 
The following activities will be completed: 
 
Obtain IRB approved written inform consent from the subject and the subject’s legal 
representative in accordance with regulation before initiating any procedures for both the 
main protocol and the 18F-AV-1451 imaging companion protocol 
 
Assess inclusion and exclusion criteria 
 
Obtain demographic data 
 
Obtain medical history and review medications  
 
Obtain history of prior procedures (radiation/PET) 
 
Record prior medication within the last 3 months 
 
Obtain Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-ID) 
Questionnaire for the 18F-AV-1451 TAU imaging companion protocol. 
 
Perform Mini Mental State Examination (MMSE) 
 
Perform physical and neurological examinations 
 
Record orthostatic vital signs, body weight and height 
 
Obtain standard single 12 lead EKG 
 
Collect non-fasting blood sample for routine laboratory test including: 
o Hematology 
o Blood chemistry 
o Liver function 
o TSH 
o B12  
 
Collect urine sample for screening urinalysis (UA) 
 
Obtain MRI: T1 sequence and two-dimensional T2*-GRE to detect micro-hemorrhages 
and T2 FLAIR sequences to identify ARIA-E 
 
Obtain fluorodeoxyglucose (FDG) PET imaging  
 
Obtain18F-AV-1451  Tau imaging pending positive FDG PET imaging results 
 
The screening visit MRI, FDG PET imaging and 18F-AV-1451 Tau PET imaging visits will be done 
on separate visits.  
 
POST 18F-AV-1451 TAU IMAGING FOLLOW-UP PHONE CALL 
A follow-up phone call to the participant or the caregiver will be conducted between 2 and 3 
business days after the imaging visit, but not before 48 hours post-injection, to confirm participant 
well-being and to collect information about any new adverse events. If both of these days are not 
business days, the follow-up phone call can occur the following business day. 
 
7.2  Visit 2 – Baseline (Day 1) 
Patients will be randomized within 60 days from the first day of screening.  


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R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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The following activities will be completed PRIOR to dosing: 
 
Review Inclusion/Exclusion qualification  
 
Review laboratory studies performed at Screening Visit (laboratory results should be 
normal to continue randomization of subject) 
 
Review of MRI and PET Scan results  
 
Inquire about occurrence of adverse events since previous visit and changes to concomitant 
medications 
 
If subject continues to be eligible for the study, he/she may be entered into the double-blind 
randomization phase and procedures listed below will occur: 
 
Record vital signs and body weight  
 
Perform Mini Mental State Examination (MMSE) 
 
Collect blood sample for ApoE genotyping test 
 
Collect blood sample for biomarker measures including: 
o Serum Aβ 40 and 42  
o sAPP-α, sAPP-β, Isoprostanes 
o Cytokines and other measures relevant to AD 
 
Perform the following assessments: 
o ADAS-Cog 11 
o CGIC 
o NPI 
o ADCS-ADL 
o Digit Span 
o COWAT 
o QoL–AD/Study Partner 
 
Dispense double blind study medication to patient and caregiver for outpatient dosing, with 
instructions to return bottle and unused study medication to clinic at next visit.  
 
Provide instructions to caregiver/subject on outpatient dosing, including storage, 
administration, and compliance assessment. 
 
Patients will be given a one-month supply of medication at this visit. The dosing instruction at this 
visit is to take one 0.5mg capsule of study drug or matching placebo once a day for one month. 
Leftover medications will be brought to clinic visits for accountability. 
 
7.3 Visit 3 – Week 4 
This visit will occur at the end of Week 4 with a visit window of +/- 5 days.  
 
The following activities will be completed: 
 
Record orthostatic vital signs and body weight  
 
Inquire about occurrence of adverse events since previous visit and any changes to 
concomitant medications since Baseline Visit 
 
Perform the following assessments: 
o ADAS-Cog 11 
o CGIC  
o NPI 
o ADCS-ADL 
o Digit Span 
o COWAT 


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THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
28 of 54
 
Assess drug adherence and accountability of study medication 
 
Dispense double blind study medication to patient and caregiver for outpatient dosing, with 
instructions to return bottle to clinic at next visit.  
 
Provide instructions to caregiver/subject on outpatient dosing, including storage, 
administration, and compliance assessment. 
 
This is a check-up visit to determine if patients are able to tolerate the medication. If so, they will 
be instructed to take the medication to an increased dosage of 1 mg rasagiline or matching placebo 
tablet once daily. 
 
7.4 Visit 4 – Week 8 
This visit will occur at the end of Week 8 with a visit window of +/- 5 days.  
 
The following activities will be completed: 
 
Record orthostatic vital signs and body weight  
 
Inquire about occurrence of adverse events since previous visit and any changes to 
concomitant medications since Baseline Visit 
 
Perform the following assessments: 
o ADAS-Cog 11 
o NPI 
o ADCS-ADL 
o Digit Span 
o COWAT 
 
Assess drug adherence and accountability for study medication 
 
Dispense double blind study medication to patient and caregiver for outpatient dosing, with 
instructions to return bottle to clinic at next visit.  
 
Provide instructions to caregiver/subject on outpatient dosing, including storage, 
administration, and compliance assessment. 
 
This is a check-up visit to determine if patients are able to tolerate the medication. If so, they will 
be instructed to take the medication with the continued dosage of 1 mg rasagiline or matching 
placebo tablet once daily. 
 
7.5 Visit 5 – Week 24 
This visit will occur at the end of Week 24 with a visit window of +/- 5 days. This visit concludes 
the treatment phase of the study. 
 
The following activities will be completed: 
 
Record orthostatic vital signs and body weight  
 
Obtain standard single 12 lead EKG 
 
Review medical history 
 
Inquire about occurrence of adverse events since previous visit and changes to concomitant 
medications 
 
Collect non-fasting blood sample for routine lab tests including: 
o Hematology 
o Blood chemistry 
o Liver function 
o TSH 


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THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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 
Collect blood sample for biomarker measures including: 
o Serum Aβ 40 and 42  
o sAPP-α, sAPP-β, Isoprostanes 
o Cytokines and other measure relevant to AD 
 
Perform the following assessments: 
o MMSE 
o ADAS-Cog 11 
o CGIC  
o NPI 
o ADCS-ADL 
o Digit Span 
o COWAT 
o QoL–AD/Study Partner 
 
Perform physical and neurological examinations 
 
Assess drug adherence and accountability of study medication 
 
Obtain fluorodeoxyglucose (FDG) PET imaging 
 
Obtain Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-
ID) Questionnaire for the 18F-AV-1451 TAU imaging companion protocol. 
 
Obtain 18F-AV-1451 Tau PET imaging. This could be done 14 days before or 7 days after 
last study treatment dose. 
 
This visit will be the end of the treatment phase and participants will then be followed up for safety 
4 weeks post-treatment. 
 
POST 18F-AV-1451 TAU IMAGING FOLLOW-UP PHONE CALL 
A follow-up phone call to the participant or the caregiver will be conducted between 2 and 3 
business days after the imaging visit, but not before 48 hours post-injection, to confirm participant 
well-being and to collect information about any new adverse events. If both of these days are not 
business 
 
7.6 Visit 6 – Follow-up Visit/End of Study/Early Discontinuation (Week 28) 
This visit will occur at the end of Week 28 with a visit window of +/- 5 days. This will be a follow-up 
visit after the treatment phase.  
The following activities will be completed: 
 
Record orthostatic vital signs and body weight  
 
Perform the following assessments: 
o ADAS-Cog 11 
o CGIC  
o NPI 
o ADCS-ADL 
o Digit Span 
o COWAT 
 
7.7 Unscheduled Visits 
Patients will have unscheduled visits if they report unusual side effects. If the patient reports abrupt 
worsening of cognition, or experiencing one of the reported adverse effects, the patient will be evaluated 
by the study clinician. 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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7.8 Study Calendar of Procedures  
The Schedule of Activities (Table 2) provides an overview of the protocol visits and procedures. 
Refer to Study Procedures (Section 8.0) for detailed information on each procedure and assessment 
required for compliance with the protocol. 
Table 2  Schedule of Activities 
 
 
Screening 
 
Treatment Phase 
 
 
Follow-Up 
Visit # 
Visit 1 
Visit 2/ 
Baseline 
Visit 3 
Visit 4 
Visit 5/ 
EOT 
Visit 6/ 
EOS/ 
Early 
Discontinuation 
Visit  Week 
Week -8 
Week 0 
Week 4 
Week 8 
Week 24 
Week 28 
Visit Window 
Days -60 to -1  
Day 1 
(± 5 
days) 
(± 5 days) 
(± 5 days) 
(± 5 days) 
Informed consent 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
X 
 
Review of medications 
X 
 
 
 
X 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Body weight 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, 
TSH, B12 liver function, 
and UA 
X 
 
 
 
X 
 
ApoE genotyping 
 
X 
 
 
 
 
AD biomarkers 
 
X 
 
 
X 
 
ECG 
X 
 
 
 
X 
 
Orthostatic vital signs 
X 
X 
X 
X 
X 
X 
Physical & Neurological 
Examinations 
X 
 
 
 
X 
 
OSU-TBI-ID 
X 
 
 
 
X 
 
MMSE 
X 
X 
 
 
X 
 
ADAS-Cog 11 
 
X 
X 
X 
X 
X 
CGIC 
 
X 
X 
 
X 
X 
ADCS-ADL 
 
X 
X 
X 
X 
X 
NPI 
 
X 
X 
X 
X 
X 
Digit Span 
 
X 
X 
X 
X 
X 
COWAT 
 
X 
X 
X 
X 
X 
QoL–AD/Study Partner 
 
X 
 
 
X 
 
MRI 
X 
 
 
 
 
 
FDG PET 
X 
 
 
 
X 
 
18F-AV-1451 Tau PET 
X 
 
 
 
    X [2] 
 
 
FU 18F-AV-1451 PET 
Phone Call [1] 
X 
 
 
 
X 
 
Record adverse events 
 
X 
X 
X 
X 
X 
Dispense trial medication 
 
X 
X 
 
 
 
Drug adherence/ 
accountability assessment 
 
 
X 
X 
X 
X 


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Amendment #5 dated 17 Feb 2017 
 
 
 
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[1]  The Follow-up 18F-AV-1451 Tau Pet Phone Call will be conducted between 2 and 3 business days after the imaging visit, but 
not before 48 post inject to confirm participant well-being. 
[2] Week 24 visit 18F-AV-1451 Tau PET can be done 14 days before or 7 days after the last study treatment dose.  
8. Study Specific Procedures 
 
8.1 Cognitive Evaluations 
 
8.1.1 
Mini-Mental State Examination (MMSE) 
The MMSE (Folstein et al., 1975) is a brief, frequently used screening instrument for AD drug 
studies. The MMSE evaluates orientation, memory, attention, concentration, naming, 
repetition, comprehension, and ability to create a sentence and to copy two overlapping 
pentagons. A lower score indicates more cognitive impairment. The highest score is 30. 
Participants with MMSE scores outside the range of 12-26 (inclusive) will not be included in 
this study. This test will be administered at Screening, Baseline, and Week 24. 
 
8.1.2 
Alzheimer’s Disease Assessment Scale-Cognitive 11 (ADAS-Cog 11) 
The ADAS-Cog (Rosen et al., 1984) is a psychometric instrument that evaluates memory, 
attention, reasoning, language, orientation, and praxis. A higher score indicates more 
impairment. Scores from the original portion of the test range from 0 (best) to 70 (worse). A 
positive change indicates cognitive worsening. This test will be administered at Baseline, 
Weeks 4, 8, 24 and 28. 
 
 
8.2 Clinical and Functional Evaluations 
 
8.2.1 
Clinician Global Impression of Change (CGIC) 
This is a rating scale of global impression of change. The CGIC is a clinician assessment of 
change in the patient’s functioning administered to the patient and the caregiver. This test will 
be conducted at Baseline, Week 4, Week 24, and Week 28. 
 
8.2.2 
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) 
The ADCS-ADL is an activities-of-daily-living inventory developed by the ADCS to assess 
functional performance in participants with AD (Galasko et al., 1997). Using a structured 
interview format, study partners are queried as to whether participants attempted each item in 
the inventory during the past 4 weeks and their level of performance. The ADCS-ADL scale 
discriminates well between normal participants and those with mild AD and it has good test-
retest reliability. The ADCS-ADL includes some items from traditional basic ADL tests (e.g., 
grooming, dressing, walking, bathing, feeding, toileting) as well as instrumental (complex) 
activities of daily living (e.g., shopping, preparing meals, using household  appliances, keeping 
appointments, reading). This test will be administered at Baseline, Weeks 4, 8, 24, and 28. 
 
8.2.3 
Neuropsychiatric Inventory (NPI) 
The behavioral outcome measure for this trial is the NPI (Cummings, 1997). The NPI is a well 
validated, reliable, multi-item instrument to assess psychopathology in AD based on interview 
with the study partner. The NPI evaluates both the frequency and severity of 10 
neuropsychiatric disturbances. Frequency assessments range from 1 (occasionally, less than 
once per week) to 4 (very frequently, once or more per day or continuously) as well as severity 
(1=mild, 2=moderate, 3=severe). The overall score and the score for each subscale are the 


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R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
32 of 54
product of severity and frequency. This test will be administered at Baseline, Weeks 4, 8, 24 
and 28. 
 
 
8.2.4 
Controlled Oral Word Association Test (COWAT) 
This is a 3-4 minute measure of phonological fluency that indexes a number of the  processes 
described as ‘executive function,’ including, planning, strategy and working memory. Study 
participants are instructed, “I want to see how many words you can say beginning with a certain 
letter in one minute. Don’t say proper nouns or numbers or the same word with a different 
ending and try not to repeat yourself. The letter is ‘-, begin.” The study participant’s responses 
are recorded on the worksheet. Study participants are then given an additional one minute for 
each of two different letters using similar instructions. 
 
Responses are then judged for their acceptability (example for the use of proper nouns, 
numbers, repetitions and stem word with a different ending). The score is the total number of 
acceptable words for the three trials combined. A higher score represents better performance. 
This test will be administered at Baseline, Week 4, Week 8, Week 24, and Week 28. 
 
8.2.5 
Digit Span  
The Digit Span Test is adopted from the Wechsler Memory Scale and consists of repetition of 
increasing long strings of digits presented at 1 per second as read by the examiner and repeated 
by the subject.  A normal Digit Span is 7 digits forward +/- 2 digits. The score is the maximum 
number of digits the patient can repeat until they fail twice in a row.  The reverse digit span is 
identical to the forward digit span except that the patient repeats the presented digits in reverse 
order.  A normal reverse digit span is 5 +/- 1 digit.  The score is the maximum number of digits 
the patient can repeat in reverse order until they fail twice in a row. This test will be 
administered at Baseline, Weeks 4, 8, 24, and 28. 
 
8.2.6    QoL-AD/Study Partner  
The QoL-AD is a commonly used 13 item QoL scale that assesses items specific to QoL in 
patients with cognitive impairment.  It is administered to the research partner with answers for 
the patient. This assessment will be performed at the Baseline and Week 24 visits.   
8.2.7    Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-ID)    
      Questionnaire 
Traumatic brain injury (TBI) can lead to tau protein deposition in the brain and these changes 
could be visualized on18F-AV-1451  Tau imaging.  To account for any contribution of TBI to 
the imaging findings, the Ohio State University (OSU) TBI Identification Method (OSU TBI-
ID) is being utilized.  The OSU TBI-ID is a standardized procedure for eliciting a person’s 
lifetime history of TBI via a 3-5 minute structured interview. While recall by an individual, 
parent or significant other is not ideal for determining lifetime exposure to potentially 
damaging brain injury, self-report remains the gold standard for research and clinical use.  
Physicians, nurses and mental health professionals working with military personnel need this 
tool to elicit a complete history of TBI. The validity of the OSU TBI-ID is not based on 
elicitation of a veridical accounting of a person's lifetime history of TBI. Instead, the OSU TBI-
ID provides data for calculating summary indices reflecting the likelihood that consequences 
have resulted from lifetime exposure to TBI. Initial validation research has supported the 
psychometric qualities of these summary indices. Reliability has been demonstrated by both 
inter-rater and test/re-test reliability (Corrigan & Bogner, 2007; Bogner & Corrigan, 2009). 
Predictive validity has been shown by the relationship between indices of lifetime history and 


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R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
33 of 54
measures of cognitive performance, affective status, interpersonal functioning and aggression 
(Corrigan & Bogner, 2007; Bogner & Corrigan, 2009). Summary indices from the OSU TBI-
ID can be used in both research and clinical care  
(35, 36).  This assessment will be 
completed at the Screening and Week 24 visits. 
9. Study Methods 
 
9.1 Safety Assessments 
At each study visit, adverse events (AEs) and serious adverse events (SAEs) will be reviewed; vital 
signs and weight will be done for safety assessments. Hematology, blood chemistry, and liver 
function tests will be collected at Screening visit and Week 24.  
 
Potential adverse events will be reviewed by the Principal Investigator and documented. Adverse 
events include signs or symptoms that may or may not be related to study medication, abnormalities 
detected on physical examination, or clinically significant laboratory abnormalities. Adverse events 
will be graded (mild: causing no limitation of usual activities; moderate: causing some limitation 
of usual activities; severe: causing inability to carry out usual activities) and recorded on case report 
forms. 
 
9.2  Concomitant Medications 
Concomitant medications will be recorded at each visit based on the study partner interview and 
any other available information. After randomization, initiation of any excluded medication, or 
change in permitted agents will be discouraged. However, follow-up of all participants, regardless 
of compliance with medication restrictions, will be continued in order to maximize the data 
available for the intent to treat analysis. 
 
Initiation during the study of medications which are excluded because of confounding effects on 
cognitive outcomes (such as sedating or anticholinergic medications) is discouraged, but will not 
require termination of study drug or exclusion from the ITT analysis. Cessation or change of anti-
dementia therapies during the study is also discouraged, but will also not prevent continued 
participation in the protocol or inclusion in the intent to treat analysis. 
 
9.3 Physical Examination 
A brief physical examination will be performed by a medically qualified professional at the 
Screening visit and Week 24. A review of the major body systems will be performed for example: 
skin, head/ears/eyes/nose/throat (HEENT), cardiovascular, pulmonary, abdomen, musculoskeletal, 
neurological, and gastrointestinal. Assessments of height (Screening visit only), weight, and vital 
signs (systolic and diastolic blood pressure, pulse, temperature, and respiration) are included and 
will be done at every visit. 
 
9.4 Neurological Examination 
This examination will be performed by a medically qualified professional and includes an 
assessment of cranial nerves, strength, coordination, reflexes, sensation, tremor and gait at 
screening and week 24 visits. 
 
9.5 Electrocardiogram (ECG) 
A standard 12-lead resting ECG will be performed at the screening and week 24 visits. The ECG 
report will be reviewed, signed, and dated by the investigator. Those with clinically significant 
ECG findings will be referred for follow-up as deemed appropriate by the investigator. 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
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R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
34 of 54
 
Excluded participants are patients who have either: 1) Screening ECG with QTc > 450 msec if male 
or QTc > 470 msec if female; or 2) A history of additional risk factors for Torsades de Pointes 
(TdP) (e.g., hypokalemia, family history of Long QT Syndrome) or are taking drugs that are known 
to cause QT-prolongation; Patients with a prolonged QTc interval in the setting of intraventricular 
conduction block (examples right bundle branch block [RBBB] or left bundle branch block 
[LBBB], may be enrolled with sponsor approval; or 3) History of atrial fibrillation. 
 
9.6 Orthostatic Vital Signs 
Orthostatic vital signs are a series of vital signs of a patient taken while the patient is supine, then 
again while standing. Patient should be lying down for 3 minutes, and then take blood pressure and 
heart rate three times, 2 minutes apart each. Patient will be asked to stand for 3 minutes, and then 
blood pressure and heart rate will be taken again three times, 2 minutes apart each. Results will be 
recorded in the source document.  
 
9.7  Clinical Laboratory Evaluation 
Hematology, chemistry, liver function, B12, TSH levels and urinalysis will be collected at 
Screening and Week 24 visits. Laboratory samples to be tested consist of the following:  
 
Hematology 
Chemistry 
Liver Function 
Other Tests 
Hemoglobin 
Na 
Albumin 
TSH 
Hematocrit 
K 
Total bilirubin 
B12 
RBC 
Cl 
Direct bilirubin 
Urinalysis 
Indices 
WBC 
CO2 
Glu 
Alkaline 
phosphatase 
 
Platelet count 
BUN 
Total Protein 
 
Differential count 
Cr 
Ca 
AST - Aspartate 
Transaminase  
 
 
 
ALT -- Alanine 
Transaminase  
 
 
Laboratory reports will be reviewed, signed and dated by the principal investigator. If any 
laboratory abnormalities have emerged in the course of the 24-week clinical trial, laboratory 
measures of that test will be repeated. The investigator will determine if abnormal values are 
clinically significant or not. If abnormalities persist, patients will be referred to their primary care 
physicians for treatment of the abnormality.  
 
Quest Diagnostics and the Cleveland Clinic Laboratory will function as the research reference 
laboratories and will conduct all laboratory assessments.  
 
9.8 Biomarker Studies and ApoE Genotyping 
Serum biomarker measures will be collected for this study. They will include the following: Serum 
Aβ 40 and 42; sAPP-α, sAPP-β, Isoprostanes; Cytokines and other measures relevant to AD at 
Baseline and Week 24 visits. These assays will be done by the Genomics laboratory of the 
University of Nevada Las Vegas and Cleveland Clinic. 
 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
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R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
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All participants will be asked to consent to the ApoE genotyping. DNA will be extracted from 
blood samples taken from participants and will be analyzed for ApoE genotype at the Baseline visit. 
This will permit secondary analyses of data on the impact of ApoE genotype on biomarkers of 
Alzheimer’s disease, clinical outcome measures and adverse events. ApoE genotyping will also be 
performed by the Genomics laboratory of the University of Nevada Las Vegas and Cleveland Clinic 
using established protocols. 
 
 
9.9  MRI 
A research grade (ADNI quality) MRI, acquired for each subject at the time of enrollment, will 
also be provided. T1, T2 and FLAIR or T2* sequence will be collected.  
3D Sagittal T1 sequence: T1-weighted MPRAGE or MPRAGE-like sequence adhering to the 
Alzheimer’s disease Neuroimaging Initiative (ADNI) specifications.  Typical scanner sequence 
parameters that could be used include: 
 
Scanner        Sequence        Type            TR (ms)    TE (ms)     TI (ms)             NEX/NSA   Flip Angle(°)  Bandwidth 
Siemens 3T   3D MPRAGE  (tfl)              2300         2.98           TI = 900           1                 9                    240 Hz/px 
GE 3T          3D                   IR-FSPGR    --              Min full     TI = 400           1                 11                  31.25 kHz 
Philips 3T      3D                     T1-TFE         Shortest      Shortest       TFE delay=900   1                    9                      Water-fat shift=1.8 
 
 
All scans in this study will be evaluated using a stringent quality control procedure to ensure 
suitability for analysis.  Quality control will be performed within 3 business days of image receipt 
so that in the event of an issue, the visit may be rescheduled if issues cannot be addressed through 
re-reconstruction. Quality control steps will include header checks, visual inspection, and 
quantitative inter-frame motion measurement.  Image headers will be checked to ensure that the 
protocol was followed with regard to injected dose, injected volume, and start time after injection, 
number of frames, scan duration, and reconstruction parameters.  Visual inspection will include 
checks for anatomical truncation (e.g., omission of lower slices of cerebellum), adequate image 
counts, and image noise such as streaking, image blur indicative of subject motion, asymmetry 
indicative of misalignment between emission and transmission scan, and other apparent artifacts. 
Quantitative motion measurement will involve calculation of the inter-timeframe translation and 
rotation, with preset thresholds above which a frame (or scan, if multiple frames) will not be 
accepted as suitable for analysis.  
 
ADMdx has developed and will utilize an automated image processing pipeline, PETMAX™, 
which has secure user access, version control with back-up, and complete audit trail for use in 
clinical trials.  PETMAX facilitates user interaction for visual inspection and quality control at 
multiple stages in the pipeline, and streamlines the execution of the many steps (including SPM 
functions) employed in image preparation and analysis. Results are logged and saved under version 
control.   
 
 
9.10 [18F]-FDG-PET Imaging 
 
 
There are two FDG-PET scans to be conducted per participant in this study. The scans will be done 
at the Screening visit for study eligibility, and at Week 24 visit for end of treatment scan and 
comparison. 
 
The scanning protocol and equipment qualification requirements for this study will be consistent 
with those implemented in ADNI 2 (30). FDG-PET imaging data will be obtained at two sites:  the 
Cleveland Clinic facilities in Cleveland, Ohio and Las Vegas, Nevada.  Each of these sites uses a 
Siemens Biograph PET/CT LSO 16 slice camera.   As part of site qualification, site practices will 
be reviewed, along with recent equipment calibration logs. If the site has a 3D-Hoffman phantom 


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scan collected within the past 12 months available, the scan will be provided for examination.  If a 
de-identified patient brain scan can be made available, it will be provided for examination.  The 
requirements for subject management in preparation for the scan, during FDG uptake, and during 
image acquisition will be reviewed with staff to ensure that these can be met. Since the Cleveland 
Clinic participates in ADNI as well as numerous other clinical trials, it is anticipated that 
requirements will be met. 
 
The scanner will have an up-to-date calibration and normalization on the date of each imaging 
session.  A daily QC check will be done at the beginning of the day the scanning will be completed.  
The scan will be visually inspected for abnormalities.  If there is a possibility that the abnormality 
could impact the PET scan quality, the visit will be rescheduled.   
 
Daily CT quality assurance will be performed as recommended by the specific vendor, and should 
typically include a "checkup/calibration" procedure and a water phantom scan. The 
checkup/calibration procedure guarantees optimum image quality by warming up the x-ray tube 
and should be performed at startup and within 1 hour prior to any scan. The water phantom provides 
quality measurements of 3 parameters. The parameters are the CRT value of water calculated in 
Hounsfield units (HU), the pixel noise of images calculated as a standard deviation, and the tube 
voltages measured directly on the x-ray tubes. These three measurements should be determined for 
all available kVp values. 
 
Ideally, no hardware or software upgrades of the PET imaging system will occur during the study 
duration.  If an upgrade needs to occur, ADMdx will be informed prior to the anticipated upgrade.  
Depending on the nature of the upgrade the site may be asked to repeat the phantom scans prior to 
scanning any additional subjects.   
 
Quality control of blood glucose meter will be performed according to the manufacturer’s or 
institution’s procedure to ensure proper functioning.  Quality control of dose calibrator will be 
performed throughout the course of the study. This typically will include daily constancy, quarterly 
linearity and annual accuracy. 
 
9.11 18F-AV-1451 Tau PET Imaging 
At Screening visit, subjects who qualify for the study will come to the imaging center at a later date 
and will have a catheter placed for IV administration of 18F-AV-1451. Vital signs will be taken in 
a supine position immediately prior to administration of 18F-AV-1451 (within 30 minutes prior to 
injection) and at the completion of imaging prior to subject discharge. Subjects will receive up to 
a target dose of 370 mBq as a single IV bolus of 18F-AV-1451. A 20 minute dynamic image starting 
approximately 80 minutes post injection will be obtained. With sponsor approval sites may elect 
an alternative imaging protocol (i.e. different duration or start time) with additional time points.  
 
All datasets will be submitted to AVID Radiopharmaceuticals for analysis. 
 
Adverse events will be continuously monitored during the imaging session. Subjects who 
experience any adverse event will not be discharged until the event has resolved or stabilized. 
 
The 18F-AV-1451 Tau PET imaging will also be performed within 30 days of Week 24/End of 
Treatment Visit. 
 
 
 


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Follow-Up Phone Call: 
A follow-up phone call to the subject, or designated decision maker, will be conducted between 2 
and 3 business days after 18F-AV-1451 imaging day, but not before 48 hours post-injection, to 
confirm subject wellbeing and to collect information about any new adverse events. If both of these 
days are not business days, the follow-up phone call can occur the following business day. 
A companion protocol for the non-optional 18F-AV-1451 PET imaging study provides detailed 
information regarding the 18F-AV-1451 component and study procedures.  
 
10. Potential Risks 
 
 
10.1 Rasagiline Treatment Risk 
The principal side effects observed in clinical trials in patients with PD include dyskinesia, nausea, 
falls, weight loss, constipation, postural hypertension, arthralgia, vomiting, abdominal pain, 
anorexia, and abnormal dreams.   
 
Drug-drug interactions are historically a concern with MAO inhibitors, particularly tyramine-rich 
foods and beverages.  Although such interactions have not been problematic in patients with 
selective MAO-B inhibitors, foods with particularly high concentrations of tyramine (aged cheese, 
sauerkraut, sausage, pickled herring) will be avoided in the course of the study.  Similarly, 
sympathomimetic agents will also be avoided in trial participants.   
 
The most significant drawback to the use of nonselective MAOIs is the risk of hypertensive 
emergencies, which can occur when a patient is exposed to sympathomimetic drugs, foods 
containing tyramine, or dopamine. By blocking the effects of MAO in the gastrointestinal tract, 
catecholamine concentrations are increased; and, in extreme cases, a hypertensive crisis can 
potentially result in a cerebrovascular accident or death. 
 
The potential for tyramine interaction with rasagiline (doses tested, 0.5-2 mg) was assessed in 5 
placebo-controlled clinical trials in healthy volunteers and PD patients. The results of the formal 
tyramine studies indicate that rasagiline can be used safely without dietary tyramine restriction at 
a dose of 1 mg/day. These data allowed removal of the dietary tyramine restriction from the 
rasagiline. This information was taken from the package insert of Azilect. 
 
 
10.2 MRI Risk 
The risks of MRI primarily arise from the possible introduction of ferromagnetic objects into a high 
magnetic field, which can create a dangerous projectile or lead to dysfunction or heating of an 
implanted medical device. All participants will be rigorously screened by MRI personnel to be 
certain that they do not have any medical contraindications for MRI, which include metallic foreign 
bodies in the brain or eye or cardiac pacemaker. There is a slight risk of anxiety due to 
claustrophobia. Any participant who experiences anxiety when placed into the MR scanner will be 
removed from the scanner, offered reassurance by the MR tech doing the scan, and offered the 
option of continuing or terminating the scan. If the participant decides that the anxiety associated 
with MRI is uncomfortable for them and they wish to terminate the scan, then the examination will 
be ended at that time. There will be no attempt to coerce participants to complete exams that they 
are uncomfortable with. Use of anxiolytic agents for completion of MRI scans is at the discretion 
of the principal investigator. 
 
 
 
 


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10.3 [18F]-FDG-PET Scan Risk 
The primary risk related to PET is that of radiation exposure associated with the CT scan or 
transmission scan and the injected radiotracers. There is also minor risk associated with the 
venipuncture and radioisotope injection (pain and bruising or painful infiltration of a failed 
injection). The radiation dose is not expected to produce any harmful effects, although there is no 
known minimum level of radiation exposure considered to be totally free of the risk of causing 
genetic defects or cancer. The risk associated with the amount of radiation exposure participants 
receive in this study is considered low and comparable to everyday risks. No PET studies will be 
performed on pregnant or potentially pregnant women, as the protocol requires female subjects to 
be postmenopausal as a condition of participation. 
 
10.4 CT Scan Risk                                                                                                                             
Subjects will also receive radiation of approximately 1 mSv from a “low dose” computed 
tomography (CT) acquired along with each PET scan.  The low-dose CT will be used to align the 
position of the subject’s head for the PET image.  The radiation dose from 1 combined PET/CT is 
about 8 mSv which is significantly less than the dose considered safe by the National Institute of 
Health (NIH) for research studies.  However, this study will have 2 combined PET/CT scans during 
the study. 
 
10.5 18F-AV-1451 Tau PET Scan Risk 
18F-AV-1451 will be administered IV up to a radioactive target dose of 370 MBq with a maximum 
human mass dose (MHD) limited to 20 μg of compound by weight. This dose is 150 fold lower 
than the NOAEL observed in the rat single dose toxicity study and is 50 fold lower than the NOAEL 
observed in the rat and dog repeat dose toxicity studies. 
 
Human dosimetry has been obtained in nine subjects. The results estimated an Effective Dose of 
8.92 mSv for an anticipated 370 MBq (10 mCi) injection and is comparable to the effective dose 
of approved 18F-labeled compounds such as FDG and florbetapir F 18 injection. 
 
The proposed dose has been shown to be well tolerated and to have acceptable image quality in 
preliminary human studies. 
 
       10.6 Radiation Risk                                                                                                                                                            
One of the risks associated with radiation exposure is cancer.  The natural incidence of getting 
cancer in the United States is about 40%.  In this research study, including the companion protocol 
there will be four PET scans: FDG PET scan at Screening and at Week 24; and 18F-AV-1451 TAU 
PET scan at Screening and at Week 24.  The annual radiation dose from the combined 2 FDG 
PET/CT scans is 16 mSv.  The annual radiation dose from the combined 2 18F-AV-1451/CT scans 
is 19.84 mSv.  The total radiation exposure for the four Pet Scans is 35.84 mSv. The maximum 
exposure allowed is 50 mSv per year.   
 
10.7  Placebo Risk 
Certain research participants in this study will receive a placebo.  Taking a placebo may be similar 
to not taking any medication.  Research participants who receive a placebo may have the disease 
stay the same or get worse, or the disease/condition may spontaneously get better just as it may 
have done without additional treatment.   
 
 
10.8   Blood Draw Risk 
The risks of blood draw include pain from the needle stick, bruising or infection at the site of 
venipuncture, or fainting as a response to blood draw. 


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11. STATISTICAL PLAN 
11.1     Sample Size Determination 
A study population of 25 subjects per arm (placebo, drug) has been estimated to be sufficient to 
detect a significant drug effect. Further, depending upon the effect size, a study population of 12 
subjects per arm, assessed using an interim analysis, may also be sufficient to demonstrate 
effect.  The number of subjects required to detect a significant change in regional cerebral glucose 
metabolism depends upon the drug action, patient variability within the regions affected, and the 
methods used to measure changes in glucose metabolism.  For drugs causing a symptomatic effect, 
with or without additional disease-modifying properties, the N required is lower than that required 
to detect a modification to the rate of decline associated with disease.  Specifically, we have 
modeled the number of subjects required to detect 5% and 10% increases in prefrontal cortex in 
mild to moderate AD patients using a region of interest approach, and have also confirmed 
estimates through review of published effect sizes from studies of donepezil, phenserine, and 
galantamine in AD patients.   
 
11.2     Statistical Methods 
Intent-to-Treat (ITT) - The primary FDG analysis will include all patients who received both a 
screening and end of study scan of acceptable quality. The primary clinical analysis will be a 
modified Intent-to-Treat (mITT) approach including all patients randomized and receiving at least 
one post-baseline assessment. 
Per-Protocol (PP) population – All Intent-to-Treat subjects who complete the study (Week 24) and 
have ingested between 80% and 120% of the protocol prescribed study medication as measured by 
pill count. 
Observed case – An observed case analysis of all patients completing the study will be conducted. 
LOCF – Clinical data imputation will use the LOCF approach for missing patients 
Responder analysis – Responders will be defined as those that have a significant improvement on 
brain metabolism on FDG for the whole brain or for any of the pre-specified regions. 
A secondary analysis will compare the changes in FDG at 6 months compared to the projected 
expected metabolism based on the Baseline FDG findings. 
 
11.3 Subject Populations for Analysis 
With a subject population of 10 patients per arm (placebo and treatment), Kadir et al detected a 
significant increase (p<0.05) in frontal, parietal, and parietotemporal glucose metabolism within 
the treatment group, and a significant difference between placebo and treatment arms in 
parietotemporal glucose metabolism (26).  The percent changes associated with these increases 
ranged from 5.5% to 8%.  In two different studies of donepezil (27, 28), the change in glucose 
metabolism was measured in subjects who improved, rather than declined, in cognitive 
scores.  Using region of interest analysis, Shimadai found significant differences (p<0.05) in frontal 
regions when comparing the ratio of pre-treatment to post-treatment in 7 responders with regard to 
ADAS-J cog score to that of 4 non-responders. Using voxel-based analyses, Mega et al found a 
significant difference in anterior cingulate, prefrontal cortex, and parietotemporal cortex between 


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Amendment #5 dated 17 Feb 2017 
 
 
 
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6 cognitive responders as compared to similar untreated subjects, even after applying a Bonferroni 
correction for random effects. 
 
Evaluation of the FDG PET scans of 70 mild AD subjects from the Alzheimer’s Disease 
Neuroimaging Initiative (ADNI) database indicates that, based upon mean and standard deviation 
of glucose metabolism in prefrontal cortex, a change in mean Standardized Uptake Value ratio 
(SUVr) of 5% could be statistically significant between two independent groups (drug, placebo) at 
70% power (p<0.05, two-tailed) with 26 subjects per arm, or at 80% power with 32 subjects per 
arm.  The number of subjects required reduces quickly with effect, as a change of 10% would 
require only 8 subjects per arm to achieve 80% power if variance within the study group is 
comparable to that within the mild AD ADNI population (greater variance would increase the 
number of subjects required or decrease the power).  Region of interest evaluation is typically more 
conservative than voxel-based analysis because effects common across subjects often involve sub-
regions and measurement of change may be diluted by the use of broader pre-determined 
measurement areas.  Use of voxel-based approaches, and in addition, multivariate methods and a 
pattern-based classification approach, are expected to increase statistical power as they improve the 
signal to noise ratio and are not limited to predefined regions.  
 
11.4 FDG PET Imaging Analysis 
 
11.4.1. Screening Classification  
The Screening FDG PET scan of each subject will be evaluated using ADMdx’s dementia 
classifier, to assess whether the subject expresses a pattern consistent with AD or alternatively, that 
of other dementias. The classifier has developed machine learning methods and a comprehensive 
set of reference data from ADNI and other sources.  The FDG PET scan of a subject will be 
independently compared to a set of canonical variant patterns that in combination characterize the 
patterns of relative hypometabolism caused by different types of dementia. A probability will be 
assigned to determine whether the subject is “AD-like” or better characterized as a different 
dementia.  
 
In addition, hypometabolism will be assessed in frontal cortex and occipital cortex, and parietal 
asymmetry checked, to identify possible atypical or comorbid presentations that may impact 
clinical attributes.  The AD-like or non-AD-like status of each subject will be reported back within 
7 days of image receipt to allow enrollment decisions. 
 
11.4.2   Screening Characterization 
The Screening FDG PET scan of each subject will be evaluated using ADMdx’s AD Progression 
classifier, to assess the subject’s disease-related hypometabolism status relative to reference 
subjects and other study subjects. The FDG PET scan of a subject will be independently compared 
to a set of canonical variant patterns that in combination characterize the patterns of relative 
hypometabolism caused by different stages of progression toward AD dementia. This numeric 
score will be used to project likely cognitive trajectory for comparison to actual results. It can also 
be used to stratify groups for sub-analyses, creating more homogeneous analysis groups at baseline. 
11.4.3   Longitudinal Voxel-based Evaluation 
The spatially normalized longitudinal FDG PET scans of each subject will be analyzed using 
ADMdx’s NPAIRS multivariate software.  Classes will be defined according to treatment or 
placebo condition, and visit.  Example analyses are shown in Table 1 below.  The output of this 


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Amendment #5 dated 17 Feb 2017 
 
 
 
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evaluation will be a series of patterns showing relative increases and decreases in cerebral glucose 
metabolism, quantification of the placement of each subject at each time point relative to these 
patterns of effect, and quantification of the contribution of each pattern to the overall effect.  Metrics 
of reproducibility and predictive power are also provided.  At preference of Sponsor, group 
assignments may be provided in a blinded manner – that is, Group A and Group B, without 
designation as treatment or placebo.  In the table below, to better illustrate the comparisons, they 
are referred to as Placebo and Treatment, but these may instead be “Group A” and “Group B.”   
 
Table 3.  NPAIRS analyses of treatment effect and stratification impact 
Analysis 
Group 
Baseline 
6 months 
1 
Treatment (within group only) 
x 
x 
2 
Placebo (within group only) 
x 
x 
3 
Treatment 
x 
x 
Placebo (both in a single analysis) 
x 
x 
4 
Treatment – mild subjects 
x 
x 
Treatment – later stage subjects 
x 
x 
Placebo – mild subjects 
x 
x 
Placebo – later stage subjects 
x 
x 
5 
Treatment – subjects age 50 - 65 
x 
x 
Treatment – subjects age >65 
x 
x 
Placebo – subjects age 50-65 
x 
x 
Placebo – subjects age >65 
x 
x 
 
SPM-t contrasts will also be performed of selected groups, at thresholds of p<0.005, and a cluster 
extent threshold of 25 voxels. These are limited to paired contrasts (e.g., baseline vs. 6 months for 
treatment group), or to contrasts of the difference images between baseline and 6 months, treatment 
vs. placebo groups.  Information is more limited with regard to individual subject distribution other 
than at specific voxel locations. 
11.4.4   Longitudinal Region of Interest Evaluation 
The SUVr calculated for each subject will be compared using t-tests, within groups and across 
groups, as shown in Table 4 below. While the pre-identified reference regions for testing will be 
whole brain, cerebellum, and pons, an alternate reference region may be identified through the use 
of NPAIRS multivariate analysis and applied. 
 
Table 4   Regions of interest for FDG analysis 
Analysis 
Change in FDG PET 
measure: 
Dorso-
lateral 
PFC 
Striatum 
Hip -
Med 
temp 
Anterior 
cingulate 
Post 
cing– 
precun 
Lateral 
temp 
Inferior 
parietal 
1 
Treatment:  6m  
vs. screening 
x 
x 
x 
x 
x 
x 
x 
2 
Placebo: 6m vs. 
screening  
x 
x 
x 
x 
x 
x 
x 
3 
Change in 
treatment vs. 
change in placebo 
groups 
x 
x 
x 
x 
x 
x 
x 
4 
1, 2, and 3 in 
substrata for 
x 
x 
x 
x 
x 
x 
x 


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Analysis 
Change in FDG PET 
measure: 
Dorso-
lateral 
PFC 
Striatum 
Hip -
Med 
temp 
Anterior 
cingulate 
Post 
cing– 
precun 
Lateral 
temp 
Inferior 
parietal 
disease severity 
and age 
11.4.5.   Correlation to Cognitive Change 
The relationship between glucose metabolism and cognitive endpoints will be evaluated as shown 
in Table 5 below. 
 
Table 5   Relationships between FDG PET measures and cognitive endpoints  
Analysis 
Change in FDG PET 
measure: 
ADAS-cog 11 
Digit 
Span 
COWAT 
MMSE 
1 
AD progression score 
x 
x 
x 
x 
2 
Dorsolateral prefrontal cortex 
SUVr 
x 
x 
x 
x 
3 
Medial temporal cortex SUVr 
x 
x 
x 
x 
4 
NPAIRS derived pattern of 
change (CV score associated 
with pattern) 
x 
x 
x 
x 
 
 
 
11.5 18F-AV-1451   Tau Imaging Analysis 
18F-AV-1451 SUVr will be determined by Avid Pharmaceuticals and analyzed. Change from 
baseline in rasagiline-treated patients will be compared to change from baseline in patients 
receiving placebo.  Correlations will be sought between 18F-AV-1451 drug-placebo differences and 
18F-AV-1451 changes in FDG PET as well as between drug-placebo difference in and changes in 
clinical outcomes.   
 
12. SAFETY AND ADVERSE EVENTS 
12.1 
Definitions 
International Conference on Harmonisation (ICH) guidelines define an adverse event (AE) as any 
medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example) symptom, or disease temporarily associated with the use of a medicinal 
product whether or not considered related to this medicinal product. 
A serious adverse event (SAE) is any medical occurrence or effect that at any dose:  
 
Results in death 
 
Is life threatening 
 
Requires hospitalization or prolongation of existing inpatient hospitalization 
 
Results in persistent or a significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Is cancer 


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 
Life threatening in the definition of a SAE refers to an event in which the subject was at 
risk of death at the time of event; it does not refer to an event which hypothetically might 
have caused death if it were more severe.  
 
      12.2 
 Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on AEs by specific 
questioning and, as appropriate, by examination. Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate AE section of the case report form 
(CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results will also 
be recorded in the source document.  
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. Serious adverse events 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 immediately. 
 
12.3 
Reporting of Serious Adverse Events 
12.3.1 Study Sponsor-Investigator Notification by Investigator  
A SAE will be reported to the study sponsor-investigator by telephone within 24 hours of the 
event. A SAE form will be completed by the investigator and faxed to the study sponsor 
within 24 hours. The investigator will keep a copy of this SAE form on file at the study site. 
Report a SAE by phone and facsimile to Michelle Sholar, 702-483-6026, fax 702-483-6028.  
At the time of the initial report the following information will be provided: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason event is classified as serious 
 
Investigator assessment of the association between the event and study treatment 
 
Within the following 48 hours, the investigator will provide further information on the AE 
in the form of a written narrative. This will include a copy of the completed SAE form and 
any other diagnostic information that will assist the understanding of the event.  Significant 
new information on ongoing SAEs will be provided promptly to the study sponsor-
investigator. 
 
12.3.2  IRB Notification by Investigator 
Reports of all SAEs (including follow-up information) will be submitted to the Cleveland 
Clinic Foundation (CCF) IRB per the guidelines of the CCF IRB Standard Operating 
Procedures. Copies of each report and documentation of IRB notification and response will 
be filed in the regulatory binder. 
The following four types of events will be reported to the IRB (these follow the Case Cancer 
IRB because this is an anti-cancer agent being used in patients with mild to moderate AD):  


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1.  Adverse events which are serious, unexpected, and related or possibly related to 
participation in the research.  
2.  Serious adverse events that are expected in some subjects, but are determined to be 
occurring at a significantly higher frequency or severity than expected.  
3.  Other unexpected adverse events, regardless of severity, that may alter IRB analysis of 
the risk versus potential benefit of the research and, as a result, warrant consideration of 
substantive changes in the research protocol or informed consent process/document.  
4.  Unanticipated problems involving risks to subjects or others or any serious or continuing 
noncompliance with this policy or the requirements or determinations of the IRB. 
 
12.3.3 FDA Notification by Sponsor-Investigator 
The FDA will be notified by telephone or by facsimile transmission of any unexpected fatal 
or life threatening experience associated with the use of the drug as soon as possible, but no 
later than seven calendar days from original receipt of the information.  
If a previous adverse event that was not initially deemed reportable is later found to fit the 
criteria for reporting, the study sponsor-investigator will submit the adverse event in a written 
report to the FDA as soon as possible, but no later than 15 calendar days from the time the 
determination is made. 
 
12.4   Unblinding Procedures 
The research coordinator will inform the sponsor-investigator of all subjects whose treatment 
was unblinded within 24 hours of unblinding. Most unblinding will be part of managing a 
SAE and will be reported with the SAE. Unblinding that was not associated with a SAE will 
be reported in a timely manner. This will be done within 24 hours by telephone or facsimile, 
and will be followed by a written narrative of the reason for unblinding within 24 hours of 
the event. 
      
 12.5   Stopping Rules 
If 4 or more patients worsen clinically in a manner greater than expected for untreated AD, the 
protocol will be stopped.  Similarly, if 4 or more patients show ARIA-E or microhemorrhages 
on the 2nd MRI, the protocol will be stopped. 
   
 12.6  Medical Monitoring 
The principal investigator will oversee the safety of patients in the rasagiline study. The safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above as well as the construction and implementation of a site data and safety monitoring plan. 
Medical monitoring will include a regular assessment of the number and type of SAEs. Medical 
monitoring for the trial would be done by Charles Bernick , MD, of the Lou Ruvo Center for Brain 
Health. 
 
 
12.6.1    Internal Data Safety Monitoring Board (DSMB) 
A data safety monitoring committee is not deemed necessary for this fifty-patient initial            study 
of rasagiline.       
      


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13. DATA HANDLING AND RECORD KEEPING 
13.1 Confidentiality and Privacy 
Information about study subjects will be kept confidential and managed according to the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). Subjects or a legally acceptable 
surrogate will provide authorization that they have been informed of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke authorization for use of the PHI 
 
The HIPAA language is included as part of the informed consent form. 
   
13.2 Source Documents 
Source documentation for all entry criteria will be available in the patient’s research record. These 
records will be retained as required by law.  
 
13.3 Case Report Forms 
The study CRFs have been constructed for this study. All data will be collected on the CRF and all 
missing data on the CRF will be explained. 
 
13.4 Records Retention 
All documents will be retained for a minimum period of two years following completion of the 
study. 
 
13.5 Database 
The database will be constructed by CCF Quantitative Health Sciences (QHS).  The database will 
be populated by the study research coordinator.   
 
14. STUDY MONITORING, AUDITING AND INSPECTING 
14.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan. The investigator will allocate 
adequate time for such monitoring activities. The Investigator will also ensure that the monitor or 
other compliance or quality assurance reviewer is given access to all the above-noted study-related 
documents and study related facilities and has adequate space to conduct the monitoring visit. 
14.2 Audit and Inspection 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor-investigator, government regulatory bodies, and institutional compliance and quality 
assurance groups of all related documents (for example, source documents, regulatory documents, 
data collection instruments, study data, etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities. Participation as an investigator in this study 
implies acceptance of potential inspection by government regulatory authorities and applicable 
Institutional compliance and quality assurance offices. 
 
15. ETHICAL CONSIDERATIONS 


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This study will be conducted according to US and international standards of Good Clinical Practice 
(GCP) (FDA Title 21 part 312 and ICH guidelines), applicable government regulations and Institutional 
research policies and procedures. 
This protocol and any amendments will be submitted to the IRB, in agreement with local legal 
prescriptions, for formal approval of the study conduct. The decision of the IRB concerning the conduct 
of the study will be made in writing to the investigator and a copy of this decision will be provided to 
the sponsor-investigator before commencement of this study. The investigator will have a list of IRB 
members and their affiliates. 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects or legally acceptable surrogates to make an informed decision.  
 
 
16. STUDY FINANCES 
 
16.1  Funding Source 
This study is being funded by the Alzheimer’s Drug Discovery Foundation (ADDF). This 
foundation established in 1998 by co-chairmen Leonard A. and Ronald S. Lauder of the Estée 
Lauder cosmetics family, provides funding to leading scientists who are conducting the most 
promising, innovative Alzheimer’s drug research worldwide. Funders did not participate in the 
design of the study and do not have any financial interest in the outcome of the study. 
 
 16.2  Conflict of Interest (COI) 
Any investigator who has a conflict of interest with this study will have the conflict reviewed by 
the Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved prior to participation in this study. All Cleveland Clinic 
investigators will follow the Institutional Conflict of Interest Policy. 
 
 16.3  Subject Stipends or Payments 
Subject stipend and study partner stipend is anticipated for this study. 
 
17.  PUBLICATION PLAN 
Dr. Jeffrey L. Cummings, principal investigator, has primary responsibility for publication of the results of 
this study. It is the full intention of the investigator to publish the results of this study as soon as possible. 
Neither the complete study nor any part of the results of the study carried out under this protocol, nor any 
of the information provided by the sponsor-investigator for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor-investigator.  Any 
investigator involved with this study is obligated to provide the sponsor-investigator with complete test 
results and all data derived from the study18. 
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Rascol O, Fitzer-Attas CJ, Hauser R, et al.  A double-blind, delayed-start trial of rasagiline in 
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additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol 
2011;10:415-423. 
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Sano M, Ernesto C, Thomas RG, Klauber MR, et al.  A controlled trial of selegiline, alpha-
tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative 
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Shankar GM and Walsh DM. Alzheimer's disease: synaptic dysfunction and Aβ. Mol 
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Open Nucl Med J 2010;2:46-52. 
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Silverman DH, Small GW, Chang CY et al. Positron emission tomography in evaluation of 
dementia: Regional brain metabolism and long-term outcome. J AMA 2001;286:2120-2127. 
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Mielke R, Herholz K, Grond M, Kessler J, Heiss WD. Clinical deterioration in probable 
Alzheimer's disease correlates with progressive metabolic impairment of association areas. 
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Schmidt ME, Gregg K, Margolin R, Lukic AS, Andrews RD, Matthews DC, Wernick MN, 
Strother SC, Brashear R, Liu E. Preliminary analysis of baseline FDG PET in PET substudies of 
Phase 3 i.v.bapineuzumab trials in mild to moderate AD:  Patterns and severity of regional brain 
hypometabolism and relationship to fibrillary amyloid burden measured by 11C-PiB PET and 
clinical outcomes. Clinical Trials in Alzheimer’s Disease Conference (CTAD). Oral presentation. 
2013. 
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Strother SC, Matthews DM, Lukic AS, Andrews RD, Wernick MN. Superior Performance of a 
Multi-Stage PET Classifier for the Alzheimer’s Disease Cascade. Organization for Human Brain 
Mapping (OHBM) conference, Quebec. 2011. 


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20. 
Mosconi L, Andrews RD, Lukic AS, Wernick MN, Strother SC, Liu E, Margolin R, Schmidt 
ME, Matthews DC on behalf of the Alzheimer’s Disease Neuroimaging Initiative. A multivariate 
FDG PET classifier metric improves prediction of cognitive change in Normals, MCI and AD 
patients. Oral presentation. Clinical Trials in Alzheimer’s Disease Conference (CTAD). 2013. 
21. 
Strother SC, Anderson J, Hansen LK, Kjems U, Kustra R, Siditis J, Frutiger S, Muley S, LaConte 
S, Rottenberg D. The quantitative evaluation of functional neuroimaging experiments: The 
NPAIRS data analysis framework. Neuroimage 2002;15:747-771. 
22. 
Strother SC, Oder A, Spring R, Grady C. The NPAIRS Computational Statistics Framework for 
Data Analysis in Neuroimaging. Proc. 19th Int. Conf. on Computational Statistics: Refereed 
Keynote, Invited and Contributed Papers, Lechevallier, Yves; Saporta, Gilbert (Eds.), pp. 111-
120, Physica-Verlag, Berlin. 2010. 
23. 
Turner L, Shamseer L, Altman DG, Weeks L, Peters J, Kober T, Dias S, Schulz KF, Plint AC, 
Moher D.  Consolidated standards of reporting trials (CONSORT) and the completeness of 
reporting of randomized controlled trials (RCTs) published in medical journals.  Cochrane 
Database Syst Rev 2012;11:MR000030.  
24. 
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, 
Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo 
MC, Thies B, Weintraub S, Phelps CH.  The diagnosis of dementia due to Alzheimer's disease: 
recommendations from the National Institute on Aging-Alzheimer's Association workgroups on 
diagnostic guidelines for Alzheimer's disease.  Alzheimers Dement 2011;7:263-269. 
25. 
Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M.  A neuropsychological 
test battery for use in Alzheimer disease clinical trials.  Arch Neurol 2007;64:1323-1329. 
26. 
Kadir A, Andreasen N, Almkvist O, Wall A, Forsberg A, Engler H, Hagman G, Larksater M, 
Winblad B, Zetterberg H, Blennow K, Langstrom B, Nordberg A.  Effect of phenserine treatment 
on brain functional activity and amyloid in Alzheimer’s disease. Ann Neurol 2008;63:621-631.  
27. 
Shimada A, Hashimoto H, Kawabe J, Higashiyama S, Kai T, Kataoka K, Tagawa R, Kawarada 
Y, Nakanishi A, Inoue K, Shiomi S, Kiriike N. Evaluation of therapeutic response to donepezil 
by positron emission tomography.  Osaka City Med J 2011;57:11-19. 
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Mega MS, Dinov ID, Porter V, Chow G, Reback E, Davoodi P, O'Connor SM, Carter MF, 
Amezcua H, Cummings JL. Metabolic patterns associated with the clinical response to 
galantamine therapy: a fludeoxyglucose f 18 positron emission tomographic study. Arch Neurol 
2005;62:721-728. 
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antagonist R317573 on regional brain activity in healthy male subjects. Psychopharmacology 
(Berl) 2010;208:109-119 
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ADNI 2 PET Technical Procedures Manual AV-45 (Florbetapir F 18) & FDG V1.0 January 14, 
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31.  Kumar P, Jha NK, Jha SK, Ramani K, Ambasta RK. Tau Phosphorylation, Molecular Chaperones, 
and Ubiquitin E3 Ligase: Clinical Relevance in Alzheimer’s Disease. J. Alzheimers Dis. 2014 
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Chien DT, Szardenings AK, Bahri S, Walsh JC, Mu F, Xia C, Shankle WR, Lerner AJ Su MY, 
Elizarov A, Kolb HC, Early clinical PET imaging results with the novel PHF-tau radioligand 
[F18]-T808, J Alzheimers Dis. 2014:38(1):171-84, 


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34. 
Zhang W, Arteaga J, Cashion DK, Chen G, Gangadharmath U, Gomez LF, Kasi D, Lam C, Liang 
Q, Liu C, Mocharla VP, Mu F, Sinha A, Szardenings AK, Wang E, Walsh JC, Xia C, Yu C, Zhao 
t, Kolb HC A highly selective and specific PET tracer for imaging of tau pathologies,  
 
J Alzheimers Dis. 2012;31(3):601-12. 
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Appendix A 
 
Technical Description of FDG PET Acquisition and Analysis 
1). Imaging Site Qualification and Preparation 
(Note that parameters and steps may be refined to align with the scanner model and practices at the 
Cleveland Clinic.) 
The scanning protocol and equipment qualification requirements for this study will be consistent with those 
implemented in ADNI 2 (30). FDG-PET imaging data will be obtained at two sites:  the Cleveland Clinic 
facilities in Cleveland, Ohio and Las Vegas, Nevada.  Each of these sites uses a Siemens Biograph PET/CT 
LSO 16 slice camera.   As part of site qualification, site practices will be reviewed, along with recent 
equipment calibration logs. If the site has a 3D-Hoffman phantom scan collected within the past 12 months 
available, the scan will be provided for examination.  If a de-identified patient brain scan can be made 
available, it will be provided for examination.  The requirements for subject management in preparation for 
the scan, during FDG uptake, and during image acquisition will be reviewed with staff to ensure that these 
can be met. Since the Cleveland Clinic participates in ADNI as well as numerous other clinical trials, it is 
anticipated that requirements will be met. 
 
The scanner will have an up-to-date calibration and normalization on the date of each imaging session.  A 
daily QC check will be done at the beginning of the day the scanning will be completed.  The scan will be 
visually inspected for abnormalities.  If there is a possibility that the abnormality could impact the PET 
scan quality, the visit will be rescheduled.   
Daily CT quality assurance will be performed as recommended by the specific vendor, and should typically 
include a "checkup/calibration" procedure and a water phantom scan. The checkup/calibration procedure 
guarantees optimum image quality by warming up the x-ray tube and should be performed at startup and 
within 1 hour prior to any scan. The water phantom provides quality measurements of 3 parameters. The 
parameters are the CRT value of water calculated in Hounsfield units (HU), the pixel noise of images 
calculated as a standard deviation, and the tube voltages measured directly on the x-ray tubes. These three 
measurements should be determined for all available kVp values. 
 
Ideally, no hardware or software upgrades of the PET imaging system will occur during the study duration.  
If an upgrade needs to occur, ADMdx will be informed prior to the anticipated upgrade.  Depending on the 
nature of the upgrade the site may be asked to repeat the phantom scans prior to scanning any additional 
subjects. 
   
Quality control of blood glucose meter will be performed according to the manufacturer’s or institution’s 
procedure to ensure proper functioning.  Quality control of dose calibrator will be performed throughout 
the course of the study. This typically will include daily constancy, quarterly linearity and annual accuracy. 


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2)  Image Data Collection 
(i). Pre-Scan Subject Preparation 
All participants will be screened by study personnel for contraindications to PET scanning (see Exclusion 
Criteria).  Scans should be scheduled at the same time of day for a given subject – i.e., if in the morning for 
the baseline scan, then in the morning for any subsequent scans.  In order to reduce the potential for first 
scan effects, prior to the first scan, for example at the Screening visit, each subject will be introduced to the 
PET scanner, sequence of data acquisition events, and FDG uptake room and activity. 
 
Subjects to be imaged in the morning are asked to omit all food and fluids (except water) from midnight 
the night before the scan until after the imaging is completed. Subjects scanned later in the day are asked 
to omit food and fluids (except water) for at least 4 hours prior to the imaging session.  When a participant 
arrives at the imaging center, compliance with the dietary requirement of not having food or drink in less 
than two hours will be confirmed.  If a participant has ingested food or drink within two hours, participants 
will wait until two hours have elapsed.  Once two hours have elapsed, blood glucose levels will be 
measured.  If blood glucose levels are not less than 180 mg/dL, then waiting an additional amount of time 
to recheck blood glucose levels will be needed.  Once blood glucose levels are below 180 mg/dL, the 
participant will be asked to use the restroom to empty his/her bladder.  Then, the participant will be asked 
to sit or recline comfortably (but not in a position that will induce sleep) in a reclining chair in a room in 
which the ambient noise is minimal and the degree of lighting can be controlled and minimized.  
Blankets/pillows may be supplied as needed to maximize comfort.  Intravenous access using a small 
butterfly needle or angiocath will be done.  185 MBq (5mCI +/- 10%) of [18F]-FDG will be drawn and 
assayed with a dose calibrator and assay time will be recorded to the nearest minute.  The [18F]-FDG will 
be injected and the syringe and IV line will be flushed with 10mL of normal saline.  The injection time will 
be recorded to the nearest minute and the IV line may be discontinued.  The dose syringe will then be re-
assayed and if the residual activity is 0.1 mCi or greater, the amount will be recorded and the amount of the 
injected dose will be corrected for the residual activity.   
(ii)  Subject Management During FDG Uptake 
Control of the subject’s activity and environment during the 30 minutes following tracer administration is 
essential. It is also necessary that the subjects’ position during the uptake period, their activity and focus, 
their visual, audio, and temperature environment, and the room’s ambient light conditions are consistent 
across all longitudinal scans. 
 
The subject will be asked to rest comfortably in the room with lights dimmed to a level similar to twilight 
for 30 minutes for incorporation of [18F]-FDG in the brain. The subject’s eyes will be open, away from 
any direct light, and the ears will remain un-occluded.  The participant will be directed to maintain their 
gaze on a constant object throughout the uptake period.  This point of focus (object) should be the same 
across subjects and across scans. The subject should also be instructed to avoid any motion, foot tapping, 
or other variable activity. Comfort should be assured in order to reduce the likelihood of movement. The 
participant must be monitored frequently to be certain of compliance and to ensure that the eyes do not 
close and they remain awake.  It is important that no sudden noises or environmental changes occur within 
or just outside of the participant’s room during [18F]-FDG uptake.  
 
Just prior to injection, and at the end of the uptake period, the subject will be asked to answer a short set of 
questions regarding their affect.  The clinician will also be asked to note the subject’s affect, and particularly 
whether the subject exhibits signs of agitation, somnolence, or depression. These observations are important 
because differences between scanning sessions in the patient’s affect can impact measured signal, creating 
confounds in the measurement of treatment effects. If a subject is notably agitated, the process should not 


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begin until that agitation can be alleviated.  If this is not reasonably achievable, the scan should be 
rescheduled. 
 
At the end of the 30-minute incorporation period, the participant will be encouraged to use the restroom to 
empty their bladder.  Ample time will be given to ensure that the participant will be on the scanner and 
ready for data acquisition to begin at 30 minutes post-injection.   
(iii)  Image Acquisition 
The participant will be positioned and secured in the scanner.  Proper participant positioning and the 
prevention of subject motion during acquisition is critical for a reliable PET scan.  Excessive motion 
between the emission scan and the CT scan used for attenuation correction is the single most common cause 
of failed studies.  For this reason, the protocol includes several steps to reduce the likelihood of movement, 
as follows, and consistent with ADNI guidelines. 
 
Time will be taken to ensure the participant is properly positioned and can comfortably maintain that 
position for 30 minutes during the scanning session.  Participants will remove any bulky items from their 
pockets and remove eyeglasses, earrings, hair clips/combs, and hearing aids (if possible).  The participant 
will be positioned so the head/neck is relaxed which may involve adding additional pads beneath the neck 
to provide sufficient support.  It will be verified that the participant’s ears are in a comfortable position, and 
not pinched, as this can cause movement to alleviate discomfort during the scan. Lasers will be used to 
ensure that there is little or no rotation in either plane.  The head will be positioned parallel to the imaginary 
line between the external canthus of the eye and the external auditory meatus.  Supportive devices under 
the back and/or legs will be used to help decrease the strain on these regions and prevention motion in the 
lower body.  Once the participant is positioned, foam pads may be placed alongside the head for additional 
support.  Velcro straps and preferably easily removed tape will be used to secure the head position.  Vacuum 
bean bags may also be used in this process.  One of the most common forms of motion in PET scans is a 
downward motion that causes the subject’s head to move lower in the field of view, ultimately truncating 
the lower portion of cerebellum from view.  To minimize the possibility of this, a (comfortable) “rod” or 
other device may ideally be positioned just below the chin, serving as a reminder to the subject not to move 
downward. The subject will be offered a “panic button” or be reassured that someone will be watching or 
able to hear them at all times.   
 
Prior to initiation of the emission scan, a short “scout” scan is to be taken in order to verify that the subject’s 
head is correctly positioned. 
 
The subject’s head position and ability to remain still must be monitored continuously throughout the 
acquisition period. If the subject moves, acquisition should cease, the head should be repositioned, the time 
at which the repositioning occurred noted, and acquisition resumed.  It is imperative that if motion occurs 
between frames, the emission frames are correctly aligned with one another, and with the transmission scan, 
before attenuation correction is applied through the use of a transmission scan. The handling of motion will 
be a topic for discussion with PET technologist and depends upon the scanner model and options available. 
 
A 30-minute dynamic, 3D scan consisting of six 5-minute frames (preferably ten 3-minute frames to allow 
for additional motion correction) will be acquired <to be verified as ADNI has indicated that Siemens 
Biograph scanners cannot collect dynamic images>.  All images will need to be corrected using measured 
attenuation using standard CT acquisition parameters.  A check will be performed to ensure that the 
emission and transmission scans are properly aligned before the participant leaves the imaging session. 
Upon completion, the participant is to be removed from the scanner and encouraged to void.  The study 
participant will be instructed to drink fluids and to void throughout the day to help reduce radiation 
exposure. 


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(iv).   Image Reconstruction 
Images will be reconstructed using parameters specific to the scanning system and will be reviewed to 
check for artifacts and motion.  Sinogram data (projection data) will be stored in a separate file.  Iterative 
reconstruction will be performed, using the parameters recommended by ADNI for the scanner model [ref].  
(v).   Image De-identification and Transfer 
The PET image sets produced by the reconstruction process will be converted to a standard Digital Imaging 
and Communications in Medicine (DICOM) file format.  Image file naming will follow a standard format 
so that all scans can be easily identified.  The file ID will be assigned by study personnel prior to the PET 
scan.  Unless designated otherwise during study preparations, the naming convention will be XXX_S_#### 
where XXX is a three digit site ID determined by the Cleveland Clinic and #### is the unique four digit 
number assigned to the subject by the site, followed by a sequence uniquely identifying the scan.   
 
All raw and processed study data including copies of the normalization and blank scans will be archived.  
Image data will be transferred to ADMdx (Chicago, IL), as soon as images have been acquired and 
reconstructed.  A secure image transfer program such as AG Mednet that ensures de-identification of the 
data prior to transmission will be employed.  Initial header checks may be performed using that software 
prior to image transmission. 
2)  MRI Scan 
A research grade (ADNI quality) MRI, acquired for each subject at the time of enrollment, will also be 
provided. T1, T2 and FLAIR or T2* sequence will be collected.  
 
3D Sagittal T1 sequence: T1-weighted MPRAGE or MPRAGE-like sequence adhering to the Alzheimer’s 
disease Neuroimaging Initiative (ADNI) specifications.  Typical scanner sequence parameters that could 
be used include: 
 
Scanner         Sequence         Type            TR (ms)   TE (ms)     TI (ms)             NEX/NSA   Flip Angle(°)  Bandwidth 
Siemens 3T   3D MPRAGE   (tfl)              2300         2.98            TI = 900             1                  9                      240 Hz/px 
GE 3T           3D                    IR-FSPGR    --              Min full      TI = 400             1                  11                    31.25 kHz 
Philips 3T     3D                    T1-TFE        Shortest    Shortest      TFE delay=900  1                  9                      Water-fat shift=1.8 
 
(i)  Image Quality Control 
All scans in this study will be evaluated using a stringent quality control procedure to ensure suitability for 
analysis.  Quality control will be performed within 3 business days of image receipt so that in the event of 
an issue, the visit may be rescheduled if issues cannot be addressed through re-reconstruction. Quality 
control steps will include header checks, visual inspection, and quantitative inter-frame motion 
measurement.  Image headers will be checked to ensure that the protocol was followed with regard to 
injected dose, injected volume, and start time after injection, number of frames, scan duration, and 
reconstruction parameters.  Visual inspection will include checks for anatomical truncation (e.g. omission 
of lower slices of cerebellum), adequate image counts, image noise such as streaking, image blur indicative 
of subject motion, asymmetry indicative of misalignment between emission and transmission scan, and 
other apparent artifacts. Quantitative motion measurement will involve calculation of the inter-timeframe 
translation and rotation, with preset thresholds above which a frame (or scan, if multiple frames) will not 
be accepted as suitable for analysis.  
 
ADMdx has developed and will utilize an automated image processing pipeline, PETMAX™, which has 
secure user access, version control with back-up, and complete audit trail for use in clinical trials.  PETMAX 
facilitates user interaction for visual inspection and quality control at multiple stages in the pipeline, and 


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streamlines the execution of the many steps (including SPM functions) employed in image preparation and 
analysis. Results are logged and saved under version control.   
(ii)  Image Processing 
Discrete timeframes for each scan will be aligned and an aggregate image created by averaging the frames. 
Each subject’s MRI will be co-registered to the baseline PET scan, and longitudinal PET scans will be co-
registered to the baseline PET scan, as well.  The MRI will be segmented into gray, white, and CSF tissue 
images. The MRI will be spatially transformed to a target template and the PET scan(s) will be likewise 
transformed using the same parameters.  The spatially transformed images will be intensity normalized to 
a mean value of 1, and smoothing applied to achieve uniform resolution with other scanners for comparison 
to reference data and use in the dementia classifiers.  A set of template ROIs will be transformed back to 
the subject’s native (unwrapped) brain for signal measurement in unwrapped space, with individualized 
masking applied using the subject’s gray matter segment. The mean, standard deviation, minimum, and 
maximum for each ROI will be measured, as well as those in different reference regions for comparison, 
including whole brain without ventricles, cerebellum, and pons. This is in order to examine consistency 
across reference regions, and to determine whether treatment effects may influence one or more reference 
regions as well as target ROIs. Standardized Uptake Value Ratios (SUVrs) will be generated by taking the 
ratio of regions of interest to the respective reference regions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NEUROLOGICAL INSTITUTE OF CLEVELAND CLINIC  
THE LOU RUVO CENTER FOR BRAIN HEALTH 
R2 Study 
 
 
Amendment #5 dated 17 Feb 2017 
 
 
 
Phase 2 Study – Rasagiline AD Protocol  
54 of 54
Appendix B. 
Study Procedure Table 
 
 
Screening 
 
Treatment Phase 
 
 
Follow-Up 
Visit # 
Visit 1 
Visit 2/ 
Baseline 
Visit 3 
Visit 4 
Visit 5/ 
EOT 
Visit 6/ 
EOS/ 
Early 
Discontinuation 
Visit  Week 
Week -8 
Week 0 
Week 4 
Week 8 
Week 24 
Week 28 
Visit Window 
Days -60 to -1  
Day 1 
(± 5 
days) 
(± 5 days) 
(± 5 days) 
(± 5 days) 
Informed consent 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
X 
 
Review of medications 
X 
 
 
 
X 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
Hematology, Chemistry, 
TSH, B12 liver function, 
and UA 
X 
 
 
 
X 
 
ApoE genotyping 
 
X 
 
 
 
 
AD biomarkers 
 
X 
 
 
X 
 
ECG 
X 
 
 
 
X 
 
Orthostatic vital signs 
X 
X 
X 
X 
X 
X 
Physical & Neurological 
Examinations 
X 
 
 
 
X 
 
OSU-TBI-ID 
X 
 
 
 
X 
 
MMSE 
X 
X 
 
 
X 
 
ADAS-Cog 11 
 
X 
X 
X 
X 
X 
CGIC 
 
X 
X 
 
X 
X 
ADCS-ADL 
 
X 
X 
X 
X 
X 
NPI 
 
X 
X 
X 
X 
X 
Digit Span 
 
X 
X 
X 
X 
X 
COWAT 
 
X 
X 
X 
X 
X 
QoL–AD/Study Partner 
 
X 
 
 
X 
 
MRI 
X 
 
 
 
 
 
FDG PET 
X 
 
 
 
X 
 
18F-AV-1451 Tau PET 
X 
 
 
 
    X [2] 
 
 
FU 18F-AV-1451 PET 
Phone Call [1] 
X 
 
 
 
X 
 
Record adverse events 
 
X 
X 
X 
X 
X 
Dispense trial medication 
 
X 
X 
 
 
 
Drug adherence/ 
accountability assessment 
 
 
X 
X 
X 
X 
[1]  The Follow-up 18F-AV-1451 Tau Pet Phone Call will be conducted between 2 and 3 business days after the imaging visit, but 
not before 48 post inject to confirm participant well-being. 
[2] Week 24 visit 18F-AV-1451 Tau PET can be done 14 days before or 7 days after the last study treatment dose.  

SAP_001.pdf: