Conditions: Alzheimer's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 159
Healthy volunteers: no

Brief summary:
AZD0530 is an inhibitor of Src and Abl family kinases1. It has been developed as treatment for malignancies because these kinases play a role in tumor invasion and proliferation. However, the Src family kinases (SFKs) are highly expressed in brain and have major effects on synaptic plasticity2. Moreover, the investigators have recently shown that a specific SFK, namely Fyn, is aberrantly activated by specific conformations of the Amyloid Beta (Aß) peptide from Alzheimer's disease (AD). Genetic deletion of Fyn rescues AD deficits in preclinical models. This clinical trial will test the potential benefit of AZD0530 for Alzheimer's disease modification.

Detailed description:

Arms:
arm 1: Patients in the experimental group (50%) will be started on this dose. After 2 weeks, patients with a plasma drug level of \<100ng/ml will receive 125mg AZD0530 daily and remain in the same experimental group as patient receiving 100mg daily. arm 2: 50% of patients will receive placebo treatment for the duration of the study,

Interventions: intervention 1: AZD0530 100mg daily intervention 2: AZD0530 125mg daily intervention 3: Placebo
Intervention descriptions: intervention 1: All patients in experimental group (50%) will be started on 100mg AZD0530 daily intervention 2: Patients with plasma drug level \<100ng/ml after 2 weeks of 100mg AZD0530 daily will receive 125mg daily of AZD0530. intervention 3: 50% of patients will receive placebo treatment for the duration of the study.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Number:  ADC-049 FYN 
 
Page 1 of 60 
 
Protocol v4.0: 31-MAY-2017 
 
 
A Phase 2a Multi-Center Study of 18F-FDG PET, Safety, and 
Tolerability of AZD0530 in Mild Alzheimer’s Disease 
 
 
Protocol Short Title:  FYN 
 
Protocol Number:  ADC-049 
 
US IND Number: 118607 
 
 
PROJECT DIRECTOR 
COORDINATION & DATA 
MANAGEMENT CENTER 
Christopher van Dyck, M.D. 
Yale University 
1 Church St. Suite 600 
New Haven, CT 06510  
  
 
Paul Aisen, M.D.  
Alzheimer’s Therapeutic Research 
Institute (ATRI) 
9860 Mesa Rim Road  
San Diego, CA 92121 
  
  
MEDICAL MONITOR 
 
PET CENTRAL READ 
Tiffany Chow, M.D. 
Alzheimer’s Therapeutic Research 
Institute (ATRI) 
9860 Mesa Rim Road 
San Diego, CA 92121    
 
  
Kewei Chen, Ph.D.  
Director of Core Resources 
Neuroimaging Research and Analysis Lab  
Banner Alzheimer’s institute  
901 E. Willetta Street 
Phoenix, AZ 85006  
 
PROTOCOL VERSION 
VERSION DATE 
Protocol v1.0 
19-NOV-2014 
Protocol v2.0 
10-AUG-2015 
Protocol v3.0 
31-MAY-2016 
Protocol v4.0 
31-MAY-2017 
 
Confidentiality Statement 
The information in this document is privileged or confidential and may not be disclosed unless such 
disclosure is required by applicable laws and regulations.  It is the property of ATRI and Yale University 
and should not be copied by or distributed to persons not involved in the study.  Persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not 
be further disclosed by them. These restrictions on disclosure will apply equally to all future information 
supplied to you, which is indicated as privileged or confidential. Any unauthorized review, use, 
disclosure, copying or distribution is strictly prohibited. 
 


Protocol Number:  ADC-049 FYN 
 
Page 2 of 60 
 
Protocol v4.0: 31-MAY-2017 
Table of Contents 
List of Abbreviations .............................................................................................................. 4 
PROTOCOL SYNOPSIS ............................................................................................................. 7 
1.0 INTRODUCTION ............................................................................................................. 8 
1.1 
Primary Aims ........................................................................................................................... 9 
1.2 
Secondary Aims ....................................................................................................................... 9 
2.0 PRELIMINARY STUDIES ............................................................................................... 9 
2.1 
Summary of Pre-Clinical Findings .................................................................................... 9 
2.2 
Summary of Clinical Findings .......................................................................................... 14 
2.3 
Safety and Compliance ....................................................................................................... 17 
3.0 BACKGROUND AND SIGNIFICANCE ....................................................................... 18 
3.1 
Rationale for Study ............................................................................................................. 18 
3.2 
Rationale for Dosage Selection ....................................................................................... 20 
3.3 
Rationale for 18F-Florbetapir PET and Biomarkers ................................................. 20 
4.0 POTENTIAL RISKS AND BENEFITS ASSOCIATED WITH THIS 
INVESTIGATIONAL PRODUCT ........................................................................................... 21 
4.1 
Potential Risks and Benefits Associated with This Investigational Product ... 21 
4.2 
Relationship of this intervention to current treatment practices in AD .......... 21 
5.0 SAMPLE SIZE AND STATISTICAL PLAN ................................................................ 22 
5.1 
Randomization ..................................................................................................................... 22 
5.2 
Power and Sample Size Determination ........................................................................ 22 
5.3 
Selection of participants to be used in analysis ........................................................ 22 
5.4 
Efficacy Analysis ................................................................................................................... 23 
5.5 
Interim Analysis ................................................................................................................... 24 
5.6 
Criteria for the termination of the trial ....................................................................... 25 
6.0 STUDY DRUG AND CONCOMITANT MEDICATIONS .......................................... 26 
6.1 
Name and Description of IP and Comparator ............................................................ 26 
6.2 
Dosage ..................................................................................................................................... 26 
6.3 
Blinding ................................................................................................................................... 26 
6.4 
Packaging/Dispensing/Labeling .................................................................................... 27 
6.5 
Storage .................................................................................................................................... 27 
6.6 
Drug Accountability ............................................................................................................ 27 
6.7 
Compliance ............................................................................................................................ 27 
6.8 
Breaking the Blind .............................................................................................................. 28 
6.9 
Concomitant AD Medications .......................................................................................... 28 
6.10 
Other Concomitant Medications .................................................................................. 28 
7.0 STUDY POPULATION ................................................................................................. 30 
7.1 
Inclusion Criteria ................................................................................................................. 30 
7.2 
Exclusion Criteria ................................................................................................................ 30 
7.3 
Recruitment and Retention Strategies ......................................................................... 32 
8.0 STUDY TIMELINE ........................................................................................................ 32 
9.0 DESCRIPTION OF STUDY VISITS ............................................................................ 33 
9.1 
Pre-screening ........................................................................................................................ 33 


Protocol Number:  ADC-049 FYN 
 
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Protocol v4.0: 31-MAY-2017 
9.2 
Screening ................................................................................................................................ 33 
9.3 
Baseline Visit (Week 0) ..................................................................................................... 34 
9.4 
Treatment Visits (Week 2 – Week 52) .......................................................................... 34 
10.0 EARLY TREATMENT/STUDY DISCONTINUATION ......................................... 35 
10.1 
Reasons for Early Discontinuation ............................................................................. 35 
11.0 INSTRUMENTS .......................................................................................................... 37 
11.1 
Cognitive Evaluations ...................................................................................................... 37 
11.2 
Clinical and Functional Evaluations ........................................................................... 38 
12.0 PROCEDURES ............................................................................................................. 39 
12.1 
Safety Assessments ........................................................................................................... 39 
12.2 
Biofluids ............................................................................................................................... 40 
12.3 
Magnetic Resonance Imaging (MRI) ........................................................................... 42 
12.4 
PET Imaging ........................................................................................................................ 43 
13.0 PERSONNEL REQUIREMENTS .............................................................................. 44 
14.0 ADVERSE EVENTS .................................................................................................... 45 
14.1 
Definition ............................................................................................................................. 45 
14.2 
Following Up on AEs ......................................................................................................... 45 
15.0 SERIOUS ADVERSE EVENTS (SAE) ...................................................................... 46 
15.1 
Definition ............................................................................................................................. 46 
15.2 
Reporting SAEs .................................................................................................................. 46 
16.0 DATA AND SAFETY MONITORING BOARD (DSMB) ....................................... 47 
17.0 RECORDING AND COLLECTION OF DATA ......................................................... 48 
17.1 
Case Report Form .............................................................................................................. 48 
17.2 
Study Files and Patient Source Documents .............................................................. 48 
18.0 ETHICS AND REGULATORY CONSIDERATIONS .............................................. 49 
18.1 
Good Clinical Practice ...................................................................................................... 49 
18.2 
Institutional Review Board (IRB) / Research Ethics Boards (REB) ................. 49 
18.3 
Informed Consent and HIPAA Compliance ............................................................... 50 
18.4 
Genetic Research and Storage of Genetic Material ................................................ 50 
18.5 
Storage of Biospecimen Samples ................................................................................. 51 
18.6 
MRI and PET Imaging and Data Storage .................................................................... 51 
18.7 
Inclusion of Children as Participants ......................................................................... 51 
18.8 
Study Monitoring .............................................................................................................. 51 
19.0 AUDIT .......................................................................................................................... 52 
20.0 RECORD RETENTION .............................................................................................. 52 
21.0 PUBLICATION POLICY ............................................................................................ 52 
22.0 SHARING OF FINAL RESEARCH DATA ............................................................... 52 
23.0 LITERATURE CITED ................................................................................................ 53 
APPENDIX 1  SCHEDULE OF EVENTS ........................................................................... 59 
APPENDIX 2  REVISION HISTORY ................................................................................. 60 


Protocol Number:  ADC-049 FYN 
 
Page 4 of 60 
 
Protocol v4.0: 31-MAY-2017 
 
List of Abbreviations  
 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale – Cognitive  
ADC 
Alzheimer’s Disease Center 
ADCS 
Alzheimer’s Disease Cooperative Study 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study - Activities of Daily 
Living Inventory 
ADEAR 
Alzheimer’s Disease Education & Referral Center, under the NIA 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
APOE/APOE4 
Apolipoprotein E (APOE) epsilon 4 (APOE4) 
AST 
Aspartate aminotransferase 
ATRI 
Alzheimer’s Therapeutic Research Institute 
Aβ 
Beta Amyloid 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating, Sum of Boxes 
CSF 
Cerebrospinal Fluid 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture System 
FDG 
Fluoro Deoxy Glucose 
FLAIR 
Fluid Attenuation Inversion Recovery 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
LAR 
Legally Authorized Representative 
LDH 
Lactate dehydrogenase 
LP 
Lumbar Puncture 
MCI 
Multiple Cerebral Infarctions 


Protocol Number:  ADC-049 FYN 
 
Page 5 of 60 
 
Protocol v4.0: 31-MAY-2017 
MMSE 
Mini-Mental State Examination 
MPRAGE 
Magnetization Prepared Rapid Gradient Echo 
MR/MRI 
Magnetic Resonance / Magnetic Resonance Imaging 
NCATS 
National Center for Advancing Translational Sciences 
NIA 
National Institute on Aging, under the NIH 
NIH 
National Institutes of Health 
NPI 
Neuropsychiatric Inventory 
PET 
Positron-Emission Tomography 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
REB 
Research Ethics Board 
RSS 
Research Satisfaction Survey 
SAE 
Serious Adverse Event 
T 
Tesla 
TFT’s 
Thyroid Function Tests 
TSH 
Thyroid Stimulating Hormone 
vMRI 
Volumetric Magnetic Resonance Imaging 
 


Protocol Number:  ADC-049 FYN 
 
Page 6 of 60 
 
Protocol v4.0: 31-MAY-2017 
SIGNATURE PAGE 
 
(SIGNATURES ON FILE AT COORDINATING CENTER) 
 
 
 
 
 
 
 
 
 
 
______________________________________________  
 
_________________________ 
Christopher van Dyck, M.D.  
 
 
 
Date (MM/DD/YYYY) 
Project Director 
Yale University 
 
 
 
 
 
______________________________________________  
 
_________________________ 
Tiffany Chow, M.D. 
 
 
 
 
 
Date (MM/DD/YYYY) 
Medical Monitor 
Alzheimer's Therapeutic Research Institute 
 
 
 
 
 
______________________________________________  
 
_________________________ 
Paul Aisen, M.D. 
 
 
 
 
 
Date (MM/DD/YYYY) 
Director 
Coordination & Data Management Center 
Alzheimer’s Therapeutic Research Institute 
 


Protocol Number:  ADC-049 FYN 
 
Page 7 of 60 
 
Protocol v4.0: 31-MAY-2017 
PROTOCOL SYNOPSIS 
 
PROTOCOL TITLE 
A Phase 2a Multi-Center Study of 18F-FDG PET, Safety, and 
Tolerability of AZD0530 in Mild Alzheimer’s Disease 
PROJECT DIRECTOR 
Christopher van Dyck, M.D. 
STUDY SPONSOR 
 
National Center for Advancing Translational Sciences 
(NCATS), through a grant to Yale University 
COORDINATING 
CENTER 
Alzheimer’s Therapeutic Research Institute (ATRI) 
STUDY DESIGN 
A Phase 2a multi-center, randomized, double-blind, 
placebo-controlled study evaluating 18F-FDG PET, Safety, 
and Tolerability of AZD0530 in 152 patients with Mild AD 
DURATION OF STUDY 
PARTICIPATION 
Each subject will have up to a 60-day screening period, 
followed by 52 weeks of treatment. 
SUMMARY OF 
INVESTIGATIONAL 
PRODUCT 
AZD0530 100mg or 125mg, or Placebo tablets taken 
orally once daily  
SUMMARY OF KEY 
ELIGIBILITY CRITERIA  
• Diagnosis of probable AD (NIA-AA criteria) 
• 
18F-Florbetapir scan with evidence of elevated Aβ  
(based on central review) 
• Age 55-85 (inclusive) 
• MMSE 18-26 (inclusive) 
• Modified Hachinski Scale Score <=4 
PRIMARY OUTCOME 
MEASURE 
Aim 1.  18F-FDG PET measurements of the cerebral 
metabolic rate for glucose (CMRgl)  
Aim 2.  Adverse events, including symptoms, and 
abnormal findings on physical examinations, neurological 
examinations, standard laboratory tests, and PK analysis 
of AZD0530 
OTHER KEY OUTCOME 
MEASURES / STUDY 
PROCEDURES   
Screening 18F-Florbetapir PET, Volumetric MRI, LP sub-
study, ADAS-Cog, MMSE, ADCS-ADL, CDR, NPI, 
genotyping, and biomarker labs 
 


Protocol Number:  ADC-049 FYN 
 
Page 8 of 60 
 
Protocol v4.0: 31-MAY-2017 
1.0 INTRODUCTION  
Alzheimer’s disease (AD) is the most common dementing illness and afflicts over 5 
million in the USA now, with an annual health care burden near $200 billion3. 
Unfortunately, no therapy available today modifies the course of AD. The clinical 
dementia of Alzheimer’s disease (AD) is coupled to a distinct pathology, with senile 
plaques consisting of Amyloid-ß (Aß) peptide, and with neurofibrillary tangles 
consisting of hyperphosphorylated tau protein. The existence of rare autosomal 
dominant cases of AD caused by mutations of the Amyloid-ß Precursor Protein 
(APP) or the Presenilin (PS1 and PS2) processing enzymes that produce Aß 
provides genetic proof that APP/Aß pathways can trigger clinical AD4-7. Other APP 
mutations reduce AD risk8. Tau mutations cause dementia in Fronto-Temporal 
Lobar Degeneration9. Biomarker studies of late onset non-familial AD now span the 
progression of disease from pre-symptomatic stage to mild cognitive impairment to 
AD10-12. Such observations have revealed that Aß dysregulation, as detected by CSF 
levels or by Positron Emission Tomography, is the earliest detectable change of the 
AD process, consistent with Aß serving as the trigger for the disease. 
 
Large extracellular and inert plaques of amyloid mark the pathology, but attention 
has focused on conformationally distinct soluble oligomers of Aß (Aßo) as being 
neurotoxic13-16. Specifically, neurotoxicity is characterized by synaptic malfunction, 
and is accompanied by loss of dendritic spines. Chronically, synaptic changes are 
followed by neurofibrillary tangles, by neuro-inflammation and by neuronal cell loss. 
Src Family Kinase, Fyn and Synaptic Function  
Fyn is a member of the Src family of intracellular non-receptor tyrosine kinases 
family17. There are nine members of Src family kinases. Five of them (Src, Fyn, Lck, 
Lyn, Yes) are expressed in the central nervous system, but Src and Fyn are most 
highly expressed in the brain. Fyn activity, like that of other Src family kinases, is 
regulated by intramolecular interactions that depend on equilibrium between 
tyrosine phosphorylation and dephosphorylation. In the basal state, catalytic 
activity is constrained by intramolecular interactions, such as engagement of the 
SH2 domain by a phosphorylated C-terminal tyrosine 527. Disruption of these 
interactions by phosphorylation at Tyr 416 in the activation loop of the kinase 
domain and/or by dephosphorylation of Tyr 527 results in Fyn activation18. 
 
There are multiple lines of evidence linking Fyn kinase function to synapse plasticity, 
and the synaptic dysfunction central to AD. Fyn has been localized to the Post 
Synaptic Density fraction of the brain and amongst its substrates are receptors for 
the major excitatory transmitter, glutamate. Fyn regulates glutamate receptor 
trafficking and synaptic plasticity2,19-21. Specifically, Fyn is known to phosphorylate 
the NMDA-type glutamate receptor subunits, NR2A and NR2B22. Treatment of rats 
with transient middle cerebral artery occlusion using an SFK inhibitor (different 
from AZD0530) has revealed a neuroprotective action, reducing stroke volumes23. 


Protocol Number:  ADC-049 FYN 
 
Page 9 of 60 
 
Protocol v4.0: 31-MAY-2017 
AZD0530  
AZD0530 is an inhibitor of Src and Abl family kinases1. It has been developed as 
treatment for malignancies because these kinases play a role in tumor invasion and 
proliferation. However, the Src family kinases (SFKs) are highly expressed in the 
brain and have major effects on synaptic plasticity2. Moreover, recent studies have 
shown that Fyn is aberrantly activated by specific conformations of the Amyloid 
Beta (Aß) peptide from Alzheimer’s disease (AD). Genetic deletion of Fyn rescues 
AD deficits in preclinical models42, 49. This project will test the potential benefit of 
AZD0530 for Alzheimer’s disease modification. 
1.1 
Primary Aims  
Aim 1.  
To assess the effect of treatment with AZD0530 on 52-week reductions in 
fluorodeoxyglucose positron emission tomography (18F-FDG PET) measurements of 
the cerebral metabolic rate for glucose (CMRgl) using statistical parametric mapping 
(SPM) statistical region of interest (sROI) in subjects with mild AD. 
Aim 2.  
To assess the safety and tolerability of treatment with AZD0530 over a 52-week 
period in subjects with mild AD as assessed by analysis of adverse events, including 
symptoms, and abnormal findings on physical examinations, neurological 
examinations, standard laboratory tests, and PK analysis of AZD0530. 
1.2 
Secondary Aims 
Aim 3.  
To assess the effect of treatment with AZD0530 on ADAS-cog, MMSE, ADCS-ADL, 
CDR-SB, and NPI in participants with mild AD.  
Aim 4.  
To assess the effect of treatment with AZD0530 on the rate of change in: total brain 
volume, ventricular volume, hippocampal volume, and entorhinal thickness, using 
volumetric magnetic resonance imaging (MRI). 
Aim 5.  
To assess the effect of treatment with AZD0530 on CSF biomarkers of AD 
(particularly CSF total tau and CSF ptau). 
Aim 6.  
To assess the influence of APOE genotype on the effects of treatment with AZD0530. 
2.0 PRELIMINARY STUDIES 
2.1 
Summary of Pre-Clinical Findings  
Fyn is Implicated in AD by Studies of Aß Oligomer Action 
A critical early step in AD pathophysiology is the process by which Aßo interacts 
with the neuronal surface to trigger downstream pathology, and studies of this 


Protocol Number:  ADC-049 FYN 
 
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Protocol v4.0: 31-MAY-2017 
pathway have further implicated Fyn in AD pathophysiology. In the only reported 
genome-wide unbiased screen for Aßo binding sites, Cellular Prion Protein (PrPC) 
was identified24. Aß binding to PrPC has consistently been shown to be of high 
affinity and is oligomer specific, with little or no affinity for fibrillary or monomeric 
states24-27.  In vivo, PrPC is not essential for certain Aß-related phenotypes26-29, but is 
required for cell death in vitro, for reduced survival of APP/PS1 transgenic lines, for 
epileptiform discharges, for synapse loss, for serotonin axon degeneration and for 
spatial learning and memory deficits4, 30-36. Critically, the ability of human AD brain-
derived Aß species to suppress hippocampal synaptic plasticity requires PrPC, and 
human AD contains PrPC-interacting Aßo species and Aß– PrPC complexes4, 37-39. 
 
Once Aßo forms and binds to PrPC at the cell surface, changes in neuronal 
biochemistry occur. Fyn was a candidate downstream mediator because PrPC 
phenotypes in fish and worm require Fyn40, 41, because Fyn regulates synaptic 
plasticity2, 19-21, and because Fyn interacts with Tau and modulates phenotypes in 
mouse AD models42, 7. It has been shown that both PrPC and Fyn are enriched in the 
Post-Synaptic Density (PSD)4. It is possible to monitor the activation of Src family 
kinases (SFK) by phospho-specific epitopes. Cultures for SFK activation after 
exposure to Aßo4 were examined. Wild type cortical neurons increase pY416-Fyn 
(SFK) in response to Aßo. This antibody detects pY416 in several SFKs, but kinase-
specific immunoprecipitations demonstrate that PrPC-dependent activation is Fyn-
specific4. In Prnp-/- cultures, activation of Fyn by Aßo is eliminated. Having 
previously detected PrPC-interacting Aß in human AD brain51, it was assessed 
whether these assemblies also activate neuronal Fyn. AD brain extracts at 6 μg 
protein/ml stimulate Fyn activation in mouse cortical cultures, but Control brain 
extracts do not4. Thus, TBS-soluble Aß derived from human AD stimulates neuronal 
Fyn via PrPC, as confirmed in a subsequent study by Lesne, Aguzzi, and colleagues44. 
Fyn Activation by Aßo–PrPC Alters Synaptic Function 
NMDA-Rs play a key role in synaptic plasticity and AD. Intracellular segments of 
NR2A and NR2B subunits contain tyrosine residues phosphorylated by SFKs45. Thus, 
Aßo/PrPC-mediated Fyn activation may be directed to NMDA-R. It has been shown 
that Aßo induces a dose-dependent increase in the phosphorylation of NMDA-R, 
specifically the Fyn-specific phosphorylation of NR2B at Y-14724. Aßo-induced 
NR2B phosphorylation is eliminated in Prnp–/– cultures, in Fyn–/– cultures, and by 
6D11 anti-PrPC antibody. Moreover, the roles of PrPC and Fyn are gene-dose-
dependent, being reduced in heterozygous neurons4. The effect is biphasic, such that 
NR2B phosphorylation is enhanced during the first 15 minutes with Aßo, but 
phosphorylation is suppressed after 1-3 hours4. 
 
Phosphorylation of NR2B at Y1472 is known to reduce AP-2 mediated endocytosis21. 
Investigators have examined the extent to which NR2B is accessible at the cell 
surface versus being sequestered intracellularly. In concert with the NR2B-pY-1472 
increase, surface NR2B increases shortly after Aßo exposure4. A calcium-sensitive 
fluorescent dye was utilized to monitor intracellular calcium in cortical neurons. 
NMDA produces increased fluorescence signal4. Pretreatment with Aßo for 15 


Protocol Number:  ADC-049 FYN 
 
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Protocol v4.0: 31-MAY-2017 
minutes generates significantly increased NMDA-induced signal, as predicted. By 60 
minutes, when NR2B receptors are dephosphorylated and internalized, NMDA-
induced calcium signals are suppressed. One hour pretreatment with Aßo 
suppresses glutamate responses in WT, but not in Prnp–/– or Fyn–/– neurons51. 
Thus, Aßo-induced, PrPC-mediated alterations in NMDA-R create transient 
increases and then decreases in neuronal calcium. 
 
It was considered whether the transient increase in surface NR2B might lead to a 
brief period of excitotoxicity. Brief exposure to Aßo reduces cell viability, with a 
release of 10% of cellular LDH. Genetic deletion of either Fyn or PrPC expression 
rescues neurons from Aßo4. Heterozygosity for null alleles of Prnp or Fyn 
significantly reduces LDH release4. Thus, Aßo requires PrPC to induce Fyn activation 
and subsequent NR2B phosphorylation. This phosphorylation is associated with 
transient increase in NR2B at the cell surface with consequent excitotoxicity. 
 
A hallmark of AD is synaptic loss46. In vitro studies have described dendritic spine 
loss after acute Aßo exposure14, 47, 48. To assess the roles of PrPC and Fyn in Aßo-
induced spine loss, neurons were cultured from embryos homozygous for null 
alleles4. Spine destabilization by Aßo is eliminated in Prnp–/– and Fyn–/– neurons. 
These studies suggest that Fyn plays a central role in coupling Aßo and PrPC to 
changes in neuronal function. Consistent with this hypothesis, when Fyn mutants 
are crossed with APP transgenic mice, Fyn gain-of-function enhances AD-related 
phenotypes while Fyn loss-of-function ameliorates AD-related phenotypes42, 49. 
Fyn Implicated in AD by Interaction with Tau 
Neurofibrillary tangles are composed of hyperphosphorylated tau and are key 
pathological markers of AD. Similar to studies of Aßo, studies of tau have implicated 
Fyn mechanistically in AD. Fyn physically associates with tau, and can 
phosphorylate tyrosine residues near the amino terminus5-8. Moreover, the Aßo– 
PrPC complex-driven activation of Fyn leads to downstream tau phosphorylation44. 
Critically, Fyn and tau interact genetically to modulate synapse loss, behavioral 
deficits and electroencephalographic abnormalities in APP transgenic mice42, 49, 50. 
Dendritic tau is required to deliver Fyn to the post-synaptic density9. Without 
functional tau, Fyn is uncoupled from NMDA-Rs, and Aß toxicity is rescued9. Two 
studies have reported a genetic association between SNPs at the FYN locus and CSF-
tau levels in AD, although this was not observed in all cohorts51, 52. Thus, PrPC/Fyn 
signaling appears to couple Aß and tau pathologies and Fyn can be considered a 
lynchpin of AD pathophysiology. 
AZD0530 Inhibits Fyn 
AZD0530 is an inhibitor of Src Family kinases, blocking Src, Fyn, Yes and Lyn, with 
2-10 nM potency53. AZD0530’s specific inhibition of Fyn and SFKs has led to its 
development as therapy for solid tumors, because Src family kinases regulate tumor 
cell adhesion, migration and invasion, and also regulate proliferation53. Clinical 
tolerability and oral bioavailability have been demonstrated, but Phase 2 studies 
have demonstrated limited benefit as a single agent in specific oncological 
indications54-58. For tumor cell migration and for oncological applications, it is 


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Protocol v4.0: 31-MAY-2017 
estimated that >98% kinase inhibition is required so clinical doses have targeted 
concentrations >20-fold above the kinase IC50, in the 200-1000 nM concentration. 
Importantly, CNS preclinical effects, and therefore the anticipated AD dosing, are 
achieved with much lower concentrations in the 5-50 nM range with 50-95% target 
inhibition. 
Efficacy And Pharmacodynamics Of AZD0530 in AD Model Mice 
To test the ability of AZD0530 to treat learning and memory deficits caused by AD 
pathophysiology, Yale investigators treated WT and APPswe/PS1∆E9 transgenic 
mice with the compound. The treatment was started when mice were 11-12 months 
of age. At this age, other cohorts from previous studies have shown a pronounced 
learning and memory deficit. The dosing was on a twice a day schedule by oral 
gavage and control groups received vehicle. The identity of the active versus vehicle 
groups and the transgene status were unknown to the researchers handling the 
mice and collecting the behavioral data. Mice were treated with 0, 2 or 5 mg/kg/d of 
AZD0530. Both 2 and 5 mg/kg/d doses were tested against vehicle in a first cohort 
and then (because the initial results suggested that 5 mg/kg/d was required for 
benefit) a second cohort of mice was tested with 0 versus 5 mg/kg/d. The data from 
the two cohorts were pooled. Different tests were performed at 1-3 weeks (early) or 
4-6 weeks (late) time points. Mice were tested in the Morris water maze at both 
ages, and also in Novel Object Recognition tests at the later time points. After 
memory testing was complete, the animals were sacrificed without ceasing their 
drug regimen for histological analysis. 
 
The results of the pooled Morris water maze data for wild type and transgenic mice 
treated for 4-5 weeks with vehicle or 5 mg/kg/d AZD0530 are shown in Fig. 1 (left 
panel). The learning trials show wild type mice have progressively shortened 
latencies to a hidden platform, and this is not altered by treatment with 5 mg/kg/d 
AZD0530. The transgenic mice are impaired and do not show as much learning, with 
significantly prolonged latencies on the later blocks of swim trials. Treatment with 
AZD0530 for 4-5 weeks eliminated the transgenic deficit, normalizing latencies to 
the hidden platform on trial blocks 4-6.  
 


Protocol Number:  ADC-049 FYN 
 
Page 13 of 60 
 
Protocol v4.0: 31-MAY-2017 
 
 
After the learning trials, the mice were tested the subsequent day in a memory test, 
the 60 second probe trial with the hidden platform removed (Fig. 1, right panel). 
Random chance results in 15 sec occupancy in each quadrant. The wild type mice 
with or without 5 weeks AZD0530 treatment preferred the target quadrant, with 
typical times of 30 seconds compared to an average of 10 sec in each of the non-
target quadrants. In contrast, the APPswe/PS1∆E9 mice treated with vehicle control 
spent much less time in the target quadrant, performing close to the chance level of 
15 seconds. The AZD0530 5 mg/kg/d treated group showed the same strong 
preference for the target quadrant as did WT mice. Thus, this dose of AZD0530 fully 
rescued both learning and memory deficits in aged AD transgenic mice. Shorter 
Figure 1. AZD0530 improves learning and memory in transgenic AD mice. 
Left panel. Spatial learning is plotted as latency to find a hidden platform in a Morris 
water maze at age 11-12 months. Mice were treated bid. by oral gavage for 3-4 weeks 
prior to the start of testing with 0 or 5 mg/kg/d AZD0530 and treatment was continued 
through the testing period. Mean ± SEM for the indicated numbers of mice per 
genotype/treatment group. By Repeated Measures ANOVA with Tukey post-hoc pairwise 
comparisons across trial blocks 3-6, the vehicle-treated APPswe/PS1∆E9 group differed 
from each of the other groups (**P < 0.001), whereas none of the other groups differed 
from each other (p > 0.05). For specific trial blocks, the vehicle-treated APPswe/PS1∆E9 
group differed from each of the other groups, ** P < 0.005 or * P < 0.05, whereas none of 
the other groups differed from each other (P > 0.05). 
Right panel. Memory performance during a 60 sec probe trial, 24 hr after learning, 
where time spent in the target quadrant was measured. Random chance is 15 sec. Mean ± 
SEM for n=9-14 in each group. Target quadrant time differed by one-way ANOVA with 
post hoc LSD pairwise correction for the indicated comparisons (*, P<0.05). 


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treatment duration or lesser doses did not have significant effects in these tests (not 
shown). 
Dog Toxicology Studies  
Previous 6-month dog and rat toxicology studies had been completed by 
AstraZeneca, and cover 6-month exposure in humans. The FDA advised that a 9-
month dog study is the appropriate preclinical study to support 12-month dosing in 
humans.  
 
From the AstraZeneca Investigator’s Brochure, Edition 10, the C-max and AUC 
values for dosing in dog at 5 mg/kg produces exposure equivalent to 125 mg in 
human, and the exposure in dogs with multiple dosing is linear from 0.5 to 5 mg/kg 
oral daily dose. Therefore, investigators at Yale initiated a 9-month dog toxicology 
study (8 dogs per dose) at 0 mg/kg/d, 0.5 mg/kg/d (NOAEL in 6 month), 2 mg/kg/d 
(equivalent to 50 mg daily in humans) and 5 mg/kg/d (a dose with mild GI toxicity 
in the 6-month study and equivalent to 50 mg daily in humans). This study was 
recently completed (See report “AZD0530: A 39-week Oral Gavage Toxicity Study in 
Dogs”) and supports a 12-month human study. 
2.2 
Summary of Clinical Findings  
Phase 1b Results 
 “A Phase Ib Multiple Ascending Dose Study of the Safety, Tolerability, and CNS 
Availability of AZD0530 in Alzheimer’s Disease” (HIC #1303011664; 
ClinicalTrials.gov identifier NCT01864655) has been completed at Yale. The primary 
aims of the study were to assess the safety and tolerability of oral AZD0530 in 
patients with AD and to determine dose levels that are well tolerated in AD patients 
and provide CSF concentrations predicted to slow AD.  
 
Subjects were enrolled in three Cohorts of 8 subjects each. Each cohort consisted of 
subjects receiving AZD0530 (n=6) or Placebo (n=2) PO daily. The first cohort 
received 50 mg, the second 100 mg and the third 125 mg.  
 
All subjects completed the study in Cohorts 1 and 2 and there were no serious 
adverse events (SAEs), significant laboratory abnormalities, or early terminations. 
In Cohort 3, there was one serious adverse event (SAE) that was also reported to the 
FDA as a Suspected Unexpected Serious Adverse Reaction (SUSAR), but all other 
subjects completed the study without SAEs, or early terminations. Adverse event 
frequencies by treatment group are shown in Table 1.  
 
Two subjects receiving AZD0530 125 mg daily had significant laboratory 
abnormalities that subsequently reversed: elevated serum creatinine, possibly 
related to study medication; worsened renal insufficiency, unlikely related to study 
medication. There were no significant hematological changes. The single SAE 
occurred in an 85 year old white female who was receiving 125 mg of AZD0530. 
After 9 days of treatment, she was hospitalized with 4 days of fatigue, anorexia, and 
body aches, and 1 day of shortness of breath, in the setting of her diuretic being held 


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for one day. The diagnosis was of congestive heart failure, bronchitis and/or 
atypical pneumonia. She was treated with additional diuretic (furosemide) and 
antibiotics (levofloxacin). Study drug was discontinued, and not restarted. She was 
discharged to short-term rehab (SNF) and has since done well, returning to baseline 
health. Because previous AstraZeneca experience with AZD0530 included a few 
subjects with reversible interstitial lung disease deemed to be possibly related to 
AZD0530, the subject was also evaluated by Yale interstitial lung disease expert, 
Danielle Antin-Ozerkis, MD. The impression was most consistent with CHF 
precipitated by pneumonia. However, Dr. Antin-Ozerkis concluded that “Drug 
toxicity is difficult to entirely rule out.”  The overall conclusion is that this event was 
“possibly related” to study drug. This SAE was reported to the DSMB, the Yale HIC, 
the NIH, and the FDA (as a SUSAR). 
Table 1. Adverse Events (preferred terms) by Treatment Group 
Adverse Events are per participant (counted only once for each adverse event) 
 
 
 
All subjects underwent standard clinical efficacy assessments at baseline and at 
Week 4 endpoint. These included Mini Mental Status Examination (MMSE), 
Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog), Alzheimer's 
Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL), Clinical 
Dementia Rating, sum of boxes score (CDR-SB), and Neuropsychiatric Inventory 
(NPI). There was a tendency for MMSE scores to improve over time, which may have 


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been due to practice effects as the MMSE was also administered at weekly visits as a 
safety measure. No statistically significant effect of treatment was observed on any 
of clinical efficacy assessment measures, which was not surprising given the small 
samples sizes and the short duration of treatment with an investigational therapy 
that is being developed primarily for longer-term disease modifying potential.  
 
The Phase 1b study collected both CSF and plasma for AZD0530 levels using a GLP-
validated LC/MS/MS assay (MPI Research, Mattawan, Mi). There was a close 
correlation between free AZD0530 in plasma and CSF AZD0530 (Fig. 3, left panel). 
CSF levels were about 1/3rd of plasma free drug levels. The free drug levels are 
calculated from the total plasma drug levels based on the molecular weight of the 
compound and a protein binding percentage in plasma of 91%. Comparisons were 
performed of the CSF levels across the dosage groups. There was variability within 
any one group, but clear dose dependency (Fig. 3, right panel). The increase in CSF 
level was greater than linear, with a 3-fold increase from 50 to 100 and a 2-fold 
increase from 100 to 125 mg, and this was most consistent with an exponential 
relationship. The trough CSF at 50 mg was 0.5 ng/ml to 1.2 ng/ml = 0.9 to 2.2 nM. 
The trough CSF at 100 mg was ng/ml to 4.5 ng/ml = 2.1 to 8.3 nM. The trough CSF at 
125 mg was 1.4 ng/ml to 7.6 ng/ml = 2.5 to 14.0 nM. Using the ratio of CSF:Brain in 
mouse, the estimated human brain concentrations at 50 mg = 3 to 7 nM, at 100 mg = 
7 to 27 nM, and at 125 mg = 8 to 46 nM. As mentioned above, the Fyn Ki for 
AZD0530 is 5 to 10 nM. Moreover, the mouse trough CSF at a dose effective in 
rescuing memory for transgenic mice is 3.1 to 7.6 ng/ml = 5.8 to 14 nM. This value 
overlaps with the human 100 mg levels and spans the human 125 mg range (Fig. 3, 
right panel).  
 
 
 


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2.3 
Safety and Compliance 
AZD0530 has been extensively studied in human subjects, including published 
studies with healthy individuals89, 90, and patients with solid tumors91, 92. 
AstraZeneca has extensive safety data of this drug in human subjects, described in 
detail in the Investigator Brochure (IB), and described in detail below. Notably, in a 
multiple ascending dose study, AZD0530 doses of 60 mg to 185 mg were well 
tolerated, and although adverse events were noticeably more frequent and severe at 
the 250 mg dose, no major safety issues were identified from adverse events at any 
of the doses studied. 
 
To date, 187 healthy volunteers and 421 patients with advanced cancer have 
received single or multiple once-daily oral doses of AZD0530 (Saracatinib). In a 
single ascending dose study, the maximally tolerated dose (MTD) was considered 
1000mg. In a multiple ascending dose study, the MTD was considered 250mg, 
although a toxicity-limiting dose was not pursued. In patients with advanced cancer, 
the MTD was 175mg. Existing preclinical toxicology in two species demonstrates 
safety through 6 months, supporting chronic administration for this duration in 
humans. In clinical oncology, the duration of AZD0530 treatment has been 2-12+ 
weeks in most trials. 
 
The doses proposed in this study, ranging from 100-125 mg have generally been 
well tolerated in both healthy volunteers, and in patients with advanced solid 
tumors. The most common adverse events at these doses have included rash, 
headache, and diarrhea. Less common adverse events have included nausea, 
vomiting, anorexia, anemia, palpitations, fatigue, influenza-like symptoms, and 
abnormal liver function tests. Other adverse effects at higher doses have included 
upper respiratory infection, myalgias, abdominal pain and tenderness, and 
epididymitis. 
 
Importantly, with AZD0530 monotherapy, febrile neutropenia or other serious 
hematologic adverse events have not been documented in doses equal to or lower 
than 175 mg. In a total of 7 phase 1 trials, including 187 healthy volunteers, no 
major safety issues were identified from adverse events in any of the doses studied, 
up to 250 mg daily (AstraZeneca Investigator’s Brochure, Edition 10, May 9, 2013). 
There is a potential for mild decreases in values for both white cell count and 
Figure 3. AZD0530 in Human CSF at Different Doses. 
Left Panel. Relationship between CSF and plasma levels of AZD0530. Each point is from a 
different individual. The different dose groups are illustrated with different colors. There 
is a tight correlation of plasma and CSF level as indicated. 
Right Panel. Each point represents trough CSF AZD0530 level from a different human 
subject for the left three columns. The mouse trough CSF values are derived from brain 
levels at the 5 mg/kg/d dose that rescued memory deficits in Fig. 1. Bars represent mean 
± sem.  


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platelets with doses of 125 mg and above, but these abnormalities never fell below 
reference levels, and levels normalized while patients remained on (AstraZeneca 
Investigator’s Brochure, Edition 10, May 9, 2013). The timing for hematologic effects 
of AZD0530 is within 14 days of drug initiation, providing the rationale for the 30-
day monitoring period in the phase 1 study (AstraZeneca Investigator’s Brochure, 
Edition 10, May 9, 2013). It should also be noted that 2/3 of the safety data have 
been generated from patients with solid tumors, and some of these patients were 
included in the study despite mild baseline pancytopenia. 
3.0 BACKGROUND AND SIGNIFICANCE 
3.1 
Rationale for Study  
Despite the enormous and growing burden of AD, there remains no effective 
disease-modifying therapy today. The approaches now in clinical trials are limited in 
their mechanism of action. Most AD clinical trials have centered on efforts to alter 
Aß itself, either its production or clearance or aggregation. No major trial has 
centered on the signal transduction downstream of toxic Aß species. In this sense, 
the focus on Fyn inhibition is highly innovative in the AD field. There are efforts to 
develop approaches to targeting tau and tau kinases in AD, but few have advanced 
in clinic trials, and none provides a unified approach to Aß and tau. Fyn is unique as 
an AD target in being central to Aß signal transduction and having major functional 
interactions with tau as well. Thus, the target is innovative in addressing toxicity 
related to both hallmarks of AD pathology. 
 
If AZD0530 blocks Fyn kinase activation in the brain of AD patients, it is predicted 
that it will provide the first disease-modifying therapy for AD. 
3.1.1 Rationale for Primary and Secondary Endpoints  
A major challenge in the development of AD treatments is the ability to evaluate 
them in a rapid, cost-effective, and rigorous way59. Due to the slow progression of 
cognitive and functional decline and the high test–retest variability of the clinical 
outcomes used in randomized clinical trials (RCTs), researchers have sought to 
develop biomarkers that reflect AD progression or pathology and that could be used 
to assess putative AD-slowing treatments with better statistical power55, 56. An 
established biomarker of AD progression is fluorodeoxyglucose positron emission 
tomography (18F-FDG PET) measurements of regional cerebral metabolic rate for 
glucose decline59-61 (CMRgl). Studies spanning more than twenty years with 18F-FDG 
PET have reported characteristic and progressive CMRgl reductions in posterior 
cingulate, precuneus, parietal, temporal and frontal regions in patients with AD and 
mild cognitive impairment (MCI). Moreover, longitudinal decline in CMRgl is 
strongly associated with concurrent cognitive and functional decline62, 63. 
 
Kewei Chen et al.63 at Banner Alzheimer’s Institute, have introduced the use of an 
empirically pre-defined statistical region-of-interest (sROI) to characterize CMRgl 
declines with optimal power and freedom from multiple comparisons, and to 
estimate the number of subjects needed to characterize AD-slowing treatment 


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effects in multi-center RCTs. They described twelve-month CMRgl declines in 69 
probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 
79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) 
using statistical parametric mapping (SPM). The AD and MCI groups each had 
significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial 
and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which 
were significantly greater than those in the NC group and correlated with measures 
of clinical decline. Using a training dataset comprised of 40% of the subject sample, 
these authors determined the settings associated with optimal CMRgl decline. The 
following settings were identified as optimal for the AD group a) a spatial resolution 
of 8 mm FWHM (i.e., no additional smoothing), b) a spared region defined by a 
significance threshold of p<0.0005, consisting of 6665 voxels associated with 
twelve-month regional-to-whole-brain CMRgl increases and located primarily in 
white matter and cerebellum, and c) a decline sROI defined by a significance 
threshold of p<0.0005, consisting of 32,807 voxels associated with twelve-month 
regional-to-spared sROI decline and located in the same regions known to be 
preferentially affected in cross-sectional and longitudinal brain-mapping studies of 
AD. They then applied these sROIs to assess CMRgl declines in independent test 
dataset comprised of the remaining 60% of the subject sample and estimated the 
samples needed for AD patients per treatment group to detect a AD-slowing 
treatment effect in a twelve-month, multi-center RCT with 80% power and two-
tailed alpha=0.05. Note: this power analysis forms the basis of this study’s proposed 
sample size. 
 
Secondary Endpoints. Although this trial will exploit the statistical power of a 
surrogate biomarker (glucose metabolism) for the primary efficacy endpoint, it will 
also acquire data for standard clinical endpoints to help power a future Phase 3 
pivotal trial. These endpoints (Aim 3) include ADAS-cog, MMSE, ADCS-ADL, CDR-SB, 
and NPI. Finally, as additional secondary endpoints, other recognized outcome 
biomarkers of AD progression have been selected in Aim 4 (MRI volumetrics) and 
Aim 5 (CSF biomarkers). 
 
Volumetric MRI allows the in vivo assessment of brain structure volume and 
provides a measure of atrophy rate. Results from volumetric MRI studies suggest 
that the patterns of atrophy in AD, which mirror the pathological progression of the 
disease, can reliably be detected and tracked across time (for review, see Atiya et 
al.64). Atrophy of the medial temporal lobe, including hippocampus and entorhinal 
cortex, has long been described in volumetric MRI studies of AD65. Hippocampal 
volume derived from MRI correlates with histological hippocampal volume and 
degree of neuronal loss and AD pathology66, and entorhinal cortical thickness 
change appears to be an early and sensitive indicator of neurodegeneration 
associated with AD67, 68. Longitudinal MRI measures of regional and whole-brain 
volumetric change provide a valuable complement to cognitive measures in that 
they are not influenced by temporary symptomatic improvements, and they provide 
an early index of the study drug’s ability to reach the target organ and have an effect 
on AD-related atrophy. 


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Subjects will have the option to participate in the CSF Substudy, in which they will 
undergo lumbar punctures (LPs) at the Baseline visit and Week 52 visit. In this 
substudy, the following putative biomarkers of AD will be measured: CSF total tau, 
and CSF pTau. These markers will be assessed at baseline and after 52 weeks of 
treatment with either AZD0530 or placebo. These putative biomarkers are among 
the leading candidates for AD biomarker development78, 79. For example, Gilman et 
al.80 reported a highly significant (p < 0.001) effect of Aβ immunization (with 
AN1792) on CSF tau with a total sample size of only 21 (N = 11 antibody responders 
and 10 placebo control participants). Critically, Aßo/PrP/Fyn signaling has been 
linked to pTau in preclinical studies44. Although not expected to be altered by 
treatment with AZD0530, CSF Aβ42 will also be assessed. 
3.2 
Rationale for Dosage Selection 
The dosing plan is based on the results of the Phase 1b trial, as well as studies of 
“Efficacy and Pharmacodynamics of AZD0530 in AD Model Mice” (See Section 2.0). 
Among subjects in the Phase 1b study in the 100 mg dose group, those with steady 
state total plasma levels above the median value 70 ng/mL in the Phase 1 MPI 
Research laboratory results (a calculated free drug concentration of 11.7 nM) also 
attained CSF levels of at least 5 nM, within the range of the Fyn Ki for AZD0530 (5 to 
10 nM) and the efficacious levels in AD model mice (5.8 to 14 nM). In preparation 
for the Phase 2 trial responsibility for conducting the plasma drug level 
measurement assay has been transferred from the MPI Research laboratory to the 
UCSD laboratory.  Cross validation studies have shown that plasma AZD0530 values 
are very tightly correlated between laboratories, but the UCSD laboratory values are 
approximately 1.5 times higher than the MPI laboratory used for Phase 1.  Based on 
these observations, the dosing plan aims to maximize the number of subjects who 
achieve total plasma AZD0530 levels >100 ng/mL as measured at the UCSD 
laboratory, while minimizing the safety and tolerability problems that would result 
from forced titration of all subjects to 125 mg daily. From the Phase 1 results, it is 
expected that approximately 50% of subject starting on 100mg AZD0530 will be 
titrated up to 125mg AZD0530 daily. 
3.3 
Rationale for 18F-Florbetapir PET and Biomarkers 
To streamline the evaluation of AZD0530, a number of biomarkers—both of AD/Aβ 
pathogenesis and of AD progression—have been incorporated.  A significant rate of 
amyloid PET negativity is evident in longitudinal studies that enroll subjects on 
clinical criteria alone—as high as 23% in the ADNI study75. Therefore, for study 
inclusion, an eligibility biomarker of AD and Aβ Pathogenesis—amyloid PET 
positivity—will be required to enrich the subject sample for individuals with true 
cases of AD and who are more likely to respond to AZD0530 as an inhibitor of Fyn in 
an Aβ-dependent pathway.  Requiring evidence of fibrillar Aβ burden using PET 
imaging for study inclusion follows emerging diagnostic recommendations73 and is 
designed to enhance the pathological specificity of the diagnosis of AD74.   
 


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To augment statistical power, the surrogate biomarker of glucose metabolism has 
been selected for the primary efficacy Aim 1. Other recognized outcome biomarkers 
of AD progression have been selected in Aim 4 (MRI volumetrics) and Aim 5 (CSF 
biomarkers). 
4.0 POTENTIAL RISKS AND BENEFITS ASSOCIATED WITH THIS 
INVESTIGATIONAL PRODUCT 
4.1 
Potential Risks and Benefits Associated with This Investigational Product 
4.1.1 Potential Benefits 
The study drug may slow cognitive decline in patients with mild AD.  The results of 
the study might help people with a similar condition in the future.  
4.1.2 Potential Risks 
AZD0530 has been extensively studied in human subjects, including healthy 
individuals 89,90, and patients with solid tumors91, 92. AstraZeneca has extensive 
safety data of this drug in human subjects, described in detail in the Investigator 
Brochure (IB) and summarized in Risks Associated with Study Drug, AZD0530. 
Overall, the safety profile of the doses of AZD0530 proposed in this project is good, 
and the Phase 1b study found that this safety profile can be also be extended to a 
patient population with AD. 
 
Conception must be avoided during maternal or paternal exposure to AZD0530.  
Women of childbearing potential are excluded from participation in this study and 
male study participants who are sexually active will be advised by site personnel 
regarding the use of appropriate forms of contraception and avoiding sperm 
donation for the duration of the trial and for a washout period of 1 week after 
cessation of study medication. 
 
There have though been cases where AZD0530 has been associated with potentially 
serious neutropenia and thrombocytopenia, although this has not been seen in 
healthy volunteers with doses up to 250 mg daily.  
 
To minimize potential risks in the study, subjects with unstable medical conditions 
will be excluded. Subject safety will be evaluated clinically and by laboratory 
measures (especially hematology studies for neutropenia, thrombocytopenia, and 
anemia), and thoracic high resolution CT (HRCT) if pulmonary symptoms arise. 
During the visits, vital signs will be recorded, and they will receive a physical and 
neurological examination by a study physician at screen and throughout the study 
(see Appendix 1, Schedule of events). Specific parameters for intervention 
discontinuation are detailed below. 
4.2 
Relationship of this intervention to current treatment practices in AD 
Currently, there is no approved treatment to prevent progression of Alzheimer’s 
disease. Approved treatments for Alzheimer’s disease include the following AChE 


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inhibitors: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne) 
which offer modest symptomatic relief (in terms of cognitive test scores and global 
functioning) for some patients but do not constitute standard treatment for the 
disease. Memantine (Namenda) is an approved treatment of moderate to severe 
Alzheimer’s disease. AZD0530 is an investigational drug that may have a disease-
modifying effect on AD. A placebo group is included in this study to allow for 
accurate assessment of safety, tolerability, and efficacy of AZD0530.  
5.0 SAMPLE SIZE AND STATISTICAL PLAN  
5.1 
Randomization 
Participants who have signed an informed consent and meet screening eligibility 
requirements will be randomly assigned using a 1:1 allocation ratio to AZD0530 or 
placebo by a random permuted block treatment assignment method, stratified by 
site.  
5.2 
Power and Sample Size Determination 
Aim 1. 18F-FDG PET 
Sample size calculations were based on a two-sided, two-sample t-test to compare 
the differences in mean change in CMRgI from baseline to month 12 by treatment 
arm. The statistical software R (version 2.14.0), http://www.r-project.org, was used 
for all power calculations. Using the reported CMRgl decline mean and standard 
deviation of 0.0514 ± 0.0309 in Chen et al.63, assuming 15% attrition, an alpha set to 
0.05, a sample size of 128 participants (64 participants per arm) is needed to detect 
a treatment effect of 30%. Assuming 15% per year attrition rate, a total of 152 
subjects need to be enrolled at the start of the study. 
Aim 2. Safety and Tolerability  
Power calculations were based on a two-sided chi-square test for detecting a 
difference between two proportions assuming a Type I error of 0.05. With a sample 
size of 64 patients in each group, and assuming an adverse event (AE) rate of 12.5% 
in the placebo group, there will be 80% power to detect an AE rate of 33.1% in the 
active treatment group (absolute difference in AE rates of 20.6% or higher). In other 
words, the AE rate will need to be as high as 33.1% in the active treatment group 
before there is sufficient power to assert that the result is statistically significant. 
5.3 
Selection of participants to be used in analysis 
In general, biomarker and clinical outcome analyses will incorporate the modified 
intent-to-treat principle (mITT), namely, all randomized participants who have been 
given study medication with a valid baseline and at least one post-baseline 
measurement will be included in the analysis while the safety analysis will be 
conducted on the intent-to-treat (ITT) population (all randomized participants).  All 
results will be reported as point estimates (proportions or mean differences across 
groups, as appropriate) and interval estimates (95% confidence intervals) with two-
sided p-values denoting statistical significance. A basic serial gatekeeping procedure 


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will be used to maintain over-all experiment-wise Type I error at a = 0.05 (two-
sided). The six hypotheses regarding (i) F-FDG PET, (ii) ADAS-Cog, (iii) ADCS-ADL, 
(iv) CDR-SB, (v) MMSE, and (vi) NPI will be tested in order using a basic serial 
testing strategy. If, for example, the p-value for FDG is ≥0.05, no subsequent 
hypotheses will be declared statistically significant. Otherwise if the p-value for FDG 
is <0.05, the ADAS-Cog hypothesis is tested by comparing the p-value for ADAS to 
0.05. This strategy continues until a p-value is ≥0.05, or the NPI hypothesis is 
declared statistically significant with p < 0.05. Regardless of the outcome of the 
multiple testing strategy, p-values and 95% confidence intervals will be reported for 
all planned analyses.  Statistical analysis will be conducted using the statistical 
software R (www.r-project.org).  
 
Demographic and baseline characteristics will be compared between the study 
groups using Fisher’s exact test for categorical variables, and two-sample t-tests for 
continuous variables.  Appropriate non-parametric alternatives will be considered, 
if parametric assumptions fail. 
5.4 
Efficacy Analysis 
5.4.1 Analysis of the Primary Outcome(s) 
Aim 1. 18F-FDG PET 
The rate of CMRgI change will be compared between the two treatment groups 
using a linear mixed-effect model with CMRgI at each time point (including baseline) 
as the outcome variable. The model will include fixed effects for time (as a 
continuous variable), time-by-treatment interaction, age, and APOE; and 
participant-specific random intercepts. The model will constrain the two treatment 
groups to have the same mean at baseline. The hypothesis will be tested using the p-
value corresponding to the mean group difference in rate of CMRgI change.  
Aim 2. Safety and Tolerability 
Summary statistics will be tabulated for the adverse events and clinical laboratory 
studies. Fisher’s Exact Test will be used to compare the frequencies of adverse 
events or laboratory abnormalities between the participants who receive AZD0530 
and those receiving placebo.  
 
Population PK analysis of concentration-time data of AZD0530 will be performed 
using a Mixed Model of Repeated Measures (MMRM). The outcome measure will be 
change from baseline in AZD0530 at each follow-up visit. The model will treat time 
as a categorical variable and include fixed effects for the treatment-by-time 
interactions, baseline AZD0530, age, and APOE. The model will assume an 
unstructured correlation and heterogeneous variance with respect to time. If the 
unstructured correlation model fails to converge, simpler structures (autoregressive 
of order one and compound symmetric) will be assumed in turn. The hypothesis will 
be tested using the p-value for the mean group difference in AZD0530 at week 52.  
 


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5.4.2 Analysis of Secondary Outcomes 
Aim 3. Clinical and Cognitive  
A similar categorical time MMRM as above will be used to estimate the mean group 
difference in each secondary outcome at 52 weeks. The outcome measure will be 
change from baseline in the outcome at each follow-up visit. The model will treat 
time as a categorical variable and include fixed effects for the treatment-by-time 
interactions and baseline outcome. In addition, age and APOE4 genotype will be 
included in the model as fixed effect covariates. The model will assume an 
unstructured correlation and heterogeneous variance with respect to time. If the 
unstructured correlation model fails to converge, simpler structures (autoregressive 
of order one and compound symmetric) will be assumed in turn. The hypothesis will 
be tested using the p-value for the mean group difference at week 52.  
 
Aim 4. Volumetric MRI 
The volumetric MRI outcomes will include (i) hippocampal volume, (ii) ventricular 
volume, (iii) total brain volume, and (iv) entorhinal thickness. The regional volume 
changes will be determined by nonlinear registration between baseline and follow- 
up images, and expressed as % deformation per years from baseline. The rate of 
volumetric MRI change will be compared between the two treatment groups using 
an ANCOVA model with % deformation per year as the outcome variable and covari- 
ates for baseline regional volume (or entorhinal thickness), treatment, age, and 
APOE. The hypothesis will be tested using the p-value corresponding to the mean 
group difference in rate of volume change.  
  
Aim 5. CSF Biomarkers 
Similar to the analysis for Hypothesis 1, the rate of CSF total Tau and pTau change 
will be compared between the two treatment groups using a linear mixed-effect 
model with observations at each time point as the outcome variable. The model will 
include fixed effects for time (as a continuous variable), time-by-treatment 
interaction, age, and APOE; and participant-specific random intercepts. The model 
will constrain the two treatment groups to have the same mean at baseline. The 
hypothesis will be tested using the p-value corresponding to the mean group 
difference in rate of change. 
 
Aim 6. APOE Genotype 
This analysis will focus on the potential influence of APOE4 genotype on outcome 
measures. Analyses of subgroups defined by the presence or absence of the APOE4 
allele (APOE+ versus APOE-) will be performed using analyses techniques analogous 
to the ones uses in Aims 1-5 to obtain separate assessment of treatment efficacy for 
both APOE4+ and APOE4- participants.  
5.5 
Interim Analysis 
There are no planned interim analysis being conducted for this study, but the DSMB 
may modify this during ongoing safety monitoring. 


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5.6 
Criteria for the termination of the trial 
The trial may be terminated by the Project Director, NCATS and/or AstraZeneca 
based on issues of safety, feasibility, and DSMB recommendations.   
 
 


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6.0 STUDY DRUG AND CONCOMITANT MEDICATIONS 
6.1 
Name and Description of IP and Comparator 
AZD0530 (saracatinib) is an inhibitor of Src Family kinases, blocking Src, Fyn, Yes 
and Lyn, with 2-10 nM potency53.  A placebo comparator will be used.  AstraZeneca 
will provide both study drug and placebo. 
6.2 
Dosage 
The AZD0530 treatment group will initially receive 100 mg PO daily. At the Week 2 
visit, total plasma drug levels will be measured (ADCS Biomarker Core, UCSD). 
Those subjects in the active treatment group who at week 2 are sufficiently 
compliant with dose regimen but have not attained a total plasma AZD0530 level of 
at least 100 ng/mL will be increased at the Week 4 visit to 125 mg of AZD0530 daily. 
All subjects will then remain on their Week 4 doses for the remainder of the study. 
 
The placebo group will receive the placebo comparator for the duration of the study. 
 
Study medication should be taken in the morning and may be taken with or without 
food.   
6.3 
Blinding 
This is a double-blind study in which subjects and site personnel will be blinded to 
both treatment assignment and dose level. In order to maintain the blind, each 
subject will be prescribed the same number of tablets (3) each day throughout the 
trial – either all placebo or a combination of placebo and AZD0530.  The following 
table describes the number and type of tablets to be taken each day based on 
treatment group and, for the AZD0530 group, dose level (see Section 6.2 for dose 
escalation rules).   
 
 
Number of Tablets per day 
Baseline – Week 4 
Week 4 – Week 52 
AZD0530 Treatment Group: 
without week 4 dose escalation 
50mg AZD0530:  2  
placebo-for-125mg: 1 
50mg AZD0530:  2  
placebo-for-125mg: 1 
AZD0530 Treatment Group: 
with week 4 dose escalation 
placebo-for-50mg:  2  
125mg AZD0530: 1 
Placebo Group 
placebo-for-50mg:  2  
placebo-for-125mg: 1 
placebo-for-50mg:  2  
placebo-for-125mg: 1 
 
A module within the Data Portal will be used to assign bottles to be dispensed to 
each subject at each visit as appropriate based on treatment assignment.  The 
module will use the week 2 compliance and plasma drug level data to determine the 
need for a dose adjustment and will assign bottles for the remainder of the study 
accordingly.   


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6.4 
Packaging/Dispensing/Labeling 
Study medication will be packaged and dispensed according to the table below. The 
dosing schedule will be clearly explained to the caregiver before dispensing the 
study drug and it will be printed on the labels.  
 
Dispensing 
Visit 
# 50mg AZD0530 or Placebo 
tablets dispensed 
# 125mg AZD0530 or 
Placebo tablets dispensed 
Baseline 
 1 bottle with 80 tablets 
 1 bottle with 40 tablets 
(placebo only) 
Week 4 
 2 bottles with 80 tablets each 
 2 bottles with 40 tablets each 
Week 13 
 3 bottles with 80 tablets each 
 3 bottles with 40 tablets each 
Week 26 
 3 bottles with 80 tablets each 
 3 bottles with 40 tablets each 
Week 39 
 3 bottles with 80 tablets each 
 3 bottles with 40 tablets each 
6.5 
Storage 
Medication should be stored in a facility at the site to which only the investigator, 
study coordinator and/or other designated personnel has access. Study medication 
must be stored at controlled room temperature (25° C, with excursions permitted to 
15° – 30° C). 
6.6 
Drug Accountability  
Study medication will be shipped to study sites from a central depot.  The 
investigator or designee must receive and store study medication supplies in a 
secure area and dispense according to protocol.  The participant will be advised to 
return all unused or partially used study medication to the investigator for counting 
and recording by study staff.   All empty bottles and unused or partially used 
supplies will be counted and verified by a clinical monitor prior to being destroyed 
according to local site procedures.  
6.7 
Compliance 
Site personnel will assess compliance at every visit after Baseline.  Participants and 
study partners will be instructed to bring medication bottles and any unused study 
medication each visit.  If they do so, site personnel will count returned tablets and 
evaluate compliance.  If they do not bring medication with them to a visit, site 
personnel will discuss adherence to study medication regimen with the participant 
and study partner.  Participants found to be < 80% or > 120% compliant will receive 
specific instruction from site personnel, including re-instruction on study 
procedures and additional telephone contact between visits.  
 
Prior to the Week 2 visit, site personnel will contact the participant and study 
partner to remind them of dose regimen, in particular to ensure that the necessary 
level of compliance is achieved to accurately measure plasma study drug levels.  
Details regarding timing of contact and compliance assessment for the week 2 blood 
draw will be provided in the Procedures Manual. 
 


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For LP sub-study participants, a similar focus on compliance, with site personnel 
discussing the dose regimen with the participant and study partner , will occur in 
the period leading up to the final LP to ensure that the necessary level of compliance 
is achieved to accurately measure CSF study drug levels.   
6.8 
Breaking the Blind  
Only in the case of an emergency, when knowledge of whether the patient has 
received the investigational product is essential for the clinical management or 
welfare of the patient, may the Investigator request to unblind a patient’s treatment 
assignment.  If the Investigator needs the blind to be unmasked for a patient for any 
reason, the Investigator must contact the Medical Monitor (and/or Project Director) 
to obtain an approval.  Breaking the blind must be reported to the Coordinating 
Center within 5 business days, documenting the date, the site personnel exposed to 
the treatment assignment, and the reason the blind was broken.  Refer to the study 
Procedures Manual for more detailed procedures related to breaking the blind and 
reporting.  
6.9 
Concomitant AD Medications 
This protocol allows concomitant treatment with cholinesterase inhibitors and 
memantine, if on a stable dose for 12 weeks prior to screening. 
 
Initiation of or modifications to concomitant AD medications during the course of 
the study should be discouraged, however, if a change occurs or a new medication is 
initiated, the site should consult with the Project Director and/or Medical Monitor 
for further guidance. 
6.10 Other Concomitant Medications 
6.10.1 Prohibited Concomitant Medications 
Use of the following medications is prohibited within 4 weeks of screening and 
throughout the study except as noted in section 6.10.2: 
• tricyclic antidepressants 
• antipsychotics (except risperidone ≤1.5 mg/day, quetiapine ≤100 mg/day, 
olanzapine ≤5 mg/day, and aripiprazole ≤10 mg/day) 
• mood-stabilizing psychotropic agents (e.g. lithium salts) 
• psychostimulants 
• opiate analgesics 
• antiparkinsonian medications (except for non-parkinsonian indications) 
• anticonvulsant medications (except gabapentin and pregabulin for non-
seizure indications 
• systemic corticosteroids 
• medications with significant central anticholinergic activity 
• anxiolytics or sedative hypnotics:  Use of short- to medium-acting 
benzodiazepines for treatment for insomnia or anxiety is permitted.  Use of 
sedatives or hypnotics should be avoided for 8 hours before administration 
of cognitive tests unless they are given chronically. 


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AZD0530 may partially inhibit the CYP3A4 enzyme, which is part of the P450 
system. For this reason, subjects taking the following drugs (sensitive CYP3A4 
substrates or CYP4A4 substrates with narrow therapeutic ranges, whose 
metabolism may be slowed by AZD0530) will be excluded from the trial: 
carbamazepine, colchicine, cyclosporine, disopyramide, fluticasone (except as a 
nasal spray which is allowable), oral steroids, quinidine, vinblastine, and vincristine.  
Subjects taking sildenafil, tadalafil, and vardenafil (also CYP3A4 substrates)—and 
their prescribing physicians—will be advised that these medications may be 
potentiated by AZD0530 (e.g., greater hypotensive effects) and that they should be 
used with greater caution and possible dose reduction. 
 
Initiation of prohibited medications during the course of the study should be 
discouraged, however, if an excluded medication is initiated after screening, the site 
should consult with the Project Director and/or Medical Monitor for further 
guidance. 
 
Investigational agents are prohibited one month prior to entry and for the duration 
of the trial. Also exclusionary is previous treatment with an investigational small 
molecule with anti-amyloid properties or passive immunization against amyloid 
within 1 year of entry or previous treatment with an active immunization against 
amyloid. 
 
Particular attention should be paid to AST and ALT and clinical symptoms of 
rhabdomyolysis in subjects taking lovastatin or simvastatin. 
 
Current use of warfarin or other anticoagulants are exclusionary for CSF substudy 
only. 
6.10.2 Permitted Concomitant Medications 
Gabapentin and pregabulin for non-seizure indications are permitted.  
 
Use of short- to medium-acting benzodiazepines for treatment for insomnia or 
anxiety is permitted.  Use of sedatives or hypnotics should be avoided for 8 hours 
before administration of cognitive tests unless they are given chronically. 
 
 


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Protocol v4.0: 31-MAY-2017 
7.0 STUDY POPULATION 
The study will enroll males and females age 55-85 with mild Alzheimer’s disease as 
specified in the entry criteria below. Subjects who do not meet all inclusion criteria, 
disease diagnostic criteria, or who meet any exclusion criteria may not be 
randomized into the study without prior approval from the Project Director (and/or 
Medical Monitor).  Efforts will be made to target at least 20% minority enrollment, 
which will be facilitated through special minority outreach effort coordinated by the 
Coordinating Center. 
7.1 
Inclusion Criteria 
Subjects must meet the following criteria: 
1. 
NIA-Alzheimer’s Association core clinical criteria for probable AD73 
2. 
18F-Florbetapir scan with evidence of elevated Aβ  (based on central review) 
3. 
Age between 55-85 (inclusive) 
4. 
MMSE81 score between 18 and 26 (inclusive) 
5. 
Stability of permitted medications for 4 weeks (see sections 6.9 and 6.10.2 
for further details).  In particular: 
• Stable doses of antidepressants lacking significant anticholinergic side 
effects (if they are not currently depressed and do not have a history of 
major depression within the past 1 year) 
• Cholinesterase inhibitors and memantine are allowable if stable for 12 
weeks prior to screen 
6. 
Geriatric Depression Scale94 less than 6  [Note: a score ≥6 on this screening 
scale may be permissible, if the subject is examined by a site clinician and 
judged not to be depressed.] 
7. 
Study partner is available who has frequent contact with the subject (e.g., 
average of 10 hours per week or more), and can accompany the subject to 
most visits to answer questions about the subject 
8. 
Visual and auditory acuity adequate for neuropsychological testing 
9. 
Good general health with no disease expected to interfere with the study 
10. 
Subject is not pregnant, lactating, or of childbearing potential (i.e., women 
must be two years post-menopausal or surgically sterile) 
11. 
Modified Hackinski95 less than or equal to 4 
12. 
Completed six grades of education or has a good work history 
13. 
Must speak English or Spanish fluently 
7.2 
Exclusion Criteria 
Subjects must not meet the following criteria: 
1. 
Any significant neurologic disease other than AD, such as Parkinson’s disease, 
multi-infarct dementia, Huntington’s disease, normal pressure 
hydrocephalus, brain tumor, progressive supranuclear palsy, seizure 
disorder, subdural hematoma, multiple sclerosis, or history of significant 
head trauma followed by persistent neurologic defaults or known structural 
brain abnormalities 


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2. 
Screening/baseline MRI scan with evidence of infection, infarction, or other 
focal lesions or multiple lacunes or lacunes in a critical memory structure 
3. 
Subjects that have any contraindications for MRI studies, including 
claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac 
pacemaker 
4. 
Major depression, bipolar disorder as described in DSM-IV within the past 1 
year or psychotic features, agitation or behavioral problems within 3 months, 
which could lead to difficulty complying with the protocol 
5. 
History of schizophrenia (DSM V criteria) 
6. 
History of alcohol or substance abuse or dependence within the past 2 years 
(DSM V criteria) 
7. 
Clinically significant or unstable medical condition, including uncontrolled 
hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, 
hepatic, endocrine, or other systemic disease in the opinion of the 
Investigator, may either put the subject at risk because of participation in the 
study, or influence the results, or the subject’s ability to participate in the 
study. 
8. 
Has had a history within the last 5 years of a primary or recurrent malignant 
disease with the exception of non-melanoma skin cancers, resected 
cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical 
carcinoma in situ, or in situ prostate cancer with normal prostate-specific 
antigen post-treatment 
9. 
Clinically significant abnormalities in B12 or TFTs that might interfere with 
the study. A low B12 is exclusionary, unless follow-up labs (homocysteine 
(HC) and methylmalonic acid (MMA)) indicate that it is not physiologically 
significant. 
10. 
Residence in skilled nursing facility. 
11. 
Use of any excluded medication as described in section 6.10.1. 
12. 
Current or recent participation in any procedures involving radioactive 
agents, including current, past, or anticipated exposure to radiation in the 
workplace, such that the total radiation dose exposure to the subject in a 
given year would exceed the limits of annual and total dose commitment set 
forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1. This 
guideline is an effective dose of 5 rem received per year. 
13. 
Neutropenia defined as absolute neutrophils count of <1,800/microliter 
14. 
Thrombocytopenia defined as platelet count <120x103/microliter 
15. 
For CSF sub-study participants, a current blood clotting or bleeding disorder, 
or significantly abnormal PT or PTT at screening 
16. 
Clinically significant abnormalities in screening laboratories, including: 
• Aspartate aminotransferase (AST) >1.5 times ULN 
• Alanine aminotransferase (ALT) > 1.5 times ULN 
• Total bilirubin >1.5 times ULN 
• Serum creatinine >2.0 times ULN 
17. 
History of interstitial lung disease 
18. 
Patients whom the PI deems to be otherwise ineligible 


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7.3 
Recruitment and Retention Strategies 
Study-wide recruitment efforts will be overseen by a recruitment team at the 
Coordinating Center, which has developed a coordinated recruitment plan to ensure 
that enrollment occurs in a timely fashion. The overall goals of the plan are to raise 
awareness of the trial among targeted populations to ensure adequate enrollment. 
The Coordinating Center partners with NIA and coordinates with its ADEAR Center 
to leverage existing resources. The recruitment and retention team will develop 
materials specific to the AZD0530 trial for use by the sites, provide ongoing 
recruitment assistance and support, and develop tracking procedures to monitor 
effectiveness of recruitment efforts. The recruitment plan for the AZD0530 trial will 
include both the utilization of participants existing at clinical trial centers and the 
recruitment of additional populations by methods of outreach. 
8.0 STUDY TIMELINE  
The approximate timeline for this study is projected as follows: 1) approximately 6 
months for study startup activities that may include FDA/IND submission, site IRB 
and regulatory approvals, and the Investigator training meeting; and 2) 
approximately 2 years for screening and treatment period, and analysis.  
 
 


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9.0 DESCRIPTION OF STUDY VISITS 
9.1 
Pre-screening 
During the prescreen phase, sites will identify potential participants through a 
variety of mechanisms (i.e. reviewing patients enrolled in ADCs, de novo 
recruitment, and referrals) and assess if they may potentially qualify for the study 
following the site’s standard practice. 
9.2 
Screening 
Up to 60 days will be permitted to allow for completion of all Screening procedures,  
assessment of eligibility criteria, and completion of all Baseline procedures, 
including randomization.  The Screening procedures will typically require 3 visits to 
complete.  
Initial Screening (Visit 1a):  
The purpose of this visit is to determine initial study eligibility. Potential 
participants, or legally authorized representatives, and their study partners must 
sign an informed consent form prior to administration of any study-related 
procedures. Information regarding the subject’s demographics, concurrent 
medications, and medical history will be gathered along with cognitive, clinical, and 
safety assessments. For a complete list of all Visit 1a procedures, refer to the 
Schedule of Events (Appendix 1).  Procedures for Visit 1a may be completed over 
multiple days. 
 
All Visit 1a procedures must be completed and all information related to eligibility, 
including screening lab results, must be reviewed by the investigator or qualified 
designee for assessment of the subject’s eligibility before the subject can proceed to 
the screening MRI scan (Visit 1b). 
MRI (Visit 1b):  
The MRI will be read locally to confirm eligibility.  The site clinician should review 
the local read for exclusionary findings prior to completion of the 18F-Florbetapir 
PET scan.  If there are no exclusionary findings on the MRI the subject will continue 
on to the 18F-Florbetapir PET scan. 
18 F-Florbetapir PET (Visit 1c):  
The 18 F-Florbetapir PET scan will be read centrally to confirm eligibility. If the 18 F-
Florbetapir PET scan shows evidence of elevated Aβ (per inclusion criteria), the 
subject may continue to baseline following clinical monitor review and verification 
that all eligibility requirements have been met. If the PET scan does not show 
evidence of elevated Aβ, then the subject will be excluded. 
9.2.1 Re-screens 
Unless otherwise approved by the Project Director, only one re-screen is allowed, 
should the original screen be a failure. The re-screen should typically occur at least 
3 months after the original screen failure.  Individuals who fail screening due to 
ineligible results on the amyloid PET scan may not be re-screened.  


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9.3 
Baseline Visit (Week 0) 
The Baseline visit may only be initiated following completion of all Screening 
assessments and required approvals.  The Baseline visit procedures may be 
completed over multiple days and will typically require at least two (2) visits.   All 
Baseline procedures, including randomization must be completed within 60 days of 
initiation of Screening Visit procedures.  
 
Baseline procedures include cognitive, functional, and behavioral assessments, 
safety assessments, review of concurrent medications and adverse events, 18F-FDG 
PET and biofluid collection (blood, plasma, and optional CSF). For a complete list of 
all Baseline procedures, refer to the Schedule of Events (Appendix 1).   
 
Baseline cognitive assessments for CSF sub-study subjects must be done prior to, or 
at least 48 hours after, the lumbar puncture.  If done on the same day, Baseline 
cognitive assessments must be done prior to the 18F-FDG PET scan.  In no instance 
should cognitive assessments be performed while the subject is in a fasted state.   
 
For further information regarding specific visit procedures, refer to section 12. 
 
Following completion of all Baseline procedures and confirmation that the Baseline 
FDG PET has passed central QC, participants who continue to meet all protocol 
inclusion criteria and no exclusion criteria, will be randomized and dispensed study 
medication.  If holding randomization for the return of FDG QC results were to 
unduly burden a participant, e.g. due to lengthy travel, the site may consult with the 
Project Director (and/or Medical Monitor) for guidance and a possible exception.   
9.4 
Treatment Visits (Week 2 – Week 52) 
Evaluations of safety and tolerability, clinical and biomarker assessments, and study 
drug dispensing will be performed throughout the treatment period.  For a complete 
list of all visits and visit procedures, refer to the Schedule of Events (Appendix 1).   
 
Timing of each follow-up visit is calculated from the Baseline visit date.  Procedures 
for each visit may be completed over multiple days, but must occur within the 
window for that visit. Visit window for each visit are as follows: 
 
Visit / Target Date 
Visit Window 
Week 2 
 10-21 days from baseline  
Week 4 
 21-35 days from baseline  
Note: there must be sufficient time between weeks 2 and 4 
for drug level data to be obtained 
Weeks 6 and 8 
 +/- 1 week from target date 
Other visits 
 +/- 2 weeks from target date 
 
Plasma drug level measured at week 2 will determine study drug allocation that will 
be dispensed at week 4 as described in Section 6.2. 


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At Week 52, the MRI, 18F-FDG PET scan, and lumbar puncture (for CSF sub-study 
participants) should occur during the 2 weeks prior to the in-clinic visit (while 
subject remains on study medication). Cognitive assessments for CSF sub-study 
subjects must be done at least 48 hours after the lumbar puncture.  If done on the 
same day, cognitive assessments must be done prior to the 18F-FDG PET scan.  In no 
instance should cognitive assessments be performed while the subject is in a fasted 
state.   
 
CSF sub-study participants who did not have a successful CSF collection at Baseline 
should still attempt a collection at Week 52.   
 
For further information regarding specific visit procedures, refer to section 12. 
10.0 EARLY TREATMENT/STUDY DISCONTINUATION  
The investigators at each site will make every reasonable effort to maximize 
participant retention. However, if an investigator removes a participant from 
treatment or study, or if a participant declines further treatment or study 
participation, an Early Discontinuation Visit will be completed as soon as possible 
following discontinuation of the study drug and or at time of study discontinuation.  
 
The Early Discontinuation Visit will contain the same assessments as the week 52 
visit, to allow collection of the main outcome measures.  Depending on when the last 
study visit was conducted, certain procedures (e.g. LP, MRI or FDG PET scan) may 
not be required at the Early Discontinuation Visit.  Refer to the Procedures Manual 
for further guidance.  If an in-person visit is not possible, site personnel will 
complete as much of the Early Discontinuation Visit as possible by telephone. All 
early treatment discontinuation participants will be strongly encouraged to 
complete all remaining study visits. 
 
Replacement participants are not required for those who discontinue from 
treatment or study (i.e. an additional participant does not need to enroll in the study 
for every participant discontinued). 
10.1 Reasons for Early Discontinuation 
AZD0530 has been associated with potentially serious neutropenia and 
thrombocytopenia, although this has not been seen in healthy volunteers with doses 
up to 250 mg daily. While we do not expect to see these adverse events with the 
doses of AZD0530 in this study, the laboratory criteria for considering drug 
discontinuation are as follows: 
a. Neutropenia defined as absolute neutrophil count of <1,500/microliter 
b. Thrombocytopenia defined as platelet count <100X103/microliter 
c. Interstitial lung disease by high resolution chest CT, attributed to drug 
exposure. The following algorithm will be used: 
 


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If the laboratory criteria for drug discontinuation due to neutropenia or 
thrombocytopenia as described above are triggered, study drug should be held and 
labs should be repeated (locally or centrally) as soon as possible for confirmation of 
the findings.  If findings are confirmed, the participant should be permanently 
discontinued from study drug.  If the study physician thinks that discontinuation of 
study drug is not warranted he/she should consult with the Project Director and/or 
Medical Monitor for final guidance. 
 
Other abnormal laboratory values will be evaluated individually. The clinical 
criterion for discontinuation is defined as a single Serious (or intolerable) Adverse 
Event that the site clinician or the DSMB consider related to study medication. 
Clinical symptoms and decisions regarding drug discontinuation will be reviewed 
and made on an individual basis by the study physician, in collaboration with the 
Project Director, Medical Monitor, and DSMB as needed. 
 
Participants may also be discontinued from treatment/study for reasons such as the 
following: 
If cough or dyspnea occurs or worsens 
while on study and cannot 
categorically be clinically ascribed to a 
cause other than saracatinib dosing: 
Interrupt saracatinib dosing. Obtain 
high resolution CT scan of thorax 
CT scan of thorax does NOT 
show interstitial lung disease 
(bilateral, diffuse, parenchymal 
lung disease) 
Consider re-commencing 
saracatinib dosing 
CT scan of thorax shows 
interstitial lung disease 
(bilateral, diffuse, parenchymal 
lung disease) 
Permanently discontinue 
saracatinib. Immediate referral 
to pulmonary specialist 


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• Adverse experience:  The participant has experienced an adverse event that, 
in the opinion of the investigator, requires early termination. This may 
include abnormal laboratory values. 
• Death 
• Safety risk: Any participant who becomes a safety risk during the trial will be 
withdrawn. 
• Protocol violation:  The participant fails to meet protocol entry criteria or did 
not adhere to protocol requirements. 
• Non-compliance: The participant is non-compliant with completion of study-
related evaluations and or intake of study drugs. 
• In the investigator’s judgment, it is in the participant’s best interest to 
discontinue participation in the treatment/study. 
• Consent is withdrawn.  The participant wishes to withdraw from the study, 
or the legally authorized representative wish the participant to be 
withdrawn.  
• The study is terminated by the Project Director/Coordinating Center, alone 
or at the recommendation of the Data Safety Monitoring Board. 
• Lost to follow up.  Participant could not be recalled back to conduct follow up 
visits. 
• Loss of informed study partner.  The participant no longer has a responsible 
study partner to oversee participant visits and administration of study drug. 
• Coordinating Center Request.  The coordinating center determines it is in the 
participant’s best interest to discontinue participation from the treatment 
and or study. 
11.0 INSTRUMENTS 
11.1 Cognitive Evaluations  
11.1.1 Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog12) 
The ADAS-Cog82 is a structured scale that evaluates memory (word recall, word 
recognition), reasoning (following commands), language (naming, comprehension), 
orientation, ideational praxis (placing letter in envelope) and constructional praxis 
(copying geometric designs). Ratings of spoken language, language comprehension, 
word finding difficulty, and ability to remember test instructions are also obtained.  
The test is scored in terms of errors, with higher scores reflecting poorer 
performance and greater impairment. For secondary analyses, the ADAS-cog 11 
(which excludes the 10-point Delayed Word Recall item assessing recall of the 
learned word list83) will be used with scores ranging from 0 (best) to 70 (worse). 
11.1.2 Mini-Mental State Examinations (MMSE) 
The MMSE81 is a brief, frequently used screening instrument for Alzheimer’s disease 
drug studies.  The MMSE scale evaluates orientation, memory, attention, 
concentration, naming, repetition, comprehension, and ability to create a sentence 
and to copy two overlapping pentagons.  The MMSE is scored as the number of 
correctly completed items with a lower score indicative of poorer performance and 


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greater cognitive impairment.  The total score ranges from 0 (worse) to 30 (perfect 
performance). 
11.2 Clinical and Functional Evaluations  
11.2.1 ADCS-AD Activities of Daily Living (ADCS-ADL-Standard) 
The Alzheimer’s Disease Cooperative Study - Activities of Daily Living Scale (ADCS-
ADL) is an activities of daily living questionnaire aimed at detecting functional 
decline in people with mild to moderate Alzheimer’s Disease. It was developed as a 
result of a research project funded by the National Institute on Aging (NIA) and 
conducted by the ADCS to develop cognitive and functional instruments for the 
assessment of patients with AD with relevance to clinical trials84. The ADCS-ADL 
was selected to best cover the assessment of patients with mild to moderate 
dementia due to AD, and has been used widely in clinical trials where patients have 
baseline MMSE scores in a range of 16-24/30 43, 93. Questions are administered to a 
qualified study partner about a set of 6 basic and 17 instrumental ADL (23 ADL 
items are covered overall). Performance of each of these activities during the past 4 
weeks, as well as the level of performance, are rated. A total score is derived by 
summing scores across items, and ranges from 0 (maximal impairment) to 78 
(maximally independent function). 
11.2.3 Geriatric Depression Scale  
The Geriatric Depression Scale (Short Form) is a self-report scale designed to screen 
for symptoms of depression in the elderly94.  The scale consists of 15 questions that 
the participant is asked to answer yes or no on the basis of how they felt over the 
past week.  The more benign items are asked first. Answers to 5 of the items are 
negatively oriented for depression (e.g., Do you feel full of energy?) and 10 
positively oriented (e.g., Do you often feel helpless?).  One point is given for each 
appropriate positive or negative answer indicative of a symptom of depression, for a 
possible total of 15 points. Total scores of 0-5 are considered likely to be normal and 
scores of 6-15 are considered to be more likely to be depressed. 
11.2.4 Neuropsychiatric Inventory (NPI) 
The NPI is a well-validated, reliable, multi-item instrument to assess 
psychopathology in AD based on interview with the study partner87, 88. The NPI 
evaluates both the frequency and severity of 10 (or 12) neuropsychiatric features, 
including delusions, hallucinations, agitation/aggression, dysphoria, anxiety, 
euphoria, apathy, disinhibition, irritability/lability, and aberrant motor behavior, as 
well as evaluates sleep and appetite/eating disorders.  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 score for each subscale is the product of severity and frequency and the total 
score is the sum of all subscales.  The 12-item NPI will be used in this study. 
11.2.5 Modified Hachinski 
The Modified Hachinski is a brief questionnaire that incorporates questions about 
medical history, cognitive symptoms and features of stroke, reported by a study 
partner as well as the neurological examination and neuroimaging studies95. 


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11.2.6 Research Satisfaction Survey 
The Research Satisfaction Survey (RSS) was adapted from the work of Larsen et al96 
to measures the satisfaction of elderly volunteers in clinical trials to treat or prevent 
cognitive loss or dementia.  The RSS builds on the Client Satisfaction Questionnaire 
(CSQ-8) which demonstrates a high degree of validity and internal consistency and 
measured consumer satisfaction with health and human service programs.  Higher 
scores on the CSQ indicate a greater level of satisfaction in service programs98; 
conversely, lower CSQ-8 scores have been associated with higher dropout rates98 
and missed appointments in treatment settings97 and in urban Community Mental 
Health program96. Open-ended questions about satisfaction are part of the CSQ, and 
allow participants to provide feedback about specific operational procedures of a 
particular service program96.  The RSS is similarly designed with a 7- item survey 
and may include additional items to inquire about the specific aspects of a given trial.  
Four items are designed to be answered with a modified likert scale and can be used 
to create a summary score with a range of 4-16, which can be analyzed with 
parametric statistics; three items provide for open ended responses about the 
intervention, the assessments and the frequency of visits and may be used to 
understand retention rates. 
11.2.7 Treatment Blinding Questionnaire 
The Treatment Blinding Questionnaire assesses the perception of blind being 
maintained until the end of the study. The questionnaire is to be completed by the 
study participant, study partner, and principal investigator at the end of study. 
12.0 PROCEDURES 
12.1 Safety Assessments 
12.1.1 Physical and Neurological Examination 
A medically qualified professional will perform a brief physical examination that 
consists of a review of the major body systems (I.E. skin, 
head/ears/eyes/nose/throat (HEENT), cardiovascular, pulmonary, abdomen, 
musculoskeletal, and extremities). Assessments of height, weight, and vital signs 
(systolic and diastolic blood pressure, pulse, temperature, oxygen saturation, and 
respiration) are included. Neurological examination will include an assessment of 
cranial nerves, strength, coordination, reflexes, sensation, tremor, gait and mental 
status. 
12.1.2 Electrocardiogram (ECG) 
An appropriately qualified individual will conduct a standard 12-lead resting ECG. 
The ECG report must be reviewed, signed, and dated by the site Principal 
Investigator (or a medically-qualified individual delegated by the PI).  Those with 
clinically significant ECG findings will be referred for follow-up as deemed 
appropriate by the investigator and may be excluded from the study. 


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12.1.3 Clinical Laboratory Evaluations 
All routine laboratory samples will be analyzed by a central laboratory, which will 
provide a procedures manual and supplies. Lab reports will be reviewed, signed and 
dated by the site Principal Investigator (or a medically-qualified individual 
delegated by the PI).  If a value is outside of the laboratory’s normal range, the 
clinician will indicate if it is clinically significant or not.  Those results that are 
deemed clinically significant may need to be repeated and follow up with the 
patient’s primary care physician for further evaluation should occur.   
 
For results that are deemed possibly related to study medication, the site 
investigator and/or the Medical Monitor and the Project Director may request 
additional unscheduled laboratory tests or may temporarily or permanently 
discontinue study medication.  Study drug will always be temporarily held for 
laboratory-related AEs deemed “severe” (corresponding to CTCAE grade 3 or 
higher). Refer to Section 10.1 for laboratory criteria for drug discontinuation. 
12.2 Biofluids 
12.2.1 CSF Substudy 
Subjects will have the option to participate in the CSF Sub-study. 
 
All samples will be collected after an 8 hour fast, preferably in the morning.  Site 
personnel should advise the subject not to take study medication on the morning of 
the procedure. Efforts should be made to conduct the follow-up LP at the same time 
of day as the Baseline LP. 
 
Prior to lumbar puncture (LP), a coagulation panel will be obtained to rule out a 
clotting disorder.  Subjects taking an anti-platelet agent (e.g. aspirin) may, at the 
discretion of the site clinician, be discontinued from that agent for a period of time 
prior to lumbar puncture and/or continue off agent for a period of time post LP. 
Participants who are taking anticoagulants (e.g. warfarin (Coumadin) and/or 
dabigatran (Pradaxa)) may not undergo an LP and are not suitable to participate in 
this substudy. 
 
When done at the same visit, the LP must always occur after (or a minimum of 72 
hours prior to) the MRI scan.  LP under fluoroscopy is permitted, if needed. Site 
personnel should advise the subject that use of fluoroscopy (x-rays) involves 
exposure to radiation. 
 
A total volume of 20 mL of CSF should be collected for each LP. To clear blood 
associated with needle insertion, the first 1-2 mL (or more if needed) of CSF should 
be discarded.  1-2 mL CSF (or volume per local laboratory requirements) will be 
sent to the local laboratory for protein, glucose, and cell count. Remaining CSF will 
be frozen on dry ice or in a -80 freezer and shipped overnight frozen to the ADCS 
Biomarker Core at UCSD for processing and analysis.  Analyses will include AD 
biomarkers (e.g. Aβ and tau, exploratory biomarkers), and, at week 52, analysis of 


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drug levels.  Samples will also be frozen and banked at the ADCS Biomarker Core at 
UCSD and Strittmatter laboratory at Yale for future analysis. 
 
Each study participant or a person designated to speak for them will be contacted 
by phone one day after the LP to confirm participant well being and to query about 
any adverse events. 
12.2.2 Plasma for Biomarkers 
Plasma samples will be collected at Baseline and at Week 52 for analysis of AD 
biomarkers (e.g. Aβ40 & 42, exploratory biomarkers).  
 
Blood for plasma collection should be collected in a uniform fashion into 10ml 
lavender top EDTA tubes (provided by Coordinating Center).  Once blood is 
collected, it is shipped overnight at ambient temperature to the ADCS Biomarker 
Core at UCSD for processing and analysis. 
 
Blood samples will be processed for plasma by the ADCS Biomarker Core and stored 
at UCSD and the Strittmatter laboratory at Yale for future analysis. 
12.2.3 Plasma for AZD0530 Levels  
AZD0530 plasma levels will be analyzed at select visits as described in the Schedule 
of Events (Appendix 1).  It is crucial that site personnel advise subjects not to take 
study medication on the morning of the collection.   
 
For participants in the CSF sub-study, at week 52, plasma for AZD0530 levels should 
be collected as close as possible to the time of the LP to allow for comparisons of 
drug levels in plasma and CSF.  
 
Plasma is collected as described above in 12.2.2 using lavender top EDTA tubes.  
Once blood is collected into a 10 mL EDTA plastic tube, it is shipped overnight at 
ambient temperature to the ADCS Biomarker Core at UCSD for analysis. 
12.2.4 APOE Genotype and other DNA Markers 
DNA will be extracted from participant blood samples at the Baseline visit and will 
be analyzed for APOE genotype. This will allow secondary analyses of data on the 
impact of the APOE genotype on putative biomarkers of AD, clinical outcome 
measures, and adverse events (Aim 6). APOE polymorphisms are an important 
genetic risk factor for AD. Individuals with one or two APOE4 alleles have a higher 
risk of developing AD and an earlier age of onset. Furthermore, those with one or 
two APOE4 alleles exhibit a more rapid rate of clinical change in some, but not all 
studies.  
 
Blood is collected in a uniform fashion using EDTA as anti-coagulant, as described in 
section 12.2.2.  Once blood is collected into a 10 mL EDTA plastic tube, it is shipped 
overnight at ambient temperature to the ADCS Biomarker Core at UCSD for APOE 
genotyping. Participants will be asked to consent to optional DNA banking for future 


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research studies. The DNA will be banked at the ADCS Biomarker Core at UCSD and 
Strittmatter laboratory at Yale. 
12.3 Magnetic Resonance Imaging (MRI) 
Subjects will have a brain MRI scan as part of the screening evaluation, as well as at 
Week 52 to enable volumetric MRI analyses as a secondary biomarker of AD 
progression (Aim 4). Measurement will rely on nonlinear registration between 
baseline and follow-up images to calculate point-by-point volumetric change68, 
along with FreeSurfer-based probabilistic-atlas image segmentation to identify and 
calculate average change across regions of interest (ROIs) as defined in the Desikan 
et al. brain atlas69. The entirety of the Desikan atlas will be available for post-hoc 
exploratory analyses, but secondary outcome measures will be limited to the 
regions noted in the study aims to reduce planned comparisons. 
12.3.1 Site Qualification 
Each site’s scanner will have an identifying number, which will be appended to the 
image header of all MRI data. Each scanner will be subjected to a pre-qualifying 
process that includes an evaluation for excessive vibration or other image artifact 
revealed through submitted MR images of an American College of Radiology 
phantom obtained by applying the study’s standardized protocol.  If the scanner has 
not been used previously in an applicable trial, then an additional qualification step 
will require the scanning of a human volunteer. If the scanner was previously used 
in an applicable trial, the qualification process can often be shortened and a human 
volunteer may not be needed, except in special circumstances. Sites must 
demonstrate the ability to follow the imaging protocol as prescribed in the MRI 
procedures manual and to provide 3D T1 MPRAGE or IR-FSPGR images using the 
procedures for submitting scans for automated segmentation. The resulting 
segmentations will be examined centrally to assess suitability for quantitative 
analysis. Because longitudinal analysis of brain volumetry will be used in this study, 
sites will be required to use the same qualified scanner for all scans of a particular 
subject. 
12.3.2 Data Acquisition 
When done at the same visit, the MRI scan must always occur prior to (or at least 72 
hours after) an LP.  
 
Briefly, the protocol for image acquisition will include a brief localizer scan, followed 
by a high-resolution 3D T1 structural series (MPRAGE or IR-SPGR), a T2-weighted 
series (FLAIR), a diffusion weighted scan and a gradient recalled echo scan. The 
volumetric analysis procedure will include corrections for gradient nonlinearities70 
and intensity non-uniformity71, 72 using methods developed within the 
Morphometry Biomedical Informatics Research Network (mBIRN; 
http://www.birncommunity.org/). Analysis procedures will be repeated for follow-
up scans.  
 
The MRI will be performed using a 1.5 or 3.0 Tesla magnet. The MRI will take 
approximately 30 minutes to complete. Injectable contrast agents will not be used.  


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Conscious sedation can be used in rare cases if deemed appropriate by the site 
clinician.  Refer to section 6.10.2 for details of timing of administration of sedating 
medications relative to cognitive testing.  
12.3.3 Clinical Read of MRIs 
Each site will be required to procure a local clinical read of each subject’s MRI data 
by qualified personnel.  At screening, this local read should be used to ensure that 
subjects do not meet exclusion criteria as described in section 7.2.   
12.3.4 Data Management and Quality Control 
MRI data will be uploaded to the secure study data portal. All imaging data will be 
de-identified through a numerical coding system.  Each MRI will be assessed 
centrally for scan quality allowing volumetric analysis.  Quality control for MRI will 
result in failure of some scans which may need to be repeated.  Repeat scans must 
be scheduled within four weeks of the visit date. 
12.4 PET Imaging 
12.4.1 Site Qualification 
Each site must be qualified for PET.  If the machine being used has already been 
certified by the ADNI PET Core and has not experienced any major software 
upgrades, re-qualification will not be required. Qualification of the PET scanner 
applies to both the 18F-FDG PET and 18F-Florbetapir imaging protocols.  
Qualification will employ the same methods utilized for site qualification in ADNI.  
Sites will be provided with a Hoffman brain phantom (if one is not available to the 
site) and a technical manual for the data acquisition using 18F, generally FDG.  The 
phantom must be scanned on two sequential days using the protocol identical to 
that required for human imaging. This enables the University of Michigan to 
ascertain the characteristics of the scanner (particularly resolution and uniformity) 
and assure that sites are capable of performing the protocol for acquisition and 
image reconstruction. All phantom images will be provided to the University of 
Michigan for review and qualification.  
12.4.2 18F-Florbetapir PET Data Acquisition 
Conscious sedation for PET imaging is not allowable. 
 
PET data will be acquired from study participants using ADNI protocols: a 20-min 
dynamic emission scan will be performed, consisting of four 5-min frames in the 3D 
mode 50 minutes after an intravenous administration of 10 mCi of 18F-Florbetapir, 
either preceded by a CT scan (for PET/CT scanners) or followed by a transmission 
scan (for PET-only scanners).  Data will be corrected for radiation-attenuation and 
scanner using transmission scans or X-ray CT, and reconstructed using 
reconstruction algorithms specified for each type of scanner as described in the PET 
technologist’s manual. 18F-Florbetapir PET data will be transferred to the study data 
portal to be retrieved by the team at Banner Alzheimer’s Institute imaging facility 
for central review and analysis following quality control checks and standardization 
by University of Michigan.  Eligibility for the study will be determined based on both 
visual and quantitative metrics for elevated amyloid burden. Visual readings from 


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the raw images will be based on recently validated algorithms76 and guidelines 
provided in the Amyvid package insert77.  The final determination regarding PET 
scan eligibility will be made available via the study data portal for the site 
investigator and coordinator to access. 
12.4.3 18F-FDG PET Data Acquisition 
Conscious sedation for PET imaging is not allowable. 
 
18F-FDG PET scans will be acquired according to a standardized protocol.  
Participants will be instructed to fast for at least four hours prior to a scan.  A 30-
min dynamic emission scan, consisting of six 5-min frames, either preceded by a CT 
scan (for PET/CT scanners) or followed by a transmission scan (for PET-only 
scanners), will be acquired starting 30 minutes after the intravenous injection of 5 
mCi of 18F-FDG, as the subject lies quietly in a dimly lit room with their eyes open 
and with minimal sensory stimulation. Data will be corrected for radiation-
attenuation and scatter using transmission scans or X-ray CT, and reconstructed 
using reconstruction algorithms specified for each type of scanner as described in 
the PET technologist’s manual. 
12.4.4 18F-Florbetapir and 18F-FDG PET Data Management and Quality Control 
The University of Michigan under the direction of Robert A. Koeppe, PhD will assess 
each PET scan for scan quality.  Quality control for PET will result in failure of some 
scans which may need to be reprocessed or repeated.  Repeat scans must be 
scheduled within four (4) weeks of the visit date. 
 
All raw and processed image data required to reconstruct the PET images (including 
the normalization, CT, transmission, and blank scans must be archived. It is 
necessary to archive and store raw and processed data at the imaging site for the 
duration of the project. 
 
Each acquired PET dataset will be reviewed and pre-processed using standardized 
procedures to identify artifacts and minimize scanner-dependent differences in 18F-
Florbetapir or 18F-FDG uptake. During the pre-processing, automated algorithms 
will be used to register and average each subject's six (FDG) or four (Florbetapir) 5-
min emission frames, transform each registered image into a 160×160×1.5 mm 
voxel matrix with sections parallel to a horizontal section through the anterior and 
posterior commissures (without any adjustment for size or shape), normalize the 
images for individual variations in absolute image intensity, and apply a filter 
function previously customized for each scanner using a Hoffmann brain phantom 
scanned during the site qualification process to ensure an isotropic spatial 
resolution of 8 mm full-width-at-half-maximum (FWHM). 
13.0 PERSONNEL REQUIREMENTS 
The Protocol Principal Investigator (PI) is responsible for the overall conduct of the 
study at the site.  The PI is to supervise project personnel and ensure that clinical 
raters maintain a high level of skill and accuracy in conducting assessments. 


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Additionally, the PI will perform or supervise clinical evaluation of all participants 
and ensure protocol adherence. Additional key personnel may be required, as 
specified in the procedures manual.  
14.0 ADVERSE EVENTS 
14.1 Definition 
An adverse event (AE) is defined as per the Code of Federal Regulation Title 21 Part 
312: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32 
 
Adverse events which occur after informed consent is signed and up to 30 days after 
the study drug has been discontinued, include but are not limited to: (1) worsening 
or change in nature, severity, or frequency of conditions or symptoms present at the 
start of the study; (2) participant deterioration due to primary illness; (3) 
intercurrent illness; and (4) drug interaction. An abnormal laboratory value will 
only be reported as an AE if the investigator considers it to be clinically significant, 
or if it leads to the participant being withdrawn from the study. 
 
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and or other clinical information. In such cases, the diagnosis should be 
documented as the AE and not the individual signs or symptoms.  Symptoms and 
conditions present at the beginning of the study will be characterized, so that AEs 
can be defined as any new symptom, or any increase in frequency or severity of an 
existing symptom. Adverse events should be described with medical terminology so 
that the event can be matched against a medical coding dictionary, such as MedDRA 
(Medical Dictionary for Regulatory Activities). 
 
Investigators should report their assessment of the potential relatedness of each AE 
to the protocol procedure(s) and also to the investigational product.  Attribution of 
AEs will be rated as definite, probable, possible, unlikely or unrelated. 
 
Following questioning and evaluation, all AEs, whether determined to be related or 
unrelated to the study drug by a medically qualified site PI or clinician must be 
documented in the participant’s records, in accordance with the investigator’s 
normal clinical practice, and on the AE eCRF. 
14.2 Following Up on AEs 
The investigator is obliged to follow participants with AEs until the events have 
subsided, the conditions are considered medically stable, or the participants are no 
longer available for follow up. Participants who discontinue due to adverse 
experiences will be treated and followed according to established medical practice. 
All pertinent information will be entered into the eCRF. All adverse events will be 
reported to the independent Data Safety Monitoring Board (DSMB). Adverse events 
will be rated as mild, moderate or severe.  


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15.0 SERIOUS ADVERSE EVENTS (SAE) 
15.1 Definition  
A serious adverse event is defined as per the Code of Federal Regulation Title 21 
Part 312: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32 
 
Medical and scientific judgment should be exercised in deciding whether reporting a 
serious adverse event is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the outcomes listed in the code of Federal Regulations Title 21 Part 
312. 
 
Hospitalizations that fulfill one of the following conditions will not have to be 
reported as SAE: 
• Admission for treatment of a pre-existing condition that is not associated 
with the development of a new AE or with a worsening of the pre-existing 
condition (i.e., work-up for persistent lab abnormality that occurred prior to 
the study) 
• Social admission (i.e., participant has no place to sleep) 
• Administrative admission (i.e., yearly physical exam) 
• Protocol-specified admission (i.e., for a procedure required by the study 
protocol) 
• Optional admission not associated with a precipitating clinical AE (i.e., pre-
planned treatments, elective cosmetic surgery) 
15.2 Reporting SAEs 
Any serious adverse event which occurs during the course of the investigation (i.e. 
anytime after informed consent, regardless of study drug exposure) or within 30 
days of receiving the last dose or last study visit must be reported to the Project 
Director and the Coordinating Center within 24 hours of learning of the event.  This 
in turn will trigger an alert to the appropriate Coordinating Center personnel and 
Protocol Project Director, which will lead to the initiation of the creation of the 
report. A notification will be sent to all participating sites and the DSMB once the 
report is available. Sites will inform their IRB of the event based on local IRB 
requirements. The Coordinating Center will also report unanticipated problems and 
SAEs to the NCATS program official, NCATS Medical Monitor(s), and to the FDA – 
IND holder, Dr. Stephen Strittmatter. 
 
The local site investigator and research staff will monitor the study procedures for 
this trial for overall safety and scientific relevance on an ongoing basis. The local site 
PI (in conjunction with, as needed, the Medical Monitor, the Project Director, and the 
DSMB) will evaluate every adverse event for safety and causality, and will determine 


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whether the adverse event affects the Risk/Benefit ratio of the study and whether 
modifications to the protocol or consent form are required. 
 
The Office for Human Research Protections considers unanticipated problems 
involving risks to subjects or others to include, in general, any incident, experience, 
or outcome that meets all of the following criteria:  
• unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied  
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research);   
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
ATRI will manage these unanticipated problems as SUSARs that involve the project 
director and DSMB or as AEs of Medical Interest, which would be reported in local 
IRB reports from sites. 
16.0 DATA AND SAFETY MONITORING BOARD (DSMB) 
The DSMB is an independent advisory group to the Coordinating Center Director, 
the Project Director, and the NCATS.  No investigator involved in the trial is a 
member of the DSMB.  
 
The initial task of the DSMB will be to review the protocol to identify any necessary 
modifications. If modifications are necessary, revisions will be reviewed by the 
DSMB prior to its recommendation on initiation of the project. The DSMB, based on 
its review of the protocol, will work with the Coordinating Center personnel to 
identify the study-specific data parameters and format of the information to be 
regularly reported. The DSMB will initially be provided with data blinded to 
treatment status, but they may request unblinded data if there is a safety concern. 
The DSMB and NIA representative will meet in person or by conference call on a 
quarterly basis. 
 
Additionally, the DSMB will be informed of the occurrence of any serious adverse 
events within 7 days of being reported to the Coordinating Center. The DSMB may at 
any time request additional information from the Coordinating Center.  
 
Based on the review of safety data, the DSMB will make recommendations regarding 
the conduct of the study. These may include amending safety monitoring 
procedures, modifying the protocol or consent, terminating the study or continuing 
the study as designed. Using the Safety Review Process and the DSMB described 
above, there is substantial oversight and case review to alert the investigators, in a 


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timely manner, to any safety issues that may arise.  For further details please refer 
to the DSMB charter. 
17.0 RECORDING AND COLLECTION OF DATA  
17.1 Case Report Form 
The Principal Investigator or designee will record all data collected (either written 
or electronic record of data).  Written or electronic data of record must be entered 
on the electronic Case Report Form (eCRF) provided for that purpose. In some 
instances no prior written or electronic record of data may exist and data recorded 
directly on the eCRF is considered source data.  The site will be suitably trained on 
the use of the eCRF and appropriate site personnel will be authorized to provide 
electronic signatures. The Principal Investigator is responsible to verify the integrity 
of the data and acknowledge as such by signature. 
 
All site entries will be made in a secured web site and the Principal Investigator will 
review the record for completeness.  If corrections are necessary to the eCRFs, the 
Principal Investigator or designee will update the eCRF and provide documentation 
for the reason for change.  
 
Completed eCRFs will be submitted according to the Coordinating Center's 
instructions, and reviewed by the Coordinating Center to determine their 
acceptability.  If necessary, data correction requests will be generated for resolution 
by the study site.  
17.2 Study Files and Patient Source Documents 
Patient confidentiality is strictly held in trust by the participating investigators and 
research staff.  This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants.  
 
The study protocol, documentation, data and all other information generated will be 
held in strict confidence.  No information concerning the study or the data will be 
released to any unauthorized third party, without prior written approval of the 
sponsoring institution. Authorized representatives of the sponsoring institution may 
inspect all documents and records required to be maintained by the Investigator, 
including but not limited to, medical records (office, clinic or hospital) and 
pharmacy records for the participants in this study.  The clinical study site will 
permit access to such records. Any data, specimens, forms, reports, and other 
records that leave the site will be identified only by a participant identification 
number (Participant ID, PID) to maintain confidentiality.  All records will be kept in 
a locked file cabinet.  All computer entry and networking programs will be done 
using PIDs only. Information will not be released without written permission of the 
participant, except as necessary for monitoring by IRB, the FDA, the NIA, and the 
OHRP. 
 


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Information about study participants will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  Those regulations require a signed participant 
HIPAA Authorization informing the participant of the following:  
• What protected health information (PHI) will be collected from participants 
in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of 
their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of participant authorization. Each site PI, under the guidance of 
his/her IRB, is responsible for ensuring that all applicable HIPAA regulations and 
State laws are met. 
18.0 ETHICS AND REGULATORY CONSIDERATIONS 
18.1 Good Clinical Practice 
This study will be conducted in compliance with the protocol and accordance with 
Good Clinical Practice (GCP) guidelines, as defined by the International Conference 
on Harmonisation (ICH) Guideline, Topic E6, the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50) – Protection of Human Subjects and Part 
56 – Institutional Review Boards (IRBs), HIPAA, State and Federal regulations and 
all other applicable local regulatory requirements and laws.    
 
Study personnel involved in conducting this study will be qualified by education, 
training and experience to perform their respective task(s) in accordance with GCP.   
 
No study document shall be destroyed without prior written agreement between 
the Coordinating Center and the investigator.  Should the investigator wish to assign 
study records to another party or move them to another location, he/she may do so 
only with the prior written consent of the Coordinating Center.  
18.2 Institutional Review Board (IRB) / Research Ethics Boards (REB) 
Institutional Review Boards and Research Ethics Boards must be constituted and 
their authority delegated through the institution's normal process of governance 
according to applicable State and Federal requirements for each participating 
location. Each participating institution must provide for the review and approval of 
this protocol and the associated informed consent documents and recruitment 
material by an appropriate IRB registered with the Office for Human Research 
Protections (OHRP). Any amendments to the protocol or consent materials must 
also be approved before they are placed into use. In the United States, only 


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institutions holding a current US Federalwide Assurance issued by OHRP may 
participate. Refer to: http://www.hhs.gov/ohrp/assurances/. 
 
The investigator must obtain approval from the IRB for all subsequent protocol 
amendments and, when warranted, changes to the informed consent document and 
recruitment materials. Protocol and informed consent form amendments can be 
made only with the prior approval of the Coordinating Center.  The investigator may 
not implement any protocol deviation without prior notification to the Coordinating 
Center and prior review and documented approval of the IRB, except where 
necessary to eliminate an immediate hazard to study participants, or when 
change(s) involve only logistical or administrative aspects of the trial (ICH 4.5.4). 
The investigator shall notify the IRB of deviations from the protocol or serious 
adverse events occurring at the site, in accordance with local procedures.  
18.3 Informed Consent and HIPAA Compliance 
Informed consent will be obtained in accordance with US 21 CFR 50.25, the Tri-
Council Policy Statement: Ethical Conduct of Research Involving Humans and the 
Health Canada and ICH Good Clinical Practice.  Applicable HIPAA privacy 
notifications will be implemented and HIPAA authorizations signed before protocol 
procedures are carried out. Information should be given in both oral and written 
form as deemed appropriate by the Site’s IRB. 
 
Prior to the beginning of the trial, the investigator should have the IRB’s written 
approval of the written informed consent form and any other written information to 
be provided to participants and be acceptable by Regulatory Affairs at the 
Coordinating Center.  Consent forms must be in a language fully comprehensible to 
the prospective participants and/or their authorized representatives and study 
partners. Participants, their relatives, guardians, or authorized representatives and 
study partners will be given ample opportunity to inquire about the details of the 
study. Prior to a participant’s participation in the trial, the written informed consent 
form should be signed and personally dated by the participant or by the 
participant’s legally acceptable representative, and by the person who conducted 
the informed consent discussion.  Participants should be provided a copy of the 
signed ICF. 
 
The informed consent will not only cover consent for the trial itself, but for the 
genetic samples/data/storage, biomarker samples/data/storage, and imaging 
scans/data/storage as well. Consent forms will specify that DNA and biomarker 
samples are for research purposes only; the tests on the DNA and biomarker 
samples are not diagnostic in nature and participants will never receive results.  
18.4 Genetic Research and Storage of Genetic Material  
The DNA is banked in locked -80 degree freezers in the ADCS Biomarker Core 
laboratory at UCSD and in the Strittmatter laboratory at Yale University.  Sample 
tubes are bar-coded and linked to participant ID number only and banked without 


Protocol Number:  ADC-049 FYN 
 
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Protocol v4.0: 31-MAY-2017 
personal identifiers. Samples are recorded into a computerized inventory database 
that is encrypted and password-protected. 
 
Only DNA from consenting participants will be banked and used to facilitate future 
research on aging and dementia, particularly in the discovery of genetic 
polymorphisms that may influence risk of developing AD.  Collection of DNA will 
permit qualified investigators to probe candidate genetic polymorphisms as 
predictors of outcome in future studies.  The samples will be stored by the ADCS as 
long as funding is available from the NIH.  If funding should lapse completely, the 
UCSD ADRC will provide responsible custodianship of the ADCS Biomarker Core. 
18.5 Storage of Biospecimen Samples  
All biospecimens being banked for future AD biomarker research will be shipped to 
and stored by the ADCS Biomarker Core at UCSD and the Strittmatter laboratory at 
Yale University. Sample tubes are bar-coded and linked to participant ID number 
only and banked without any personal identifiers. Samples are tracked by a 
computerized inventory database that is encrypted and password-protected at 
UCSD.  Similarly, at Yale, sample records will be computerized, locked, and password 
protected. 
 
Only biospecimens from consenting participants will be banked and used to 
facilitate future research on aging and dementia.  The samples will be stored by the 
ADCS as long as funding is available from the NIH.  If funding should lapse 
completely, the UCSD ADRC will provide responsible custodianship of the ADCS 
Biomarker Core. 
18.6 MRI and PET Imaging and Data Storage  
MRI and PET scans will be labeled according to each site’s imaging machine 
capabilities using Subject ID and scanner specific series descriptions as detailed in 
the Technical Manual. All imaging data will be de-identified using participant 
identifiers as detailed in the Technical Manual and checked centrally to confirm the 
absence of participant identifying information. MRI scan findings of clinical 
significance, as determined by the local clinical read and the site PI, may be shared 
with the study participant and the participant’s local physician. 
18.7 Inclusion of Children as Participants 
Children will not be included. 
18.8 Study Monitoring  
The clinical monitor is responsible for inspecting the electronic case report forms 
and source documentation at regular intervals throughout the study to verify 
adherence to the protocol, completeness and accuracy of the data, and adherence to 
local regulations on the conduct of clinical research. The monitoring visits must be 
conducted according to the applicable ICH and GCP guidelines to ensure protocol 
adherence, quality of data, drug accountability, compliance with regulatory 
requirements and continued adequacy of the investigational site and its facilities.  


Protocol Number:  ADC-049 FYN 
 
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Protocol v4.0: 31-MAY-2017 
The Site Investigator will cooperate in the monitoring process by ensuring the 
availability of the eCRFs, source documents and other necessary documents at the 
time of the monitoring visits. Site Investigator will promptly address any matters 
brought to his/her attention by the monitor. The Site Investigator may also be asked 
to meet in-person with the site monitor during certain visits. 
19.0 AUDIT 
In accordance with ICH GCP, representatives of the Coordinating Center and/or 
regulatory agency may select this study for audit.  The Investigator and study staff 
are responsible for maintaining the site master file containing all study-related 
regulatory documentation as outlined by Regulatory Affairs that will be suitable for 
inspection at any time by the Coordinating Center, its designees, and/or regulatory 
agencies. Inspection of site facilities (e.g., pharmacy, laboratories) to evaluate the 
trial conduct and compliance with the protocol may also occur.  
20.0 RECORD RETENTION 
Essential documents and study records must be retained for a minimum of seven 
years following primary publication of study results.  The Coordinating Center will 
notify sites when retention of such documents is no longer required.   
21.0 PUBLICATION POLICY   
The results of this study will be published.  To coordinate dissemination of data 
from this study, a publication committee will be formed.  The committee will consist 
of Dr. van Dyck, Dr. Strittmatter, interested Principal Investigators and appropriate 
Coordinating Center personnel.  The committee will solicit input and assistance 
from other Investigators as appropriate and adhere to all Coordinating Center 
Publications Policies. 
22.0 SHARING OF FINAL RESEARCH DATA  
Data from this research will be shared with other researchers pursuant to the 
02/26/2003 “NIH Final Statement on Sharing Research Data”. The NIH policy can be 
found at:   
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html 
 
NIH believes that data sharing is important for further translation of research 
results into knowledge, products, and procedures to improve human health.  The 
NIH endorses the sharing of final research data to serve these and other important 
scientific goals.  To protect participants’ rights and confidentiality, identifiers will be 
removed from the data before they are shared. 


Protocol Number:  ADC-049 FYN 
 
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Protocol v4.0: 31-MAY-2017 
23.0 LITERATURE CITED 
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29. Cisse, M., et al. Ablation of cellular prion protein does not ameliorate abnormal neural 
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protein transgenic mice.  J Neurosci 31, 10427-10431 (2011). 
30. Resenberger, U.K., et al.  The cellular prion protein mediates neurotoxic signaling of 
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31. Bate, C. & Williams, A. Amyloid-beta-induced synapse damage is mediated via cross-
linkage of cellular prion proteins.  J Biol Chem 286, 37955-37963 (2011).  
32. Alier, K., Ma, L., Yang, J., Westaway, D. & Jhamandas, J.H. Abeta Inhibition of Ionic 
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34. Gimbel, D.A., et al. Memory impairment in transgenic Alzheimer mice requires cellular 
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35. Kudo, W., et al. Cellular prion protein is essential for oligomeric amyloid-beta-induced 
neuronal cell death.  Hum Mol Genet 21, 1138-1144 (2012).  
36. You, H., et al. Abeta neurotoxicity depends on interactions between copper ions, prion 
protein, and N-methyl-D-aspartate receptors.  Proc Natl Acad Sci USA 109, 1737-1742 
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37. Zou, W.Q., et al. Amyloid-{beta}42 Interacts Mainly with Insoluble Prion Protein in the 
Alzheimer Brain.  J Biol Chem 286, 15095-15105 (2011).  
38. Freir, D.B., et al. Interaction between prion protein and toxic amyloid beta assemblies 
can be therapeutically targeted at multiple sites.  Nat Commun 2, 336 (2011).  
39. Barry, A.E., et al. Alzheimer's disease brain-derived amyloid-beta-mediated inhibition 
of LTP in vivo is prevented by immunotargeting cellular prion protein.  J Neurosci 31, 
7259-7263 (2011).  


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40. Bizat, N., et al. Neuron dysfunction is induced by prion protein with an insertional 
mutation via a Fyn kinase and reversed by sirtuin activation in Caenorhabditis 
elegans.  J Neurosci 30, 5394-5403 (2010).  
41. Malaga-Trillo, E., et al. Regulation of embryonic cell adhesion by the prion protein.  
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42. Chin, J., et al. Fyn kinase induces synaptic and cognitive impairments in a transgenic 
mouse model of Alzheimer's disease.  J Neurosci 25, 9694-9703 (2005). 
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44. Larson, M., et al.  The Complex PrPc-Fyn Couples Human Oligomeric Abeta with 
Pathological Tau Changes in Alzheimer's Disease.  J Neurosci 32, 16857-16871 (2012). 
45. Salter, M.W. & Kalia, L.V. Src kinases: a hub for NMDA receptor regulation.  Nat Rev 
Neurosci 5, 317-328 (2004).  
46. Scheff, S.W., DeKosky, S.T. & Price, D.A. Quantitative assessment of cortical synaptic 
density in Alzheimer's disease.  Neurobiol Aging 11, 29-37 (1990). 
47. Lacor, P.N., et al. Abeta oligomer-induced aberrations in synapse composition, shape, 
and density provide a molecular basis for loss of connectivity in Alzheimer's disease.  J 
Neurosci 27, 796-807 (2007).  
48. Shankar, G.M., et al. Natural oligomers of the Alzheimer amyloid-beta protein induce 
reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent 
signaling pathway.  J Neurosci 27, 2866-2875 (2007).  
49. Roberson, E.D., et al. Amyloid-beta/Fyn-induced synaptic, network, and cognitive 
impairments depend on tau levels in multiple mouse models of Alzheimer's disease.  J 
Neurosci 31, 700-711 (2011). 
50. Chin, J., et al. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in 
human amyloid precursor protein transgenic mice.  J Neurosci 24, 4692-4697 (2004). 
51. Cruchaga, C., et al. SNPs associated with cerebrospinal fluid phospho-tau levels 
influence rate of decline in Alzheimer's disease.  PLoS Genet 6(2010).  
52. Bekris, L.M., et al. Tau phosphorylation pathway genes and cerebrospinal fluid tau 
levels in Alzheimer's disease.  American journal of medical genetics.  Part B, 
Neuropsychiatric genetics : the official publication of the International Society of 
Psychiatric Genetics 159B, 874-883 (2012).  
53. Hennequin, L.F., et al. N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-
yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly 
selective, orally available, dual-specific c-Src/Abl kinase inhibitor.  J Med Chem 49, 
6465-6488 (2006).  
54. Gangadhar, T.C., Clark, J.I., Karrison, T. & Gajewski, T.F. Phase II study of the Src kinase 
inhibitor saracatinib (AZD0530) in metastatic melanoma.  Invest New Drugs (2012).  
55. Gucalp, A., et al. Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor for the 
treatment of patients with hormone receptor-negative metastatic breast cancer.  
Clinical breast cancer 11, 306-311 (2011).  
56. Mackay, H.J., et al.  A phase II trial of the Src kinase inhibitor saracatinib (AZD0530) in 
patients with metastatic or locally advanced gastric or gastro esophageal junction 


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1158-1163 (2012).  
57. Fury, M.G., et al. Phase II study of saracatinib (AZD0530) for patients with recurrent 
or metastatic head and neck squamous cell carcinoma (HNSCC).  Anticancer Res 31, 
249-253 (2011).  
58. Renouf, D.J., et al.  A phase I/II study of the Src inhibitor saracatinib (AZD0530) in 
combination with gemcitabine in advanced pancreatic cancer.  Invest New Drugs 30, 
779-786 (2012).  
59. Reiman, E.M. & Langbaum, J.B.S. Brain imaging in the evaluation of putative 
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York, 2009). 
60. Alexander, G.E., Chen, K., Pietrini, P., Rapoport, S.I. & Reiman, E.M. Longitudinal PET 
Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure 
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61. Reiman, E.M., et al. Declining brain activity in cognitively normal apolipoprotein E 
epsilon 4 heterozygotes: A foundation for using positron emission tomography to 
efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci USA 98, 
3334-3339 (2001). 
62. Landau, S.M., et al. Associations between cognitive, functional, and FDG-PET measures 
of decline in AD and MCI. Neurobiol Aging 32, 1207-1218 (2011). 
63. Chen, K., et al. Twelve-month metabolic declines in probable Alzheimer's disease and 
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64. Atiya, M., Hyman, B.T., Albert, M.S. & Killiany, R. Structural magnetic resonance 
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65. Jack, C.R., Jr., et al. Medial temporal atrophy on MRI in normal aging and very mild 
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66. Jack, C.R., Jr., et al. Antemortem MRI findings correlate with hippocampal 
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67. Knight, W.D., et al. Acceleration of cortical thinning in familial Alzheimer's disease. 
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68. Holland, D., et al. Subregional neuroanatomical change as a biomarker for Alzheimer's 
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69. Desikan, R.S., et al. An automated labeling system for subdividing the human cerebral 
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70. Jovicich, J., et al. Reliability in multi-site structural MRI studies: effects of gradient 
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72. Arnold, J.B., et al. Qualitative and quantitative evaluation of six algorithms for 
correcting intensity nonuniformity effects. NeuroImage 13, 931-943 (2001). 
73. McKhann, G.M., et al. The diagnosis of dementia due to Alzheimer's disease: 
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263-269 (2011). 
74. Clark, C.M., et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 
305, 275-283 (2011). 
75. Landau, S.M., et al. Amyloid deposition, hypometabolism, and longitudinal cognitive 
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76. Mintun, M., et al. Evaluation of a binary read methodology for florbetapir-PET images. 
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80. Gilman, S., et al. Clinical effects of Abeta immunization (AN1792) in patients with AD 
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91. Baselga, J., et al. Phase I safety, pharmacokinetics, and inhibition of SRC activity study 
of saracatinib in patients with solid tumors.  Clinical cancer research: an official 
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Protocol v4.0: 31-MAY-2017 
APPENDIX 1 
 
SCHEDULE OF EVENTS 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Name (Week)a 
 
0 
2 
4 
6 
8 
13 
19 
26 
32 
39 
45 
52f  
Visit Name 
Screening 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Geriatric Depression Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MMSE 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
ADAS-Cog 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
ADCS-ADL 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
CDR-SB 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
NPI 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Physical Examination 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological Examination 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Modified Hachinski 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Venipuncture 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labs c 
Xd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
APOE Genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
DNA Banking 
 
X 
 
 
 
 
 
 
 
 
 
 
 
AZD0530 plasma level 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
AD Biomarkers (plasma) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
Xe 
Florbetapir PET 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FDG PET 
 
X 
 
 
 
 
 
 
 
 
 
 
Xe 
LP/CSF AD Biomarkers 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
Xe 
AZD0530 CSF level 
(optional) 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Medication 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
Research Satisfaction Survey 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Treatment Blinding 
Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a See section 9.4 for definition of visit windows. 
b Vital signs will include sitting blood pressure, pulse, temperature, respiration rate, weight, and 
oxygen saturation  
c Screening labs include: Hematology, Chemistry Panel, TSH, Vitamin B12.  Follow-Up labs include: 
Hematology and Chemistry Panel 
d At Screening and Week 45, PT/PTT will also be collected for patients in the CSF sub-study. 
e These assessments will occur two weeks prior to the week 52 visit; 7 consecutive days of study 
medication compliance prior to the week 52 LP are necessary for a valid CSF drug level. 
f The Early Discontinuation Visit will contain the same assessments as the week 52 visit.  
 
 


Protocol Number:  ADC-049 FYN 
 
Page 60 of 60 
 
Protocol v4.0: 31-MAY-2017 
APPENDIX 2 
 
REVISION HISTORY 
 
Protocol 
Version 
Summary of Changes 
v2.0 
10-AUG-2015 
• 
Changed Coordinating Center from ADCS to ATRI throughout 
• 
Corrected typographical errors 
• 
Added Appendix 2 – Revision History 
v3.0 
31-MAY-2016 
• 
Updated Medical Monitor name and contact information. (Cover Page, 
Signature Page) 
• 
Revised timeframe for completion of all screening and baseline procedures to 
60 days. (Synopsis, Sections 9.2 and 9.3) 
• 
Added language consistent with IB regarding avoiding conception during 
participation in the trial (Section 4.1.2) 
• 
Corrected modified intent-to-treat definition to reflect inclusion of 
randomized participants with a valid baseline and post-baseline 
measurement. (Section 5.3) 
• 
Added study sponsor, NCATS to list of entities that could terminate the trial 
and recipients of reports regarding SAEs and unanticipated problems. 
(Sections 5.6 and 15.2) 
• 
Clarified that any designated personnel may access study drug. (Section 6.5) 
• 
Added focused period of compliance assessment in the period leading up to 
the final study LP.  (Section 6.7 and Appendix 1) 
• 
Added exceptions to some excluded medication categories. (Section 6.10.1) 
• 
Revised entry criteria for exclusionary neutropenia and thrombocytopenia.  
(Section 7.2) 
• 
Added requirement to hold randomization until the Baseline FDG PET has 
passed central QC.  (Section 9.3) 
• 
Clarified procedures to follow and considerations to be made if the laboratory 
criteria for discontinuation are triggered. (Section 10.1) 
• 
Revised requirement about discontinuation of anti-platelet meds pre/post LP 
– that this should left to the discretion of the site clinician.  (Section 12.2.1) 
• 
Clarified that sedation is not allowed for PET imaging. (Sections 12.4.2 and 
12.4.3) 
• 
Added language clarifying the Office for Human Research Protections 
definition of “unanticipated problems” (Section 15.2) 
• 
Clarified that biospecimen samples are only banked for those who consent to 
banking. (Section 18.5) 
• 
Clarified that CSF drug levels will be analyzed at the final visit for LP sub-
study participants.  (Appendix 1) 
• 
Other formatting and grammatical corrections. (Throughout)  
v4.0 
31-MAY-2017 
• 
Incorporated revisions to Section 5 and to description of secondary analysis 
(changed from ADAS-cog12 to ADAS-Cog11) to be consistent with the 
Statistical Analysis Plan 
• 
Corrected acronym use for CDR-Sum of Boxes. 
• 
Updated ATRI address