Clinical trial NCT03520998
Conditions: Alzheimer Disease Mild to Moderate Alzheimer Disease
Sponsor: Alkahest, Inc.
Start date: 2018-04-16; Completion date: 2019-05-24
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is evaluating the safety, tolerability, and feasibility of GRF6019, a plasma-derived product, administered as an intravenous (IV) infusion, to subjects with mild to moderate Alzheimer's disease.

Detailed description:
This is a randomized, double-blind, dose-comparison concurrent control study to assess the safety, tolerability, and feasibility of GRF6019, a plasma-derived product, administered by intravenous (IV) infusion to subjects with mild to moderate Alzheimer's disease.

Subjects will be randomized 1:1 to a low dose or a high dose of active treatment in a double-blind manner. All subjects will receive one infusion per day at the randomized dose for 5 consecutive days during Week 1 and, again, during Week 13 (for a total of 10 doses per subject). All IV infusions will take place at an inpatient research unit while the follow-up visits after each treatment period will be on an outpatient basis. Subjects will participate for a total of 6 months in this study.

Arms: arm 1: Subjects will receive a low dose of GRF6019 for 5 consecutive days at Week 1 and Week 13. arm 2: Subjects will receive a high dose of GRF6019 for 5 consecutive days at Week 1 and Week 13.
Interventions: intervention 1: GRF6019
Intervention descriptions: intervention 1: GRF6019 for IV infusion

Protocol documents:
Prot_000.pdf: 
Study Title A Prospective, Randomized, Double-Blind, Dose-Comparison 
Concurrent Control Study to Assess the Safety and Tolerability of 
GRF6019 Infusions in Subjects with Mild to Moderate Alzheimer’s 
Disease 
NCT Number NCT03520998 
Document Description Protocol (Version 7.0) 
Document Date 02 November 2018 
 


 
Protocol# ALK6019-201 
 
 
v7.0 02NOV2018 
 
__________________________________________________________________________________________ 
CONFIDENTIAL/PROPRIETARY  
 
Page 1 of 100 
 
 
A Prospective, Randomized, Double-Blind, Dose-Comparison Concurrent Control Study to 
Assess the Safety and Tolerability of GRF6019 Infusions in Subjects with Mild to Moderate 
Alzheimer’s Disease 
 
Protocol Number: 
ALK6019-201 
Clinical Phase: 
2 
Sponsor: 
Alkahest, Inc.  
125 Shoreway Road, Suite D 
San Carlos, CA 94070 
Investigational Drug: 
GRF6019 
Indication: 
Alzheimer’s Disease  
Authorized Representative: 
 
 
125 Shoreway Road, Suite D 
San Carlos, CA 94070 
Telephone: 650-801-0469 
Fax: 650-801-0480 
Principal Investigator: 
 
Version Number: 
V7.0 
Version Date: 
02NOV2018 
Replaces Version(s): 
V6.0, 12OCT2018 
 
CONFIDENTIAL STATEMENT 
The information contained in this document and all information provided as related to this clinical study are 
the confidential and proprietary information of the Sponsor and except as may be required by federal, state or 
local laws or regulations may not be disclosed to others without prior written permission of the Sponsor.  The 
Principal Investigator may, however, disclose such information to supervised individuals working on the 
clinical study, provided such individuals agree to maintain the confidentiality of such information. 
 
 


 
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 TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................................. 6 
LIST OF DEFINITIONS ........................................................................................................................................................ 8 
PROTOCOL APPROVAL PAGE .......................................................................................................................................... 9 
STATEMENT OF COMPLIANCE ...................................................................................................................................... 10 
PROTOCOL SUMMARY .................................................................................................................................................... 11 
SCHEMATIC OF STUDY DESIGN ................................................................................................................................... 13 
1 
KEY ROLES ................................................................................................................................................................. 13 
1.1 
AUTHORIZED REPRESENTATIVE (SIGNATORY) / RESPONSIBLE PARTY ........................................... 13 
1.2 
STUDY ORGANIZATION .................................................................................................................................. 13 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ..................................... 13 
2.1 
BACKGROUND INFORMATION ...................................................................................................................... 13 
2.2 
RATIONALE ........................................................................................................................................................ 14 
2.3 
POTENTIAL RISKS AND BENEFITS ............................................................................................................... 16 
2.3.1 
KNOWN POTENTIAL RISKS .................................................................................................................... 16 
2.3.2 
KNOWN POTENTIAL BENEFITS ............................................................................................................. 17 
3 
OBJECTIVES AND PURPOSE ................................................................................................................................... 17 
4 
STUDY DESIGN AND ENDPOINTS ......................................................................................................................... 17 
4.1 
DESCRIPTION OF THE STUDY DESIGN ........................................................................................................ 17 
4.2 
STUDY ENDPOINTS .......................................................................................................................................... 18 
4.2.1 
PRIMARY ENDPOINTS ............................................................................................................................. 18 
4.2.2 
SECONDARY ENDPOINTS ....................................................................................................................... 18 
4.2.3 
EXPLORATORY ENDPOINTS .................................................................................................................. 19 
5.1 
INCLUSION CRITERIA ...................................................................................................................................... 19 
5.2 
EXCLUSION CRITERIA ..................................................................................................................................... 20 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................................................ 21 
5.4 
SUBJECT WITHDRAWAL OR TERMINATION .............................................................................................. 22 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION ............................................................................ 22 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION .............................................. 22 


 
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5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ...................................................................... 23 
6 
STUDY AGENT ........................................................................................................................................................... 23 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ...................................................................................... 23 
6.1.1 
ACQUISITION ............................................................................................................................................. 23 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING .................................................... 23 
6.1.3 
PRODUCT STORAGE AND STABILITY ................................................................................................. 24 
6.1.4 
PREPARATION ........................................................................................................................................... 24 
6.1.5 
DOSING AND ADMINISTRATION .......................................................................................................... 24 
6.1.6 
ROUTE OF ADMINISTRATION ................................................................................................................ 24 
6.1.7 
DOSING SCHEDULE .................................................................................................................................. 25 
6.1.8 
DURATION OF THERAPY ........................................................................................................................ 25 
6.2 
STUDY AGENT ACCOUNTABILITY ............................................................................................................... 25 
7 
STUDY PROCEDURES AND SCHEDULE ............................................................................................................... 26 
7.1 
STUDY PROCEDURES/EVALUATIONS ......................................................................................................... 26 
7.1.1 
STUDY SPECIFIC PROCEDURES ............................................................................................................ 26 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ........................................................................................... 33 
7.2.1 
CLINICAL LABORATORY EVALUATIONS ........................................................................................... 33 
7.2.2 
OTHER ASSAYS OR PROCEDURES ........................................................................................................ 33 
7.2.3 
SPECIMEN PREPARATION, HANDLING, STORAGE, AND SHIPPING ............................................. 35 
7.3 
STUDY SCHEDULE ........................................................................................................................................... 35 
7.3.1 
SCREENING ................................................................................................................................................ 35 
7.3.2 
BASELINE ................................................................................................................................................... 36 
7.3.3  
RANDOMIZATION ..................................................................................................................................... 36 
7.3.4 
TREATMENT .............................................................................................................................................. 37 
7.3.5 
FOLLOW-UP ................................................................................................................................................ 37 
7.3.6 
FINAL STUDY VISIT ................................................................................................................................. 39 
7.3.7 
EARLY TERMINATION ............................................................................................................................. 39 
7.3.8 
SCHEDULE OF EVENTS TABLE .............................................................................................................. 39 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................... 39 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ......................................................... 40 


 
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8 
ASSESSMENT OF SAFETY ....................................................................................................................................... 40 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ................................................................................................ 40 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) ............................................................................................. 40 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) ......................................................................... 41 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ................................................................................................ 42 
8.2.1 
SEVERITY OF EVENT ............................................................................................................................... 42 
8.2.2 RELATIONSHIP TO STUDY AGENT .............................................................................................................. 42 
8.2.3 
EXPECTEDNESS ........................................................................................................................................ 43 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................................ 43 
8.3.1 
POST-STUDY AEs AND SAEs ................................................................................................................... 44 
8.4 
REPORTING PROCEDURES ............................................................................................................................. 44 
8.4.1 
ADVERSE EVENT REPORTING ............................................................................................................... 44 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING ............................................................................................. 45 
8.4.3 
ADVERSE EVENTS OF SPECIAL INTEREST ......................................................................................... 46 
8.4.4 
REPORTING OF PREGNANCY ................................................................................................................. 46 
8.5 
STUDY HALTING RULES ................................................................................................................................. 46 
8.6 
SAFETY OVERSIGHT ........................................................................................................................................ 47 
9 
CLINICAL MONITORING ......................................................................................................................................... 47 
10 
STATISTICAL CONSIDERATIONS ...................................................................................................................... 48 
10.1 
STATISTICAL AND ANALYTICAL PLANS ................................................................................................... 48 
10.2 
STATISTICAL HYPOTHESES ........................................................................................................................... 48 
10.3 
ANALYSIS DATASETS ..................................................................................................................................... 48 
10.4 
DESCRIPTION OF STATISTICAL METHODS ................................................................................................ 48 
10.4.1 
GENERAL APPROACH .............................................................................................................................. 48 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT(S) ....................................................................................... 49 
10.4.3 
ANALYSIS OF THE SECONDARY ENPOINT(S) .................................................................................... 49 
10.4.4 
SAFETY ANALYSES .................................................................................................................................. 49 
10.4.5 
ADHERENCE AND RETENTION ANALYSES ........................................................................................ 50 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS .................................................................................................. 50 
10.4.7 
PLANNED INTERIM ANALYSES ............................................................................................................. 50 


 
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10.4.8 
ADDITIONAL SUB-GROUP ANALYSES ................................................................................................ 50 
10.4.9 
MULTIPLE COMPARISON/MULTIPLICITY ........................................................................................... 50 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA ......................................................................... 50 
10.4.11 
EXPLORATORY ANALYSES ................................................................................................................ 50 
10.5 
SAMPLE SIZE ..................................................................................................................................................... 51 
10.6 
MEASURE TO MINIMIZE BIAS ....................................................................................................................... 51 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES .......................................................... 51 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING .......................................................................................... 52 
10.6.3 
BREAKING THE STUDY BLIND/PARTICIPANT CODE ....................................................................... 52 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................................................. 52 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................................ 52 
12.1 
ETHICAL STANDARD ....................................................................................................................................... 52 
12.2 
INSTITUTIONAL REVIEW BOARD ................................................................................................................. 53 
12.3 
INFORMED CONSENT PROCESS .................................................................................................................... 53 
12.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS .......................................................................................................................................................... 53 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION ............................................................................ 53 
12.4 
PARTICIPANT AND DATA CONFIDENTIALITY .......................................................................................... 54 
12.5 
FUTURE USE OF STORED SPECIMENS ......................................................................................................... 54 
13 
DATA HANDLING AND RECORD KEEPING ..................................................................................................... 55 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 55 
13.1.1 
INVESTIGATOR RESPONSIBILITIES ..................................................................................................... 55 
13.1.2 
STUDY FILES .............................................................................................................................................. 55 
13.2 
STUDY RECORDS RETENTION ....................................................................................................................... 56 
13.3 
PROTOCOL DEVIATIONS ................................................................................................................................ 56 
13.4 
PUBLICATION AND DATA SHARING POLICY ............................................................................................ 57 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY ............................................................ 57 
15 
LITERATURE REFERENCES ................................................................................................................................ 58 
16 
APPENDICES .......................................................................................................................................................... 61 
17 
SCHEDULE OF EVENTS ....................................................................................................................................... 83 
18 
REVISION HISTORY .............................................................................................................................................. 85 


 
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LIST OF ABBREVIATIONS 
AD 
Alzheimer’s Disease 
ADAS-Cog/11 Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
ADCS-ADL23 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living23 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change rating 
AE 
Adverse Event 
ApoE 
Apolipoprotein E 
ARIA 
Amyloid Related Imaging Abnormalities 
ASL 
Arterial Spin Labeling 
BLA 
Biologics License Application 
CDR-SOB 
Clinical Dementia Rating Scale – Sum of Boxes 
CFR 
Code of Federal Regulations 
CFT 
Category Fluency Test 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
ICH E6 R2 
International Conference on Harmonization Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance, Revision 2 
IEC 
Independent Ethics Committee 
IRB 
Investigational Review Board 
ITT 
Intent-To-Treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHIS 
Modified Hachinski Ischemia Scale 
MMSE 
Mini-Mental State Examination 
MRI 
Magnetic Resonance Imaging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NODscid 
Non-obese diabetic severe combined immunodeficiency 
NPI-Q 
Neuropsychiatric Inventory Questionnaire 
NSG 
NODscid Gamma 
PET 
Positron-Emission Tomography 
PT 
Preferred Term 
SAE 
Serious Adverse Event 


 
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SOC 
System Organ Class 
SUSARS 
Suspected Unexpected Serious Adverse Reactions 
UPCR 
Urine Protein-to-Creatinine Ratio 
vMRI 
Volumetric Magnetic Resonance Imaging  
WHO 
World Health Organization 
 
 
 


 
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LIST OF DEFINITIONS 
 
Infusion Nurse 
The unblinded study personnel qualified by training and experience responsible 
for administering the infusion of the investigational product during the Infusion 
Period.  The Infusion Nurse ensures that appropriate blinding techniques are used 
to prevent the inadvertent unblinding of study staff and study participants during 
and immediately following the Infusion Period.   
Infusion Period 
For 100 and 250 mL administrations, the Infusion Period is estimated to be 
between 2 hours to a maximum of 3 hours. 
Outcomes Assessor 
The blinded study personnel qualified by training and experience responsible for 
observing study subjects during the infusion of the investigational product and 
collecting and/or managing adverse events (AEs) that occur before, during, and 
after the Infusion Period. 
 
 


 
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PROTOCOL APPROVAL PAGE 
 
 
 
Study Title: 
A Prospective, Randomized, Double-Blind, Dose-Comparison 
Concurrent Control Study to Assess the Safety and Tolerability of 
GRF6019 Infusions in Subjects with Mild to Moderate Alzheimer’s 
Disease 
Protocol Number: 
ALK6019-201 
Version/Date:  
V7.0_02NOV2018 
Sponsor Name and 
Address: 
 
Alkahest, Inc. 
125 Shoreway Road, Suite D 
San Carlos, CA 94070 
 
 
 
I, the undersigned, have read and approve this protocol and agree on its content.  It is confirmed that the 
information and guidance given in this protocol complies with scientific principles, the guidelines of Good 
Clinical Practices, the Declaration of Helsinki in the latest relevant version, and applicable legal and regulatory 
requirements. 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor Representative (print) 
 
Signature  
 
Date 
 
 


 
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STATEMENT OF COMPLIANCE 
Protocol Title: 
A Prospective, Randomized, Double-Blind, Dose-Comparison Concurrent Control 
Study to Assess the Safety and Tolerability of GRF6019 Infusions in Subjects with Mild 
to Moderate Alzheimer’s Disease 
Protocol Number: 
ALK6019-201 
Protocol Version 7.0_02NOV2018 
 
By my signature, I: 
• Confirm that my staff and I have carefully read and understand this protocol or protocol amendment 
and are thoroughly familiar with the appropriate use of the investigational drug described herein. 
• Agree to comply with the conduct and terms of the study specified herein and with any other study 
conduct procedures provided by the Sponsor, Alkahest, Inc., or their designee 
• Agree to assume responsibility for the proper conduct of the study at this site, including complying with 
current relevant versions of the US Food and Drug Administration (FDA) regulations, the International 
Conference on Harmonization (ICH) GCP guidelines, the Declaration of Helsinki, and all applicable 
rules, regulations, and federal, state, and local laws relating to the conduct of clinical studies and the 
protection of human subjects.  
• Agree not to implement deviations from or changes to the protocol or protocol amendments without 
agreement from the Sponsor and prior submission to and written approval (where required) from the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except when necessary to 
eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where 
permitted by all applicable regulatory requirements).  
• Agree to onsite monitoring of all source documents by Alkahest, Inc. or designee and to on-site 
inspection of source documents by appropriate regulatory authorities, including but not limited to the 
FDA, local governing regulatory bodies, and IRB/IEC inspectors. 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 
 
 
 


 
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PROTOCOL SUMMARY 
 
 
Title: 
A Prospective, Randomized, Double-Blind, Dose-Comparison Concurrent Control Study to 
Assess the Safety and Tolerability of GRF6019 Infusions in Subjects with Mild to Moderate 
Alzheimer’s Disease (AD) 
 
Précis:  
This is a prospective, randomized, double-blind, dose-comparison concurrent control study 
to assess the safety, tolerability, and feasibility of GRF6019, a 
human plasma protein 
fraction, administered by intravenous (IV) infusion to subjects with mild to moderate AD. 
 
Subjects will be randomized to one of two doses of active treatment in a double-blind 
manner: 20 subjects at 100 mL and 20 subjects at 250 mL.  Dosing groups will be stratified 
by sex.  All subjects will receive one infusion per day at the randomized dose for 5 
consecutive days during weeks 1 and 13 and will have a total study duration of 
approximately 7 months. 
 
The infusion duration for all subjects will be between 2 hours to a maximum of 3 hours to 
maintain blinding.  Flow rates will be titrated according to dose-specific guidelines to ensure 
that the entire assigned dose is administered during this interval.  The following measures 
will be taken to ensure adequate allocation concealment during infusions: blinding of 
subjects, trial partners, study coordinators, physicians, and cognitive test administrators to 
treatment dose; use of blinded Outcomes Assessors and unblinded Infusion Nurses; standard 
time for attachment to the IV infusion setup (up to 180 minutes); and measures to block 
view of vial(s) and infusion pump throughout the infusion. 
 
All subjects will undergo a screening visit, baseline visit, treatment visits, follow-up visits 
and an end of study/early termination visit.  During each 5-day dosing period, subjects will 
reside in inpatient units to facilitate safety evaluation.  Subjects will be discharged from the 
inpatient facility the day after the 5th day of dosing.  Safety and tolerability assessments will 
occur at every visit.  Neurocognitive and motor assessments will be performed at baseline 
and at periodic interim visits following dosing.  Subjects who are eligible and consent to 
participate in the optional cerebrospinal fluid (CSF) biomarker research will undergo two 
lumbar punctures for CSF collection, the first occurring prior to initial dosing, and the 
second occurring following final dosing.   
 
Objectives: 
The primary objective of the study is to assess the safety, tolerability, and feasibility of 2 
dose levels of GRF6019 in subjects with mild to moderate AD.  As a secondary objective, 
the study will assess the potential effects on cognition of the 2 dose levels using various 
cognitive measures.  The exploratory objectives include changes on MRI and analysis of 
blood and CSF for specific biomarkers associated with AD. 
 
Endpoints: 
Primary endpoints will be assessed as follows: 
• Incidence of treatment-emergent adverse events (AEs) identified by MedDRA preferred 
term (PT) and grouped by MedDRA System Organ Class. 
• Feasibility and tolerability of each dose level. 
 
Secondary efficacy endpoints will be assessed as follows: 


 
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• Changes in scores on the Mini-Mental State Examination (MMSE). 
• Changes in scores on the 11-item Alzheimer’s Disease Assessment Scale-Cognitive 
Subscale (ADAS-Cog/11). 
• Changes in scores on the Grooved Pegboard Test. 
• Changes in scores on the Category Fluency Test (CFT). 
• Changes in the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SOB). 
• Changes in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living23 
(ADCS-ADL23). 
• Changes on the Alzheimer’s Disease Cooperative Study – Clinical Global Impression of 
Change rating (ADCS-CGIC). 
• Changes on the Neuropsychiatric Inventory Questionnaire (NPI-Q). 
• Changes in the Savonix Neurocognitive Assessments and Digit Span. 
 
Secondary safety endpoints will be assessed as follows:  
• Changes from baseline in clinical laboratory parameters.  
• Changes from baseline in vital sign measurements. 
• Changes from baseline in the Columbia-Suicide Severity Rating Scale (C-SSRS). 
• Changes on MRI scans designed to assess for Amyloid Related Imaging Abnormalities 
(ARIA). 
 
Secondary feasibility endpoint will be assessed by: 
• Subject compliance with the study visit schedule and study visit procedures 
• Subject retention 
• Success of blinding 
 
Exploratory endpoints will be assessed as follows: 
• Changes in imaging endpoints such as volumetric MRI (vMRI), functional 
MRI (fMRI), and Arterial Spin Labeling (ASL)  
• Changes in blood-based biomarkers 
• Changes in CSF biomarkers (in participating subjects) 
 
Population: 
Approximately 40 subjects between 60 and 90 years of age with a diagnosis of probable 
mild to moderate AD.  Assuming a drop-out rate of 25%, enrollment at this level will yield 
approximately 30 evaluable subjects.   
 
Phase: 
2 
Number of Sites: 
Up to 10 sites in the United States 
Description of 
Study Agent: 
GRF6019: A 
human plasma protein fraction for IV infusion 
 
Study Duration: 
Approximately 15 months 
Participant 
Duration: 
Approximately 7 months  
 
 


 
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SCHEMATIC OF STUDY DESIGN 
 
 
 
 
 
1 
KEY ROLES 
 
1.1 
AUTHORIZED REPRESENTATIVE (SIGNATORY) / RESPONSIBLE PARTY 
 
 
Alkahest, Inc.  
125 Shoreway Road, Suite D  
San Carlos, CA 94070  
Telephone: 650-801-0469 
 
 
1.2 
STUDY ORGANIZATION 
The name and contact information of the responsible party and individuals involved with the study (e.g., investigator(s), 
Sponsor’s medical expert and study monitor, Sponsor’s representative(s), laboratories, steering committees, and 
oversight committees [including independent ethics committees (IECs) and Institutional Review Boards (IRBs)], as 
applicable) will be maintained by the Sponsor and provided to the investigator. 
 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
BACKGROUND INFORMATION 
Alzheimer’s Disease (AD) is a progressive pathophysiological disorder associated with cognitive decline.  The initial 
symptoms typically include an inability to retain recently acquired information, whereas memory for remote events may 
be spared until late stage disease.  As of 2018, approximately 5.7 million Americans have AD.  This number includes an 
estimated 5.5 million people age 65 and older.  By mid-century, that number is expected to grow to 14 million.  By 2050 
nearly 1 million new cases will be diagnosed per year (Alzheimer’s Association 2018).  
During the course of the disease, synapses and ultimately neurons are lost within the cerebral cortex, hippocampus, and 
subcortical structures (including selective cell loss in the nucleus basalis of Meynert), locus coeruleus, and nucleus raphe 
dorsalis.  Cerebral glucose use and perfusion is reduced in some areas of the brain (e.g., the parietal lobe and temporal 
cortices in early-stage disease, prefrontal cortex in late-stage disease).  Neuritic or senile plaques (composed of neurites, 


 
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astrocytes, and glial cells around an amyloid core) and neurofibrillary tangles (composed of paired helical filaments) are 
likely to play a role in the pathogenesis of AD.  The pathologic changes often precede symptoms of impaired cognition 
and memory (Mayeux 2010). 
Effectiveness of existing approved therapies, including acetylcholinesterase inhibitors (e.g., donepezil) and N-Methyl-D-
aspartic acid (NMDA) receptor agonists (e.g., memantine) varies across the population.  These drugs neither provide 
relief from all symptoms of AD nor do they prevent the long-term progression of the disease.  There are currently no 
disease modifying agents for use in AD (Alzheimer’s Association 2018) and given the increasing prevalence and 
socioeconomic impact of the disease, identifying treatments for maintaining or improving cognitive function is an area of 
substantial unmet medical need.   
In 2011, data in parabiotic animal models suggested that increased levels of systemic chemokines and increased immune 
signaling molecules may affect the aging brain, and that rejuvenating factors from young animals may ameliorate the 
effects of aging (Villeda 2011).  Following their initial findings, the same team of investigators performed a study to 
explore the therapeutic effects of systemic exposure of aged mice to young plasma by direct injection (Villeda 2014).  At 
the cognitive level, systemic administration of young plasma into aged mice improved age-related impairments.  In 
addition, the data demonstrated that exposure of old mice to young plasma counteracts age-related impairment at the 
molecular and structural levels in the hippocampus (Villeda 2014).  These studies lay the foundation for the hypothesis 
that soluble circulating factors from young plasma may have beneficial effects on human cognition.   
Results from nonclinical studies conducted at Alkahest (see Section 2.2, “Rationale” below) suggest there is a beneficial 
effect of young human plasma and plasma protein fraction in age-related cognitive decline and histopathological 
endpoints in mouse models.  These studies have raised the intriguing possibility that there are factors present in human 
plasma that may prove beneficial against brain aging and ameliorate some of the age-associated memory impairments in 
people, especially in those experiencing rapid cognitive decline from age-associated neurodegenerative diseases.   
2.2 
RATIONALE 
 
Alkahest’s study ALK6019-201 will evaluate 2 dose levels of GRF6019 administered via intravenous (IV) infusion.  
GRF6019 has been manufactured specifically for investigational purposes.  It is a purified 
 plasma protein fraction 
made from pooled human plasma 
 
.   
 
The rationale for using a plasma protein fraction was based on several factors.  Although plasma is widely used and 
considered safe, there are inherent risks such as the potential transfer of unknown pathogens to recipients, 
histoincompatibility, and allergic reactions to proteins such as clotting factors and immunoglobulins.  Therefore, the 
Blood Products Industry has developed safer products based on pooling plasma of highly selected donations, 
fractionating them into more defined products, and adding additional processing steps to reduce the potential for 
pathogen transmission.  Leveraging this fractionation technology, GRF6019 is a 
 
 
Nonclinical studies conducted at Alkahest have demonstrated that both young whole plasma and 
 
 plasma protein fraction confer beneficial outcomes in age-related cognitive decline and histopathological 
endpoints in mouse models (
 


 
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).  Mild to 
moderate AD patients will be selected for inclusion in this clinical study as they have identifiable deficits in cognitive 
function and suffer from a disease with limited treatment options, making them a population for whom the balance of 
risk to potential benefit of treatment with GRF6019 is reasonable.     
 
Nonclinical studies were initiated at Alkahest to test whether the positive effects observed with young mouse plasma 
could be replicated using 
 human plasma.  Treatment of aged NODscid (non-obese diabetic severe combined 
immunodeficiency) mice with 
 human plasma (100-150 µl per injection, two injections per week for 3-5 
weeks) resulted in improved cognitive and motor performance in standard behavioral tests.  These cognitive changes 
were further supported by electrophysiological and histological correlates of enhanced memory.  Together, these results 
provided support for the hypothesis that 
 plasma infusions may have functional benefits to man, potentially 
ameliorating or halting the progression of cognitive decline associated with AD 
   
 
Nonclinical studies conducted at Alkahest evaluated the effects of both young plasma and plasma protein fraction using 
various dosing paradigms in NODscid, NSG (NODscid Gamma) and C57BL/6J mice.  Initially, mice were dosed with 
150 µL of 
 plasma, 
 plasma protein fraction or saline (control) via IV infusions 2 times per week for 5 weeks 
(
).  A subsequent study examined the same dosing regimen for a period of 23 weeks, to assess the effects 
of treatment on age-dependent changes in behavioral and cognitive function over a period of approximately 6 months 
(
).  Following these early studies, a novel dosing regimen of 150 µL for 7 consecutive days (referred to 
as “pulsed dosing”) was evaluated both alone and compared to other intermittent weekly dosing regimens (
).  A final study examined pulsed dosing of 150 µL for 5 
consecutive days (
), which is the pulsed dosing regimen chosen for ALK6019-201. 
 
Based on these nonclinical studies, significant improvements in cognitive performance and histological correlates were 
observed with a 
 plasma protein fraction.  In addition, studies with 
 plasma demonstrated that the beneficial 
effect was observed long after initial dosing, indicating there is not a requirement for continuous repeat dosing.  The 
effects were long-lived but did diminish over time such that 3 months after dosing benefits just reached significance.   
 
Together, these studies indicate that 5 consecutive days of dosing (“pulsed dosing”) of GRF6019, a batch o
 
 
  If safety and efficacy are 
demonstrated with GRF6019, pulsed dosing may be more convenient than weekly or monthly dosing for patients.   
 
A prospective, randomized, double-blind, dose-comparison concurrent control study design has been selected to reduce 
or eliminate bias while facilitating the identification of a safe and feasible dosing paradigm, trends in changes of 
neurocognitive endpoints, and potential plasma derived factors that may affect these parameters.  Within-patient and 
between-group cognitive changes associated with the 2 dose levels of GRF6019 will be evaluated. 
 
Thus, while the primary objective of this study is safety and tolerability, and the study does not have the statistical power 
to test specific hypotheses regarding changes in cognitive function, the results are nevertheless expected to lay the 
foundation for larger trials designed and powered to characterize the potential benefits of GRF6019 in AD and other 
neurodegenerative disorders typified by cognitive dysfunction. 
 
Human dose levels were selected based on known safety through clinical experience in man and scaling from efficacy in 
nonclinical studies.  No safety concerns were observed in nonclinical studies using repeated doses of 150 µL in mice.  In 
determining potentially efficacious human doses, different methods can be used. Allometric scaling is primarily 
performed based on body surface area conversion in mg/m2.  Using allometric scaling, a dose of 150 µL yields an 


 
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equivalent human dose using body surface area scaling of 28.4 mL.  Allometric scaling is used for small molecules 
whose elimination is dependent on hepatic metabolism. Alternative scaling methods include mg/kg (recommended for 
macromolecules >100 kDa) and volumetric scaling based on relative blood volumes. Because GRF6019 contains a 
complex mixture of proteins with a molecular weight predominantly <100kDa), and because the beneficial effects of 
these proteins on cognition are believed to occur in the circulation, the concentration of these proteins per blood volume 
may be the scaling method most likely to accurately estimate the human potential effective dose.  
 
Using isometric scaling based on blood volume, the mouse dose of 150 µL is equivalent to a human dose of 413 mL, as 
outlined in Table 1.  The top dose used in this study is 250 mL GRF6019, which is below the equivalent human dose of 
413 mL.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3 
POTENTIAL RISKS AND BENEFITS 
 
2.3.1 
KNOWN POTENTIAL RISKS 
 
Collected human plasma may be used as a therapeutic product (known as “plasma” or “fresh frozen plasma”) or as 
source material for the production of pharmaceutical fractionated products (known as “plasma products” or “plasma 
derivatives”) (Burnouf 2007).  GRF6019, a 
 human plasma protein fraction, 
 
erves as a viable source of soluble, infusible plasma proteins from 
 healthy donors.  
 
 
 
 
 
  ABO antigen typing is not required prior to 
administration.  Finally, the additional steps taken during production to remove viral pathogens provide an increased 
margin of pathogen safety in comparison to fresh frozen plasma.   
 GRF6019 is not expected to significantly alter the 
urinalyses of recipients, their bleeding times, coagulation times, prothrombin times, prothrombin consumption, 
platelet counts or fibrinogen levels when given in quantities of up to 1000 mL.  Hypotension may occur, particularly 
following rapid infusion or intraarterial administration to patients on cardiopulmonary bypass.  The blood pressure 
may normalize spontaneously after the slowing or discontinuation of the infusion.  
 


 
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GRF6019 is made from human plasma and may carry a risk of transmitting infectious agents, e.g., viruses, the 
variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.  The 
risk that GRF6019 can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, 
testing donated plasma, and including manufacturing steps with the capacity to inactivate and/or remove pathogens.   
 
2.3.2 
KNOWN POTENTIAL BENEFITS 
 
There is no known reported benefit of administering GRF6019 to patients with mild to moderate AD.  However, if 
the findings in the nonclinical models are replicated in humans, there could be a substantial benefit to individual 
patients, including improvements in cognitive function, executive cognitive function, daily function, and/or 
neuropsychiatric symptoms.   
 
3 
OBJECTIVES AND PURPOSE 
The primary objective of this study is to assess the safety, tolerability, and feasibility of GRF6019, a 
 human plasma 
protein fraction administered by IV infusion in subjects with mild to moderate AD.  Secondarily, this study aims to 
assess the effects of the study agent on subjects’ cognitive function.  As an exploratory objective, blood and plasma will 
be collected and analyzed to identify specific biomarkers associated with cognitive functional changes and/or indicators 
of AD progression.  In addition, subjects who are eligible and consent to participate in the optional CSF biomarker 
research at participating sites will undergo two lumbar punctures for CSF collection.  The CSF will then be utilized to 
assess the potential therapeutic effects of GRF6019 on AD biomarkers of neuronal death, synaptic function, 
inflammation, and growth factors.  Finally, changes in imaging results as measured by volumetric Magnetic Resonance 
Imaging (vMRI), functional MRI (fMRI), and Arterial Spin Labeling (ASL) may be evaluated to identify potential 
indicators of AD progression and potential therapeutic effect 
 
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This is a prospective, randomized, double-blind, dose-comparison concurrent control study conducted at up to 10 sites in 
the United States.   
 
Study subjects will be dosed for 5 consecutive days (“pulsed dosing”) with GRF6019 during two dosing periods over the 
approximately 6-month treatment period.  Subjects will be randomized to one of two dose levels: 100 mL or 250 mL.  
Subjects will receive one infusion per day at the randomized dose for 5 consecutive days during Week 1 and again during 
Week 13.   
 
During the 5-day dosing periods, subjects will reside in inpatient study observation units and will be discharged after the 
5th day of dosing.  Trial partners will have the option to stay with the subjects or may seek lodging nearby. 
 
Subjects will be invited to participate in optional CSF biomarker research at participating sites.  The CSF collection 
procedure, as well as the potential risks and benefits, will be explained to all study participants.  Participation in the CSF 


 
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biomarker research is optional and not required for inclusion in the study.  Subjects who are eligible and consent to 
participate will undergo two lumbar punctures for CSF collection, the first occurring prior to initial dosing, and the 
second occurring following final dosing. 
 
Safety and tolerability assessments will occur at every visit.  Neurocognitive and motor assessments will be performed at 
baseline and at periodic interim assessments following dosing.  In the event of early termination of a subject who has 
received at least one dose of GRF6019, the end of study procedures will be performed unless the subject has withdrawn 
consent.  Dosing groups will be stratified by sex.  A comprehensive efficacy and safety assessment of all data in toto will 
be conducted at the end of the study. 
 
The overall duration of the study is approximately 15 months from study initiation (i.e., first subject enrolled) to study 
completion (i.e., last subject last visit).  The recruitment period is expected to be approximately 8 months.  The subject 
participation period is approximately 7 months from screening through end of study, unless prematurely discontinued. 
 
4.2 
STUDY ENDPOINTS 
 
4.2.1 
PRIMARY ENDPOINTS 
 
The primary endpoints in this study pertain to the safety, tolerability and feasibility of each dose level. 
 
Safety endpoints are as follows: 
• 
Incidence of treatment-emergent adverse events (AEs) identified by MedDRA preferred term (PT) and 
grouped by MedDRA System Organ Class (SOC). 
 
Tolerability endpoints are as follows: 
• 
Number of subjects completing 8 weeks (i.e. through Visit 10) after receiving at least 5 infusions. 
• 
Number of subjects completing 24 weeks (i.e. through End of Study) after receiving at least 10 infusions. 
 
Feasibility endpoints are as follows: 
• 
Number of subjects completing 5 and 10 infusions.  
 
4.2.2 
SECONDARY ENDPOINTS 
 
This study is neither designed nor powered to detect statistically significant differences in cognitive or motor 
domains between the Baseline and End of Study values.  However secondary cognitive endpoints will be 
summarized over the study period from Baseline values using descriptive statistics: 
• 
Changes in scores on the Mini-Mental State Examination (MMSE) (Folstein 1975) (Appendix 1). 
• 
Changes in scores on the 11-item Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-
Cog/11) (Rosen 1984) (Appendix 2). 
• 
Changes in scores on the Grooved Pegboard Test (Lafayette 2002). 
• 
Changes in scores on the Category Fluency Test (CFT) (Acevedo 2000). 
• 
Changes in the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SOB) (Hughes 1982) (Appendix 3). 
• 
Changes in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living23 (ADCS-ADL23) 
(Galasko 1997) (Appendix 4). 
• 
Changes on the Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (ADCS-
CGIC) (Ferris 1997) (Appendix 5). 


 
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• 
Change on the Neuropsychiatric Inventory Questionnaire (NPI-Q) (Kaufer 2000) (Appendix 6). 
• 
Change on the Savonix Neurocognitive Assessments and Digit Span (Appendix 7). 
 
Secondary safety endpoints include:  
• 
Changes from baseline in clinical laboratory parameters.  
• 
Changes from baseline in vital sign measurements. 
• 
Changes from baseline in the Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner 2011)  
(Appendix 8). 
• 
Changes on MRI scans designed to assess for ARIA. 
 
Secondary feasibility endpoints include: 
• 
Subject compliance with the study visit schedule, procedures, and infusions, and any required adaptations 
that are necessary for the study completion. 
• 
Success of blinding.  This will be assessed based on all occurrences (intentional or unintentional) of 
unblinding of blinded study subjects, their trial partners or study personnel (e.g. investigators, medical 
providers, cognitive testing raters, the Sponsor or their representatives).  
 
4.2.3 
EXPLORATORY ENDPOINTS 
 
The exploratory endpoints include assessment of changes in composition and distribution of blood-based and CSF 
(in consenting subjects) biomarkers, as well as changes in imaging results as measured by vMRI, fMRI, and ASL.   
 
The serial compositional analysis of individual subject’s plasma will be performed to identify specific biomarkers 
associated with cognitive functional changes and/or indicators of AD progression.  DNA will be extracted from 
blood samples to explore epigenetic changes.  In addition, subjects who consent to participate in the optional CSF 
biomarker research will undergo two lumbar punctures for CSF collection, the first occurring prior to initial dosing, 
and the second occurring following final dosing.  The CSF will be utilized to assess the potential therapeutic effects 
of GRF6019 on AD biomarkers of neuronal death, synaptic function, inflammation, and growth factors.  5 
STUDY 
ENROLLMENT AND WITHDRAWAL 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible for inclusion, all subjects must meet the following criteria: 
• 
Male or female, aged 60-90 years (inclusive). 
• 
Diagnosis of probable AD based upon the National Institute on Aging-Alzheimer’s Association (NIA-AA) 
Criteria. 
• 
MMSE Score 12-24 inclusive. 
• 
Modified Hachinski Ischemia Scale (MHIS) score of ≤ 4.   
• 
Have a dedicated, reliable and competent trial partner (e.g., caregiver or family member) who has frequent 
contact with the subject (defined as approximately 10 hours per week) who is willing to provide support to the 
subject to ensure compliance with study requirements.  The trial partner should understand the nature of the 
study and be willing to complete the trial partner scales and functional assessments throughout the study. 
• 
The subject (with support of a trial partner) must be able to follow the study protocol, receive the treatment in 
the established timeframe, and continue during the follow-up interval.   
• 
The subject and trial partner must be sufficiently fluent in English and have visual and auditory acuity sufficient 
to be capable of reliably completing all study assessments. 


 
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• 
Provided a signed and dated informed consent form (either the subject and/or subject’s legal representative as 
well as the trial partner) in accordance with local regulations/guidelines/IRB/IEC. 
• 
Adequate renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 using 
the Modification of Diet in Renal Disease (MDRD) study equation (MDRD for Adults (Conventional Units) | 
NIDDK, n.d.).  
• 
Systolic ejection fraction of ≥ 55% on trans-thoracic echocardiogram. 
• 
Willing to spend up to 7 nights in an inpatient study unit during both dosing periods. 
 
In order to be eligible for inclusion in the optional CSF biomarker research, all subjects must meet the following 
criteria: 
• 
Currently enrolled in the ALK6019-201 study. 
• 
Provided a signed and dated informed consent form for CSF collection (either the subject and/or subject’s legal 
representative) in accordance with local regulations/guidelines/IRB/IEC. 
• 
Not yet dosed in the ALK6019-201 study. 
 
5.2 
EXCLUSION CRITERIA 
A subject will not be eligible for inclusion if any of the following criteria apply: 
• 
Positive screening for Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV). 
• 
Evidence of clinically relevant neurological disorder(s) other than AD. 
• 
History of blood coagulation disorders or hypercoagulability; any concurrent use of an anticoagulant therapy.  
(e.g., heparin, warfarin, thrombin inhibitors, Factor Xa inhibitors).  Use of antiplatelet drugs (e.g., aspirin or 
clopidogrel) is acceptable. 
• 
Initiation or change in the dosage of cholinesterase inhibitors (AChEI), memantine, Axona, vitamin E 
supplementation, or selegiline within 3 months prior to screening.  
• 
Prior hypersensitivity reaction to any human blood product or intravenous infusion; any known clinically 
significant drug allergy.  
• 
Treatment with any human blood product, including transfusions and intravenous immunoglobulin, during the 
6 months prior to screening.  
• 
History of immunoglobulin A (IgA), haptoglobulin or C1 inhibitor deficiency; stroke, anaphylaxis, or 
thromboembolic complications of intravenous immunoglobulins.  
• 
Heart disease, including myocardial infarction, unstable, new onset or severe angina, or congestive heart 
failure (New York Association Class II, III or IV) in the 6 months prior to dosing;  
• 
Poorly controlled high blood pressure (systolic blood pressure of 160 mmHg or higher and/or diastolic blood 
pressure of 100 mmHg or higher) despite treatment during the 3 months prior to dosing, or treatment 
refractory high blood pressure, defined as treatment requiring 3 or more antihypertensives from different 
classes. 
• 
History of Torsades de Pointes dysrhythmia or hypocalcemia of any kind, including secondary to absorption 
syndromes secondary to gastric bypass surgery. 
• 
Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of 
Gilbert's syndrome or asymptomatic gallstones).  
• 
Uncontrolled diabetes defined as HbA1c > 7.5% or requiring insulin. 
• 
Clinically significant abnormalities in complete blood count, complete metabolic panel, serum albumin, serum 
lipids, blood coagulation tests, or the levels of thiamine, pyridoxine, cobalamin and thyroid stimulating 
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• 
Hemoglobin < 10 g/dL in women and < 11 g/dL in men. 
• 
Urine protein-to-creatinine ratio (UPCR) of > 1.5 grams of protein per gram of creatinine. 
• 
Clinically significant abnormalities on screening electrocardiogram (ECG) including QTc intervals (using 
Fridericia’s correction formula) of ≥ 450 ms in men and ≥ 470 ms in women. 
• 
Clinically significant abnormalities on echocardiogram. 
• 
Inadequate venous access to allow IV drug delivery or multiple blood draws.  
• 
Concurrent participation in another interventional clinical trial.  Prior clinical trial subjects must have been off 
study agents for at least 30 days (or 5 half-lives, whichever is longer), 4 months for disease modifying 
therapies, and 1 year for vaccine or immunotherapy trials prior to screening.  
• 
Concurrent daily treatment with benzodiazepines, long-acting opioids, or other medications that, in the 
investigator’s opinion, interfere with cognition.  [Note: intermittent treatment with low-doses of shorter half-
life benzodiazepines (e.g. lorazepam, alprazolam) may be permitted, provided that no dose is administered 
within the 72 hours preceding any cognitive assessment].  
• 
A history of a major psychiatric disorder diagnosed before the onset of AD, including schizophrenia, major 
depression or bipolar disorder, and/or alcohol/substance dependency.  Psychiatric symptoms that occur in the 
context of AD (e.g. psychosis, irritability, depression) are not exclusionary unless the PI believes they could 
interfere with study procedures.  
• 
Active suicidal ideation with at least some intent to act, with or without a specific plan, in the past 6 months. 
• 
Presence of a pacemaker or any other implant that would be a contraindication to an MRI exam or 
claustrophobia that would not enable the subject to undergo an MRI. 
• 
>2 lacunar strokes or other imaging abnormality on baseline MRI that would make the interpretation of 
subsequent MRI scans of the brain difficult.  
• 
Any other condition and/or situation that the investigator believes may interfere with the safety of the subject, 
the intent and conduct of the study, or interpretation of study data. 
A subject will not be eligible for inclusion in the optional CSF biomarker research if any of the following criteria 
apply: 
• 
Allergy or sensitivity to lidocaine or other local anesthetics to be used for the lumbar puncture. 
• 
Skin infection near the site of the lumbar puncture. 
• 
Suspicion of cord mass or signs of cord compression. 
• 
Suspicion of intracranial mass or raised intracranial pressure (e.g., as evidenced by papilledema). 
• 
Altered mental status (from baseline). 
• 
Use of oral antiplatelet therapy (e.g. clopidogrel, prasugrel, ticagrel) within 5 days prior to the lumbar 
puncture. Use of aspirin is permitted.  
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
We do not anticipate any particular challenges in meeting recruitment goals of enrolling a total of 20 subjects per group 
in this study.  Similarly, as AD has a higher prevalence in women, we do not anticipate difficulties in enrolling female 
subjects.  Subjects will be recruited continuously until the desired sample size is achieved.  Subjects who withdraw or are 
withdrawn during screening or prior to completing Visit 8 may be replaced to enroll sufficient evaluable subjects.   
We expect enrollment in this trial to be consistent with the observation that typically the majority of subjects enrolled in 
clinical trials conducted in the United States are non-Hispanic whites.  If the risk/benefit analysis of GRF6019 justifies 
larger subsequent trials, special efforts will be made to enroll subjects from diverse ethnic and racial groups. 
 


 
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This trial is enrolling subjects with AD who may have sufficient cognitive impairment to be considered a vulnerable 
population.  In this situation, the subject’s agreement to participate in the study will still be obtained to their best level of 
his or her understanding, and recruitment will not proceed if the subject refuses, shows significant distress or the trial 
partner and/or legally authorized representative refuse.  For subjects who are, in the opinion of the investigator, unable to 
give informed consent, consent will be obtained from the legally authorized representative.  Subjects will receive a 
modest stipend for participation in the study. 
 
The expected length of participation in the study, seven months, is not expected to be unduly onerous on subjects or their 
trial partners.  During the two treatment periods at weeks 1 and 13, subjects will be housed in inpatient clinical trial units.  
If the trial partner does not reside within a reasonable distance from the inpatient facility, they will be given the option to 
stay with the subjects or to stay in a nearby hotel/motel.  Financial support for meal and miscellaneous expenses may be 
provided as appropriate (it is expected that meals will be provided by the study facilities as needed).  Use of visit 
transport services and study buddies (registered and trained personnel that can stand in for the trial partner for required 
visits) may also be incorporated into the trial to support both the subject and their trial partner in maintaining study visit 
compliance. 
 
A description of the clinical trial will be posted on clinicaltrials.gov that will provide additional transparency to the 
public and possibly aid study recruitment.  In addition, advocacy groups and patient networks will be approached for 
recruitment as needed. 
 
5.4 
SUBJECT WITHDRAWAL OR TERMINATION 
 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION 
 
 
 
A subject will be withdrawn from the study for the following medical or administrative reasons: 
• 
Occurrence of a treatment-emergent AE that represents an unacceptable risk to the subject and 
when continued participation in the investigational study is not warranted, in the judgment of the 
investigator.  The investigator must follow the subject until the AE resolves or is stable, unless the 
subject is lost to follow up. 
• 
Subject and/or trial partner noncompliance, defined as refusal or inability to adhere to the trial 
schedule or procedures.   
• 
At the request of the subject or the subject’s legally authorized representative (e.g., subject 
withdraws consent), investigator, Sponsor, or regulatory authority. 
• 
Pregnancy. 
 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
 
 
 
Subjects will be encouraged to complete the study and all assessments.  However, subjects may voluntarily withdraw 
at any time, and the investigator may discontinue individual subjects from the study at any time.   
 
Approximately 40 subjects (approximately 20 in the 100 mL group and 20 in the 250 mL group) will be enrolled in 
the study with the intent of obtaining at least 30 evaluable subjects who have received at least 5 doses and completed 
through Visit 8.   
 
Subjects who have received at least one infusion but are withdrawn or withdraw from the study will be encouraged to 
complete the end of study procedures within 4-6 weeks of their last visit.  For post-study AE and SAE reporting, see 
Section 8.3.1.  The primary reason for study discontinuation will be documented on the case report form (CRF). 


 
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5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
 
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, the Sponsor and/or their 
representatives will arrange discontinuation procedures and notify the appropriate regulatory authority(ies) and IRBs.  In 
terminating the study, the Sponsor and the investigator will continue to protect the subjects’ privacy and identity as 
required by relevant statutes and regulations. 
 
Alkahest, Inc. has the right to terminate a study site from participating in the study at any time. Reasons for study or site 
termination may include, but are not limited to: 
• 
(Immediate) risk to subject safety. 
• 
Unsatisfactory subject enrollment. 
• 
Unacceptable Protocol Deviations as assessed by Sponsor. 
• 
Inaccurate or incomplete data entry and recording; fabricated data. 
• 
Investigational site non-compliance with ICH/GCP. 
• Unacceptable emergent safety profile. 
 
6 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
 
6.1.1 
ACQUISITION 
 
The study agent will be commercially manufactured by Grifols in their Clayton, North Carolina facility in 
accordance with license BL 101140.  The material will be supplied to the sites directly from a study drug depot.   
 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
 
 
 
 
 
 
   
GRF6019 will be supplied in 250 mL glass vials bearing a label that meets applicable regulations for investigational 
protein products (further manufactured) per 21 CFR 312.6.  The label will clearly identify the study agent and 
manufacturer, and will display other required information specifically applicable to its intended use, including but 
not limited to: 
• 
Federal law statement 
• 
Storage information 
• 
Volume (accurate within ± 10%) 
• 
Expiration date 
 


 
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6.1.3 
PRODUCT STORAGE AND STABILITY 
 
The study agent should be stored at room temperature not exceeding 30°C (86°F).  Solution that has been frozen 
should not be used.  Do not use after expiration date. 
 
Solutions which are turbid should not be used.  Administration of the study agent must begin within 4 hours of the 
container being entered.  Vials which are cracked or have been previously entered or damaged should not be used, as 
this may have allowed the entry of microorganisms.  
   
 
6.1.4 
PREPARATION 
 
The study agent is compatible with the usual carbohydrate and electrolyte solutions.  Remove seal to expose stopper.  
Always swab stopper top immediately with suitable antiseptic prior to entering the vial. 
 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, 
whenever solution and container permit.   
 
Only 16-gauge (or larger) needles or dispensing pins should be used with 250 mL vials.  Needles, dispensing pins, or 
equivalent should only be inserted within the stopper area delineated by the raised ring.  The stopper should be 
penetrated perpendicular to the plane of the stopper within the ring.  IV tubing should be vented, as the study agent is 
supplied in glass bottles.   
 
6.1.5 
DOSING AND ADMINISTRATION 
 
The study agent will be infused in accordance with the Infusion Administration Manual provided to sites.  The 
purpose of the Infusion Administration Manual is to promote safe administration of GRF6019 and maintain 
appropriate blinding of staff and study subjects.  The manual will include provisions for masking study agent and 
concealing the IV apparatus from view of blinded staff and study subjects during the Infusion Period. 
 
The study agent and dose to be administered will be provided by an unblinded pharmacist (or other qualified 
personnel responsible for drug accountability) to an unblinded Infusion Nurse.  Administration of the study agent 
will be performed by the unblinded Infusion Nurse, and study outcome measures (including AEs and vital signs) 
will be assessed by a blinded Outcomes Assessor.   
 
Infusion Nurses will be qualified by training and experience to administer infusions under the direction of the 
Principal Investigator.  Only authorized Infusion Nurses may administer the study agent, and only subjects enrolled 
in the study may receive the study agent in accordance with applicable regulatory requirements. 
 
6.1.6 
ROUTE OF ADMINISTRATION 
 
The study agent will be administered by IV route only. 
 
 


 
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6.1.7 
DOSING SCHEDULE 
 
Subjects will be randomized to a dose level of 100 mL or 250 mL of study agent, and they will remain on the same 
dose for the duration of the study.  Subjects will receive one infusion per day for 5 consecutive days at Weeks 1 and 
13.   
 
Randomization to all dosing groups will be stratified by sex. 
 
6.1.8 
DURATION OF THERAPY 
 
From screening to exit, the duration of study involvement for each subject and their trial partner is ~7 months. 
 
All subjects will receive 5 consecutive days of therapy at the beginning of weeks 1 and 13.  Thus, the cumulative 
duration of therapy for all subjects will be 10 exposure days.  The duration of therapy for a subject to be considered 
evaluable in the intent-to-treat population is 5 exposure days. 
 
6.2 
STUDY AGENT ACCOUNTABILITY 
 
Under the supervision of the Principal Investigator, the unblinded study pharmacist or other qualified personnel is 
responsible for ensuring adequate accountability of all used and unused study agent.  This includes acknowledgment of 
receipt of each shipment of study agent (quantity and condition), subject dispensing records, and returned or destroyed 
study agent.  Dispensing records will document quantities received and quantities dispensed to subjects including the 
date dispensed, the intended subject’s study identifier, the initials of the individual responsible for dispensing the study 
agent, and the initials of the Infusion Nurse administering the study agent.  Drug accountability will be monitored by an 
unblinded CRA. 
 
Accountability records must be maintained and readily available for inspection by representatives of Alkahest, Inc. or 
their designee and are open to inspection by regulatory authorities at any time.  The accounts of any study agent 
accidentally wasted or intentionally disposed of must be maintained.   
 
The disposal of used, partially used, or wasted study agent must be performed in accordance with the institution’s drug 
disposal policy.  At study initiation, the clinical study monitor will evaluate the site’s standard operating procedure for 
study drug disposal/destruction in order to ensure that it complies with study requirements.  At the end of the study, 
following final drug reconciliation by the monitor, the study site will be instructed by the Sponsor to return or destroy 
all unused study agent, including empty containers.  A copy of the institution’s drug disposal policy should be 
maintained or referenced in the site’s regulatory binder. 
 
 


 
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7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 
STUDY SPECIFIC PROCEDURES 
 
7.1.1.1 Screening Procedures 
During screening, the following will be performed: 
• 
C-SSRS 
• 
Assessment of probable AD including MMSE 
• 
MHIS 
• 
Medical history 
• 
Demographics 
• 
Review of medications 
• 
Vital signs 
• 
Physical examination 
• 
12-Lead ECG 
• 
Blood and urine collection for laboratory evaluations 
• 
Echocardiogram* 
• 
MRI* 
• 
PET Scan (optional; to be performed after all screening procedures have been completed, and the subject 
meets criteria for inclusion)  
 
*Note: the echocardiogram and screening MRI should be performed after all other screening procedures have been 
completed, and the subject meets all other criteria for inclusion.  The echocardiogram and screening MRI may be 
completed in any order.  
 
Detailed descriptions of each of these procedures are provided in the sections immediately following.  Information 
pertaining to all study activities performed during screening, and the sequence of events, is provided in Section 7.3.1 
Screening. 
 
7.1.1.1.1 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a simple series of questions for the assessment of suicidal ideation and behavior in clinical trials 
(Posner 2011) (Appendix 8).  The C-SSRS was designed to distinguish the domains of suicidal ideation and suicidal 
behavior in subjects who have expressed wishes to be dead or suicidal thoughts.  Four constructs are measured.  The 
first is the severity of ideation, which is rated on a 5-point ordinal scale in which 1=wish to be dead, 2=nonspecific 
active suicidal thoughts, 3=suicidal thoughts with methods, 4=suicidal intent, and 5=suicidal intent with plan.  The 
second is the intensity of ideation subscale, which comprises 5 items, each rated on a 5-point ordinal scale: 
frequency, duration, controllability, deterrents, and reason for ideation.  The third is the behavior subscale, which is 
rated on a nominal scale that includes actual, aborted, and interrupted attempts; preparatory behavior; and non-
suicidal self-injurious behavior.  And the fourth is the lethality subscale, which assesses actual attempts; actual 
lethality is rated on a 6-point ordinal scale, and if actual lethality is zero, potential lethality of attempts is rated on a 
3-point ordinal scale.  The use of a standardized measure such as the C-SSRS comprehensively assesses suicidal 
behavior and ideation. 
 
The C-SSRS will be administered by interview at screening to assess suicidal ideation and behavior over the course 


 
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of the subject’s lifetime and in the past 6 months.  The C-SSRS will be repeated on Visits 8 and 16 to assess suicidal 
ideation and behavior for the time period since the subject’s last C-SSRS assessment.     
 
7.1.1.1.2 Assessment of Probable Alzheimer’s Disease 
Subjects will undergo an assessment for AD using NIA-AA criteria (McKhann 2011).  Probable AD is diagnosed 
when the subject meets criteria for dementia per MMSE score (12-24 inclusive) (Refer to Section 7.1.1.1.3), and in 
addition, has the following characteristics: 
• 
Insidious onset.  Symptoms have a gradual onset over months to years, not sudden over hours or days; 
• 
Clear-cut history of worsening of cognition by report or observation; and 
• 
The initial and most prominent cognitive deficits are evident on history and examination in one of the 
following categories: 
o Amnestic presentation: It is the most common syndromic presentation of AD.  The deficits 
should include impairment in learning and recall of recently learned information.  There should 
also be evidence of cognitive dysfunction in at least one other cognitive domain, as defined 
earlier in the text.   
o Nonamnestic presentations:  
1. Language presentation: The most prominent deficits are in word-finding, but deficits in 
other cognitive domains should be present.   
2. Visuospatial presentation: The most prominent deficits are in spatial cognition, including 
object agnosia, impaired face recognition, simultanagnosia, and alexia.  Deficits in other 
cognitive domains should be present.   
3. Executive dysfunction: The most prominent deficits are impaired reasoning, judgment, 
and problem solving.  Deficits in other cognitive domains should be present.   
 
The diagnosis of probable AD should not be applied when there is evidence of one or more of the following: 
• 
Substantial concomitant cerebrovascular disease defined by a history of a stroke temporally related to the 
onset or worsening of cognitive impairment. 
• 
The presence of multiple or extensive infarcts or severe white matter hyperintensity burden. 
• 
Core features of dementia with Lewy bodies other than dementia itself. 
• 
Prominent features of behavioral variant frontotemporal dementia. 
• 
Prominent features of semantic variant primary progressive aphasia or non-fluent/agrammatic variant 
primary progressive aphasia. 
• 
Evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity 
or use of medication that could have a substantial effect on cognition. 
 
Previous radiologic imaging and/or assessment of AD CSF biomarkers will be collected, if available, to support the 
clinical diagnosis of AD.  Amyloid imaging by Positron Emission Tomography (PET) performed within 12 months 
of screening will be used, if available, to estimate beta-amyloid neuritic plaque density at baseline (See Section 
7.2.2.2). 
 
7.1.1.1.3 Mini-Mental Status Examination 
The MMSE (Folstein 1975) (Appendix 1) consists of the following 5 components: orientation to time and place (2 
items), registration of 3 words (1 item), attention and calculation (1 item), recall of 3 words (1 item), and language (6 
items).  The scores from the 5 components are summed to obtain the overall MMSE total score.   
 
If a subject has 1 missing item, the following algorithm will be used to compute the total score: Total score = [(total 


 
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score from completed items) / (maximum total score for completed items)] x (maximum total score [=30] for all 
items in the scale).  The total score is then rounded to the next highest integer.   
 
If there is more than 1 missing item, the total score will be considered missing at that time point.  The MMSE total 
score can range from 0 to 30, with higher scores indicating better mental status.  Change scores will not be calculated 
for the individual items.   
 
7.1.1.1.4 Modified Hachinski Ischemic Scale 
The MHIS (Rosen 1980) is an 8-item scale that examines clinical features that may be consistent with vascular 
dementia and is commonly used as a screening tool to exclude patients with multi-infarct dementia from entrance 
into clinical trials assessing neuropsychopharmacologic therapy in patients with AD.  The scale is completed by the 
physician based on clinical information obtained from diagnostic information and physical examination.  The scale 
takes about 10 to 15 minutes to complete, depending on the availability of the data needed.  Scores for the 8 items are 
added together for a total score.  Subjects who score 5 or greater are more likely to have a dementia of vascular 
etiology and thus are excluded from participating in the trial. 
 
7.1.1.1.5 Medical History 
The investigator or designee will obtain a detailed medical history through interview with the subject and the 
subject’s trial partner during screening.  The medical history should focus on recent history, with an emphasis on the 
history of cognitive symptoms related to probable AD.  Additionally, the medical history should include: 
• 
Current/past illnesses and conditions 
• 
Current symptoms 
• 
Surgeries and procedures 
• 
Allergies 
• 
Family history 
• 
Social history (e.g. exercise, smoking, alcohol, illegal substances) and current living situation 
• 
Cause of parental death (if not living) 
• 
Prior radiologic imaging, CSF assessments, and/or PET Scan results (if available and within 12 months of 
screening) 
 
7.1.1.1.6 Demographics 
Information pertaining to the subject’s socioeconomic status (e.g. highest level of income achieved, education, 
longest held occupation), ethnicity, race, marital status, and family size will be collected by interview with the 
subject and the subject’s trial partner at screening. 
 
7.1.1.1.7 Review of Medications 
The investigator or designee should obtain a complete list of the subject’s current medications, including over-the-
counter drugs, herbal supplements and/or vitamins, as well as those taken by the subject in the past 12 months.  
Assessment of eligibility should include a review of permitted and prohibited medications.  Any additions, 
discontinuation or dosage changes in medication during the course of the study will be recorded. 
 
7.1.1.1.8 Vital Signs 
Vital signs will include seated systolic and diastolic blood pressure (mmHg), heart rate (beats per minute [bpm]), 
respiration rate (breaths per minute), and oral temperature.  Vital signs will be measured after the subject has been 
seated for 5 minutes. 
 


 
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7.1.1.1.9 Physical Examination 
A full physical examination will be performed to assess the following organ systems: skin, ENT (ears, nose, and 
throat), head, eyes, lungs/chest, heart, abdomen, musculoskeletal, extremities, neurologic and lymphatic systems.  
Height and weight will also be documented. 
 
7.1.1.1.10 12-Lead ECG 
A 12-lead ECG will be performed after the subject has rested quietly for at least 5 minutes in a supine position.  In 
some cases, it may be appropriate to repeat abnormal ECGs to rule out technical factors contributing to ECG artifacts 
or abnormality.  It is important that leads are placed in the same positions each time for consistency.  The overall 
conclusion with the interpretation of the ECGs will be recorded on the appropriate CRF.  The interpretation of the 
ECGs will be recorded as normal, abnormal but not clinically significant (NCS), or abnormal and clinically 
significant (CS).  Corrected QTc intervals will be calculated using Fridericia’s correction formula.   
 
7.1.1.1.11 Echocardiogram  
During screening, an echocardiogram will be performed to evaluate the subject’s left ventricular (LV) systolic 
function to ensure the subject’s ejection fraction is ≥ 55% (Gebhard 2012).   
 
7.1.1.1.12 Biological Specimen Collection  
Biological samples will be obtained, analyzed, and stored appropriately for additional analysis.  Blood and CSF (in 
participating subjects) will be drawn by a qualified medical provider, and urine specimens will also be collected.  
These samples may be used for re-testing, further evaluation of an AE and/or assessment, and follow-up of other 
exploratory endpoints.  The timing and frequency for specimen collection and laboratory evaluations to be performed 
are described in the study’s laboratory manual and Section 17 Schedule of Events. 
 
Samples that remain after study testing is complete will be stored in the event additional testing (e.g., further 
evaluation of an AE or assessment of effect) is required.  Samples will be stored in a deidentified coded form.   
 
7.1.1.1.13 Magnetic Resonance Imaging 
The screening MRI should only be performed after the subject has met all other inclusion criteria and none of the 
exclusion criteria (except the echocardiogram, which can be performed before or after the MRI).  The sequence may 
also include vMRI, fMRI, and/or ASL.  Additional information is provided in Section 7.2.2.3. 
 
7.1.1.2 Procedures to Assess Safety 
Subjects enrolled in the trial will be monitored closely to assess safety and tolerability of the study agent and 
intervention.  Study-specific procedures that will be used for this purpose are summarized below.  Information 
regarding the timing and frequency of these procedures is provided in Section 7.3 Study Schedule.   
• 
Review of AEs 
• 
Review of medications 
• 
Vital signs 
• 
C-SSRS 
• 
12-Lead ECGs 
• 
Targeted physical exams  
• 
End of Study (or Early Termination) Physical Examination 
• 
Blood Draw and Urine Collection for Laboratory Evaluations 
• 
MRI to assess for ARIA 
 


 
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7.1.1.2.1 Review of Adverse Events 
AEs will be reviewed, documented, and reported as required at each visit.  For definitions, guidance, and additional 
information regarding AEs, refer to Section 8.   
 
7.1.1.2.2 Review of Medications 
The investigator or designee should review the subject’s current medications, including over-the-counter drugs, 
herbal supplements and/or vitamins, as well as those taken by the subject since the last visit.  Changes to the 
subject’s list of medications should be reviewed and recorded.  Review of medications should occur at every visit. 
 
7.1.1.2.3 Vital Signs 
Refer to Section 7.1.1.1.8 for a description of Vital Signs.  Vital Signs will be collected at every visit.  During 
infusions, vital signs will be collected according to the Infusion Administration Manual by the blinded Outcomes 
Assessor.    
 
7.1.1.2.4 Columbia-Suicide Severity Rating Scale 
Refer to Section 7.1.1.1.1 for a description of the C-SSRS.  
 
7.1.1.2.5 12-Lead ECG 
Refer to Section 7.1.1.1.10 for information pertaining to 12-Lead ECGs. 
 
7.1.1.2.6 Targeted Physical Exams 
While the subject is inpatient, a targeted physical exam, including auscultation of the heart and lungs, an assessment 
of peripheral edema, and weight, will be performed per the Study Schedule (Section 7.3).   
 
7.1.1.2.7 Physical Exam 
Refer to Section 7.1.1.1.9 for a description of the physical exam.  The physical exam, including measurements of 
height and weight, will be performed at screening and repeated at End of Study (or early termination).   
 
7.1.1.2.8 Blood and Urine Collection for Laboratory Evaluations 
As described in Section 7.1.1.1.12, subjects will have blood and urine specimens collected for clinical evaluation 
(Section 7.2.1 Clinical Laboratory Evaluations).  Refer to Section 17 Schedule of Events for timing and frequency of 
blood and urine collection for laboratory evaluations.   
 
7.1.1.3 Procedures to Assess Efficacy 
Procedures to assess efficacy include neuropsychological and motor function testing and radiologic imaging.  
Information regarding the timing and frequency of these procedures is provided in 7.3 Study Schedule. 
 
Cognitive and motor function will be assessed using neuropsychological and motor function testing performed by 
qualified evaluators who have undergone standardized rater training.  Raters must be certified, as appropriate.  The 
same evaluator should be used for the duration of each subject’s participation unless a change in rater is unavoidable.  
The established order of behavioral and cognitive testing during visits with multiple assessments will be as follows 
(unless otherwise specified):  
 
1. C-SSRS* (refer to Section 7.1.1.1.1)  
2. MMSE* (refer to Section 7.1.1.1.3) 
3. Savonix Neurocognitive Assessments and Digit Span  


 
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4. ADAS-Cog/11 
5. Grooved Pegboard  
6. CFT  
7. CDR-SOB (subject and trial partner) 
8. ADCS-ADL23 (trial partner) 
9. ADCS-CGIC (subject and trial partner)  
10. NPI-Q (trial partner self-administered). Note: The trial partner may complete the NPI-Q at any available 
time during applicable visits 
 
Assessments with an asterisk (*) should only be performed during follow-up when required per protocol. 
Descriptions of each neuropsychological and motor function assessment are provided below. 
 
7.1.1.3.1 Savonix Neurocognitive Assessments and Digit Span 
Assessments of cognitive function will be performed throughout the study using the Savonix Neurocognitive 
Assessments, a digitized neurocognitive testing app on a compatible iPad device.  The Savonix digitized 
neurocognitive testing platform is a multi-faceted 21 CFR Part 11 and Health Insurance Portability and 
Accountability Act (HIPAA) compliant computer-based application for iOS or Android devices that integrates 
multiple aspects of common neurocognitive tests into one computerized assessment.  Measured elements across brain 
domains include instant verbal memory, delayed verbal memory, impulse control, focus, attention, emotional 
regulation, emotion identification, information processing, flexible thinking, working memory, executive function, 
spatial memory, decision making, and emotionality (Appendix 7).   
 
Assessments using a digital interface are expected to provide more granular neurocognitive data while at the same 
time being less burdensome to the subject.  This pilot experience will also lay the foundation for use of this digital 
platform in future trials.   
.   
Subjects will be provided instructions and asked to complete either a full or brief battery at every study visit, starting 
at baseline.  The full battery of tests includes the Savonix-8 and Digit Span (forwards and backwards) and takes 
approximately 30-40 minutes to complete.  The Savonix-8 consists of: 
• 
Verbal Memory – immediate and delayed 
• 
Go/No-Go 
• 
Verbal Interference 
• 
Complex Figure Copy 
• 
N-back 
• 
Maze Task 
• 
Emotion Identification Task 
• 
Trails A and B 
 
The brief battery will be administered during infusion visits and should be completed prior to starting the infusion.  
The brief battery takes approximately 15-20 minutes to complete and consists of: 
• 
Go/No-Go 
• 
Color Interference 
• 
N-back 
• 
Trail-Making tasks 
• 
Digit Span 
 


 
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7.1.1.3.2 The Alzheimer’s Disease Assessment Scale – Cognitive Subscale 
The ADAS-Cog/11 (Rosen 1984) (Appendix 2) includes 11 items assessing cognitive function (Skinner 2012).  The 
domains include memory, language, praxis, and orientation.  There are 70 possible points, 48 for the first 9 items, 
and 22 for the last two items, word recall, and recognition.  Test performance is assessed for errors in following 
ordered commands, naming of real objects and of fingers, constructional praxis (copying of geometric forms), 
ideational praxis (preparation of a letter for mailing), orientation, a 10-item word recall task and a 12-item and 12 
foils word recognition task.  Higher scores reflect greater cognitive impairment.  Individual testing domains may be 
separated out for the purposes of statistical analysis. 
 
7.1.1.3.3 Grooved Pegboard Test 
The Grooved Pegboard Test is a manual dexterity test measuring visual-motor coordination (Lafayette 2002).  The 
test consists of a pegboard with 25 holes with randomly positioned slots and pegs with a key along one side.  The 
subject is to insert the pegs as quickly as possible into the slots in sequence, first with the dominant hand and then 
with the non-dominant hand.  The score is the time it takes for the subject to complete the task. 
 
7.1.1.3.4 Category Fluency Test  
The CFT is one of the validated nine components of the neuropsychological test battery.  Category fluency tasks are 
an important component of neuropsychological assessment, especially when evaluating for dementia syndromes.  
Subjects are asked to name as many different types of animals, vegetables, and fruits, in that order, as they can in a 
60 second period.   The number of correct, non-repeated responses for each individual category constitute the raw 
score for the specific category.  The total category fluency score is calculated by adding the number of correct 
responses for the pooled categories (Acevedo 2000). 
 
7.1.1.3.5 Clinical Dementia Rating Scale – Sum of Boxes  
The Clinical Dementia Rating Scale (CDR) is a global assessment instrument that yields global and sum of boxes 
(SOB) scores, with the global score regularly used in clinical and research settings to stage dementia severity.  The 
CDR is obtained via semi-structured interviews with patients and informants (e.g. trial partners) to characterize 
functioning in 6 domains: memory, orientation, judgment and problem solving, community affairs, home and 
hobbies and personal care (Hughes 1982).  Each domain is rated on a 5-point scale, and the CDR-SOB score is 
obtained by summing each of the domain box scores.  The CDR-SOB is considered a more detailed quantitative 
general index than the global score and provides more information than the global CDR score in patients with mild 
dementia (O’Bryant 2008) (Appendix 3).  Individual testing domains may be separated out for the purposes of 
statistical analysis. 
 
7.1.1.3.6 Alzheimer’s Disease Cooperative Study Group – Activities of Daily Living23  
The ADCS-ADL23 assesses the competence of patients with AD in performing basic and instrumental activities of 
daily living.  The ADCS-ADL23 contains 23 items covering physical and mental functioning and independence in 
self-care.  For each activity of daily living (ADL), an informant (e.g., trial partner) is first asked if the patient 
attempted the activity during the past 4 weeks.  If a patient did attempt the ADL, the informant (e.g., trial partner) is 
asked to choose the single most accurate definition of the patient’s level of performance.  The scores range from 0 to 
78, with higher scores indicating less functional impairment (Galasko 1997) (Appendix 4). 
 
7.1.1.3.7 Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change  
The ADCS-CGIC is a systematic method for assessing clinically significant change in a clinical trial as viewed by an 
independent skilled and experienced clinician (Ferris 1997, Schneider 1997) (Appendix 5).  The ADCS-CGIC 
focuses on clinicians' observations of change in the subject's cognitive, functional, and behavioral performance since 


 
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the beginning of a trial.  It relies on both direct examination of the subject and interview of informants (e.g. trial 
partner). 
 
7.1.1.3.8 Neuropsychiatric Inventory Questionnaire  
The NPI-Q evaluates the most frequent neuropsychiatric manifestations of dementia and determines their frequency 
and intensity (Kaufer 2000) (Appendix 6).  It is designed to be a self-administered questionnaire completed by 
informants (e.g. trial partners) about subjects for whom they care.  Generally, the NPI-Q is used to evaluate changes 
in subject behavior that have appeared during a given period.   
 
The NPI-Q comprises 12 domains: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressivity 
and restlessness, irritability, anxiety, aberrant motor behavior, appetite and eating disorders, and nocturnal behavior.  
Initial responses to each domain question are "Yes" (present) or "No" (absent).  If the response to the domain 
question is "No", the informant goes to the next question.  If "Yes", the informant then rates both the severity of the 
symptoms present within the last month on a 3-point scale and the associated impact of the symptom manifestations 
on them (i.e., trial partner distress) using a 5-point scale.  Thus, the NPI-Q evaluates response to therapy and 
provides symptom severity and distress ratings for each symptom reported, and total severity and distress scores 
reflecting the sum of individual domain scores. 
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 
 
Biological samples (e.g. whole blood, serum, urine) will be collected for laboratory evaluations in accordance 
with the Schedule of Events (Section 17).  Clinical sample processing and laboratory evaluations will be 
conducted by a central lab’s registered and certified Clinical Laboratory Improvement Amendments (CLIA) 
facilities.  STAT laboratory evaluations will be conducted at the clinical site.  Refer to the study’s laboratory 
manual for complete information regarding all laboratory evaluations to be performed, sample collection 
procedures, and related requirements. 
 
The investigator is responsible for determining and documenting if out of range laboratory values are clinically 
significant or not.  All clinically significant values will be recorded as AEs in the CRF and followed until 
resolution, unless the subject is lost to follow up.  Once resolved, the appropriate CRF page(s) will be updated.   
 
7.2.2 
OTHER ASSAYS OR PROCEDURES 
 
7.2.2.1  
Apolipoprotein E (ApoE) Genotype Testing 
 
ApoE genotype is a known risk factor for AD pathogenesis, with presence of the ApoE ε4 allele carrying increased 
risk.  This risk is further influenced by age, sex, race, and ethnicity.  Thus, determining ApoE genotype at baseline 
will allow for the assessment of possible differential effects of ApoE genotype on safety, treatment efficacy, 
neuroimaging and other exploratory measures.   
 
7.2.2.2 
Positron Emission Tomography (Optional) 
Documented PET Scan is optional and not required for inclusion in the study.   
 
Subjects who have had a PET Scan using any radioligand within 12 months of screening will be asked to provide 
copies of the images and results.  The historical scan will be used to estimate the density of beta-amyloid neuritic 
plaque. 


 
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Subjects who meet eligibility criteria and who have not had a PET Scan within 12 months of screening will be given 
the option of having a PET Scan performed and read by a central reader.  The results of the scan will be made 
available to the subject.   
 
7.2.2.3  
Magnetic Resonance Imaging 
MRI [3 Tesla (T) preferred but 1.5T will be accepted] will be used to evaluate subjects’ eligibility for inclusion in the 
study and to assess safety (ARIA) at Visit 8.  MRI may also be used to compare neural activity and brain atrophy at 
screening/baseline, after the first series of pulsed doses, and at end of study.  During the MRI, the subject will be 
asked to lie on a narrow bed in a large tunnel while images are captured by the MRI machine.  The screening and 
Visit 8 scans will be interpreted by local radiologists to confirm eligibility and the continued safety of subjects.  The 
MR images may also be analyzed centrally at the end of the study by an outside party. 
 
The MRI exam after dosing on Visit 8 will be used to evaluate subjects for possible ARIA.  ARIA are MRI 
abnormalities, including signal changes thought to represent vasogenic edema and/or microhemorrhages that have 
been seen in subjects enrolled in clinical trials of experimental amyloid-modifying therapies.  
 
 
 
7.2.2.4 Proteomic and Genetic Biobanking 
Blood and plasma will be collected from subjects at multiple timepoints throughout the trial for biobanking.  For 
information regarding the timing and procedures for sample collection and related requirements, refer to the study’s 
laboratory manual and Section 17 Schedule of Events.   
 
Plasma will be analyzed by proteomics using mass spectrometry and targeted approaches to assess the specific 
signature of proteins in subjects at baseline and to assess the changes in the proteome with repeated GRF6019 
infusions.  These methodologies will provide a broad overview of the proteins that are present in the plasma sample 
by assessing 1000-5000 analytes and allow generation of a proteomic signature.  From this signature, we hope to 
identify key proteins that are drivers of cognitive function and/or indicators of disease progression.  Blood samples 
will be retained for analysis of emergent genetic markers of disease.  By understanding the composition and function 
of plasma samples from the trial, we seek to identify the biomarkers relevant to further optimizing treatment in AD.  
For information regarding future use of stored samples, see Section 12.5 Future Use of Stored Specimens. 
 
7.2.2.5 Cerebrospinal Fluid Biomarker Collection (Optional) 
Participation in the cerebrospinal fluid (CSF) biomarker research is optional and not required for inclusion in the 
study.  
 
The CSF collection procedure, as well as the potential risks and benefits, will be explained to all study participants at 
participating sites.  Subjects who are eligible and consent to participate will undergo two lumbar punctures for CSF 
collection, the first occurring prior to initial dosing, and the second occurring following final dosing.  If a subject 
withdraws from the study early but is willing to provide the second (final) CSF sample, this can be obtained as long 
as the subject received at least two infusions of GRF6019.  If the subject is currently taking antiplatelet therapy (e.g. 
clopidogrel, prasugrel, ticagrel), this medication must be withheld for 5 days prior to each lumbar puncture 
(treatment with aspirin can continue). 
 
The lumbar punctures should be performed by a physician experienced in the procedure and according to the site’s 
standard procedures.  Both lumbar punctures should be performed at approximately the same time of day and the 
time should be recorded.  For each lumbar puncture, 12-15 mL of CSF will be collected by gravity (not aspiration). 


 
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The first 2 mL should be collected for erythrocyte analysis.  The remainder should be collected into a low-protein-
bonding polypropylene CSF collection tube without additives.  The CSF should be kept at room temperature until 
centrifugation.  The centrifugation should occur within 1 hour of collection, and the time documented.  The tube 
should be centrifuged at 2,000 g for 10 minutes.  The supernatant will be divided into approximately 10 aliquots of 
approximately 1 mL each.  The aliquots should be pipetted into polypropylene tubes with screw caps and 
immediately frozen.  Each aliquot tube should be at least 75% filled, and the number of aliquots should be adjusted 
to achieve this (depending on the final CSF volume collected). 
 
CSF aliquots will be thawed and analyzed for specific AD biomarker assessments including 
 
.  CSF samples will also be analyzed by proteomics using mass spectrometry 
and targeted approaches to assess the specific signature of proteins in subjects at baseline and to assess the changes 
in the proteome with repeated GRF6019 infusions.  These methodologies will provide a broad overview of the 
proteins that are present in the CSF samples and allow generation of a proteomic signature.  From this signature, we 
hope to identify key proteins that are drivers of cognitive function and/or indicators of disease progression.  For 
information regarding future use of stored samples, see Section 12.5 Future Use of Stored Specimens. 
 
7.2.3 
SPECIMEN PREPARATION, HANDLING, STORAGE, AND SHIPPING 
 
Refer to the study’s laboratory manual for specimen preparation, handling, storage, and shipping procedures.   
 
7.3 
STUDY SCHEDULE 
 
Visit windows (when noted) should be benchmarked relative to Visit 3 for a subject, such that subjects complete the 
entire study by Day 168 (±7 days).  Study visit procedures are listed in the recommended order in which they should 
be completed.   
 
7.3.1 
SCREENING 
 
Visit 1, Screening (Day -28 to -8) 
□ Informed consent of subject (and/or the subject’s legally authorized representative) and the subject’s trial 
partner must be obtained prior to any study-related assessments 
□ Administer the C-SSRS 
□ Assess for probable AD using NIA-AA criteria including MMSE  
□ Conduct the MHIS  
□ Obtain medical history, including medical records to support AD diagnosis if available 
□ Collect demographic information 
□ Review subject’s current and prior medications 
□ Review and provide the subject (and subject’s trial partner) with a list of permitted and prohibited 
medications 
□ Collect vital signs, height, and weight 
□ Perform the physical exam 
□ Perform 12-Lead ECG 
□ Collect specimens for the laboratory panel 
□ Perform transthoracic echocardiogram 
□ Complete MRI 
□ Complete PET Imaging (optional)  


 
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Note: The Screening Visit may be split to allow for sufficient time to complete all required procedures.  AEs and 
concomitant medications should be collected during split visits, as applicable.  Any PET Imaging should be 
completed after the MRI but before Visit 3.  The optional PET scan should only be performed after the subject 
has met criteria for inclusion in the study. 
 
7.3.2 
BASELINE 
 
Visit 2, Baseline (Days -7 to -1) 
□ Re-review screening assessments for eligibility (e.g., MMSE scores, lab values) 
□ Review AEs and concomitant medications 
□ Collect the following: 
o Vital signs 
o Samples for proteomics/epigenetics/biobanking (fasting samples are preferred) 
o Buccal swab for ApoE Genotype testing 
□ Ensure the subject has had an opportunity to eat a meal prior to commencing cognitive and motor testing 
□ Perform cognitive and motor testing in the following order unless otherwise specified: 
1. Savonix Full Battery  
2. ADAS-Cog/11 
3. Grooved Pegboard 
4. CFT 
5. CDR-SOB (subject and trial partner) 
6. ADCS-ADL23 (trial partner) 
7. ADCS-CGIC (subject and trial partner) 
8. NPI-Q (trial partner self-administered; may be completed by the trial partner at any available time 
during the visit) 
□ Confirm subject eligibility prior to initiating treatment 
□ In consenting, eligible subjects, perform initial lumbar puncture and obtain CSF samples for optional 
biomarker research.  
 
Note: The Baseline Visit may be split to allow collection of all required assessments. 
 
7.3.3  
RANDOMIZATION 
 
It is recommended that subjects be randomized at the start of Visit 3, prior to receiving their first dose.  However, 
subjects may be randomized at any time after eligibility has been confirmed but prior to receiving their first dose on 
Visit 3. 
 
Subjects who are randomized but do not receive any dose of the study agent, may be re-screened and randomized if 
they meet all of the study eligibility requirements. 
 
 


 
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7.3.4 
TREATMENT 
 
There are two inpatient treatment periods scheduled during the trial, each with a total of 5 infusions.  It is anticipated 
that sites will infuse subjects with 5 doses over 5 days.  A “grace day” is allowed in the event of unanticipated safety 
or health concerns during each inpatient treatment period. 
 
Visits 3-7 (Days 1-5) and 11-15 (Days 85*-89): 
*Day 85 has a ± 7-day window.  Visits 12-16 should follow consecutively.  
□ Perform the following procedures prior to administering study treatment: 
o Review AEs and concomitant medications 
o Obtain blood and urine samples for comprehensive laboratory panel; fasting samples preferred 
(Visits 4, 6, 12, and 14 Only) 
o Obtain samples for proteomics/epigenetics/biobanking; fasting samples preferred (Visits 3 and 11 
Only) 
o Obtain i-STAT safety laboratory test samples and assess results before each infusion 
o Perform targeted physical exam (i.e. auscultation of heart and lungs and assessment of peripheral 
edema)  
o Measure and record the subject’s weight in kilograms 
o Perform 12-lead ECG (Visit 11 Only) 
o Ensure the subject has had an opportunity to eat a meal prior to cognitive and motor testing 
o Administer the Savonix Brief Battery  
o Perform ADAS-Cog/11 (Visit 11 Only) 
o Collect pre-infusion vital signs  
□ Administer study treatment and perform safety assessments per the Infusion Administration Manual 
□ Post-infusion: perform 12-lead ECG (Visits 7 and 15 Only) 
 
7.3.5 
FOLLOW-UP 
 
Visits 8 and 16 (Day 6 and Day 90 – Last Day of Inpatient Stay): 
□ Review AEs and concomitant medications 
□ Collect the following: 
o Vital signs and subject’s weight in kilograms 
o Blood and urine samples for comprehensive laboratory panel (fasting samples preferred) 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred) 
o i-STAT safety laboratory test samples and assess results before discharge 
□ Perform targeted physical exam (i.e. auscultation of heart and lungs and assessment of peripheral edema)  
□ Ensure the subject has had an opportunity to eat a meal prior to cognitive and motor testing 
□ Perform cognitive assessments in the following order:  
1. C-SSRS 
2. MMSE 
3. Savonix Full Battery  
4. ADAS-Cog/11 
□ Complete MRI (Visit 8 + 4 days Only) 
□ In consenting, eligible subjects, perform final lumbar puncture (after final dosing) and obtain CSF samples 
for optional biomarker research (Visit 16 or within 5 days following) 
 
 


 
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Visit 9 (Day 28 ±7 days) and Visit 17 (Day 112 ±7 days) 
□ Review AEs and concomitant medications 
□ Collect the following: 
o Vital signs 
o Blood samples for interim safety labs (Note: Subjects randomized prior to August 30, 2018, will not 
participate in the additional interim safety labs at Visit 9 and Visit 17.) 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred) 
□ Ensure the subject has had an opportunity to eat a meal prior to cognitive and motor testing 
□ Perform cognitive and motor testing in the following order unless otherwise specified: 
1. Savonix Full Battery  
2. ADAS-Cog/11 
3. Grooved Pegboard  
4. CFT  
5. CDR-SOB (subject and trial partner) 
6. ADCS-ADL23 (trial partner) 
7. ADCS-CGIC (subject and trial partner)  
8. NPI-Q (trial partner self-administered; may be completed by the trial partner at any available time 
during the visit) 
 
Visit 10 (Day 56 ±7 days) and Visit 18 (Day 140 ±7 days) 
□ Review AEs and concomitant medication 
□ Collect the following: 
o Vital signs  
o Blood and urine samples for comprehensive laboratory panel (fasting samples preferred) 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred) 
□ Ensure the subject has had an opportunity to eat a meal prior to cognitive and motor testing 
□ Perform cognitive assessments in the following order unless otherwise specified:  
1. Savonix Full Battery  
2. ADCS-ADL23 (trial partner) 
3. NPI-Q (trial partner self-administered; may be completed by the trial partner at any available time 
during the visit) 
 
 


 
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7.3.6 
FINAL STUDY VISIT 
 
Visit 19, End of Study (Day 168 ±7 days) 
□ Review AEs and concomitant medication 
□ Collect the following: 
o Vital signs and subject’s weight in kilograms 
o Blood and urine samples for exit laboratory panel (fasting samples preferred) 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred) 
□ Perform the physical exam 
□ Ensure the subject has had an opportunity to eat a meal prior to cognitive and motor testing 
□ Perform cognitive and motor testing in the following order unless otherwise specified: 
1. MMSE 
2. Savonix Full Battery  
3. ADAS-Cog/11 
4. Grooved Pegboard  
5. CFT  
6. CDR-SOB (subject and trial partner) 
7. ADCS-ADL23 (trial partner) 
8. ADCS-CGIC (subject and trial partner)  
9. NPI-Q (trial partner self-administered; may be completed by the trial partner at any available time 
during the visit) 
□ Complete MRI  
 
Note: Visit 19 may be split to allow for sufficient time to complete all required procedures.  
 
7.3.7 
EARLY TERMINATION  
 
If a subject has received at least one infusion but is terminated or terminates from the study early, the site should try 
to perform all assessments scheduled at the End of Study Visit.  In addition, if a subject withdraws from the study 
early but is willing to provide the second (final) CSF sample (and has consented and is eligible to participate in the 
optional CSF biomarker research), this can be obtained as long as the subject received at least two infusions of 
GRF6019. 
 
7.3.8 
SCHEDULE OF EVENTS TABLE 
 
A tabular summary of all procedures that will be accomplished at each study visit can be found in Section 17 
Schedule of Events. 
 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
All prescription, over-the-counter, and non-prescription medications (including herbal therapies and supplements) must 
be documented in the source documents and CRFs.  All subjects should be maintained on the same medications at the 
same dosage and administration for treatment of AD throughout the entire study period, as medically feasible, with no 
introduction of new chronic therapies.  Any changes in medications should be documented with reason for change (e.g., 
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7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
The following are prohibited: 
• 
Concurrent participation in another therapeutic treatment trial for AD.  If there was prior clinical trial 
participation, then the last dose of the investigational agent for symptomatic therapies must have been at least 30 
days (or 5 half-lives whichever is longer), 4 months for disease modifying therapies, and 1 year for vaccine or 
immunotherapy trials prior to screening. 
• 
Concurrent daily treatment with benzodiazepines, long-acting opioids, or other medications that, in the 
investigator’s opinion, interfere with cognition.  [Note: intermittent treatment with low-doses of shorter half-life 
benzodiazepines (e.g. lorazepam, alprazolam) may be permitted, provided that no dose is administered within the 
72 hours preceding any cognitive assessment].   
• 
Any anticoagulant therapy; antiplatelet drugs (e.g., aspirin or clopidogrel) are acceptable. 
• 
Any drugs of the interferon class. 
• 
Systemic steroids (e.g., hydrocortisone, cortisone, betamethasone, prednisone, prednisolone, triamcinolone, 
dexamethasone, fludrocortisone) for longer than 5 consecutive days; ophthalmic, topical, intra-articular and 
inhaled steroids are allowed. 
 
8 
ASSESSMENT OF SAFETY 
 
Assessment of safety will be conducted by blinded study personnel except in extraordinary circumstances where 
knowledge of the dose received by a subject is essential.  Any instances of unblinding will be managed as indicated 
in Section 10.6.3 Breaking the Study Blind/Participant Code. 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) 
 
Per 21 CFR 312.32(a) an AE is any untoward (unfavorable, harmful, or pathologic) medical occurrence in a subject 
administered a medicinal (investigational) product even if the event does not necessarily have a causal relationship 
with this treatment.   
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding that is 
deemed clinically significant), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not related to the medicinal (investigational) product.   
 
An AE does include any: 
• 
Exacerbation of a pre-existing illness 
• 
Subjective or objective symptoms spontaneously offered by the subject and/or observed by the investigator or 
study staff 
• 
Increase in frequency or intensity of a pre-existing episodic event or condition 


 
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• 
Condition detected or diagnosed after study drug administration even though it may have been present prior to 
the start of the study (unless it can be demonstrated by medical record review that the onset of the event preceded 
the date/time of Informed Consent) 
• 
Continuous persistent disease or symptoms present at baseline that worsen following the start of the study 
• 
Symptoms associated with disease not previously reported by the subject 
• 
Lack of efficacy in the acute treatment of a life-threatening disease 
• 
Untoward medical occurrences considered by the investigator to be related to study-mandated procedures 
• 
Abnormal assessments (e.g., change on physical examination, ECG findings), if they represent a clinically 
significant finding, that were not present at Baseline or worsened during the course of the study 
• 
Laboratory test abnormalities, if they represent a clinically significant finding, symptomatic or not, which were 
not present at Baseline or worsened during the course of the study 
 
An AE DOES NOT include a/an: 
• 
Elective medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion)  
• 
Pre-existing diseases or conditions present or detected at the start of the study that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for cosmetic elective 
surgery, social and/or convenience admissions) 
• 
The disease or disorder being studied or sign or symptom associated with the disease or disorder unless more 
severe than expected for the subject’s condition 
• 
Overdose of either study drug or concurrent medication without any signs or symptoms. 
• 
Symptoms associated with AD that are consistent with the subject’s usual clinical course unless the symptom(s) 
meet(s) the criteria for “serious” 
• 
Pregnancy 
 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
An SAE is any AE occurring at any dose that results in any of the following outcomes (note that if either the 
investigator or the Sponsor believes that the event is serious, the event must be considered serious and evaluated for 
expedited reporting).  Note that the terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers 
to the grade of an AE.  “Serious” is a regulatory definition.  A serious adverse event (experience) or reaction is an 
untoward medical occurrence that, at any dose, fulfills one or more of the following criteria: 
a. Results in death (i.e., the AE actually causes or leads to death) 
b. Is life-threatening 
• 
An AE is considered “life-threatening” if, in the view of either the investigator or Sponsor, its occurrence 
places the patient or subject at immediate risk of death; it does not include AEs which, had it occurred in a 
more severe form, might have caused death 
c. Results in inpatient hospitalization or prolongation of existing hospitalization. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study is not 
considered an AE 


 
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• 
Complications that occur during hospitalization are AEs; if a complication prolongs hospitalization, the 
event is an SAE 
• 
“Inpatient” hospitalization means the subject has been formally admitted to a hospital for medical reasons 
that may or may not be overnight; it does not include presentation at a casualty or emergency room unless 
the event meets the definition of an Important Medical Event (in the opinion of the Investigator or Sponsor) 
d. Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
The term ‘disability’ means a substantial disruption of a person’s ability to conduct normal life functions; 
this definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, accidental trauma (i.e., sprained ankle) that 
may interfere or prevent everyday life functions but do not constitute a substantial disruption 
e. Results in a congenital anomaly in the offspring of a subject who received drug 
f. Results in an Important Medical Event.  Important Medical Events are events that may not result in death, be life-
threatening, or require hospitalization but may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition; examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
• 
Medical and scientific judgment should be used in deciding whether prompt reporting is appropriate in this 
situation 
 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 
SEVERITY OF EVENT  
 
Each AE or suspected adverse reaction must be assessed for its seriousness and severity.  Severity will be 
assessed by the investigator or designee using the following definitions:  
 
SEVERITY 
DEFINITION 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual 
activity 
SEVERE 
Incapacitating with inability to work or do usual activity 
 
Outcome will be assessed using the following categories: recovered/resolved, not recovered/ not resolved, 
recovered/resolved with sequelae, fatal, or unknown. 
 
8.2.2 RELATIONSHIP TO STUDY AGENT 
 
Investigators are required to assess the causal relationship (i.e., whether there is reasonable possibility that the study 
drug caused the event) using the following definitions: 
• 
Unrelated: another cause of the adverse event is more plausible; a temporal sequence cannot be established 
with the onset of the adverse event and administration of the study agent; or a causal relationship is 
considered biologically implausible. 


 
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• 
Possibly Related: There is a clinically plausible time sequence between onset of the adverse event and 
administration of the study agent, but the adverse event could also be attributed to concurrent or underlying 
disease, or the use of other drugs or procedures.  Possibly related should be used when the study agent is one 
or several biologically plausible adverse event causes. 
• 
Definitely Related: The adverse event is clearly related to use of the study agent. 
 
If either the investigator or the Sponsor considers the event related, then the event will be considered related for 
reporting purposes.   
 
8.2.3 
EXPECTEDNESS 
 
The Sponsor or designee will be responsible for determining whether an AE is expected or unexpected.  An AE will 
be considered unexpected if the nature, severity, or frequency of the event is not consistent with the Reference Safety 
Information described in the Investigator’s Brochure.   
 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the Investigator’s Brochure listed 
only cerebral vascular accidents.  "Unexpected" as used in this definition, also refers to AEs or suspected adverse 
reactions that are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug but are not specifically mentioned as occurring with the particular drug 
under investigation.  For example, although angioedema is anticipated to occur in some patients exposed to drugs in 
the angiotensin-converting enzyme (ACE) inhibitor class and angioedema would be described in the Investigator’s 
Brochure as a class effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes (FDA 2012). 
 
This definition of “unexpected” relies entirely on the Reference Safety Information in the Investigator’s Brochure as 
the basis for determining if newly acquired information generated from clinical trials or reported from other sources 
is unexpected.  The suspected adverse reactions listed in the Investigator’s Brochure (i.e., “expected”) are those 
observed with the investigational drug and for which a causal relationship between the event and the drug is 
suspected or confirmed. 
 
Sponsor assessment of expectedness and relationship to study drug/causality will determine the need for expedited 
reporting of AEs. 
 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP  
 
At every clinic visit, subjects will be assessed for AEs and SAEs.  After the subject has had an opportunity to 
spontaneously mention any problems, the investigator should inquire about AEs by asking a non-leading question such 
as the following: 
1. “How are you feeling?” 
2. “Have you had any changes since your last assessment/visit?” 
3. “Have you taken any new medicines since your last assessment/visit?” 
 
 


 
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8.3.1 
POST-STUDY AEs AND SAEs 
The investigator is not obligated to actively seek SAE information in former study participants, but the investigator is 
encouraged to notify Alkahest, Inc. or their designee of any AE or SAE occurring within 30 days after a subject 
completes the study (or has their last visit) that the investigator judges may be reasonably related to study treatment 
or study participation. 
 
8.4 
REPORTING PROCEDURES 
 
8.4.1 
ADVERSE EVENT REPORTING 
 
All subjects who have given informed consent will be evaluated for AEs.  All AEs that occur after the time of 
treatment with the study agent will be considered Treatment Emergent AEs.  Subjects with Treatment-Emergent AEs 
must be followed until the AE is resolved or is stable, unless the subject is lost to follow up. 
 
Each AE or suspected adverse reaction must be described as follows: the date of onset, date of resolution, severity 
(mild, moderate, severe), frequency of the event (single episode, intermittent, continuous), action taken with study 
treatment (no action taken, treatment held, treatment discontinued), outcome, causality* (unrelated, possibly related, 
definitely related), and seriousness criteria.  Each AE or suspected adverse reaction must be recorded separately. 
 
*Note: Causality assessment will be made only when the AE occurs after the subject has initiated at least one 
infusion of the study agent.  An AE occurring before the subject’s exposure to study agent will always be labeled as 
“unrelated”. 
 
Any AE occurring during the study must be documented in the subject’s medical records and as an AE in the CRF.  
Any SAE occurring during the study must be documented in the subject’s medical records and as an SAE in the 
CRF. 
 
A separate set of SAE pages should be used for each SAE.  However, if at the time of initial reporting, multiple 
SAEs are present that are temporally and/or clinically related, they may be reported on the same SAE page. 
 
The investigator should attempt to establish a diagnosis of the event (that meets the definition of an AE or SAE) 
based on signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be documented as 
the AE and/or SAE and not the individual signs or symptoms.  The diagnosis will become the basis for the verbatim 
term as reported by the investigator.  If no diagnosis is known and clinical signs and symptoms are not present, the 
abnormal finding should be recorded. 
 
In addition to the investigator’s own description of the AE, each AE will be encoded according to the MedDRA. 
 
The investigator will take all appropriate and necessary therapeutic measures required for resolution of the AE.  Any 
medication necessary for the treatment of an AE must be recorded on the concomitant medication CRF.   
 
The SAE pages of the CRF should be completed as thoroughly as possible and signed by the investigator or his/her 
designee before transmittal to the study Contract Research Organization (CRO).  It is very important that the 
investigator provide his/her assessment of causality to study drug as well as an applicable diagnosis at the time of the 
initial SAE report. 
 


 
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8.4.2 
SERIOUS ADVERSE EVENT REPORTING  
 
8.4.2.1 
Timeframes for Reporting SAEs 
Under 21 CFR 312.32(c), the Sponsor is required to notify FDA and all participating investigators in a safety report 
of potentially serious risks from clinical trials [i.e., Suspected Unexpected Serious Adverse Reactions (SUSARS)], as 
soon as possible after the Sponsor receives the safety information and determines that the information qualifies for 
reporting: 
 
• 
No later than 7 calendar days for events that are life threatening (in the opinion of the investigator or 
the Sponsor) or that involve Death as an outcome. 
• 
No later than 15 calendar days for all other SUSARS. 
 
As such, prompt notification of the Sponsor, and/or the Sponsor’s representatives, and promptly providing requested 
follow-up information regarding SAEs is essential so that ethical and regulatory responsibilities and legal obligations 
can be satisfied.  Investigators are responsible for reporting SAEs according to the following timeframes:  
 
• 
All SAEs occurring during the study should be reported immediately. 
• 
The SAE Report Form and relevant source documents, if applicable, must be completed and emailed to 
Safety.Alkahest@apcerls.com within 24 hours of observation or learning of the event.  
• 
Follow-up information must be sent to the CRO within 24 hours of receipt of information by the 
investigational site. 
 
SAEs will be followed until resolution, the condition stabilizes, the event is otherwise explained or is judged by the 
investigator to be no longer clinically significant, or until the subject is lost to follow up. 
 
8.4.2.2 
SAE Information to Report 
All information available regarding an SAE must be submitted in the timeframes indicated.  At a minimum, SAE 
reports must contain the subject ID, the SAE verbatim term, onset date, relationship to study drug/causality, and a 
brief narrative of the event.  Please note that relationship to study drug/causality as well as the reported verbatim 
term are very important and should be included in the initial report as it may impact expedited regulatory reporting 
requirements for the event.  The date of SAE discovery by the site staff should be documented in the source 
documents. 
 
The investigator must record all relevant information regarding an AE/SAE in the applicable sections of the CRF.  It 
is not acceptable for the investigator to send photocopies of the subject’s medical records in lieu of completion of the 
appropriate AE/SAE pages.  However, there may be instances when copies of medical records for certain cases are 
requested by the CRO and/or the Sponsor.  If medical records are submitted to the CRO then all subject personal 
identifiers must be completely and thoroughly redacted prior to submission. 
 
A blank SAE Report Form and instructions for SAE reporting will be provided to the site and will be maintained in 
the investigator’s study file.  The SAE Report Form must be completed and emailed to Safety.Alkahest@apcerls.com 
according to the timeframes specified in Section 8.4.2.1.  The SAE Report Form should include copies of relevant 
source documents, if applicable.  Reconciliation of any discrepancy noted during monitoring and amending the CRF 
is required. 
 
If new information about an SAE is received or corrections to data are needed, the investigator should complete a 
new SAE Report Form and check the “follow-up” box on the form.  This follow-up SAE Report Form should be 


 
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submitted within 24 hours of learning of the information, especially if the new information concerns seriousness, 
relatedness, or the event term of an AE. 
 
Sites acting under their local IRB should submit all applicable events, unanticipated problems, and safety reports to 
the site’s local IRB, if applicable.  All safety reporting deviations should also be submitted to their local IRB, if 
applicable. 
   
8.4.3 
ADVERSE EVENTS OF SPECIAL INTEREST 
 
The following will be considered adverse events of special interest (AESI):  
• 
Clinically-significant peripheral edema or pulmonary edema.  
• 
Systolic blood pressure (BP) < 90 or > 160 mm Hg and/or diastolic BP < 60 or > 100 mm Hg, or a change 
of > 25% from Day 1 (Visit 3) pre-infusion systolic and/or diastolic BP.   
• 
Reduced kidney function (eGFR < 45 mL/min/1.73 m2).  
• 
Suspected transmission of blood-borne infectious agents.  
 
AESI occurring during the study should be reported within 48 hours of observation or learning of the event, unless 
the event is serious, in which case the event must be reported according to the timeframes specified in Section 
8.4.2.1. 
 
8.4.4 
REPORTING OF PREGNANCY 
 
While pregnancy itself is not considered an AE, pregnancy occurring in a clinical study must be followed to collect 
information regarding the experiences of gestation and pregnancy with study agent exposure.  The investigator must 
report any pregnancy that occurs in a female study subject subsequent to first exposure to the study agent until End 
of Study, or 3 months following a subject’s last dose.  All pregnancies will be reported to the IRB, Sponsor, and 
CRO.  In the event of a pregnancy, treatment will be discontinued, and the subject will undergo continued safety 
follow-up through pregnancy outcome. 
 
Any pregnancy must be followed by the investigator until delivery or to the end of pregnancy.  Any anomalies, 
complications, abnormal outcomes, or birth defect observed in the child must be reported as an SAE within 24 
hours of the investigator or study personnel’s first knowledge. 
 
8.5 
STUDY HALTING RULES 
 
If any of the following safety events occur, a Safety Evaluation Meeting (defined below) will be triggered: 
• 
Three or more SAEs in the same system/organ/class (SOC) that are assessed as possibly or definitely related to 
the study agent by the investigator and confirmed as such by the Sponsor (see Section 8.2.2 Relationship to 
Study Agent). 
• 
Within or between any of the dosing groups: an overall pattern of symptomatic, clinical, or laboratory events 
associated with the study agent that the Sponsor’s Program Physician or designee consider a serious potential 
safety concern (e.g. suspicious overall pattern). 
Events that are more likely related to the infusion procedure, such as infiltration or hematoma, will not be considered 
“drug related” and will not contribute to the count of definitely-related SAEs that would trigger a Safety Evaluation 


 
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Meeting. 
 
Safety Evaluation Meeting 
If safety events of potential concern occur during the trial (as defined above) a Safety Evaluation Meeting will be 
triggered, and dosing may be temporarily halted based on the observations.  The Sponsor will inform investigators and 
the FDA in the event of any temporary halt in dosing at any time during the conduct of the study.  The purpose of the 
meeting is for investigators, the Sponsor, and the CRO Medical Monitor to discuss and evaluate the safety of the subjects 
using available aggregated safety data and without compromising study blinding.   
 
Attendants at the Safety Evaluation Meeting will include the Alkahest Program Physician (or his/her designee), the CRO 
Medical Monitor, and a majority of active investigators participating in the trial.  After sufficient data review the Sponsor 
will choose one of the following courses of action: 
1. Continue dosing with no change to protocol. 
2. Halt dosing in all groups and stop the study.  
3. Continue with a modified protocol design and amend the protocol as appropriate. 
 
8.6 
SAFETY OVERSIGHT 
 
Safety oversight will be provided by the Sponsor’s Program Physician or his or her designee and the CRO’s Medical 
Monitor in concert with the Principal Investigators at each participating site.  As all subjects are on active drug, there will 
be no formal Data Safety Monitoring Board (DSMB) established.  As needed, blinded Safety Evaluation Meetings will 
be convened as described in Section 8.5 to monitor the ongoing safety of the study.  The Sponsor’s Program Physician or 
designee is the final authority for safety oversight in the study. 
 
9 
CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). 
 
• 
Monitoring for this study will be performed by the Study CRO in accordance with the Clinical Monitoring Plan 
(CMP). 
• 
A mix of on-site and centralized risk-based monitoring will be performed to ensure the safety of clinical 
subjects and the accuracy and completeness of study data.   
• 
The Sponsor will be provided with copies of monitoring reports per the timelines specified within the CMP. 
• 
Details of clinical site monitoring are documented in the Study’s CMP.  The CMP describes in detail who 
will conduct monitoring, at what frequency monitoring will be done, at what level of detail monitoring will 
be performed, and the distribution of monitoring reports. 
• 
Independent audits may be conducted by the Sponsor in accordance with the Sponsor’s clinical quality 
oversight plan or equivalent to ensure monitoring practices are performed consistently across all participating 
sites and that monitors are following the CMP. 
 
 


 
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10 
STATISTICAL CONSIDERATIONS 
10.1 
STATISTICAL AND ANALYTICAL PLANS 
A Statistical Analysis Plan (SAP) with analytical details and assumptions will be developed during the conduct of the 
study.  The finalization of the SAP will occur prior to clinical database lock and unblinding of the study data. 
 
10.2 
STATISTICAL HYPOTHESES 
 
In as much as the study design is focused on safety and tolerability, the statistical approach toward the secondary 
endpoints will be primarily descriptive with only modest amounts of hypothesis testing; within-subject changes from 
baseline for each dosing group and among-group differences will be evaluated.   
 
10.3 
ANALYSIS DATASETS 
 
Four analysis datasets are possible however, analyses may not necessarily be conducted with all four: 
 
• 
Intention-to-Treat (ITT) Dataset: all randomized participants. 
• 
Safety Dataset: all subjects who received at least one dose of the study agent.   
• 
Evaluable Dataset:  all subjects who receive at least 5 of the 10 planned doses. 
• Per Protocol Dataset:  a subset of the Evaluable Dataset comprised of subjects who have no 
Major Protocol Deviations. 
 
The presentation of baseline characteristics will be conducted on the ITT dataset.  All safety analyses will be performed 
for the Safety Dataset.  Analyses of the secondary endpoints will focus on the Evaluable and/or Per Protocol Datasets. 
 
10.4 
DESCRIPTION OF STATISTICAL METHODS  
 
10.4.1 
GENERAL APPROACH 
 
Using the Evaluable and/or Per Protocol Datasets, all secondary cognitive-score endpoints (e.g., MMSE, 
ADAS-Cog, etc.) will be summarized serially over time using descriptive statistics to assess the within-
subject changes and among-group differences.  Overall baseline and demographic data will be summarized 
using descriptive statistics; among-groups testing will be used to evaluate the effectiveness of the 
randomization in producing homogeneous pre-treatment groups.   
 
For analysis of the primary and secondary endpoints, the following will be considered:  
• 
For endpoints that are continuous in nature: 
o Number of observations, mean, median, minimum and maximum, and standard deviation (SD) values will 
be presented as descriptive summary. 
o For inferential statistics: 
 
If the Normality assumption is met, Paired t-test, or Analysis of Covariance (ANCOVA) using the 
baseline value as a covariate will be used. 
 


 
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 
If the Normality assumption is not met, a rank –ANCOVA analysis i.e., an ANCOVA analysis on 
rank-transformed data or other non-parametric methods will be used. 
• 
For endpoints that are categorical in nature: 
o Frequency counts and percentages will be presented as descriptive summary. 
o Chi-square test or Logit model will be used for inferential statistics. 
 
Subject disposition (e.g., the number of subjects randomized, completed, and discontinued) will be 
summarized and medical history data will be listed.  Prior and concomitant medications taken from screening 
and during the study will be categorized by World Health Organization (WHO) classification for therapeutic 
class and drug name, listed and summarized by number and percentage of subjects.   
 
Final analyses are not limited to the summaries described herein.  As noted above, analytical details and 
assumptions will be fully presented in the SAP. 
 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
Summary tabulations of the reported adverse events will be presented by group after the Verbatim Terms have 
been coded to PTs and SOCs using the MedDRA Version 21.0 coding dictionary.  The summaries will include 
severity and attribution to the study agent.  Multiple reports of the same AE by the same subject will be counted 
only once at the highest severity and strongest attribution to the study agent. 
 
The AE analyses will focus on those that are Treatment-Emergent, however any AEs that are reported after 
consent has been signed and prior to initial dosing will be tabulated as Intercurrent Events. 
 
Additional details are presented in Section 10.4.4.   
 
10.4.3 
ANALYSIS OF THE SECONDARY ENPOINT(S) 
 
The study is not designed to detect significant changes in cognition over time.  However, using available data from 
analysis of the secondary endpoints, including changes in cognition scores from baseline, descriptive 
summarization will be developed.  Of particular interest will be the within-subject changes from baseline and their 
distribution around a null value of zero and a comparison among groups to evaluate any trends in dose response.  
Appropriate paired sample tests (paired t-test or Wilcoxon Signed Rank tests) may be conducted to evaluate 
within-subject changes from baseline, using a two-tailed α-level of 0.05.  Among-group differences may be 
assessed by One-way ANCOVA or its nonparametric equivalent test.  Alternatively, since the dose groups are 
ordinal, regression and graphical methods may be employed to evaluate any dose-response trends. 
 
10.4.4 
SAFETY ANALYSES 
 
Safety, tolerability, and feasibility will be evaluated by examining the occurrence of AEs, including Treatment-
Emergent AEs, and AEs leading to discontinuation from the study.  AEs will be summarized by severity and by 
study drug dose.   
 
Actual and changes from baseline in clinical laboratory measurements and vital signs will also be assessed and 
summarized.  Abnormal values will be determined and flagged in the listings.  Laboratory shift tables or graphics 
displaying the change (number of subjects) relative to the reference range from baseline to each study visit may 
also be presented for each test.  The investigator should exercise his or her medical and scientific judgment in 


 
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deciding and documenting whether an abnormal laboratory finding, or other abnormal assessment is clinically 
significant. 
 
Per-subject extent of exposure will be listed. 
 
10.4.5 
ADHERENCE AND RETENTION ANALYSES 
 
Feasibility as measured by subject adherence with the study visit schedule, visit procedures, infusions, and subject 
retention.  Subject adherence may vary across the different groups offering another feasibility measurement as 
would a comparison of the number of subjects who complete two series of 5 pulsed doses to subjects who complete 
only the first series.  Reasons for study discontinuation will be compared across groups and across other subgroups 
of subjects, as appropriate. 
 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS 
 
See Section 10.4.1. 
 
10.4.7 
PLANNED INTERIM ANALYSES 
 
No interim analyses are planned.  If a Safety Evaluation Meeting is triggered (see Section 8.5), an ad hoc interim 
safety analysis will be performed.  If such an ad hoc safety interim analysis is conducted, the dose assignment will 
remain masked.   
 
10.4.8 
ADDITIONAL SUB-GROUP ANALYSES 
 
Not applicable. 
 
10.4.9 
MULTIPLE COMPARISON/MULTIPLICITY 
 
No adjustments for multiplicity will be employed. 
 
10.4.10 TABULATION OF INDIVIDUAL RESPONSE DATA 
 
This will be further defined in the SAP. 
 
10.4.11 EXPLORATORY ANALYSES 
 
Not applicable. 
 
 


 
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10.5 
SAMPLE SIZE 
 
A total of 40 subjects (20 in the 100 mL group and 20 in the 250 mL group) will be randomized in the study with the 
intent of obtaining ~30 evaluable subjects who have received at least 5 doses and completed through Visit 8.  Subjects 
who discontinue prior to completing Visit 8 may be replaced.  Subjects who withdraw or are withdrawn during screening 
will be replaced.  Subjects who are randomized but do not receive any dose of the study agent, may be re-screened and 
randomized if they meet all of the study eligibility requirements. 
 
The study is not powered for detecting statistically significant differences in pharmacodynamic parameters or to assess 
the cognitive effects of GRF6019 infusions in AD.  However, using the statistical approximation described by Hanley 
(aka the “Rule of Threes”), the upper bound of the 95% confidence interval for the rate of an unreported AE is at most 
5.0% (3/number of subjects receiving active drug).  In addition, the proposed sample size may be sufficient to identify 
trends in the effects of plasma-derived factors and in the relationship between dose and response. 
 
10.6 
MEASURE TO MINIMIZE BIAS 
 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES 
 
To minimize the potential bias, the study will be double-blinded at randomization and through the end of study.  A 
stratified permuted block randomization will be implemented by sex.  The randomization will be web-based and 
centralized.  The randomization codes will be generated by a statistician who has no involvement in the study other 
than generation and maintenance of the randomization codes.   
 
All study outcome measures will be assessed by blinded Outcomes Assessors.  However, study agent and 
information regarding the volume to be administered, will be provided by an unblinded pharmacist, or other 
qualified staff responsible for drug accountability, to an unblinded Infusion Nurse.  Administration of the study 
agent will be performed by the unblinded Infusion Nurse.  To ensure that Outcomes Assessors, subjects, and trial 
partners are unaware of the dose being administered, appropriate measures will be taken to mask the infusion pump 
and glass vial(s) containing the study agent such that they will only be visible as necessary to the unblinded Infusion 
Nurse for appropriate dosing.  In addition, a curtain, drape, or equivalent will be used to shield the infusion 
administration setup from view of all but the unblinded Infusion Nurse, and the unblinded Infusion Nurse will be 
responsible for concealing and returning used and partially used vials to the pharmacy at the end of the Infusion 
Period.   
 
Communication between the Outcomes Assessor and the Infusion Nurse will be restricted to only that required to 
ensure immediate safety of subjects (e.g. requests to start/stop/change infusion rates outside of the standard infusion 
protocol due to AEs).  The Outcomes Assessors will observe the subject during the infusion of the study agent and 
collect and/or manage/report AEs and SAEs.   
 
 
 
  
 
Except for the unblinded CRA(s) whose sole responsibility is to ensure the study agent is being dispensed, 
administered, and disposed of properly, the study Sponsor and their representatives will be blinded with respect to 
dose. 


 
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10.6.2 
EVALUATION OF SUCCESS OF BLINDING 
 
Evaluation of success of blinding will be assessed as part of study feasibility.  Success of blinding will be assessed 
based on all occurrences (intentional or unintentional) of unblinding of blinded study subjects, their trial partners, or 
study personnel (e.g. investigators, medical providers, cognitive testing raters, the Sponsor, or their representatives).  
All intentional and unintentional unblinding will be documented and reported.   
 
10.6.3 
BREAKING THE STUDY BLIND/PARTICIPANT CODE 
 
Due to the dose-comparison concurrent control study design, it is not expected that the study blind would need to be 
broken for safety reasons.  Any noted intentional or unintentional breaking of the blind should be reported to the 
Sponsor’s Study Team Lead.  Subjects who have been unblinded prior to dosing day 5 will be replaced.  If 
unintentional unblinding occurs during the study, root cause analysis will be evaluated, and corrective actions 
implemented. 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
Each participating site will maintain appropriate medical and research records for this trial, in compliance with  
ICH E6 R2 and regulatory and institutional requirements for the protection of confidentiality of participants.  Each site 
will permit authorized representatives of regulatory agencies, the IRB/IEC, the Sponsor, or the Sponsor’s representatives 
to examine (and when permitted by applicable law, to copy) clinical records for the purposes of quality assurance 
reviews, audits, and evaluation of the study safety, progress, and data validity.   
 
Source data are all information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  Examples of these original documents and data records 
include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, participant’s 
memory aids or evaluation checklists, pharmacy dispensing records, recorded audio tapes of counseling sessions, 
recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and participant files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical trial.   
 
It is not acceptable for the CRF to be the only record of a subject’s participation in the study.  This is to ensure that 
anyone who would access the subject’s medical record has adequate knowledge that the subject is participating in a 
clinical trial.  Source document templates will be developed for this study. 
 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 
ETHICAL STANDARD 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the Protection of Human 
Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, ICH E6 R2, 21 CFR, part 320, 1993, 
Retention of Bioavailability and Bioequivalence Testing Samples and the Declaration of Helsinki. 
 
 
 


 
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12.2 
INSTITUTIONAL REVIEW BOARD 
 
This protocol and any accompanying material to be provided to the subject (such as advertisements, subject information 
sheets, or descriptions of the study used to obtain informed consent) will be submitted by the investigator to an IRB or 
IEC.  Approval from the IRB/IEC must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, documents reviewed, and date on which the committee 
met and granted the approval.   
 
All changes to the consent form will be IRB approved; a determination will be made regarding whether previously 
consented participants need to be re-consented. 
 
Any modifications or amendment to the protocol must also be submitted to the IRB/IEC for approval prior to 
implementation. 
 
12.3 
INFORMED CONSENT PROCESS 
 
12.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the subject (or the 
subject’s legally authorized representative) and trial partner.  Written documentation of informed consent is required 
prior to any invasive study procedures.  The following consent materials are submitted with this protocol: 
• 
ALK6019-201 Informed Consent Form 
 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
It is the responsibility of the investigator or designee to obtain written informed consent from each subject 
participating in this study and/or their legally authorized representative and the subject’s trial partner (if not the same 
person as the legally authorized representative) after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and prior to undertaking any study-related procedures. 
 
Subjects and/or trial partners should have the opportunity to discuss the study with their family members or other 
advisors and the time to consider participation in the trial carefully.  Participants may withdraw consent at any time 
throughout the course of the trial.  The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to participate in this study. 
 
The investigator or designee must utilize an IRB/IEC-approved consent form that contains the elements required by 
ICH GCP and applicable regulatory requirements for documenting written informed consent.  Each informed consent 
will be appropriately signed and dated by the subject and/or their legally authorized representative and the subject’s 
trial partner (if not the same person as the legally authorized representative) and the person obtaining consent.  A 
copy of the signed consent form will be provided to the subject and/or their legally authorized representative and the 
trial partner (if not the same person as the legally authorized representative).  By signing the informed consent form, 
all parties agree they will complete the evaluations required by the study, unless they withdraw voluntarily or are 
terminated from the study for any reason. 
 
Investigators will be expected to maintain a screening log of all potential study candidates that includes limited 


 
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information about the potential candidate (e.g., date of screening).   
 
All subjects who provide consent will be assigned a unique study number.  This number will be used to identify the 
subject throughout the clinical study and must be used on all study documentation related to the study subject.  Once 
a number is assigned to a subject, that number will remain with that study subject and will not be reused. 
 
If an individual’s medical chart or results of diagnostic tests performed as part of an individual’s regular 
medical care are going to be used for screening, written informed consent must be obtained prior to review of 
that information in accordance with HIPAA. 
 
The Screening period for a subject commences at the point at which the subject signs the informed consent form and 
must be completed within 28 days prior to study drug treatment. 
 
Due to the nature of the assessments in the trial, subjects and trial partners will need to speak English.  Therefore, 
there will be no need to translate the informed consent form into other language versions. 
 
12.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
Subject and trial partner confidentiality is held in strict trust by the participating investigators, their staff, the Sponsor and 
their agents.  This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the 
clinical information relating to participants.  Therefore, 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 Sponsor. 
 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB/IEC or government 
regulatory agencies may inspect 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. 
 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their identities are protected 
from unauthorized parties.  Only subject initials and an identification code (i.e., not names) should be recorded on non-
local lab samples, requisitions and any documents submitted to the CRO, Sponsor and/or IRB/IEC.  The investigator 
must keep a subject log showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the 
trial.  The study subject’s contact information will be securely stored at each clinical site for internal use during the 
study.  At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by 
local IRB/IEC and Institutional regulations. 
 
12.5 
FUTURE USE OF STORED SPECIMENS 
 
With the subject’s (or the subject’s legally authorized representative’s) approval and as approved by local IRBs under 
separate consent, de-identified biological samples may be stored by Alkahest, or designee, indefinitely for future use.  
These samples could will be used for research into the causes of AD, its complications, and other conditions for which 
elderly individuals are at increased risk, and to improve treatment options.  Alkahest will also be provided with a code-
link that will allow linking the biological specimens with the phenotypic data from each subject, maintaining the masking 
of the identity of the study subject. 
 
During the conduct of the study, an individual subject can choose to withdraw consent to have biological specimens 


 
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stored for future research.  However, withdrawal of consent for biospecimen storage will not be possible after the study is 
completed. 
 
When the study is completed, access to study data and/or samples will be managed by Alkahest.  In the event Alkahest 
transfers ownership to another commercial sponsor, ownership of the samples may be transferred as well. 
 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI.  The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.  Black 
or blue ink is required to ensure clarity of reproduced copies.  When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change.  DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
For each subject who receives an infusion, the CRF must be completed within approximately 14 days of each 
completed visit.  The investigator will review and approve the CRF for each study subject after all data have been 
entered, the CRFs have been source document verified by the CRA, and all queries have been resolved.  This also 
applies to records for those subjects who fail to complete the study.  If a subject withdraws from the study, the reason 
must be noted on the CRF.  If a subject is withdrawn from the study because of an AE, thorough efforts should be 
made to clearly document the outcome. 
 
All data collection and recordkeeping procedure must be compliant with applicable ICH GCP. 
 
13.1.1 
INVESTIGATOR RESPONSIBILITIES 
 
The investigator will comply with the protocol (which has been approved/given favorable opinion by an IRB/IEC), 
ICH GCP, and applicable regulatory requirements as described in the Clinical Study Agreement.  The investigator is 
ultimately responsible for the conduct of all aspects of the study at the study site and verifies by signature the 
integrity of all data transmitted to the Sponsor.  The term “investigator” as used in this protocol as well as in other 
study documents, refers to the investigator or authorized study personnel that the investigator has designated to 
perform certain duties.  Sub-investigators or other authorized study personnel are eligible to sign for the investigator, 
except where the investigator’s signature is specifically required. 
 
13.1.2 
STUDY FILES 
 
The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented and the study data to be subsequently verified.  These documents should be classified into two separate 
categories (although not limited to) the following: (1) investigator’s study file, and (2) subject clinical source 
documents. 
 
The investigator’s study file will contain the protocol/amendments, CRF and query forms (if paper CRFs are 
utilized), IRB/IEC approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence. 


 
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Subject clinical source documents would include (although are not limited to) the following: subject hospital/clinic 
records, physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, radiologic imaging, X-
ray, pathology and special assessment reports, consultant letters, screening and enrollment log, etc. 
 
13.2 
STUDY RECORDS RETENTION 
 
All clinical study documents must be retained by the investigator until two years after the Investigational New Drug 
(IND) application is discontinued and regulatory authorities have been notified.  Before the investigator destroys any 
material related to the clinical study, he/she must obtain approval in writing from the Sponsor. 
 
The investigator should keep a file where the full name and address of the subject and all signed informed consents are 
included for at least 15 years after completion of the trial.  Any original study-related information that permits 
verification of inclusion and exclusion criteria, including clinical history, a copy of all data collection logs, and 
documents on the use of the study agent, must be stored for as long a time period as permitted by the center.   
 
Should the investigator wish to move study records to another location, arrangements must be made to store these in 
sealed containers so that they can be returned sealed to the investigator in case of a regulatory audit.  Where source 
documents are required for the continued care of the Subject, appropriate copies should be made for storage outside of 
the site. 
 
13.3 
PROTOCOL DEVIATIONS 
 
A protocol deviation is any noncompliance with the clinical trial protocol or with GCP.  The noncompliance may be 
either on the part of the subject, the investigator, or the study site staff.  When deviations occur, corrective actions are 
to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
Protocol Deviations will be categorized as either Major or Minor and will be defined in the study-specific Protocol 
Deviation Plan.   
 
Major Protocol Deviations are departures from the approved protocol relating to the conduct of the study which may 
affect the rights, safety and/or wellbeing of study participants, or the study outcomes or data quality.  Major Protocol 
Deviations may result in data that are not deemed evaluable for the per protocol analysis and/or may require that subjects 
be discontinued from the study.  Major Protocol Deviations are Significant Clinical Issues.  
 
Minor Protocol Deviations are departures from the approved protocol relating to the conduct of a study that does not 
affect the rights, safety and/or wellbeing of study participants, or the study outcomes or data quality.  Minor Protocol 
Deviations do not require review by the medical monitor.  Minor Protocol Deviations would not generally preclude 
subject data from the per protocol analysis population.   
 
Note: persistently missed or incomplete study procedures and/or study evaluations will be considered Major Protocol 


 
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Deviations. 
 
All deviations will be logged and tracked by the site and CRO.  Periodic review of Protocol Deviations will inform 
assessment of site performance. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations promptly to the study CRO 
and/or Sponsor.  All deviations must be addressed in study source documents.  Protocol Deviations must be sent to the 
local IRB per their guidelines.  The site PI/study staff is responsible for knowing and adhering to their IRB requirements. 
 
13.4 
PUBLICATION AND DATA SHARING POLICY 
 
In compliance with The International Committee of Medical Journal Editors (ICMJE) clinical trials registration policy 
and Section 801 of the Food and Drug Administration Amendments Act of 2007, this study will be registered by the 
Sponsor in ClinicalTrials.gov, a public trials registry which is sponsored by the National Library of Medicine. 
 
Notwithstanding the Sponsor’s requirements for registration and data sharing in ClinicalTrials.gov, any formal 
presentation or publication of data collected as a direct or indirect result of this trial will be considered as a joint 
publication by the investigator(s) and the Sponsor.  In the case of multicenter studies, it is mandatory that the first 
publication be made based on the totality of data obtained from all centers, analyzed as stipulated in the protocol, and 
presented and interpreted as documented in the final Clinical Study Report.  The resulting publication will name 
investigators according to the policy of the chosen journal.  Where it is not permitted for all investigators to be included 
as authors, the publication will name all investigators within the publication. 
 
Individual investigators may publish data arising from their own subjects.  The investigator will provide the Sponsor with 
copies of written publications (including abstracts and posters) at least 60 days in advance of submission.  This review is 
to permit the Sponsor to review the communication for accuracy (thus avoiding potential discrepancies with submissions 
to regulatory authorities), to verify that confidential information is not inadvertently divulged (
 
), to allow adequate input or supplementary information that may not have been available to the investigator, 
and to allow establishment of co-authorship. 
 
Investigators participating in multicenter studies must agree not to engage in presentations based on data gathered 
individually or by a subgroup of centers before publication of the first main publication, unless this has been agreed 
otherwise by all other investigators and the Sponsor.  However, in the event that no publication of the overall results has 
been submitted after approval of the Clinical Study Report, investigators may publish results of one or more center’s 
subjects to the same review as outlined above.  The Sponsor will circulate proposed multicenter publications to all 
investigators for review. 
 
Data will be reviewed by all participating investigators prior to publication.  The study Sponsor will have 60 days to 
review all definitive publications, such as manuscripts and book chapters, and a minimum of 30 days to review all 
abstracts. 
 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY 
 
A separate financial agreement will be made between each principle investigator and Alkahest, Inc. or its authorized 
representative before the study drug is shipped.  For this study, each investigator and sub-investigator (as designated on 
the FDA Form 1572) will provide a signed Financial Disclosure Form in accordance with 21 CRF 54.  Each investigator 


 
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will notify Alkahest, Inc. or its authorized representative of any relevant changes during the conduct of the study for 1 
year after the study has been completed.  Alkahest and the study CRO will evaluate any disclosed conflicts of interest 
and will establish a mechanism for their management. 
15 
LITERATURE REFERENCES 
 
Acevedo A. Category fluency test: normative data for English and Spanish-speaking elderly. J Int Neuropsych Soc. 
2000;6(7):760-769. 
 
ALK-2015-R002. Effects of young and old human plasma on cognition in NODscid mice. 
 
Alzheimer’s Association. 2018 Alzheimer's Disease Facts and Figures. Alzheimers Dement. 2018;14(3):367-429. 
Benton AL. Development of a multilingual aphasia battery: progress and problems. J Neurol Sci. 1969;9:39-48. 
 
 
 
 
 
 
Burnouf T. Modern plasma fractionation. Transfus Med Rev. 2007;21(2):101-17. 
 
Cai K, Miller JL, Stenland CJ, Gilligan KJ, Hartwell RC, Terry JC, et al. Solvent-dependent precipitation of 
prion protein. Biochim Biophys Acta. 2002;1597:28-35. 
 
Food and Drug Administration (FDA), U.S. Department of Health and Human Services. Guidance for Industry and 
Investigators: Safety Reporting Requirements for INDs and BA/BE Studies. December, 2012. 
 
Ferris SH, Mackell JA, Mohs R, Scheider LS, Galasko D, Whitehouse P, et al. A multicenter evaluation of new treatment 
efficacy instruments for Alzheimer’s disease clinical trials: overview and general results. Alz Dis Assoc Dis. 
1997;11(Suppl 2):S1-S12. 
 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state." A practical method for grading the cognitive state of 
patients for the clinician. J Psychiatric Res. 1975;12(3):189-198. 
 
 
 
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. An inventory to assess activities of daily 
living for clinical trials in Alzheimer’s Disease. Alz Dis Assoc Disord. 1997;11 (Suppl 2):S33-39. 
 
Gebhard C, Stahli B, Jenni R, Tanner FC. Effect of age on left ventricular ejection fraction assessed by 
echocardiography. Eur Heart J. 2012;33:1. 
 
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Brit J 
Psychiat. 1982;140:566-572. 
 


 
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Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation of the NPI-Q, a brief clinical 
form of the neuropsychiatric inventory. J Neuropsychiatry Clin Neurosci. 2000 Spring;12(2):233-239. 
 
Lafayette Instrument Company. Grooved Pegboard Test User Instructions (Model 32025); 2002. 
Mayeux R. Early Alzheimer’s disease. N Engl J Med. 2010;362:2194-2201. 
 
McKhann GM, Knopman, DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on 
diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-269. 
 
MDRD for Adults (Conventional Units) | NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases 
Available at: https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-
evaluation/glomerular-filtration-rate-calculators/mdrd-adults-conventional-units. (Accessed: 16th February 2018) 
 
O’Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, et al. Staging dementia using Clinical Dementia 
Rating Scale Sum of Boxes scores: a Texas Alzheimer’s Research Consortium study. Arch Neurol. 2008;65:1091-1095. 
 
 
 
Polacchini A, Metelli G, Francavilla R, Baj G, Florean M, Mascaretti LG, et al. A method for reproducible measurements 
of serum BDNF: comparison of the performance of six commercial assays. Sci Rep. 2015;5:17989. 
 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-Suicide Severity Rating 
Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am 
Psychiatry. 2011 December;169(12):1266-1277. 
 
 
 
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141(11):1356-1364. 
 
Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. 1980. Pathological verification of ischemic score in differentiation 
of dementia. Arch Neurology. 1980;7:486-488. 
 
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg, B, et al. Validity and reliability of the Alzheimer’s 
Disease Cooperative Study-Clinical Global Impression of Change. Alzheimers Dis Assoc Disord. 1997;11 (Suppl 
2):S22-S52. 
 
Skinner J, Carvalho JO, Potter GG, Thames A, Zelinski E, Crane PK, et al. The Alzheimer’s Disease Assessment Scale-
Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI. Brain Imaging 
Behav. 2012;6 (4):1-24. 
 
Stenland CJ, Lee DC, Brown P, Petteway SR Jr, Rubenstein R. Partitioning of human and sheep forms of 
the pathogenic prion protein during the purification of therapeutic proteins from human plasma. 
Transfusion. 2002;42:1497-500. 
 
Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, et al. The ageing systemic milieu negatively 
regulates neurogenesis and cognitive function. Nature. 2011;477:90-94. 


 
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Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related 
impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014 Jun;20(6):659-663.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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16 
APPENDICES 
 
The neurocognitive assessments in this section and associated information are provided as EXAMPLES ONLY.  The 
actual neurocognitive assessments, related source documents, and instructions for administration and scoring are included 
in the Rater Reference Manual.    
 
 


 
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Appendix 1.  
Mini-Mental State Examination (MMSE) 
 
Instructions for Administration and Scoring 
 
Orientation (10 points): 
• Ask for the date.  Then specifically ask for parts omitted (e.g., "Can you also tell me what season it is?").  One point for 
each correct answer. 
• Ask in turn, ""Can you tell me the name of this facility (town, county, etc.)?" One point for each correct answer. 
 
Registration (3 points): 
• Say the names of three unrelated objects clearly and slowly, allowing approximately one second for each.  After you have 
said all three, ask the patient to repeat them.  The number of objects the patient names correctly upon the first repetition 
determines the score (0-3).  If the patient does not repeat all three objects the first time, continue saying the names until the 
patient is able to repeat all three items, up to six trials.  Record the number of trials it takes for the patient to learn the words.  
If the patient does not eventually learn all three, recall cannot be meaningfully tested. 
• After completing this task, tell the patient, "Try to remember the words, as I will ask for them in a little while.” 
 
Attention and Calculation (5 points): 
• Ask the patient to begin with 100 and count backward by sevens.  Stop after five subtractions (93, 86, 79, 72, 65).  Score 
the total number of correct answers. 
• If the patient cannot or will not perform the subtraction task, ask the patient to spell the word "world" backwards.  The 
score is the number of letters in correct order (e.g., dlrow=5, dlorw=3). 
 
Recall (3 points): 
• Ask the patient if he or she can recall the three words you previously asked him or her to remember.  Score the total 
number of correct answers (0-3). 
 
Language and Praxis (9 points): 
• Naming: Show the patient a wrist watch and ask the patient what it is.  Repeat with a pencil.  Score one point for each 
correct naming (0-2). 
• Repetition: Ask the patient to repeat the sentence after you ("No ifs, ands, or buts.").  Allow only one trial.  Score 0 or 1. 
• 3-Stage Command: Give the patient a piece of blank paper and say, "Take this paper in your right hand, fold it in half, and 
put it on the floor." Score one point for each part of the command correctly executed. 


 
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• Reading: On a blank piece of paper print the sentence, "Close your eyes," in letters large enough for the patient to see 
clearly.  Ask the patient to read the sentence and do what it says.  Score one point only if the patient actually closes his or 
her eyes.  This is not a test of memory, so you may prompt the patient to "do what it says" after the patient reads the 
sentence. 
• Writing: Give the patient a blank piece of paper and ask him or her to write a sentence for you.  Do not dictate a sentence; 
it should be written spontaneously.  The sentence must contain a subject and a verb and make sense.  Correct grammar and 
punctuation are not necessary. 
• Copying: Show the patient the picture of two intersecting pentagons and ask the patient to copy the figure exactly as it is.  
All ten angles must be present and two must intersect to score one point.  Ignore tremor and rotation. 
 
Interpretation of the MMSE 
 
Method  
Score  
Interpretation 
Single Cutoff 
<24 
Abnormal 
Range 
<21 
>25 
Increased odds of dementia 
Decreased odds of dementia 
Education 
21 
<23 
<24 
Abnormal for 8th grade education 
Abnormal for high school education 
Abnormal for college education 
Severity 
24-30 
18-23 
0-17 
No cognitive impairment 
Mild cognitive impairment 
Severe cognitive impairment 
 
 
 
Reference:  
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state." A practical method for grading the cognitive state of 
patients for the clinician. J Psychiatric Res. 1975;12(3):189-198. 
 
 
 


 
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Appendix 2.  
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-COG/11): Assessment 
Categories, Descriptions, and Scoring  
 
1. Immediate word recall 
   In this task, the subject is given 3 tries to learn a list of 10 words.  The subject must first read the words aloud, 
memorize them and then reproduce them.  The subject’s score is the average number of words not recalled in 3 trials 
(maximum 10). 
2. Naming objects and fingers 
   For this item, the subject is asked to name the 12 real objects presented randomly as well as the fingers of his/her 
dominant hand.  The objects presented: flower, bed, whistle, pencil, rattle, mask, scissors, comb, wallet, harmonica, 
stethoscope, and tweezers.  The score varies from 0 to 5. 
3. Commands 
   The subject is asked to carry out 1 to 5 commands.  Score varies from 0 to 5. 
4. Constructional praxis 
   This task assesses the subject’s ability to copy 4 geometric forms: a circle, a superimposed rectangle, a diamond and a 
square.  Score varies from 0 to 4. 
5. Ideational praxis 
   This task is designed to determine whether the individual can perform a complex sequence of actions.  The score varies 
from 0 to 5. 
6. Orientation 
   The components of this task are person, day of the week, day of the month, month, year, season, time of day, and 
specific place.  One point is given for each incorrect answer (maximum 8). 
7. Word recognition 
   In this task, the subject must read and memorize a list of 12 words.  These words are then randomly mixed with 12 
words the subject has not seen, and the subject is asked to decide whether or not the word has already been read.  The 
subject has 3 tries, in each of which, the word order is changed.  The score is calculated. 


 
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8. Remembering test instructions 
   This item evaluates the individual’s ability to remember the instructions of the recognition task.  Score varies from 0 to 
5. 
9. Spoken language ability 
   This item is an overall rating of the quality of speech, such as clarity and capacity to make someone understand.  Score 
varies from 0 to 5. 
10. Word-finding difficulty in spontaneous speech 
   This task analyzes the decrease in expressive speech, but only as refers to difficulty in word choice.  Score varies from 
0 to 5. 
11. Comprehension 
   This item evaluates the individual’s ability to understand the examiner’s speech.  Score varies from 0 to 5. 
  
References: 
Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of 
dementia. Arch Neurology. 1980;7:486-488. 
Skinner J, Carvalho JO, Potter GG, Thames A, Zelinski E, Crane PK, et al. The Alzheimer’s Disease Assessment Scale-
Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI. Brain Imag 
Behav. 2012;6:489-501. 
 
 
 


 
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Appendix 3. Clinical Dementia Rating Scale – Sum of Boxes (CDR-SOB) 
The CDR rates the severity of AD using a 5-point scale assessing signs and symptoms of the disease as they affect the 
patient’s ability to function in the 6 cognitive categories of memory, orientation, judgment and problem solving, 
community affairs/involvement, home life and hobbies and personal care.  The CDR is completed by a specially trained 
researcher or clinician after performing a face-to-face, semi-structured interview with the patient and a reliable informant 
(e.g., trial partner).  The informant is interviewed first, and the results of that interview are used to assess patient recall of 
events and to confirm the accuracy of patient responses.  In each cognitive category, the patient receives a score of 0 (no 
cognitive impairment) to 3 (severe cognitive impairment).  The CDR can be scored to obtain a global score by using an 
algorithm that weights memory more heavily than the other categories, or it can be scored using the sum of boxes (SOB) 
method in which all categories are weighted equally; in general, the higher the score, the greater the severity of dementia 
The memory, orientation, judgment and problem solving, community affairs/involvement, and home life and hobbies 
categories are scored using a 5-point ordinal scale, as follows: 
–0 indicates no impairment 
–0.5 indicates very mild impairment 
–1 indicates mild impairment 
–2 indicates moderate impairment 
–3 indicates severe impairment 
The personal care category is scored using a 4-point ordinal scale, as follows: 
–0 indicates no impairment 
–1 indicates mild impairment 
–2 indicates moderate impairment 
–3 indicates severe impairment 
 
The descriptors for each score on the CDR scoring sheet vary based on the category being evaluated; the selection criteria 
for each score are clearly described on the scoring sheet.  In the CDR-SOB scoring method, all 6 categories are weighted 
equally, and the scores for each of the categories are summed to obtain a total score; the total score can be 0 to 18.  The 
advantages of the SOB scoring method include greater ease in calculating dementia severity, the ability to better detect 
subtleties in dementia severity and increased precision in serially tracking the severity of dementia.  SOB scores are used 
to rate dementia severity as follows: 
–0 indicates normal cognitive functioning 
–0.5–4.0 indicates questionable cognitive impairment 


 
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- 0.5–2.5 indicates questionable impairment 
- 3.0–4.0 indicates very mild dementia 
–4.5–9.0 indicates mild dementia 
–9.5–15.5 indicates moderate dementia 
–16.0–18.0 indicates severe dementia 
 
References 
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. An inventory to assess activities of daily living 
for clinical trials in Alzheimer’s Disease. Alz Dis Assoc Disord. 1997;11 (Suppl 2):S33-39. 
 
O’Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, et al. Staging dementia using Clinical Dementia 
Rating Scale Sum of Boxes scores: a Texas Alzheimer’s Research Consortium study. Arch Neurol. 2008;65:1091-1095.  
 
 


 
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Appendix 4. Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL23) 
The ADCS-ADL23 contains 23 items covering physical and mental functioning and independence in self-care.  For each ADL, an 
informant/trial partner is first asked if the patient attempted the activity during the past 4 weeks.  If a patient did attempt the ADL, the 
informant/trial partner is asked to choose the single most accurate definition of the patient’s level of performance.  The scores range 
from 0 to 78, with higher scores indicating less functional impairment.  Included below are the standard questions used for assessment 
of mild to moderate AD. 
***************************************************************************** 
1. Regarding eating: Which best describes subjects’ usual performance during the past 4 weeks? 
  Ate without physical help 
  Used a fork or spoon, but not a knife to eat 
  Used fingers to eat 
  Usually or always was fed by someone else 
2. Regarding walking (or getting around in a wheelchair), in the past 4 weeks, which best describes his/her optimal performance: 
  Mobile outside of home without physical help 
  Mobile across a room without physical help 
  Transferred from bed to chair without help 
  Required physical help to walk or transfer 
3. Regarding bowel and bladder function at the toilet, which best describes his/her usual performance in the past 4 weeks: 
  Did everything necessary without supervision or help 
  Needed supervision, but no physical help, and was usually continent 
  Needed physical help, and was usually continent 
  Needed physical help, and was usually incontinent 
4. Regarding bathing, in the past 4 weeks, which best describes his/her usual performance: 
  Bathed without reminding or physical help 
  No physical help, but needed supervision/reminders to bathe completely 
  Needed minor physical help (e.g., with washing hair) to bathe completely 
  Needed to be bathed completely 
5. Regarding grooming, in the past 4 weeks, which best describes his/her optimal performance: 
  Cleaned and cut fingernails, without physical help 


 
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  Brushed or combed hair without physical help 
  Kept face and hands clean without physical help 
  Needed help for grooming of hair, face, hands, and fingernails 
6a. Regarding dressing, in the past 4 weeks, did subject select his/her first set of clothes for the day? 
Yes / No / don't know - If Yes, which best describes his/her usual performance: 
  Without supervision or help 
  With supervision 
  With physical help 
6b. Regarding physically getting dressed, which best describes his/her usual performance in the past 4 weeks (check one): 
  Dressed completely without supervision or physical help 
  Dressed completely with supervision, but without help 
  Needed physical help only for buttons, clasps, or shoelaces 
  Dressed without help if clothes needed no fastening or buttoning 
  Always needed help, regardless of type of clothing 
  Don’t know 
7. In the past 4 weeks, did subject use a telephone 
Yes / No / don't know - If Yes, which best describes his/her highest level of performance: 
  Made calls after looking up numbers in white or yellow pages, or by dialing directory assistance 
  Made calls only to well-known numbers without referring to a directory, list, or preprogrammed numbers 
  Made calls only to well-known numbers by using a directory or list 
  Answered the phone; did not make calls 
  Did not answer the phone, but spoke when put on the line 
8. In the past 4 weeks, did subject watch television? 
Yes / No / don't know - If Yes, ask each of the following (Yes / No): 
          a. Did subject usually select or ask for different programs or his/her favorite show? 
          b. Did subject usually talk about the content of a program while watching it? 
          c. Did subject talk about the content of a program within a day (24 hours) after watching it? 
9. In the past 4 weeks, did subject ever appear to pay attention to conversation or small talk for at least 5 minutes? 
(note subject did not need to initiate the conversation) 


 
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Yes / No / don't know - If Yes, which best describes his/her usual degree of participation: 
  Usually said things what were related to the topic 
  Usually said things that were not related to the topic 
  Rarely or never spoke 
10. Did subject clear the dishes from the table after a meal or snack? 
Yes / No / don't know - If Yes, which best describes how he/she usually performed: 
  Without supervision or help 
  With supervision 
  With physical help 
11. In the past 4 weeks, did subject usually manage to find his/her personal belongings at home? 
Yes / No / don't know - If Yes, which best describes how he/she usually performed: 
  Without supervision or help 
  With supervision 
  With physical help 
12. In the past 4 weeks, did subject obtain a hot or cold beverage for him/herself? 
Yes / No / don't know - If Yes, which best describes his/her highest level of performance: 
  Made a hot beverage, usually without physical help 
  Made a hot beverage, usually if someone else heated the water 
  Obtained a cold beverage, usually without physical help 
13. In the past 4 weeks, did subject make him/herself a meal or snack at home? 
Yes / No / don't know - If Yes, which best describes his/her highest level of performance: 
  Cooked or microwaved food, with little or no help 
  Cooked or microwaved food, with extensive help 
  Mixed or combined food items for a meal or snack, without cooking or microwaving (e.g., made a sandwich) 
14. In the past 4 weeks, did subject dispose of garbage or litter in an appropriate place or container at home? 
Yes / No / don't know - If Yes, which best describes how he/she usually performed: 
  Without supervision or help 
  With supervision 
  With physical help 


 
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15. In the past 4 weeks, did subject get around (or travel) outside of his/her home? 
Yes / No / don't know - If Yes, which best describes his/her optimal performance: 
  Alone, went at least 1 mile away from home 
  Alone, but remained within 1 mile of home 
  Only when accompanied and supervised, regardless of the trip 
  Only with physical help, regardless or the trip 
16. In the past 4 weeks, did subject ever go shopping? 
Yes / No / don't know - If yes, ask A and B 
A) Which one best describes how subject usually selects items? 
  Without supervision or physical help 
  With some supervision or physical help 
  Not at all, or selected mainly random or inappropriate items 
B) Did subject usually pay for items without supervision or physical help? 
  Yes 
  No 
17. In the past 4 weeks, did subject keep appointments, meetings with other people, such as relatives, a doctor, the hairdresser, etc.? 
  Usually remembered, may have needed written reminders, e.g., notes, a diary, or calendar 
  Only remembered the appointment after verbal reminders on the day 
  Usually did not remember, in spite of verbal reminders on the day 
18. In the past 4 weeks, was subject ever left on his/her own? 
Yes / No / don't know - If yes, ask all questions: 
Was subject left: 
     Yes / No 
          a) away from home for 15 minutes or longer, during the day? 
          b) at home for an hour or longer, during the day 
          c) at home, for less than 1 hour during the day 
19. In the past 4 weeks, did subject talk about current events? (This means events or incidents that occurred during the past month.) 
Yes / No / don't know - If yes, ask all questions: 
Did subject talk about events that (Yes / No):  


 
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          a) he/she heard or read about or saw on TV but did not take part in? 
          b) he/she took part in outside home involving family, friends, or neighbors? 
          c) events that occurred at home that he/she took part in or watched 
20. In the past 4 weeks, did subject read a magazine, newspaper or book for more than 5 minutes at a time? 
Yes / No / don't know - If yes, ask all questions: 
Did subject usually (Yes / No): 
          a) talk about details of what he/she read while or shortly (less than 1 hour) after reading? 
          b) talk about what he/she read 1 hour or longer after reading? 
21. In the past 4 weeks, did subject ever write things down? 
Yes / No / don't know (Note: if subject wrote things only after encouragement or with help, the response should still be ‘Yes’.) 
If yes, which best describes the most complicated things that he/she wrote: 
  Letters or long notes that other people understood 
  Short notes or messages that other people understood 
  His/her signature or name 
22. In the past 4 weeks, did subject perform a pastime, hobby, or game? 
Yes / No / don't know - If yes, how did subject usually perform his/her most common pastimes: 
  Without supervision or help 
  With supervision 
  With help 
  If subject performs hobbies/pastimes only at day care, check here 
23. In the past 4 weeks, did subject use a household appliance to do chores? 
Examples include washer, dryer, vacuum, dishwasher, toaster, toaster over, range, microwave, food processor 
Yes / No / don't know 
Reference: 
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. An inventory to assess activities of daily living for clinical 
trials in Alzheimer’s Disease. Alz Dis Assoc Disord. 1997;11 (Suppl 2):S33-39. 
Questionnaire modified from electronic form developed at the Palo Alto Veterans Affairs Hospital by Wes Ashford, M.D., Ph.D., Jerome Yesavage, 
M.D. Available at: http://www.medafile.com/cln/ADCSADLm.htm 
 
 


 
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Appendix 5.  
Alzheimer’s Disease Cooperative Study- Clinical Global Impression of Change (ADCS-CGIC) 
 
The ADCS-CGIC evaluates the patient in five treatment domains: 1) cognition (immediate and delayed memory, praxis, 
attention, and executive function); 2) clinical global change; 3) activities of daily living; 4) behavioral symptoms 
(agitation and other noncognitive symptoms); 5) cognition in severely impaired patients.   
Instructions for Administration of the ADCS-CGIC 
The ADCS-CGIC consists of two parts; Part I, the baseline evaluation (includes information from both the subject and 
informant); Part II, ADCS_CGIC forms for both subject and informant. 
The overall intent of the ADCS-CGIC is to provide a reliable means to assess global change from baseline in a clinical 
trial.  It provides a semi structured format to enable clinicians to gather necessary clinical information from both the 
patient and informant to make a global impression of change. 
Part I is used to record baseline information to serve as a reference for future ratings.  Part II is composed of two 
sections, a subject interview form and an informant interview form.  These forms are used to record information from 
separate interviews with both the subject and informant from which an impression of change score is made. 
Baseline Evaluation 
At baseline, the clinician interviews the patient and caregiver, recording onto Part I notes about baseline status for later 
reference.  At baseline only, clinical information about the subject from any source can be used.  The clinician indicates 
on a checklist the sources of information compiled during the baseline evaluation. 
Parts I and II share a similar format for recording relevant clinical information.  The column headed “Area” identifies 
various areas that a clinician might consider while evaluating a patient for potential clinical change, including what might 
be expected to be assessed in performing an ordinary but brief comprehensive office interview to determine a subject’s 
baseline status and eligibility for a clinical trial.  The “Probes” column provides sample items that a clinician might find 
useful in assessing an area, and these are intended as guides for collecting relevant information.  The last column 
provides space for notes.  For the baseline form, there are separate spaces for notes taken from the informant and patient 
interviews. 
There is no specified amount of time to complete the baseline form. 
 


 
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Follow-up Visits 
Part II is administered at each follow-up visit.  At each follow-up visit, the order of interviews should be the same for all 
participants, with all subjects being interviewed first or, alternatively, all informants being interviewed first. 
After completing the interviews, the clinician records the clinical impression of change on a 7-point Likert-type scale 
(from marked improvement to marked worsening).  The ADCS-CGIC is a rating of change and not of severity.  The 
clinician may refer to the baseline data in Part I. 
The clinician, alone, must make decisions about change, without consulting other staff.  The clinician should avoid 
asking opinions of the interviewee, which may contaminate the ratings, such as opinions regarding change in symptoms 
or side effects.  At the beginning of the interview, the clinician may wish to caution the informant to refrain from 
mentioning this information. 
The time allotted for the subsequent ratings of change is 20 minutes each per subject or information interview.  This time 
was chosen on the basis of the mean time reported by clinicians who often assess clinical change. 
 
References: 
Ferris SH, Mackell JA, Mohs R, Scheider LS, Galasko D, Whitehouse P, et al. A multicenter evaluation of new treatment 
efficacy instruments for Alzheimer’s disease clinical trials: overview and general results. Alz Dis Assoc Dis. 
1997;11(Suppl 2):S1-S12. 
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg, B, et al. Validity and reliability of the Alzheimer’s 
Disease Cooperative Study-Clinical Global Impression of Change. Alzheimers Dis Assoc Disord 1997;11 (Suppl 
2):S22-S52. 
 
 
 


 
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Appendix 6.  
Neuropsychiatric Inventory-Questionnaire (NPI-Q) 
 
The NPI-Q is designed to be a self-administered questionnaire completed by informants about patients for whom they 
care.  Each of the 12 NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain.  Initial 
responses to each domain question are "Yes" (present) or "No" (absent).  If the response to the domain question is "No", 
the informant goes to the next question.  If "Yes", the informant then rates both the Severity of the symptoms present 
within the last month on a 3-point scale and the associated impact of the symptom manifestations on them (i.e. Caregiver 
Distress) using a 5-point scale.  The NPI-Q provides symptom Severity and Distress ratings for each symptom reported, 
and total Severity and Distress scores reflecting the sum of individual domain scores.   
 
Most informants will be able to complete the NPI-Q in 5 minutes or less.  It is recommended that responses to the NPI-Q 
be reviewed for completeness by a clinician and for clarifying uncertainties after each administration.  The first time an 
informant completes the NPI-Q, it may be useful to verbally review the instructions.  In some instances, it may be 
necessary to conduct the NPI-Q in part or entirely as an interview. 
Questions 
1. Delusions: Does the patient have false beliefs, such as thinking that others are stealing from him/her or planning to 
harm him/her in some way? 
2. Hallucinations: Does the patient have hallucinations such as false visions or voices? Does he or she seem to hear 
things that are not present? 
3. Agitation/Aggression: Is the patient resistive to help from others at times, or hard to handle? 
4. Depression/Dysphoria: Does the patient seem sad or say that he/she is depressed? 
5. Anxiety: Does the patient become upset when separated from you?  Does he/she have any other signs of nervousness 
such as shortness of breath, sighing, being unable to relax, or feeling excessively tense? 
6. Elation/Euphoria: Does the patient appear to feel too good or act excessively happy? 
7. Apathy/Indifference: Does the patient seem less interested in his/her usual activities or in the activities/plans of 
others? 
8. Disinhibition: Does the patient seem to act impulsively, for example, talking to strangers as if he/she knows them, or 
saying things that may hurt people’s feelings? 


 
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9. Irritability/Lability: Is the patient impatient and cranky? Does he/she have difficulty coping with delays or waiting 
for planned activities? 
10. Motor Disturbance: Does the patient engage in repetitive activities such as pacing around the house, handling 
buttons, wrapping string, or doing other things repeatedly? 
11. Nighttime Behaviors: Does the patient awaken you during the night, rise too early in the morning, or take excessive 
naps during the day? 
12. Appetite/Eating: Has the patient lost or gained weight, or had a change in the type of food he/she likes? 
Reference: 
Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation of the NPI-Q, a brief clinical 
form of the neuropsychiatric inventory. J Neuropsychiatry Clin Neurosci. 2000 Spring;12(2):233-239. 
 
 
 


 
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Appendix 7.  
Savonix 8 Mobile Application: Overview  
 
Savonix Mobile is a battery of digitized neurocognitive assessments delivered via HIPPA and COPPA 
compliant Android and iOS mobile operating systems and supported by a web-based client dashboard system for 
data tracking and analytics.   
 
Savonix Mobile provides a screening tool for markers of multiple domains of cognitive and emotional 
function that are impaired in a wide range of mental health problems.  Savonix Mobile delivers tests that are 
capable of assessing function in 14 cognitive and emotional domains: 
• Verbal Memory (Immediate) 
• Verbal Memory (Delayed) 
• Impulse Control 
• Focus 
• Sustained Attention 
• Emotion Regulation 
• Emotion Recognition 
• Information Processing Speed 
• Cognitive Flexibility 
• Working Memory 
• Executive Function 
• Visual Spatial Memory 
• Decision Making (Risk Taking/Loss Aversion Scale) 
• Emotionality (Positivity/Negativity Bias) 
 
Features of Savonix Mobile 
Age-Gated and Color-Blind versions 
Modified versions of the Savonix Mobile accommodate children and color-blind individuals. 
 
Savonix Mobile Assessment Administration 
Within the application, users are presented with a short demographics questionnaire to establish factors such as 
identity, gender, age and education level to provide normative/percentile scores in the results section.  A brief screen is 
presented that demonstrates how to take the Savonix Mobile assessment and gives the user instructions to follow to 
begin the assessment.  In addition to written instructions, audio instructions are available for the user to toggle on and 
off.   
Users are informed that they may take short breaks between tasks but may not exit the app until the entire assessment is 
complete. 
A practice condition precedes each task to give the user a chance to learn the interface before scoring begins.  Before 
each task, countdown screens are used to prepare the user to begin. 
 
Repeat Assessment 
Savonix Mobile uses parallel forms of configurable tasks as a built-in method for controlling for practice effects 


 
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across repeat administrations.  Pseudorandomization of remaining tasks ensures that the same test is not 
repeated for the same user.   
 
Savonix Mobile Task 
Parallel Forms 
Verbal Memory Recognition 
3 
Go / No-Go Task 
Randomized 
Verbal Interference 
Randomized 
N-back Task 
Randomized 
Emotion Identification 
Randomized 
Trailmaking Task 
6 
Maze Task 
6 
Complex Figure Copy 
3 
Digit Span 
Randomized 
 
Reporting 
Scores will be provided directly to the CRO for data analysis via a CSV file that includes each user’s demographic 
information, performance across domains on each administration of Savonix Mobile, raw trial-by-trial data, as well 
as descriptive means and variances of response times, correct and incorrect responses, and completion times for 
applicable tasks.  Scores will not be available to subjects or study staff.  To support quality data collection, 
statistics regarding whether tests were completed or not will be provided to study staff on an ongoing basis. 
 
Description of Savonix Mobile Tasks 
Verbal Memory Recognition Task 
This task measures immediate and delayed verbal learning.  Users are presented with a list of words, which they are 
asked to memorize and later recognize from memory.  Words are closely matched on concreteness, length, and 
frequency of use.  After the memorization period, the user is asked to recognize as many words from the list as possible 
from a series of words, comprised of listed words and foil words.  A delayed memory recognition trial is completed 
approximately 30 minutes later after a number of intervening tasks.  The outcome variables are the number of words 
correctly and incorrectly recognized across the immediate and delayed trials. 
 
Go / No-Go Task 
This task measures impulse control.  A green circle is presented frequently (Go) and a red square infrequently (No-Go) 
on the screen.  The user is required to inhibit the screen tap responses on the square and tap quickly on the circle when 
presented.  This task measures target detection rate; response time and errors of commission and omission.  It is used to 
assess the capacity for suppressing well-learned, automatic responses.  The outcome variables are the number correct and 
incorrect responses, and response times for correct and incorrect responses. 
 
Verbal Interference Task 
This task taps the ability to inhibit automatic and irrelevant responses as a measure of focus.  The user is presented with 
colored words, one at a time.  Each word is drawn from the following set of words: red, yellow, green and blue.  Below 
each colored word is a response pad with the four possible colors displayed in black and in fixed format.  The test has 
two parts.  In trial 1, the user is required to identify the name of each word as quickly as possible.  In trial 2, the user is 
required to name the color each word is printed in on the screen as quickly as possible.  Each part lasts for 1 minute.  


 
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Responses are made on the screen by tapping the appropriate color word on the touch screen.  The outcome variables are 
the number of correct responses and response times compared between the two trials. 
 
N-Back Task 
This is a measure of sustained attention in a continuous performance task.  Users are presented with a sequence of 
stimuli on the screen and asked to indicate when the current stimulus matches the one from n steps earlier in the 
sequence.  The load factor n can be adjusted to make the task more or less difficult.  1-N means that you have to 
remember the position of the item, ONE turn back.  2-N means that you have to remember the position of the item TWO 
turns back, and so on.  A 1-back is used in the child’s version of the assessment, and a 2-back is used in the adult 
version.  The outcome variables include response times and number correct and in correct. 
 
Emotion Identification Task 
This is test of emotional recognition.  Users are presented with a series of faces with different emotional expressions (i.e. 
surprise, fear, disgust, happy, sad, neutral).  Users tap a button on the touch screen to correctly match the name of the 
emotion expressed on the face for each trial in the test.  The goal is to identify the correct emotional expression presented 
by the faces.  The outcome variable is the total correct versus incorrect and the response time for each face presented. 
 
Trail Making Task 
Part 1 of this task is a measure of visual scanning and information processing speed.  The user is presented with a pattern 
of 13 numbers (1-13) on the screen and is required to touch numbers in ascending sequence (i.e., 1, 2, 3…).  As each 
number is touched in correct order, a line is drawn automatically to connect it to the preceding number or letter in the 
sequence.  This allows the user to visualize the path touched.  The outcome variable is time to completion as well as 
number of correct responses versus incorrect responses. 
 
Part 2 of this task is a measure of cognitive flexibility and attention switching.  The user is presented with a pattern of 13 
numbers (1-13) and 12 letters (A-L) on the screen and is required to touch numbers and letters alternatively in ascending 
sequence (i.e.  1, A, 2, B, 3, C...).  As each number or letter is touched in correct order, a line is drawn automatically to 
connect it to the preceding number or letter in the sequence.  This allows the user to visualize the path touched.  The 
outcome variable is time to completion as well as number of correct responses versus incorrect responses in comparison 
with results from Trail Making Part 1. 
 
Maze Task 
This task is used as a measure of working memory and executive function.  The user is presented with a 6x6 grid of tiles 
on the device screen.  The object of the task is to identify the hidden path through the grid, from the beginning point at 
the bottom of the grid to the end point at the top.  The user is able to navigate around the grid by tapping on individual 
tiles in the grid.  The hidden path must be discovered in order by tapping on consecutive tiles.  A total of 15 correct 
moves are required to complete the maze.  The user is presented with a green “check mark” if they make a correct move, 
red “x” if they make an incorrect move, and a blue “?” if they have tapped out of order.  The task serves to assess how 
quickly the user learns the route through the maze and their ability to remember that route.  One maze is presented across 
two trials to assess for learning between trials.  The outcome variable is the total number of correct responses versus 
errors and time to completion. 
 
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This task is a measure of visual spatial memory.  Users are required to view and memorize a complex figure made of 
lines and shapes.  Then they are asked to reproduce the figure from memory by drawing lines and dragging shapes on the 
touchscreen device.  Each shape has foils that are similar but not identical to the original shape.  Incorrect lines, omitted 
lines, incorrect shapes, and omitted shapes each count as errors.  The outcome variable is accuracy of the reproduced 
figure against the original figure, as measured by errors versus correct features. 
 
Digit Span Task 
This task is used as a measure of attention and working memory.  The Forward Digit Span task consists of a number of 
trials in which a series of digits are presented at a constant rate on the device screen.  Immediately after each trial, the 
user is required to enter the digits on a keypad in the order in which they were flashed.  In the Reverse Digit Span task, 
the user is required to enter the digits in reverse order.  Sequence length varies between three and ten, with two trials for 
each length and with trials presented in ascending sequence order.  The task ends when the participant fails 2 trials of 
any sequence length or when all trials are completed.  The outcome variables are the longest sequence lengths correctly 
completed forwards and backwards.   
 
Additional Reading  
 
Clark CR, Paul RH, Williams LM, Arns M, Fallahpour K, Handmer C, et al. Standardized assessment of cognitive 
functioning during development and aging using an automated touchscreen battery. Arch Clin Neuropsychology. 
2006;21:449-467. 
Mathersul D, Palmer D, Gur R, Gur R, Cooper N, Gordon E, et al. Explicit identification and implicit recognition of 
facial emotions: II. Core domains and relationships with general cognition. J Clin Exp Neuropsych. 2009;31(3):278-
291.  
Paul RH, Haque O, Gunstad J, Tate DF, Grieve SM, Hoth K, et al. Subcortical hyperintensities impact cognitive 
function among a select subset of healthy elderly. Arch Clin Neuropsych. 2005;20(6): 697-704. 
Paul RH, Gunstad J, Cooper N, Williams LM, Clark R, Cohen RA, Lawrence JJ, et al. Cross-cultural assessment of 
neuropsychological performance and electrical brain function measures: additional validation of an International 
brain database. Int J Neurosci. 2007;117:549-568. 
Rowe D L, Cooper NJ, Liddell BJ, Clark RC, Gordon E, Williams LM. Brain structure and function correlates of 
General and Social Cognition. J Integ Neurosci. 2007;6(1):35-74. 
Williams L, Mathersul D, Palmer D, Gur R, Gur R, Gordon E. Explicit identification and implicit recognition of facial 
emotions:  I. Age effects in males and females across 10 decades. J Clin Exp Neurospsych. 2009;31:257-277. 


 
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Appendix 8.  
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
 


 
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17 
SCHEDULE OF EVENTS 
 
 
 


 
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Notes:  *To be performed during screening period after all other criteria have been met. Transthoracic echocardiogram and MRI may be 
performed in either order, but prior to the optional PET Scan. The optional PET Scan should only be performed after all screening 
procedures have been completed, and the subject meets criteria for inclusion. 
  
X1: to be performed prior to infusion start. 
  
X2: to be performed after infusion. 
  
a: Screening, Baseline, and EOS/ET visits may be split to allow for sufficient time to complete all procedures. AEs and concomitant 
medications should be reviewed during split visits, as applicable. 
  
b: The treatment window is 5 + 1 days. If study treatment is administered over a period of 6 days, then Visits 8 and/or 16 may occur 1 
day later. The visit window for Visit 11 is Day 85 ± 7 days; visits 12-16 should follow consecutively. 
  
c: includes all comprehensive labsf, infectious serology (HIV, hepatitis B, hepatitis C), cobalamin (vitamin B12) level, pyridoxine 
(vitamin B6) level, thiamine (vitamin B1) level, thyroid-stimulating hormone (TSH) level, direct antiglobulin test, RBC antibody 
screen, brain natriuretic peptide (BNP), serum IgA, haptoglobin, and C1 inhibitor. 
Urine drug screen: cannabinoids, benzodiazepine, barbiturates, opiates, cocaine, amphetamines, methadone, phencyclidine. 
Urinalysis: urine protein, UPCR.  
  
d: includes all comprehensive labsf, infectious serology, direct antiglobulin test, RBC antibody screen. 
  
e: Samples for i-STAT labs should be collected and results interpreted PRIOR to infusion start. Using i-STAT Chem-8+ cartridge: 
sodium (Na), potassium (K), chloride (Cl), total carbon dioxide (TCO2), anion gap, ionized calcium, glucose, urea nitrogen 
(BUN)/urea, creatinine (Crea), hematocrit, hemoglobin.  
  
f: comprehensive labs: alkaline phosphatase (ALP), ALT (SGPT), amylase, AST (SGOT), bicarbonate, bilirubin (direct, indirect, and 
total), ionized calcium, chloride, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), creatinine kinase (CK or 
CPK), creatinine, gamma-GT (GGT), glucose (random), iron, lactate dehydrogenase (LDH or LD), lipase, magnesium, phosphate, 
potassium, protein total, sodium, triglycerides, blood urea nitrogen (BUN), eGFR, albumin, aPTT, PT, INR, complete blood count 
(CBC) with differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils). 
Urinalysis: blood, glucose, ketone, protein, pH, specific gravity, nitrite, leukocytes, bilirubin, urobilinogen, urine creatinine, urine 
albumin, albumin/creatinine ratio, urine sodium, sodium/creatinine ratio, urine potassium, potassium/creatinine ratio, and reflex urine 
microscopy if indicated. 
  
g: interim safety labs: blood creatinine, BUN, eGFR. Note: Subjects randomized prior to August 30, 2018, will not participate in the 
additional interim safety labs at Visit 9 and Visit 17. 
  
h: Window for completing the MRI is Visit 8 + 4 days. 
  
i: In consenting, eligible subjects, the optional lumbar puncture should be performed at any time during the Baseline Visit window. 
The second (final) lumbar puncture should be performed within 5 days following the final dose. 
 
 


 
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18 
REVISION HISTORY 
Protocol Version 7.0 dated 02NOV2018 
Replaces: Protocol Version 6.0 dated 12OCT2018 
In this table, changes from Version 6.0 dated 12OCT2018 are described and their rationale is given. 
Location 
Description 
Purpose 
Throughout 
Protocol Version previously read: 
v6.0_12OCTMAR2018 
 
Now reads: v7.0_02NOV2018 
Version control. 
 
 
 
 
 
 
   
 
 
 
 
 
Throughout 
Grammar and style changes 
For protocol clarity and standardization. 
List of 
Definitions, 
Protocol 
Summary 
The Infusion Period will be now be between 2 hours to 
a maximum of 3 hours. 
The Infusion Period was previously 
increased to from 2.0 to 2.5 hours to 2.5 
to 3 hours; to maintain blinding and 
continuity, all patients will now be 
infused between 2 hours to a maximum of 
3 hours. 
Protocol 
Summary, 4.1 
Description of 
the Study 
Design 
Extension of study duration to ~19 months was 
reverted to ~15 months and recruitment period of ~12 
months was reverted to ~8 months. 
Study duration and recruitment period 
were decreased as additional subjects will 
not be needed 
 
2.2 Rationale  
Text content and Table 1 changed to reflect revised 
dosing. 
Required changes 
 
 
7.3.3 
Randomization, 
10.5 Sample 
Size 
The following sentence was added to both sections, 
“Subjects who are randomized but do not receive any 
dose of the study agent, may be re-screened and 
randomized if they meet all of the study eligibility 
requirements.” 
Content added to clarify potential re-
screening for eligible subjects. 
17 Schedule of 
Events 
Note “c”: removed propoxyphene from urine drug 
screen. 
Screening for this substance is not 
required. 
 
 
 
 


 
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Protocol Version 6.0 dated 12OCT2018 
Replaces: Protocol Version 5.0 dated 30AUG2018 
In this table, changes from Version 5.0 dated 30AUG2018 are described and their rationale is given. 
Location 
Description 
Purpose 
7.3 Study 
Schedule / 
17 Schedule 
of Events 
• 
Amended the Study Schedule and Schedule of Events 
to include i-STAT labs on V4, V6, V8, V12, V14, and 
V16. 
• 
Amended the Study Schedule and Schedule of Events 
to include the following per Clarification Memo #4: 
“Note: subjects randomized prior to August 30, 2018, 
will not participate in the additional interim safety labs 
at Visit 9 and Visit 17.” 
• 
Added i-STAT lab evaluations for 
increased safety monitoring after 
FDA request. 
• 
Per Protocol V5.0 (30AUG2018), 
blood samples are to be collected at 
Visit 9 and Visit 17 for interim safety 
labs. However, subjects who were 
randomized prior to August 30, 2018, 
will not participate in the additional 
interim safety labs at Visit 9 and 
Visit 17 since they will be following 
the previous protocol version.  
 
Protocol Version 5.0 dated 30AUG2018 
Replaces: Protocol Version 4.0 dated 27MAR2018 
In this table, changes from Version 4.0 dated 27MAR2018 are described and their rationale is given. 
Location 
Description 
Purpose 
Title Page, Protocol 
Approval Page, 1.1 
Authorized 
Representative 
(Signatory) / 
Responsible Party 
Updated Sponsor’s mailing address and 
authorized representative. 
Administrative. 
Throughout 
Protocol Version Previously read: 
v4.0_27MAR2018 
 
Now reads: v5.0_30AUG2018 
Version control. 
 
 
 
 
 
  
 
 
 
  


 
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Location 
Description 
Purpose 
List of Definitions / 
Protocol Summary 
Extended the Infusion Period to be a maximum 
of 3 hours. 
Infusion rates will be adjusted such that 
the Infusion Period will be of 
approximately the same duration for all 
doses (e.g., 100 mL, 250 mL, 
 
). 
Protocol Summary, 
4.2.2 Secondary 
Endpoints, 7.1.1.2 
Procedures to Assess 
Safety  
Moved the following from list of exploratory 
endpoints to secondary safety endpoints: 
“Changes on MRI scans designed to assess for 
Amyloid Related Imaging Abnormalities 
(ARIA)” and updated other sections of the 
Protocol accordingly. 
Evaluating changes on MRI scans to 
assess for ARIA is a secondary safety 
endpoint.  
Protocol Summary, 4.1 
Description of the 
Study Design 
Extended study duration to ~19 months. 
To account for extended recruitment 
period to enroll an additional 20 subjects. 
2.2 Rationale 
Incorporated isometric scaling as rationale for 
human dosage levels. 
Isometric scaling may be the most likely 
to accurately estimate the human potential 
effective dose. 
4.1 Description of the 
Study Design, 5.4.2 
Handling of Participant 
Withdrawals or 
Termination, 7.3.7 
Early Termination 
Updated language to clarify that subjects who 
have received at least one dose of GRF6019 but 
withdraw/terminate from the study early may be 
invited to complete the end of study procedures.  
 
To clarify that end of study procedures do 
not need to be completed for subjects who 
terminate from the study prior to initial 
dosing (e.g. Visit 3).  
5.1 Inclusion Criteria, 
7.1.1.1.11 
Echocardiogram 
Removed the upper limit for systolic ejection 
fraction.  Subjects will be eligible for inclusion 
if they have a systolic ejection fraction that is 
greater than or equal to 55% and no other 
clinically significant abnormalities are noted. 
Unless there is evidence of cardiac 
pathology on echocardiography, an 
elevated ejection fraction is not a safety 
concern.  Echocardiography will be used 
at screening to exclude subjects with an 
ejection fraction of less than 55% and 
subjects with other echocardiographic 
abnormalities, including impaired 
diastolic function (e.g. impaired diastolic 
relaxation) or hypertrophic 
cardiomyopathy.   
5.2 Exclusion Criteria 
Previously read:  
• 
Heart disease (or history thereof), as 
evidenced by myocardial infarction, 
unstable, new onset or severe angina, or 
congestive heart failure (New York 
Association Class II, III or IV) in the 6 
months prior to dosing; uncontrolled high 
blood pressure (systolic blood pressure of 
160 mmHg or higher and/or diastolic blood 
pressure of 100 mmHg or higher) despite 
treatment during the 3 months prior to 
Protocol clarity and standardization. 
 
Addition of exclusion criterion for 
subjects with treatment-refractory 
hypertension because such subjects may 
be more likely to experience a 
hypertension during GRF6019 infusions. 


 
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Location 
Description 
Purpose 
dosing. 
 
Now reads: 
• 
Heart disease, including myocardial 
infarction, unstable, new onset or severe 
angina, or congestive heart failure (New 
York Association Class II, III or IV) in the 
6 months prior to dosing;  
• 
Poorly controlled high blood pressure 
(systolic blood pressure of 160 mmHg or 
higher and/or diastolic blood pressure of 
100 mmHg or higher) despite treatment 
during the 3 months prior to dosing, or 
treatment refractory high blood pressure, 
defined as treatment requiring 3 or more 
antihypertensives from different classes. 
5.2 Exclusion Criteria, 
7.5 Prohibited 
Medications, 
Treatments, and 
Procedures 
Removed typical and atypical antipsychotics 
from the list of prohibited medications.  
 
Determined that typical and atypical 
antipsychotics would not have a 
significant impact on cognition, therefore 
concurrent use is allowed.  
5.2 Exclusion Criteria 
Previously read: Any major psychiatric 
disorder including psychosis, claustrophobia, 
major depression or bipolar disorder, and/or 
alcohol/substance dependency. 
 
Now reads: A history of a major psychiatric 
disorder diagnosed before the onset of AD, 
including schizophrenia, major depression or 
bipolar disorder, and/or alcohol/substance 
dependency.  Psychiatric symptoms that occur 
in the context of AD (e.g. psychosis, irritability, 
depression) are not exclusionary unless the PI 
believes they could interfere with study 
procedures. 
Protocol clarity and standardization. 
5.4.1 Reasons for 
Withdrawal or 
Termination 
Removed the following bullet point: “Treatment 
with a prohibited concomitant medication other 
than the use of appropriate medications for the 
treatment of AEs under direction of the 
investigator.” 
Treatment with a prohibited concomitant 
medication will be considered on a case-
by-case basis as a reason for withdrawal 
or termination, but not result in automatic 
subject withdrawal.  
5.4.1 Reasons for 
Withdrawal or 
Termination 
Removed “or change in trial partner” to reflect 
Protocol Clarification Memo #3. 
Protocol clarity and standardization. 
5.5 Premature 
Termination or 
Amended to state that the Sponsor reserves the 
right to terminate the study at any time and 
To clarify that the Sponsor, not the 
investigator, may terminate the study; 


 
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Location 
Description 
Purpose 
Suspension of Study 
included minor updates to the list of potential 
reasons for study or site termination. 
investigators may terminate the study at 
their site at any time.  
7.1.1.1 Screening 
Procedures, 17 
Schedule of Events 
Modified to reflect that the echocardiogram and 
MRI performed at screening may be completed 
in either order after all other screening 
procedures have been completed. 
To enhance feasibility, as the sequence of 
these procedures is inconsequential. 
7.1.1.2.1 Review of 
Adverse Events 
 
Previously read: AEs will be reviewed, 
documented, and reported as required at each 
visit, beginning at baseline.  
 
Now reads: AEs will be reviewed, documented, 
and reported as required at each visit. 
Modified to reflect that AEs and 
concomitant medications may need to be 
assessed during split screening visits, as 
applicable. 
3 Objectives and 
Purpose, 7.1.1.1.13 
Magnetic Resonance 
Imaging, 7.2.2.3 
Magnetic Resonance 
Imaging 
Amended to reflect Protocol Clarification 
Memos #1 and #2.  
Protocol clarity and standardization. 
7.3 Study Schedule 
Previously read: Visit windows (when noted) 
should be benchmarked relative to the baseline 
visit for a subject, such that subjects complete 
the entire study by Day 168 (±7 days). 
 
Now reads: Visit windows (when noted) should 
be benchmarked relative to Visit 3 for a subject, 
such that subjects complete the entire study by 
Day 168 (±7 days). 
Protocol clarity; Visit 3 corresponds to 
Day 1.  
7.3.1 Screening, 17 
Schedule of Events 
Clarified that AEs and concomitant medications 
should be collected during split visits, as 
applicable. 
Protocol clarity and standardization. 
7.3.4. Treatment, 17 
Schedule of Events 
Added a ± 7-day window for Visit 85. 
To enhance protocol feasibility. 
7.3.4. Treatment, 7.3.5 
Follow-Up, 17 
Schedule of Events 
Modified the schedule for collecting STAT 
safety laboratory samples. 
Based on data from 24 subjects dosed, no 
clinically significant changes in Na, K, 
Ca, creatinine, or hematocrit have been 
detected during the dosing period. 
Therefore, the frequency of pre-infusion 
i-STAT lab monitoring has been reduced 
to every other day during each dosing 
period. 
7.3.5 Follow-Up, 17 
Schedule of Events 
Added interim safety labs (blood creatinine, 
blood urea nitrogen, and glomerular filtration 
rate) at Visits 9 and 17. 
To more precisely evaluate potential 
changes in creatinine levels kidney 
function over time.  
8 Assessment of Safety 
Amended the Safety Section to clarify reporting 
For protocol clarity and standardization. 


 
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Location 
Description 
Purpose 
requirements for SAEs, AESI, and pregnancy. 
8.2.2 Relationship to 
Study Agent 
Previously read: Final assessment of causality 
will be made by the Sponsor. 
 
Now reads: If either the investigator or the 
Sponsor considers the event related, then the 
event will be considered related for reporting 
purposes. 
Sponsor decided to use a more 
conservative approach to causality 
determination. 
8.4.3 Adverse Events 
of Special Interest 
Previously read: 
• 
AEs related to increased blood volume or 
shifts of fluid between the intravascular and 
extravascular space 
• 
Suspected transmission of blood-borne 
infectious agents 
 
Now reads:  
• 
Clinically-significant peripheral edema or 
pulmonary edema.  
• 
Systolic blood pressure (BP) <90 or >160 
mm Hg and/or diastolic BP <60 or >100 
mm Hg, or a change of >25% from Day 1 
(Visit 3) pre-infusion in systolic and/or 
diastolic BP.   
• 
Reduced kidney function (eGFR < 45 
mL/min/1.73 m2).  
• 
Suspected transmission of blood-borne 
infectious agents. 
Protocol clarity and standardization. 
8.5 Study Halting 
Rules 
Modified to state that if a Safety Evaluation 
Meeting is triggered, dosing may be temporarily 
halted. 
Depending on the reason for the Safety 
Evaluation Meeting, dosing may or may 
not need to be halted. 
9 Clinical Monitoring 
Minor updates and clarifications. 
To align with study plans and processes. 
10.4.5 Adherence and 
Retention Analyses 
Removed the “overall trial partner survey” as a 
measure of feasibility. 
Currently, there is no plan to administer 
an overall trial partner survey as an 
assessment of feasibility. 
12.3.1 Consent/Assent 
and Other 
Informational 
Documents Provided to 
Participants 
Removed CSF Consent Form (optional). 
A separate ICF has not been utilized.  
Rather, the main ICF includes a 
description of the optional CSF collection 
procedure and a separate signature line 
for subjects/LARs to provide informed 
consent for the optional procedure.   
13.3 Protocol 
Deviations 
Amended the definitions of Major and Minor 
Protocol Deviations. 
Modified to align with Sponsor’s 
definitions. 
15 Literature 
References 
Updated the following references to most recent 
versions: Alzheimer’s Association 2018, 
 
Administrative. 


 
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Location 
Description 
Purpose 
 
 
 
 
Protocol Version 4.0 dated 27MAR2018 
Replaces: Protocol Version 3.1 dated 21FEB2018 
In this table, changes from Version 3.1 dated 21FEB2018 are described and their rationale is given. 
Location 
Description 
Purpose 
7.2.3 
Specimen 
Preparation, 
Handling, 
Storage, and 
Shipping  
Removed reference to laboratory manual addendum. 
Standard and specialty lab specimen 
preparation, handling, storage, and 
shipping procedures are described in the 
body of the laboratory manual. 
7.3 Study 
Schedule / 
17 Schedule 
of Events 
Amended the Study Schedule such that STAT labs will only 
be performed on V3-6, V8, V11-14, and V16. 
Removed the STAT labs on V7/V15 to 
reduce subject burden without 
compromising safety. 
Throughout 
Clarified that the optional CSF collection will only be 
performed at participating sites. 
For protocol clarity, as not all sites will 
perform this optional procedure. 
Throughout 
Changed all references to the GRF6019 Infusion 
Administration Guidelines to reflect the actual document 
title: Infusion Administration Manual. 
For protocol clarity. 
Throughout 
Protocol Version Previously read: v3.1_21FEB2018 
 
Now reads: v4.0_27MAR2018 
Version control. 
 
Protocol Version 3.1 dated 21FEB2018 
Replaces: Protocol Version 3.0 dated 16FEB2018 
In this table, changes from Version 3.0 dated 16FEB2018 are described and their rationale is given. 
Location 
Description 
Purpose 
5.2 Exclusion 
Criteria 
Previously read: Clinically significant abnormalities 
on screening electrocardiogram (ECG) including QTc 
intervals (using Fridericia’s correction formula) of ≥ 
Modified to be less restrictive. 


 
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Location 
Description 
Purpose 
430 ms in men and ≥ 450 ms in women. 
 
Now reads: Clinically significant abnormalities on 
screening electrocardiogram (ECG) including QTc 
intervals (using Fridericia’s correction formula) of ≥ 
450 ms in men and ≥ 470 ms in women. 
7.3 Study Schedule / 
17 Schedule of 
Events 
Extended the visit window for Visit 8 MRI, such 
that the MRI may be performed at Day 6 + 4 days. 
To enhance protocol feasibility. 
Throughout 
Protocol Version Previously read: 
v3.0_16FEB2018 
 
Now reads: v3.1_21FEB2018 
Version control. 
 
Protocol Version 3.0 dated 16FEB2018 
Replaces: Protocol Version 2.0 dated 09NOV2017 
In this table, changes from Version 2.0 dated 09NOV2017 are described and their rationale is given. 
Location 
Description 
Purpose 
List of Definitions 
Specified that the Outcomes Assessor is responsible for 
monitoring subjects before, during, and after the infusion 
period.  
For protocol clarity and 
standardization. 
5.1 Inclusion 
Criteria 
Previously read: Willing to spend up to 6 nights in an 
inpatient study observation unit during both dosing 
periods. 
 
Now reads: Willing to spend up to 7 nights in an 
inpatient study observation unit during both dosing 
periods. 
To account for new treatment visit 
window. 
5.2 Exclusion 
Criteria 
Added exclusion criteria pertaining to the C-SSRS 
administered at screening.   
Subjects reporting active suicidal 
ideation with at least some intent to 
act in the past 6 months will be 
excluded from the trial for safety 
reasons.   
5.2 Exclusion 
Criteria 
Previously read: Prior hypersensitivity reaction to any 
human blood product or intravenous infusion; any 
known drug allergy. 
 
Now reads: Prior hypersensitivity reaction to any human 
blood product or intravenous infusion; any known 
clinically significant drug allergy. 
Modified to be less restrictive, such 
that subjects with drug allergies 
deemed not clinically significant who 
meet all other eligibility criteria may 
be enrolled. 
7.3.3 
Added section to the Study Schedule so that 
To allow sites flexibility as to when 


 
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Randomization 
randomization may occur any time after 
confirmation of eligibility (following Baseline) but 
prior to the subject’s first infusion on Visit 3.  
Included a recommendation to randomize subjects 
at the start of Visit 3, as this may reduce the risk of 
randomizing a subject to treatment who 
discontinues/withdraws prior to Visit 3. 
randomization occurs.   
 
7 Study 
Procedures and 
Schedule / 17 
Schedule of 
Events 
UPCR to be performed at screening ONLY. Added 
the following urine tests as part of comprehensive 
labs: albumin/creatinine, sodium/creatinine, and 
potassium/creatinine. Removed stat urinalysis and 
amended the tests performed as part of the 
urinalysis for comprehensive labs.  
Added additional testing for safety. 
Determined that stat urinalysis would 
not be necessary for guiding dosing 
decisions.  
7 Study 
Procedures and 
Schedule / 17 
Schedule of 
Events 
Added a targeted physical exam prior to dosing on 
Visits 3-7 and 11-15; and prior to discharge on V8 
and V16. 
To assess for safety. 
7 Study 
Procedures and 
Schedule / 17 
Schedule of 
Events 
Fasting lab samples are preferred for all visits 
except screening; amended the order of procedures 
on applicable visits accordingly. 
Fasting samples are preferable for 
proteomics. 
7 Study 
Procedures and 
Schedule / 17 
Schedule of 
Events 
Added ECGs to V7 (after dosing), V11 (prior to 
dosing), and V15 (after dosing).  
To assess for safety.  
7 Study 
Procedures and 
Schedule / 17 
Schedule of 
Events 
Added weight measurements prior to dosing on 
Visits 3-7 and 11-15; and prior to discharge on V8 
and V16. 
To assess for fluid retention during 
dosing based on changes in weight. 
7.3 Study 
Schedule / 17 
Schedule of 
Events 
Removed NPI-Q from Visits 8 and 16.  
Do not expect the NPI-Q to provide 
relevant data immediately post-
inpatient. 
7 Study 
Procedures and 
Schedule 
Where applicable, added a note indicating that the 
NPI-Q may be completed by the trial partner at 
any available time during applicable visits. 
To enhance protocol feasibility.  
7.3 Study 
Schedule / 17 
Schedule of 
Events 
Added ADCS-ADL to Visits 9 and 17. 
To assess activities of daily living at 
additional timepoints. 
7.3 Study 
Added visit window for Visit 8 MRI, such that the 
To enhance protocol feasibility. 


 
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Schedule / 17 
Schedule of 
Events 
MRI may be performed at Day 6 + 2 days. 
8.5 Study Halting 
Rules 
Clarified that the Sponsor is responsible for 
deciding whether to halt the study. 
Protocol clarity and standardization. 
10.6 Measures to 
Minimize Bias 
 
 
 
13.3 Protocol 
Deviations 
Previously, protocol noncompliance was 
categorized as either a violation or deviation.  
Now, Protocol Deviations will be categorized as 
either Major or Minor.  
Protocol clarity and standardization. 
15 Literature 
References 
Added reference for MDRD for Adults 
(Conventional Units) calculator. 
To provide a resource for calculating 
MDRD. 
16 Appendices 
Added a preface to the Appendices that reads: 
Please be advised that the neurocognitive assessments in 
this section and associated information are provided as 
EXAMPLES ONLY.  The actual neurocognitive 
assessments, related source documents, and instructions 
for administration and scoring are included in the Rater 
Reference Manual.   
  
To clarify that the Appendices should 
not be the primary source of reference 
for performing the neurocognitive 
assessments.  Rather, all essential 
documents, materials, and 
instructions are provided in the Rater 
Reference Manual which is 
maintained separately from the 
protocol. 
Throughout 
Previously, subjects would receive the infusion at a 
standardized flow rate.  As a result, the interval for 
administering 100 mL was shorter than the interval for 
administering the 250 mL dose.  To maintain blinding, 
all subjects would remain connected to the IV apparatus 
for a set period of time.  
 
The Infusion Period has been modified so that all 
subjects, regardless of dose level, will receive their 
assigned dose over the course of 2 – 2.5 hours to 
maintain blinding.  Flow rates will be titrated according 
to the GRF6019 Infusion Administration Guidelines.  
Masking procedures have been updated accordingly.    
It was determined that subjects would 
likely be able to tell when their 
infusion had stopped.  Thus, the 
infusion administration and masking 
procedures were revised to maintain 
blinding.    
Throughout 
Modified applicable sections of the protocol to 
reflect the updated schedule for administering the 
C-SSRS. 
The C-SSRS will be administered at 
screening to evaluate subject 
eligibility.  The C-SSRS will be 
repeated following each dosing 
interval but prior to discharge to 
evaluate for safety.   
Throughout 
Clarified testing schedules for the Savonix full and 
brief batteries.  Updated Schedule of Events 
accordingly. 
The brief battery will be performed at 
the start of the infusion visits.  The 
full battery will be performed at all 
other visits, beginning at Baseline. 


 
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Protocol Version 2.0 dated 09NOV2017 
Replaces: Protocol Version 1.0 dated 02AUG2017 
In this table, changes from Version 1.0 dated 02AUG2017 are described and their rationale is given. 
Location 
Description 
Purpose 
Throughout 
Protocol Title Previously read: An Open Label, Multiple-
Dose Study to Assess the Safety and Tolerability of 
GRF6019 Infusions in Subjects with Mild to Moderate 
Alzheimer’s Disease (AD) 
 
Now reads: A Prospective, Randomized, Double-Blind, 
Dose-Comparison Concurrent Control Study to Assess the 
Safety and Tolerability of GRF6019 Infusions in Subjects 
with Mild to Moderate Alzheimer’s Disease (AD) 
 
Updated study design 
pursuant to direction from the 
agency 
Throughout 
Update of study design description from an open label 
multiple dose study to a prospective, randomized, double-
blind dose comparison concurrent control study 
 
Updated study design 
pursuant to direction from the 
agency 
Throughout 
Protocol Version Previously read: v1.0_02AUG2017 
 
Now reads: v2.0_09NOV2017 
 
Version Control 
Throughout 
Grammar and style changes 
For protocol clarity and 
standardization 
Throughout 
Update duration of treatment to be approximately 6 months, and 
total duration in the study to be approximately 7 months. 
 
Improved protocol clarity 
Page 8 
Measures added to ensure adequate allocation concealment.  
Added List of Definitions for Infusion Nurse, Infusion Period and 
Outcomes Assessor 
 
For clarity of updated study 
design pursuant to direction 
from the agency 
Throughout 
Added Cerebrospinal Fluid (CSF) biomarker 
analysis as an exploratory aim. Added CSF 
collection as an optional procedure. Amended 
applicable sections of the Protocol accordingly. 
To assess potential therapeutic effects 
of GRF6019 on AD biomarkers of 
neuronal death, synaptic function, 
inflammation, and growth factors. 
Throughout 
Protocol Version Previously read: 
v2.0_09NOV2017 
 
Now reads: v3.0_16FEB2018 
Version Control. 
Throughout 
Grammar and style changes 
For protocol clarity and 
standardization. 


 
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Location 
Description 
Purpose 
Protocol 
Summary/Precis 
Measures added to ensure adequate allocation concealment.  
Paragraph 3 added to summarize the infusion process and 
methods for blinding during infusion. 
 
Updated study design 
pursuant to direction from the 
agency 
2.2 Rationale, 
Paragraph 8 
Previously read: An open-label, two-arm study design has 
been selected to identify a safe and feasible dosing 
paradigm, trends in changes of neurocognitive endpoints, 
and potential plasma derived factors that may affect these 
parameters. 
 
Now reads: A prospective, randomized, double-blind, 
dose-comparison concurrent control study design has been 
selected to reduce or eliminate bias while facilitating the 
identification of a safe and feasible dosing paradigm, trends 
in changes of neurocognitive endpoints, and potential 
plasma derived factors that may affect these parameters. 
 
Updated study design 
pursuant to direction from the 
agency 
2.2 Rationale, 
Paragraph 9 
Previously read: … the results (of this trial) are 
nevertheless expected to lay the foundation for larger trials 
exploring the potential benefit of GRF6019 in AD and 
other neurodegenerative disorders typified by cognitive 
dysfunction. 
 
Now reads: … the results (of this trial) are nevertheless 
expected to lay the foundation for larger trials designed and 
powered to characterize the potential benefits of GRF6019 
in AD and other neurodegenerative disorders typified by 
cognitive dysfunction. 
 
Clarification of purpose of 
study design pursuant to 
direction of the agency 
3. Objectives and 
Purpose 
Previously read:  As an exploratory objective, serial 
compositional analysis of subject plasma will be performed 
to identify specific biomarkers… 
 
Now reads: As an exploratory objective, blood and plasma 
will be collected and analyzed to identify specific 
biomarkers… 
 
Improved protocol clarity 
4.2.2 Secondary 
Endpoints, 
Paragraph 1 
Confirmation that “This study is neither designed nor 
powered to detect statistically significant differences in 
cognitive and motor outcomes…” 
 
Clarification of purpose of 
study design pursuant to 
direction of the agency 
4.2.2 Secondary 
Endpoints 
Addition of secondary feasibility endpoint related to 
success of blinding 
Updated study design 
pursuant to direction from the 
agency 
4.2.3 Exploratory 
Endpoints 
Previously read:  Cellular samples will be recovered from 
subject’s plasma to explore epigenetic changes. 
Improved protocol clarity 


 
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Location 
Description 
Purpose 
 
Now reads: DNA will be extracted from blood samples to 
explore epigenetic changes.  
 
5.3 Strategies for 
Recruitment and 
Retention, 
Paragraph 4 
Clarification that if a trial partner does not reside within a 
reasonable distance from the inpatient facility, they will be 
given the option to stay with the subjects or to stay in a 
nearby hotel/motel. 
Improved protocol clarity 
5.4.2 Handling of 
Participant 
Withdrawals or 
Termination 
Addition that subjects who discontinue or are unblinded 
prior to Visit 8 may be replaced. 
Updated study design 
pursuant to direction from the 
agency 
6.1.3 Product 
Storage and 
Stability 
Previously read:  Partially used vials must be discarded. 
Vials which are cracked or have been previously entered or 
damaged should not be used, as this may have allowed the 
entry of microorganisms. 
 
Now reads:  Vials which are cracked or have been 
previously entered or damaged should not be used, as this 
may have allowed the entry of microorganisms. 
 
Correction to enable drug 
accountability 
6.1.4 Preparation 
Added: IV tubing should be vented,
 
  
 
Clarification 
6.1.5 Dosing 
Administration 
Measures added to ensure adequate allocation concealment. 
Section updated to include provisions for the management 
and maintenance of study blinding during dosing, including 
the use of unblinded Infusion Nurses and blinded 
Outcomes Assessors.  
 
Administration Guidelines changed from Appendix 9 to a 
stand-alone manual. 
 
Updated study design 
pursuant to direction from the 
agency 
6.2 Study Agent 
Accountability 
Measures added to ensure adequate allocation concealment. 
Addition and explanation of the role of unblinded study 
staff (study pharmacist, Infusion Nurse, CRA) in 
accountability of the study agent.   
 
Updated study design 
pursuant to direction from the 
agency 
7.1.1.2.3 Vital 
Signs 
Previously read:  Vital signs will be collected at every visit 
and at multiple time points during the infusion (Appendix 
9). 
 
Now reads: Vital Signs will be collected at every visit.  During 
infusions, vital signs will be collected within an hour of infusion 
start, every 15 minutes during the ~2.5 hour infusion period, and 
at 3 and 6 hours following conclusion of the infusion period.  
Updated for clarity of study 
procedures.  Updated for 
study design pursuant to 
direction from the agency 


 
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Location 
Description 
Purpose 
Vital signs will be collected by the blinded Outcomes Assessor.    
 
7.1.1.3.1 Savonix 
Neurocognitive 
Assessments 
Clarification that administration of the test should begin no 
later than one hour after starting the infusion. 
Improved protocol clarity 
7.2.2.2 PET; 
7.3.1 Screening, 
Visit 1 
Section updated to remove use of specific radioligand 
(Florbetapir) for PET testing.  Any radioligand will be 
accepted for this optional procedure. 
 
Parameters eased for this non-
critical test 
7.2.2.4 Proteomic 
and Genetic 
Biobanking, 
Paragraph 1 
Previously read:  Plasma and cellular samples will be 
collected… 
 
Now reads: Blood and plasma will be collected… 
Improved protocol clarity 
7.2.2.4 Proteomic 
and Genetic 
Biobanking, 
Paragraph 2 
Previously read:  Cellular samples derived from plasma 
will be retained… 
 
Now reads: Blood samples will be retained… 
 
Improved protocol clarity 
7.2.2.4 Proteomic 
and Genetic 
Biobanking, 
Paragraph 2 
Added: For information regarding future use of stored samples, 
see Section 12.5 Future Use of Stored Specimens. 
 
Updated pursuant to direction 
from the agency 
8. Assessment of 
Safety 
Added: Assessment of safety will be conducted by blinded study 
personnel except in extraordinary circumstances where 
knowledge of the dose received by a subject is essential.  Any 
instances of unblinding will be managed as indicated in Section 
10.6.3. 
 
Updated study design 
pursuant to direction from the 
agency 
8.4.3 Adverse 
Events of Special 
Interest 
Previously read:   
• 
Adverse Events related to increased blood volume 
 
Now reads: The following will be considered adverse events of 
special interest:  
• 
AEs related to increased blood volume or shifts of 
fluid between the intravascular and extravascular 
space 
• 
Suspected transmission of blood-borne infectious 
agents 
 
Expanded AESI 
8.5 Study Halting 
Rules, Safety 
Eval. Meeting 
Amended outcomes from Safety Evaluation Meeting to 
align with blinded study design.  Measures added to ensure 
adequate allocation concealment. 
 
Updated study design 
pursuant to direction from the 
agency 
8.6 Safety 
Oversight 
Updated Safety Oversight section and role of Safety 
Evaluation Meetings for blinded study design  
Updated study design 
pursuant to direction from the 


 
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Location 
Description 
Purpose 
agency 
10.1 Statistical 
and Analytical 
Plans 
Added: The finalization of the SAP will occur prior to 
clinical database lock and unblinding of the study data. 
Updated study design 
pursuant to direction from the 
agency 
10.2 Statistical 
Hypothesis 
Within-subject changes from baseline for each dosing 
group and among-group differences will (changed from 
“may”) be evaluated. 
 
Updated study design 
pursuant to direction from the 
agency 
10.4.1 General 
Approach 
Further details on the analysis of the primary and 
secondary endpoints have been clarified.  Increased 
robustness of general statistical approach regarding primary 
and secondary analysis of endpoints that are continuous as 
well as categorical.  Update to include subjects randomized 
as part of the disposition summary. 
Updated study design 
pursuant to direction from the 
agency 
10.4.3 Analysis 
of Secondary 
Endpoint(s) 
Previously read:  Among-group differences may be 
assessed by One-way Analysis of Variance or its 
nonparametric equivalent Kruskal-Wallis test. 
 
Now reads: Among-group differences may be assessed by 
One-way Analysis of Covariance (ANCOVA) or its 
nonparametric equivalent test. 
Improved protocol clarity 
10.4.7 Planned 
Interim Analyses 
Added: If such an ad hoc safety interim analysis is conducted, 
the treatment assignment will remain masked.   
 
Updated study design 
pursuant to direction from the 
agency 
10.5 Sample Size 
Updated to reflect target of 40 subjects randomized (vs. 
enrolled) 
Updated study design 
pursuant to direction from the 
agency 
10.6.1 
Enrollment/ 
Randomization/ 
Masking 
Procedures 
Section updated to address design deficiencies and 
measures to minimize bias are elucidated.   The trial 
continues to be randomized and is now designed to be 
blinded to the study subjects, sponsor, investigators, 
medical providers, and outcome assessors.  The details of 
the enrollment, randomization and masking procedures to 
minimize bias are detailed in this section, including labs. 
 
Updated study design 
pursuant to direction from the 
agency 
10.6.2 Evaluation 
of Success of 
Blinding 
Section added. 
Updated study design 
pursuant to direction from the 
agency 
10.6.3 Breaking 
the Study Blind/ 
Participant Code 
Section added. 
Updated study design 
pursuant to direction from the 
agency 
12.5 Future Use 
of Stored 
Specimens 
Amended to address potential privacy issues subjects need 
to be aware of at time of informed consent regarding future 
use of retained samples, including how confidentiality will 
be maintained, how long samples will be held by Alkahest, 
Updated pursuant to direction 
from the agency 


 
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Location 
Description 
Purpose 
how they will be used, and what happens if Alkahest 
transfers ownership to another commercial sponsor. 
19.  Revision 
History 
Addition of revision history table for Protocol Version 2.0 
dated 09NOV2017 
Version control 
 

SAP_001.pdf: 
Study Title A Prospective, Randomized, Double-Blind, Dose-Comparison 
Concurrent Control Study to Assess the Safety and Tolerability of 
GRF6019 Infusions in Subjects with Mild to Moderate Alzheimer’s 
Disease 
NCT Number NCT03520998 
Document Description Statistical Analysis Plan (Final Version 2.1) 
Document Date 09 June 2019 
 


Alkahest, Inc. 
. 
 PROTOCOL ALK6019-201 
STATISTICAL ANALYSIS PLAN 
PROTOCOL: ALK6019-201 
A Prospective, Randomized, Double-Blind, Dose-
Comparison Concurrent Control Study to 
Assess the Safety and Tolerability of GRF6019 Infusions 
in Subjects with Mild to Moderate 
Alzheimer’s Disease 
SPONSOR: 
Alkahest, Inc. 
125 Shoreway Road, Suite D 
San Carlos, CA 94070 
PRODUCT :  
GRF6019 
AUTHORS: 
 
 
Cognitive Research Corporation 
200 Central Ave. Suite 1230 
Saint Petersburg, Florida 33701 
 
 
FHL Health LLC  
6701 Democracy Blvd. Suite 300 
Bethesda, MD 20817 
DATE: 
June 09, 2019 
STATUS: 
Final Version 2.1 


 
 
 
Alkahest, Inc. 
 
. 
 
 
PROTOCOL ALK6019-201 
   
Statistical Analysis Plan: Final Version 2.1 June 09, 2019 
Page | 2 
 
Statistical Analysis Plan 
Protocol：ALK6019-201 
Final Version:2.1 
Date:  09 June 2019 
 
 
 
 
CRC REPRESENTATIVE 
DOCUMENT REVIEWED AND APPROVED BY: 
SIGNATURE: 
DATE: 
NAME: 
 
DEPARTMENT/TITLE: President, Cognitive Research Corporation 
STATISTICAL CRO REPRESENTATIVE  
DOCUMENT REVIEWED AND APPROVED BY: 
SIGNATURE: 
DATE: 
NAME: 
 
DEPARTMENT/TITLE: President, FHL Health 
SPONSOR COMPANY REPRESENTATIVE  
DOCUMENT REVIEWED AND APPROVED BY: 
SIGNATURE: 
DATE: 
NAME: 
 
DEPARTMENT/TITLE: Vice President, Clinical Development, Alkahest, Inc. 


 
 
 
Alkahest, Inc. 
 
. 
 
 
PROTOCOL ALK6019-201 
   
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TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................... 3 
AMENDMENT HISTORY ...................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................. 5 
1  INTRODUCTION ............................................................................................. 7 
1.1  Study Objectives ....................................................................................................... 7 
1.2  Study Design ............................................................................................................ 7 
1.3  Sample Size Estimation ............................................................................................ 8 
1.4  Randomization and Blinding ..................................................................................... 8 
1.5  Study Data ................................................................................................................ 9 
2  GENERAL ANALYSIS DEFINITIONS ............................................................ 9 
2.1  Treatment Groups .................................................................................................... 9 
2.2  Statistical Hypothesis Tests ...................................................................................... 9 
2.3  Study Phase, Visit, and Day ..................................................................................... 9 
2.4  Analysis Sets .......................................................................................................... 10 
2.5  Definition of Subgroups .......................................................................................... 12 
2.6  Descriptive Summaries ........................................................................................... 13 
3  PLANNED INTERIM ANALYSIS .................................................................. 13 
4  SUBJECT INFORMATION ............................................................................ 13 
4.1  Disposition Information ........................................................................................... 13 
4.2  Protocol Deviations ................................................................................................. 13 
4.3  Demographics and Baseline Characteristics .......................................................... 14 
4.3.1 
Demographic Parameters .................................................................................................. 14 
4.3.2 
Baseline Assessment of Modified Hachinski Ischemia Scale (MHIS) ............................... 14 
4.3.3 
Baseline Assessment of Columbia-Suicide Severity Rating Scale (C-SSRS) .................. 14 
4.3.4 
APOE Genotype ................................................................................................................ 15 
4.4  Medical History ....................................................................................................... 15 
4.4.1 
Subject Medical History ..................................................................................................... 16 
4.4.2 
Family Medical History ...................................................................................................... 16 
4.4.3 
Social History ..................................................................................................................... 16 
4.4.4 
Exercise/Activity Level ....................................................................................................... 16 
4.4.5 
Tobacco Use...................................................................................................................... 16 
4.4.6 
Alcohol and Illicit Substance Use ...................................................................................... 17 
4.5  Prior and Concomitant Medications ........................................................................ 17 
4.6  Extent of Exposure ................................................................................................. 17 
4.7  Treatment Completion ............................................................................................ 18 
4.8  Tolerability .............................................................................................................. 18 
4.9  Visit Compliance ..................................................................................................... 18 
5  EFFICACY ..................................................................................................... 18 
5.1  Mini-Mental State Examination (MMSE) ................................................................. 19 
5.2  Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS Cog/11) ....... 19 
5.3  Grooved Pegboard Test (GPT) .............................................................................. 20 
5.4  Category Fluency Test (CFT) ................................................................................. 20 
5.5  Clinical Dementia Rating Scale – Sum of Boxes (CDR-SOB) ................................ 20 


 
 
 
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5.6  Alzheimer’s Disease Cooperative Study – Activities of Daily Living 23 (ADCS-
ADL23) ............................................................................................................................ 20 
5.7  Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change 
rating (ADCS-CGIC) ........................................................................................................ 21 
5.8  Neuropsychiatric Inventory Questionnaire (NPI-Q) ................................................ 21 
6  SAFETY ........................................................................................................ 22 
6.1  Adverse Events ...................................................................................................... 22 
6.1.1 
Coding of AEs .................................................................................................................... 22 
6.1.2 
Treatment-Emergent AE .................................................................................................... 22 
6.1.3 
Period Allocation of AE ...................................................................................................... 22 
6.1.4 
Variables Attributed to Adverse Events: ............................................................................ 23 
6.1.5 
Analysis Methods .............................................................................................................. 23 
6.2  Clinical Laboratory Evaluations .............................................................................. 24 
6.3  Vital Signs ............................................................................................................... 24 
6.4  Electrocardiogram .................................................................................................. 25 
6.5  Physical Examinations ............................................................................................ 25 
6.6  C-SSRS since Last Visit ......................................................................................... 25 
6.7  MRI Testing, Echocardiogram, and PET Scan ....................................................... 25 
7  EXPLORATORY ........................................................................................... 25 
8  CHANGES FROM PROTOCOL .................................................................... 25 
9  REFERENCES .............................................................................................. 26 
10  TABLES, LISTINGS, AND FIGURES FOR CSR APPENDIX 14 ................ 27 
11  LISTINGS FOR CSR APPENDIX 16.2 ........................................................ 31 
12  ATTACHMENTS ......................................................................................... 33 
 


 
 
 
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AMENDMENT HISTORY 
Not applicable 
LIST OF ABBREVIATIONS 
AD 
Alzheimer’s Disease 
ADAS Cog/11 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study – Clinical Global 
Impression of Change rating 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALS 
Amylotrophic lateral sclerosis 
ANCOVA 
Analysis of Covariance 
APOE 
Apolipoprotein E 
ASL 
Arterial Spin Labeling 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CDR 
Clinical Dementia Rating Scale 
CDR-SOB 
Clinical Dementia Rating Scale – Sum of Boxes 
CFT 
Category Fluency Test 
CS 
Clinically significant 
CSF 
cerebrospinal fluid 
CSR 
Clinical Study Report 
eCRF 
electronic Case Report Form 
EVAL 
Evaluable Population 
fMRI 
Functional Magnetic Resonance Imaging 
GPT 
Grooved Pegboard Test 
ITT 
Intent-to-treat 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHIS 
Modified Hachinski Ischemia Scale 
MMSE 
Mini-Mental State Examination 
NCS 
Not clinically significant 
NPI-Q 
Neuropsychiatric Inventory Questionnaire 
PPROT 
Per protocol 
SAE 
serious adverse event 
SAF 
Safety Population  
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOB 
Sum of Boxes 
TEAE 
Treatment-emergent AE 
TFLs 
Tables, Figures, and Listings 


 
 
 
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vMRI 
Volumetric Magnetic Resonance Imaging 
WHO 
World Health Organization 


 
 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses for 
the study entitled “A Prospective, Randomized, Double-Blind, Dose-Comparison 
Concurrent Control Study to Assess the Safety and Tolerability of GRF6019 
Infusions in Subjects with Mild to Moderate Alzheimer’s Disease” (V6.0 
12OCT2018, V7.0 02NOV2018). Analysis related to exploratory objectives 
(assessment of changes in composition and distribution of blood-based and CSF (in 
consenting subjects) biomarkers, as well as changes in imaging results as measured by 
vMRI, fMRI, and ASL) will be described in a separate plan. Mock shells for the 
CSR Appendix 14 are also produced as a separate working document to 
facilitate programming of Tables, Figures, and Listings (TFLs) according to the 
finalized SAP. The SAP is to be interpreted in conjunction with the protocol. If the 
final clinical study report contains changes to any planned statistical analyses, 
the justification for any such differences will be fully documented in the CSR. 
1.1 Study Objectives 
Primary Objective 
To assess the safety, tolerability and feasibility of GRF6019, a 
 human plasma 
protein fraction administered by IV infusion in subjects with mild to moderate 
Alzheimer’s Disease (AD). 
Secondary Objective 
To assess the effects of the study agent on subjects’ cognitive function. 
Exploratory Objectives 
 To identify specific biomarkers associated with cognitive functional 
changes and/or indicators of AD progression  
 To assess the potential therapeutic effects of GRF6019 on AD biomarkers 
of neuronal death, synaptic function, inflammation, and growth factors 
utilizing the CSF collected in the optional CSF biomarker research. 
 To identify potential indicators of AD progression and potential therapeutic 
effect based on brain imaging performed at the start and end of study for 
comparison. 
1.2 Study Design 
This is a prospective, randomized, double-blind, dose-comparison concurrent 
control study to assess the safety, tolerability, and feasibility of GRF6019, a 
 
human plasma protein fraction, administered by intravenous (IV) infusion to 
subjects with mild to moderate AD, and will be conducted at up to 10 sites in the 
United States. 
The overall duration of the study is approximately 15 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The 
recruitment period is expected to be approximately 12 months. The subject 
participation period is approximately 7 months from screening through end of 
study, unless prematurely discontinued. 


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The study consists of approximately 40 subjects randomized to one of the 
following two dose levels: 20 subjects at 100 mL and 20 subjects at 250 mL. All 
subjects will receive one infusion per day at the randomized dose for 5 
consecutive days during weeks 1 and 13. 
All subjects will undergo a screening visit, baseline visit, treatment visits, follow-
up visits and an end of study/early termination visit. During the two 5-day dosing 
periods, subjects will reside in inpatient study observation units to facilitate safety 
evaluation. Subjects will be discharged from the inpatient facility the day after the 
5th day of dosing. Subjects who are eligible and consent to participate in the 
optional cerebrospinal fluid (CSF) biomarker research at participating sites will 
undergo two lumbar punctures for CSF collection, the first occurring prior to initial 
dosing, and the second occurring following final dosing. 
Safety and tolerability assessments will occur at every visit. Neurocognitive and 
psychomotor assessments will be performed at baseline and at periodic interim 
assessments following dosing. In the event of early termination of a subject, the 
end of study procedures will be performed unless the subject has withdrawn 
consent. A comprehensive efficacy and safety assessment of all data in toto will 
be conducted at the end of the study. 
 
 
 
   
1.3 Sample Size Estimation 
A total of approximately 40 subjects (20 in the 100 mL and 20 in the 250 mL 
groups) will be randomized in the study with the intent of obtaining ~30 evaluable 
subjects who have received at least 5 doses and completed through Visit 8. 
Subjects who discontinue prior to Visit 8 may be replaced. Subjects who 
withdraw or are withdrawn during screening will be replaced. 
The primary endpoint of this study is safety and tolerability. Using the statistical 
approximation described by Hanley (aka the “Rule of Threes”), the upper bound 
of the 95% confidence interval for the rate of an unreported AE is at most 7.5% 
(3/number of subjects receiving active drug). In addition, the proposed sample 
size may be sufficient to identify trends in the effects of plasma-derived factors 
and in the relationship between dose and cognitive effects. 
1.4 Randomization and Blinding 
The study will be randomized with a mixed block size of 2 and 4 and stratified by 
sex. The randomization will be web-based and centralized. The randomization 
codes will be generated by a statistician who has no involvement in the study 
other than generation and maintenance of the randomization codes. 


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All study outcome measures will be assessed by blinded Outcomes Assessors. 
The Outcomes Assessors will observe the subject during the infusion of the study 
agent and collect and/or manage/report adverse events (AEs) and serious 
adverse events (SAEs). To ensure that Outcomes Assessors, subjects, and trial 
partners are unaware of the dose being administered, appropriate measures will 
be taken to mask the infusion pump and glass vials containing the study agent 
such that they will only be visible as necessary to the unblinded Infusion Nurse 
for appropriate dosing. In addition, a curtain, drape, or equivalent will be used to 
shield the infusion administration setup from view of all but the unblinded Infusion 
Nurse. Communication between the Outcomes Assessor and the Infusion Nurse 
will be restricted to only that required to ensure immediate patient safety. 
Finally, to avoid potential unblinding based on patient albumin levels, serum 
albumin lab results will remain blinded until the conclusion of the study.  
1.5 Study Data 
The study data being analyzed per this Statistical Analysis Plan includes all 
clinical data captured by eCRF as well as safety lab data. The eCRF database 
will be locked for the final analyses and the final data transfers from the central 
lab will be utilized.  Savonix Neurocognitive Assessments, Imaging data, and 
biomarker data, are not included in the eCRF database. 
2 
GENERAL ANALYSIS DEFINITIONS 
All analysis dataset preparations and statistical analyses will be performed using 
SAS® version 9.4 or higher.  No imputation will be performed for missing data 
unless stated otherwise. Listings for CSR Appendix 16.2 will include all the 
subject data points being collected or derived for analyses, and will be sorted by 
treatment group, site, and subject number. 
2.1 Treatment Groups 
The 
 treatment groups will be labelled as 100 mL, 250mL, 
 
within the statistical output.
 
  
2.2 Statistical Hypothesis Tests 
Inasmuch as the study design is focused on safety and tolerability, the statistical 
approach taken with the secondary endpoints will be primarily descriptive with 
only modest amounts of hypothesis testing; within-subject changes from baseline 
for each dosing group and between-group differences will be evaluated for the 
purpose of designing future studies. Inferential statistics for any within-group and 
between-group comparisons will be described for each specific endpoint as 
applicable. For all statistical tests, the nominal two-sided p values will be 
reported. 
2.3 Study Phase, Visit, and Day 


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Phase 
Screening/ 
Baseline 
Treatment:  
Period 1 
Follow-up: Period 1 
Treatment: 
Period 2 
Follow-up: 
Period 2 
Visit 
1 to 2 
3 to 7 
8 
9 
10 
11 to 15 
16 
17 
18 
19/Exit 
Day 
-28 to -1 
1 to 5 
6 
28±7 
56±7 
85-89 
90 
112±7 
140±7 
168±7 
The study is set up as shown above, along with assigned study period, visit, and 
day. In general, the baseline is defined as the last assessment before the first 
intake of the study medication unless otherwise specified. All scheduled 
assessments after first administration of study drug will be used. 
Repeat/unscheduled assessments will not be used in descriptive statistics or any 
per-time point analyses but will be shown in listings as applicable. Pre-dose 
unscheduled assessments will be taken into account for baseline determination 
and post first dose unscheduled assessments will be taken into account for 
worst-case determination as applicable. 
Reference date refers to the start date of the first study drug administration. All 
efficacy and safety assessments at all visits will be assigned a day relative to this 
date. The relative day will be defined as: visit date – reference date + 1 for visits 
on or after the reference date and visit date – reference date for visits before the 
reference date.  Consequently, there is no 'Day 0' defined. 
2.4 Analysis Sets 

Screened set (SCRN): All subjects who were screened and entered into
EDC.

Screen Failure set (SCRF): All subjects who were entered as screen
failures in the EDC.

Intention-to-Treat Dataset (ITT): All subjects who were randomized.

Safety set (SAF): All subjects who received at least one dose of the study
agent.

Evaluable set (EVAL):All subjects who received at least 5 of the 10
planned doses.

Per Protocol set (PPROT): A subset of the Evaluable set comprised of
subjects who do not have any of the deviations listed below or any other
deviation affecting efficacy identified prior to database lock.


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Deviation 
Type 
Deviation 
Additional 
Clarification 
Eligibility 
Inclusion 
Criteria Not 
Met 
Diagnosis of probable AD based upon the National 
Institute on Aging-Alzheimer’s Association (NIA-
AA) Criteria 
Subjects with a 
clinical diagnosis of 
AD according to NIA-
AA criteria who have 
a negative amyloid 
PET scan will also be 
excluded. 
Eligibility 
Inclusion 
Criteria Not 
Met 
MMSE Score 12-24 inclusive 
 
Eligibility 
Inclusion 
Criteria Not 
Met 
Modified Hachinski Ischemia Scale (MHIS) score of 
<=4 
Eligibility 
Exclusion 
Criteria Met 
Evidence of clinically relevant neurological 
disorder(s) other than AD 
Eligibility 
Exclusion 
Criteria Met 
Initiation or change in the dosage of cholinesterase 
inhibitors (AChEI), memantine, Axona, vitamin E 
supplementation, or selegiline within 3 months prior 
to screening 
Will be determined 
based upon actual 
date of change and 
proximity to 
screening. Will be 
determined prior to 
database lock 
Eligibility 
Exclusion 
Criteria Met 
Treatment with any human blood product, including 
transfusions and IV immunoglobulin, during the 6 
months prior to screening 
 
Eligibility 
Exclusion 
Criteria Met 
Concurrent daily treatment with benzodiazepines, 
long-acting opioids, or other medications that, in 
the investigator’s opinion, interfere with cognition 
Eligibility 
Exclusion 
Criteria Met 
Concurrent participation in another interventional 
clinical trial. Prior clinical trial subjects must have 
been off study agents for at least 30 days (or 5 
half-lives, whichever is longer), 4 months for 
disease modifying therapies, and 1 year for 
vaccine or immunotherapy trials prior to screening. 


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Deviation 
Type 
Deviation 
Additional 
Clarification 
Eligibility 
Exclusion 
Criteria Met 
A history of a major psychiatric disorder diagnosed 
before the onset of AD, including schizophrenia, 
major depression or bipolar disorder, and/or 
alcohol/substance dependency. Psychiatric 
symptoms that occur in the context of AD (e.g. 
psychosis, irritability, depression) are not 
exclusionary unless the PI believes they could 
interfere with study procedures 
 
Eligibility 
Exclusion 
Criteria Met 
>2 lacunar strokes or other imaging abnormality on
baseline MRI that would make the interpretation of
subsequent MRI scans of the brain difficult.
Only if the MRI 
findings are indicative 
of another cause of 
dementia/cognitive 
impairment 
Eligibility 
Exclusion 
Criteria Met 
Any other condition and/or situation that the 
investigator believes may interfere with the safety 
of the subject, the intent and conduct of the study, 
or interpretation of study data 
Only when interfering 
with the interpretation 
of study data 
Compliance 
Incorrect treatment dispensed and administered to 
subject 
Compliance 
Received less than 5 doses 
Out of 
Window 
Efficacy Procedures performed outside of the 
protocol window which are a consistent pattern or 
potential risk to study data outcomes 
Study Drug 
Temp 
Excursion 
Study drug temperature excursions when 
determined to have impacted the quality of the 
study drug  
Concomitant 
meds 
Use of prohibited concomitant medications as 
defined in the protocol that have an effect on 
cognition 
Decisions regarding which subjects are included in PPROT will be made before 
database lock. 
A summary table of number (%) of patients in each analysis set and applicable 
treatment assignment will be provided (Table 14.1.1).     
2.5 Definition of Subgroups 
Subjects will be categorized into mild and moderate AD based on the baseline 
Mini-Mental State Examination (MMSE) with the recalculated total score >20 and 
<=20, respectively.  


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2.6 Descriptive Summaries 
All tabulated summaries will include the two treatment groups 
 
and overall (includes data from both treatment groups).  For endpoints 
that are continuous in nature: number of observations, mean, median, minimum 
and maximum, and standard deviation (SD) values will be presented as 
descriptive summary.  For endpoints that are categorical in nature: frequency 
counts and percentages will be presented in the descriptive summary.  
The number of decimal places to display for calculated data will be determined 
by the original scale of the data.  Means, medians, and confidence intervals will 
be reported with one (1) additional decimal place.  Standard deviation will be 
reported with two (2) additional decimal places.  Minimum and maximum will be 
reported with the same number of significant digits as the method of capture. 
For all efficacy and safety tables summarizing change from baseline, the 
baseline and post-baseline results at all planned timepoints will be included.  
3 
PLANNED INTERIM ANALYSIS 
No interim analyses are planned.  
4 
SUBJECT INFORMATION 
In general, all subject-level parameters will be summarized for the SAF set 
unless stated otherwise. 
4.1 Disposition Information  
Summaries will be provided for the following disposition information: Number of 
subjects screened, screening failures, randomized, completed study, 
discontinued study with the reasons of discontinuation from study, discontinued 
from study drug with the reasons of discontinuation from study drug, and 
discontinued from study but completed study drug dosing. The randomized 
treatment group will be shown for ITT set (Table 14.1.2).   
4.2 Protocol Deviations  
The number and percentage of subjects with protocol deviations will be tabulated 
per coded protocol deviation by severity (major vs minor) for the ITT set (Table 
14.1.3.1). 
The success of blinding will be assessed based on all occurrences (intentional or 
unintentional) of unblinding of blinded study subjects, their trial partners or study 
personnel (e.g. investigators, medical providers, cognitive testing raters, the 
Sponsor or their representatives) during infusions. Number of subjects with any 
occurrence of unblinding will be summarized on any day any period, any day 
each period, and each day within each period (Table 14.1.3.2). 


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4.3 Demographics and Baseline Characteristics  
Descriptive statistics or frequency tabulation will be provided for the following 
parameters. The ‘Declined to answer/don't know’ will not be added for the 
denominator unless stated otherwise. 
4.3.1 Demographic Parameters 
Descriptive statistics or frequency tabulation will be provided for following 
parameters (Table 14.1.4.1): 
Age (years)
Sex (Male, Female)
Race (White, Black or African American, Asian, American Indian or Alaska
Native, Native Hawaiian or Other Pacific Islander, Other Race, Multiple –
derived if multiple races are checked) 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
Marital status (Single, Married, Widowed, Divorced/Separated)
Family size
Longest held career (Professional, Homemaker, Trade person,
Arts/Entertainment)
Annual household income ever reported (Less than $50,000, $50,000 to
$99.999, $100,000 to $199,999, $200,000 or more).
Weight at baseline (kg)
Height at baseline (cm)
Body Mass Index (BMI) at baseline = Weight at baseline (kg) / [Height at
baseline (m)]2 (rounded to 1 decimal. Although available in the raw data,
BMI will be recalculated from last weight and height measurement before 
start of treatment) 
Duration of AD (years)
Any Prior Treatments for AD (Yes/No)
4.3.2 Baseline Assessment of Modified Hachinski Ischemia Scale (MHIS)  
No tabulation summary will be provided for MHIS data, which will be included in a 
subject data listing only.   
4.3.3 Baseline Assessment of Columbia-Suicide Severity Rating Scale (C-
SSRS)  
The C-SSRS is a simple series of questions for the assessment of suicidal 
ideation and behavior in clinical trials (Posner 2011). The C-SSRS (including 
Actual Attempts Lethality) in both Lifetime and Last 6 Months are evaluated at 
screening visit.  
Descriptive statistics or frequency tabulation will be provided for following C-
SSRS parameters (Table 14.1.4.2):  
 Suicidal Ideation (Yes/No): Wish to be Dead, Non-Specific Active Suicidal
Thoughts, Active Suicidal Ideation without Intent to Act, Active Ideation 
with Some Intent without Specific Plan, Active Ideation with Specific 
Plan and Intent  


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 Intensity of Ideation
Most Severe Suicidal Ideation (1-5)
Frequency of Suicidal Ideation (1-5)
Duration of Suicidal Ideation (1-5)
Deterrents of Suicidal Ideation (0-5)
Controllability of Suicidal Ideation (0-5)
Reason of Suicidal Ideation (0-5)
 Suicidal Behavior:
Actual Attempt (Yes/No)
Total Number of Attempts
Interrupted Attempt (Yes/No)
Total Number of Interrupted Attempts
Aborted Attempt (Yes/No)
Total Number of Aborted Attempts
Preparatory Acts or Behavior (Yes/No)
Suicidal Behavior (Yes/No)
 Lethality - Most recent attempt:
Actual Lethality/Medical Damage (0-5)
Potential Lethality (0-2)
 Lethality - Most lethal attempt:
Actual Lethality/Medical Damage (0-5)
Potential Lethality (0-2)
 Lethality - Initial/First attempt:
Actual Lethality/Medical Damage (0-5)
Potential Lethality (0-2)
4.3.4 APOE Genotype  
Frequency tabulation will be provided for APOE Genotype (E2/E2, E2/E3, E2/E4, 
E3/E3, E3/E4, E4/E4) (Table 14.1.4.3) 
4.4 Medical History  
The investigator or designee will obtain a detailed medical history through 
interview with the subject and the subject’s trial partner during screening. The 
medical history should focus on duration of disease and recent history, with an 
emphasis on the history of cognitive symptoms related to probable AD. 
Additionally, the medical history should include: 

Current/past illnesses and conditions

Current symptoms

Surgeries and procedures

Allergies

Family history

Social history (e.g. exercise, smoking, alcohol, illegal substances) and
current living situation

Cause of parental death (if not living)


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
Prior radiologic imaging, CSF assessments, and/or PET Scan results (if
available and within 12 months of screening)
4.4.1 Subject Medical History 
All reported subject medical history findings will be summarized by MedDRA 
system organ class and preferred term, in order of descending overall frequency 
(Table 14.1.5.1). 
4.4.2 Family Medical History 
All reported family medical histories will be listed by type of family member 
(Father, Mother, Brother, Sister, Son, Daughter, Half-Brother, Half-Sister) for 
following parameters: 

Status (Living, Deceased)

Age at time of death (Years)

History of neurological disease (Any, Alzheimer's, Parkinson's, Lewy body
dementia, Frontotemporal dementia, Amyotrophic Lateral Sclerosis (ALS)
or Lou Gehrig's disease, Vascular dementia, Other neurological Family
Hx)
4.4.3 Social History 
A frequency tabulation will be summarized for the following parameters (Table 
14.1.5.2): 

Current Living Situation (In my home, In a relative or friend's home, In a
care facility, Other, Declined to answer/don't know)

Living conditions (Alone, With Family, With a Friend(s)/Roommate(s), With
a Professional Caregiver, With One or More Pets, Declined to
answer/don't know).  Various living conditions will be arranged in order of
descending overall frequency.
4.4.4 Exercise/Activity Level 
Descriptive statistics or frequency tabulation will be provided for all evaluated 
parameters related to exercise/activity level (Table 14.1.5.3): 

Walk or bike at least 10 minutes (Yes, No)

Days/week walking or biking>=10 minutes

Hours/day walking or biking (derived by total minutes/60)

Any other activity/sports (Yes, No)

Days/week for other activity/sports

Hours/day for other activity/sports (derived by total minutes/60)
4.4.5 Tobacco Use  
Descriptive statistics or frequency tabulation will be provided for the following 
parameters related to tobacco use (Table 14.1.5.4): 

Smoking status (Never Smoked, Current Smoker, Ex-Smoker)

Number of years smoked

Average cigarettes/day

Average pipes/day


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
Average cigars/day

Average cigarettes, pipes or cigars/day (derived by adding average
cigarettes/day, average cigars/day, and average pipes/day)
4.4.6 Alcohol and Illicit Substance Use 
Frequency tabulation will be provided for the following parameters related to 
alcohol use (Table 14.1.5.5): 

Had alcohol in past 6 months (Yes, No)

Drinks on a typical day (One or two, Three to five, Six or more)

Frequency of 6+ drinks (Less than monthly, Monthly, Weekly, Daily or
almost daily)

Problem with alcohol when young (Yes, No, Declined to answer)

Any DUI (Yes, No, Declined to answer)

Used illicit substances in the past (Yes, No)
4.5 Prior and Concomitant Medications 
Subject’s current medications, including over-the-counter drugs, herbal 
supplements and/or vitamins, as well as those taken by the subject in the past 12 
months (including previous treatments for AD) will be coded using the World 
Health Organization-Drug Dictionary and summarized separated for each of 
following two categories: 
1) Prior medication: medication that ended before the first dose of study drug.
2) Concomitant medication: medication received at or after the first dose of
study drug, medication that was received before initial dosing and continued
after initial dosing of study drug, or medication with missing stop date.
A frequency tabulation of prior and concomitant medications will be shown by 
ATC class level 4 and preferred term (Table 14.1.6.1 and 14.1.6.2). 
4.6 Extent of Exposure  
The extent of exposure (days) per period is defined as date of last study drug 
intake – date of first study drug intake + 1 within each period.  For subjects that 
have a “grace day” (i.e. they received 5 infusions over a period of 6 days instead 
of 5 infusions over 5 consecutive days), such dosing “grace day” is not 
considered an interruption. Extent of exposure as well as actual volume 
administered will be summarized descriptively per period and overall (two periods 
combined) (Table 14.1.7.1). 
Descriptive statistics of actual infusion rate (mL/hour) will be summarized at each 
time point per infusion day (Table 14.1.7.2).  The numbers of below, within and 
above the designated infusion rate reference will be tabulated at each time point 
per infusion day (Table 14.1.7.3).  In addition, descriptive statistics or frequency 
tabulation will be provided for the following infusion parameters collected at each 
infusion day (Table 14.1.7.4): 

Required adjustment to flow rate (Yes, No)

Entire assigned dose administered (Yes, No)


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
Actual Volume Administered (mL)

Maximum flow rate (mL/hour)

Device used to administer infusion (Baxter Flo Gard, Other)
4.7 Treatment Completion 
Treatment completion is calculated as the actual volume administered, as a 
percentage of the volume expected. The expected doses per treatment period 
will be calculated as [5 x total daily dose volume] for all subjects, regardless of 
study completion status. The expected doses overall will be calculated as [10 x 
total daily dose volume] for all subjects, regardless of study completion status. 
Treatment completion will be summarized descriptively and categorically (<75% 
and >=75%) per period and overall (Table 14.1.8.1).  
In addition, number of subjects completing 1-4, 5, 6-9, and 10 infusions will be 
summarized (Table 14.1.8.2). 
4.8 Tolerability 
Number of subjects completing 8 weeks (i.e. through Visit 10) after receiving at 
least 5 infusions, and number of subjects completing 24 weeks (i.e. through End 
of Study) after receiving at least 10 infusions will be tabulated (Table 14.1.9.1 
and 14.1.9.2). 
4.9 Visit Compliance 
Number of subjects with a visit at each scheduled analysis timepoint will be 
summarized (Table 14.1.10.1). 
Kaplan-Meier curves of the time to completion or discontinuation of the trial will 
be produced. Note at the final analysis all subjects will have the event of 
completion or discontinuation and no subjects will be censored. Log-rank test p 
value may be reported (Figure 14.1.10.2). 
5 
EFFICACY 
The study is not designed to detect significant changes in cognition over time. 
However, using available data from analysis of the secondary endpoints, 
including changes in cognition scores from baseline, descriptive summarization 
as well as appropriate 95% confidence limits will be developed. Of particular 
interest will be the within-subject changes from baseline and their distribution 
around a null value of zero and a comparison among groups to evaluate any 
trends in dose response. For each efficacy endpoint, paired t-test may be 
conducted to evaluate within-subject changes from baseline. Between-group 
differences may be assessed by Analysis of Covariance (ANCOVA) including 
baseline and sex as the covariates. Between-group difference may be assessed 
by analysis of Covariance (ANCOA) including baseline and sex as the 
covariates. Figures, including line graphs or bar graphs, may be generated to 
show treatment group differences on selected endpoints. 


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For analysis purposes, results at early termination visits will not be included in 
tabulated summaries. 
Following efficacy endpoints will be analyzed based on both EVAL and PPROT 
sets.  
5.1 Mini-Mental State Examination (MMSE) 
The MMSE (Folstein 1975) consists of the following 5 components:  

Orientation to time and place (2 items)

Registration of 3 words (1 item)

Attention and calculation (1 item)

Recall of 3 words (1 item)

Language (6 items)
The scores from the 5 components are summed to obtain the overall MMSE total 
score. The MMSE total score can range from 0 to 30, with higher scores 
indicating better mental status. 
Although available in the raw data, the MMSE total score will be recalculated. If a 
subject has 1 missing item, the following algorithm will be used to compute the 
total score: Total score = [(total score from completed items) / (maximum total 
score for completed items)] x (maximum total score [=30] for all items in the 
scale). The total score is then rounded to the next highest integer. If there is 
more than 1 missing item, the total score will be considered missing at that time 
point.  
Changes from baseline for the recalculated MMSE total score will be 
summarized at each scheduled timepoint (Days 6, 90, and 168) (Table 14.2.1).     
5.2 Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS 
Cog/11) 
The ADAS-Cog/11 (Rosen 1984) includes 11 items assessing cognitive function:  

Word Recall: the mean of the three trials is used, rounded to 2 decimal
places

Command

Constructional Praxis

Naming Objects and Fingers

Ideational Praxis

Orientation

Word Recognition

Remembering Test Instructions

Comprehension

Word Finding Difficulty

Spoken Language Ability
Although available in the raw data, the ADAS-Cog/11 total score is derived as a 
linear sum of the scores recorded for the 11 individual domains. Higher scores 
reflect greater cognitive impairment.  


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Changes from baseline for the total score as well as 11 individual domain scores 
and will be summarized at each scheduled timepoint (Days 28, 112, and 168) 
(Table 14.2.2). 
5.3 Grooved Pegboard Test (GPT) 
The Grooved Pegboard Test is a manual dexterity test measuring visual-motor 
coordination (Lafayette 2002). The test consists of a pegboard with 25 holes with 
randomly positioned slots and pegs with a key along one side. The subject is to 
insert the pegs as quickly as possible into the slots in sequence, first with the 
dominant hand and then with the non-dominant hand. The score is the time it 
takes for the subject to complete the task with each hand.  For subjects who fail 
to complete the test in 5 minutes the score is the number of total pegs inserted.  
In addition, to time to completion, the number of pegs dropped (for each hand) is 
recorded.   
Changes from baseline for these GPT scores will be summarized for each hand 
(dominant and non-dominant) at each scheduled timepoint (Days 6, 28, 85, 90, 
112, and 168) (Table 14.2.3). 
5.4 Category Fluency Test (CFT) 
Category fluency tasks are an important component of neuropsychological 
assessment, especially when evaluating for dementia syndromes. Subjects are 
asked to generate words from a specified semantic category (e.g., name as 
many different types of animals, vegetables, or fruits in a 60 second period) 
(Acevedo 2000). The number of correct, non-repeated responses constitutes the 
primary CFT raw score. In addition, the number of repetitions and other errors is 
recorded.  
Changes from baseline for CFT scores will be summarized for each scheduled 
timepoint (Days 28, 112, and 168) (Table 14.2.4).  
5.5 Clinical Dementia Rating Scale – Sum of Boxes (CDR-SOB) 
The Clinical Dementia Rating Scale (CDR) is a global assessment instrument 
that yields Global and Sum of Boxes (SOB) scores, with the global score 
regularly used in clinical and research settings to stage dementia severity. The 
CDR is obtained via semi-structured interviews with patients and informants (e.g. 
trial partners) to characterize functioning in 6 domains: memory, orientation, 
judgment and problem solving, community affairs, home and hobbies and 
personal care (Hughes 1982). Each domain is rated on a 5-point scale, and the 
CDR-SOB score is obtained by summing each of the domain box scores. The 
CDR-SOB is considered a more detailed quantitative general index than the 
Global score (O’Bryant 2008).  
Changes from baseline for CDR global and CDR-SOB scores will be summarized 
at each scheduled timepoint (Days 28, 112, and 168) (Table 14.2.5).     
5.6 Alzheimer’s Disease Cooperative Study – Activities of Daily Living 23 
(ADCS-ADL23) 


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The ADCS-ADL is an inventory of informant-based items used to assess 
activities of daily living and instrumental activities of daily living, (i.e., functional 
performance) for AD subjects (Galasko 1997). The interviewer asks the subject’s 
caregiver a total of 23 questions regarding the subject’s ability to maintain good 
hygiene, use a telephone, initiate conversations, etc. A score of up to 4 points 
may be assigned to each question. A higher score indicates less impairment; the 
maximum achievable score (indicating no ADL impairment) is 78. The sum of the 
responses for the 23 items of the inventory will be calculated for the total score 
and recorded into eCRF. 
Changes from baseline for ADCS-ADL23 total score will be summarized for 
subject and trial partner separately, and at each scheduled timepoint (Days 28, 
56, 112, 140, and 168) (Table 14.2.6.1 and 14.2.6.2).     
5.7 Alzheimer’s Disease Cooperative Study – Clinical Global Impression 
of Change rating (ADCS-CGIC) 
The ADCS-CGIC is a process for obtaining an assessment of meaningful clinical 
change over time (Schneider 1997). It is a systematic method for assessing 
clinically significant change in a clinical trial as viewed by an independent skilled 
and experienced clinician. The ADCS-CGIC focuses on clinicians' observations 
of change in the subject’s cognitive, functional and behavioral performance since 
the beginning of a trial. It relies on both direct examination of the subject and 
interview of informants. Unlike a targeted symptom scale, it takes into account a 
subject's overall functioning in the cognitive, behavioral and functional activity 
domains. 
The ADCS-CGIC is a single value score based on a 7-point scale using the 
following values: 
1 = Marked Improvement 
2 = Moderate Improvement 
3 = Minimal Improvement 
4 = No Change 
5 = Minimal Worsening 
6 = Moderate Worsening 
7 = Marked Worsening 
Changes from baseline for ADCS-CGIC rating (1-7) will be summarized at each 
scheduled timepoint (Days 28, 112, and 168) (Table 14.2.7).     
5.8 Neuropsychiatric Inventory Questionnaire (NPI-Q) 
The NPI-Q evaluates the most frequent neuropsychiatric manifestations of 
dementia and determines their frequency and intensity (Kaufer 2000). It is 
designed to be a self-administered questionnaire completed by informants (e.g. 
trial partners) about subjects for whom they care. Generally, the NPI-Q is used to 
evaluate changes in subject behavior that have appeared during a given period. 
The NPI-Q comprises 12 domains: delusions, hallucinations, dysphoria, apathy, 
euphoria, disinhibition, aggressivity and restlessness, irritability, anxiety, aberrant 


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motor behavior, appetite and eating disorders, and nocturnal behavior. Initial 
responses to each domain question are "Yes" (present) or "No" (absent). If the 
response to the domain question is "No", the informant goes to the next question. 
If "Yes", the informant then rates both the severity of the symptoms present 
within the last month on a 3-point scale and the associated impact of the 
symptom manifestations on them (i.e., trial partner distress) using a 5-point 
scale. Thus, the NPI-Q evaluates response to therapy and provides symptom 
severity and distress ratings for each symptom reported, and total severity and 
distress scores reflecting the sum of individual domain scores. 
Change from baseline for NPI-Q total severity score and total distress score will 
be summarized at each scheduled timepoint (Days 28, 56, 112, 140, and 168) 
(Table 14.2.8).     
6 
SAFETY  
All safety analyses will be done on the Safety Set. 
6.1 Adverse Events 
6.1.1 Coding of AEs 
The verbatim terms of AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Events are looked at on the level of their 
preferred term and system organ class. 
6.1.2 Treatment-Emergent AE 
Pre-treatment AEs are defined as AEs that were reported or worsened after 
signing the ICF up to the start of study drug dosing. Treatment-emergent AEs 
(TEAE) are defined as AEs that were reported or worsened on or after the start 
of study drug dosing and up to and including the end of the follow-up. 
6.1.3 Period Allocation of AE 
Adverse events are allocated to a period based on their start date and time. If the 
start date and time of an event falls between (or on) the start and stop date and 
time of a period, the AE is attributed to that period (treatment-emergent 
principle). 
Rule: period start datetime ≤ AE start datetime ≤ period stop datetime. 
In case of partial AE start dates and or times, the events are allocated to the 
periods using the available partial information on start and end datetime; no 
imputation will be done. If, for instance, for the AE start date only month and year 
are available, these data are compared to the month and year information of the 
periods. This rule may lead to multiplication of the event as a consequence of its 
assignment to multiple periods. In case of a completely missing AE start date, the 
event is allocated to the first period, except if the end date of the AE falls before 
the start of this period. In case of any other missing scenarios, the period 
allocation of AE will be determined by manual data review prior to database lock. 


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6.1.4 Variables Attributed to Adverse Events: 

AE term (verbatim and MedDRA preferred term and system organ class)

Onset datetime, End datetime, and duration of AE

Serious AE (Yes/No), if yes classification will be listed

Severity (Mild, Moderate, Severe)

Relation to study treatment (Unrelated, Possibly Related, Definitely
Related)

Frequency (Single Episode, Intermittent, Continuous)

Action taken with study treatment (No Action Taken, Treatment Held,
Treatment Discontinued)

Other Action due to AE (Medication Therapy, Non-Drug Therapy, Other)

Outcome of AE (Recovered/Resolved, Not Recovered/Not Resolved,
Resolved/Resolved with Sequelae, Fatal, Unknown)

AE leading to death (Yes/No)
  
 AE of special interest 
6.1.5 Analysis Methods 
There will be no formal statistical testing unless indicated otherwise. 
A summary will be provided for the following TEAEs per period and overall (Table 
14.3.1.1.1-14.3.1.1.3): 

Subjects with Any TEAE

Subjects with Any Study Drug-Related1 TEAE

Subjects with Any TEAE with an Outcome of Death

Subjects with Any Serious TEAE

Subjects with Any Study Drug-Related Serious TEAE

Subjects with Any TEAE Leading to Discontinuation of Study Drug

Subjects with Any Study Drug-Related TEAE Leading to Discontinuation
of Study Drug

Subjects with Any TEAE of Special Interest

Subjects with Any Study Drug-Related TEAE of Special Interest
The adverse events will be shown by MedDRA system organ class and preferred 
term, in order of descending overall frequency. For each AE, the percentage of 
subjects who experience at least 1 occurrence of the given event will be 
summarized per period and overall. Incidence tabulations will be provided for 
overall summary (Table 14.3.1.2.1-14.3.1.2.3), summary by highest severity 
(Table 14.3.1.3.1-14.3.1.3.3), and summary by relatedness (Table 14.3.1.4.1-
14.3.1.4.3). 
Incidence of Serious TEAEs, TEAEs of Special Interest, TEAEs Leading to 
Subject Withdrawal and TEAEs Leading to Death will be tabulated by MedDRA 
System Organ Class and Preferred Term (Table 14.3.1.5.1-14.3.1.5.4), and listed 
as well (Listing 14.3.1.6.1-14.3.1.6.4). 
Adverse events with preferred terms associated with blood pressure changes will 
also be presented by infusion period, SOC, PT, and treatment group. Infusion 


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period will be further categorized by whether the event start date occurred during 
the infusion period or after the infusion period. Examples of such events can be 
identified by the following preferred terms: blood pressure decreased, blood 
pressure diastolic decreased, blood pressure systolic decreased, blood pressure 
increased, increased blood pressure, blood pressure diastolic increased, blood 
pressure systolic increased, hypotension, hypertension, low blood pressure, high 
blood pressure. This is a non-exhaustive list and a review of AE MedDRA coding 
will be conducted prior to lock to identify all events associated with blood 
pressure changes. (Table 14.3.1.7.1-14.3.1.7.3). 
6.2 Clinical Laboratory Evaluations 
Numeric measurements of hematology, serum chemistry, urinalysis and urine 
chemistry will be investigated. Changes from baseline for all safety lab 
parameters will be summarized at each scheduled timepoint (Table 14.3.2.1.1-
14.3.2.1.3). Frequency tables for categorical test results will be tabulated at each 
scheduled timepoint (Table 14.3.2.2). Shift tables from the baseline to each post-
baseline scheduled timepoint will be presented (Table 14.3.2.3.1-14.3.2.3.3). 
6.3 Vital Signs 
Summary statistics will be presented for the actual values and change from 
baseline values (as appropriate) at each time point for all vital signs 
(Temperature, Pulse Rate, Systolic Blood Pressure (BP), Diastolic BP, 
Respiratory Rate) and weight. Changes from baseline for all vital sign 
parameters and weight will include pre-dose at Day 1 to pre-dose at subsequent 
days and at all timepoints during infusion (Table 14.3.3.1).  In addition, changes 
from baseline for all vital sign parameters will include pre-dose at each infusion 
day to all post-dose timepoints within each infusion day (Table 14.3.3.2).   
The incidence of the following categorized blood pressure values and changes 
from baseline will be summarized (Table 14.3.3.3): 

Systolic BP > 180

Systolic BP > 200

Systolic BP < 90

Diastolic BP > 110

Diastolic BP > 120

Diastolic BP < 50

An absolute change of >30% from Day 1 pre-dose (baseline) in systolic
and/or diastolic BP. This change includes positive and negative percent
changes.


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6.4 Electrocardiogram 
P-R interval, QT interval, QRS duration, Ventricular heart rate and QTc intervals
using Bazett’s correction formula and Fridericia's correction formula will be
investigated. QTc values will be used as reported, they will not be recalculated.
Changes from baseline for all Electrocardiogram (ECG) parameters will be
summarized at each scheduled timepoint (Days 5, 85, and 89) (Table 14.3.4.1).
In addition, frequency tabulation of the overall ECG results (Normal, Abnormal
NCS, and Abnormal CS) will be summarized (Table 14.3.4.2).
6.5 Physical Examinations  
For physical examination data, when calculating the percentage reporting each 
category, the “Not Done” category will not be included in the denominator. 
Number (%) of subjects with abnormal physical examinations will be tabulated at 
screening and Day 168 (Tables 14.3.5.1). Normal/abnormal shift from screening 
to Day 168 will also be provided (Tables 14.3.5.2). 
6.6 C-SSRS since Last Visit 
The frequency of individual C-SSRS since last visit assessments (Yes/No) will be 
summarized at each scheduled timepoint (Days 6 and 90) (Tables 14.3.6). 
6.7 MRI Testing, Echocardiogram, and PET Scan 
All recorded MRI testing, Echocardiogram, and PET scan results captured in the 
CRF will be listed as part of CSR Appendix 16.2.  
7 
EXPLORATORY 
All exploratory analyses will be described in a separate plan. 
8 
CHANGES FROM PROTOCOL 
The Per Protocol dataset is defined in the protocol as: a subset of the Evaluable 
Dataset comprised of subjects who have no Major Protocol Deviations. All failed 
eligibility criteria are considered a Major Protocol Deviation, however, not all 
eligibility criteria failures should automatically remove a subject from the Per 
Protocol dataset. This SAP clarifies which protocol deviations will exclude a 
subject from the per protocol dataset and all protocol deviations will be reviewed 
by the study team prior to database lock to identify the final Per Protocol dataset 
definition.  
Blood pressure values that constituted an AESI were at the discretion of the PI. 
As such, ranges for blood pressures of special interest (BPSI) were identified and 
will be analyzed according to section 6.3. 


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9 
REFERENCES 
Acevedo A. Category fluency test: normative data for English and Spanish-
speaking elderly. J Int Neuropsych Soc.2000; 6(7):760-769. 
Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”: a Practical Method 
for Grading the Cognitive State of Subjects for the Clinician. J Psychiatr Res. 
1975; 12:189-198. 
Galasko D, Bennet D, Sano M et al and the Alzheimer’s Disease Cooperative 
Study. An Inventory to Assess Activities of Daily Living for Clinical Trials in 
Alzheimer’s Disease. Alzheimer Dis Assoc Disord. 1997; 11 (suppl 2): S22-S33-
S39. 
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for 
the staging of dementia. Brit J Psychiat. 1982; 140: 566-572. 
Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. 
Validation of the NPI-Q, a brief clinical form of the neuropsychiatric inventory. J 
Neuropsychiatry Clin Neurosci. 2000 Spring; 12 (2): 233-239. 
Lafayette Instrument Company. Grooved Pegboard Test User Instructions 
(Model 32025); 2002. 
O’Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, et al. 
Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a 
Texas Alzheimer’s Research Consortium study. Arch Neurol. 2008; 65: 1091-
1095. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. 
The Columbia-Suicide Severity Rating Scale: initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. Am 
Psychiatry. 2011 December; 169 (12):1266-1277. 
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease Am 
J Psychiatry. 194; 141:1356-1364. 
SAS Institute Inc.  The SAS System, Version 9.4.  Cary, NC, SAS Institute Inc. 
2012. 
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg, B, et al. 
Validity and reliability of the Alzheimer’s Disease Cooperative Study-Clinical 
Global Impression of Change. Alzheimers Dis Assoc Disord. 1997; 11 (Suppl 
2):S22-S52. 


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10 TABLES, LISTINGS, AND FIGURES FOR CSR APPENDIX 14 
Following tables, listings, and figures are to be included in the post-text Appendix 
14 of CSR and may be modified with Sponsor’s approval. 
Number 
Title 
Population 
Table 14.1.1 
Analysis Populations 
SCRN 
Table 14.1.2 
Subject Disposition 
ITT 
Table 14.1.3.1 
Protocol Deviations 
ITT 
Table 14.1.3.2 
Assessment of Unblinding by Blinded Outcome 
Assessors 
SAF 
Table 14.1.4.1 
Demographics  
SAF 
Table 14.1.4.2 
Baseline Assessment of Columbia-Suicide 
Severity Rating Scale (C-SSRS) 
SAF 
Table 14.1.4.3 
APOE Genotype 
SAF 
Table 14.1.5.1 
Medical History 
SAF 
Table 14.1.5.2 
Social History 
SAF 
Table 14.1.5.4 
Exercise-Activity Level 
SAF 
Table 14.1.5.5 
Tobacco Use 
SAF 
Table 14.1.5.6 
Alcohol and Illicit Substance Use 
SAF 
Table 14.1.6.1 
Prior Medication 
SAF 
Table 14.1.6.2 
Concomitant Medication 
SAF 
Table 14.1.7.1 
Exposure to Study Drug 
SAF 
Table 14.1.7.2 
Actual infusion rate at each time point per infusion 
day 
SAF 
Table 14.1.7.3 
Numbers of below, within and above the 
designated infusion rate reference 
SAF 
Table 14.1.7.4 
Overall infusion parameters per infusion day 
SAF 
Table 14.1.8.1 
Completion of Study Drug 
SAF 
Table 14.1.8.2 
Number of subjects completing 5 and 10 infusions 
SAF 
Table 14.1.9.1 
Number of subjects completing 8 weeks after 
receiving at least 5 infusions 
SAF 
Table 14.1.9.2 
Number of subjects completing 24 weeks after 
receiving at least 10 infusions 
SAF 
Table 14.1.10.1 
Visit Compliance 
SAF 
Figure 14.1.10.2 
Kaplan-Meier curves of the time to completion or 
discontinuation of the trial 
SAF 
Table 14.2.1 
Changes in scores on the Mini-Mental State 
Examination (MMSE)  
EVAL, 
PPROT 
Table 14.2.2 
Changes in scores on the 11-item Alzheimer’s 
Disease Assessment Scale-Cognitive Subscale 
(ADAS-Cog/11) 
EVAL, 
PPROT 
Table 14.2.3 
Changes in scores on the Grooved Pegboard Test 
EVAL, 
PPROT 
Table 14.2.4 
Changes in scores on the Category Fluency Test 
EVAL, 


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Number 
Title 
Population 
(CFT) 
PPROT 
Table 14.2.5 
Changes in the Clinical Dementia Rating Scale – 
Sum of Boxes (CDR-SOB) 
EVAL, 
PPROT 
Table 14.2.6.1 
Changes in the Alzheimer’s Disease Cooperative 
Study – Activities of Daily Living23 (ADCS-ADL23) 
for Subjects 
EVAL, 
PPROT 
Table 14.2.6.2 
Changes in the Alzheimer’s Disease Cooperative 
Study – Activities of Daily Living23 (ADCS-ADL23) 
for Partners 
EVAL, 
PPROT 
Table 14.2.7 
Changes on the Alzheimer’s Disease Cooperative 
Study – Clinical Global Impression of Change 
(ADCS-CGIC) 
EVAL, 
PPROT 
Table 14.2.8 
Change on the Neuropsychiatric Inventory 
Questionnaire (NPI-Q) 
EVAL, 
PPROT 
Table 14.3.1.1.1 
Overall Summary of Treatment-Emergent Adverse 
Events (TEAE) 
SAF 
Table 14.3.1.1.2 
Overall Summary of Treatment-Emergent Adverse 
Events (TEAE) in Period 1 
SAF 
Table 14.3.1.1.3 
Overall Summary of Treatment-Emergent Adverse 
Events (TEAE) in Period 2 
SAF 
Table 14.3.1.2.1.1 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by MedDRA System Organ Class and 
Preferred Term 
SAF 
Table 14.3.1.2.1.2 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by MedDRA Preferred Term 
SAF 
Table 14.3.1.2.2.1 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by MedDRA System Organ Class and 
Preferred Term in Period 1 
SAF 
Table 14.3.1.2.2.2 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by MedDRA Preferred Term in Period 1 
SAF 
Table 14.3.1.2.3.1 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by MedDRA System Organ Class and 
Preferred Term in Period 2 
SAF 
Table 14.3.1.2.3.2 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by MedDRA Preferred Term in Period 2 
SAF 
Table 14.3.1.3.1 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by Severity and MedDRA System Organ 
Class and Preferred Term 
SAF 
Table 14.3.1.3.2 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by Severity and MedDRA System Organ 
Class and Preferred Term in Period 1 
SAF 
Table 14.3.1.3.3 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by Severity and MedDRA System Organ 
Class and Preferred Term in Period 2 
SAF 


 
 
 
Alkahest, Inc. 
 
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PROTOCOL ALK6019-201 
   
Statistical Analysis Plan: Final Version 2.1 June 09, 2019 
Page | 29 
Number 
Title 
Population 
Table 14.3.1.4.1 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by Relationship to Study Drug and 
MedDRA System Organ Class and Preferred 
Term 
SAF 
Table 14.3.1.4.2 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by Relationship to Study Drug and 
MedDRA System Organ Class and Preferred 
Term in Period 1 
SAF 
Table 14.3.1.4.3 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) by Relationship to Study Drug and 
MedDRA System Organ Class and Preferred 
Term in Period 2 
SAF 
Table 14.3.1.5.1 
Incidence of Serious Treatment-Emergent 
Adverse Events (TEAEs) by MedDRA System 
Organ Class and Preferred Term 
SAF 
Table 14.3.1.5.2 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) of Special Interest by MedDRA System 
Organ Class and Preferred Term 
SAF 
Table 14.3.1.5.3 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) Leading to Subject Withdrawal by 
MedDRA System Organ Class and Preferred 
Term 
SAF 
Table 14.3.1.5.4 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) Leading to Death by MedDRA System 
Organ Class and Preferred Term 
SAF 
Table 14.3.1.6.1 
Listing of Serious Treatment-Emergent Adverse 
Events (TEAEs) 
SAF 
Table 14.3.1.6.2 
Listing of Treatment-Emergent Adverse Events 
(TEAEs) of Special Interest 
SAF 
Table 14.3.1.6.3 
Listing of Treatment-Emergent Adverse Events 
(TEAEs) Leading to Subject Withdrawal 
SAF 
Table 14.3.1.6.4 
Listing of Treatment-Emergent Adverse Events 
(TEAEs) Leading to Death 
SAF 
Table 14.3.1.7.1 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) for Preferred Terms Associated with 
Blood Pressure Changes by MedDRA System 
Organ Class and Preferred Term 
SAF 
Table 14.3.1.7.2 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) for Preferred Terms Associated with 
Blood Pressure Changes by MedDRA System 
Organ Class and Preferred Term in Period 1 
SAF 
Table 14.3.1.7.3 
Incidence of Treatment-Emergent Adverse Events 
(TEAEs) for Preferred Terms Associated with 
Blood Pressure Changes by MedDRA System 
SAF 


 
 
 
Alkahest, Inc. 
 
. 
 
 
PROTOCOL ALK6019-201 
   
Statistical Analysis Plan: Final Version 2.1 June 09, 2019 
Page | 30 
Number 
Title 
Population 
Organ Class and Preferred Term in Period 2 
Table 14.3.2.1.1 
Changes in hematology measurements 
SAF 
Table 14.3.2.1.2 
Changes in serum chemistry measurements 
SAF 
Table 14.3.2.1.3 
Changes in urinalysis measurements 
SAF 
Table 14.3.2.2 
Frequency of categorical laboratory assessments 
SAF 
Table 14.3.2.3.1 
Shift Table in hematology measurements 
SAF 
Table 14.3.2.3.2 
Shift Table in serum chemistry measurements 
SAF 
Table 14.3.2.3.3 
Shift Table in urinalysis measurements 
SAF 
Table 14.3.3.1 
Changes from baseline in vital sign measurements 
and weight  
SAF 
Table 14.3.3.2 
Changes from pre-dose in vital sign 
measurements within each infusion day 
SAF 
Table 14.3.3.3 
Blood pressure measurements of special interest 
SAF 
Table 14.3.4.1 
Changes from baseline in ECG measurements 
SAF 
Table 14.3.4.2 
Frequency of overall ECG results 
SAF 
Table 14.3.5.1 
Frequency of abnormal physical examination 
results 
SAF 
Table 14.3.5.2 
Shift Table in physical examination results 
SAF 
Table 14.3.6 
Frequency of Columbia-Suicide Severity Rating 
Scale (C-SSRS) Since Last Visit 
SAF 


 
 
 
Alkahest, Inc. 
 
. 
 
 
PROTOCOL ALK6019-201 
   
Statistical Analysis Plan: Final Version 2.1 June 09, 2019 
Page | 31 
11 LISTINGS FOR CSR APPENDIX 16.2 
Number 
Title 
Population 
Listing 16.2.1.1 
Analysis Populations 
SCRN 
Listing 16.2.1.2 
Screen Failures 
SCRF 
Listing 16.2.1.3 
Subject Disposition 
ITT 
Listing 16.2.1.4 
Protocol Deviations 
ITT 
Listing 16.2.1.5 
Informed Consent 
ITT 
Listing 16.2.1.6 
Study Visits 
ITT 
Listing 16.2.2.1 
Inclusion Criterion Not Met or Exclusion 
Criteria Met 
ITT 
Listing 16.2.2.2 
Assessment for AD using NIA-AA criteria 
ITT 
Listing 16.2.2.3 
Drug Testing/Serology Screen 
ITT 
Listing 16.2.2.4 
Randomization 
ITT 
Listing 16.2.3.1 
Demographics 
ITT 
Listing 16.2.3.2 
Baseline Characteristics 
ITT 
Listing 16.2.3.3 
Baseline Assessment of Modified Hachinski 
Ischemia Scale (MHIS) 
ITT 
Listing 16.2.3.4.1 
Columbia-Suicide Severity Rating Scale (C-
SSRS) Lifetime 
ITT 
Listing 16.2.3.4.2 
Columbia-Suicide Severity Rating Scale (C-
SSRS) Last 6 Months 
ITT 
Listing 16.2.3.5 
APOE Genotype 
ITT 
Listing 16.2.4.1.1 
Medical History 
SAF 
Listing 16.2.4.1.2 
Alzheimer's Disease History 
SAF 
Listing 16.2.4.2 
Family Medical History 
SAF 
Listing 16.2.4.3 
Social History 
SAF 
Listing 16.2.4.4 
Exercise/Activity Level 
SAF 
Listing 16.2.4.5 
Tobacco Use 
SAF 
Listing 16.2.4.6 
Alcohol and Illicit Substance Use 
SAF 
Listing 16.2.4.7 
PET Scan 
SAF 
Listing 16.2.4.8 
Echocardiogram Results 
SAF 
Listing 16.2.5.1.1 
Prior Medications 
SAF 
Listing 16.2.5.1.2 
Previous Treatment for Alzheimer's Disease 
SAF 
Listing 16.2.5.2 
Concomitant Medications 
SAF 
Listing 16.2.5.3 
Extent of Exposure 
SAF 
Listing 16.2.5.4 
Infusion Rate 
SAF 
Listing 16.2.5.5 
Daily Summary of Infusion Administration 
SAF 
Listing 16.2.5.6 
Treatment Completion 
SAF 
Listing 16.2.5.7 
Tolerability 
SAF 
Listing 16.2.5.8 
Assessment of Blinding 
SAF 
Listing 16.2.6.1 
Mini-Mental State Examination (MMSE) 
ITT 
Listing 16.2.6.2 
Alzheimer’s Disease Assessment Scale-
Cognitive Subscale (ADAS Cog/11) 
ITT 


Alkahest, Inc. 
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PROTOCOL ALK6019-201 
Statistical Analysis Plan: Final Version 2.1 June 09, 2019 
Page | 32 
Number 
Title 
Population 
Listing 16.2.6.3 
Grooved Pegboard Test (GPT) 
ITT 
Listing 16.2.6.4 
Category Fluency Test (CFT) 
ITT 
Listing 16.2.6.5 
Clinical Dementia Rating Scale – Sum of 
Boxes (CDR-SOB) 
ITT 
Listing 16.2.6.6 
Alzheimer’s Disease Cooperative Study – 
Activities of Daily Living 23 (ADCS-ADL23) 
ITT 
Listing 16.2.6.7 
Alzheimer’s Disease Cooperative Study – 
Clinical Global Impression of Change rating 
(ADCS-CGIC) 
ITT 
Listing 16.2.6.8 
Neuropsychiatric Inventory Questionnaire 
(NPI-Q) 
ITT 
Listing 16.2.7.1 
Non Treatment Emergent Adverse Events 
SAF 
Listing 16.2.7.2 
Treatment Emergent Adverse Events 
SAF 
Listing 16.2.8.1 
Clinical Laboratory Results 
SAF 
Listing 16.2.8.2 
ECG Results 
SAF 
Listing 16.2.8.3 
MRI Testing 
SAF 
Listing 16.2.9 
Vital Signs 
SAF 
Listing 16.2.10 
Physical Examinations 
SAF 
Listing 16.2.11 
Columbia-Suicide Severity Rating Scale (C-
SSRS) Since Last Assessment 
SAF 


Alkahest, Inc. 
. 
PROTOCOL ALK6019-201 
Statistical Analysis Plan: Final Version 2.1 June 09, 2019 
Page | 33 
12 ATTACHMENTS 
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