Conditions: Severe Alzheimer Disease
Keywords: Brain Diseases Nervous System Diseases Central Nervous System Diseases Neurodegenerative Diseases Neurocognitive Disorders Mental Disorders Dementia Tauopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 26
Healthy volunteers: no

Brief summary:
This study will evaluate the safety, tolerability, and potential cognitive benefit of the experimental treatment GRF6019 in subjects with severe Alzheimer's disease.

Detailed description:
This is a randomized, double-blind, placebo-controlled study to assess the safety, tolerability and potential cognitive benefit of GRF6019, a human plasma protein fraction. GRF6019 or placebo will be administered intravenously to subjects with severe Alzheimer's disease every day for 5 consecutive days. The total study duration for each subject is approximately 9 weeks.

Arms:
arm 1: Subjects will receive intravenously 250 mL of GRF6019 each day for 5 consecutive days. arm 2: Subjects will receive intravenously 250 mL of placebo each day for 5 consecutive days.

Interventions: intervention 1: GRF6019 intervention 2: Placebo
Intervention descriptions: intervention 1: GRF6019 for IV infusion intervention 2: Placebo for IV infusion

Protocol document:
Prot_000.pdf: 


 
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CONFIDENTIAL/PROPRIETARY                                                                                                   Page 1 of 69 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................................... 1 
LIST OF ABBREVIATIONS .............................................................................................................. 5 
LIST OF DEFINITIONS ..................................................................................................................... 6 
PROTOCOL APPROVAL PAGE ...................................................................................................... 7 
STATEMENT OF COMPLIANCE .................................................................................................... 8 
PROTOCOL SUMMARY ................................................................................................................... 9 
SCHEMATIC OF STUDY DESIGN ................................................................................................ 11 
1 
KEY ROLES ........................................................................................................................... 11 
1.1 
AUTHORIZED REPRESENTATIVE (SIGNATORY) / RESPONSIBLE PARTY ........ 11 
1.2 
STUDY ORGANIZATION .................................................................................................... 11 
2 
INTRODUCTION .................................................................................................................. 11 
2.1 
BACKGROUND INFORMATION ...................................................................................... 11 
2.2 
RATIONALE .......................................................................................................................... 12 
2.3 
POTENTIAL RISKS AND BENEFITS ............................................................................... 15 
2.3.1 
KNOWN POTENTIAL RISKS ................................................................................................ 15 
2.3.2 
KNOWN POTENTIAL BENEFITS ......................................................................................... 15 
3 
OBJECTIVES AND PURPOSE ........................................................................................... 15 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................. 16 
4.1 
DESCRIPTION OF THE STUDY DESIGN ........................................................................ 16 
4.2 
STUDY ENDPOINTS ............................................................................................................ 16 
4.2.1 
PRIMARY ENDPOINTS ......................................................................................................... 16 
4.2.2 
SECONDARY ENDPOINTS ................................................................................................... 17 
4.2.3 
EXPLORATORY ENDPOINTS .............................................................................................. 17 
5 
STUDY ENROLLMENT AND WITHDRAWAL .............................................................. 17 


 
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5.1 
INCLUSION CRITERIA ....................................................................................................... 17 
5.2 
EXCLUSION CRITERIA ...................................................................................................... 18 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ............................................. 19 
5.4 
SUBJECT WITHDRAWAL OR TERMINATION ............................................................ 19 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION ........................................................ 19 
5.4.2 
HANDLING OF PARTICPANT WITHDRAWALS OR TERMINATION ............................ 20 
5.4 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................... 20 
6 
STUDY AGENT ..................................................................................................................... 20 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ..................................................... 20 
6.1.1 
ACQUISITION ......................................................................................................................... 20 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING ................................. 20 
6.1.3 
PRODUCT STORAGE AND STABILITY .............................................................................. 21 
6.1.4 
PREPARATION ....................................................................................................................... 21 
6.1.5 
DOSING AND ADMINISTRATION ...................................................................................... 21 
6.1.6 
ROUTE OF ADMINISTRATION ............................................................................................ 22 
6.1.7 
DOSING SCHEDULE .............................................................................................................. 22 
6.1.8 
DURATION OF THERAPY .................................................................................................... 22 
6.2 
STUDY AGENT ACCOUNTABILITY ................................................................................ 22 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................... 23 
7.1 
STUDY PROCEDURES/EVALUATIONS .......................................................................... 23 
7.1.1 
STUDY SPECIFIC PROCEDURES ........................................................................................ 23 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ........................................................... 28 
7.2.1 
CLINICAL LABORATORY EVALUATIONS ....................................................................... 28 
7.2.2 
OTHER ASSAYS OR PROCEDURES .................................................................................... 28 
7.2.3 
SPECIMEN PREPARATION, HANDLING, STORAGE, AND SHIPPING .......................... 29 
7.3 
STUDY SCHEDULE .............................................................................................................. 29 
7.3.1 
SCREENING ............................................................................................................................ 29 
7.3.2 
BASELINE ............................................................................................................................... 30 
7.3.3 
RANDOMIZATION ................................................................................................................. 30 
7.3.4 
TREATMENT .......................................................................................................................... 30 
7.3.5 
FOLLOW-UP VISITS .............................................................................................................. 31 
7.3.6 
FINAL STUDY VISIT ............................................................................................................. 31 
7.3.7 
EARLY TERMINATION VISIT .............................................................................................. 32 
7.3.8 
SCHEDULE OF EVENTS TABLE .......................................................................................... 32 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................ 32 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ...................... 32 
8 
ASSESSMENT OF SAFETY ................................................................................................ 32 


 
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8.1 
SPECIFICATION OF SAFETY PARAMETERS .............................................................. 32 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) ......................................................................... 32 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) ...................................................... 33 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ................................................................ 34 
8.2.1 
SEVERITY OF EVENT ........................................................................................................... 34 
8.2.2 
RELATIONSHIP TO STUDY AGENT ................................................................................... 35 
8.2.3 
EXPECTEDNESS .................................................................................................................... 35 
8.3 
TIME PERIOD/FREQUENCY FOR EVENT ASSESSMENT/FOLLOW-UP ................ 36 
8.3.1 
POST-STUDY AE AND SAE .................................................................................................. 36 
8.4 
REPORTING PROCEDURES .............................................................................................. 36 
8.4.1 
ADVERSE EVENT REPORTING ........................................................................................... 36 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING ......................................................................... 37 
8.4.3 
ADVERSE EVENTS OF SPECIAL INTEREST ..................................................................... 38 
8.4.4 
REPORTING OF PREGNANCY ............................................................................................. 38 
8.5 
STUDY HALTING RULES ................................................................................................... 39 
8.6 
SAFETY OVERSIGHT ......................................................................................................... 39 
9 
CLINICAL MONITORING ................................................................................................. 40 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 40 
10.1 
STATISTICAL DESIGN MODEL AND ANALYTICAL PLANS .................................... 40 
10.2 
STATISTICAL HYPOTHESES ........................................................................................... 40 
10.3 
ANALYSIS DATASETS ........................................................................................................ 40 
10.4 
DESCRIPTION OF STATISTICAL METHODS ............................................................... 41 
10.4.1 
GENERAL APPROACH .......................................................................................................... 41 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT ........................................................................ 41 
10.4.3 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINTS ............................................ 41 
10.4.4 
ANALYSIS OF THE SECONDARY SAFETY ENDPOINTS ................................................ 41 
10.4.5 
ADHERENCE AND RETENTION ANALYSES .................................................................... 42 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS .............................................................................. 42 
10.4.7 
PLANNED INTERIM ANALYSES ......................................................................................... 42 
10.4.8 
ADDITIONAL SUBGROUP ANALYSES .............................................................................. 42 
10.4.9 
MULTIPLE COMPARISON/MULTIPLICITY ....................................................................... 42 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA ....................................................... 42 
10.4.11 
EXPLORATORY ANALYSES .............................................................................................. 42 
10.5 
SAMPLE SIZE ........................................................................................................................ 43 
10.6 
MEASURES TO MINIMIZE BIAS ...................................................................................... 43 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES ...................................... 43 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING ...................................................................... 43 
10.6.3 
BREAKING THE STUDY BLIND/SUBJECT CODE ............................................................ 43 


 
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11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............ 44 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................... 44 
12.1 
ETHICAL STANDARD ......................................................................................................... 44 
12.2 
INSTITUTIONAL REVIEW BOARD ................................................................................. 44 
12.3 
INFORMED CONSENT PROCESS .................................................................................... 45 
12.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS ............................ 45 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION ........................................................ 45 
12.4 
DATA CONFIDENTIALITY ................................................................................................ 45 
12.5 
FUTURE USE OF STORED SPECIMENS ......................................................................... 46 
13 
DATA HANDLING AND RECORD KEEPING ................................................................ 47 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ............................ 47 
13.1.1 
INVESTIGATOR RESPONSIBILITIES.................................................................................. 47 
13.1.2 
STUDY FILES .......................................................................................................................... 47 
13.2 
STUDY RECORDS RETENTION ....................................................................................... 48 
13.3 
PROTOCOL DEVIATIONS ................................................................................................. 48 
13.4 
PUBLICATION AND DATA SHARING POLICY ............................................................ 49 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY .................... 50 
15 
SCHEDULE OF EVENTS .................................................................................................... 51 
15.1 
SCHEDULE OF EVENTS TABLE ...................................................................................... 51 
16 
REFERENCES ....................................................................................................................... 53 
16.1 
PUBLISHED REFERENCES ............................................................................................... 53 
16.2 
UNPUBLISHED REFERENCES .......................................................................................... 55 
17 
APPENDICES ........................................................................................................................ 56 
18 
REVISION HISTORY ........................................................................................................... 65 
18.1  
SUMMARY OF CHANGES .................................................................................................. 65 
 
 


 
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LIST OF ABBREVIATIONS 
AD 
Alzheimer’s Disease 
ADCS-ADL-
Severe 
Alzheimer’s Disease Cooperative Study Group Activities of Daily Living 
Inventory for Severe Alzheimer’s Disease 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study – Clinical Global Impression of 
Change Caregiver Input 
ADL 
Activities of daily living 
AE 
Adverse Event 
ApoE 
Apolipoprotein E 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CRO 
Contract Research Organization 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
ICH E6 R2 
International Conference on Harmonization Guidance for Industry, Good 
Clinical Practice: Consolidated Guidance, Revision 2 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHIS 
Modified Hachinski Ischemia Scale 
MMSE 
Mini-Mental State Examination 
NIA-AA 
National Institute on Aging – Alzheimer’s Association 
NODscid 
Non-obese diabetic severe combined immunodeficiency 
NPI 
Neuropsychiatric Inventory 
NPI-NH 
Neuropsychiatric Inventory Nursing Home Version 
NSG 
NODscid Gamma 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analytical Plan 
SIB 
Severe Impairment Battery 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UPCR 
Urine Protein-to-Creatinine Ratio 
US 
United States 
 
 
 


 
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LIST OF DEFINITIONS 
 
Infusion Nurse 
The unblinded study personnel, qualified by training and experience, responsible 
for administering the investigational product/placebo.  The Infusion Nurse ensures 
that the investigational product (GRF6019)/placebo is allocated appropriately and 
administered at the correct infusion rate.  The Infusion Nurse is also responsible 
for ensuring that appropriate blinding techniques are used to prevent inadvertent 
unblinding of study staff and subjects during and immediately following the 
Infusion Period.   
Infusion Period 
The period during which GRF6019/placebo is infused. 
Outcomes Assessor 
The blinded study personnel, qualified by training and experience, responsible 
for observing study subjects during the infusion of the investigational 
product/placebo 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 Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Safety and Tolerability of Pulsed GRF6019 Infusions in Subjects 
with Severe Alzheimer’s Disease 
Protocol Number: 
ALK6019-202 
Version/Date:  
V3.0_10JUL2019 
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 Practice, the Declaration of Helsinki in the latest relevant version, and applicable legal and 
regulatory requirements. 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
Sponsor Representative (print) 
Signature  
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: D8B978FB-444E-4AA5-9E13-1855E6E7A705
10-Jul-2019


 
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STATEMENT OF COMPLIANCE 
 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety 
and Tolerability of Pulsed GRF6019 Infusions in Subjects with Severe 
Alzheimer’s Disease 
Protocol Number: 
ALK6019-202 
 
Version/Date: 
V3.0_10JUL2019 
 
 
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 agent 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), 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 onsite 
inspection of source documents by appropriate regulatory authorities, including but not limited to the 
FDA, local governing regulatory bodies, and IRB inspectors. 
 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 
 


 
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PROTOCOL SUMMARY 
 
 
Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Safety and Tolerability of Pulsed GRF6019 Infusions in Subjects with 
Severe Alzheimer’s Disease 
 
Précis:  
This is a randomized, double-blind, placebo-controlled study to assess the 
safety and tolerability of GRF6019, a 
 human plasma protein fraction, 
administered by intravenous (IV) infusion in subjects with severe 
Alzheimer’s disease (AD). 
 
The study consists of approximately 20 subjects who will be randomized in 
a 2:1 ratio to active GRF6019 or placebo.  Treatment groups will be 
stratified by sex.  Subjects will receive one infusion per day of active or 
placebo treatment for 5 consecutive days during Week 1 of the study.  The 
total study duration for the subjects will be approximately 9 weeks. 
 
The infusion procedure of active and placebo agents will be identical to 
maintain blinding.  The following measures will be taken to ensure 
adequate allocation concealment during infusions: blinding of subjects, 
study coordinators, physicians, and cognitive test administrators to 
treatment allocation; use of blinded Outcomes Assessors and unblinded 
Infusion Nurses; and measures to block view of the 
 and other 
infusion equipment/supplies throughout the infusion. 
 
All subjects will undergo a screening visit, baseline visit, treatment period, 
follow-up visits, and an-end-of-study/early-termination visit.  Safety and 
tolerability assessments will occur at every visit.  Cognitive and other 
assessments will be performed at Baseline and periodically during 
subsequent visits through End of Study/Early Termination. 
 
Objectives: 
The primary objective of the study is to assess the safety and tolerability of 
an infusion dosing regimen of GRF6019 in subjects with severe AD.  As a 
secondary objective, the study will assess the potential effects of GRF6019 
on cognition and function.  The exploratory objectives include serial 
compositional analysis of plasma proteins to identify specific biomarkers 
associated with cognitive function and/or indicators of disease progression. 
 
Endpoints: 
Primary Endpoint(s):  
• 
Incidence of treatment-emergent AEs and SAEs identified by 
MedDRA preferred term (PT) and grouped by MedDRA System 
Organ Class (SOC) 
 
Secondary Endpoint(s):  
• 
Changes in safety laboratory parameters 
• 
Changes in vital signs 
• 
Changes in body weight 


 
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• 
Changes in physical exam 
• 
Changes in electrocardiogram (ECG) parameters 
• 
Changes in the Mini-Mental Status Examination (MMSE) 
• 
Changes in the Severe Impairment Battery (SIB) 
• 
Changes in the Alzheimer’s Disease Cooperative Study Group 
Activities of Daily Living Inventory for Severe Alzheimer’s Disease 
(ADCS-ADL-Severe) 
• 
Changes in the Alzheimer’s Disease Cooperative Study – Clinical 
Global Impression of Change Caregiver Input (ADCS-CGIC) 
• 
Change on the Neuropsychiatric Inventory (NPI) or NPI Nursing 
Home Version (NPI-NH) 
 
Exploratory Endpoint(s): 
• 
Proteomic assessment of plasma for investigation of study-related 
biomarkers  
 
Population: 
Approximately 20 subjects between 60 and 95 years of age with severe AD.  
Assuming a drop-out rate of 20%, enrollment of 20 subjects would yield 
approximately 16 evaluable subjects. 
 
Phase: 
2  
 
Number of Sites: 
Up to 4 sites in the United States (US) 
Description of Study 
Agent: 
GRF6019: A 
 human plasma protein fraction for IV infusion. 
 
Study Duration: 
Approximately 12 months 
 
Subject Duration: 
Approximately 9 weeks 
 
 












 
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4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
 
This will be a prospective, randomized, double-blind, placebo-controlled study conducted at up to four (4) sites in 
the United States.   
 
During the Screening Period, subjects will undergo all Screening assessments including an echocardiogram.  
During the Baseline Period, subjects and their caregivers will complete a series of cognitive and functional 
assessments. 
 
Subjects that meet eligibility for inclusion in the trial will be randomized in a 2:1 ratio to GRF6019 (Group 1) or 
placebo (Group 2).  Treatment groups will be stratified by sex. There will be one (1) dosing period during which 
subjects randomized to GRF6019 will receive GRF6019, while subjects randomized to placebo will receive 
placebo.  The dosing period consists of 5 consecutive days (“pulsed dosing”) of IV infusions of 250 mL of either 
GRF6019 or placebo. 
 
During the 5-day dosing period, subjects who do not already reside in a long-term care/skilled nursing facility will 
be admitted to such a facility to facilitate safety evaluation.  Safety and tolerability assessments will occur at 
every visit.  Cognitive and functional assessments will be performed at Baseline and periodically at subsequent 
visits through End of Study/Early Termination.  In the event of early termination of a subject who has received at 
least one dose, the End of Study procedures will be performed unless the subject/subject’s legally authorized 
representative has withdrawn consent.  A comprehensive safety and efficacy assessment of all data in toto will be 
conducted at the end of the study. 
 
The overall duration of the study is approximately 12 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 9 months.  
The subject participation period is 9 weeks from Screening through End of Study, unless prematurely 
discontinued. 
 
4.2 
STUDY ENDPOINTS 
 
4.2.1 
PRIMARY ENDPOINTS 
 
The primary endpoints pertain to safety and tolerability of the GRF6019 dosing regimen in subjects with 
severe AD.   
 
The primary safety endpoint is as follows: 
• 
Incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) identified 
by MedDRA PT and grouped by MedDRA SOC. 
 
Tolerability endpoint is as follows: 
• 
Number of subjects completing 4 weeks after receiving at least 5 infusions. 
 
 


 
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4.2.2 
SECONDARY ENDPOINTS 
 
This study is not powered to detect statistically significant differences in cognitive domains between the 
baseline and end of study values.  Secondary endpoints will be summarized over the study period from 
baseline values using descriptive statistics. 
 
Secondary safety endpoints are as follows: 
• 
Changes from baseline in clinical laboratory parameters.  
• 
Changes from baseline in vital sign measurements. 
• 
Changes in body weight from baseline to Visit 8. 
• 
Changes from baseline in physical exam parameters at Visit 10 or End of Study/Early Termination. 
• 
Changes from baseline in ECG recordings. 
 
Secondary efficacy endpoints are as follows: 
• 
Changes in the MMSE (Folstein 1975, Appendix 1). 
• 
Changes in the SIB (Panisset 1994, Appendix 2). 
• 
Changes in the ADCS-ADL-Severe (Galasko 2005, Appendix 3). 
• 
Changes in the ADCS-CGIC (Ferris 1997, Schneider 1997, Appendix 4). 
• 
Change on the NPI/NPI-NH (Cummings 1994, Wood 2000, Appendix 5). 
 
Secondary feasibility endpoints include: 
• 
Subject compliance with the study visit schedule, procedures, infusions, and any required adaptations 
that are necessary for study completion. 
• 
Success of blinding.  This will be assessed based on all occurrences (intentional or unintentional) of 
unblinding of blinded study subjects 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 
biomarkers.  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.   
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible for inclusion, all subjects must meet the following criteria: 
1. Male or female, aged 60-95 years (inclusive). 
2. Diagnosis of AD based upon the National Institute on Aging-Alzheimer’s Association (NIA-AA) 
Criteria. 
3. MMSE Score 0 – 10 (inclusive). 
4. Modified Hachinski Ischemia Scale (MHIS) score of ≤ 4. 
5. If on medications for cognition (e.g., rivastigmine, galantamine, donepezil, memantine), must be on 
stable dosage for at least 8 weeks prior to Baseline. 


 
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6. If on daily antidepressant medications and/or benzodiazepines and/or typical or atypical 
antipsychotics, must be on stable dosage for 8 weeks prior to Baseline. If on prn dosing with atypical 
antipsychotics and/or benzodiazepines, these should not be given within 24 hours before each day of 
cognitive and other ratings (V1, V2, V8, V9, V10).  
7. The subject (with support of a caregiver and/or staff) must be able to follow the study protocol, receive 
the treatment in the established timeframe, and continue during the follow-up interval.   
8. The subject must be sufficiently fluent in English and have visual and auditory acuity sufficient to be 
capable of reliably completing all study assessments. 
9. Provided a signed and dated informed consent form (subject’s legal representative) in accordance with 
local regulations/guidelines/IRB. 
10. 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 and no microalbuminuria.  
11. Systolic ejection fraction of ≥ 55% on trans-thoracic echocardiogram. 
 
5.2 
EXCLUSION CRITERIA 
 
An individual will not be eligible for inclusion if any of the following criteria apply: 
1. Evidence of clinically relevant neurological disorder(s) other than probable AD. 
2. History of 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 allowed. 
3. Prior hypersensitivity reaction to any human blood product or intravenous infusion; any known 
clinically significant drug allergy.  
4. Treatment with any human blood product, including transfusions and intravenous immunoglobulin, 
during the 6 months prior to Screening.  
5. History of immunoglobulin A (IgA), haptoglobulin or C1 inhibitor deficiency.  
6. History of anaphylaxis or thromboembolic events as a complication of intravenous immunoglobulins.  
7. Unstable coronary heart disease, e.g. myocardial infarction or severe or unstable angina in the 6 
months prior to dosing. 
8. Clinically significant abnormalities on echocardiogram. 
9. Moderate to severe congestive heart failure (New York Association Class III or IV). 
10. 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. 
11. History of Torsades de Pointes dysrhythmia. 
12. Clinically significant abnormalities on screening ECG including QTc intervals (using Fridericia’s 
correction formula) of ≥ 450 ms in men and ≥ 470 ms in women. 
13. History of hypocalcemia of any kind, including secondary to absorption syndromes secondary to 
gastric bypass surgery. 
14. Clinically significant liver disease or biliary abnormalities.  
15. Uncontrolled diabetes defined as HbA1c >7.5%. 
16. Malignancy for which the subject has undergone resection and/or radiation and/or chemotherapy in the 
past 3 years; treated basal cell carcinoma and/or fully cured squamous cell carcinoma is allowed. 
17. Clinically significant abnormalities in complete blood count, complete metabolic panel, serum 
albumin, blood coagulation tests, or the levels of thiamine, pyridoxine, cobalamin and thyroid 
stimulating hormone. 


 
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18. Hemoglobin <10 g/dL in women and <11 g/dL in men. 
19. Urine protein-to-creatinine ratio (UPCR) of > 1.5 grams of protein per gram of creatinine. 
20. Inadequate venous access to allow IV drug delivery or blood draws.  
21. Concurrent participation in any other therapeutic treatment trial.  If there was prior clinical trial 
participation, subject must have discontinued investigational agents for at least 30 days for small 
molecules, and 1 year for active or passive immunotherapies prior to Screening.  
22. Subjects who have a level of agitation that, in the opinion of the investigator, could interfere with 
study procedures. 
23. 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. 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
The Sponsor does not anticipate any specific challenges in meeting recruitment goals of enrolling  and retaining a 
total of approximately 20 subjects in this study.  Subjects will be recruited continuously until the planned sample 
size is achieved.  Subjects who withdraw or are withdrawn during Screening, as well as subjects who discontinue, 
may be replaced (see Section 5.4.2 Handling of Participant Withdrawals or Termination).  
 
This trial is enrolling subjects with severe AD who have sufficient cognitive impairment to be considered a 
vulnerable population.  In this situation, consent will be obtained from the legally authorized representative.  The 
subject’s agreement to participate in the study will be obtained via an informed assent form and/or to their best 
level of his or her understanding.  Recruitment will not proceed if the subject refuses, shows significant distress, 
or the legally authorized representative refuses.   
 
The expected length of participation in the study, ~9 weeks, is not expected to be unduly onerous on subjects.  
Financial support for meal, travel, and miscellaneous expenses may be provided, as appropriate, and based on 
local regulations and guidelines.  It is expected that meals will be provided by the study facilities as needed.  Use 
of visit transport services may also be incorporated into the trial to support the subject in maintaining study visit 
compliance. 
 
A description of the clinical trial will be posted on clinicaltrials.gov to 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 an 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, 
Sponsor, or medical monitor.  The investigator must follow the subject until the AE resolves or is 
stable, unless the subject is lost to follow up. 
• 
Treatment with a prohibited concomitant medication other than the use of appropriate medications 
for the treatment of AEs under direction of the investigator. 
• 
Subject noncompliance, defined as refusal or inability to adhere to the trial schedule or procedures. 
• 
At the request of the subject’s legally authorized representative (e.g., withdraws consent), 


 
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investigator, Sponsor, or regulatory authority. 
• 
Pregnancy. 
 
5.4.2 
HANDLING OF PARTICPANT 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 20 subjects will be enrolled in the study with the intent of obtaining ~16 evaluable subjects 
who have received at least 5 doses and completed through Visit 8.  Subjects who discontinue or are unblinded 
prior to completing Visit 8 may be replaced.  Subjects who withdraw or are withdrawn during Screening will 
be replaced.   
 
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 approximately 4 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). 
 
5.4 
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 statues 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. 
• 
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 
 
GRF6019 is manufactured by Grifols Therapeutics, Inc. (Clayton, North Carolina, US).  The placebo control 
agent will be 0.9% sodium chloride injection, USP (saline).  The study agent and placebo will be supplied to 
the sites directly from a depot.   
 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
 




 
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6.1.6 
ROUTE OF ADMINISTRATION 
 
The study agent and placebo will be administered by IV route only. 
 
6.1.7 
DOSING SCHEDULE 
 
Subjects will be randomized to receive either GRF6019 or placebo.  Randomization to treatment group will 
be stratified by sex.  Subjects will receive one infusion of 250 mL per day for 5 consecutive days at Week 1. 
 
6.1.8 
DURATION OF THERAPY 
 
From Screening to End of Study, the duration of study involvement for each subject is approximately 9 
weeks.  
 
All subjects will receive 5 consecutive days of therapy during Week 1.  Thus, the duration of therapy for all 
subjects will be 5 exposure days.  The duration of therapy for a subject to be considered evaluable in the 
intent-to-treat population is 4 exposure days. 
 
6.2 
STUDY AGENT ACCOUNTABILITY 
 
Under the supervision of the investigator, the unblinded study pharmacist or other qualified personnel is 
responsible for ensuring adequate accountability of all used and unused study agent and placebo control agent.  
This includes acknowledgment of receipt of each shipment of study agent and placebo (quantity and condition), 
subject dispensing records, and returned or destroyed study agent/placebo.  Dispensing records will document 
quantities received and quantities dispensed to subjects including the date dispensed, intended subject’s study 
identifier, initials of the individual responsible for dispensing, and initials of the Infusion Nurse administering the 
study agent.  Drug accountability will be monitored by an unblinded clinical study monitor.  
 
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/placebo accidentally wasted or intentionally disposed of must be maintained.  
 
The disposal of used, partially used, or wasted study agent/placebo must be performed in accordance with the 
institution’s drug disposal policy, or as directed by Sponsor.  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/placebo, including empty 
containers.  A copy of the institution’s drug disposal policy should be maintained or referenced in the 
investigator’s study file. A certificate of (study agent/placebo) destruction must be provided to the Sponsor if 
destroyed on site. 
 
 


 
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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: 
• 
Assessment of AD  
• 
MMSE 
• 
MHIS 
• 
Medical history 
• 
Demographics 
• 
Review of medications 
• 
Vital signs 
• 
Physical examination 
• 
12-lead ECG 
• 
Echocardiogram 
• 
Blood and urine collection for laboratory evaluations 
 
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 Assessment of 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 (Refer to Section 7.1.1.1.2) 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.   
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.   
 
 


 
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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 nonfluent/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 cerebrospinal fluid biomarkers will be evaluated, if 
available, to support the clinical diagnosis of AD.   
 
7.1.1.1.2 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 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.   
 
7.1.1.1.3 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. 
 
7.1.1.1.4 Medical History 
The investigator or designee will obtain a detailed medical history through interview with the 
subject’s caregiver(s) 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 of any active medical condition. 
• 
Surgeries and procedures. 
• 
Allergies. 
• 
Family history in biological parents, siblings, and offspring of AD, other dementias, or neurological 


 
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disorders, if known. 
• 
Social history (e.g. smoking, alcohol, illegal substances), if known. 
• 
Prior imaging, cerebrospinal fluid assessments, or other relevant diagnostic tests, including genetics, 
if available.  
 
7.1.1.1.5 Demographics 
Demographic information such as the subject’s education level, ethnicity, and race may be collected at 
Screening if available. 
 
7.1.1.1.6 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. 
 
7.1.1.1.7 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 body temperature.  Vital signs should be measured after the 
subject has been seated for 5 minutes. 
 
7.1.1.1.8 Physical Examination 
A complete physical examination will be performed to assess the following organ systems: skin, ears, nose, 
throat, head, eyes, lungs/chest, heart, abdomen, musculoskeletal, extremities, neurologic, and lymphatic 
systems.  Height and weight will also be documented as specified in Section 15 Schedule of Events. 
 
7.1.1.1.9 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.   
 
7.1.1.1.10 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).   
 
7.1.1.1.11 Biological Specimen Collection  
Biological samples will be obtained, analyzed, and stored appropriately for future analysis.  Blood 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 in Section 15 Schedule of Events.   
 
 


 
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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.  
Subjects (or their legally authorized representatives) can opt out of storage of samples for future analysis.   
 
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 
• 
12-Lead ECGs 
• 
Targeted physical exams  
• 
Weight 
• 
End of Study (or Early Termination) physical examination 
• 
Blood and urine collection for clinical laboratory evaluations 
 
7.1.1.2.1 Review of Adverse Events 
AEs will be reviewed, documented, and reported as required at each visit (from time of consent through End 
of Study).  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 7.1.1.1.7 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 12-Lead ECG 
Refer to Section 7.1.1.1.9 for information pertaining to 12-Lead ECGs. 
 
7.1.1.2.5 Targeted Physical Exams 
During the dosing period, 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).  
 
7.1.1.2.6 Physical Examination 
Refer to Section 7.1.1.1.8 for a description of the complete physical exam.  The complete physical exam will 
be performed at Screening and repeated at End of Study (or Early Termination).   
 
7.1.1.2.7 Blood and Urine Collection for Laboratory Evaluations 
As described in Section 7.1.1.1.11, subjects will have blood and urine samples collected for clinical 


 
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evaluation (Section 7.2.1 Clinical Laboratory Evaluations).  Refer to Section 15 Schedule of Events for timing 
and frequency of blood and urine collection for laboratory evaluations.   
 
7.1.1.3 
Procedures to Assess Efficacy 
Cognitive function will be assessed using assessment scales administered by qualified raters.  Raters must be 
certified, as appropriate.  The same rater should be used for the duration of each subject’s participation unless 
a change in rater is unavoidable.  Additionally, for scales that require an informant (e.g., caregiver), the 
informant should be consistent throughout the duration of each subject’s participation unless a change is 
unavoidable.  Informants must have frequent contact with the subject (defined as approximately 10 hours per 
week).  The following scales will be used during the course of this study: 
• 
MMSE 
• 
SIB 
• 
ADCS-ADL-Severe 
• 
ADCS-CGIC 
• 
NPI or NPI-NH 
 
Information regarding the timing and frequency of these procedures is provided in 7.3 Study Schedule. 
 
7.1.1.3.1 Mini-Mental Status Examination  
Refer to Section 7.1.1.1.2 for information pertaining to the MMSE.  
 
7.1.1.3.2 Severe Impairment Battery 
The SIB is designed to assess cognitive abilities in patients with severe AD.  The SIB is divided into scorable 
subscales that cover orientation to time and place, attention, language, praxis, visuospatial ability, 
construction, memory, orientation to name, and social interaction.  Scoring gives credit to nonverbal and 
partially correct answers, thus decreasing the need for language output.  There are 57 items, and it takes 
approximately 20 minutes to complete.  The range of possible scores is 0-133 (Panisset 1994, Appendix 2). 
 
7.1.1.3.3 Alzheimer’s Disease Cooperative Study Group Activities of Daily Living Inventory for Severe 
Alzheimer’s Disease  
The ADCS-ADL-Severe assesses the competence of patients with AD in performing basic activities of daily 
living.  The ADCS-ADL-Severe contains 19 items covering physical and mental functioning and 
independence in self-care (e.g. dressing, grooming, bathing, eating, walking, and toileting).  For each ADL, 
an informant (e.g., caregiver) is first asked if the patient attempted the activity during the past 4 weeks.  If a 
patient did attempt the ADL, the informant is asked to choose the single most accurate definition of the 
patient’s level of performance.  The scores range from 0 to 54, with higher scores indicating less functional 
impairment (Galasko 2005, Appendix 3). 
 
7.1.1.3.4 Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change Caregiver Input 
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.  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 (Ferris 1997, 
Schneider 1997, Appendix 4).  
 
 
 


 
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7.1.1.3.5 Neuropsychiatric Inventory or Neuropsychiatric Inventory – Nursing Home Version 
The NPI (Cummings 1994) comprises 10 behavioral areas and 2 types of neurovegetative changes (12 
domains): delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep and nighttime behavior 
disorders, and appetite/eating changes.  Information is gathered from caregivers familiar with the patient’s 
behavior. To serve as an informant, the caregiver must have at least daily contact with the patient. Initial 
responses to each domain screening question are "Yes" (present) or "No" (absent).  If the response to the 
domain question is "No," the interviewer goes to the next question.  If "Yes," the interviewer proceeds to ask 
the informant a series of subquestions for that domain.  For each behavioral domain, there are 4 scores: 
frequency, severity, domain total score (frequency x severity), and occupational disruptiveness.  Thus, the 
NPI evaluates response to therapy and provides symptom severity and distress ratings for each symptom 
reported, as well as total severity and distress scores reflecting the sum of individual domain scores 
 
The NPI-NH was derived from the NPI (Cummings 1994) to evaluate the neuropsychiatric manifestations and 
psychopathology of patients with AD and other dementias who reside in nursing homes, extended care 
facilities, or other long-term care settings.  The NPI-NH is an interview-based scale designed to be 
administered to an informed professional nursing home caregiver (as opposed to a family or home-based 
caregiver in the standard NPI) involved in the daily care of the subject.  Generally, the NPI-NH is used to 
evaluate changes in subject behavior that have appeared during a given period (Wood 2000, Appendix 5). 
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 
 
Biological samples (e.g. whole blood, serum, urine, buccal swab) will be collected for laboratory evaluations 
in accordance with the Schedule of Events (Section 15).  Clinical sample processing and laboratory 
evaluations will be conducted by certified Clinical Laboratory Improvement Amendments (CLIA) facilities.  
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, and other exploratory measures.   
 
7.2.2.2 
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 


 
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the study’s laboratory manual and Section 15 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. 
 
7.2.3 
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 33 ± 7 days.  Study visit procedures are listed in the recommended order in 
which they should be completed.   
 
7.3.1 
SCREENING 
 
Screening Visit (Day -28 to -8)  
□ Obtain informed consent from the subject’s legally authorized representative and informed assent from 
the subject, if applicable, prior to performing any study-related assessments. 
□ Assess for probable AD using NIA-AA criteria and administer the MMSE. 
□ Conduct the MHIS. 
□ Obtain medical history to determine eligibility based on inclusion/exclusion criteria. 
□ Collect demographic information. 
□ Review subject’s current and prior medications. 
□ Collect vital signs, height, and weight. 
□ Perform the physical exam. 
□ Perform the 12-lead ECG. 
□ Collect blood and urine specimens for labs. 
□ Perform transthoracic echocardiogram. 
 
Note: The Screening Visit may be split to allow sufficient time to complete all required procedures.  AEs and 
concomitant medications should be recorded during split visits, if applicable.  
 
 


 
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7.3.2 
BASELINE 
 
Baseline Visit (Days -7 to -1) 
□ Re-review Screening assessments for eligibility. 
□ Review AEs and concomitant medications. 
□ Collect vital signs. 
□ Ensure the subject has had an opportunity to eat a meal or snack prior to administering cognitive and 
functional assessments. 
□ Administer cognitive and functional assessments in the following order: 
1. SIB 
2. ADCS-ADL-Severe 
3. ADCS-CGIC 
4. NPI or NPI-NH 
 
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. 
 
7.3.4 
TREATMENT 
 
The treatment period includes a total of 5 infusions during Week 1.  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 the treatment period. 
 
Visits 3 -7 (Days 1-5)  
□ Perform the following procedures prior to administering study treatment: 
o Review AEs and concomitant medications. 
o Obtain samples for proteomics/epigenetics/biobanking; fasting samples preferred (Visit 3 
Only). 
o Obtain sample for ApoE genotype testing (Visit 3 Only). 
o Obtain pre-infusion safety laboratory samples and assess results prior to the next day’s 
infusion (Visits 4, 5, and 6 Only). (When using an i-STAT Handheld Blood Analyzer, the 
blood sample(s) may be obtained on the same day as the infusion, provided that all pre-
infusion safety lab results are available and interpreted prior to the subject’s infusion start on 
Visits 5, 6, and 7.) 
o Collect urine for urinalysis (Visit 6 Only). 
o Measure and record the subject’s weight in kilograms. 
o Perform targeted physical exam (i.e. auscultation of heart and lungs and assessment of 
peripheral edema) (Visits 3, 5, and 7 Only). 
o Perform 12-lead ECG (Visits 3 and 5 Only). 
o Collect pre-infusion vital signs.  
□ Administer study treatment and perform safety assessments per the Infusion Administration Manual.  


 
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7.3.5 
FOLLOW-UP VISITS 
 
Follow-up Visit 8 (Day 6 + 3 days)  
□ Review AEs and concomitant medications. 
□ Collect the following: 
o Vital signs and subject’s weight in kilograms. 
o Blood and urine samples for safety labs (fasting samples preferred). 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred). 
□ Perform 12-lead ECG. 
□ Ensure the subject has had an opportunity to eat a meal or snack prior to administering cognitive and 
functional assessments. 
□ Administer cognitive and functional assessments in the following order:  
1. SIB 
2. ADCS-CGIC 
 
Follow-up Visit 9 (Day 12 ± 3 days) 
□ Review AEs and concomitant medications. 
□ Collect the following: 
o Vital signs and subject’s weight in kilograms. 
o Blood samples for safety labs (fasting samples preferred). 
□ Ensure the subject has had an opportunity to eat a meal or snack prior to administering cognitive and 
functional assessments. 
□ Administer cognitive and functional assessments in the following order:  
1. SIB 
2. ADCS-CGIC 
3. NPI or NPI-NH 
 
7.3.6 
FINAL STUDY VISIT 
 
Visit 10, End of Study (Day 33 ± 7 days) 
□ Review AEs and concomitant medications. 
□ Collect the following: 
o Vital signs and subject’s weight in kilograms. 
o Blood and urine samples for exit safety labs (fasting samples preferred). 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred). 
□ Perform the physical exam. 
□ Perform the 12-lead ECG. 
□ Ensure the subject has had an opportunity to eat a meal prior to administering the cognitive and 
functional assessments. 
□ Administer cognitive and functional assessments in the following order: 
1. MMSE 
2. SIB 
3. ADCS-ADL-Severe 
4. ADCS-CGIC 
5. NPI or NPI-NH 
 
 


 
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7.3.7 
EARLY TERMINATION VISIT 
 
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.   
 
7.3.8 
SCHEDULE OF EVENTS TABLE 
 
A tabular summary of all procedures by study visit can be found in Section 15 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., AE, etc.). 
 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
The following are prohibited: 
• Concurrent participation in any other therapeutic treatment trial.  If there was prior clinical trial 
participation, subject must have discontinued investigational agents for at least 30 days for small 
molecules, and 1 year for active or passive immunotherapies prior to Screening.  
• 
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. 
• 
Any drugs of the interferon class. 
• 
Systemic corticosteroids (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 whether GRF6019 or placebo was received by a subject is essential.  Any instances of unblinding 
will be managed as indicated in Section 10.6.3 Breaking the Study Blind/Subject 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 


 
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(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 or the subject’s caregiver 
and/or observed by the investigator or study staff. 
• 
Increase in frequency or intensity of a pre-existing episodic event or condition. 
• 
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/caregiver. 
• 
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) 
 
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. 


 
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• 
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. 
• 
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. 
 
Note: 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: the terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the grade of an 
AE.  “Serious” is a regulatory definition.   
 
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:  
 
 




 
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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/FREQUENCY FOR EVENT ASSESSMENT/FOLLOW-UP 
 
At every study visit, subjects will be assessed for AEs and SAEs.  After the subject/subject’s caregiver 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?” 
 
8.3.1 
POST-STUDY AE AND SAE 
 
The investigator is not obligated to actively seek SAE information in former study subjects, 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, 


 
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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 AEs, 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. 
 
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. 
 


 
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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 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 AEs of special interest (AESI):  
• 
Clinically-significant peripheral edema or pulmonary edema. 
• 
Reduced kidney function (eGFR <45 mL/min/1.73 m2). 
• 
Suspected transmission of blood-borne infectious agents. 
 
AESIs 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 or female partner of a male 
subject subsequent to first exposure to the study agent until End of Study, or 3 months following a subject’s 


 
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last dose in the event of early termination.  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(s) 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 (see Section 8.2.2 Relationship to Study Agent). 
• 
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 Meeting. 
 
Safety Evaluation Meeting 
 
If safety events of potential concern occur during the trial (i.e., 3 related events in the same SOC or a suspicious 
overall pattern, 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, unless the Sponsor deems unblinding 
necessary for safety evaluation.   
 
Attendants at the Safety Evaluation Meeting will include the Program Physician of Alkahest (or his/her designee), 
the CRO Medical Monitor, and available 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 site investigators.  There will be no formal Data Safety Monitoring Board 
(DSMB) established.  As needed, 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. 


 
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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) 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 tasks and scope 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 or the Sponsor’s designee to ensure monitoring 
practices are performed consistently across all participating sites and that monitors are following the CMP. 
 
10 
STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL DESIGN MODEL AND ANALYTICAL PLANS 
 
A Statistical Analysis Plan (SAP) with analytical details and assumptions will be developed and finalized before 
database lock and unblinding of the study data. 
 
10.2 STATISTICAL HYPOTHESES 
 
Because the primary objective of the study is safety and tolerability, it is not designed to detect statistically 
significant differences between active and placebo on efficacy endpoints.  The statistical approach toward 
secondary efficacy endpoints will be primarily descriptive; 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 subjects. 
• 
Safety Dataset: all subjects who received at least one dose of the study agent.   
• 
Evaluable Dataset:  all subjects who receive at least 4 of the 5 planned doses. 
o Per Protocol Dataset:  a subset of the Evaluable Dataset. A detailed description of the reasons for 
exclusion from the Per Protocol population will be included in the Statistical Analysis Plan (SAP). 
 
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. 
 


 
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10.4 DESCRIPTION OF STATISTICAL METHODS  
 
10.4.1 
GENERAL APPROACH 
 
Using the Evaluable and/or Per Protocol Datasets, all secondary endpoints will be summarized serially over 
time using descriptive statistics to assess the within-subject changes and between-group differences.  Overall 
baseline and demographic data will be summarized using descriptive statistics; between-groups testing will 
be used to evaluate the effectiveness of the randomization in producing homogeneous pre-treatment groups.   
 
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 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 
 
Safety and tolerability will be evaluated by examining the occurrence of AEs, including Treatment-Emergent 
AEs and AEs leading to discontinuation from the study.   
 
Summary tabulations of reported AEs 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 EFFICACY ENDPOINTS 
 
The study is not powered to detect significant changes in cognition, function, ADLs, etc.; however, using 
available data from analysis of the secondary efficacy endpoints, including changes in scores from baseline, 
descriptive summaries 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 between groups to evaluate any 
trends in differences between subjects randomized to active and placebo agents.   
 
10.4.4 
ANALYSIS OF THE SECONDARY SAFETY ENDPOINTS 
 
Actual values and changes from baseline in clinical laboratory measurements, vital signs, and body weight 
will be assessed and summarized.  Abnormal lab or vital sign 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 deciding and documenting whether an abnormal 


 
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laboratory finding or other abnormal assessment is clinically significant. 
 
For secondary safety endpoints that are continuous in nature (e.g. clinical laboratory parameters, systolic and 
diastolic blood pressure, heart rate, respiratory rate, temperature, body weight) the mean, median, minimum, 
maximum, and standard deviation will be plotted over time. 
 
For secondary safety endpoints that are categorical in nature (e.g. physical exam or ECG abnormalities), the 
frequency counts and percentages will be presented as a descriptive summary. 
 
Per-subject extent of exposure will be listed. 
 
10.4.5 
ADHERENCE AND RETENTION ANALYSES 
 
Subject adherence with study visit schedule, visit procedures, infusions, and subject retention will be 
assessed.   
 
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 interim analysis is conducted, the treatment 
assignment will remain masked, unless unblinding is deemed necessary by the Sponsor for safety 
evaluation.   
 
10.4.8 
ADDITIONAL SUBGROUP 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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their representatives.  If unintentional unblinding occurs during the study, root cause analysis will be 
evaluated, and corrective actions implemented as appropriate. 
 
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 subjects.  Each site 
will permit authorized representatives of regulatory agencies, the IRB, 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, subject’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 
subject 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. 
 
12.2 INSTITUTIONAL REVIEW BOARD 
 
This protocol and any accompanying material to be provided to the subject/subject’s legally authorized 
representative (such as advertisements, information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB.  Approval from the IRB 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 subjects need to be re-consented. 
 
Any modifications or amendments to the protocol must also be submitted to the IRB for approval prior to 
implementation. 
 


 
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12.3 INFORMED CONSENT PROCESS 
 
12.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
 
Consent/assent forms describing in detail the study intervention, study procedures, and risks are given to the 
subject and/or the subject’s legally authorized representative and written documentation of informed consent 
is required prior to performing any study-related procedures.  
 
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 or their legally authorized representative after adequate explanation of the aims, 
methods, objectives, and potential hazards of the study and prior to performing any study-related procedures. 
 
Subjects and/or their legally authorized representatives should have the opportunity to discuss the study with 
family members or other advisors and be given adequate time to consider participation carefully.  Subjects or 
their legally authorized representatives may voluntarily withdraw consent at any time throughout the course 
of the study.  The rights and welfare of subjects will be protected by emphasizing that the quality of their 
medical care will not be adversely affected if they or their legally authorized representative declines 
participation in the study. 
 
The investigator or designee must utilize an IRB-approved consent/assent 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 (if appropriate) and/or their 
legally authorized representative and the person obtaining consent.  A copy of the signed consent form (and 
assent form if applicable) will be provided to the subject and/or their 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 information about the potential candidate (e.g., date of screening).  
 
All consented subjects 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 the Health Insurance Portability and Accountability Act (HIPAA). 
 
12.4 DATA CONFIDENTIALITY  
 
Subject 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 subjects.  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 


 
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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, 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 subjects in this study.  
The clinical study site will permit the study monitor to 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.  
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 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, 
de-identified biological samples may be stored at Alkahest, or designee, for future use.  These samples could be 
used for research and to improve treatment.  Alkahest will also be provided with a code-link that will allow 
linking the biological samples with the specific data from each subject, maintaining the masking of the identity of 
the study subject.  Subjects/subject’s legally authorized representatives may choose whether the Sponsor can store 
and use samples for further research. 
 
During the conduct of the study, an individual subject (or subject’s legally authorized representative) can choose 
to withdraw consent to have biological samples stored for future research.  However, withdrawal of consent for  
storage of biological samples 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, or designee.  In 
the event Alkahest transfers ownership to another commercial Sponsor, ownership of the samples may be 
transferred as well.  
 
 


 
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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 
investigator.  The investigator is responsible for ensuring the accuracy, completeness, and timeliness of the data 
reported. 
 
Source documents provide evidence for the existence of the subject and substantiate the integrity of the data 
collected.  Source documents are filed at the investigator’s site.  Data entered in the CRFs that are transcribed 
from source documents must be consistent with the source documents or the discrepancies must be explained.  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.  The investigator may need to request previous medical 
records or transfer records, depending on the trial; also, current medical records must be available. 
 
For each subject who receives the study agent/placebo, the CRF must be completed in a timely manner.  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, 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 procedures 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), 
ICH GCP, and applicable regulatory requirements.  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, IRB approval with correspondence, 
informed consents, drug records, staff curriculum vitae and authorization forms, and other appropriate 
documents and study-specific manuals (e.g., lab manual). 
 
Subject clinical source documents would include (although are not limited to) the following: subject 


 
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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 study 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 
 
Protocol Deviations are any change, divergence, or departure from the study design or procedures defined in the 
protocol.  Noncompliance with the clinical trial protocol 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 a study-specific Protocol 
Deviation plan.   
 
Major Protocol Deviations are departures from the approved protocol relating to the conduct of the study 
which may significantly impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect the rights, safety, or wellbeing of study participants.  Major Protocol Deviations may 
result in data that are not deemed evaluable for the per protocol analysis and/or may require that subjects 
are discontinued from the study.   
 
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.  
 
All deviations will be logged and tracked at the site and study level.  Periodic review of Protocol Deviations will 


 
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serve as an indicator 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.  Notification of 
Protocol Deviations must be sent to the local IRB per their guidelines.  The site investigator and applicable study 
staff are 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 90 days 
to review all definitive publications, such as manuscripts and book chapters, and a minimum of 30 days to review 
all abstracts. 
 
 


 
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14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY 
 
A separate financial disclosure agreement will be made between each principal investigator and Alkahest, Inc. or 
its authorized representative before the study agent is shipped.  Each investigator will notify Alkahest, Inc. or its 
authorized representative of any relevant changes during the conduct of the study and 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. 
 


 
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15 
SCHEDULE OF EVENTS 
15.1 SCHEDULE OF EVENTS TABLE 
 
 




 
 
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16 
REFERENCES 
16.1 PUBLISHED REFERENCES 
 
Alzheimer’s Association. 2018 Alzheimer's Disease Facts and Figures. Alzheimers Dement. 2018;14(3):367-
429. 
 
 
 
 
 
 
 
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. 
 
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric 
Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44:2308-2314. 
 
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. 
 
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. 
 
 
 
 
Galasko D, Schmitt F, Thomas R, Jin S, Bennett D, Ferris D; Alzheimer's Disease Cooperative Study. 
Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease. J Int Neuropsychol 
Soc. 2005 Jul;11(4):446-453. 
 


 
 
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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. 
 
Larson EB, Shadlen MF, Wang L, McCormick WC, Bowen JD, Teri L, et al. Survival after initial diagnosis 
of Alzheimer disease. Ann Intern Med. 2004;140(7):501-509. 
 
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. 
 
Panisset M, Roudier M, Saxton J, Boller F. Severe impairment battery. A neuropsychological test for severely 
demented patients. Arch Neurol. 1994 Jan;51(1):41–45. 
 
 
 
 
 
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. 
 
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. 
 
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. 
 
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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Wood S, Cummings JL, Hsu MA, Barclay T, Wheatley MV, Yarema KT, Schnelle JF. The use of the 
neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr 
Psychiatry. 2000 Winter;8(1):75-83. 
 
16.2 UNPUBLISHED REFERENCES 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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17 
APPENDICES 
 
The cognitive and functional assessments in this section and associated information are provided as EXAMPLES 
ONLY.  The actual assessments, related source documents, and instructions for administration and scoring are 
included in a rater reference manual or equivalent. 
 
Appendix 1. The Mini-Mental Status Examination 
 
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). 
 


 
 
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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. 
• 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. Severe Impairment Battery 
 
The SIB is designed to assess cognitive abilities in patients with severe AD.  The SIB is divided into 9 subscales, 
each of which yield scores that are downward extensions of instruments used to assess mild to moderate dementia. 
These subscales include orientation, attention, language, praxis, visuospatial perception, construction, memory, 
orientation to name, and social interaction. Language is further divided into several subcategories as listed below. 
There are 51 items and it takes approximately 20 minutes to complete.  The range of possible scores is 0-100. 
The items in the SIB are composed of single one-step commands. They are represented in conjunction with 
gestural cues and can be repeated a number of times to facilitate comprehension. Only one answer is timed (verbal 
fluency). Scoring gives credit to nonverbal and partially correct responses. 
Domain 
Items/Cues 
1. Orientation 
• Name 
• Place (town) 
• Time (month and time of day) 
2. Attention 
• Digit span 
• Counting to visual and auditory stimuli 
3. Language 
• Auditory and reading comprehension 
• Verbal fluency (food and months of the year) 
• Naming from description, pictures of objects, objects, colors, and 
forms 
• Repetition 
• Reading 
• Writing 
• Copying of written material 
4. Praxis 
How to use a cup and a spoon 
5. Visuospatial perception 
Discrimination of color and forms 
6. Construction 
Spontaneous drawing, copying, and tracing a figure 
7. Memory 
Immediate, short- and long-term recall for examiner’s name, objects, 
colors, forms, and a short sentence 
8. Orientation to name 
When the patient’s name is called from behind 
9. Social interaction  
Shaking hands and following general directions 
 
Reference:  
Panisset M, Roudier M, Saxton J, Boller F. Severe Impairment Battery: a neuropsychological test for severely 
demeted patietns. Arch Neurol. 1994 ;51:41-45. 
 


 
 
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Appendix 3. Alzheimer’s Disease Cooperative Study Group Activities of Daily Living Inventory for Severe 
Alzheimer’s Disease (ADCS-ADL-Severe) 
 
The ADCS-ADL-Severe assesses the competence of patients with AD in performing basic activities of daily living.  
The ADCS-ADL-Severe contains 19 items covering physical and mental functioning and independence in self-care 
(see listing below).  For each ADL, an informant (e.g., caregiver) is first asked if the patient attempted the activity 
during the past 4 weeks.  If a patient did attempt the ADL, the informant is asked to choose the single most 
accurate definition of the patient’s level of performance.  The scores range from 0 to 54, with higher scores 
indicating less functional impairment. 
 
ADL 
Point Range 
1. Walks 
0-3 
2. Grooms 
0-3 
3. Bathes 
0-3 
4. Eats 
0-3 
5. Dresses 
0-4 
6. Toileting 
0-3 
7. Turns faucet on 
0-1 
8. Turns faucet off 
0-1 
9. Turns lights on  
0-1 
10. Turns lights out 
0-1 
11. Finds belongings 
0-3 
12. Disposes of litter 
0-3 
13. Clears table 
0-3 
14. Travels beyond home 
0-4 
15. Conversation 
0-3 
16. Watches TV 
0-4 
17. Uses telephone 
0-5 
18. Obtains beverage 
0-3 
19. Can be left alone 
0-3 
TOTAL 
0-54 
 
 
Reference: 
Galasko D, Schmitt F, Thomas R, Jin S, Bennett D, Ferris D; Alzheimer's Disease Cooperative Study. Detailed 
assessment of activities of daily living in moderate to severe Alzheimer's disease. J Int Neuropsychol Soc. 2005 
Jul;11(4):446-453.  
 


 
 
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Appendix 4. Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change Caregiver 
Input (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 informant 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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CONFIDENTIAL/PROPRIETARY                                                                                                   Page 62 of 69 
 
 
Appendix 5. Neuropsychiatric Inventory and Neuropsychiatric Nursing Home Version 
 
The NPI is an outcome measure designed to assess psychiatric symptoms in patients with dementia in outpatient 
settings with information provided by a familial and/or professional caregivers (informant). The NPI-NH was 
developed for use with professional caregivers (informants) in a nursing home setting as a questionnaire about 
patients for whom they care.  Each of the 12 NPI-NH domains contains a screening question that reflects cardinal 
symptoms of that domain.  Initial responses to each domain screening question are "Yes" (present) or "No" 
(absent).  If the response to the domain question is "No", the interviewer goes to the next question.  If "Yes," the 
interviewer proceeds to ask the informant a series of subquestions for that domain.  For each behavioral domain, 
there are 4 scores: frequency, severity, domain total score (frequency x severity), and caregiver distress 
(NPI)/occupational disruptiveness (NPI-NH).  Thus, the NPI and NPI-NH evaluate response to therapy and provide 
symptom severity and distress ratings for each symptom reported, as well as total severity and distress scores 
reflecting the sum of individual domain scores.  It takes approximately 20-30 minutes to complete the interview. 
 
12 Domains/Screening Questions: NPI 
1. Delusions: Does the patient have beliefs you know are not true? For example, insisting that people are trying to 
harm him/her or steal from him/her? Has he/she said that family members are not who they say they are or that the 
house is not their home?  
2. Hallucinations: Does the patient have hallucinations such as seeing false visions or hearing imaginary voices? 
Does he/she seem to see, hear, or experience things that are not present?  
3. Agitation/Aggression: Does the patient have periods when he/she refuses to cooperate or won’t let people help 
him/her? Is he/she hard to handle? 
4. Depression/Dysphoria: Does the patient seem sad or depressed? Does he/she say that he/she is sad or 
depressed? 
5. Anxiety: Is the patient very nervous, worried, or frightened for no apparent reason? Does he/she seem very 
tense or fidgety? Is the patient afraid to be apart from you? 
6. Elation/Euphoria: Does the patient seem too cheerful or too happy for no reason?  


 
 
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CONFIDENTIAL/PROPRIETARY                                                                                                   Page 63 of 69 
 
 
7. Apathy/Indifference: Has the patient lost interest in the world around him/her? Has he/she lost interest in doing 
things or lack motivation for participating in new activities? Is he/she more difficult to engage in conversation or 
doing chores? Is the patient apathetic or indifferent? 
8. Disinhibition: Does the patient seem to act impulsively without thinking? Does he/she say or do things that are 
not usually said or done in public? Does he/she do things that are embarrassing to you or others? 
9. Irritability/Lability: Does the patient get irritated and easily disturbed? Are his/her moods very changeable? Is 
he/she extremely impatient? 
10. Aberrant Motor Behavior: Does the patient pace, do things over and over such as opening closets or drawers, 
or repeatedly pick at things or wind string or threads? 
11. Nighttime Behaviors (only given to caregivers who work the night shift): Does the patient have difficulty 
sleeping (do not count as present if the patient simply gets up once or twice per night only to go to the bathroom 
and falls back asleep immediately)? Is he/she up at night? Does he/she wander at night, get dressed, or disturb your 
sleep? 
12. Appetite/Eating: Has he/she had any changes in appetite, weight, or eating habits (count as NA if the patient is 
incapacitated and has to be fed)? Has there been any change in the type of food he/she prefers? 
12 Domains/Screening Questions: NPI-NH 
1. Delusions: Does the resident have beliefs you know are not true? For example, saying that people are trying to 
harm him/her or steal from him/her? Has he/she said that family members or staff are not who they say they are or 
that his/her spouse is having an affair? Has the resident had any other unusual beliefs? 
2. Hallucinations: Does the resident have hallucinations – meaning, does he/she see, hear, or experience things 
that are not present?  
3. Agitation/Aggression: Does the resident have periods when he/she refuses to let people help him/her? Is he/she 
hard to handle? Is he/she noisy or uncooperative? Does the resident attempt to hurt or hit others? 
4. Depression/Dysphoria: Does the resident seem sad or say that he/she is depressed? Does the resident cry at 
times? 
5. Anxiety: Is the resident very nervous, worried, or frightened for no reason? Does he/she seem very tense and 
unable to relax? Is the resident afraid to be apart from you or from others that he/she trusts? 


 
 
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6. Elation/Euphoria: Does the resident seem too cheerful or too happy for no reason? I don’t mean normal 
happiness but, for example, laughing at things that others do not find funny? 
7. Apathy/Indifference: Does the resident sit quietly without paying attention to things going on around him/her? 
Has he/she lost interest in doing things or lack motivation for participating in activities? Is it difficult to involve the 
resident in conversation or in group activities? 
8. Disinhibition: Does the resident do or say things that are not usually done or said in public? Does he/she seem 
to act impulsively without thinking? Does the resident say things that are insensitive or hurt people’s feelings? 
9. Irritability/Lability: Does the resident get easily irritated or disturbed? Are his/her moods very changeable? Is 
he/she extremely impatient? 
10. Aberrant Motor Behavior: Does the resident have repetitive activities or “habits” that he/she performs over 
and over such as pacing, wheeling back and forth, picking at things, or winding string? (Do not include simple 
tremors or tongue movements). 
11. Nighttime Behaviors (only given to caregivers who work the night shift): Does the resident have difficulty 
sleeping (do not count as present if the resident simply gets up once or twice per night only to go to the bathroom 
and falls back asleep immediately)? Is he/she awake at night? Does he/she wander at night, get dressed, or go into 
others’ room? 
12. Appetite/Eating: Does the resident have an extremely good or poor appetite, changes in weight, or unusual 
eating habits (not applicable if the resident is incapacitated and has to be fed)? Has there been any change in the 
type of food he/she prefers? 
 
References: 
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric 
Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44:2308-2314. 
Wood S, Cummings JL, Hsu MA, Barclay T, Wheatley MV, Yarema KT, Schnelle JF. The use of the 
neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry. 
2000 Winter;8(1):75-83. 











SAP_001.pdf: 
 
 
Alkahest, Inc. 
 
 
 PROTOCOL ALK6019-202 
 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL: ALK6019-202 
 
A Randomized, Double-Blind, Placebo-Controlled Study 
to Assess the Safety and Tolerability of Pulsed GRF6019 
Infusions in Subjects with Severe 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: 
 
 December 11, 2019 
 
STATUS: 
 
Final Version 1.1 
 
 
 
 
 
 
 
 




 
 
 
Alkahest, Inc. 
 
 
PROTOCOL ALK6019-202 
   
Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 3 
TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................... 3 
AMENDMENT HISTORY ...................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................. 5 
1 INTRODUCTION ............................................................................................. 6 
1.1 Study Objectives ..................................................................................................... 6 
1.2 Study Design .......................................................................................................... 6 
1.3 Sample Size Estimation .......................................................................................... 7 
1.4 Randomization and Blinding ................................................................................... 7 
1.5 Study Data .............................................................................................................. 8 
2 GENERAL ANALYSIS DEFINITIONS ............................................................ 8 
2.1 Treatment Groups ................................................................................................... 8 
2.2 Statistical Hypothesis Tests .................................................................................... 9 
2.3 Study Phase, Visit, and Day .................................................................................... 9 
2.4 Analysis Datasets ................................................................................................... 9 
2.5 Definition of Subgroups ......................................................................................... 11 
2.6 Descriptive Summaries ......................................................................................... 11 
3 PLANNED INTERIM ANALYSIS................................................................... 12 
4 SUBJECT INFORMATION ............................................................................ 12 
4.1 Disposition Information ......................................................................................... 12 
4.2 Protocol Deviations ............................................................................................... 12 
4.3 Demographics and Baseline Characteristics ......................................................... 12 
4.3.1 
Demographic Parameters .................................................................................................. 13 
4.3.2 
Baseline Assessment of Modified Hachinski Ischemia Scale (MHIS) ............................... 13 
4.3.3 
APOE Genotype ................................................................................................................ 13 
4.3.4 
Echocardiogram Baseline Assessment ............................................................................. 13 
4.4 Medical History ..................................................................................................... 13 
4.4.1 
Subject Medical History ..................................................................................................... 14 
4.4.2 
Family Medical History ...................................................................................................... 14 
4.4.3 
Social History ..................................................................................................................... 14 
4.4.4 
Tobacco Use...................................................................................................................... 14 
4.4.5 
Alcohol and Illicit Substance Use ...................................................................................... 15 
4.5 Prior and Concomitant Medications ...................................................................... 15 
4.6 Extent of Exposure ............................................................................................... 15 
4.7 Treatment Completion .......................................................................................... 15 
4.8 Tolerability ............................................................................................................ 16 
4.9 Visit Compliance ................................................................................................... 16 
5 EFFICACY ..................................................................................................... 16 
5.1 Mini-Mental State Examination (MMSE) ................................................................ 16 
5.2 Severe Impairment Battery (SIB) .......................................................................... 17 
5.3 Alzheimer’s Disease Cooperative Study Group Activities of Daily Living Inventory 
for Severe Alzheimer’s Disease (ADCS-ADL Severe) ................................................... 17 
5.4 Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change 
Caregiver Input rating (ADCS-CGIC) ............................................................................. 17 
5.5 Neuropsychiatric Inventory Questionnaire (NPI or NPI-NH) .................................. 18 


 
 
 
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Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 4 
6 SAFETY ........................................................................................................ 18 
6.1 Adverse Events ..................................................................................................... 18 
6.1.1 
Coding of AEs .................................................................................................................... 18 
6.1.2 
Treatment-Emergent AE .................................................................................................... 19 
6.1.3 
Variables Attributed to Adverse Events: ............................................................................ 19 
6.1.4 
Analysis Methods .............................................................................................................. 19 
6.2 Clinical Laboratory Evaluations ............................................................................. 20 
6.3 Vital Signs ............................................................................................................. 20 
6.4 Electrocardiogram ................................................................................................. 21 
6.5 Physical Examinations .......................................................................................... 21 
7 EXPLORATORY ........................................................................................... 21 
8 CHANGES FROM PROTOCOL .................................................................... 21 
9 REFERENCES .............................................................................................. 21 
10 TABLES, LISTINGS, AND FIGURES FOR CSR APPENDIX 14 ................ 23 
11 LISTINGS FOR CSR APPENDIX 16.2 ........................................................ 26 
12 ATTACHMENTS ......................................................................................... 28 
 


 
 
 
Alkahest, Inc. 
 
 
PROTOCOL ALK6019-202 
   
Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 5 
AMENDMENT HISTORY 
Not applicable 
LIST OF ABBREVIATIONS 
AD 
Alzheimer’s Disease 
ADCS-ADL-
Severe 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living 
Inventory for Severe Alzheimer’s Disease 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study – Clinical Global 
Impression of Change Caregiver Input 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ApoE 
Apolipoprotein E 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CRO 
Contract Research Organization 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
ICH E6 R2 
International Conference on Harmonization Guidance for Industry, 
Good Clinical Practice: Consolidated Guidance, Revision 2 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHIS 
Modified Hachinski Ischemia Scale 
MMSE 
Mini-Mental State Examination 
NIA-AA 
National Institute on Aging – Alzheimer’s Association 
NODscid 
Non-obese diabetic severe combined immunodeficiency  
NPI 
Neuropsychiatric Inventory 
NPI-NH 
Neuropsychiatric Inventory Nursing Home Version 
NSG 
NODscid Gamma 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIB 
Severe Impairment Battery 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UPCR 
Urine Protein-to-Creatinine Ratio 
US 
United States 


 
 
 
Alkahest, Inc. 
 
 
PROTOCOL ALK6019-202 
   
Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 6 
1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses for 
the study entitled “A Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Safety and Tolerability of Pulsed GRF6019 Infusions in Subjects with 
Severe Alzheimer’s Disease” (V2.0 03DEC2018). A Statistical Analysis Plan 
(SAP) with analytical details and assumptions will be developed and finalized 
before database lock and unblinding of the study data. Analysis related to 
exploratory objectives (serial compositional analysis of plasma proteins to identify 
specific biomarkers associated with cognitive function and/or indicators of 
disease progression) 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 and tolerability of GRF6019, a 
 human plasma protein 
fraction administered by IV infusion in subjects with severe AD.  
Secondary Objective 
To assess the potential effects of GRF6019 on subjects’ cognition and function.  
Exploratory Objectives 
Blood and plasma will be collected and analyzed to identify specific biomarkers 
associated with cognitive functional changes and/or indicators of AD progression.  
1.2 Study Design 
This is a prospective, randomized, double-blind, placebo-controlled study 
conducted at up to four (4) sites in the United States. 
The overall duration of the study is approximately 12 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 9 months. The subject 
participation period is approximately 9 weeks from Screening through End of 
Study, unless prematurely discontinued. 
Subjects that meet eligibility for inclusion in the trial will be randomized in a 2:1 
ratio to GRF6019 (Group1) or placebo (Group 2). Treatment groups will be 
stratified by sex. There will be one (1) dosing period during which subjects 
randomized to GRF6019 will receive GRF6019, while subjects randomized to 
placebo will receive placebo. The dosing period consists of 5 consecutive days 
(“pulsed dosing”) of IV infusions of 250 mL of either GRF6019 or placebo.  


 
 
 
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Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 7 
During the Screening Period, subjects will undergo all Screening assessments 
including an echocardiogram. During the Baseline Period, subjects and their 
caregivers will complete a series of cognitive and functional assessments.  
During the 5-day dosing period, subjects who do not already reside in a long-
term care/skilled nursing facility will be admitted to such a facility to facilitate 
safety evaluation.  
Safety and tolerability assessments will occur at every visit. Cognitive and 
functional assessments will be performed at Baseline and periodically at 
subsequent visits through End of Study/Early Termination. In the event of early 
termination of a subject who has received at least one dose, the End of Study 
procedures will be performed unless the subject/subject’s legally authorized 
representative has withdrawn consent. A comprehensive safety and efficacy 
assessment of all data in toto will be conducted at the end of the study.  
1.3 Sample Size Estimation 
Approximately 20 subjects will be randomized in a 2:1 ratio to active GRF6019 or 
placebo with the intent of obtaining ~16 evaluable subjects. Subjects who 
discontinue prior to completing Visit 8 may be replaced. Subjects who withdraw 
or are withdrawn during Screening will be replaced. 
 
 
  
The primary endpoints pertain to safety and tolerability of the GRF6019 dosing 
regimen in subjects with severe AD.  
1.4 Randomization and Blinding 
To minimize the potential bias at the time of randomization, the study will be 
double-blind and randomized with a 2:1 ratio to GRF6019 (Group 1) or placebo 
(Group 2). A stratified block randomization will be implemented by sex. 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 or 
other blinded raters. However, 
 GRF6019 or 
placebo will be dispensed by an unblinded pharmacist, or other qualified staff 
responsible for drug accountability, to an unblinded Infusion Nurse who will 
administer the infusion. To ensure that Outcomes Assessors, raters, and other 
study personnel as well as subjects and their caregivers are unaware of the 
allocation, appropriate measures will be taken to mask the study agent/placebo 
containers and IV setup such that they will only be visible as necessary to the 
unblinded Infusion Nurse. In addition, a curtain, drape, or equivalent may 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 containers of the study agent or placebo to the 
pharmacy at the end of the Infusion Period. The unblinded Infusion Nurse will 


 
 
 
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Page | 8 
enter the infusion data and blinding assessment into the eCRF to avoid 
unblinding of the source data during data entry. 
During the infusion, communication between the blinded Outcomes Assessor 
and the unblinded Infusion Nurse should be limited to only that required to 
ensure the immediate safety of subjects. The Outcomes Assessors will observe 
the subject during the infusion and collect and/or manage/report AEs and SAEs.  
Except for the unblinded CRA(s) whose sole responsibility is to ensure the study 
agent/placebo is being dispensed, administered, and disposed of properly, the 
study Sponsor and their representatives will be blinded with respect to the 
infusion product.  
1.5 Study Data 
The study data includes all clinical data captured by eCRF and 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.  Biomarker data is considered 
exploratory and will not be included in the eCRF database. 
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 three separate 
categories (although not limited to) the following: (1) investigator’s study file, (2) 
subject blinded clinical source documents, and (3) subject unblinded clinical 
source documents.  
The investigator’s study file will contain the protocol/amendments, CRF, IRB 
approval with correspondence, informed consents, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and study-
specific manuals (e.g., lab manual).  
Subject clinical source documents would be separated according to blinded 
source and unblinded source and 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.  
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 two treatment groups will be labelled as GRF6019 250 mL or placebo within 
the statistical output.  




 
 
 
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Page | 10 
• Safety Dataset (SAF): All subjects who received at least one dose of the 
study agent.  
• Evaluable Dataset (EVAL): All subjects who receive at least 4 of the 5 
planned doses.  
• Per Protocol Dataset (PPROT): A subset of the Evaluable Dataset 
comprised of subjects who do not have any of the deviations listed below 
or any other deviation affecting efficacy identified prior to database lock. 
 
Deviation 
Type 
Deviation 
Additional 
Clarification 
Eligibility 
Inclusion 
Criteria Not 
Met 
Diagnosis of AD based upon the National 
Institute on Aging-Alzheimer’s Association (NIA-
AA) Criteria 
Eligibility 
Inclusion 
Criteria Not 
Met 
MMSE Score 0-10 inclusive 
Eligibility 
Inclusion 
Criteria Not 
Met 
Modified Hachinski Ischemia Scale (MHIS) 
score of <=4 
Eligibility 
Inclusion 
Criteria Not 
Met 
If on medications for cognition (e.g., 
rivastigmine, galantamine, donepezil, 
memantine), must be on stable dosage for at 
least 8 weeks prior to Baseline 
Will be 
dependent 
upon timing of 
dose change 
Eligibility 
Inclusion 
Criteria Not 
Met 
If on daily antidepressant medications and/or 
benzodiazepines and/or typical or atypical 
antipsychotics, must be on stable dosage for 8 
weeks prior to Baseline. If on prn dosing with 
atypical antipsychotics and/or benzodiazepines, 
these should not be given within 24 hours before 
each day of cognitive and other ratings (V1, V2, 
V8, V9, V10) 
Will be 
dependent 
upon timing of 
dose change 
Eligibility 
Exclusion 
Criteria Met 
Evidence of clinically relevant neurological 
disorder(s) other than AD 
Eligibility 
Exclusion 
Criteria Met 
Treatment with any human blood product, 
including transfusions and IV immunoglobulin, 
during the 6 months prior to screening 


 
 
 
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Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 11 
Deviation 
Type 
Deviation 
Additional 
Clarification 
Eligibility 
Exclusion 
Criteria Met 
Concurrent participation in any other therapeutic 
treatment trial. If there was prior clinical trial 
participation, subject must have discontinued 
investigational agents for at least 30 days for 
small molecules, and 1 year for active or 
passive immunotherapies prior to Screening  
Eligibility 
Exclusion 
Criteria Met 
Subjects who have a level of agitation that, in 
the opinion of the investigator, could interfere 
with study procedures 
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 
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 the PPROT will be made 
before database lock. 
A summary table of number (%) of subjects in each analysis set and applicable 
treatment assignment will be provided (Table 14.1.1). 
The presentation of baseline characteristics will be conducted on the ITT dataset. 
All safety analyses will be performed for the SAF dataset. Analyses of the 
secondary endpoints will focus on the EVAL and/or PPROT datasets.     
2.5 Definition of Subgroups 
Not applicable. 
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, standard error of the mean (SEM), 


 
 
 
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Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 12 
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 of efficacy data are planned. Safety data will be assessed in 
an ongoing manner.  
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, randomized not treated, 
completed study, discontinued from study drug with the reasons of 
discontinuation from study drug, and discontinued from study but completed 
study drug dosing with the reasons of discontinuation. The SCRN set will be 
used for the subject disposition table (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 caregivers 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 during treatment phase, 
each day during treatment phase within the study, and any day during the study 
(Table 14.1.3.2). 
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. 


 
 
 
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4.3.1 Demographic Parameters 
Descriptive statistics or frequency tabulation will be provided for following 
parameters (Table 14.1.4.1): 
▪ Age (years) : calculated as the integer part of (Date of Informed Consent – 
Date of Birth + 1)/365.25 
▪ Sex (Male, Female) 
▪ Race (Caucasian, Black or African American, Asian, American Indian or 
Alaskan Native, Native Hawaiian or Other Pacific Islander, Other Race, 
Multiple – derived if multiple races are checked, Not Done/Refused) 
▪ Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
▪ Education Level (No high school, Some High School, High school 
diploma/GED, Undergraduate, Masters, Doctoral, Unknown) 
▪ Marital status (Single, Married, Widowed, Divorced/Separated) 
▪ Family size 
▪ Longest held career (Professional, Homemaker, Trade person, 
Arts/Entertainment, Declined to answer/Don’t know, Other) 
▪ Highest historical level of annual household income ever reported (Less 
than $50,000, $50,000 to $99,999, $100,000 to $199,999, $200,000 or 
more, Declined to answer/Don’t know).   
▪ 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 APOE Genotype  
Frequency tabulation will be provided for APOE Genotype (E2/E2, E2/E3, E2/E4, 
E3/E3, E3/E4, E4/E4) (Table 14.1.4.2) 
4.3.4 Echocardiogram Baseline Assessment 
No tabulation summary will be provided for echocardiogram data, which will be 
included in a subject data listing only. 
4.4 Medical History  
The investigator or designee will obtain a detailed medical history through 
interview with the subject and the subject’s caregiver(s) 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 


 
 
 
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▪ Current symptoms and any active medical condition 
▪ Surgeries and procedures 
▪ Allergies 
▪ Family history in biological parents, siblings, and offspring of AD, other 
dementias, or neurological disorders, if known.  
▪ Social history (e.g. smoking, alcohol, illegal substances), if known. 
▪ Prior imaging, cerebrospinal fluid assessments, or other relevant 
diagnostic tests, including genetics, if available.  
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) 
▪ Cause of death 
▪ 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 Tobacco Use  
Descriptive statistics or frequency tabulation will be provided for the following 
parameters related to tobacco use (Table 14.1.5.3): 
▪ Smoking status (Never Smoked, Current Smoker, Ex-Smoker) 
▪ Number of years smoked 
▪ Average cigarettes/day 
▪ Average pipes/day 
▪ Average cigars/day 
▪ Average cigarettes, pipes or cigars/day (derived by adding average 
cigarettes/day, average cigars/day, and average pipes/day) 


 
 
 
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4.4.5 Alcohol and Illicit Substance Use 
Frequency tabulation will be provided for the following parameters related to 
alcohol and illicit substance use (Table 14.1.5.4): 
▪ Consumed alcohol in past 6 months (Yes, No) 
▪ Problem with alcohol when young (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) is defined as date of last study drug intake – date 
of first study drug intake + 1 within the dosing 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 overall (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) 
▪ Actual Volume Administered (mL) 
▪ Maximum flow rate (mL/hour) 
▪ Volume of Saline Flush 
▪ Device used to administer infusion (Baxter Flo Gard, Other) 
 
Unscheduled changes in flow rate will be included in the subject data listing only 
4.7 Treatment Completion 
Treatment completion is calculated as the actual volume administered, as a 
percentage of the volume expected. The expected dose overall will be calculated 


 
 
 
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as [5 x total daily dose volume] for all subjects, regardless of study completion 
status. Treatment completion will be summarized descriptively and categorically 
(<75% and >=75%) overall (Table 14.1.8.1).  
In addition, number of subjects completing 1, 2, 3, 4, and 5 infusions will be 
summarized (Table 14.1.8.2). 
4.8 Tolerability 
Number of subjects completing 4 weeks after receiving at least 5 infusions will be 
tabulated (Table 14.1.9). 
4.9 Visit Compliance 
Number of subjects with a visit at each scheduled analysis timepoint will be 
summarized (Table 14.1.10). 
5 
EFFICACY 
The study is not powered to detect significant changes in cognition, function, 
ADLs, etc.; however, using available data from analysis of the secondary efficacy 
endpoints, including changes in scores from baseline, descriptive summaries 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 
between groups to evaluate any trends in differences between subjects 
randomized to active and placebo agents. 
For analysis purposes, results at early termination visits will not be included in 
tabulated summaries unless the number of early termination visits is > 5. 
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.  


 
 
 
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Changes from baseline for the recalculated MMSE total score will be 
summarized at each scheduled timepoint (Days 6 and 33) (Table 14.2.1).     
5.2 Severe Impairment Battery (SIB) 
The SIB is designed to assess cognitive abilities in patients with severe AD. The 
SIB is divided into scorable subscales that cover orientation to time and place, 
attention, language, praxis, visuospatial ability, construction, memory, orientation 
to name, and social interaction. Scoring gives credit to nonverbal and partially 
correct answers, thus decreasing the need for language output. There are 51 
items, and it takes approximately 20 minutes to complete. The range of possible 
scores is 0-100 (Panisset 1994).  
Although available in the raw data, the SIB scores will be recalculated. Changes 
from baseline for recalculated SIB subscale scores and the recalculated total 
score will be summarized at each scheduled timepoint (Days 6, 12, and 33) 
(Table 14.2.2).     
5.3 Alzheimer’s Disease Cooperative Study Group Activities of Daily 
Living Inventory for Severe Alzheimer’s Disease (ADCS-ADL Severe) 
The ADCS-ADL-Severe assesses the competence of patients with AD in 
performing basic activities of daily living. The ADCS-ADL-Severe contains 19 
items covering physical and mental functioning and independence in self-care 
(e.g. dressing, grooming, bathing, eating, walking, and toileting). For each ADL, 
the informant (e.g., caregiver) is first asked if the patient attempted the activity 
during the past 4 weeks. If a patient did attempt the ADL, the informant is asked 
to choose the single most accurate definition of the patient’s level of 
performance. The score ranges from 0 to 54, with higher scores indicating less 
functional impairment (Galasko 2005).  
Although available in the raw data, the ADCS-ADL Severe total score will be 
recalculated. Changes from baseline for recalculated ADCS-ADL Severe total 
score will be summarized at the scheduled timepoint (Day 33) (Table 14.2.3).     
5.4 Alzheimer’s Disease Cooperative Study – Clinical Global Impression 
of Change Caregiver Input rating (ADCS-CGIC) 
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. The ADCS-CGIC focuses on clinicians’ observations of change in the 
subject’s cognitive, functional, and behavioral performance since the beginning of 
the trial. It relies on both direct examination of the subject and interview of 
informants (Ferris 1997, Schneider 1997). 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 


 
 
 
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2 = Moderate Improvement 
3 = Minimal Improvement 
4 = No Change 
5 = Minimal Worsening 
6 = Moderate Worsening 
7 = Marked Worsening 
ADCS-CGIC rating (1-7) will be summarized at each scheduled timepoint (Days 
6, 12, and 33) (Table 14.2.4).     
5.5 Neuropsychiatric Inventory Questionnaire (NPI or NPI-NH) 
The NPI (Cummings 1994) comprises 10 behavioral areas and 2 neurovegetative 
areas (12 domains): delusions, hallucinations, agitation/aggression, 
depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, 
irritability/lability, aberrant motor behavior, sleep and nighttime behavior 
disorders, and appetite/eating changes. Information is gathered from caregivers 
familiar with the patient’s behavior. To serve as an informant, the caregiver must 
have at least daily contact with the patient. Initial responses to each domain 
screening question are “Yes” (present) or “No” (absent). If the response to the 
domain question is “No,” the interviewer goes to the next question. If “Yes,” the 
interviewer proceeds to ask the informant a series of sub questions for that 
domain. For each behavioral domain, there are 4 scores: frequency, severity, 
domain total score (frequency x severity), and caregiver distress 
(NPI)/occupational disruptiveness (NPI-NH). Thus, the NPI evaluates response 
to therapy and provides symptom severity and distress ratings for each symptom 
reported, as well as total severity and distress scores reflecting the sum of 
individual domain scores. 
The NPI-NH was derived from the NPI (Cummings 1994) to evaluate the 
neuropsychiatric manifestations and psychopathology of patients with AD and 
other dementias who reside in nursing homes, extended care facilities, or other 
long-term care settings. The NPI-NH is an interview-based scale designed to be 
administered to an informed professional nursing home caregiver (as opposed to 
a family or home-based caregiver in the standard NPI) involved in the daily care 
of the subject. Generally, the NPI-NH is used to evaluate changes in subject 
behavior that have appeared during a given period (Wood 2000).  
Change from baseline for NPI or NPI-NH total severity score and total distress 
score will be calculated and summarized at each scheduled timepoint (Days 12 
and 33) (Table 14.2.5).     
6 
SAFETY  
All safety analyses will be done on the Safety Set. 
6.1 Adverse Events 
6.1.1 Coding of AEs 


 
 
 
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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 Variables Attributed to Adverse Events: 
▪ AE term (verbatim and MedDRA preferred term and system organ class) 
▪ Onset datetime, End datetime, Study Day and duration of AE 
▪ Serious AE (Yes/No), if yes classification will be listed (Death, Life-
threatening Disability or Permanent Damage, Hospitalization – initial or 
prolonged, Congenital Anomaly/Birth Defects, Other Serious (Important 
Medical Events)). 
▪ AE of special interest 
▪ Frequency (Single Episode, Intermittent, Continuous) 
▪ Severity (Mild, Moderate, Severe) 
▪ Relation to study treatment (Unrelated, Possibly Related, Definitely  
▪ Related) 
▪ Action taken with study treatment (No Action Taken, Treatment Held, 
Treatment Discontinued) 
▪ Other Action due to AE (No Action, Medication Therapy, Non-Drug 
Therapy, Other) 
▪ Outcome of AE (Recovered/Resolved, Not Recovered/Not Resolved, 
Recovered/Resolved with Sequelae, Fatal, Unknown) 
▪ AE leading to death (Yes/No) 
6.1.4 Analysis Methods 
There will be no formal statistical testing unless indicated otherwise. 
A summary will be provided for the following TEAEs overall (Table 14.3.1.1): 
• Subjects with Any TEAE 
• Subjects with Any Study Drug-Related 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 


 
 
 
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summarized. Incidence tabulations will be provided for overall summary (Table 
14.3.1.2.1-14.3.1.2.2), summary by highest severity (Table 14.3.1.3), and 
summary by relatedness (Table 14.3.1.4). 
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 
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 14.3.1.5.5.). 
6.2 Clinical Laboratory Evaluations 
Numeric measurements of hematology, serum chemistry, and urinalysis 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). 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 (Oral 
Temperature, Pulse Rate, Systolic Blood Pressure, Diastolic Blood Pressure, 
Respiration 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 as well 
as 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 blood pressure changes will be summarized 
(Table 14.3.3.3): 
• Systolic BP > 180 
• Systolic BP > 200  
• Systolic BP < 90 
• Diastolic BP > 110  


 
 
 
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• Diastolic BP > 120 
• Diastolic BP < 50 
• A change of >30% from Day 1 pre-dose (baseline) in systolic and/or 
diastolic BP. This change includes positive and negative percent changes. 
6.4 Electrocardiogram 
P-R interval, QT interval, QRS duration, Ventricular heart rate and QTc intervals 
using 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 3, 6 and 33) (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 Days 1, 3, 5 and 33 (Tables 14.3.5.1). Normal/abnormal shift from 
pre-dose at Day 1 to pre-dose at subsequent days will also be provided (Tables 
14.3.5.2). 
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 
9 
REFERENCES 
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein 
J. the neuropsychiatric Inventory: comprehensive assessment of 
psychopathology in dementia. Neurology. 1994;44:2308-2314. 


 
 
 
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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 Subjects for the Clinician. J Psychiatr Res. 
1975; 12:189-198. 
Galasko D, Schmitt F, Thomas R, Jin S, Bennett D, Ferris D; Alzheimer’s disease 
Cooperative Study. Detailed assessment of activities of daily living in moderate to 
severe Alzheimer’s disease. J Int Neuropsychol Soc. 2005 Jul;11(4):446-453. 
Panisset M, Roudier M, Saxton J, Boller F. Severe Impairment Battery: a 
neuropsychological test for severely demented patients. Arch Neurol. 1994 
;51:41-45. 
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. 
Wood S, Cummings JL, Hsu MA, Barclay T, Wheatley MV, Yarema KT, Schnelle 
JF. The use of the neuropsychiatric inventory in nursing home residents. 
Characterization and measurement. Am J Geriatr Psychiatry. 2000 
Winter;8(1):75-83. 


 
 
 
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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 
SCRN 
Table 14.1.3.1 
Protocol Deviations 
ITT 
Table 14.1.3.2 
Assessment of Unblinding 
ITT 
Table 14.1.4.1 
Demographics  
SAF 
Table 14.1.4.2 
APOE Genotype 
SAF 
Table 14.1.5.1 
Medical History 
SAF 
Table 14.1.5.2 
Social History 
SAF 
Table 14.1.5.3 
Tobacco Use 
SAF 
Table 14.1.5.4 
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 infusions 
SAF 
Table 14.1.9 
Number of subjects completing 4 weeks after 
receiving at least 5 infusions 
SAF 
Table 14.1.10 
Visit Compliance 
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 Severe Impairment 
Battery Total score 
EVAL, 
PPROT  
Table 14.2.3 
Changes in the Alzheimer’s Disease 
Cooperative Study – Activities of Daily Living 
Severe (ADCS-ADL Severe) 
EVAL, 
PPROT  
Table 14.2.4 
Alzheimer’s Disease Cooperative Study – 
Clinical Global Impression of Change (ADCS-
CGIC) 
EVAL, 
PPROT  
Table 14.2.5 
Change on the Neuropsychiatric Inventory 
Questionnaire (NPI or NPI-NH) total severity 
score and total distress score 
EVAL, 
PPROT  
Table 14.3.1.1 
Overall Summary of Treatment-Emergent 
Adverse Events (TEAE) 
SAF 


 
 
 
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Number 
Title 
Population 
Table 
14.3.1.2.1 
Incidence of Treatment-Emergent Adverse 
Events (TEAEs) by MedDRA System Organ 
Class and Preferred Term 
SAF 
Table 
14.3.1.2.2 
Incidence of Treatment-Emergent Adverse 
Events (TEAEs) by MedDRA Preferred Term 
SAF 
Table 14.3.1.3 
Incidence of Treatment-Emergent Adverse 
Events (TEAEs) by Severity and MedDRA 
System Organ Class and Preferred Term 
SAF 
Table 14.3.1.4 
Incidence of Treatment-Emergent Adverse 
Events (TEAEs) by Relationship to Study Drug 
and MedDRA System Organ Class and 
Preferred Term 
SAF 
Table 
14.3.1.5.1 
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 
14.3.2.1.1 
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 
14.3.2.3.1 
Shift Table in hematology measurements 
SAF 


 
 
 
Alkahest, Inc. 
 
 
PROTOCOL ALK6019-202 
   
Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 25 
Number 
Title 
Population 
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 changes of special interest 
 
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 


 
 
 
Alkahest, Inc. 
 
 
PROTOCOL ALK6019-202 
   
Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 26 
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 
SCRN 
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 
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 
APOE Genotype 
ITT 
Listing 16.2.3.5 
Echocardiogram 
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 
Tobacco Use 
SAF 
Listing 16.2.4.5 
Alcohol and Illicit Substance Use 
SAF 
Listing 16.2.4.6 
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 
Severe Impairment Battery 
ITT 
Listing 16.2.6.3 
Alzheimer’s Disease Cooperative Study – 
Activities of Daily Living Inventory for Severe 
Alzheimer’s Disease (ADCS-ADL Severe) 
ITT 
Listing 16.2.6.4 
Alzheimer’s Disease Cooperative Study – 
Clinical Global Impression of Change 
Caregiver Input rating (ADCS-CGIC) 
ITT 
Listing 16.2.6.5 
Neuropsychiatric Inventory Questionnaire (NPI 
or NPI-NH) 
ITT 


 
 
 
Alkahest, Inc. 
 
 
PROTOCOL ALK6019-202 
   
Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 27 
Number 
Title 
Population 
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 16.2.9 
Vital Signs 
SAF 
Listing 16.2.10 
Physical Examinations 
SAF 


 
 
 
Alkahest, Inc. 
 
 
PROTOCOL ALK6019-202 
   
Statistical Analysis Plan: Final Version 1.1, December 11, 2019 
Page | 28 
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