Conditions: Parkinson Disease
Keywords: Brain Diseases Central Nervous System Diseases Nervous System Diseases Neurodegenerative Diseases Neurocognitive Disorders Mental Disorders Parkinson's Disease Dementia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 79
Healthy volunteers: no

Brief summary:
This study will evaluate the safety, tolerability, and potential effects on cognition of GRF6021, a plasma-derived product, administered as an intravenous (IV) infusion, to subjects with Parkinson's disease and cognitive impairment.

Detailed description:
This is a randomized, double-blind, placebo-controlled study to assess the safety and tolerability of GRF6021, a plasma derived product, administered by intravenous (IV) infusion to subjects with Parkinson's disease (PD) and cognitive impairment. The study duration for the subjects will be approximately 7 months.

Arms:
arm 1: Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. arm 2: Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13.

Interventions: intervention 1: GRF6021 intervention 2: Placebo
Intervention descriptions: intervention 1: GRF6021 for IV infusion intervention 2: Placebo for IV infusion

Protocol document:
Prot_000.pdf: 


 
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CONFIDENTIAL/PROPRIETARY                                                                                                  Page 2 of 111
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................................... 2 
LIST OF ABBREVIATIONS .............................................................................................................. 6 
LIST OF DEFINITIONS ..................................................................................................................... 9 
PROTOCOL APPROVAL PAGE .................................................................................................... 10 
STATEMENT OF COMPLIANCE .................................................................................................. 11 
PROTOCOL SUMMARY ................................................................................................................. 12 
SCHEMATIC OF STUDY DESIGN ................................................................................................ 15 
1 
KEY ROLES ........................................................................................................................... 15 
1.1 
AUTHORIZED REPRESENTATIVE (SIGNATORY) / RESPONSIBLE PARTY ........ 15 
1.2 
STUDY ORGANIZATION .................................................................................................... 15 
2 
INTRODUCTION .................................................................................................................. 15 
2.1 
BACKGROUND INFORMATION ...................................................................................... 15 
2.2 
RATIONALE .......................................................................................................................... 17 
2.3 
POTENTIAL RISKS AND BENEFITS ............................................................................... 19 
2.3.1 
KNOWN POTENTIAL RISKS ................................................................................................ 19 
2.3.2 
KNOWN POTENTIAL BENEFITS ......................................................................................... 20 
3 
OBJECTIVES AND PURPOSE ........................................................................................... 20 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................. 20 
4.1 
DESCRIPTION OF THE STUDY DESIGN ........................................................................ 20 
4.2 
STUDY ENDPOINTS ............................................................................................................ 21 
4.2.1 
PRIMARY ENDPOINT............................................................................................................ 21 
4.2.2 
SECONDARY ENDPOINTS ................................................................................................... 21 
4.2.3 
EXPLORATORY ENDPOINTS .............................................................................................. 22 
5 
STUDY ENROLLMENT AND WITHDRAWAL .............................................................. 22 


 
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5.1 
INCLUSION CRITERIA ....................................................................................................... 22 
5.2 
EXCLUSION CRITERIA ...................................................................................................... 23 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ............................................. 25 
5.4 
SUBJECT WITHDRAWAL OR TERMINATION ............................................................ 25 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION ........................................................ 25 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION ........................... 25 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................... 26 
6 
STUDY AGENT ..................................................................................................................... 26 
6.1 
STUDY AGENT AND CONTROL DESCRIPTION .......................................................... 26 
6.1.1 
ACQUISITION ......................................................................................................................... 26 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING ................................. 26 
6.1.3 
PRODUCT STORAGE AND STABILITY.............................................................................. 26 
6.1.4 
PREPARATION ....................................................................................................................... 27 
6.1.5 
DOSING AND ADMINISTRATION ...................................................................................... 27 
6.1.6 
ROUTE OF ADMINISTRATION ............................................................................................ 27 
6.1.7 
DOSING SCHEDULE .............................................................................................................. 27 
6.1.8 
DURATION OF THERAPY .................................................................................................... 28 
6.2 
STUDY AGENT ACCOUNTABILITY................................................................................ 28 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................... 28 
7.1 
STUDY PROCEDURES/EVALUATIONS .......................................................................... 28 
7.1.1 
STUDY SPECIFIC PROCEDURES ........................................................................................ 28 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ........................................................... 37 
7.2.1 
CLINICAL LABORATORY EVALUATIONS ....................................................................... 37 
7.2.2 
OTHER TESTS OR PROCEDURES ....................................................................................... 37 
7.2.3 
SPECIMEN PREPARATION, HANDLING, STORAGE, AND SHIPPING .......................... 38 
7.3 
STUDY SCHEDULE .............................................................................................................. 38 
7.3.1 
SCREENING ............................................................................................................................ 38 
7.3.2 
RANDOMIZATION ................................................................................................................. 39 
7.3.3 
BASELINE ............................................................................................................................... 39 
7.3.4 
TREATMENT .......................................................................................................................... 40 
7.3.5 
FOLLOW-UP............................................................................................................................ 41 
7.3.6 
FINAL STUDY VISIT ............................................................................................................. 42 
7.3.7 
EARLY TERMINATION ......................................................................................................... 43 
7.3.8 
SCHEDULE OF EVENTS TABLE .......................................................................................... 43 
7.4 
CONCOMITANT MEDICATIONS ..................................................................................... 43 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ...................... 43 
8 
ASSESSMENT OF SAFETY ................................................................................................ 43 


 
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8.1 
SPECIFICATION OF SAFETY PARAMETERS .............................................................. 43 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) ......................................................................... 43 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) ...................................................... 45 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ................................................................ 46 
8.2.1 
SEVERITY OF EVENT ........................................................................................................... 46 
8.2.2 
RELATIONSHIP TO STUDY AGENT ................................................................................... 46 
8.2.3 
EXPECTEDNESS .................................................................................................................... 46 
8.3 
TIME PERIOD/FREQUENCY FOR EVENT ASSESSMENT/FOLLOW-UP ................ 47 
8.3.1 
POST-STUDY AE AND SAE .................................................................................................. 47 
8.4 
REPORTING PROCEDURES .............................................................................................. 47 
8.4.1 
ADVERSE EVENT REPORTING ........................................................................................... 47 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING ......................................................................... 48 
8.4.3 
ADVERSE EVENTS OF SPECIAL INTEREST ..................................................................... 49 
8.4.4 
REPORTING OF PREGNANCY ............................................................................................. 50 
8.5 
STUDY HALTING RULES ................................................................................................... 50 
8.6 
SAFETY OVERSIGHT ......................................................................................................... 51 
9 
CLINICAL MONITORING ................................................................................................. 51 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 52 
10.1 
STATISTICAL DESIGN MODEL AND ANALYTICAL PLANS .................................... 52 
10.2 
STATISTICAL HYPOTHESES ........................................................................................... 52 
10.3 
ANALYSIS DATASETS ........................................................................................................ 52 
10.4 
DESCRIPTION OF STATISTICAL METHODS ............................................................... 53 
10.4.1 
GENERAL APPROACH .......................................................................................................... 53 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT ........................................................................ 53 
10.4.3 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINTS ............................................ 54 
10.4.4 
ANALYSIS OF THE SECONDARY SAFETY ENDPOINTS ................................................ 54 
10.4.5 
ADHERENCE AND RETENTION ANALYSES .................................................................... 54 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS .............................................................................. 54 
10.4.7 
PLANNED INTERIM ANALYSES ......................................................................................... 54 
10.4.8 
ADDITIONAL SUBGROUP ANALYSES .............................................................................. 55 
10.4.9 
MULTIPLE COMPARISON/MULTIPLICITY ....................................................................... 55 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA ....................................................... 55 
10.4.11 
EXPLORATORY ANALYSES .............................................................................................. 55 
10.5 
SAMPLE SIZE........................................................................................................................ 55 
10.6 
MEASURES TO MINIMIZE BIAS ...................................................................................... 56 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES ...................................... 56 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING ...................................................................... 57 
10.6.3 
BREAKING THE STUDY BLIND/SUBJECT CODE ............................................................ 57 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............ 57 


 
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12 
ETHICS/PROTECTION OF HUMAN SUBJECTS........................................................... 57 
12.1 
ETHICAL STANDARD ......................................................................................................... 57 
12.2 
INSTITUTIONAL REVIEW BOARD/ ETHICS COMMITTEE ..................................... 58 
12.3 
INFORMED CONSENT PROCESS .................................................................................... 58 
12.3.1 
CONSENT FORMS .................................................................................................................. 58 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION ........................................................ 58 
12.4 
PARTICIPANT AND DATA CONFIDENTIALITY.......................................................... 59 
12.5 
FUTURE USE OF STORED SPECIMENS ......................................................................... 59 
13 
DATA HANDLING AND RECORD KEEPING ................................................................ 60 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ............................ 60 
13.1.1 
INVESTIGATOR RESPONSIBILITIES ................................................................................. 60 
13.1.2 
STUDY FILES .......................................................................................................................... 60 
13.2 
STUDY RECORDS RETENTION ....................................................................................... 61 
13.3 
PROTOCOL DEVIATIONS ................................................................................................. 61 
13.4 
PUBLICATION AND DATA SHARING POLICY ............................................................ 62 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY .................... 63 
15 
SCHEDULE OF EVENTS .................................................................................................... 64 
15.1 
SCHEDULE OF EVENTS TABLE ...................................................................................... 64 
16 
REFERENCES ....................................................................................................................... 68 
16.1 
PUBLISHED REFERENCES ............................................................................................... 68 
16.2 
UNPUBLISHED REFERENCES .......................................................................................... 71 
17 
APPENDICES ........................................................................................................................ 72 
17.1  
IMPORTANT SAFETY CONTACT INFORMATION ..................................................... 90 
18 
REVISION HISTORY ........................................................................................................... 91 
18.1 
SUMMARY OF CHANGES .................................................................................................. 91 
 
 


 
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LIST OF ABBREVIATIONS 
α-Syn 
Alpha-synuclein 
ACE 
Angiotensin converting enzyme 
AD 
Alzheimer’s disease 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIC 
Ambulatory infusion center 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANSM 
    Agence Nationale de Sécurité du Médicament et des Produits de Santé 
ApoE 
Apolipoprotein E 
APTT 
Activated partial thromboplastin time 
ASL MRI 
Arterial-spin labeling magnetic resonance imaging 
AST 
Aspartate transaminase 
BNP 
Brain natriuretic peptide 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CDR-CCB 
Cognitive Drug Research Computerized Cognition Battery 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CISI-PD 
Clinical Impression of Severity Index – Parkinson’s Disease 
CJD 
Creutzfeldt-Jakob disease 
CK 
Creatinine kinase 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CRA 
Clinical research associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DBP 
Diastolic blood pressure 
DBS 
Deep brain stimulation 
dCDT 
Digital clock drawing test 
D-KEFS 
Delis-Kaplan Executive Function System  
DNA 
Deoxyribonucleic acid 
DSMB 
Drug Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
ENT 
Ear, nose, throat 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDS-15 
Geriatric Depression Scale-15 
GGT 
Gamma-glutamyl transpeptidase 


 
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HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HCV Ab 
Hepatitis C antibody 
HDL 
High-density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HIV Ab 
Human immunodeficiency virus antibody 
HR 
Heart rate 
ICH 
International Conference on Harmonization 
ICH E6 R2 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance, Revision 2 
ICMJE 
International Committee of Medical Journal Editors 
ICSR 
Individual Case Safety Report 
IEC  
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IMP 
Investigational medical product 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LV 
Left ventricular 
MCI 
Mild cognitive impairment 
MDRD 
Modification in diet in renal disease 
MDS-PD 
Movement Disorder Society’s Clinical Diagnostic Criteria for Parkinson’s 
Disease 
MDS-UPDRS 
Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHIS 
Modified Hachinski Ischemic Scale 
MoCA 
Montreal Cognitive Assessment  
MRI 
Magnetic resonance imaging 
NODscid 
Non-obese diabetic severe combined immunodeficiency 
NSG 
NODscid gamma 
PD 
Parkinson’s disease 
PDD 
Parkinson’s disease dementia 
PD-MCI 
Parkinson’s disease with mild cognitive impairment 
PDQ-39 
Parkinson’s Disease Quality of Life Questionnaire-39 
PT 
Preferred Term 
PT/INR 
Prothrombin time/international normalized ratio 


 
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PTT 
Prothrombin time 
RBC 
Red blood cell 
RR 
Respiration rate 
SAE 
Serious adverse event 
SAP 
Statistical Analytical Plan 
SBP 
Systolic blood pressure 
SE-ADL 
Schwab and England Activities of Daily Living 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
S-STS 
Sheehan-Suicidality Tracking Scale 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
tf-fMRI 
Task-free functional magnetic resonance imaging 
TGA 
Therapeutic Goods Administration 
TSH 
Thyroid-stimulating hormone 
UPCR 
Urine protein-to-creatinine ratio 
US 
United States 
vCJD 
Variant Creutzfeldt-Jakob disease 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
 
 


 
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LIST OF DEFINITIONS 
 
Infusion Nurse 
The unblinded study personnel, qualified by training and experience, responsible 
for administering the study agent/placebo.  The Infusion Nurse ensures that the 
study agent (GRF6021/placebo) is allocated appropriately, administered at the 
correct infusion rate, and appropriate blinding techniques are used to prevent 
inadvertent unblinding of study staff and study subjects.   
Infusion Period 
The period during which GRF6021/placebo is infused (estimated to be 
approximately
). 
Outcomes Assessor 
The blinded study personnel qualified by training and experience to be 
responsible for observing study subjects during the infusion of GRF6021/placebo 
and collecting and/or managing adverse events (AEs) that occur before, during, 
and after the Infusion Period. 




 
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STATEMENT OF COMPLIANCE 
 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety 
and Tolerability of GRF6021 Infusions in Subjects with Parkinson’s Disease 
and Cognitive Impairment 
Protocol Number: 
ALK6021-201 
 
Version/Date: 
V5.0_23SEP2019 
 
 
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 United States (US) Food and Drug Administration (FDA) 
regulations, the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines, the Declaration of 
Helsinki, and all applicable rules, regulations, and federal, state, and local laws relating to the conduct 
of clinical studies and the protection of human subjects.  
• 
Agree not to implement deviations from or changes to the protocol or protocol amendments without 
agreement from the Sponsor and prior submission to and written approval (where required) from the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except when necessary to 
eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where 
permitted by all applicable regulatory requirements).  
• 
Agree to onsite monitoring of all source documents by Alkahest, Inc. or designee and to onsite 
inspection of source documents by appropriate regulatory authorities, including but not limited to the 
FDA, local governing regulatory bodies, and IRB/IEC inspectors. 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 
 


 
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PROTOCOL SUMMARY 
 
 
Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Safety and Tolerability of GRF6021 Infusions in Subjects with Parkinson’s 
Disease and Cognitive Impairment  
 
Précis:  
This is a randomized, double-blind, placebo-controlled study to assess the 
safety and tolerability of GRF6021, a 
 human 
 fraction, 
administered by intravenous (IV) infusion to subjects with Parkinson’s 
disease (PD) and cognitive impairment. 
 
The study consists of approximately 90 subjects who will be randomized in 
a 2:1 ratio to active treatment (approximately 60 subjects) or placebo 
(approximately 30 subjects).  Subjects will receive one infusion per day of 
active or placebo treatment for 5 consecutive days during week 1 and week 
13.  The study duration for the subjects will be approximately 7 months. 
 
Each infusion will have a duration of approximately 
 with a 
maximum of 
.  The infusion 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, trial partners, study coordinators, physicians, and cognitive/motor 
test administrators to treatment allocation; use of blinded Outcomes 
Assessors and unblinded Infusion Nurses; and measures to block view of 
the infusion setup to avoid unblinding.   
 
All subjects will undergo a screening visit, including a magnetic resonance 
imaging (MRI) scan, baseline visit, two treatment periods, follow-up visits, 
and an end-of-study/early-termination visit.  During each 5-day treatment 
period, administration of GRF6021/placebo can occur in an 
inpatient/hospital setting or in outpatient infusion centers or equivalent 
facilities with appropriate medical personnel.  All infusions must be 
performed by adequately trained personnel under the supervision of the 
investigator.  Safety and tolerability assessments will occur at every visit.  
Neurocognitive and motor assessments will be performed at baseline and at 
periodic visits following dosing.  Subjects who provide explicit consent to 
undergo a second, optional MRI scan will have an additional MRI scan at 
Visit 16 to assess for changes from screening. 
 
Objectives: 
The primary objective of the study is to assess the safety and tolerability of 
an infusion dosing regimen of GRF6021 in subjects with PD and cognitive 
impairment.  As a secondary objective, the study will assess the potential 
effects of GRF6021 on cognition and motor function as well as changes 
from baseline in clinical laboratory parameters, vital signs, body weight, 
and the Sheehan-Suicidality Tracking Scale (S-STS).  The exploratory 
objectives include serial compositional analysis of plasma to identify 


 
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specific biomarkers associated with cognitive and motor function and/or 
indicators of disease progression, and changes on MRI (in consenting 
subjects).   
 
Endpoints: 
Primary Endpoint:  
• 
Incidence of treatment-emergent adverse events (TEAEs) and 
serious adverse events (SAEs) identified by the Medical Dictionary 
for Regulatory Activities (MedDRA) preferred term (PT) and 
grouped by MedDRA System Organ Class (SOC). 
 
Secondary Efficacy Endpoints:  
• Change from baseline in the Montreal Cognitive Assessment 
(MoCA). 
• Change from baseline in Continuity and Power of Attention, 
Working Memory, and Episodic Memory on the Cognitive Drug 
Research Computerized Cognition Battery (CDR-CCB). 
• Change from baseline in Delis-Kaplan Executive Function System 
(D-KEFS) Verbal Fluency. 
• Change from baseline in the Movement Disorder Society’s Unified 
Parkinson’s Disease Rating Scale (MDS-UPDRS) 1, 2, 3, and total 
score. 
• Change from baseline in the Schwab and England Activities of 
Daily Living (SE-ADL) Scale. 
• Change from baseline in the Clinical Impression of Severity Index – 
PD (CISI-PD).  
• Change from baseline in the PD Quality of Life Questionnaire-39 
(PDQ-39). 
• Change from baseline in the Geriatric Depression Scale-15 (GDS-
15). 
• Change from baseline in the digital clock drawing test (dCDT). 
 
Secondary Safety Endpoints: 
• Change from baseline in clinical laboratory parameters. 
• Change from baseline in vital sign measurements. 
• Change from baseline in body weight. 
• Change from baseline in the S-STS. 
 
Exploratory Endpoints: 
• 
Proteomic assessment of plasma for investigation of study-related 
biomarkers. 
• 
Change from baseline in various MRI assessments (in consenting 
subjects). 
 
Population: 
Approximately 90 subjects between 40 and 85 years of age with a diagnosis 
of either PD with mild cognitive impairment (PD-MCI) or PD with 
dementia (PDD).  Assuming a drop-out rate of 25%, enrollment at this level 


 
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will yield approximately 68 evaluable subjects. 
 
Phase: 
2 
 
Number of Sites: 
Up to 40 sites in the US and ex-US 
Description of Study 
Agent: 
GRF6021: A 
 human 
 fraction for IV infusion 
 
Description of 
Placebo Control 
Agent: 
0.9% sodium chloride injection (saline) 
 
Study Duration: 
 
Approximately 24 months 
 
Subject Duration: 
Approximately 7 months  
 
 






 
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These studies complemented the findings from the initial studies conducting by Villeda et al (Villeda 2011, 
Villeda 2014) and confirmed that factors present in human plasma protect against brain aging and ameliorate age-
related cognitive and motor impairments in mice, laying the foundation for testing this 
 fraction in 
humans experiencing cognitive decline from age-related neurodegenerative diseases. 
 
2.2 
RATIONALE 
 
Protocol ALK6021-201 will evaluate GRF6021 administered via IV infusion.  Nonclinical studies conducted by 
Alkahest have demonstrated that both Young Plasma and GRF6021 confer beneficial outcomes in cognitive 
decline, motor function, neuroinflammation, synaptic density, and neurogenesis in mouse models (ALK-2015-
R002, VIV-2016-R003, VIV-2016-R009, VIV-2016-R014, VIV-2016-R020, VIV-2016-R021, VIV-2016-R024, 
VIV-2017-R025, VIV-2017-R036, VIV-2017-R038, VIV-2018-R069, 2018-CET01, 2018-CRL03, 2018-QPS01).   
 
Initial Alkahest nonclinical studies were performed to test whether the positive effects observed with young 
mouse plasma could be replicated using Young Plasma.  Treatment of aged NODscid (non-obese diabetic severe 
combined immunodeficiency) mice with Young Plasma (100-150 µl per injection, two injections per week for 3-5 
weeks) resulted in improved cognitive and motor performance in standard behavioral tests (ALK-2015-R002).   
These cognitive changes were further supported by electrophysiological and histological correlates of enhanced 
memory.  Together, these results provided support for the hypothesis that young human plasma infusions may 
have functional clinical benefits, potentially ameliorating or halting the progression of age-related cognitive 
decline.   
 
Subsequent nonclinical studies at Alkahest were performed to test the effects of GRF6021 using various dosing 
paradigms in NODscid, NSG (NODscid Gamma), C57BL/6J, and Line 61 α-Synuclein (α-Syn) transgenic mice.  
Initially, mice were dosed with 150 µL of Young Plasma, GRF6021, or saline (control) via IV infusions 2 times 
per week for 5 weeks (VIV-2016-R003).  A subsequent study examined the same dosing regimen for a period of 
23 weeks, to assess the effects of treatment on age-dependent changes in behavioral and cognitive function over a 
period of approximately 6 months (VIV-2016-R014).  Following these studies, a novel dosing regimen for 
GRF6021 that consisted of one 150 µL dose every day for 7 consecutive days (referred to as “pulsed dosing”) was 
assessed, both alone and compared to other intermittent weekly dosing regimens (VIV-2016-R009, VIV-2016-
R021, VIV-2016-R024, VIV-2017-R025, 2018-CET-01, 2018-CRL03, 2018-QPS01).  Additional studies 
examined dosing of 150 µL for 5 consecutive days (VIV-2017-R038) as well as subsequent booster dosing for 5 
consecutive days (VIV-2017-R036) which is the pulsed-dosing regimen chosen for ALK6021-201.   
 
These studies demonstrated that pulsed dosing with GRF6021 led to significant improvements in cognitive 
performance, motor function, and histological correlates.  Furthermore, the beneficial effects lasted up to 3 
months after the end of dosing, suggesting that continuous repeat dosing may not be required (VIV-2017-R036, 
VIV-2017-R038).  After pulsed dosing with GRF6021 in old mice, there is a well-defined timecourse of effects 
on the brain.  Within hours of the end of dosing, C-fos expression increases, demonstrating that GRF6021 
administered intravenously results in neuronal activation (2018-CET01).  Over the course of a few days to a few 
weeks, there is a reduction in age-related neuroinflammation, and an improvement in age-related deficits in 
cognition and locomotion (2018-CET-01, 2018-CRL03, 2018-QPS01).  Lastly, there is an increase in synaptic 
density and hippocampal neurogenesis; the latter lasts for up to 11 weeks after the end of dosing (VIV-2017-
R038).  Together, these studies indicate that 5 consecutive days of dosing (“pulsed dosing”) of GRF6021 and 
cognitive and other testing for a period of 11 weeks thereafter, followed by a second “booster” dosing period is a 
reasonable study design in human subjects (VIV-2017-R036).     






 
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The capacity of the GRF6021 manufacturing process to inactivate and/or remove viruses was evaluated in 
viral validation studies designed in accordance with the quality standards established by the European 
Committee for Medicinal Products for Human Use (CHMP) and the US FDA.  Studies were performed using 
relevant viruses or models of human viruses that represent a wide range of physicochemical properties.  
Human immunodeficiency virus (HIV) type 1 was used as a relevant bloodborne pathogen, bovine viral 
diarrhea virus was used to model hepatitis C virus (HCV), and pseudorabies virus was used as a surrogate for 
large, enveloped deoxyribonucleic acid (DNA) viruses to model hepatitis B virus (HBV) for which there is 
not practicable assay system.  Reovirus type 3 was used to model non-enveloped viruses, hepatitis A virus 
was used as a relevant non-enveloped virus, and porcine parvovirus was used as a surrogate for human 
parvovirus B19.  The clearance capacities for all individual processing steps that achieved at least 1 log10 
were combined to determine the overall clearance capacities, which demonstrate that the manufacturing 
process for GRF6021 has the capacity to remove and/or inactivate a diverse variety of enveloped and non-
enveloped virus challenges and thereby provides assurance that the process yields a margin of safety from the 
risk of transmission of infectious viruses. 
 
GRF6021 is contraindicated in patients with severe anemia, congestive heart failure, or increased blood 
volume (PI) and these are exclusion criteria in this study.  GRF6021 is depleted of the majority of 
immunogenic proteins during the manufacturing process, and thus is not expected to alter the blood typing 
characteristics of the recipient and should not sensitize humans to its subsequent administration 
 
.  ABO antigen typing is not required prior to administration.  GRF6021 is not expected to significantly 
alter the urinalyses of recipients, their bleeding times, coagulation times, prothrombin times, prothrombin 
consumption, platelet counts, or fibrinogen levels when given in quantities of up to 1000 mL 
   
 
Based on the cumulative review 
 (PSUR), the production steps 
taken to increase the safety margin and avoid virus transmissions, and the multiple safety minimization steps 
implemented in this study, the benefit-risk balance for GRF6021 as an investigative product in PD-MCI and 
PDD is favorable. 
 
2.3.2 
KNOWN POTENTIAL BENEFITS 
 
There is no known reported benefit of administering GRF6021 to patients with PD-MCI or PDD.   
 
3 
OBJECTIVES AND PURPOSE 
 
The primary objective of this study is to assess the safety and tolerability of GRF6021, a 
 human 
 
fraction administered by IV infusion, in subjects with PD and cognitive impairment.  Secondarily, this study aims 
to assess the effects of GRF6021 on subjects’ cognitive and motor function.  Exploratory objectives include blood 
and plasma collection to identify specific biomarkers associated with cognitive and motor changes and/or 
indicators of PD-MCI and PDD progression.  In addition, MRI of the brain will be conducted after the second 
treatment period in consenting subjects to identify potential therapeutic effects of GRF6021.   
 
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
 
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US.   
 
During the screening period (Day -35 through Day -8), subjects will undergo all screening assessments, including 
a screening MRI and an echocardiogram, and complete two training sessions on the Continuity and Power of 
Attention, Working Memory, and Episodic Memory on the CDR-CCB.  During the Baseline Visit (Day -7 
through Day -1), subjects will complete cognitive and motor testing.  Subjects will then be randomized in a 2:1 
ratio to GRF6021 (Group 1) or placebo (Group 2).   
 
There will be two (2) dosing periods.  Each dosing period (Treatment 1, starting at Week 1; and Treatment 2, 
starting at Week 13) consists of 5 consecutive days (“pulsed dosing”) of IV infusions of 
 of either 
GRF6021 or placebo.  During each 5-day treatment period, the administration of GRF6021/placebo will occur in 
a setting with appropriate medical monitoring by adequately trained personnel. The infusions can occur in the 
inpatient/hospital setting or in an outpatient infusion center or equivalent medical facility. Following a 4-hour 
post-infusion monitoring period, the subject may return home if medically stable based on the investigator’s 
clinical judgement. Should further monitoring be required, subjects may need to remain at and/or be transferred to 
an appropriate facility for extended outpatient monitoring and/or inpatient observation. 
 
 
Safety and tolerability assessments will occur at every visit.  Cognitive and motor testing will be performed at 
Baseline and at periodic interim visits following dosing.  Cognitive and motor testing may take up to 
approximately 2.5 hours.  It is preferred that the sequence of tests administered should be consistent for all 
subjects.  Subjects (and/or their trial partners, if applicable) may take breaks between assessments as needed.  
 
In the event of early termination of a subject who has received at least one infusion, the end of study procedures 
will be performed unless the subject has withdrawn consent.  A comprehensive efficacy and safety assessment of 
all data in toto will be conducted at the end of the study. 
 
Subjects will also be invited to participate in an additional MRI obtained at Visit 16 to detect potential changes in 
brain atrophy, cortical thinning, functional connectivity, and cerebral blood flow after treatment.  The MRI 
procedure, as well as the potential risks and benefits, will be explained to all study participants.  Participation in 
the Visit 16 MRI scan is optional and not required for inclusion in the study.  
 
The overall duration of the study/recruitment period is approximately 24 months from study initiation (i.e., 
following consent of first subject) to study completion (i.e., last subject, last visit).  The subject participation 
period is approximately 7 months from Screening through End of Study, unless prematurely discontinued.  
 
4.2 
STUDY ENDPOINTS 
 
4.2.1 
PRIMARY ENDPOINT 
 
Primary Endpoint:  
• Incidence of TEAEs and SAEs identified by MedDRA PT and grouped by MedDRA SOC.  
 
4.2.2 
SECONDARY ENDPOINTS 
 
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the Baseline and End of Study values.  Secondary endpoints will be summarized over the study period from 
Baseline values using descriptive statistics. 
 
Secondary Efficacy Endpoints:  
• 
Change from baseline in the MoCA (Nasreddine 2005)(Appendix 1). 
• 
Change from baseline in Continuity and Power of Attention, Working Memory, and Episodic Memory 
on the CDR-CCB (Wesnes 1977, Wesnes 2000). 
• 
Change from baseline in D-KEFS Verbal Fluency (Delis 2001, Delis 2004, Emre 2004).   
• 
Change from baseline in the MDS-UPDRS 1, 2, 3, and total score (Fahn 1987, Movement Disorders 
Task Force 2003)(Appendix 2). 
• 
Change from baseline in the SE-ADL Scale (Schwab 1968)(Appendix 3). 
• 
Change from baseline in the CISI-PD (Martinez-Martin 2006)(Appendix 4).  
• 
Change from baseline in the PDQ-39 (Peto 1998)(Appendix 5). 
• 
Change from baseline in the GDS-15 (Yesavage 1983)(Appendix 6). 
• 
Change from baseline in the dCDT (Müller 2017).  
 
Secondary Safety Endpoints: 
• 
Change from baseline in clinical laboratory parameters. 
• 
Change from baseline in vital sign measurements. 
• 
Change from baseline in body weight. 
• 
Change from baseline in the S-STS (Sheehan 2014)(Appendix 7). 
 
4.2.3 
EXPLORATORY ENDPOINTS 
 
The exploratory endpoints include assessment of changes in composition and distribution of blood-based 
biomarkers and changes in MRI assessments (in consenting subjects).   
 
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 disease progression.  DNA will 
be extracted from blood samples to explore epigenetic changes.   
 
In addition, brain imaging (MRI) will be conducted in consenting subjects to identify potential therapeutic 
effects of GRF6021.  The following changes from baseline may be evaluated: 
• 
Brain morphometry as measured by MRI. 
• 
Functional connectivity as measured by task-free functional MRI (tf-fMRI), where available. 
• 
Cerebral blood flow assessments as measured by arterial-spin labeling (ASL) MRI, where available. 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible for inclusion, all subjects must meet the following criteria: 
1. Aged 40-85 years at time of enrollment, inclusive. 
2. Diagnosis of clinically established or clinically probable PD according to MDS-PD criteria (Postuma 
2015)(Appendix 8) with at least 1 year of PD symptoms. 
3. Diagnosis of PD-MCI (Level I, i.e. impairment on a scale of global cognitive abilities validated for 


 
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use in PD) or probable or possible PDD according to MDS criteria (Litvan 2012, Emre 
2007)(Appendix 9). 
4. Score on the MoCA of 13-25, inclusive (Nasreddine 2005)(Appendix 1). 
5. Hoehn and Yahr Stages 1-4. 
6. If on dopaminergic therapy (e.g., levodopa, dopamine agonists, monoamine oxidase inhibitors, 
catechol-O-methyl transferase inhibitors, amantadine), must be on stable dosage at least 4 weeks 
prior to baseline. 
7. If on medications for cognition (e.g., rivastigmine, galantamine, donepezil, memantine), must be on 
stable dosage for at least 8 weeks prior to baseline. 
8. If on antidepressant medications, must be on stable dosage for at least 8 weeks prior to baseline. 
9. If on clozapine, quetiapine, or pimavanserin, must be on stable dosage for 8 weeks prior to baseline. 
10. 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. 
12. Modified Hachinski Ischemic Scale (MHIS) score of 4 or less (Rosen 1980). 
13. Female subjects must not be pregnant or breastfeeding.  Women of childbearing potential (WOCBP) 
must have a negative pregnancy test at screening (Visit 1), Visit 3 (prior to study treatment), and 
Visit 11 (prior to study treatment).  WOCBP must agree to use highly effective contraception prior 
to study entry (Clinical Trial Facilitation Group 2014).  A woman is considered of childbearing 
potential following menarche and until becoming postmenopausal (no menses for at least 2 years 
without an alternative cause).  Should a woman become pregnant or suspect she is pregnant while 
she or her partner is participating in the study, she should inform her treating physician immediately. 
14. Have a dedicated, reliable, and competent trial partner (e.g., caregiver or family member) who has 
frequent contact with the subject (defined as approximately 10 hours per week) who is willing to 
provide support to the subject to ensure compliance with study requirements.   
15. The subject (with support of a trial partner) must be able to follow the study procedures, receive the 
treatment in the established timeframe, and continue during the follow-up interval.   
16. The subject and trial partner must be able to understand the procedures and agree to complete the 
required assessments. 
17. Provide a signed and dated informed consent form (either the subject or the subject’s legal 
representative) in accordance with local regulations and/or IRB/IEC guidelines. 
 
5.2 
EXCLUSION CRITERIA 
 
An individual will not be eligible for inclusion if any of the following criteria apply: 
1. History of blood coagulation disorders or hypercoagulability.  
2. Current use of anticoagulant therapy (e.g., heparin, warfarin, thrombin inhibitors, Factor Xa 
inhibitors).  Use of antiplatelet drugs (e.g., aspirin or clopidogrel) is acceptable. 
3. Prior hypersensitivity reaction to any human blood product or any IV infusion; any clinically 
significant known drug allergy. 
4. Treatment with any human blood product, including transfusions and IV immunoglobulin, during the 
6 months prior to screening. 
5. History of immunoglobulin A (IgA) or haptoglobin deficiency, stroke, anaphylaxis, or 
thromboembolic complications of IV immunoglobulins.  
6. Heart disease, as evidenced by myocardial infarction, unstable, new onset or severe angina, or 
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dosing. 
7. Presence of signs and/or symptoms of hypervolemia or volume overload, including but not limited to 
pulmonary edema and/or clinically significant peripheral edema.  
8. Patients with recent or planned surgery sensitive to blood volume changes including 
cardiopulmonary bypass technique. 
9. Poorly controlled high blood pressure (BP) (systolic BP of 160 mmHg or higher and/or diastolic BP 
of 100 mmHg or higher) despite treatment during the 3 months prior to dosing, or treatment 
refractory high BP, defined as treatment requiring 3 or more antihypertensives from different 
classes. 
10. Supine hypertension (systolic BP of 160 mmHg or higher and/or diastolic BP of > 90 mmHg when 
in a supine position). 
11. Symptomatic orthostatic hypotension (drop in systolic BP of 20 mmHg or higher, or 30 mmHg in 
the presence of essential hypertension, and/or a drop in diastolic BP of 10 mmHg or higher, after 3 
minutes of standing despite adequate hydration); symptoms can include, but are not limited to, 
lightheadedness, visual blurring, dizziness, and/or syncope.  
12. History of Torsades de Pointes dysrhythmia. 
13. Clinically significant abnormalities on screening electrocardiogram (ECG) including QTc intervals 
(using Fridericia’s correction formula) of ≥ 450 ms in men and ≥ 470 ms in women. 
14. Clinically significant abnormalities on echocardiogram.  
15. Hypocalcemia of any kind, including secondary to absorption syndromes related to gastric bypass 
surgery. 
16. Current, active liver disease or known hepatic or biliary abnormalities.  
17. Uncontrolled diabetes defined as hemoglobin A1c (HbA1c) > 7.5%. 
18. Clinically significant abnormalities in complete blood count, complete metabolic panel, serum 
albumin, serum lipids, coagulation, or levels of thiamine, pyridoxine, cobalamin, and thyroid 
stimulating hormone. 
19. Positive urine drug screen.  The presence of opioids, benzodiazepines, and/or amphetamines in the 
urine drug screen may be allowed if these are prescribed and the dose stable for at least 8 weeks 
prior to screening.  
20. Hemoglobin < 10 g/dL in women and < 11 g/dL in men. 
21. Urine protein-to-creatinine ratio (UPCR) of > 1.5 grams of protein per gram of creatinine. 
22. Inadequate venous access to allow IV drug delivery or multiple blood draws.  
23. 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.  
24. If on deep brain stimulation (DBS), DBS surgery within 12 months of screening and/or a change in 
DBS settings within 12 weeks of screening.  DBS settings must not be changed at any point during 
the subject’s participation in the trial.  
25. Presence of a pacemaker or any other implant that would be an MRI contraindication, including 
DBS if not MRI compatible.  
26. More than 2 lacunar strokes or other clinically-relevant imaging abnormality on screening MRI.  
27. Any other condition and/or situation that the investigator believes may interfere with the safety of 
the subject, study conduct, or interpretation of study data. 
 
 
 


 
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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 90 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).  
 
The expected length of participation in the study of approximately 7 months is not expected to be challenging to 
subjects or their trial partners.  During the study, financial support for meal and miscellaneous expenses will be 
available, 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 
both the subject and their trial partner in maintaining study visit compliance.  A description of the study will be 
included in local clinical trial databases, as required.   
 
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 adverse event (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 or the subject’s legally authorized representative (e.g., subject 
withdraws consent), investigator, Sponsor, or regulatory authority. 
• 
Pregnancy. 
 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION  
 
 
Subjects will be encouraged to complete the study and all assessments.  Subjects may voluntarily withdraw at 
any time, and the investigator may discontinue individual subjects from the study at any time.   
 
Approximately 90 subjects (GRF6021: 60; placebo: 30) will be enrolled in the study with the intent of 
obtaining ~68 evaluable subjects. Subjects who discontinue or are unblinded prior to 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 4-6 weeks of their last visit.  The primary reason 
for study discontinuation will be documented on the case report form (CRF). 
 
 
 




 
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damaged should not be used, as this may have allowed the entry of microorganisms.  Neither the study agent 
nor the placebo contain preservatives. 
 
6.1.4 
PREPARATION 
 
All vials/containers of study agent/placebo should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit.  GRF6021 should not be mixed 
with protein hydrolysates or solutions containing alcohol.  The study agent and placebo should be prepared in 
accordance with the Infusion Administration Manual (Appendix 11).  
 
6.1.5 
DOSING AND ADMINISTRATION 
 
The study agent/placebo will be infused in accordance with the Infusion Administration Manual (Appendix 
11).  The purpose of the Infusion Administration Manual is to promote safe administration of the study 
agent/placebo; maintain appropriate blinding of staff and study subjects; and provide guidance on the 
management of potential risks, including but not limited to hypersensitivity reactions.  The Manual includes 
provisions for masking the study agent/placebo and concealing the IV setup from view of blinded staff and 
study subjects. 
 
The study agent/placebo to be administered will be dispensed by an unblinded pharmacist (or other qualified 
personnel responsible for drug accountability) to an unblinded Infusion Nurse.  Administration of the study 
agent/placebo will be performed by the unblinded Infusion Nurse, and safety measures (including AEs and 
vital signs) will be assessed by a blinded Outcomes Assessor.   
 
Infusion Nurses will be qualified by training and experience to administer infusions under the direction of the 
Principal Investigator.  Only authorized Infusion Nurses may administer the study agent/placebo, and only 
subjects enrolled in the study may receive the study agent/placebo in accordance with applicable regulatory 
requirements. 
 
A physician or physician-designated equivalent (e.g., physician assistant, nurse practitioner) should be 
available (i.e., on site or in the immediate vicinity) during the entire infusion and ~ 4-hour post infusion 
monitoring period.  S/he should be qualified by training and/or experience in acute cardiac life support, or 
equivalent.  Each site must have appropriate equipment and/or medications to treat emergencies (e.g., a crash 
cart or equivalent, epinephrine). 
 
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 GRF6021 (Group 1: active dosing in both treatment periods) or placebo 
(Group 2: placebo dosing in both treatment periods).  Subjects will receive one infusion of 
 per day 
for 5 consecutive days at Weeks 1 and 13.   
 
 


 
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6.1.8 
DURATION OF THERAPY 
 
From screening to exit, the duration of study involvement for each subject and their trial partner is ~7 months. 
 
All subjects will receive 5 consecutive days of therapy at the beginning of Weeks 1 and 13.  Thus, the 
cumulative duration of therapy for all subjects will be 10 exposure days.  The duration of therapy for a subject 
to be considered evaluable is 5 exposure days (see Section 10.3 Analysis Datasets). 
 
6.2 
STUDY AGENT ACCOUNTABILITY 
 
Under the supervision of the Principal Investigator, the unblinded study pharmacist or other qualified personnel is 
responsible for ensuring adequate accountability of all used and unused study agent and placebo control agent.  
This includes acknowledgment of receipt of each shipment of study agent/placebo (quantity and condition) within 
the interactive response technology (IRT) system, 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 unblinded Infusion Nurse administering the study agent/placebo.  Drug 
accountability will be monitored by an unblinded Clinical Research Associate (CRA). 
 
Accountability records must be maintained and readily available for inspection by representatives of Alkahest, 
Inc. or their designee and are open to inspection by regulatory authorities at any time.  The accounts of any study 
agent/placebo accidentally wasted or intentionally disposed of must be maintained.   
 
All unused, partially used, and used study agent/placebo should be kept securely at the site until otherwise 
instructed.  All unused, partially used, and used containers of study agent/placebo at the site should not be 
returned or destroyed without prior written approval from the Sponsor and must be performed in accordance with 
the site’s drug disposal/destruction policy, or equivalent.  The clinical study monitor will evaluate the site’s 
procedure(s) for study drug disposal/destruction in order to ensure that it complies with study requirements.  A 
copy of the site’s drug disposal policy should be maintained or referenced in the investigator’s study file. 
 
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: 
• 
S-STS 
• 
Assessment of PD, including Hoehn and Yahr 
• 
MHIS 
• 
MoCA 
• 
Medical history 
• 
Demographics 
• 
Review of medications 
• 
Vital signs (including seated, supine, and standing BP) 


 
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• 
Physical examination 
• 
12-Lead ECG 
• 
Screening Safety Lab Panel and pregnancy test for WOCBP 
• 
Echocardiogram*  
• 
Screening MRI*  
 
*Note: it is recommended, but not required, that the echocardiogram and screening MRI be performed after 
all other screening procedures have been completed, and the subject meets all criteria for inclusion into the 
study.  The echocardiogram and screening MRI may be completed in any order. 
 
Detailed descriptions of each of these procedures are provided in the sections immediately following.  
Information pertaining to all study activities performed during screening, and the sequence of events, is 
provided in Section 7.3.1 Screening. 
 
7.1.1.1.1 Sheehan-Suicidality Tracking Scale 
The S-STS was developed to provide a brief but efficient instrument for use in assessing change in suicidal 
ideation and behavior while providing a comprehensive description of suicidal ideation and behavior.  The 
primary goals in the design of the S-STS were for the scale to be: 1) short and inexpensive; 2) simple, clear, 
and easy to administer or self-rate; 3) highly sensitive (i.e., able to detect a high proportion of patients who 
are suicidal); 4) specific (i.e., able to screen out those who are not suicidal); 5) sensitive to change in suicidal 
ideation and behavior; 6) compatible with the regulatory categories of assessment for suicidal ideation and 
behavior; 7) useful in clinical as well as research settings; 8) useful in detecting an efficacy signal for anti-
suicidal medications; and 9) capable of use in pediatric and geriatric settings (Sheehan 2014).  The standard 
version of the S-STS (Appendix 7) is a 16-item scale that assesses the seriousness of suicidality phenomena 
on a Likert-type scale (0-4) ranging from “not at all” (0) to “extremely” (4).  It also assesses the frequency of 
key phenomena and the overall time spent in suicidality.   
 
7.1.1.1.2 Assessment of Parkinson’s Disease and Cognitive Impairment 
The diagnosis of PD will be verified using MDS-PD criteria (Postuma 2015)(Appendix 8).  The prerequisite 
to apply the MDS-PD criteria is the presence of parkinsonism, defined as bradykinesia, in combination with 
either rest tremor, rigidity, or both.  These features must be clearly demonstrable and not attributable to 
confounding factors (Postuma 2015).  The stage of the disease will be classified using the Hoehn and Yahr 
scale.    
 
Subjects will also be evaluated for PD-MCI (Level I) and PDD based on MDS criteria (Litvan 2012, Emre 
2007).  PD-MCI is a syndrome defined by clinical, cognitive, and functional deficits (Litvan 2012)(Appendix 
9).  The MDS criteria for MCI were developed to address issues relatively specific to PD.  The criteria were 
also designed to be consistent with the MDS proposed PDD criteria (Emre 2007)(Appendix 10) and thereby 
allow differentiation between MCI and dementia in patients with PD.   
 
Global cognition (a requisite for the diagnosis of PD-MCI Level I) will be assessed using the MoCA 
(Nasreddine 2005)(Appendix 1)(see Section 7.1.1.3.1).  The score range for PD-MCI is 19-25.2, and for PDD 
it is 11.4-21.  While the score ranges overlap, differentiation between the conditions is dependent upon 
associated functional impairment (Doerflinger 2012).  Per the inclusion criteria for this study, subjects must 
have a MoCA score of 13-25, inclusive (see Section 5.1 Inclusion Criteria). 
 


 
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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 (an example of the full assessment for this study can be downloaded using 
the following link: Modified Hachinski Ischemia Scale).  The scale is completed by the physician based on 
clinical information obtained from diagnostic testing 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 this trial.  
 
7.1.1.1.4 Medical History 
The investigator or designee will obtain a detailed medical history through interview with the subject and the 
subject’s trial partner during screening.  The medical history should focus on recent history, with an emphasis 
on the history of cognitive and motor symptoms related to PD.  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 PD, AD, or other dementias or 
neurological disorders 
• 
Social history (e.g. exercise, smoking, alcohol, illegal substances) and current living situation 
• 
Cause of parental death (if not living) 
• 
Prior imaging, CSF assessments, or other relevant diagnostic test results, including genetics 
 
7.1.1.1.5 Demographics 
Demographic information such as the subject’s education level, ethnicity, and race will be collected by 
interview with the subject and the subject’s trial partner at screening. 
 
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 and any dose changes in the last 3 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 BP (mmHg), heart rate (beats per minute [bpm]), 
respiration rate (breaths per minute), and body temperature.  Vital signs will be measured after the subject has 
been seated for 5 minutes.   
 
In addition, at screening and at every visit during both treatment periods (including follow-up Visits 8 and 
16), orthostatic (supine and standing) BP will also be measured.  Orthostatics are collected as follows:  
• 
After a 10-minute rest in a supine position, supine BP should be measured while the subject is 
lying down.   


 
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• 
The subject should then stand for 3 minutes, if physically able or can be held in standing position 
with assistance, and the BP is taken again.   
 
At Visits 3-7 and Visits 11-15, seated, supine, and standing BP should be measured prior to infusion start and 
at the end of each infusion (~
  
 post infusion start).  Refer to the Infusion Administration 
Manual for further guidance (Appendix 11).    
 
7.1.1.1.8 Physical Examination 
A full physical examination will be performed to assess the following organ systems: skin, ENT (ears, nose, 
and throat), head, eyes, lungs/chest, heart, abdomen, musculoskeletal, extremities, neurologic and lymphatic 
systems.  The neurological exam will include cranial nerves (visual fields, fundoscopic exam, pupillary light 
reflex, extraocular muscles, facial sensation and symmetry, palate and tongue, and head turning and shoulder 
shrug); motor function including muscle strength, tone, bulk, and abnormal movements; reflexes (biceps, 
triceps, knees, ankles, and plantar); coordination (finger-to-nose, heel-knee-shin); sensory function (light 
touch and pinprick); and gait.  Height will be measured at screening and weight will be monitored during the 
trial. 
 
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, or abnormal and clinically significant.  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 percentage is ≥ 55% (Gebhard 2012).   
 
7.1.1.1.11 Screening Safety Lab Panel 
Biological samples will be analyzed at screening.  Samples that remain after study screening is complete may 
be stored at the central lab in the event additional testing (e.g., further evaluation of an AE or assessment of 
effect) is required.  Blood will be drawn by a qualified medical provider, and urine specimens will also be 
collected.  The timing and frequency for specimen collection and laboratory evaluations to be performed are 
further described in Section 15 Schedule of Events.  
 
The labs that will be tested at screening include:  
• 
Serum pregnancy test in WOCBP only 
• 
Hematology: complete blood count (CBC), neutrophils, total lymphocytes, monocytes, eosinophils, 
basophils, iron, vitamin B12 (cobalamin) 
• 
Chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, eGFR, 
protein (total), albumin, IgA, bilirubin [total, indirect, direct], aspartate transaminase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), 
amylase, lipase, lactate dehydrogenase (LDH), creatinine kinase (CK), glucose, HbA1C, phosphate, 


 
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magnesium, cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein 
[LDL], haptoglobin) 
• 
Coagulation: (prothrombin Time INR, prothrombin time (PTT), activated partial thromboplastin time 
(APTT) 
• 
Immunochemistry: thyroid-stimulating hormone (TSH ultrasensitive), hepatitis B surface antigen 
(HBsAg), hepatitis C antibody (HCV Ab), Human immunodeficiency virus antibody (HIV Ab, HIV-
1/HIV-2), brain natriuretic peptide (BNP) 
• 
Urinalysis: specific gravity, pH, glucose, protein, ketones, bilirubin, urobilinogen, hemoglobin, 
leucocyte esterase, nitrite, white blood cells (WBC), red blood cells (RBC), hyaline casts, granular 
casts, waxy casts, WBC casts, epithelial cells, bacteria, color, sample aspect 
• 
Urine chemistry: protein, microalbumin, creatinine, sodium, potassium, microalbumin/creatinine, 
protein/creatinine ratio, sodium/creatinine ratio, potassium/creatinine ratio 
• 
Urine drug screen: cocaine, amphetamines, barbiturates, benzodiazepines, cannabinoids, opiates, 
phencyclidine, propoxyphene, methadone 
• 
Other testing: direct antiglobulin test, ionized calcium, vitamin B6 (pyridoxine), vitamin B1 
(thiamine), and C1 inhibitor* 
 
*Note: Results of the C1 inhibitor test are not required for eligibility, and thus need not be available 
prior to randomization and dosing.   
 
7.1.1.1.12 Magnetic Resonance Imaging 
The screening MRI is required and will assess for lacunar strokes and other abnormalities (see Section 5.2 
Exclusion Criteria).   
 
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 
• 
Weight 
• 
S-STS 
• 
12-Lead ECGs 
• 
Targeted physical exams  
• 
End of Study (or Early Termination) physical exam 
• 
Blood draw and urine collection for laboratory evaluations 
 
7.1.1.2.1 Review of Adverse Events 
AEs will be reviewed, documented, and reported as required at each visit, beginning at Screening.  For 
definitions, guidance, and additional information regarding AEs, refer to Section 8.  
 


 
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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 (see the  
Schedule of Events) with additional measurements during each treatment period.  During infusions, vital signs 
will be collected according to the Infusion Administration Manual (Appendix 11) by the blinded Outcomes 
Assessor.    
 
7.1.1.2.4 Sheehan-Suicidality Tracking Scale 
Refer to Section 7.1.1.1.1 for a description of the S-STS.  
 
7.1.1.2.5 12-Lead ECG 
Refer to Section 7.1.1.1.9 for information pertaining to 12-Lead ECGs. 
 
7.1.1.2.6 Targeted Physical Exams 
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 in Section 7.3.    
 
7.1.1.2.7 Physical Exam 
Refer to Section 7.1.1.1.8 for a description of the Physical Exam.  The physical exam, including 
measurements of height and weight, will be performed at screening.  The physical exam and weight 
measurement will be repeated at End of Study (or early termination).   
 
7.1.1.2.8 Blood and Urine Collection for Laboratory Evaluations 
Subjects will have blood and urine specimens collected for clinical evaluation and safety monitoring.  
Samples that remain may be stored at the central lab in the event additional testing (e.g., further evaluation of 
an AE or assessment of effect) is required.  The timing and frequency of labs for clinical evaluation and safety 
monitoring are provided below and specified in Section 15 Schedule of Events.  
 
7.1.1.2.8.1 Pregnancy Testing  
For WOCBP, serum and/or urine pregnancy testing should be conducted at Visits 3 and 11 with results 
available prior to infusion start. 
7.1.1.2.8.2 Pre-infusion Safety Labs 
Pre-infusion Safety Labs will be performed at each site’s local laboratory or via an i-STAT Handheld Blood 
Analyzer.  When sending samples to the local laboratory, samples for the Pre-Infusion Safety Labs should be 
collected prior to infusion start on Visits 3, 4, 6, 11, 12, and 14. This is to allow sufficient turn-around time 
for local laboratories to receive, process, and report results prior to the subject’s next infusion. 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 4, 5, 7, 12, 13, and 15.   


 
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Pre-infusion Safety Labs include: 
• 
Sodium 
• 
Potassium 
• 
Ionized calcium 
• 
BUN 
 
• 
Creatinine 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelets* 
 
*Please note that the i-STAT Chem 8+ test cartridges can perform all Pre-Infusion Safety Labs with the 
exception of the platelet count. The platelets lab will need to be obtained and assessed via the site’s local 
laboratory prior to the next day’s infusion.   
 
7.1.1.2.8.3 Comprehensive Labs 
Samples for Comprehensive Labs will be collected prior to infusion start on Visits 6 and 14 as well as during 
follow-up on Visits 8, 9, 16, and 17.  These include: 
• 
Hematology: CBC, neutrophils, total lymphocytes, monocytes, eosinophils, basophils, and iron 
• 
Chemistry: sodium, potassium, chloride, bicarbonate, BUN, creatinine, eGFR, protein (total), 
albumin, IgA, bilirubin (total, indirect, direct), AST, ALT, GGT, alkaline phosphatase, amylase, 
lipase, LDH, CK, glucose, phosphate, magnesium, cholesterol, triglycerides, HDL, LDL 
• 
Coagulation: prothrombin time/international normalized ratio PT/INR, PTT, APTT 
• 
Urinalysis: specific gravity, pH, glucose, protein, ketones, bilirubin, urobilinogen, hemoglobin, 
leucocyte esterase, nitrite, WBC, RBC, hyaline casts, granular casts, waxy casts, WBC casts, 
epithelial cells, bacteria, color, sample aspect 
• 
Urine chemistry: microalbumin, creatinine, sodium, potassium, microalbumin/creatinine, 
sodium/creatinine ratio, potassium/creatinine ratio 
• 
Ionized calcium 
 
7.1.1.2.8.4 Exit Safety Lab Panel 
The labs that will be tested as part of the Exit Safety Lab Panel include:  
• 
Hematology: CBC, neutrophils, total lymphocytes, monocytes, eosinophils, basophils, and iron 
• 
Chemistry: sodium, potassium, chloride, bicarbonate, BUN [urea], creatinine, eGFR, protein (total), 
albumin, IgA, bilirubin (total, indirect, direct), AST, ALT, GGT, alkaline phosphatase, amylase, 
lipase, LDH, CK, glucose, phosphate, magnesium, cholesterol, triglycerides, HDL, LDL 
• 
Coagulation: PT/INR, PTT, APTT) 
• 
Immunochemistry: HBsAg, HCV Ab, HIV Ab (HIV-1/HIV-2) 
• 
Urinalysis: specific gravity, pH, glucose, protein, ketones, bilirubin, urobilinogen, hemoglobin, 
leucocyte esterase, nitrite, WBC, RBC, hyaline casts, granular casts, waxy casts, WBC casts, 
epithelial cells, bacteria, color, sample aspect 
• 
Urine chemistry: microalbumin, creatinine, sodium, potassium, microalbumin/creatinine, 
sodium/creatinine ratio, potassium/creatinine ratio 
• 
Other testing: direct antiglobulin test, ionized calcium 
 
7.1.1.3 Procedures to Assess Efficacy 
Procedures to assess efficacy include cognitive and motor function testing.  Information regarding the timing 
and frequency of these procedures is provided in Section 15 Schedule of Events. 
 


 
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Cognitive and motor function will be assessed using validated instruments including computer-based 
assessments and devices.  All testing will be performed by qualified evaluators who have undergone 
standardized rater training and certification, as appropriate.  The same evaluator should be used for the 
duration of each subject’s participation unless a change in rater is unavoidable.  When possible, all cognitive 
and motor testing should be performed when the subject is in the “ON” state and at approximately the same 
time after the last dose of each subject’s PD medication(s).  The preferred order of behavioral and cognitive 
testing during visits with multiple assessments is as follows:  
1. MoCA  
2. CDR-CCB  
3. D-KEFS 
4. dCDT 
5. MDS-UPDRS 1/2/3 
6. SE-ADL 
7. CISI-PD 
8. PDQ-39 
9. GDS-15 
 
Descriptions of each neuropsychological and motor function assessment are provided below. 
 
7.1.1.3.1 Montreal Cognitive Assessment 
The MoCA (Nasreddine 2005)(Appendix 1) is a commonly used screening test easily administered by 
nonspecialist staff.  It assesses the domains of attention and concentration, executive functions, memory, 
language, visuoconstructional skills, conceptual thinking, calculations, and orientation.  The total possible 
score is 30 points with a score of 26 or more considered normal.   
 
7.1.1.3.2 Cognitive Drug Research Computerized Cognition Battery 
The CDR-CCB is the most widely used automated cognitive function assessment system in clinical research 
worldwide (Wesnes 1977, Wesnes 2000, Wesnes 2013).  It was developed to assess both enhancement and 
impairment of human cognitive function.  There are several core tests available. The core tests have remained 
constant over the last three decades while being steadily supplemented with others as required.  In this study, 
the following will be measured using the CDR-CCB system: Continuity and Power of Attention, Working 
Memory, and Episodic Memory.  Subjects will have two CDR-CCB training sessions during the screening 
period to ensure adequate performance at the Baseline Visit (Visit 2).   
 
7.1.1.3.3 Delis-Kaplan Executive Function Verbal Fluency 
The D-KEFS Verbal Fluency test is used for assessment of executive function, which is one of the main 
cognitive domains impaired in PD (Delis 2001, Delis 2004, Emre 2004) (an example of the full assessment 
for this study can be downloaded using the following link: Delis-Kaplan Executive Function Verbal Fluency).  
The D-KEFS Verbal Fluency Test has three conditions: Letter Fluency, Category Fluency, and Category 
Switching.  In the Letter Fluency condition, subjects are asked to say as many words that start with a 
particular letter (e.g., F, A, S) as possible over three trials of 60 seconds.  The Category Fluency condition 
requires subjects to say as many words belonging to a particular semantic category (e.g., animals, tools) as 
they can in two trials of 60 seconds.  In the final condition, subjects are asked to switch between words 
belonging to two different semantic categories in one trial of 60 seconds (e.g., fruits and furniture).  The test 
requires subjects to exercise mental flexibility, avoid perseverative responses, and engage in an effective and 


 
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quick mental search.  Importantly, this test provides auxiliary information regarding verbal fluency to the 
CDR-CCB, which does not include assessments in this critical cognitive domain.   
 
7.1.1.3.4 Digital Clock Drawing Test 
The conventional clock drawing test is a rapid and inexpensive screening tool for detection of moderate and 
severe dementia.  Modern digitizing devices offer the opportunity to measure subtle changes of visuo-
constructive demands and executive functions that may be used as a fast and easy-to-perform screening 
instrument for the early detection of cognitive impairment (Müller 2017).  The pen-like dCDT device gathers 
the x-y coordinates that describe the movement of the stylus as it changes its position during the assessment.  
It also assesses when the stylus or writing device is not exerting pressure on the writing surface (i.e., in-air 
movements performed by the hand while transitioning from one stroke to the next), making it a more sensitive 
tool than the conventional clock test with increased diagnostic accuracy (Müller 2017).  
 
7.1.1.3.5 Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale 
The MDS-UPDRS (Fahn 1987, Movement Disorder Society Task Force 2003)(Appendix 2) was developed in 
an effort to incorporate elements from existing scales to provide a comprehensive but efficient and flexible 
means to monitor PD-related disability and impairment.  The MDS-UPDRS has four components (Part 1, 
Mentation, Behavior, and Mood; Part 2, Activities of Daily Living; Part 3, Motor; Part 4, Complications).  
Parts 2 and 3 are the most widely used for both clinical and research purposes.  One of the core advantages of 
the UPDRS is that it was developed as a compound scale to capture multiple aspects of PD.  It assesses both 
motor disability (Part 2) and motor impairment (Part 3).  In addition, Part 1 addresses mental dysfunction and 
mood.  The rating for each item is from 0 (normal) to 4 (severe).  The total score for each Part is obtained 
from the sum of the corresponding item scores.  For this study, Parts 1-3 will be completed, and the estimated 
time for completion is 20-30 minutes. 
 
7.1.1.3.6 Schwab and England Activities of Daily Living Scale 
The SE-ADL evaluates patients’ perceptions of global functional capacity and dependence (Schwab 
1968)(Appendix 3).  Scoring is expressed in terms of percentage, in 10 steps from 100 to 0 (100%, normal 
status; 0%, bedridden with vegetative dysfunction), so that the lower the score, the worse the functional 
status.  The rating is made by a trained clinician. 
 
7.1.1.3.7 Clinical Impression of Severity Index – Parkinson’s Disease 
The CISI-PD is a severity index formed by four items (motor signs, disability, motor complications, and 
cognitive status), rated 0 (not at all) to 6 (very severe or completely disabled) (Martinez-Martin 
2006)(Appendix 4).  A total score is calculated by summing the item scores.  The scale is completed by a 
clinician.  It only takes a few minutes to complete once the state of the subject is known. 
 
7.1.1.3.8 Parkinson’s Disease Quality of Life Questionnaire-39 
The PDQ-39 is a self-administered questionnaire of 39 questions relating to 8 key areas of health and daily 
activities, including both motor and non-motor symptoms (Peto 1998)(Appendix 5).  The eight dimensions 
include: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, 
communication, and bodily discomfort.  It is scored on a scale of 0-100 with lower scores indicating better 
health and high scores indicating more severe symptoms.    
 


 
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7.1.1.3.9 Geriatric Depression Scale-15 
The GDS-15 is a site-administered questionnaire of depression in older adults that will be read to the subject, 
and the answers will be recorded by the rater.  The GDS-15 is a shortened form of a 30-item questionnaire in 
which participants are asked to respond by answering yes or no in reference to how they felt over the past 
week (Yesavage 1983)(Appendix 6).  Questions from the long form GDS which had the highest correlation 
with depressive symptoms in validation studies were selected for the short version which is more easily used 
by mildly to moderately demented patients who have short attention spans and/or feel easily fatigued.  Of the 
15 items, 10 indicate the presence of depression when answered positively, while the rest (question numbers 
1, 5, 7, 11, 13) indicate depression when answered negatively.  It takes about 5 to 7 minutes to complete. 
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 
 
Biological samples (e.g. whole blood, serum, urine) will be collected for laboratory evaluations in accordance 
with Section 7.1.1.1.11 Screening Safety Lab Panel, Section 7.1.1.2.8 Blood and Urine Collection for Lab 
Evaluations, and the Schedule of Events.  .  Clinical sample processing and laboratory evaluations will be 
conducted by a central lab’s registered and certified Clinical Laboratory Improvement Amendments (CLIA) 
facilities.  Pre-infusion laboratory evaluations will be conducted at the clinical site.  Refer to the study’s 
laboratory manual for complete information regarding all laboratory evaluations to be performed, sample 
collection procedures, and related requirements. 
 
The investigator is responsible for determining and documenting whether out of range laboratory values are 
clinically significant.  All clinically significant values will be recorded as AEs in the CRF and followed until 
determined to be stable or resolved, unless the subject is lost to follow up.  Once resolved, the appropriate 
CRF page(s) will be updated.  
 
7.2.2 
OTHER TESTS OR PROCEDURES 
 
7.2.2.1  
Apolipoprotein E (ApoE) Genotype Testing 
 
ApoE genotype is a known risk factor for neurodegeneration and dementia pathogenesis, with presence of the 
ApoE ε4 allele carrying increased risk.  This risk is further influenced by age, sex, race, and ethnicity.  Thus, 
determining ApoE genotype at baseline will allow for the assessment of possible differential effects of ApoE 
genotype on safety, treatment efficacy, neuroimaging, and other exploratory measures.  DNA for ApoE 
analysis will be obtained from a blood serum sample collected during Visit 3 prior to the subject’s first 
infusion. 
 
7.2.2.2  
Magnetic Resonance Imaging 
MRI will be used to evaluate subjects’ eligibility for inclusion in the study at screening.  Structural images 
will be interpreted by a central reader at screening and any exclusionary findings will be reported.  Where 
available, functional imaging will also be acquired to assess for functional connectivity as measured by tf-
fMRI and cerebral blood flow as measured by ASL MRI.  In consenting subjects, an additional MRI at Visit 
16 will assess for changes in brain atrophy as measured by MRI, functional connectivity as measured by tf-
fMRI, and cerebral blood flow as measured ASL MRI.  During the MRI, the subject will be asked to lie on a 
narrow bed in a large tunnel while images are captured by the MRI machine.  Participation in the screening 


 
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MRI is required, while participation in the additional MRI at Visit 16 is optional and not required for 
inclusion in the study. 
 
7.2.2.3  
Proteomic and Genetic Biobanking 
Blood samples will be collected for biobanking during Visits 3 and 11 (prior to infusion), all follow-up visits 
(Visits 8-10, 16-18), and End of Study (Visit 19) or Early Termination Visit.  For more information regarding 
the timing and procedures for sample collection and related requirements, refer to 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 
GRF6021 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, it is hoped that key proteins that are drivers of cognitive function and/or indicators of disease 
progression can be identified.  Blood samples will be collected for analysis of emergent genetic markers of 
disease.  By understanding the composition and function of plasma samples from the trial, the goal is to 
identify the biomarkers relevant to further optimizing treatment in PD, PD-MCI, and PDD.  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 
 
To ensure follow-up visits occur at approximately the same intervals following both treatment periods, visit 
windows should be calculated as follows: 
 
• 
Visit windows for Visits 1-10 should be calculated relative to Day 1. 
• 
Visit windows for Visits 11-19 should be calculated relative to Day 85 ±7 (i.e., first day of dosing for 
Treatment Period 2). 
 
Study visit procedures are listed in the recommended order in which they should be completed. 
 
7.3.1 
SCREENING 
 
Visit 1, Screening Visit (Day -35 to -8) 
□ Informed consent of subject (or the subject’s legally authorized representative) as documented by a 
signed and dated informed consent form must be obtained prior to any study-related assessments. 
□ Administer the S-STS. 
□ Administer the MoCA. 
□ Administer the MHIS. 
□ Verify diagnosis of PD according to MDS criteria, including Hoehn and Yahr stage. 
□ Verify diagnosis of PD-MCI or PDD according to the consensus criteria. 
□ Obtain medical history, including medical records and test results to support PD, PD-MCI, or PDD 
diagnosis if available. 


 
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□ Collect demographic information. 
□ Review subject’s current and prior medications. 
□ Review and provide the subject (and subject’s trial partner) with a list of permitted and prohibited 
medications. 
□ Collect vital signs (including sitting, supine, and standing BP), height, and weight. 
□ Perform a complete physical and neurological exam. 
□ Perform 12-lead ECG. 
□ Collect blood and urine samples required for the Screening Safety Lab Panel.  
□ Perform transthoracic echocardiogram. 
□ Complete screening MRI scan.  
□ Verify that the subject fulfills all of the inclusion criteria and none of the exclusion criteria. 
 
During the screening period, subjects should complete two training sessions with the CDR-CCB system prior 
to baseline testing at Visit 2.  The two training sessions may be scheduled at any time during the screening 
window. 
 
Note: The Screening Visit may be split to allow for sufficient time to complete all required procedures.  
Review AEs and concomitant medications during split visits, as applicable.   
 
7.3.2 
RANDOMIZATION 
 
Subjects will be randomized after eligibility has been confirmed (including MRI and echocardiography 
results). 
 
7.3.3 
BASELINE 
 
Visit 2, Baseline (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 commencing cognitive and 
motor testing and that the subject is in the ON state.  PD medications should be taken at the standard 
intervals for each subject and testing should be scheduled to facilitate the subject being in the ON 
state. 
□ It is preferred that cognitive and motor function testing is performed in the following order (breaks are 
permitted between assessments as needed): 
1. CDR-CCB 
2. D-KEFS 
3. dCDT 
4. MDS-UPDRS 1/2/3  
5. SE-ADL 
6. CISI-PD 
7. PDQ-39 
8. GDS-15 
 
 


 
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7.3.4 
TREATMENT 
 
There are two treatment periods scheduled during the trial.  During each treatment period, subjects will 
receive a total of 5 infusions of their assigned treatment (i.e., either GRF6021 or placebo).  It is anticipated 
that sites will infuse subjects with 5 doses over 5 consecutive days.  A “grace day” is allowed in the event of 
unanticipated safety or health concerns during each treatment period. 
 
Visits 3-7 (Days 1-5) and 11-15 (Day 85*-89): 
*Day 85 has a ± 7-day window 
□ Perform the following procedures prior to administering study treatment: 
o Review AEs and concomitant medications. 
o Obtain blood and urine samples for Comprehensive Labs (Visits 6 and 14 Only); fasting samples 
preferred. 
o Obtain samples for proteomics/epigenetics/biobanking; fasting samples preferred (Visits 3 and 11 
Only). 
o Obtain sample for ApoE testing (Visit 3 Only). 
o For WOCBP Only: perform pregnancy testing and review results (Visits 3 and 11 Only). 
o Obtain Pre-infusion Safety Lab samples and assess results prior to the next day’s infusion (Visits 
3, 4, 6, 11, 12, and 14 Only). When using an i-STAT Handheld Blood Analyzer, the blood 
sample(s) may be obtained on the same day as the infusion (Visits 4, 5, 7, 12, 13, and 15). 
o Perform targeted physical exam (i.e. auscultation of heart and lungs and assessment of peripheral 
edema) (Visits 3, 5, 7, 11, 13, and 15 Only). 
o Measure body weight in kilograms. 
o Perform 12-lead ECG (Visit 7, 11, and 15 Only). 
o Administer the S-STS (Visit 3 Only). 
o Collect vital signs (including sitting, supine, and standing BP).  
□ Administer study treatment and perform safety assessments per the Infusion Administration Manual 
(Appendix 11). 
□ Administer the S-STS after the subject’s final infusion (Visit 7 Only). 
 


 
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7.3.5 
FOLLOW-UP 
 
Visits 8 and 16 (Day 6 + 3 Days and Day 90 + 7 Days): 
□ Review AEs and concomitant medications. 
□ Collect the following: 
o Vital signs (including sitting, supine, and standing BP) and subject’s weight in kilograms. 
o Blood and urine samples for Comprehensive Labs (fasting samples preferred). 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred). 
□ Ensure the subject has had an opportunity to eat a meal or snack prior to commencing cognitive and 
motor testing and that the subject is in the ON state.  PD medications should be taken at the standard 
intervals for each subject and testing should be scheduled to facilitate the subject being in the ON 
state. 
□ It is preferred that cognitive and motor function testing is performed in the following order (breaks 
are permitted between assessments as needed):  
1. CDR-CCB 
2. D-KEFS 
3. dCDT 
4. MDS-UPDRS 1/2/3 
□ Consenting subjects will undergo an additional MRI scan (Visit 16 + 7 days Only). 
 
Note: Visit 16 (Day 90) may be split to allow for sufficient time to complete all required procedures. Review 
AEs and concomitant medications during split visits, as applicable.  
 
Visit 9 (Days 28 ± 7 Days) and Visit 17 (Day 112 ± 7 Days): 
□ Review AEs and concomitant medications. 
□ Collect the following: 
o Vital signs. 
o Blood and urine samples for Comprehensive Labs (fasting samples preferred). 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred). 
□ Ensure the subject has had an opportunity to eat a meal or snack prior to commencing cognitive and 
motor testing and that the subject is in the ON state.  PD medications should be taken at the standard 
intervals for each subject and testing should be scheduled to facilitate the subject being in the ON 
state. 
□ It is preferred that cognitive and motor function testing is performed in the following order(breaks are 
permitted between assessments as needed):  
1. MoCA 
2. CDR-CCB 
3. MDS-UPDRS 1/2/3 
4. PDQ-39 (Visit 9 Only) 
 


 
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Visit 10 (Day 56 ± 7 Days) and Visit 18 (Day 140 ± 7 Days): 
□ Review AEs and concomitant medications. 
□ Collect the following: 
o Vital signs. 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred). 
□ Ensure the subject has had an opportunity to eat a meal or snack prior to commencing cognitive and 
motor testing and that the subject is in the ON state.  PD medications should be taken at the standard 
intervals for each subject and testing should be scheduled to facilitate the subject being in the ON 
state. 
□ It is preferred that cognitive and motor function testing be performed in the following order (breaks are 
permitted between assessments as needed):  
1. CDR-CCB 
2. D-KEFS 
3. dCDT 
4. MDS-UPDRS 1/2/3 
5. SE-ADL (Visit 10 Only) 
6. CISI-PD (Visit 10 Only) 
7. PDQ-39 
8. GDS-15 
 
7.3.6 
FINAL STUDY VISIT 
 
Visit 19, End of Study (Day 168 ± 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 Lab Panel (fasting samples preferred). 
o Samples for proteomics/epigenetics/biobanking (fasting samples preferred). 
□ Perform the physical exam.  
□ Ensure the subject has had an opportunity to eat a meal or snack prior to commencing cognitive and 
motor testing and that the subject is in the ON state.  PD medications should be taken at the standard 
intervals for each subject and testing should be scheduled to facilitate the subject being in the ON 
state. 
□ It is preferred that cognitive and motor function testing be performed in the following order (breaks are 
permitted between assessments as needed):  
1. CDR-CCB 
2. MDS-UPDRS 1/2/3 
3. SE-ADL 
4. CISI-PD 
5. PDQ-39 
 


 
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7.3.7 
EARLY TERMINATION 
 
If a subject has received at least one infusion but is terminated or terminates from the study early, the site 
should try to perform all assessments scheduled at the End of Study Visit.  In addition, if a subject withdraws 
from the study early but is willing to undergo the additional MRI scan, this can be obtained as long as the 
subject received at least two infusions of GRF6021/placebo. 
 
7.3.8 
SCHEDULE OF EVENTS TABLE 
 
A tabular summary of all procedures that will be accomplished at each study visit can be found in Section 15 
Schedule of Events. 
 
7.4 
CONCOMITANT MEDICATIONS 
 
All concomitant prescription medications taken during study participation will be recorded on the CRFs.  For this 
protocol, a prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician.  Medications to be reported in the CRF are concomitant prescription medications, 
over-the-counter medications, and non-prescription medications. 
 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
The following concomitant medications, treatments, and procedures 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. 
• 
If on DBS, a change in DBS settings at any point during the subject’s participation in the trial.  
 
8 
ASSESSMENT OF SAFETY 
 
Assessment of safety will be conducted by blinded study personnel except in extraordinary circumstances where 
knowledge of whether GRF6021 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 pharmaceutical (investigational) product even if the event does not necessarily have a 


 
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causal relationship with this treatment.   
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding that 
is deemed clinically significant), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not related to the medicinal (investigational) product.   
 
An AE does include any: 
• 
Exacerbation of a pre-existing illness. 
• 
Subjective or objective symptoms spontaneously offered by the subject and/or observed by the 
investigator or study staff. 
• 
Increase in frequency or intensity of a pre-existing episodic event or condition. 
• 
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. 
• 
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 PD, PD-MCI, and PDD that are consistent with the subject’s usual 
clinical course unless the symptom(s) meet(s) the criteria for “serious.” 
• 
Pregnancy. 
 


 
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8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
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.   
A serious adverse event (experience) or reaction is an untoward medical occurrence that, at any dose, fulfills 
one or more of the following criteria: 
a. Results in death (i.e., the AE actually causes or leads to death). 
b. Is life-threatening. 
• 
An AE is considered “life-threatening” if, in the view of either the investigator or Sponsor, its 
occurrence places the patient or subject at immediate risk of death; it does not include AEs which, 
had it occurred in a more severe form, might have caused death. 
c. Results in inpatient hospitalization or prolongation of existing hospitalization. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study 
is not considered an AE; hospitalization for participating in this 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 
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mentioned as occurring with the particular drug under investigation.  For example, although angioedema is 
anticipated to occur in some patients exposed to drugs in the angiotensin-converting enzyme (ACE) inhibitor 
class and angioedema would be described in the Investigator’s Brochure as a class effect, the first case of 
angioedema observed with the drug under investigation should be considered unexpected for reporting 
purposes (FDA 2012). 
 
This definition of “unexpected” relies entirely on the Reference Safety Information in the Investigator’s 
Brochure as the basis for determining if newly acquired information generated from clinical trials or reported 
from other sources is unexpected.  The suspected adverse reactions listed in the Investigator’s Brochure (i.e., 
“expected”) are those observed with the investigational drug and for which a causal relationship between the 
event and the drug is suspected or confirmed. 
 
Sponsor assessment of expectedness and relationship to study drug/causality will determine the need for 
expedited reporting of AEs. 
 
8.3 
TIME PERIOD/FREQUENCY FOR EVENT ASSESSMENT/FOLLOW-UP 
 
At every clinic visit, subjects will be assessed for AEs and SAEs.  After the subject has had an opportunity to 
spontaneously mention any problems, the investigator should inquire about AEs by asking a non-leading question 
such as the following: 
1. 
“How are you feeling?” 
2. 
“Have you had any changes since your last assessment/visit?” 
3. 
“Have you taken any new medicines since your last assessment/visit?” 
 
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. 
 


 
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*Note: Causality assessment will be made only when the AE occurs after the subject has initiated at least one 
infusion of the study agent.  An AE occurring before the subject’s exposure to study agent will always be 
labeled as “unrelated”. 
 
Any AE occurring during the study must be documented in the subject’s medical records and as an AE in the 
CRF.  Any SAE occurring during the study must be documented in the subject’s medical records and as an 
SAE in the CRF. 
 
A separate set of SAE pages should be used for each SAE.  However, if at the time of initial reporting, 
multiple SAEs are present that are temporally and/or clinically related, they may be reported on the same SAE 
page. 
 
The investigator should attempt to establish a diagnosis of the event (that meets the definition of an AE or 
SAE) based on signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs or symptoms.  The diagnosis will become the 
basis for the verbatim term as reported by the investigator.  If no diagnosis is known and clinical signs and 
symptoms are not present, the abnormal finding should be recorded. 
 
In addition to the investigator’s own description of the AE, each AE will be encoded according to the 
MedDRA. 
 
The investigator will take all appropriate and necessary therapeutic measures required for resolution of the 
AE.  Any medication necessary for the treatment of an AE must be recorded on the concomitant medication 
CRF.   
 
The SAE pages of the CRF should be completed as thoroughly as possible and signed by the investigator or 
his/her designee before transmittal to the study Contract Research Organization (CRO).  It is very important 
that the investigator provide his/her assessment of causality to study drug as well as an applicable diagnosis at 
the time of the initial SAE report. 
 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING 
 
8.4.2.1 
Timeframes for Reporting SAEs 
 
The Sponsor will notify the FDA as well as the competent authority of each participating country, including 
the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM), Therapeutic Goods 
Administration (TGA), 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 


 
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timeframes:  
 
• 
All SAEs occurring during the study should be reported immediately. 
• 
The SAE Report Form and relevant source documents, if applicable, must be completed and emailed 
to Safety.Alkahest@apcerls.com within 24 hours of observation or learning of the event.  
• 
Follow-up information must be sent to the CRO within 24 hours of receipt of information by the 
investigational site. 
 
SAEs will be followed until resolution, the condition stabilizes, the event is otherwise explained or is judged 
by the investigator to be no longer clinically significant, or until the subject is lost to follow up. 
 
8.4.2.2 
SAE Information to Report 
 
All information available regarding an SAE must be submitted in the timeframes indicated.  At a minimum, 
SAE reports must contain the subject ID, the SAE verbatim term, onset date, relationship to study 
drug/causality, and a brief narrative of the event.  Please note that relationship to study drug/causality as 
well as the reported verbatim term are very important and should be included in the initial report as it 
may impact expedited regulatory reporting requirements for the event.  The date of SAE discovery by the site 
staff should be documented in the source documents. 
 
The investigator must record all relevant information regarding an AE/SAE in the applicable sections of the 
CRF.  It is not acceptable for the investigator to send photocopies of the subject’s medical records in lieu of 
completion of the appropriate AE/SAE pages.  However, there may be instances when copies of medical 
records for certain cases are requested by the CRO and/or the Sponsor.  If medical records are submitted to 
the CRO then all subject personal identifiers must be completely and thoroughly redacted prior to submission. 
 
A blank SAE Report Form and instructions for SAE reporting will be provided to the site and will be 
maintained in the investigator’s study file.  The SAE Report Form must be completed and emailed to 
Safety.Alkahest@apcerls.com according to the timeframes specified in Section 8.4.2.1.  The SAE Report 
Form should include copies of relevant source documents, if applicable.  Reconciliation of any discrepancy 
noted during monitoring and amending the eCRF 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/IEC should submit all applicable events, unanticipated problems, and safety 
reports to the site’s local IRB/IEC, if applicable.  All safety reporting deviations should also be submitted to 
their local IRB/IEC, if applicable. 
 
8.4.3 
ADVERSE EVENTS OF SPECIAL INTEREST 
 
Please note that for an event to be classified as an AE of special interest (AESI), the event should meet the 
definition of an Adverse Event per Section 8.1.1. Thus, if the investigator considers the event to be an AE, 
and it meets one or more of the criteria listed below, then the event should be classified as an AESI and 


 
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reported according to the timeframe specified.  
 
The following will be considered AEs of special interest (AESI) if they qualify as AEs per the preceding 
paragraph:  
• 
Clinically significant peripheral edema or pulmonary edema. 
• 
Clinically significant systolic BP >160 but <170 mmHg over consecutive timepoints spanning 30 or 
more minutes. 
• 
Clinically significant systolic BP <90 or >170 mmHg at a single timepoint. 
• 
Clinically significant diastolic BP >100 but <110 mmHg over consecutive timepoints spanning 30 or 
more minutes. 
• 
Clinically significant diastolic BP <60 or >110 at a single timepoint. 
• 
A change of >25% from baseline in systolic and/or diastolic BP. 
• 
Reduced kidney function (eGFR < 45 mL/min/1.73 m2). 
• 
Suspected transmission of blood-borne infectious agents.  
 
AESI occurring during the study should be reported within 48 hours of observation or learning of the event, 
unless the event is serious, in which case the event must be reported according to the timeframes specified in 
Section 8.4.2.1. 
 
Note: Blood pressures meeting the parameters above that are not considered adverse events need not be 
reported within the 48-hour window. Rather, these will be considered “blood pressures of special interest” 
and analyzed separately. 
 
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 
last dose in the event of early termination.  All pregnancies will be reported to the IRB/IEC, 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 SOC that are assessed as possibly or definitely related to the study agent 
by the investigator and confirmed as such by the Sponsor (see Section 8.2.2 Relationship to Study Agent). 
• 
Within or between any of the dosing groups: an overall pattern of symptomatic, clinical, or laboratory 
events associated with the study agent that the Sponsor’s Program Physician or designee consider a 
serious potential safety concern (e.g., suspicious overall pattern). 




 
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• 
Monitoring for this study will be performed by the study CRO in accordance with the Clinical Monitoring 
Plan (CMP). 
• 
A mix of on-site and centralized monitoring will be performed to ensure the safety of clinical subjects and 
the accuracy and completeness of study data.  
• 
The Sponsor will be provided with copies of monitoring reports per the timelines specified within the 
CMP. 
• 
Details of clinical site monitoring 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 in accordance with a quality oversight plan or 
equivalent 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, the study 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 any amount of the study agent.   
• 
Evaluable Dataset: all subjects who receive at least 5 of the 10 planned doses, have a diagnosis 
of PD and cognitive impairment per the inclusion criteria, and complete through Visit 8. 
– 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.   
 
For analysis of the primary and secondary endpoints, the following will be considered:  
• 
For endpoints that are continuous in nature: 
– Number of observations, mean, median, minimum and maximum, and standard deviation (SD) 
values will be presented as descriptive summary 
– For inferential statistics: 
 
If the Normality assumption is met, Paired t-test, or Analysis of Covariance (ANCOVA) using 
the baseline value as a covariate will be used 
 
If the Normality assumption is not met, a rank –ANCOVA analysis i.e., an ANCOVA analysis on 
rank-transformed data or other non-parametric methods will be used 
• For endpoints that are categorical in nature: 
– Frequency counts and percentages will be presented as descriptive summary 
– Chi-square test or Logit model will be used for inferential statistics 
 
Subject disposition (e.g., the number of subjects randomized, completed, and discontinued) will be 
summarized, and medical history data will be listed.  Prior and concomitant medications taken from 
screening and during the study will be categorized by World Health Organization 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 the reported adverse events will be presented by group after the verbatim terms have 
been coded to PTs and SOCs using the MedDRA Version 21.0 coding dictionary.  The summaries will 
include severity and attribution to the study agent.  Multiple reports of the same AE by the same subject will 
be counted only once at the highest severity and strongest attribution to the study agent. 
 
The AE analyses will focus on those that are Treatment-Emergent, however any AEs that are reported after 
consent has been signed and prior to initial dosing will be tabulated as Intercurrent Events. 
 
Additional details are presented in Section 10.4.4.   
 


 
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10.4.3 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINTS 
 
The study is not powered to detect significant changes in cognition, motor function, activities of daily living, 
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.  
Appropriate paired sample tests (paired t-test or Wilcoxon Signed Rank tests) may be conducted to evaluate 
within-subject changes from baseline, using a two-tailed α-level of 0.05.  Between-group differences may be 
assessed by One-way ANCOVA or its nonparametric equivalent test. 
 
10.4.4 
ANALYSIS OF THE SECONDARY SAFETY ENDPOINTS 
 
Actual values and changes from baseline in clinical laboratory measurements, vital signs, body weight, and S-
STS scores will also 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 
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 BP, heart rate, respiratory rate, body temperature, body weight, S-STS score) 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 the study visit schedule, visit procedures, infusions and subject retention will be 
assessed.  Subject adherence may vary across the different groups offering another feasibility measurement as 
would a comparison of the number of subjects who complete two series of 5 pulsed doses to subjects who 
complete only the first series.  Reasons for study discontinuation will be compared across groups and across 
other subgroups of subjects, as appropriate. 
 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS 
 
See Section 10.4.1. 
 
10.4.7 
PLANNED INTERIM ANALYSES 
 
An unblinded interim analysis of the safety endpoints, including the primary endpoint and secondary safety 
endpoints, was conducted when approximately 20 subjects completed Visit 8 (end of first dosing period).   
The requirement that subjects remain on an inpatient unit during each treatment period was included in the 


 
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protocol to enable safety monitoring during dosing.  The Sponsor reviewed the safety data from this interim 
analysis to assess whether the need for inpatient stays during dosing should remain a requirement.  The 
unblinded safety analysis was performed following a data-cut on 09JUN2019 and included 32 subjects. Based 
on the results of the interim safety analysis and feedback from FDA, the inpatient requirement is no longer 
required as reflected in this version of the Protocol.   
 
An unblinded interim analysis of the MoCA, CDR-CCB, and MDS-UPDRS3 secondary efficacy endpoints is 
planned when approximately 40 subjects have completed Visit 8 (end of first dosing period).  As the study is 
not powered for efficacy and no decisions will be made regarding stopping the trial, statistical testing will be 
performed at the 0.05 level using two-tailed tests on both the Evaluable and Per Protocol datasets.  To 
minimize potential bias of the remaining efficacy and safety data, only aggregated summary tables will be 
provided.   
 
Safety will be monitored on an ongoing basis.  If a Safety Evaluation Meeting is triggered (see Section 8.5), 
an ad hoc interim safety analysis will be performed.  If such an ad hoc safety interim analysis is conducted, 
the 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. 
 
10.5 SAMPLE SIZE 
 
A total of approximately 90 subjects will be randomized in a 2:1 ratio to active treatment (approximately 60 
subjects) or placebo (approximately 30 subjects), with the intent of obtaining ~68 evaluable subjects who have 
received at least 5 doses and completed the study through Visit 8.  Subjects who discontinue prior to completing 
Visit 8 may be replaced.  Subjects who withdraw or are withdrawn during screening will be replaced.   
 
The study is not statistically powered to detect differences in measures of clinical efficacy or biomarker 
endpoints.  To evaluate potential safety signals, the statistical approximation described by Hanley (aka the “Rule 
of Threes” in which the upper bound of the 95% confidence interval for the frequency of an unreported AE is at 
most 3/n % where n represents the number of subjects who received active GRF6021 in the study) will be used.  
In a sample of 60 subjects, the upper bound of the 95% confidence interval for the frequency of an unobserved 


 
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AE is approximately 5%.  In addition, the proposed sample size may be sufficient to identify trends in efficacy 
endpoints that will be used to determine the appropriate sample size for subsequent studies. 
 
10.6 MEASURES TO MINIMIZE BIAS 
 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES 
 
To minimize the potential bias at the time of randomization, the study will be double-blinded and randomized 
in a 2:1 ratio (active: placebo), with a mixed block size.  In addition to mixed block size, to reduce the 
potential impact of sex on study outcomes, the randomization will be stratified by sex; this is to assure a 
balanced distribution of evaluable male and female subjects in both treatment groups.  The randomization will 
be web-based and centralized.  The randomization codes will be generated by a statistician that 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, vials containing 
 of the study agent or vials containing placebo will be provided by an 
unblinded pharmacist, or other qualified staff responsible for drug accountability, to an unblinded Infusion 
Nurse who will administer the study agent or placebo.  To ensure that Outcomes Assessors, raters, and other 
study personnel, as well as subjects and trial partners 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.  These measures include, but are not limited to, covering the vial 
and drip chamber with an opaque black bag or equivalent; using a curtain, drape, or equivalent to shield the 
infusion administration setup as applicable; concealing vials/containers of study agent/placebo during 
transport; and returning used containers of the study agent/placebo to the unblinded pharmacist, or other 
qualified site personnel responsible for drug accountability, promptly at the end of the Infusion Period.   
 
Communication between the blinded Outcomes Assessor and the unblinded Infusion Nurse will be restricted 
to only that required to ensure the immediate safety of subjects.  The Outcomes Assessor will observe the 
subject during the infusion and collect and/or manage/report AEs and SAEs.   
 
Finally, to avoid potential unblinding based on subject 
 levels, 
 lab results (aside from 
those tested at screening) will remain blinded until the conclusion of the study.  Unblinding of 
 
lab results would only occur for emergent safety reasons. 
 
Aside from designated personnel whose sole responsibility necessitates access to unblinding information 
(e.g., the unblinded CRA whose sole responsibility is to ensure study agent/placebo accountability, the 
unblinded clinical supply manager, etc.), the Sponsor and their representatives will be blinded with respect to 
subjects’ treatment allocation through database lock unless breaking the blind is required for safety reasons 
(see 10.6.3 Breaking the Study Blind/Subject Code).  The unblinded interim analyses will be performed by 
unblinded statisticians who are not members of the protocol study team. The data will be provided in 
aggregate fashion so the difference between study agent and placebo is compared but individual treatment 
allocation remains blinded. 
 
 
 
 


 
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10.6.2 
EVALUATION OF SUCCESS OF BLINDING 
 
Success of blinding will be assessed based on all occurrences (intentional or unintentional) of unblinding of 
blinded study subjects, their trial partners, or study personnel (e.g. investigators, medical providers, 
cognitive/motor testing raters, the Sponsor or their representatives).  All intentional and unintentional 
unblinding will be documented and reported.   
 
10.6.3 
BREAKING THE STUDY BLIND/SUBJECT CODE 
 
The study blind can be broken for safety reasons if the information is required for the management of SAEs or 
severe AEs.  Only the Investigator can obtain the treatment allocation for their subject through the IRT.  
Before breaking the blind, every attempt should be made to discuss the need with the Sponsor’s Program 
Physician, or designee.  When some degree of unblinding must occur, this should be limited to the fewest 
number of people on a need-to-know basis.   
 
Any noted intentional or unintentional breaking of the blind should be documented and reported to the 
Sponsor’s Study Team Lead.   If unintentional unblinding occurs during the study, root cause analysis will be 
evaluated, and corrective actions implemented. 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
Each participating site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6 R2 and regulatory and institutional requirements for the protection of confidentiality of subjects.  Each site 
will permit authorized representatives of regulatory agencies, the IRB/IEC, the Sponsor, or the Sponsor’s 
representatives to examine (and when permitted by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits, and evaluation of the study safety, progress, and data validity.   
 
Source data are all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  Examples of these original documents and data 
records include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, 
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, 


 
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part 320, 1993, Retention of Bioavailability and Bioequivalence Testing Samples and the Declaration of Helsinki. 
 
12.2 INSTITUTIONAL REVIEW BOARD/ ETHICS COMMITTEE 
 
This protocol and any accompanying material to be provided to the subject (such as advertisements, subject 
information sheets, or descriptions of the study used to obtain informed consent) will be submitted by the 
investigator to an IRB or IEC.  Approval from the IRB/IEC must be obtained before starting the study and should 
be documented in a letter to the investigator specifying the protocol number, protocol version, documents 
reviewed, and date on which the committee met and granted the approval.  
 
All changes to the consent form will be IRB/IEC 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/IEC for approval prior to 
implementation. 
 
12.3 INFORMED CONSENT PROCESS 
 
12.3.1 
CONSENT FORMS 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the subject or 
healthcare power of attorney or equivalent legal representative, and written documentation of informed 
consent is required prior to 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 undertaking any study-related procedures. 
 
Subjects should have the opportunity to discuss the study with their family members or other advisors and the 
time to consider participation in the trial carefully.  The subjects may withdraw consent at any time 
throughout the course of the trial.  The rights and welfare of the subjects will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to participate in this 
study. 
 
The investigator or designee must utilize an IRB/IEC-approved consent form that contains the elements 
required by ICH GCP and applicable regulatory requirements for documenting written informed consent.  
Each informed consent will be appropriately signed and dated by the subject and/or their legally authorized 
representative and the person obtaining consent.  A copy of the signed consent form 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 


 
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limited information about the potential candidate (e.g., date of screening).  
 
All subjects who provide consent will be assigned a unique study number.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study documentation related to the 
study subject.  Once a number is assigned to a subject, that number will remain with that study subject and 
will not be reused. 
 
If an individual’s medical chart or results of diagnostic tests performed as part of an individual’s regular 
medical care are going to be used for screening, written informed consent must be obtained prior to review 
of that information in accordance with the Health Insurance Portability and Accountability Act (HIPAA). 
 
12.4 PARTICIPANT AND 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 data will be 
released to any unauthorized third party without prior written approval of the Sponsor. 
 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB/IEC, or 
government regulatory agencies may inspect documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in 
this study.  The clinical study site will permit access to such records. 
 
The study subject’s contact information will be securely stored at each clinical site for internal use during the 
study.  At the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by local IRB/IEC and Institutional regulations.  Study subjects’ research data, which is for purposes of 
statistical analysis and scientific reporting, that is transmitted to the Sponsor, CRO, and/or IRB/IEC will not 
include contact or identifying information.  Rather, individual subjects and their research data will be identified 
by a unique study number.  This unique study number should be recorded on non-local lab samples, requisitions, 
and any documents submitted to the CRO, Sponsor, and/or IRB/IEC.  The study data entry and study management 
systems used by clinical sites and by research staff will be secured and password protected. 
 
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 
IRB/IECs, 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 specimens with the specific data from each subject, maintaining the masking of the identity 
of the study subject.  Subjects may choose whether the Sponsor can store and use samples for further research.  
 
An individual subject can choose to withdraw consent to have biological specimens stored for future research.  
Samples from subjects who provide consent for future research purposes are collected, stored, and code-linked to 
the subject until the end of the study at which time the samples are deidentified and may no longer be connected 
to the individual subject.  Throughout the study, at any time, the subject and/or the subject’s LAR is able to 
withdraw consent, and the individual samples can be retrieved and destroyed.  However, after the samples have 


 
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been deidentified, this may not be possible. 
 
When the study is completed, access to study data and/or samples will be managed by Alkahest.  In the event 
Alkahest transfers ownership to another commercial Sponsor, ownership of the samples may be transferred as 
well. 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
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 eCRFs 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 enrolled in the study, the eCRF must be completed in a timely manner.  The investigator will 
review and approve the eCRF for each study subject after all data have been entered, the eCRFs 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 eCRF.  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/IEC), 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. 


 
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The investigator’s study file will contain the protocol/amendments, eCRF, IRB/IEC 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 
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 
 
A Protocol Deviation is any noncompliance with the clinical trial protocol or with GCP.  The noncompliance may 
be either on the part of the subject, the investigator, or the study site staff.  When deviations occur, corrective 
actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
Protocol Deviations will be categorized as either Major or Minor and will be defined in the study-specific 
Protocol Deviation Plan.   
 
Major Protocol Deviation: a departure 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. 
Examples of Major Protocol Deviations include, but are not limited to: 


 
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• Failure to obtain informed consent (i.e., no evidence of informed consent) 
• Enrolling subjects in violation of key eligibility criteria designed to ensure a specific subject population 
• A drug dispensing or dosing error that could have affected the safety of the subject  
• Failing to collect data necessary to interpret primary endpoints, as this may compromise the scientific value 
of the trial 
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.  Observations categorized as Major may include those 
situations where there is a pattern of deviation, numerous Minor observations, or other significant deviation. 
 
Minor Protocol Deviation: a departure 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.  
Examples of Minor Protocol Deviations include, but are not limited to: 
• A protocol visit date outside of a visit window 
• An isolated case of a missed or incomplete study procedure (e.g., laboratory test)  
• An isolated incident of a missed or incomplete study evaluation (e.g., examination) 
Minor Protocol deviations would not generally preclude subject data from the per protocol analysis population. 
Observations categorized as Minor may become Major if not corrected.  
 
All deviations will be logged and tracked by the site and CRO.  Periodic review of Protocol Deviations will serve 
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/IEC per their guidelines.  The site PI/study staff are responsible 
for knowing and adhering to their IRB/IEC 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 


 
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inadvertently divulged (including patent protection), 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. 
 
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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Annual Scientific Meeting, February, 2013, Washington, D.C. 
 
Wesnes K.  The effects of psychotropic drugs upon human behavior.  Mod Probl Pharmacopsych.  1977;12:37-58. 
 
Wesnes K.  The value of assessing cognitive function in drug development.  Dialogues Clin Neurosci. 
2000;2:183-202. 
 
Yesavage JA, Brink TL, Rose TL, Lum O, Huang W, Adey MB, et al.  Development and validation of a geriatric 
depression screening scale: A preliminary report. J Psych Res. 1983;17:37-49. 
 
 


 
 
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16.2 UNPUBLISHED REFERENCES 
 
2018-CET-01.  Actual effects of 
 on neuronal activation in aged wild type 
mice. 
 
2018-CRL03.  Effects of 
 in the MPTP mouse model of Parkinson’s disease. 
 
2018-QPS01.  Effects of 
 in line 61 mice. 
 
ALK-2015-R002.  Effects of young and old human plasma on cognition in NODscid mice. 
 
 
  April, 2018. 
 
VIV-2016-R003.  Effects of young human plasma 
 on neurogenesis, 
inflammation and cognition. 
 
VIV-2016-R009.  Effects of 
 on cognition, behavior and histopathological 
endpoints in aged NSG mice. 
 
VIV-2016-R014.  Young plasma and 
 effects on behavior and survival in 
aging NODScid mice. 
 
VIV-2016-R020.  Effects of 
 on cognition. 
 
VIV-2016-R021.  Effects of young and aged human plasma and
 on 
histopathological endpoints in aged NSG mice. 
 
VIV-2016-R024.  Effects of human plasma and 
 on cognition, behavior and 
histopathologic endpoints in aged NSG mice. 
 
VIV-2017-R025.  Effects of 
 on cognition in aged NSG mice (2). 
 
VIV-2017-R036.  Effects of 
 on histopathological endpoints in aged NSG 
mice. 
 
VIV-2017-R038.  Effects of 
 on cognition, behavior and histopathological 
endpoints in aged C57BL/6J mice. 
 
VIV-2018-R069.  Effects of 
 on cognition and neurogenesis in aged, 
C57BL/6J mice. 
 
 
 


 
 
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17 
APPENDICES 
 
Appendix 1.  
Montreal Cognitive Assessment 
The MoCA (Nasreddine 2005) is a commonly used screening test easily administered by nonspecialist staff.  It 
assesses the domains of attention and concentration, executive functions, memory, language, visuoconstructional 
skills, conceptual thinking, calculations, and orientation.  The total possible score is 30 points with a score of 26 or 
more considered normal. For additional information, the assessment can be downloaded using the following link: 
Montreal Cognitive Assessment (V7.1). 
 
 
 


 
 
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Appendix 2.  
Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale 
The MDS-UPDRS (Fahn 1987, Movement Disorder Society Task Force 2003) was developed as an effort to 
incorporate elements from existing scales to provide a comprehensive but efficient and flexible means to monitor 
PD-related disability and impairment.  The MDS-UPDRS has four components (Part 1, Mentation, Behavior, and 
Mood; Part 2, Activities of Daily Living; Part 3, Motor; Part IV, Complications).  For the current study, only Parts 
1, 2, 3 and total score will be utilized.  The rating for each item is from 0 (normal) to 4 (severe).  The total score for 
each Part is obtained from the sum of the corresponding item scores.  The estimated time for completion of Parts 1-
3 is 20-30 minutes. For additional information, the full assessment can be downloaded using the following link: 
MDS-UPDRS. 
 
 
 
 


 
 
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Appendix 3.  
Schwab and England Activities of Daily Living 
The SE-ADL evaluates patients’ perception of global functional capacity and dependence (Schwab 1968).  Scoring 
is expressed in terms of percentage, in 10 steps from 100 to 0 (100%, normal status; 0%, bedridden with vegetative 
dysfunction), so that the lower the score, the worse the functional status. The rating is made by an 
observer/professional. For additional information, the full assessment can be downloaded using the following link: 
Schwab and England Activities of Daily Living Scale.  
 
 
 
 


 
 
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Appendix 4.  
Clinical Impression of Severity Index – Parkinson’s Disease 
The CISI-PD (V2) is a severity index formed by four items (motor signs, disability, motor complications and 
cognitive status), rated 0 (not at all) to six (very severe or severely disabled). A total score is calculated by 
summing the item scores.  The scale is completed by a clinician at the time of assessment.  It takes a few seconds 
to complete once the state of the patient is known (Martinez-Martin 2006). For additional information, the full 
assessment can be downloaded using the following link: Clinical Impression of Severity Index: Parkinson’s 
Disease (V2). 
 
 
 
 
  
 


 
 
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Appendix 5.  
Parkinson’s Disease Quality of Life Questionnaire-39 
The PDQ-39 is a self-administered questionnaire of 39 questions relating to 8 key areas of health and daily 
activities, including both motor and non-motor symptoms (Peto 1998).  The eight dimensions include: mobility, 
activities of daily living, emotional well-being, stigma, social support, cognitions, communication, and bodily 
discomfort.  It is scored on a scale of 0-100 with lower scores indicating better health and high scores indicating 
more severe symptoms.  For additional information, the full assessment can be downloaded using the following 
link: Parkinson’s Disease Quality of Life Questionnaire-39. 
 
 
 
 
 


 
 
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Appendix 6.  
Geriatric Depression Scale-15 
The GDS-15 is shortened form of a 30-item questionnaire in which participants are asked to respond by answering 
yes or no in reference to how they felt over the past week (Yesavage 1983).  The GDS-S should be given orally. A 
clear YES or NO answer is required for each question. If necessary, repeat the question but do not accept a 
qualified answer from the test-taker.  Cross off either yes or no for each question. Depressive answers (errors) are 
circled on the form and are bolded below.  Count up 1 for each depressive answer (error).  The final score is the 
tally of the number of depressive answers with the following scores indicating depression: 0-4 No depression,  
5-10 Suggestive of a mild depression, and 11 + Suggestive of severe depression. For additional information, the 
full assessment can be downloaded using the following link: Geriatric Depression Scale-15.  
 
 
 


 
 
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Appendix 7. 
Sheehan Suicidality Tracking Scale 
The S-STS was developed to provide a brief but efficient instrument for use in assessing change in suicidal 
ideation and behavior while providing a comprehensive description of suicidal ideation and behavior (Sheehan 
2014). The primary goals in the design of the S-STS were for the scale to be: 1) short and inexpensive; 2) simple, 
clear, and easy to administer or self-rate; 3) highly sensitive (i.e., able to detect a high proportion of patients who 
are suicidal); 4) specific (i.e., able to screen out those who are not suicidal); 5) sensitive to change in suicidal 
ideation and behavior; 6) compatible with the regulatory categories of assessment for suicidal ideation and 
behavior; 7) useful in clinical as well as research settings; 8) useful in detecting an efficacy signal for anti-suicidal 
medications; and 9) capable of use in pediatric and geriatric settings.  The standard version of the S-STS is a 16-
item scale that assesses the seriousness of suicidality phenomena on a Likert-type scale (0-4) ranging from “not at 
all” (0) to “extremely” (4).  It also assesses the frequency of key phenomena and the overall time spent in 
suicidality. For additional information, the full assessment can be downloaded using the following link: Sheehan 
Suicidality Tracking Scale.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix 8.  
Movement Disorder Society’s Parkinson’s Disease Criteria 
 
 
 
 
 
Provided for use in clinical trial documentation in Postuma 2015. 


 
 
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Appendix 9.  
Criteria for Parkinson’s Disease with Mild Cognitive Impairment
Reprinted with permission from Litvan 2012. 
 
 
 
 


 
 
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Appendix 10.  Parkinson’s Disease with Dementia Criteria
 
Reprinted with permission from Emre 2007. 




 
 
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• 
An appropriately qualified blinded Outcomes Assessor will monitor the subject throughout the infusion and 
for approximately 4 hours after the infusion has been completed. This person’s qualifications must enable 
them to identify AEs, monitor vital signs, and take the appropriate course of action when an AE or clinically-
significant vital sign change occurs.  
• 
Sites must identify and follow procedures that ensure adequate blinding of blinded study personnel, subjects, 
and trial partners before, during, and after the Infusion Period. This may include the use of study drug 
container covers and/or the use of drapes to separate the unblinded Infusion Nurse and infusion apparatus 
from the blinded Outcomes Assessor, PI, subject, and trial partner.     
• 
The unblinded pharmacist, or other qualified site personnel responsible for drug accountability, must retain 
all used vials/containers for drug accountability, unless otherwise agreed to with the Sponsor.  These should 
be kept in a secure location with limited access to minimize the risk of unblinding blinded study staff.  
Partially-used vials/containers may not be re-used. 
4. INSTRUCTIONS FOR THE UNBLINDED INFUSION NURSE 
4.1. Equipment and Supplies 
The following equipment and supplies will be needed for each infusion: 
 
Infusion Supplies (Provided by Sponsor) 
• 
GRF6021 or placebo 
• 
Hangers for 
 IV vials (for blinding) 
• 
Black IV Cover Bags 
 (for blinding) 
 
Infusion Supplies (Not provided) 
• 
Volumetric infusion pump 
• 
IV spike set (vented) 
• 
Pump-compatible IV tubing (without inline filter) 
• 
IV Start Kit or equivalent supplies 
• 
18-20 gauge peripheral IV catheter 
• 
Piggyback setup if saline bags will be used to flush the IV line post infusion 
• 
0.9% saline for injection (50 mL bags or 10 mL syringes) for post IV line or peripheral IV 
flush 
• 
Gloves  
• 
Alcohol pads 
• 
IV pole 
• 
Injectable cap and luer-lock connector (if applicable) 
• 
Epinephrine Pen/Epi Kit   
• 
Heparin Lock and syringe (if used) 
• 
Sharps container  
• 
Privacy screen/blinding setup during infusion  
 


 
 
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General Study Supplies                        
• 
Infusion source notes for the unblinded Infusion Nurse  
• 
Study Drug Infusion Rate Table (See Table 1. Study Drug Infusion Rates) 
 
If the site is unable to source needed infusion supplies, the Sponsor will assist in provisioning the required 
materials.  
 
4.2. Blinding  
Each site is required to ensure an appropriate blinding setup is prepared before each infusion and must 
document the setup employed.  This may include any or all of the following: 
• 
A privacy screen (or similar) to shield subject, subject’s trial partner, and all blinded study 
personnel from the infusion setup  
• 
Opaque bag or similar, to mask the content of the glass vial/container 
• 
Other masking devices 
 
4.3. Prior to Infusion 
The unblinded Infusion Nurse will take care to ensure the appropriate blinding of the study drug at all times.  
Prior to infusion:  
a. Verify subject identity. 
b. Verify randomization assignment/ kit number.   
c. Visually inspect the study drug vial for particulate matter or cracks in the vial. Do not use the 
solution if the vial is cracked or if the solution contains discrete foreign particulate matter.  Do 
not shake.  Do not use if the vial has been frozen. Study drug should be stored and infused at 
room temperature. 
d. Obtain the study drug vial from the pharmacy and ensure that it is not visible when being 
transported to the infusion room or while setting up the IV apparatus. 
e. Follow site procedures for peripheral IV catheter insertion, IV setup, and locking (if applicable). 
f. The study drug vial should be spiked no more than 4 hours before infusion start. 
 
It is recommended to prime the line using the study drug (either GRF6021 or placebo), while being 
careful to limit the amount of study drug that is lost (no more than 2-3 mL is ideal). The amount of 
study drug lost during priming should be noted in the infusion source record, without disclosing any 
information that could be potentially unblinding. 
 
4.3.1. Considerations if Using a Heparin or Saline Lock 
If the peripheral IV site will be locked with saline or heparin, the following steps should be considered:  
• 
Locked peripheral IV sites should be assessed prior to and after each use to inspect for 
swelling, redness, pain, warmth, and phlebitis. 




 
 
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Any communication between blinded and unblinded staff should be done with extreme care taken to 
not unblind the subject, the PI, or any other blinded staff. If accidental unblinding occurs, 
immediately contact your site’s unblinded CRA for further instruction.  
4.5. Post-Infusion 
a. Depending on your infusion line’s loading volume, sufficient saline should be used to flush the IV line 
to ensure 
 of study drug was infused into the subject.   
b. When the infusion is complete, flush the peripheral IV catheter as ordered if it will remain in place (see 
Section 4.3.1) or discontinue it as appropriate.  
c. The unblinded Infusion Nurse will document the following information on the subject’s infusion source 
record:     
• 
Subject ID 
• 
Date and time of infusion start and stop 
• 
Infusion vial label checked for accuracy; record unique vial ID number 
• 
Actual volume infused (if less than 
) 
• 
What infusion method or pump that was used 
• 
Titration steps (e.g. changes in flow rate and time of change) 
• 
Vascular access device and status (including all flushes) 
d. Following the infusion, the infusion source record should be maintained with the subject’s records.  
e. The unblinded Infusion Nurse should return the used vial to the unblinded pharmacist, or other qualified 
personnel responsible for drug accountability. During transport, ensure the vial/container is concealed 
from view.  
 
5. INSTRUCTIONS FOR THE BLINDED OUTCOMES ASSESSOR AND INVESTIGATOR 
 
5.1. Equipment and Supplies 
The Outcomes Assessor will need the following equipment and supplies for each infusion: 
• 
Source notes for the blinded Outcomes Assessor 
• 
Sphygmomanometer, or equivalent device for measuring BP and heart rate 
• 
Pulse oximeter (optional) 
• 
Thermometer 
• 
Body weight scale 
5.2. Prior to Infusion 
The blinded Outcomes Assessor will check the following information prior to infusion start: 
a. 
Subject identification to ensure it is the correct subject. 
b. 
Verify eligibility criteria (e.g. subject’s history and diagnosis, including allergies and previous 
reactions to blood or blood products). 
c. 
Review AEs and concomitant medications. 
d. 
Baseline vital signs (temperature, seated BP, orthostatic BP, heart rate, respiratory rate, and 
weight) within 1 hour of the start of the infusion and record data on source document. 












 
 
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5.4.2 
Previously read: Approximately 90 subjects 
(GRF6021: 60; placebo: 30) will be enrolled in 
the study with the intent of obtaining ~68 
evaluable subjects who have received at least 5 
doses and completed through Visit 8. 
 
Now reads: Approximately 90 subjects (GRF6021: 60; 
placebo: 30) will be enrolled in the study with the intent 
of obtaining ~68 evaluable subjects. 
 
Additional detail not 
required in this section as 
it is detailed in Section 10 
Statistical Considerations. 
6.1.2, 10.6.1 
Clarified that saline placebo is supplied in 
 
 glass vials. 
Revised for clarity. 
7.1.1.1.8 
Provided additional detail regarding assessment 
of motor function as part of the neurological 
exam.  
Revised to clarify the 
motor function portion of 
the neurological exam. 
7.1.1.2.8.2, 7.3.4 
Modified to reflect Protocol Clarification 
Memorandum #2. 
Revised to provide 
additional clarity to sites 
using an i-STAT 
handheld device to assess 
pre-infusion safety labs. 
7.2.1 
Removed sentence indicating total blood volume 
collected during the study. 
This information is 
conveyed in the Informed 
Consent Form and may 
vary depending on 
whether unscheduled labs 
are collected. 
7.3 
Previously read: Visit windows (when noted) 
should be benchmarked relative to Visit 3 for a 
subject, such that subjects complete the entire 
study by Day 168 (± 7 days).  
 
Now reads: To ensure follow-up visits occur at 
approximately the same intervals following both 
treatment periods, visit windows should be calculated 
as follows: 
 
• 
Visit windows for Visits 1-10 should be 
calculated relative to Day 1. 
• 
Visit windows for Visits 11-19 should be 
calculated relative to Day 85 ±7 (i.e., first day 
of dosing for Treatment Period 2). 
Revised to ensure follow-
up assessments are 
conducted at consistent 
intervals post-treatment. 


 
 
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7.3.5 
• Visit 16 day interval was changed from “90 + 
3 Days” to “90 + 7 Days.” 
• Text added: “Note: Visit 16 (Day 90) may be 
split to allow for sufficient time to complete 
all required procedures. Review AEs and 
concomitant medications during split visits, 
as applicable.” 
 
Revised to enhance study 
feasibility. 
8.4.3 
• Modified to reflect Protocol Clarification 
Memorandum #3. 
• The qualification of “Clinically significant” 
was added to measurements of systolic and 
diastolic blood pressure. 
• The following note was added: “Note: Blood 
pressures meeting the parameters above that 
are not considered adverse events need not be 
reported within the 48-hour window. Rather, 
these will be considered “blood pressures of 
special interest” and analyzed separately.” 
Revised to provide clarity 
regarding Adverse Events 
of Special Interest and 
reporting requirements. 
10.3 
• The safety dataset includes all subjects who 
received any amount of the study agent as 
opposed to “at least one dose.” 
 
 
 
 
• In the description of the evaluable dataset, 
added the following text, “have a diagnosis 
of PD and cognitive impairment per the 
inclusion criteria” 
 
Since the IMP is 
administered by IV 
infusion, subjects who 
receive any volume of 
IMP will be considered 
part of the safety dataset. 
 
Revised to ensure that 
only subjects who have a 
diagnosis of PD and 
cognitive impairment are 
included in the evaluable  
dataset. 
10.4.7 
Updated to include the outcome of the interim 
safety analysis. 
 
 
Updated since the 
planned interim safety 
analysis was completed 
in June 2019. 
13.1 
Previously read: For each subject who receives 
the study agent, the eCRF must be completed […]  
 
Revised for clarity, as 
screen failure data is 
captured in the eCRF. 


 
 
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Now reads: For each subject enrolled in the 
study, the eCRF must be completed […] 
13.3 
Major and Minor Protocol Deviation content 
updated. 
Updated to reflect revised 
Alkahest Standard 
Operating Procedures 
related to Major and 
Minor Protocol 
Deviations. 
15.1 
• Table modified to Word format (previously 
embedded Excel image) for ease/tracking of 
revisions. 
• Visit 16 day interval was changed from “90 + 
3 Days” to “90 + 7 Days.” 
• Note X4 updated as subjects should be 
randomized at least 5 days prior to treatment 
start to ensure study drug availability. 
• Note b updated as treatment window is 6 days 
in the event of a “grace” day. 
• Note c updated with the following content, 
“The windows for Visits 16,17,18, and 19 
should be calculated relative to the day of the 
subject’s first infusion during Treatment 
Period 2 (i.e., 85 ± 7 days).” 
• Note e updated to include cross-reference to 
Section 7.1.1.1.11 and list of labs was 
removed. 
• Note f updated to include cross-reference to 
Section 7.1.1.2.8.4 and list of labs was 
removed. 
• Note g updated to include the following, 
“When using an i-STAT Handheld Blood 
Analyzer, the blood sample(s) may be 
obtained on the same day as the infusion for 
assessment prior to infusion start.” In addition, 
cross-reference to Section 7.1.2.8.2 was added 
and list of labs was removed. 
• Note I was updated to include cross-reference 
to Section 7.1.1.2.8.3 and list of labs was 
removed. 
• Note j was updated by removing content 
related to time period for additional MRI and 
Updated ensure follow-up 
assessments are 
conducted at consistent 
intervals post-treatment, 
to promote study 
feasibility, and for 
content standardization. 



































SAP_001.pdf: