Clinical trial NCT04001517
Conditions: Dementia With Lewy Bodies (DLB)
Sponsor: EIP Pharma Inc
Start date: 2019-09-30; Completion date: 2020-06-30
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, proof-of-principle study of neflamapimod versus matching placebo (randomized 1:1) administered with food for 16 weeks in subjects with DLB. The primary objective is to evaluate the effect of neflamapimod on cognitive function as assessed in a study-specific Cogstate Neuropsychological Test Battery (NTB). Secondary endpoints include the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI-10), Timed Up and Go Test, and electroencephalogram (EEG) as a potential biomarker for DLB.

Detailed description:

Arms: arm 1: 40 mg capsules administered orally, BID or TID with food for 16 weeks; subjects will follow the BID regimen if weighing \<80 kg or the TID regimen if weighing ≥80 kg arm 2: 40 mg matching placebo capsules administered orally, BID or TID with food for 16 weeks; subjects will follow the BID regimen if weighing \<80 kg or the TID regimen if weighing ≥80 kg
Interventions: intervention 1: Neflamapimod
Intervention descriptions: intervention 1: Double-Blind, Placebo-Controlled

Protocol documents:
Prot_000.pdf: 
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EIP PHARMA, INC 
CLINICAL STUDY PROTOCOL 
Title 
A Double-Blind, Placebo-Controlled 16-Week Study of the Cognitive 
Effects of the Oral P38 Alpha Kinase Inhibitor Neflamapimod in 
Dementia with Lewy Bodies (DLB) 
Investigational 
Product 
Neflamapimod 
Development Phase 
2 
EIP Study Number 
EIP19-NFD-501 
IND Number 
125198 
EudraCT Number 
2019-001566-15 
Date (Version) 
12 April 2019 (Version 1.0) 
Sponsor Address 
EIP Pharma, Inc. 
210 Broadway, Suite 201 
Cambridge MA 02139 USA 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of EIP Pharma, Inc. is strictly prohibited except to the extent required under applicable laws or regulations. 
Persons to whom the information is disclosed must be informed that the information is confidential and may not be 
further disclosed by them. 


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SPONSOR PROTOCOL APPROVAL PAGE 
Signature 
 
 
Sponsor Responsible Person 
 
 
Title 
 
 
Date 
John J. Alam, M.D.
President and CEO
12 April 2019


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INVESTIGATOR’S SIGNATURE OF AGREEMENT PAGE 
 
I have read the protocol and, on behalf of my institution, agree to comply with all the conditions and 
instructions contained in this the protocol and with all applicable regulations. 
 
 
Signature 
 
 
Principal Investigator (printed name): 
Title: 
Institution: 
Address: 
Telephone number:   
Date 


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SPONSOR CONTACT INFORMATION 
Sponsor Responsible Person  
and Study Director: 
John J. Alam, MD 
210 Broadway, Suite 201 
Cambridge, MA 02139, USA 
Telephone: +1 617-863-3751 
E-mail: 38Tjalam@eippharma.com38T  
Contract Research Organization: 
Worldwide Clinical Trials 
Medical Monitor: 
William Gerson, DO 
Worldwide Clinical Trials 
Serious Adverse Event Reporting: 
Worldwide Clinical Trials 


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SYNOPSIS 
Study Title 
A Double-Blind, Placebo-Controlled 16-Week Study of the Cognitive Effects of the Oral 
P38 Alpha Kinase Inhibitor Neflamapimod in Dementia with Lewy Bodies (DLB) 
Protocol Number (date, 
Version) 
EIP19-NFD-501 
Study Phase 
2 
Study Centers 
Approximately 20 study centers in the United States (US) and 2 study centers in the 
Netherlands 
Indication 
Dementia with Lewy Bodies (DLB) 
Study Objective 
The primary objective is to evaluate the effect of neflamapimod on cognitive function as 
assessed in a study-specific Neuropsychological Test Battery (NTB) comprised of: 
• 
Cogstate Detection test (DET) 
• 
Cogstate Identification test (IDN) 
• 
Cogstate One Card Learning test (OCL) 
• 
Cogstate One Back test (ONB) 
• 
Letter Fluency Test 
• 
Category Fluency Test (CFT) 
The secondary objectives are to:  
• 
Evaluate the effects of neflamapimod on informant/caretaker evaluation of 
cognition and function, as assessed by the Clinical Dementia Rating Scale-Sum of 
Boxes (CDR-SB). 
• 
Assess the effects of neflamapimod on general cognition, as assessed by the Mini 
Mental State Examination (MMSE). 
• 
Assess the effects of neflamapimod on episodic memory, as assessed by the 
International Shopping List Test (ISLT). 
• 
Assess the effects of neflamapimod on select domains of the 10-item 
Neuropsychiatric Inventory (NPI-10), including depression (dysphoria), anxiety, 
hallucinations, and agitation/aggression. 
• 
Evaluate the effects of neflamapimod on motor function as assessed by the 
Timed Up and Go Test (TUG). 
• 
Evaluate the effects of neflamapimod on quantitative electroencephalography 
(EEG) parameters. 


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Study Endpoints 
Primary endpoints: 
• 
Change in the composite score of the NTB, including assessments of attention, 
executive function, and visuospatial function in neflamapimod treated-subjects as 
compared to the placebo-treated subjects.  
Secondary endpoints: 
• 
Change in CDR-SB in neflamapimod-treated subjects compared to placebo-
recipients. 
• 
Change in MMSE in neflamapimod-treated subjects compared to placebo-
recipients.  
• 
Change in NPI-10 domains in neflamapimod-treated subjects compared to 
placebo-recipients. 
• 
Change in International Shopping List Test immediate & delayed recall and 
recognition in neflamapimod-treated subjects compared to placebo-recipients. 
• 
Change in Timed Up and Go Test. 
• 
Change in EEG parameters. 
Number of Subjects 
80 subjects are planned to be enrolled 
Subject Population 
Subjects aged ≥55 years with mild-to-moderate (MMSE 15-28) probable DLB by 
consensus criteria (McKeith et al, 2017), including a positive DaTscan™, who are 
currently receiving cholinesterase inhibitor therapy. If the DaTscan is negative, but the 
subject has historical polysomnography (PSG)-verified REM sleep behavioral disorder 
(RBD), this will also qualify as probable DLB.  
Inclusion Criteria 
1. Men and women aged ≥55 years. 
2. Subject or subject’s legally authorized representative is willing and able to provide 
written informed consent. 
3. Probable DLB and identified cognitive deficits, according to current consensus 
criteria (McKeith et al, 2017), specifically one core clinical feature and a positive 
DaTscan. If a negative DaTscan, but the subject has historical PSG-verified RBD, the 
subject would also qualify. 
4. MMSE score of 15-28, inclusive, during Screening. 
5. Currently receiving cholinesterase inhibitor therapy, having received such therapy for 
greater than 3 months and on a stable dose for at least 6 weeks at the time of 
randomization. Except for reducing the dose for tolerability reasons, the dose of 
cholinesterase inhibitor may not be modified during the study. 
6. Normal or corrected eye sight and auditory abilities, sufficient to perform all aspects 
of the cognitive and functional assessments. 
7. No history of learning difficulties that may interfere with their ability to complete the 
cognitive tests. 
8. Must have reliable informant or caregiver. 


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Exclusion criteria 
1. Diagnosis of any other ongoing central nervous system (CNS) condition other than 
DLB, including, but not limited to, post-stroke dementia, vascular dementia, 
Alzheimer’s disease (AD), or Parkinson’s disease (PD).  
2. Suicidality, defined as active suicidal thoughts within 6 months before Screening or at 
Baseline, defined as answering yes to items 4 or 5 on the C-SSRS, or history of 
suicide attempt in previous 2 years, or, in the Investigator’s opinion, at serious risk of 
suicide. 
3. Ongoing major and active psychiatric disorder and/or other concurrent medical 
condition that, in the opinion of the Investigator, might compromise safety and/or 
compliance with study requirements. 
4. Diagnosis of alcohol or drug abuse within the previous 2 years. 
5. Poorly controlled clinically significant medical illness, such as hypertension (blood 
pressure >180 mmHg systolic or 100 mmHg diastolic); myocardial infarction within 
6 months; uncompensated congestive heart failure or other significant 
cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or 
metabolic/endocrine disorders or other disease that would interfere with assessment 
of drug safety. 
6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 × the upper 
limit of normal (ULN), total bilirubin >1.5 × ULN, and/or International Normalized 
Ratio (INR) >1.5. 
7. Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus 
infection. 
8. Participated in a study of an investigational drug less than 3 months or 5 half-lives of 
an investigational drug, whichever is longer, before enrollment in this study. 
9. History of previous neurosurgery to the brain. 
10. If male with female partner(s) of child-bearing potential, unwilling or unable to 
adhere to contraception requirements specified in the protocol. 
11. If female who has not has not reached menopause >1 year previously or has not had a 
hysterectomy or bilateral oophorectomy/salpingo-oophorectomy, has a positive 
pregnancy test result during Screening and/or is unwilling or unable to adhere to the 
contraception requirements specified in the protocol.  
Study Drug Details 
Neflamapimod 40 mg capsule or matching placebo capsules. 
Duration of treatment 
Screening window of 21 days (unless DaTscan is required, in which case Screening 
window may be extended to 35 days), 16 weeks of treatment, a 2-week follow-up visit for 
a total of 21 weeks study duration.  
Study Design and Methods 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, proof-of-
principle study of neflamapimod versus matching placebo (randomized 1:1) administered 
with food for 16 weeks in subjects with DLB. Subjects weighing <80 kg will receive 
2 capsules per day (in divided doses) and those weighing ≥80 kg will receive 3 capsules 
per day (in divided doses). Subjects receiving two capsules per day will be administered 
1 capsule, twice daily (BID) with food (i.e., with the morning and evening meals), either 
neflamapimod 40 mg or placebo. Subjects receiving 3 capsules per day will be 


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administered 1 capsule three times daily (TID) with food (i.e., with the morning, mid-day, 
and evening meals), either neflamapimod 40 mg or placebo. Doses should be administered 
at least 3 hours apart.  
Following completion of informed consent procedures, subjects will enter the Screening 
phase of the study. 
One to two Screening visits are planned, during which safety screening measures will be 
undertaken, a practice NTB will be performed, and the required diagnosis and cognitive 
impairment will be confirmed. Screening will be conducted within 21 days before Baseline 
(Day 1). If a DaTscan™ is required to determine study eligibility, Screening may be 
extended to 35 days. 
Once eligibility is confirmed and before the first dose of study drug, subjects will be 
randomly assigned on a 1:1 basis to placebo or neflamapimod for the 16-week treatment 
period. Investigators and subjects will be blinded to the treatment assignment. Randomized 
subjects will be stratified by International Shopping List Test (ISLT) Total Recall score at 
Baseline (< 21 vs. >21), i.e. by wheter patients have an episodic memory defect at baseline 
or not. 
Subjects will receive study drug for 16 weeks. Dosing will start on Day 1 following 
completion of all baseline procedures. During the 16-week treatment period, subjects will 
return to the clinic every 2 weeks for the first month and then every 4 weeks thereafter. A 
Final Study Visit (i.e. Follow-Up Visit) will be conducted 2 weeks (+/-3 days) after 
completion of study drug or after the Early Termination (ET) visit. 
The NTB, ISLT, and NPI-10 will be conducted at Screening, Baseline (Day 1), Week 4 
(Day 28), Week 8 (Day 56), and Week 16 (Day 112) or ET if early termination. The CDR-
SB and TUG will be conducted at Baseline (Day 1), Week 8 (Day 56), and Week 16 (Day 
112) or ET. The MMSE will be conducted at Screening, Baseline (Day 1), Week 8 (Day 
56), and Week 16 (Day 112) or ET. EEGs will be conducted at Baseline (Day 1) and Week 
16 (Day 112) or ET.  Samples for plasma biomarkers will be obtained at Screening, 
Baseline (Day 1) and Week 16 (Day 112) or ET. 
Therapy 
Neflamapimod 40 mg capsule(s) or matching placebo capsules will be administered orally, 
BID or TID depending on weight, with food for 16 weeks. All subjects will be 
administered 1 capsule, BID or TID, with food. 
Doses must be taken within 30 minutes following a meal or snack. Doses should be taken 
at approximately same times each day throughout the study and at least 3 hours apart.  
All subjects will receive matched (by size and color) capsules that contain 40 mg 
neflamapimod, or placebo, respectively. Subjects weighing less than 80 mg will receive 
one 40 mg neflamapimod capsule or one placebo capsule to be taken BID with food (i.e., 
with the morning and evening meals); subjects weighing 80 mg or more will receive one 
40 mg neflamapimod capsules or one placebo capsule to be taken TID (i.e., with the 
morning, mid-day, and evening meals). Subjects will be randomized 1:1 placebo or 
neflamapimod.  
 


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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL PAGE ........................................................................................ 2 
INVESTIGATOR’S SIGNATURE OF AGREEMENT PAGE ............................................................ 3 
SPONSOR CONTACT INFORMATION ............................................................................................... 4 
SYNOPSIS .................................................................................................................................................. 5 
TABLE OF CONTENTS .......................................................................................................................... 9 
LIST OF TABLES ................................................................................................................................... 12 
LIST OF ABBREVIATIONS ................................................................................................................. 13 
1. 
INTRODUCTION....................................................................................................................... 15 
1.1. 
Scientific Rationale ........................................................................................................ 15 
1.2. 
Pre-Clinical Pharmacology Results .............................................................................. 16 
1.3. 
Prior Clinical Experience .............................................................................................. 17 
2. 
OBJECTIVES ............................................................................................................................. 19 
2.1. 
Primary Objective .......................................................................................................... 19 
2.2. 
Secondary Objectives .................................................................................................... 19 
3. 
INVESTIGATIONAL PLAN .................................................................................................... 20 
3.1. 
Overall Study Design and Plan ..................................................................................... 20 
3.1.1. 
Screening ......................................................................................................... 20 
3.1.2. 
Treatment Period ............................................................................................. 20 
3.1.3. 
Early Termination (ET) ................................................................................... 20 
3.2. 
Discussion of Study Design ............................................................................................ 21 
3.2.1. 
Rationale for Dose Selection ........................................................................... 21 
4. 
SELECTION OF STUDY POPULATION............................................................................... 23 
4.1. 
Inclusion Criteria ........................................................................................................... 23 
4.2. 
Exclusion Criteria .......................................................................................................... 23 
4.3. 
Removal of Subjects from Treatment .......................................................................... 24 
5. 
TREATMENTS ADMINISTERED .......................................................................................... 25 
5.1. 
Packaging and Labeling ................................................................................................ 25 
5.2. 
Study Drug Supply, Storage, and Handling ................................................................ 25 
5.3. 
Drug Accountability, Disposal, Return, or Retention of Unused Study 
Drug ................................................................................................................................ 25 
5.4. 
Method of Assigning Subjects to Treatment Group ................................................... 26 
5.5. 
Study Blinding and Breaking the Blind ....................................................................... 26 
5.6. 
Dose Modification for Toxicity ..................................................................................... 26 


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5.7. 
Prior and Concomitant Therapy .................................................................................. 26 
5.8. 
Contraception and Pregnancy ...................................................................................... 29 
5.9. 
Treatment Compliance .................................................................................................. 30 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................... 31 
6.1. 
Schedule of Assessments ................................................................................................ 31 
6.2. 
Study Assessments ......................................................................................................... 35 
6.2.1. 
Baseline and Disease Characteristics .............................................................. 35 
6.2.2. 
Computed Tomography (CT) / Magnetic Resonance Imaging 
(MRI) ............................................................................................................... 35 
6.2.3. 
DaTscan (if Required) ..................................................................................... 35 
6.2.4. 
Cognitive Function Tests ................................................................................. 35 
6.2.5. 
Timed Up and Go Test (TUG) ........................................................................ 37 
6.2.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................... 37 
6.2.7. 
Electroencephalography (EEG) ....................................................................... 37 
6.2.8. 
Physical Examination and Vital Signs ............................................................ 37 
6.2.9. 
12-Lead Electrocardiogram ............................................................................. 37 
6.2.10. 
Clinical Laboratory Assessments .................................................................... 38 
6.2.11. 
Pharmacokinetics (PK) .................................................................................... 39 
6.2.12. 
Biomarker Testing ........................................................................................... 39 
6.2.13. 
Withdrawal of Subjects ................................................................................... 39 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS/SAFETY 
REPORTING .............................................................................................................................. 40 
7.1. 
Definitions and Criteria ................................................................................................. 40 
7.1.1. 
Adverse Events ................................................................................................ 40 
7.1.2. 
Serious Adverse Events ................................................................................... 40 
7.1.3. 
Unexpected Adverse Drug Reactions .............................................................. 41 
7.1.4. 
Abnormal Laboratory Values .......................................................................... 41 
7.1.5. 
Assessing Intensity and Relationship .............................................................. 41 
7.2. 
Reporting Procedures and Requirements ................................................................... 43 
7.2.1. 
Adverse Events (AE) ....................................................................................... 43 
7.2.2. 
Serious Adverse Events (SAE) ........................................................................ 43 
8. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ................................................. 45 
8.1. 
Data Management and Quality Assurance Considerations ....................................... 45 


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8.2. 
Sample Size ..................................................................................................................... 45 
8.3. 
Analysis Sets ................................................................................................................... 45 
8.4. 
Safety ............................................................................................................................... 46 
8.5. 
Efficacy ........................................................................................................................... 46 
8.6. 
Interim Analysis ............................................................................................................. 46 
9. 
STUDY MANAGEMENT .......................................................................................................... 47 
9.1. 
Ethics and Consent ........................................................................................................ 47 
9.1.1. 
Regulations and Guidelines ............................................................................. 47 
9.1.2. 
Independent Ethics Committee ........................................................................ 47 
9.1.3. 
Informed Consent ............................................................................................ 47 
9.2. 
Indemnification .............................................................................................................. 47 
9.3. 
Discontinuation of the Study by the Sponsor .............................................................. 47 
9.4. 
Study Documentation .................................................................................................... 48 
9.5. 
Study Monitoring and Auditing ................................................................................... 48 
9.6. 
Use of Study Findings .................................................................................................... 48 
9.7. 
Publications .................................................................................................................... 48 
9.8. 
Recording, Access and Retention of Source Data ....................................................... 48 
9.9. 
Protocol Violations ......................................................................................................... 49 
10. 
REFERENCES ............................................................................................................................ 50 


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LIST OF TABLES 
Table 5-1: 
CYP3A4 Inhibitors .......................................................................................................... 28 
Table 5-2: 
CYP3A4 Inducers ............................................................................................................ 29 
Table 6-1: 
Schedule of Assessments ................................................................................................. 32 
Table 6-2: 
Clinical Laboratory Analytes ........................................................................................... 38 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APOE 
Apoliprotein E 
APP 
Amyloid-precursor-protein 
AST 
Aspartate aminotransferase 
AUC 
Area under the time concentration curve 
BID 
bis in die (twice a day) 
CDR-GS 
Clinical Dementia Rating Scale-Global Score 
CDR-SB 
Clinical Dementia Rating Scale-Sum of Boxes 
CFT 
Category Fluency Test 
CL 
Clearance 
CNS 
Central nervous system 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Computed tomography 
CYP 
Cytochrome P450 
DET 
Cogstate Detection test 
DLB 
Dementia with Lewy Bodies 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEG 
Electroencephalography 
ET 
Early Termination 
FDA 
Food and Drug Administration 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IDN 
Cogstate Identification Test 


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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
ISLT 
International Shopping List Test 
LFT 
Liver function test 
MAP 
Mitogen-activated protein 
MAPKα 
p38 mitogen activated protein kinase alpha 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MMSE 
Mini Mental State Examination 
MRI 
Magnetic resonance imaging 
MWM 
Morris-Water-Maze 
NPI-10 
10-item Neuropsychiatric Inventory 
NTB 
Neuropsychological Test Battery 
OCL 
Cogstate One Card Learning test 
ONB 
Cogstate One Back Test 
p38α 
Mitogen-activated protein kinase 14 
PD 
Parkinson’s disease 
PK 
Pharmacokinetic 
PSG 
Polysomnography 
qEEG 
Quantitative electroencephalograph 
RBD 
REM sleep behavioral disorder 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SPECT 
Single-photon emission computed tomography 
TID 
Three times daily 
TUG 
Timed Up and Go Test 
ULN 
Upper limit of normal 
US 
United States 
 


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1. 
INTRODUCTION 
1.1. 
Scientific Rationale 
This is a double-blind, placebo-controlled 16-week treatment study of neflamapimod 40 mg administered 
twice daily (BID) or 3 times daily (TID), based on subject weight, in subjects with Dementia with Lewy 
Bodies (DLB). The primary objective of this proof-of-concept study is to determine whether 
neflamapimod can improve cognitive function in subjects with DLB, as assessed by a neuropsychological 
test battery (NTB).  
DLB is common, representing 10-20% of the dementia population, with an estimated 1.4 million affected 
individuals in the United States (US). There is evidence that the prognosis is even more severe than other 
dementia disorders, including Alzheimer’s disease (AD). DLB is characterized by progressive dementia 
and fluctuating cognition (deficits in memory, attention) and is also associated with sleep disturbances, 
visual hallucination, and Parkinsonism (tremor, gait disturbance). DLB has now been identified as a 
separate disease, although it remains difficult to differentiate it from the related dementias of AD and 
Parkinson’s disease (PD) dementia (McKeith et al, 2017; Walker et al, 2015).  
The clinical presentation of DLB demonstrates progressive cognitive decline accompanied by mild-to-
moderate motor symptoms that are similar to those seen in PD (Park et al, 2011). DLB is a progressive 
disorder with average time from diagnosis to death approximately 7 years. There are no treatments 
approved for the underlying disease process and only symptomatic treatments for parkinsonian 
symptoms. Although not approved for DLB, cholinesterase inhibitors are often used.  
Neflamapimod is a highly specific inhibitor of the intra-cellular enzyme mitogen-activated protein kinase 
14 (p38α) that is currently being evaluated in a phase 2b clinical study in early AD. In the brain, p38α 
regulates inflammation through effects on microglia. Moreover, under conditions of stress and disease, 
p38α is also expressed in neurons and of the various p38 isoforms, the α isoform is the most important 
regulator of the stress response in neurons (Lawson et al, 2013). In the neuron, p38α also appears to play 
a critical role in inflammation-driven toxicity to synapses (Watterson et al, 2013; Prieto et al, 2015). As a 
result of this understanding, p38 mitogen activated protein kinase alpha (MAPKα) has been recognized as 
a leading therapeutic target to improve synaptic function and synaptic plasticity for a broad range of 
central nervous system (CNS) disorders (Corrêa et al, 2012; Sandersen et al, 2016).  
More recently, using selective inhibitors of p38α, two groups have demonstrated that short-term (2-
3 weeks) treatment reverses spatial learning deficits in the Radial Arm Water Maze and Morris-Water-
Maze (MWM) tests in the Alzheimer’s APP/PS1 transgenic mouse (Roy et al, 2015) and the Aged Rat 
(Alam, 2015) models, respectively. Further, genetic reduction of neuronal p38α in amyloid-precursor-
protein (APP) overexpressing transgenic mice improves synaptic transmission and plasticity (i.e., 
prevents synaptic dysfunction), reduces memory loss, and reduces amyloid pathology (Colié et al, 2017). 
Genetically knocking down p38α in neurons also protected mice from developing age-related 
hippocampal dysfunction and decline in neurogenesis (Cortez et al, 2017). 
Regarding neflamapimod in preclinical and early phase studies, it has been shown to reverse spatial 
learning deficits, as assessed in the Morris-Water-Maze test, in aged rats (Alam et al, 2015). The spatial 
learning deficits in the aged rat is considered to be the result of inflammation-induced hippocampal 
synaptic dysfunction. Moreover, in Phase 2a clinical studies in patients with early AD, neflamapimod 
demonstrated medium to large effect size within-subject improvement in performance on tests of 


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immediate and delayed recall (i.e., tests of episodic memory). These preliminary clinical results are being 
evaluated in a 24-week placebo-controlled study in early AD that is ongoing.  
Neflamapimod has not been evaluated previously in DLB. However, though patients present with a 
broader set of cognitive deficits (e.g., visual-spatial deficits), episodic memory deficits attributable to 
hippocampal dysfunction are prominent, though generally considered qualitatively different from that in 
in AD (Park, et al 2011; Galvin, 2015; Adamowitz et al, 2017). As a result, based on the prior rationale 
for p38α kinase inhibition to address hippocampal dysfunction as well the preliminary clinical evidence 
with neflamapimod in patients with AD, neflamapimod could be expected to improve episodic memory in 
patients with DLB. 
In addition, based on the potential to impact broadly the disease pathogenesis of DLB, neflamapimod 
might be expected to impact synaptic dysfunction regions outside the hippocampus as well. For example, 
with respect to underlying disease pathogenesis, based on genetic evaluation, DLB appears to be 
overlapping with disease pathogenesis for both AD and PD (Guerreiro et al, 2016). Apoliprotein E 
(APOE) genotype variants are associated with both DLB and AD, while the major biologic impact of the 
disease-associated APOE4 variant is to augment the neuroinflammatory response (Keene et al, 2011). As 
such, inflammation-induced synaptic dysfunction, regardless of the brain region impacted, is likely to be 
drivers of disease in both settings; a concept that is supported by the finding of elevated markers of 
inflammation in the brain of both disorders (Mrak and Griffin, 2007). With respect to disease pathogenic 
mechanisms that are common to DLB and PD, the most important is considered to be the neurotoxicity of 
α-synuclein, the constituent of “Lewy bodies” that is the major pathologic correlate of both diseases. 
Importantly, p38 kinase has been linked to the neurotoxicity of α-synuclein in a range of in vitro and in-
vivo model systems (Obergasteiger, et al, 2018; Chen et al, 2018). 
The primary objective of this study is to assess the impact of neflamapimod on cognitive function 
domains (attention, executive function, visuospatial function) that depend on proper synaptic function in 
the frontal and parieto-occipital regions of the brain. A secondary objective is to evaluate the effects of 
neflamapimod on episodic memory function, which depends primarily on hippocampal synaptic function. 
1.2. 
Pre-Clinical Pharmacology Results 
To obtain preclinical proof-of-principle for an effect on hippocampal synaptic dysfunction, neflamapimod 
was tested in the aged rat model of age-related cognitive decline. When tested in a MWM test, rats show 
cognitive deficits starting at 20 to 22 months of age. This deficit has been shown to be a result of 
inflammation-induced impairment of synaptic plasticity in the hippocampus (38TKelly, 20038T; 38TLynch, 201038T). 
The published results (38Alam, 201538T) showed that neflamapimod administered for 3 weeks fully reversed 
the spatial learning deficits in the MWM test in 20- to 22-month old rats with identified cognitive deficits, 
with the performance of aged rats treated with neflamapimod at the optimal dose being significantly 
better than vehicle (placebo)- treated aged rats (P = 0.007) and being similar to that of young rats. These 
data combined with dose-response data in previous animal and clinical studies, were then utilized to 
identify doses for the Phase 2a clinical studies in early AD.  
Neflamapimod also was studied in an induced-stroke model in rats:  transient ischemia of sufficient 
duration was induced such that significant neurologic disability developed without mortality and the 
neurologic disability did not substantially reverse during follow-up without therapy. These rats were then 
treated with vehicle (control) or neflamapimod. Starting at 48-hours after stroke, administration of 


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neflamapimod for 6 weeks led to substantial improvement on multiple parameters of neurologic function 
compared to vehicle controls (P <0.001 for each of global neurologic scores, motor- and sensory-specific 
tests). As recovery after stroke is dependent on neuronal and synaptic plasticity (38TChollet, 201338T), these 
results further confirm that neflamapimod is active in reversing impaired synaptic plasticity in animal 
models. 
Based on the scientific rationale and emerging mechanistic understanding of the effects of inhibition of 
neuronal p38α (refer to Section 1.1), the demonstrated positive pharmacological effects of neflamapimod 
may be due to reversing proteostasis defects within neurons, including impaired autophagy and 
endolysosomal dysfunction (38TAlam & Scheper, 201638T). The proteostasis-reversing potential of 
neflamapimod was recently confirmed in a human in vitro system (Down Syndrome fibroblasts), where 
neflamapimod at concentrations below 10 nM reversed endosomal abnormalities and improved lysosomal 
function (confidential data on file). 
1.3. 
Prior Clinical Experience 
Neflamapimod has been tested clinically in AD and also in earlier studies in rheumatoid arthritis and the 
risks to date are well documented.  
With respect to completed clinical studies, neflamapimod has been given to 90 healthy volunteers in 
single-dose studies, 16 healthy volunteers in multiple-dose studies for 10 days, 56 patients (57 courses of 
therapy, because 1 patient participated in 2 studies) with rheumatoid arthritis for up to 123 days, 
5 patients with myelodysplastic syndrome (MDS) for 9 to 60 days, and 25 patients with early AD for up 
to 12 weeks. The highest dose levels have been evaluated in patients with rheumatoid arthritis, at doses up 
to 750 mg BID for one month and 250 mg BID for 12 weeks. In addition, 161 patients have been enrolled 
in a 24-week, double-blind placebo controlled (1:1 randomization) Phase 2b clinical study in patients with 
mild AD.  
In clinical studies prior to those conducted in patients with AD, headache, common cold, gastroenteritis, 
diarrhea, and sleeplessness/ insomnia were the most common adverse events (AEs) reported. 
Gastroenteritis and diarrhea, which have been primarily mild, appear to have the strongest association 
with neflamapimod treatment.  
During 12 weeks of dosing at 250 mg BID in 44 patients with rheumatoid arthritis elevations in liver 
transaminase levels were noted in 6 patients (14% of 44), 3 of whom were discontinued prematurely from 
treatment due to these findings. Patients were asymptomatic, there were no associated increases in 
bilirubin, and the elevations resolved with treatment discontinuation. 
Twenty-five patients received neflamapimod at either 40 mg or 125 mg BID in Phase 2a studies of 6- or 
12-weeks neflamapimod dosing in patients with early AD. One patient discontinued prematurely, 
attributed primarily to persistent cerebrospinal fluid (CSF) leakage after pre-dosing baseline CSF 
collection because the patient discontinued due to vomiting within 4 days of starting dosing. There were 
no severe or serious adverse events (SAEs) reported. The most common AEs across the 2 studies were 
mild somnolence (sleepiness or drowsiness) reported in 5 patients, and self-limited mild diarrhea (loose 
stools) reported in 4 patients. There were no abnormalities in liver function tests (LFTs), nor any trends in 
changes in LFT parameters, noted in either study in patients with early AD.  


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In the 12-week Phase 2a study in patients with early AD, though the magnitude of changes were not 
clinically significant, statistically significant overall increases for heart rate, body weight, and body mass 
index, and decreases for systolic and diastolic blood pressures were observed.  
In the ongoing blinded Phase 2b clinical study of neflamapimod in mild AD, 2 SAEs have been reported, 
one a severe unrelated hypokalemia and the other a mild, possibly related non-cardiac chest pain. With 
the exception of the case of severe hypokalemia, all other events were mild to moderate in nature and 
primarily unrelated. The events deemed at least possibly related and reported more than once include 
rash, thrombocytopenia, headache, anxiety and lethargy (each reported twice). 
Given the potential benefits to patients with DLB, the safety margin relative to animal toxicity findings, 
and the prior clinical experience at substantially higher dose levels, the benefit/risk profile is favorable for 
the planned study at a dose of 40 mg given BID or TID, based on subject weight.  


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2. 
OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to evaluate the effect of neflamapimod on cognitive function as assessed in a 
study-specific Neuropsychological Test Battery (NTB) comprised of: 
• 
Cogstate Detection test (DET) 
• 
Cogstate Identification test (IDN) 
• 
Cogstate One Card Learning test (OCL) 
• 
Cogstate One Back test (ONB) 
• 
Letter Fluency Test 
• 
Category Fluency Test (CFT) 
2.2. 
Secondary Objectives 
The secondary objectives are to: 
• 
Evaluate the effects of neflamapimod on informant/caretaker evaluation of cognition and 
function, as assessed by the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) 
• 
Assess the effects of neflamapimod on general cognition, as assessed by the Mini Mental State 
Examination (MMSE) 
• 
Assess the effects of neflamapimod on episodic memory, as assessed by the International 
Shopping List Test (ISLT). 
• 
Assess the effects of neflamapimod on select domains of the 10-item Neuropsychiatric Inventory 
(NPI-10), including depression (dysphoria), anxiety, hallucinations, and agitation/aggression. 
• 
Evaluate the effects of neflamapimod on motor function as assessed by the Timed Up and Go 
Test (TUG). 
• 
Evaluate the effects of neflamapimod on quantitative electroencephalography (EEG) parameters. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, proof-of-principle study of 
neflamapimod versus matching placebo (randomized 1:1) administered with food for 16 weeks in subjects 
with DLB. Subjects will be randomized to neflamapimod BID/placebo or neflamapimod TID/placebo 
depending on weight, with subjects weighing <80 kg receiving capsules BID and those weighing ≥80 kg 
receiving capsules TID. Subjects receiving study drug BID will be administered 1 capsule, BID with food 
(i.e., with the morning and evening meals), either neflamapimod 40 mg or placebo. Subjects receiving 
study drug TID will be administered 1 capsule TID with food (i.e., with the morning, mid-day, and 
evening meals), either neflamapimod 40 mg or placebo. Doses should be administered at least 3 hours 
apart.  
3.1.1. 
Screening 
Following completion of informed consent procedures, subjects will enter the Screening phase of the 
study. 
One to two Screening visits are planned, during which safety screening measures will be undertaken, a 
practice NTB will be performed, and the required diagnosis and cognitive impairment will be confirmed. 
Screening will be conducted within 21 days before Baseline (Day 1). If a DaTscan™ is required to 
determine study eligibility, Screening may be extended to 35 days. 
3.1.2. 
Treatment Period 
Once eligibility is confirmed during the Screening period and before the first dose of study drug, subjects 
will be randomly assigned on a 1:1 basis to placebo or neflamapimod for the 16-week treatment period. 
Investigators and subjects will be blinded to the treatment assignment. Randomization will be stratified by 
ISLT Total Recall score at Baseline (< 21 vs. > 21), i.e. by wheter patients have an episodic memory 
defect at baseline or not. 
Subjects will receive study drug for 16 weeks. Dosing will start on Day 1 following completion of all 
baseline procedures. During the 16-week treatment period, subjects will return to the clinic every 2 weeks 
for the first month and then every 4 weeks thereafter. A Follow-Up will be conducted 2 weeks (±3 days) 
after completion of study drug or after the Early Termination visit. 
The NTB, ISLT, and NPI-10 will be conducted at Screening, Baseline (Day 1), Week 4 (Day 28), Week 8 
(Day 56), and Week 16 (Day 112) or ET if early termination. The CDR-SB and TUG will be conducted at 
Baseline (Day 1), Week 8 (Day 56), and Week 16 (Day 112) or ET. The MMSE will be conducted at 
Screening, Baseline (Day 1), Week 8 (Day 56), and Week 16 (Day 112) or ET. EEGs will be conducted at 
Baseline (Day 1) and Week 16 (Day 112) or ET.  Samples for plasma biomarkers will be obtained at 
Screening, Baseline (Day 1) and Week 16 (Day 112). 
3.1.3. 
Early Termination (ET) 
Subjects who prematurely discontinue study drug for any reason will be asked to return to the clinic for an 
Early Termination (ET) visit within 3 days following the last study drug dose; if it is determined that the 
subject will discontinue study drug while at the study center for a scheduled visit, then the ET visit should 


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be conducted at that time. These subjects will also be asked to return to the clinic for a Follow-up Visit 2 
weeks (±3 days) following the last study drug dose.  
Every effort should be made to ensure a subject returns for this visit. 
Refer to Section 4.3 for details regarding removal of subjects from treatment. 
3.2. 
Discussion of Study Design 
Several design features are employed to minimize bias, including the study being double-blind, placebo-
controlled, randomized, and multi-centered. The use of placebo control permits blinded prospective 
comparison between treatment groups. Random assignment of subjects to study treatment avoids bias and 
helps support both known and unknown risk factors being distributed evenly between treatment groups. 
Furthermore, randomization is stratified by ISLT Total Recall score at Baseline (< 21 vs. > 21; i.e. by 
wheter patients have an episodic memory defect at baseline or not) to further balance characteristics of 
subjects receiving neflamapimod versus placebo. The multi-center nature of the study provides assurance 
that the results are likely to have general applicability. 
3.2.1. 
Rationale for Dose Selection 
3.2.1.1. 
Efficacy Considerations 
The 40 mg BID regimen was initially chosen as the most likely active dose for the prior Phase 2a clinical 
studies in AD based on the results of the effects of neflamapimod on hippocampal synaptic dysfunction 
(assessed in the MWM test) in aged rats, which demonstrated that the optimal dose in aged rats was 
1.5 mg/kg. The 1.5 mg/kg dose was then correlated to dose-response in rat arthritis models and in human 
clinical studies in rheumatoid arthritis to derive the predicted dose of 40 mg BID. Furthermore, plasma 
drug levels obtained in the aged rat at 1.5 mg/kg correspond to those that were seen subjects with AD at 
40 mg BID. The predicted cognitive effect at 40 mg BID has been preliminarily demonstrated in humans, 
as there were statistically significant improvement from baseline in tests of episodic memory function in 
both phase 2a clinicals studies utilizing this dose. As well there was evidence of target engagement and 
pharmacological activity at this dose level in the two phase 2a studies, i.e., reductions in amyloid plaque 
load by PET scan and reductions in interleukin-8 levels in CSF, respectively.  
Interim pharmacokinetic results from a Phase 2b clinical study in early AD indicate the median 12-hour 
plasma drug concentration exposure of neflamapimod in the minority of subjects who weigh ≥80 kg is 
approximately 33% lower that seen in subjects who weigh <80 kg. The median 12-hour plasma drug 
exposure was 65 ng*hr/mL in subjects weighing 80 kg or more, and 98 ng*hr/mL in those weighing less 
than 80 kg. As a higher proportion of subjects with DLB compared to AD are male, and therefore a higher 
proportion of subjects are expected to weigh ≥80 kg, to achieve consistent target plasma drug 
concentrations in the current study subjects who weigh ≥80 kg will receive 40 mg TID (i.e., 120 mg per 
day, rather than 80 mg per day) of neflamapimod. The median 12-hour plasma drug concentration 
exposure by utilizing this approach is expected to be approximately 100 ng*hr/mL (i.e., 0.1 µg*hr/mL). 
3.2.1.2. 
Safety Considerations 
Based on the clinical experience to date at higher doses and the results from animal toxicology studies, 
the neflamapimod doses of 40 mg BID in those weighing <80 kg and 40 mg TID in those weighing 
≥80 kg is expected to be well tolerated and to have a low risk of drug toxicity. 


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Dose-limiting toxicity in clinical studies, defined as elevations in liver transaminase levels, was noted in 6 
patients of 44 subjects (14%) with RA treated with neflamapimod 250 mg BID (a dose level that achieved 
median 12-hours plasma drug concentration exposure of 453 ng*hr/mL); 3 of the 6 subjects with 
transaminase elevations were discontinued prematurely from treatment due to these findings. Patients 
were asymptomatic, there were no associated increases in bilirubin, and the elevations resolved with 
treatment discontinuation. 
In the Phase 2a studies (Study 303) of 6- or 12-weeks neflamapimod dosing in patients with early AD, a 
total of 25 subjects were enrolled. With regard to safety, neflamapimod was well tolerated, with 24 of 
25 subjects completing their scheduled dosing period (8 completed 6 weeks of neflamapimod 
administration, and 16 completed 12 weeks of neflamapimod administration). The one subject who 
discontinued early did so within the first week of study drug administration due to an AE of vomiting, 
attributed primarily to persistent CSF leakage after the predose/baseline CSF collection. There were no 
severe or serious AEs reported. The most common AEs across the 2 studies were mild somnolence 
(sleepiness or drowsiness) reported in 5 patients, and self-limiting mild diarrhea (loose stools) reported in 
4 patients. There was also one event of moderate diarrhea, which was considered not related, as the event 
did not recur during additional 8 weeks of treatment after having resolved during a brief treatment 
interruption. No treatment-related or clinically relevant trends in the analysis of safety laboratory and 12-
lead electrocardiogram (ECG) parameters were observed. More specifically, there were no abnormalities 
in LFTs nor any trends in changes in LFT parameters noted in either study. LFT abnormalities, 
specifically increases in liver transaminases, were seen in 10% to 15% of patients in a prior study in 
patients with RA at a dose of 250 mg BID for 3 months. Due to the use of higher doses and different 
formulations in the RA studies, the plasma drug concentrations were 4- to 5-fold higher than in the Phase 
2a mild AD studies. 
A Phase 2b study of neflamapimod in early AD (MMSE 20 to 28) is ongoing. A total of 161 patients have 
been randomized on a blinded basis to either placebo or 40 mg capsules BID with food for 24 weeks. As 
of November 12, 2018, the annual data safety cutoff date, blinded data were available for 101 patients. As 
of that date, a total of 70 AEs had been reported across 43 patients. There were two SAEs reported, one a 
severe unrelated hypokalemia and the other a mild, possibly related non-cardiac chest pain. With the 
exception of the case of severe hypokalemia, all other AEs were mild to moderate in nature and primarily 
unrelated. The events deemed at least possibly related and reported more than once include rash, 
thrombocytopenia, headache, anxiety and lethargy (each reported twice). This study is ongoing and all 
data are blinded. 
The expected plasma drug concentrations in the current study provides a 5-fold margin based on plasma 
drug levels to no adverse effect level in long term animal toxicity studies and 10-fold margin to minimal 
and/or equivocal findings for hematological, hepatic and neuropathological changes (evidence of axonal 
damage) in chronic (9- and 12-month) dog toxicology studies. Further details are provided in the 
Investigator Brochure (IB). 


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4. 
SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects meeting all of the following criteria are eligible for enrollment in this study: 
1. Men and women aged ≥55 years. 
2. Subject or subject’s legally authorized representative is willing and able to provide written 
informed consent. 
3. Probable DLB and identified cognitive deficits, according to current consensus criteria 
(McKeith et al, 2017), specifically one core clinical feature and a positive DaTscan. If a 
negative DaTscan, but the subject has historical polysomnography (PSG)-verified REM sleep 
behavioral disorder (RBD), the subject would also qualify. 
4. MMSE score of 15-28, inclusive, during Screening. 
5. Currently receiving cholinesterase inhibitor therapy, having received such therapy for greater 
than 3 months and on a stable dose for at least 6 weeks at the time of randomization. Except 
for reducing the dose for tolerability reasons, the dose of cholinesterase inhibitor may not be 
modified during the study. 
6. Normal or corrected eye sight and auditory abilities, sufficient to perform all aspects of the 
cognitive and functional assessments. 
7. No history of learning difficulties that may interfere with their ability to complete the 
cognitive tests. 
8. Must have reliable informant or caregiver. 
4.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for enrollment in this study: 
1. Diagnosis of any other ongoing CNS condition other than DLB, including, but not limited to, 
post-stroke dementia, vascular dementia, AD, or PD.  
2. Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, 
defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale 
(C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator’s opinion, at 
serious risk of suicide. 
3. Ongoing major and active psychiatric disorder and/or other concurrent medical condition that, in 
the opinion of the Investigator, might compromise safety and/or compliance with study 
requirements. 
4. Diagnosis of alcohol or drug abuse within the previous 2 years. 


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5. Poorly controlled clinically significant medical illness, such as hypertension (blood pressure 
>180 mmHg systolic or 100 mmHg diastolic); myocardial infarction within 6 months; 
uncompensated congestive heart failure or other significant cardiovascular, pulmonary, renal, 
liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that 
would interfere with assessment of drug safety. 
6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 × the upper limit of 
normal (ULN), total bilirubin >1.5 × ULN, and/or International Normalized Ratio (INR) >1.5. 
7. Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection. 
8. Participated in a study of an investigational drug less than 3 months or 5 half-lives of an 
investigational drug, whichever is longer, before enrollment in this study. 
9. History of previous neurosurgery to the brain. 
10. If male with female partner(s) of child-bearing potential, unwilling or unable to adhere to 
contraception requirements specified in the protocol. 
11. If female who has not has not reached menopause >1 year previously or has not had a 
hysterectomy or bilateral oophorectomy/salpingo-oophorectomy, has a positive pregnancy test 
result during Screening and/or is unwilling or unable to adhere to the contraception requirements 
specified in the protocol. 
4.3. 
Removal of Subjects from Treatment 
In accordance with the current revision of the Declaration of Helsinki and other applicable regulations, a 
subject has the right to withdraw from the study at any time and for any reason without prejudice to his or 
her future medical care by the physician or at the institution. A subject’s participation may also be 
discontinued by the Investigator or Sponsor due to compliance, safety, or other administrative reason (see 
also Section 6.2.13). 
The subject must be discontinued from the study for the occurrence of an unacceptable toxicity, including 
any of the following: 
• 
Any clinically significant infection. (Clinically significant is defined as any infection requiring 
hospitalization and/or intravenous antibiotics and/or considered to be opportunistic.) 
• 
ALT or AST >8×ULN; ALT or AST >5×ULN for >2 weeks; or ALT or AST >3×ULN and total 
bilirubin >2×ULN or INR >1.5; or ALT or AST >3×ULN with the appearance of worsening of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia. 
Refer to Section 3.1.3 for details regarding follow-up after early discontinuation. Additional care and 
treatment will be provided to subjects once study discontinuation, including any required follow-up visits 
for resolution for study-related AEs, is completed.  


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5. 
TREATMENTS ADMINISTERED 
Neflamapimod 40 mg capsules or matching placebo capsules will be administered orally, BID or TID 
with food for 16 weeks. Subjects will follow the BID regimen if weighing <80 kg or the TID regimen if 
weighing ≥80 kg. 
Furthermore, all subjects will be administered 1 capsule, BID or TID, with food:  
• 
Subjects following the BID regimen will receive one 40 mg neflamapimod capsule or one 
placebo capsule to be taken twice daily with food (i.e., with the morning and evening meals);  
• 
Subjects following the TID regimen will receive one 40 mg neflamapimod capsules or one 
placebo capsule to be taken three times daily (i.e., with the morning, mid-day, and evening 
meals).  
Doses must be taken within 30 minutes following a meal or snack. Doses should be taken at 
approximately same times each day throughout the study and at least 3 hours apart.  
The first dose of study drug in each treatment period will be administered at the study center.  
The Investigator or other designated, qualified site personnel should review dosing instructions with the 
subject. Subjects will be instructed to return all study containers, regardless of whether empty or 
containing unused study drug. 
If a subject misses 1 study drug dose (i.e., 1 capsule), the subject should resume dosing at the next 
scheduled administration time, at which time both the missed dose and the current dose (i.e., 2 capsules) 
are to be taken. If the subject misses 2 study drug doses (i.e., 2 capsules), the subject should take 2 doses 
(i.e., 2 capsules) at the next scheduled administration time. Subjects may not take more than 2 doses (i.e., 
2 capsules) at any given administration time.  
5.1. 
Packaging and Labeling 
EIP Pharma will supply placebo or neflamapimod capsules via blister packs on an individual subject 
basis.  
Both neflamapimod and placebo capsules are opaque in color. Label details will be in accordance with 
local and national requirements.  
5.2. 
Study Drug Supply, Storage, and Handling 
Study drug will be supplied to the site on an individual subject basis. Both neflamapimod and placebo 
capsules are opaque in color. Study drug is labeled in accordance with local and national requirements.  
Neflamapimod capsules should be stored at room temperature. 
While at the clinical site, study drug access should be limited to the Investigator and other qualified site 
personnel. 
5.3. 
Drug Accountability, Disposal, Return, or Retention of Unused 
Study Drug 
The site designated pharmacist or other qualified personnel will document receipt from Sponsor, 
dispensing to subjects, and return to the study center from subject on the drug accountability log(s).  


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Subjects will be instructed to return all blister packs to the study center, regardless of whether empty or 
containing unused study drug. EIP Pharma or designee will review accountability records throughout the 
conduct of the study.  
The site should maintain all study drug containers (used and unused) until final review of accountability is 
conducted by the EIP Pharma or designee, and instructions regarding return or disposal, as applicable, are 
provided.  
5.4. 
Method of Assigning Subjects to Treatment Group 
After subjects have completed the Screening Visit and are deemed eligible, they will be randomized on a 
1:1 basis in a blinded manner to receive either placebo or 40 mg neflamapimod utilizing an automatically 
generated random code. Randomization will be stratified by ISLT Total Recall score at Baseline (< 21 vs. 
> 21), i.e. by wheter patients have an episodic memory defect at baseline or not.  Randomization and 
stratification will be administered via Interactive Response Technology (IRT). 
Subjects will follow the BID regimen if weighing <80 kg or the TID regimen if weighing ≥80 kg. 
Study drug for the entire 16-week period will then be sent on a per subject basis to the site.  
5.5. 
Study Blinding and Breaking the Blind 
Subjects and site personnel associated with study conduct will be blinded to treatment assignment.  
During the conduct of the study, the blind should be broken on an individual subject basis in the event of 
an emergency where it is necessary for the Investigator to know which treatment the subject is receiving 
before the subject can be treated. The code may also be broken if someone not in the study uses study 
drug (e.g., if a child in the participant’s household takes study drug, the blind may be broken to determine 
treatment for the child).  
When it is necessary to break the blind, the researcher may unblind the treatment immediately 
(i.e., without prior notice to the Medical Monitor, sponsor, or other) but must notify the Independent 
Ethics Committee (IEC) per local regulations and Sponsor as soon as possible, preferably by telephone 
and then in writing, regarding the necessity of code breaking.  
If the code is broken for a subject, this must be documented in the electronic case report form (eCRF) and 
source documents, together with the reasons for breaking the code. 
5.6. 
Dose Modification for Toxicity 
No dose modifications are permitted during the study. If a subject is unable to tolerate the assigned study 
drug dose then the subject should be discontinued from study drug treatment (Section 4.3). 
5.7. 
Prior and Concomitant Therapy 
Any medications taken from Screening through the Final Study Visit (i.e. Follow-Up Visit), including all 
prescription and over-the-counter medications as well as supplements, will be documented in the subject’s 
source document and in the eCRF.  
While drug-drug interaction studies have not been conducted, in vitro testing indicates that neflamapimod 
is metabolized by oxidation in the liver by the cytochrome P450 (CYP) system (combination of CYP3A4 


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and CYP2C19 isozymes). Until the metabolism is better characterized, concomitant strong inhibitors of 
CYP3A4 are prohibited and strong inducers of CYP3A4 should be used with caution in subjects 
receiving neflamapimod, as the use of such drugs could impact neflamapimod metabolism in subjects 
who have an underlying CYP2C19 genotypic variant that impacts activity of that CYP2C19.  
The following medications are prohibited during study participation: 
• 
Strong CYP3A4 inhibitors (see Table 5-1). 
• 
Any other investigational drug. If a subject has previously participated in a study of an 
investigational drug, last dosing must have occurred 3 months or 5 half-lives of the investigation 
drug, whichever is longer, before enrollment in this study.  
The Medical Monitor should be contacted with any questions regarding concomitant use of medications 
that are thought to modulate CYP3A4 activity. 


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Table 5-1: 
CYP3A4 Inhibitors  
Prohibited:  
Strong Inhibitors 
≥5-fold increase in AUC  
or >80% decrease in CL 
Allowed:   
Moderate inhibitors 
≥2 but <5-fold increase in AUC 
or 50-80% decrease in CL 
Allowed: 
Weak inhibitors 
≥1.25 but <2-fold increase in AUC 
or 20-50% decrease in CL 
boceprevir 
cobicistat 
clarithromycin 
conivaptan 
danoprevir/ritonavir 
diltiazem 
elvitegravir/ritonavir 
grapefruit juice 
idelalisib 
indinavir/ritonavir  
itraconazole 
ketoconazole  
lopinavir/ritonavir 
nefazodone 
nelfinavir 
paritaprevir/ritonavir/ombitasvir 
posaconazole 
ritonavir  
saquinavir/ritonavir  
telaprevir 
tipranavir/ritonavir 
troleandomycin 
voriconazole 
Aprepitant 
cimetidine 
ciprofloxacin 
clotrimazole 
crizotinib 
cyclosporine 
dronedarone  
erythromycin  
fluconazole 
fluvoxamine 
imatinib 
tofisopam 
verapamil 
chlorzoxazone 
cilostazol 
fosaprepitant 
istradefylline 
ivacaftor 
lomitapide 
ranitidine 
ranolazine 
tacrolimus 
ticagrelor 
 
Abbreviations: AUC, area under the concentration-time curve; CL, clearance. 


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Table 5-2: 
CYP3A4 Inducers  
Use with Caution: 
Strong Inducers 
≥80% decrease in AUC 
Allowed:  
Moderate Inducers 
50-80% decrease in AUC 
Allowed:   
Weak Inducers 
20-50% decrease in AUC 
carbamazepine enzalutamide 
mitotane 
phenytoin 
rifampin 
St. John’s wort 
bosentan 
efavirenz 
etravirine 
modafinil 
 
armodafinil  
rufinamide 
Abbreviations: AUC, area under the concentration-time curve. 
5.8. 
Contraception and Pregnancy 
This section should be read in conjunction with the selection criteria that relate to age and contraception: 
• 
Exclusion criteria #10 and #11 (Section 4.2) 
No signs of embryo-fetal toxicity or teratogenic effects of neflamapimod were observed in rats. Testing in 
rabbits was not performed due to lack of exposure following administration of the neflamapimod 
formulation. No human studies of effects of neflamapimod on conception, pregnancy, or lactation have 
been performed. Females should not be exposed to neflamapimod if pregnant, breastfeeding, or 
attempting to conceive. The following guidelines for contraception should be followed from before first 
dose on Day 1 through 91 days following the last dose of study drug: 
Female subjects of child-bearing potential (have not experienced menopause and have not had a 
hysterectomy or bilateral oophorectomy/salpingo-oophorectomy) or female subjects who have 
experienced menopause within the previous year must have a negative pregnancy test during 
Screening and must use at least 1 of the following contraceptive methods: complete abstinence 
regardless of menstrual cycle timing, contraceptive (oral, transdermal, injectable, or implantable), 
intrauterine device, or barrier method of contraception. 
Male subjects with female partners of child-bearing potential must use at least 1 of the following 
contraceptive methods: hormonal contraceptives (oral, injectable, patch, intrauterine devices), male 
sterilization, or total abstinence from heterosexual intercourse, when this is the preferred and usual 
lifestyle of the subject. 
• 
Abstinence is defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments when this is the preferred and usual lifestyle of the subject.  
Note that periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable 
methods of contraception. 
Any pregnancy should be reported to the Investigator, and, in turn, the pregnancy should be reported to 
Worldwide Clinical Trials within 24 hours of the Investigator’s awareness of the pregnancy. If a female 


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subject becomes pregnant, study drug will be permanently discontinued and the subject will be 
discontinued from the study. 
With proper informed consent (separate pregnancy informed consent form), the subject or partner will be 
followed through the completion of the pregnancy and outcome of the pregnancy reported, and the infant 
will be followed for 12 months after birth. 
5.9. 
Treatment Compliance 
Treatment compliance will be assessed by reviewing the count of returned capsules at each visit. Any 
apparent discrepancies between quantity of capsules returned and the number expected based on dosing 
schedule will be discussed with the subject to ensure an understanding of dosing instructions.  
Repeated non-compliance with dosing instructions may necessitate discontinuation from the study, based 
on the Investigator’s judgment (Section 4.3). 


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6. 
STUDY ASSESSMENTS AND PROCEDURES 
6.1. 
Schedule of Assessments 
The schedule of assessments is presented in Table 6-1. 


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Table 6-1: 
Schedule of Assessments 
Assessment 
Study Period / Week / Study Day 
ScreeningP 
Treatment Period 
Early 
Termination 
Follow- 
Up 
Screening 
VisitPa 
Baseline 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
 
Week 
16 
 
ET Visitc 
Follow- 
Up VisitPd 
Within 21-
35 days of 
D1 
D1Pb 
D14 
(±3) 
D28 
(±3) 
D56 
(±5) 
D84 
(±5) 
D112 
(±5) 
Within 
3 days after 
last dose 
Within 
14 days 
(±3) of 
last dose 
Informed Consent 
XPe 
 
 
 
 
 
 
 
 
Medical history review 
X 
 
 
 
 
 
 
 
 
Pregnancy testing 
XPf 
 
 
 
 
 
 
 
 
Physical examinationPg 
X 
 
 
 
 
 
X 
X 
X 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
chemistryPi 
X 
X 
 
X 
X 
X 
X 
X 
 
Coagulation studiesPi 
X 
 
 
 
X 
 
 
 
X 
12-lead 
electrocardiogramPj 
X 
 
 
 
 
 
 
 
 
DaTscan™, if needed 
Xk 
 
 
 
 
 
 
 
 
CT/MRI 
XPl 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
X 
X 
X 
X 
X 
 
MMSEm 
X 
X 
 
 
X 
 
X 
X 
 
NTBm, International 
Shopping List Test 
(ISLT) 
X 
X 
 
X 
X 
 
X 
X 
 
CDR-SB 
 
X 
 
 
X 
 
X 
X 
 
NPI-10 
X 
X 
 
X 
X 
 
X 
X 
 
Timed Up and Go (TUG) 
 
X 
 
 
X 
 
X 
X 
 
EEGn 
 
X 
 
 
 
 
X 
X 
 
Dispense study drug 
 
X 
X 
X 
X 
X 
 
 
 
Pharmacokinetic 
samplingo 
 
 
X 
X 
X 
 
 
 
 
Plasma sample for protein 
biomarker testingp 
Xq 
X 
 
 
 
 
X 
X 
 


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Assessment 
Study Period / Week / Study Day 
ScreeningP 
Treatment Period 
Early 
Termination 
Follow- 
Up 
Screening 
VisitPa 
Baseline 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
 
Week 
16 
 
ET Visitc 
Follow- 
Up VisitPd 
Within 21-
35 days of 
D1 
D1Pb 
D14 
(±3) 
D28 
(±3) 
D56 
(±5) 
D84 
(±5) 
D112 
(±5) 
Within 
3 days after 
last dose 
Within 
14 days 
(±3) of 
last dose 
Prior/concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final study drug 
reconciliation 
 
 
 
 
 
 
X 
X 
 
 
CDR-SB:  Clinical Dementia Rating Scale – Sum of Boxes; C-SSRS:  Columbia-Suicide Rating Scale; CT:  Computed 
tomography; D=day; MMSE: Mini-Mental State Examination; MRI:  Magnetic resonance imaging; NPI-10: 10-item 
Neuropsychiatric Inventory; NTB:  Neuropsychological Test Battery. 
 
a. 
One to two Screening visits are planned during which safety screening procedures are to be completed and reviewed, 
including a practice NTB and the required diagnostic and cognitive impairment procedures.  Screening will be conducted 
within 21 days before Baseline (Day 1); if a DaTscan and/or MRI or CT scan is required to determine study eligibility, 
Screening may be extended to 35 days. (If necessary, a second visit may be conducted on a different day to allow for 
scheduling purposes.) All screening assessments should be conducted within 21-35 days of Day 1 and can be condensed to 
one visit. 
b. 
On Day 1, all procedures should be conducted prior to first dose of study drug. 
c. 
Subjects who prematurely discontinue study drug for any reason will be asked to return to the study center for an Early 
Termination visit within 3 days following the last study drug dose; if it is determined that the subject will discontinue study 
drug while at the study center for a scheduled visit, then the Early Termination visit should be conducted at that time.  
d. 
The Follow-up Visit should be conducted within 14 (±3) days of the last dose of study drug for subjects who complete the 
study or discontinue early. 
e. 
Informed consent procedures, including signing of informed consent, must be completed before any study-specific 
procedures are performed. 
f. 
Female subjects who have reached menopause in the previous year must have a serum or urine pregnancy test performed 
during Screening; subjects with positive results are not eligible for study participation. 
g. 
Refer to Section 6.2.8 for details regarding physical examination.  
h. 
Vital signs include blood pressure, pulse, respiratory rate, and body temperature. Vital signs should be measured after the 
subject has been in sitting position for 5 minutes. 
i. 
Details of clinical laboratory sampling for chemistry, hematology, and coagulation studies are discussed in Section 6.2.10. 
j. 
Details of 12-lead ECG assessment are discussed in Section 6.2.9. 
k. 
Subjects are required to have a prior DaTscan. If a DaTscan has not been performed within the previous 2 years, it is to be 
performed during Screening only after subject has been deemed eligible based on all other inclusion/exclusion criteria (e.g., 
medical history, laboratory testing) and prior to randomization. Note that if DaTscan results are negative (i.e., no evidence of 


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reduced uptake in the basal ganglia), the subject is required to have historical PSG-verified RBD to be eligible for study 
participation. 
l. 
If MRI or CT has not been performed within 3 years before Screening and/or results are not available, MRI or CT scan must 
be performed to exclude other disease as part of Screening only after subject has been deemed eligible based on all other 
inclusion/exclusion criteria (e.g., medical history, laboratory testing) and prior to randomization (see Section 6.2.2). 
m. Refer to Section 6.2.4 for details regarding cognitive function tests. 
n. 
EEG need not performed at the ET visit for subjects who discontinue prior to Week 4 (Day 28). 
o. 
Refer to Section 6.2.11 for details regarding PK sampling. 
p. 
Refer to Section 6.2.12 for details regarding plasma biomarker sampling. 
q. 
Only plasma Aβ42/40 ratio is required at Screening. 
 
 


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6.2. 
Study Assessments 
The subject or subject’s legally authorized representative must provide written informed consent before 
the performance of any study-related procedures. 
6.2.1. 
Baseline and Disease Characteristics  
Details regarding DLB history, including method(s) of diagnosis will be collected during Screening, as 
specified in the eCRF. Subjects without documentation of prior diagnostic DLB tests (DaTscan and/or 
known amyloid biomarker status) are to have such tests performed during Screening (see Section 6.2.3). 
6.2.2. 
Computed Tomography (CT) / Magnetic Resonance Imaging (MRI) 
The subject must have had MRI or CT scan within 3 years of Screening, with findings negative for 
evidence of other neurodegenerative or other brain disease that could account for their cognitive 
symptoms. MRI/CT results should be available and reviewed before Screening diagnostic tests are 
performed. If MRI or CT has not been performed within 3 years before Screening and/or results are not 
available, MRI or CT scan must be performed as part of Screening to exclude other disease.  
6.2.3. 
DaTscan (if Required) 
Subjects are required to have a prior DaTscan (i.e., single-photon emission computed tomography 
[SPECT] with Ioflupane I 123 Injection) to be eligible for study participation.  
The DaTscan is a radiopharmaceutical indicated for striatal dopamine transporter visualization using 
SPECT brain imaging. Ioflupane I 123 Injection is to be administered and SPECT imaging is to be 
performed and interpreted per the prescribing information (GE Healthcare, 2015). If a DaTscan has not 
been performed within the previous 2 years, it is to be performed during Screening only after subject has 
been deemed eligible based on all other inclusion/exclusion criteria (e.g., medical history, laboratory 
testing) and prior to randomization.  
Note that if DaTscan results are negative (i.e., no evidence of reduced uptake in the basal ganglia), the 
subject is required to have historical PSG-verified RBD to be eligible for study participation. 
6.2.4. 
Cognitive Function Tests 
Cognitive function tests include a Neuropsychological Test Battery (NTB) as well as the Letter Fluency 
Test and Category Fluency Test (CFT), which are all components of the primary objective/endpoint to 
assess attention, executive function, and visuospatial function.  
Cognitive function tests to be performed as components of the secondary objective include the CDR-SB, 
MMSE, NPI-10, Timed Up and Go (TUG), and International Shopping List Test (ISLT).  
At Baseline and on any visits at which both NTB and other cognitive tests are conducted, the NTB should 
be performed prior to the other tests. 
6.2.4.1. 
Neuropsychological Test Battery (NTB) 
The NTB includes:   
• 
Cogstate Detection test (DET) 
• 
Cogstate Identification test (IDN) 


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• 
Cogstate One Card Learning test (OCL) 
• 
Cogstate One Back test (ONB) 
• 
Letter Fluency Test:  The Letter Fluency Test is a measure of phonemic fluency and is a 
subtest of the Multilingual Aphasia Examination (Benton et al, 1994). The LFT uses the 3-
letter set of F, A, and S or C, F, and L to assess phonemic fluency. Individuals are given 1 
minute to name as many words as possible beginning with one of the letters. The procedure is 
then repeated for the remaining two letters. The administration of phonemic and semantic 
fluency (CFT) takes approximately 5 minutes. Admissible responses are summed and 
compared to a normative sample.  
• 
Category Fluency Test (CFT): The CFT is a measure of verbal fluency and is sometimes 
called semantic fluency. In the standard version of the task, participants are given 1 minute to 
produce as many unique words as possible within a category. The subject's score is the 
number of unique correct words.  
6.2.4.2. 
Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB) 
The Clinical Dementia Rating Scale (CDR) (Hughes, 1982) is a semi-structured interview resulting in a 
semi-quantitative scoring of cognitive impairment in milder and more progressed forms of dementia. It is 
sensitive in both AD dementia and Mild Cognitive Impairment, and is an approved regulatory endpoint 
recognized by the FDA. The CDR yields both a global score (CDR-GS) and Sum of Boxes score (CDR-
SB). While the CDR-GS is typically utilized for staging purposes, the CDR-SB score is a more detailed 
quantitative general index than the CDR-GS and it provides more information than the CDR total score in 
cases of mild dementia (O’Bryant, et al, 2010). 
The CDR interview is to be conducted with the subject and Caregiver by an experienced and certified 
clinician at the time points specified in Table 6-1. 
6.2.4.3. 
Mini-Mental State Examination (MMSE) 
The MMSE (Folstein et al, 1975) consists of 11 tests of orientation, memory (recent and immediate), 
concentration, language, and praxis. Scores range from 0 to 30, with lower scores indicating greater 
cognitive impairment. It is based on the performance of the subject and takes approximately 5 to 
10 minutes to administer. 
Standardized MMSE will be conducted by the Investigator or designee at the time points specified in 
Table 6-1. 
6.2.4.4. 
International Shopping List Test (ISLT) 
Word learning tests have been commonly utilized to assess episodic memory. In DLB, the recognition 
component is considered to be of particular utility (Wesnes et al, 2015). The ISLT is one such word 
learning test that has been utilized in a number of proof-of-concept clinical studies with novel 
therapeutics (Nathan et al, 2013; Maher-Edwards et al, 2015). Immediate and Delayed Recall, as well as 
Recognition, will be assessed. 
6.2.4.5. 
10-item Neuro-Psychiatric Inventory (NPI-10) 
The NPI-10 is designed to assess psychopathology in the person with dementia and to help distinguish 
between the different causes of dementia. The NPI-10 examines 10 sub-domains of behavioral 
functioning: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, 


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disinhibition, irritability/lability, and aberrant motor activity. For this study, the following domains are of 
specific interest: depression (dysphoria), anxiety, hallucinations, and agitation/aggression. The NPI-10 is 
administrated to caregivers of dementia subjects. A screening question is asked about each included sub-
domain. If the responses to these questions indicate that the subject has problems with a particular sub-
domain of behavior, the caregiver is only then asked all the questions about that domain, rating the 
frequency of the symptoms on a 4-point scale, their severity on a 3-point scale, and the distress the 
symptom causes them on a 5-point scale (Cummings, 1997).The NPI-10 takes approximately 10 minutes 
to complete.  
6.2.5. 
Timed Up and Go Test (TUG) 
The Timed Up and Go Test is designed to assess mobility. It measures the time in seconds for a person to 
rise from sitting from a standard arm chair, walk 3 meters, turn, walk back to the chair, and sit down. The 
subject wears regular footwear and uses his/her customary walking aid. A score of >15 seconds indicates 
client has increased risk of falls. The test takes 1 to 2 minutes to complete.  
The Timed Up and Go Test is to be administered at the time points specified in Table 6-1.  
6.2.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a clinician-administered instrument that assesses suicidal ideation and behavior (38TPosner et 
al, 201138T). The “Baseline” version of the instrument will be administered to subjects during Screening, and 
the “Since Last Visit” version will be used at subsequent time points specified in Table 6-1. 
6.2.7. 
Electroencephalography (EEG) 
Quantitative electroencephalography (qEEG) will be performed with the subject awake in accordance 
with the 10-20 International System of Electrode placement at the time points specified in Table 6-1 
according to a standard protocol that will be provided in a separate EEG manual. Slowing of the dominant 
frequency band by qEEG over posterior aspects of the brain has been recognized to be prominent in DLB 
(Olde Dubbelink et al 2013; Peraza et al, 2018), and various patterns have been identified to differentiate 
DLB from AD. EEG has also been recognized to be potential biomarker for DLB in the most recent 
consensus report of the DLB consortium (McKeith et al, 2017). 
6.2.8. 
Physical Examination and Vital Signs 
Physical examination will include a review of all body systems and measurement of weight, per each 
Investigators standard practice. Physical examination findings will be documented in the subject’s source 
documents.  
Vital signs include measurement of blood pressure, pulse, respiratory rate, and body temperature. Vital 
signs are to be measured with the subject in a sitting position after 5 minutes. 
Any physical examination finding or vital sign measurement that represents a worsening from Baseline 
condition and is considered by the Investigator to be clinically significant will be recorded as an AE (see 
Section 7). 
6.2.9. 
12-Lead Electrocardiogram 
A 12-lead ECG will be performed during Screening using validated machinery available locally to each 
clinical site. ECG parameters to be captured include heart rate (bpm), PR interval, QRS duration, QT 
interval, corrected QT interval (using Fridericia’s formula) , and RR interval Each report will be reviewed 


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by the Investigator or qualified sub-investigator and assessed as normal, abnormal – not clinically 
significant, or abnormal – clinically significant. Abnormal, clinically significant findings are to be 
reported as part of the subject’s medical history.  
6.2.10. 
Clinical Laboratory Assessments 
Blood samples will be collected at the time points specified in Table 6-1 for assessment of routine 
chemistry and hematology analytes. Additional blood samples will be collected for coagulation studies at 
the time points specified in Table 6-1.  
All samples will be analyzed via a central laboratory.  
Table 6-2: 
Clinical Laboratory Analytes 
Serum Chemistry  
Hematology 
• 
Albumin 
• 
Alkaline phosphatase 
• 
ALT 
• 
AST 
• 
Bilirubin (total and direct) 
• 
Glucose 
• 
Blood urea nitrogen 
• 
Calcium 
• 
Bicarbonate/Carbon Dioxide 
• 
Chloride  
• 
Total cholesterol 
• 
Triglycerides 
• 
Creatinine 
• 
Gamma-glutamyl transferase 
• 
Lactate dehydrogenase 
• 
Phosphate 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid 
• 
Differential (absolute and percent) 
• 
Basophils 
• 
Eosinophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Neutrophils 
• 
Erythrocytes 
• 
Mean corpuscular hemoglobin 
• 
Mean corpuscular hemoglobin concentration 
• 
Mean corpuscular volume 
• 
Hemoglobin 
• 
Leukocytes 
• 
Platelets 
Coagulation Studies 
• 
Prothrombin time 
• 
Partial thromboplastin time 
• 
INR 
Clinical laboratory findings that represent a worsening from Baseline value and are considered by the 
Investigator to be clinically significant will be recorded as an AE (refer to Section 7). 


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6.2.11. 
Pharmacokinetics (PK) 
Blood samples for PK are to be collected at the timepoints specified in Table 6-1. The actual sample 
collection time on the designated visit days is per study center / subject convenience. The actual sample 
collection date and time relative to the most recent study drug dose is to be documented. 
6.2.12. 
Biomarker Testing 
Plasma samples for protein biomarker assessment are to be collected at the timepoints specified in 
Table 6-1. At Screening all subjects will only have the Aβ42/40 plasma ratio assessed from these 
samples.  Subsequent samples will be stored for future protein biomarker testing once applicable assays 
are identified or developed; note that such samples will be not be used for genetic testing.  
For purposes of use during analysis of the clinical results, biomarker status (positive/negative) will be 
determined by historical amyloid PET, if available. If prior amyloid PET is not available, then biomarker 
status is to be determined by historical biomarker testing in CSF. If prior CSF is not available, then 
biomarker status is to be determined by Screening Aβ42/40 plasma ratio. 
6.2.13. 
Withdrawal of Subjects 
A subject may be discontinued from study treatment at any time if the subject, the Investigator, or the 
Sponsor feels that it is not in the subject’s best interest to continue. The following is a list of possible 
reasons for study treatment discontinuation: 
• 
Subject withdrawal of consent (or withdrawal of surrogate consent) 
• 
Subject develops suicidal ideations or attempts suicide 
• 
Subject is not compliant with study procedures 
• 
AE that in the opinion of the Investigator would be in the best interest of the subject to 
discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
If a subject is withdrawn from treatment due to an AE, the subject will be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized.  
A subject may be withdrawn from the study at any time if the subject, the Investigator, or the Sponsor 
feels that it is not in the subject’s best interest to continue.  
All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified, 
and without prejudice. 
Reasonable attempts will be made by the Investigator to provide a reason for subject withdrawals. The 
reason for the subject’s withdrawal from the study will be specified in the subject’s source documents.  
Refer to Table 6-1 for assessments to be performed for subjects who prematurely discontinue study drug. 


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7. 
ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS/SAFETY REPORTING 
The Investigator is responsible for reporting of events meeting the criteria and definition of an AE or SAE 
as provided in this protocol.  
7.1. 
Definitions and Criteria  
7.1.1. 
Adverse Events  
Per International Council for Harmonisation (ICH) E2A: An AE is any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.  
Medical interventions such as surgeries, diagnostic procedures, and therapeutic procedures are not AEs 
but the action taken to treat the medical condition. They should be recorded as treatment of the AEs. 
7.1.2. 
Serious Adverse Events 
An SAE or reaction is any untoward medical occurrence that at any dose:  
• 
Results in death  
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital anomaly or birth defect  
• 
Is an important medical event (e.g., intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias, or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse; malignancy)  
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the subject was 
at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.  
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also usually 
be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias, or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse.  


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Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. An SAE is not 
necessarily severe; e.g., an overnight hospitalization for a diagnostic procedure must be reported as an 
SAE even though the occurrence is not medically serious. By the same token, a severe AE is not 
necessarily serious: nausea of several hours’ duration may be rated as severe but may not be considered 
serious. 
The following hospitalizations are not considered serious: 
• 
A visit to the emergency room or other hospital department <24 hours, that does not result in 
admission (unless considered ‘important medical event’ or event life-threatening). 
• 
Elective surgery, planned prior to signing the informed consent form (ICF). 
• 
Medical/surgical admission for purpose other than remedying ill health state and was planned 
prior to entry into the study. 
• 
Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, care-giver 
respite, family circumstances, administrative). 
7.1.3. 
Unexpected Adverse Drug Reactions  
An unexpected adverse drug reaction (ADR) is a reaction for which the nature or severity is not consistent 
with the applicable product information (Investigator’s Brochure, Package Insert for marketed products). 
Until product information is amended, expedited reporting is required for additional occurrences of the 
reaction. Reports that add significant information on specificity or severity of a known, already 
documented SAE constitute unexpected events. For example, an event more specific or more severe than 
described in the Investigator's Brochure would be considered "unexpected.” Specific examples would be 
(a) acute renal failure as a labeled ADR with a subsequent new report of interstitial nephritis and 
(b) hepatitis with a first report of fulminant hepatitis.  
Guidance on reporting AEs and SAEs is described in Section 7.2. 
7.1.4. 
Abnormal Laboratory Values 
Any abnormality in a laboratory value that is new in onset or which has worsened in severity or frequency 
from the baseline condition and meets 1 of the following criteria will be recorded on the AE pages of the 
eCRF:  
• 
Requires therapeutic intervention or diagnostic tests. 
• 
Leads to discontinuation of investigational product. 
• 
Has accompanying or inducing symptoms or signs. 
• 
Is judged by the Investigator as clinically significant. 
7.1.5. 
Assessing Intensity and Relationship  
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to the investigational 
product: 
• 
Intensity refers to the severity of an event and references impact on a subject’s functioning. 


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• 
Relationship refers to the likelihood that the event being assessed was caused by the 
investigational product. 
Intensity 
Each AE will be classified according to the following criteria: 
Mild: 
The AE does not interfere in a significant manner with the subject’s normal level of 
functioning. 
Moderate: 
The AE produces some impairment of functioning, but is not hazardous to the 
subject’s health. 
Severe: 
The AE produces significant impairment of functioning or incapacitation and is a 
definite hazard to the subject’s health. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum intensity 
for the experience should be noted. If the intensity category changes over a number of days, those 
changes should be recorded separately (with distinct onset dates). 
Relationship 
Each AE will be assessed as to its relationship to the investigational product, based on the following 
criteria. Although the attribution by the Investigator will be collected for reported events, for analytic 
purposes a temporal association with the use of the investigational product will be assumed sufficient for 
at least plausible association. 
Not related: 
No causal relationship exists between the investigational product and the AE, but an 
obvious alternative cause exists, e.g., the subject’s underlying medical condition or 
concomitant therapy. 
Possibly related: 
A connection with the administration of the investigational product appears unlikely, 
but cannot be ruled out with certainty. An AE may be considered possibly related if 
or when it meets 2 of the following criteria: (1) it follows a reasonable temporal 
sequence from administration of the investigational product; (2) it could not readily 
have been produced by the subject’s clinical state, environmental or toxic factors, or 
other modes of therapy administered to the subject; or (3) it follows a known pattern 
of response to the investigational product. 
Related: 
There is a reasonable/plausible possibility that the AE may have been caused by the 
investigational product. 
When assessing the relationship to the investigational product, the following criteria will be considered: 
• 
Positive rechallenge 
• 
Positive dechallenge (resolution upon stopping suspect the investigational product, in absence of 
other intervention or treatment) 
• 
Known class effect 
• 
Biological plausibility 
• 
Lack of alternative explanation—concomitant drug or disease 


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7.2. 
Reporting Procedures and Requirements 
7.2.1. 
Adverse Events (AE) 
AEs occurring from when the subject signs the ICF until the last study event will be recorded. Any AEs 
occurring before the start of treatment (i.e., before the first dose of the investigational product)” will be 
recorded in the medical history. Also, the sign, symptom, or disease present before starting the treatment 
period are only considered AEs if they worsen after starting the treatment period. 
If the Investigator detects an AE in a study subject after the last scheduled follow-up visit and considers 
the event possibly related or related to prior study treatment, the Investigator should report it to 
Worldwide Clinical Trials. 
The Investigator should report all AEs on the AE page(s) of the eCRF and source documents, regardless 
of seriousness, severity, and causality. Whenever possible, an AE will be reported using a diagnostic term 
rather than symptoms, (e.g., “common cold” or “upper respiratory infection” rather than “runny nose, 
cough, mild fever”) and should be described with the attributes described in Section 7.1.5. 
7.2.2. 
Serious Adverse Events (SAE) 
Each AE will be assessed to determine whether it meets seriousness criteria (Section 7.1.2). If the AE is 
considered serious, the Investigator should report this event to Worldwide Clinical Trials outlined below 
and also to the IEC according to its standard operating procedures. 
The Investigator must report all SAEs via an eCRF in the EDC system within 24 hours of learning 
about the event regardless of relationship to study drug. 
If the Investigator/site experiences a temporary disruption of the EDC system, a back-up paper SAE 
Report Form will be available for Investigator/site staff to complete. If a paper SAE Report Form is 
utilized, it must follow the same timelines and be emailed or faxed within 24 hours of learning about the 
event regardless of relationship to study drug. 
SAE Reporting: 
E-mail:  drugsafety@worldwide.com  
Fax: +1-866-387-5539 (US) or +44 208 043 4813 (ROW) 
If notification is made via email or fax, site staff must enter the SAE information into the EDC system as 
soon as the system becomes available. Should a paper SAE form be used, the original SAE form should 
be kept at the site. 
Each SAE should be followed up until resolution or stabilization. For reported deaths, the Investigator 
should supply Worldwide Clinical Trials and the IEC with any additional requested information (e.g., 
autopsy reports and terminal medical reports). 
The Sponsor or designee is responsible for notifying the relevant regulatory authorities of certain events. 
It is the Investigator’s responsibility to notify the IEC of all SAEs that occur at the Investigator’s site. 
Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety 
Reports) that occur during the clinical trial. 


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SAEs that are ongoing at the Follow-up visit should be followed until resolution, until the condition 
stabilizes, until the subject is lost to follow-up or otherwise explained. 
If the Investigator detects an SAE in a study subject after the last scheduled follow-up visit, and considers 
the SAE related or possibly related to prior study treatment, the Investigator should report it to the 
Sponsor. 


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8. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
8.1. 
Data Management and Quality Assurance Considerations  
This study will employ eCRFs via an electronic data capture (EDC) system. The site will be trained on 
specific forms and procedures for source documentation and maintenance of an audit trail of the data that 
is entered on the eCRF prior to study initiation. 
Study personnel at each site will enter data from source documents corresponding to a subject’s visit into 
the protocol-specific eCRF when the information corresponding to that visit is available. Subjects will not 
be identified by name in the study database or on any study documents to be collected by the Sponsor (or 
designee), but will be identified by subject number (6 digits: the first 3 for the study center and the last 
3 for the subject). 
The Investigators will prepare and maintain adequate and accurate source documents designed to record 
all observations and other pertinent data for each subject treated with the study drug. 
If a correction is required for an eCRF, the time and date will be automatically recorded by the EDC 
system indicating the person updating eCRF data in order to create an audit trail. The Investigator is 
responsible for all information collected on subjects enrolled in this study. All data collected during the 
course of this study must be reviewed and verified for completeness and accuracy by the Investigator.  
Queries will be issued for any inconsistencies, omissions, and discrepancies and will be resolved by the 
appropriate parties.  
Database lock will occur once quality assurance procedures have been completed. 
The statistical analysis of this data will be performed by the Sponsor or designee. All AEs will be coded 
using the latest version of the Medical Dictionary for Regulated Activities (MedDRA). Concomitant 
medications will be coded using the latest version of the World Health Organization Drug Dictionary.  
All procedures for the handling and analysis of data will be conducted using good computing practices 
meeting United States Food and Drug Administration (FDA), European Medicines Agency, and ICH 
guidelines for the handling and analysis of data for clinical studies. Data management details will be 
outlined in a separate Data Management Plan. 
8.2. 
Sample Size 
A total of approximately 80 subjects are planned to be enrolled, of whom 40 are planned to receive 
neflamapimod and 40 are planned to receive placebo.  
As there is no prior experience with neflamapimod in patients with DLB upon which to base assumptions 
of treatment effect, no formal sample size calculation has been performed. However, based on prior 
experience with NTB in clinical studies, 40 subjects per treatment arm should provide a reasonably robust 
first assessment of whether neflamapimod improves cognitive function in patients with DLB. 
8.3. 
Analysis Sets 
The safety analysis set will include any subject who receives at least 1 dose of study drug. 
The efficacy analysis set will include any subject who receives at least 1 dose of study drug and at least 
one post-dose cognitive assessment. 


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Analyses will be fully outlined in a Statistical Analysis Plan finalized prior to the end of enrollment.  
8.4. 
Safety 
The incidence of treatment-emergent AE and SAEs, the causal relationship between an AE/SAE, and the 
Study Drug and severity will be tabulated by treatment (dose) group. 
Individual clinically-significant changes in clinical laboratory and ECG parameters will be listed along 
with median and mean and standard deviation by treatment group.  
8.5. 
Efficacy 
The primary efficacy variable is: 
• 
Change in the composite score of the NTB, including assessments of attention, executive 
function, and visuospatial function in neflamapimod treated-subjects as compared to the 
placebo-treated subjects. 
Secondary efficacy variables are: 
• 
Change in CDR-SB in neflamapimod-treated subjects compared to placebo-recipients. 
• 
Change in MMSE in neflamapimod-treated subjects compared to placebo-recipients.  
• 
Change in NPI-10 domains in neflamapimod-treated subjects compared to placebo-
recipients. 
• 
Change in ISLT in neflamapimod-treated subjects compared to placebo-recipients. 
• 
Change in Timed Up and Go Test. 
• 
Change in EEG parameters. 
The estimand of this study is the change from baseline to Week 16 in the composite score of the NTB in 
patients 55 years of age and older with probable DLB, comparing subjects treated with neflamapimod to 
those treated with placebo. The NTB includes assessments of episodic memory, executive function, 
visuospatial function, and attention. The primary endpoint will be analyzed using the Mixed Model 
Repeated Measures (MMRM) analysis method with the NTB change from baseline composite score as 
the dependent variable, and will use an unstructured covariance matrix. This analysis will be performed 
on the efficacy analysis population, which will include all subjects who receive at least one dose of study 
drug and provide at least one post-dose cognitive assessment. Additional covariates to be included in the 
MMRM model will be provided in the Statistical Analysis Plan (SAP) which will be finalized prior to 
study unblinding. Z-scores may be calculated and used in order to create standardized change scores to be 
used for the analysis. Additionally, sensitivity analyses will be performed on the primary endpoint 
specifically to address different missing data scenarios, both Missing at Random and Missing Not at 
Random. Further descriptions of the sensitivity analyses, as well as any additional efficacy populations 
that may be used to assess efficacy will also be provided in the SAP. Secondary efficacy endpoints will 
utilize the same analysis method and model as the primary endpoint. 
8.6. 
Interim Analysis 
No interim analysis is planned.  


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9. 
STUDY MANAGEMENT  
9.1. 
Ethics and Consent 
9.1.1. 
Regulations and Guidelines 
The study will be performed in accordance with this protocol, United States Investigational New 
Drug Application regulations (21 CFR 312) or local national laws (as applicable) and ICH guidelines 
for Good Clinical Practice.  
9.1.2. 
Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IEC. Approval is required for the 
study protocol, investigational drug brochure, protocol amendments, ICFs, subject information sheets, 
and advertising materials. No investigational product will be shipped to a site until written IEC 
authorization has been received by the Sponsor or its designee. 
9.1.3. 
Informed Consent 
For each study subject, written informed consent must be obtained from the subject or subject’s legally 
authorized representative before the performance of any protocol-related activities. As part of this 
procedure, the Investigator or a designated representative must explain orally and in writing the nature, 
duration, and purpose of the study, and the action of the investigational product in such a manner that the 
subject and (if applicable) legally authorized representative are aware of the potential risks, 
inconveniences, or adverse effects that may occur. Subjects should be informed that they may withdraw 
from the study at any time. They will receive all information that is required by local regulations and ICH 
guidelines. The Investigator or a designated representative will provide the Sponsor or its designee with a 
copy of the IEC-approved ICF before the start of the study. 
9.2. 
Indemnification 
The Sponsor’s indemnification of the Investigator and institution during the conduct of this study is 
addressed in a letter of indemnification provided as a separate document. Other indemnification or 
insurance will be provided as necessary under local regulations. 
9.3. 
Discontinuation of the Study by the Sponsor 
The planned study period is approximately 2 years, until the last visit of the last subject (including the 
follow-up visit). The planned subject participation is approximately 21 weeks, including 16 weeks of 
treatment. Once the subjects have ended their participation in the study, they will return to their standard 
of care treatment as determined by their physician.  
The Sponsor reserves the right to discontinue the study at this site or at multiple sites for safety or 
administrative reasons at any time. If the Sponsor or Investigator discovers conditions arising during the 
study that suggest the study should be halted, then this can happen only after appropriate consultation 
between the Sponsor and Investigator. Conditions that may warrant study termination include, but are not 
limited to: 
• 
The discovery of any unexpected, significant, or unacceptable risk to the subjects enrolled in the 
study. 


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• 
Failure of the Investigator to enter subjects at an acceptable rate. 
• 
Unsatisfactory subject enrollment with respect to quality and/or quantity or data recording is 
inaccurate and/or incomplete on a chronic basis. 
• 
Insufficient adherence to the protocol requirements. 
• 
A decision on the part of the Sponsor to suspend or discontinue development of study drug. 
Should the study be terminated and/or the site closed for whatever reason, all documentation and 
investigational product pertaining to the study must be returned to the Sponsor or its designee. 
9.4. 
Study Documentation 
By signing a copy of Form FDA 1572 or other country-specific regulatory forms, the Investigator 
acknowledges that he/she has received a copy of the IB on neflamapimod and assures the Sponsor that 
he/she will comply with the protocol and the provisions stated in Form FDA 1572 and other country-
specific forms. No changes in this protocol can be made without the Sponsor’s written approval. 
9.5. 
Study Monitoring and Auditing  
This study will be monitored for quality assurance at all stages of its development by the clinical research 
personnel employed by the Sponsor or its designee. Monitoring will include personal visits and telephone 
communication to assure that the investigation is conducted according to the protocol, standard operating 
procedures, Guidelines of Good Clinical Practice, and applicable regulatory requirements. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly. On-site review of eCRFs will include a review of forms for completeness and clarity, 
and consistency with source documents available for each subject.  
9.6. 
Use of Study Findings  
By signing the study protocol, the Investigator agrees to the use of results of the study for the purposes of 
national and international registration. If necessary, the authorities will be notified of the Investigator’s 
name, address, qualifications, and extent of involvement. Reports covering clinical and biometric aspects 
of the study will be prepared by the Sponsor or its designee. 
9.7. 
Publications 
The clinical study will be registered at 38Twww.clinicaltrials.gov38T and 38Twww.clinicaltrialsregister.eu38T. The 
preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among the study Sponsor and 
participating institutions. The publication or presentation of any study results shall comply with all 
applicable privacy laws.  
9.8. 
Recording, Access and Retention of Source Data 
The Investigators must make study data accessible to the monitor, other authorized representatives of the 
Sponsor (or designee) and Regulatory Agency inspectors upon request. 


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A file for each subject must be maintained that includes the signed Informed Consent and copies of all 
source documentation related to that subject. The Investigator must ensure the reliability and availability of 
source documents from which the information on the eCRF was derived. 
All study documents (subject files, signed ICFs, Study File Notebook, etc.) must be kept secured for a 
period of two years following marketing of the investigational product. There may be other circumstances 
for which the Sponsor is required to maintain study records and, therefore, the Sponsor should be contacted 
prior to removing study records for any reason. 
9.9. 
Protocol Violations 
A protocol violation occurs when the subject, Investigator, or Sponsor fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety, and primary endpoint criteria. 
Protocol violations for this study include, but are not limited to, the following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice guidelines will also result in a protocol violation. The 
Sponsor will determine if a protocol violation will result in withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the Investigator and a Protocol Violation Form 
detailing the violation will be generated. This form will be signed by a Sponsor representative and the 
Investigator. A copy of the form will be filed in the site’s regulatory binder and in the Sponsor’s files.  


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10. 
REFERENCES 
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SAP_001.pdf: 
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D A T E  O F P L A N:  
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S T U D Y D R U G:  
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P R O T O C O L N U M B E R:  
EI P 1 9 -N F D -5 0 1  
S T U D Y TI T L E:  
A D O U B L E -B LI N D, P L A C E B O -C O N T R O L L E D 1 6 -W E E K S T U D Y O F T H E 
C O G NI TI V E E F F E C T S O F T H E O R A L P 3 8 A L P H A KI N A S E I N HI BI T O R 
N E F L A M A PI M O D I N D E M E N TI A WI T H L E W Y B O DI E S ( D L B)  
S P O N S O R:  
EI P P h ar m a, I nc.  
T he Y ar d, S uite 6 1 0 7  
1 2 0 St. J a mes Street, 6t h Fl o or  
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t hat t he i nf or mati on is c o nfi de ntial a n d ma y n ot be f urt her discl ose d b y t he m.  


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A n oi xis C or p orati o n  
Si g nat ure  
Date  
T his d oc u me nt has bee n re vie we d a n d acce pte d b y: 
 
J o h n J. Ala m, M. D., Presi de nt a n d C E O  
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List of A b bre vi ati o ns  
A b bre vi ati o n  
Defi niti o n  
A D  
Alz hei mer’s disease  
A D R  
A d verse dr u g reacti o n  
A N C O V A  
A nal ysis of c o varia nce  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A S T  
As partate a mi n otra nsferase  
BI D  
bis i n die (t wice a da y)  
C D R -G S  
Cli nical De me ntia Rati n g Scale -Gl o bal Sc ore  
C D R -S B  
Cli nical De me ntia Rati n g Scale -S u m of B o xes  
C F T  
Cate g or y Fl ue nc y Test  
C P  
C o m pleter p o p ulati o n  
C S F  
Cere br os pi nal fl ui d  
C S R  
Cli nical St u d y Re p ort  
C -S S R S  
C ol u m bia -S uici de Se verit y Rati n g Scale  
C T  
C o m p ute d t o m o gra p h y  
D E T  
C o gstate Detecti o n test  
D L B  
De me ntia wit h le w y b o dies  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
E D C  
Electr o nic data ca pt ure  
E E G  
Electr oe nce p hal o gra p h y  
E E P  
E val ua ble efficac y p o p ulati o n  
E T  
Earl y Ter mi nati o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
I B 
I n vesti gat or Br oc h ure 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 
I D N 
C o gstate I de ntificati o n Test  
I E C 
I n de pe n de nt Et hics C o m mittee 
I N D 
I n vesti gati o nal Ne w Dr u g 
I N R 
I nter nati o nal n or malize d rati o 


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I S L T 
I nter nati o nal S h o p pi n g List Test 
I S R L 
I nter nati o nal S h o p pi n g List Test –  Dela ye d Recall  
I S R N 
I nter nati o nal S h o p pi n g List Test –  Rec o g niti o n  
L F T  
Letter fl ue nc y test  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M M R M  
Mi xe d M o del Re peate d Meas ures  
M M S E  
Mi ni Me ntal State E xa mi nati o n  
M RI  
Ma g netic res o na nce i ma gi n g  
N PI -1 0  
1 0 -ite m Ne ur o ps yc hiatric I n ve nt or y 
N T B  
Ne ur o ps yc h ol o gical Test Batter y  
O C L  
C o gstate O ne Car d Lear ni n g test  
O N B  
C o gstate O ne Bac k Test  
P A C C  
Precli nical Alz hei mer C o g niti ve C o m p osite  
P K  
P har mac o ki netic  
P S G  
P ol ys o m n o gra p h y  
q E E G  
Q ua ntitati ve electr oe nce p hal o gra p h  
R B D  
R E M slee p be ha vi oral dis or der  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
TI D  
T hree ti mes dail y  
T U G  
Ti me d U p a n d G o Test  
U L N  
U p per li mit of n or mal  
 


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Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -5 0 1   
 
 
 
 
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T A B L E O F C O N T E N T S  
1.  
I N T R O D U C TI O N ........................................................................................................ 9  
2.  
S T U D Y O BJ E C TI V E S  .............................................................................................. 1 0  
2. 1.  
Pri mar y O bjecti ve  ....................................................................................................... 1 0  
2. 2.  
Sec o n dar y O bjecti ves  ................................................................................................. 1 0  
2. 3.  
E x pl orat or y Efficac y a n d Safet y O bjecti ves  .............................................................. 1 0  
3.  
S T U D Y D E SI G N  ....................................................................................................... 1 1  
3. 1.  
Sa m ple Size J ustificati o n  ............................................................................................ 1 1  
3. 2.  
St u d y d urati o n a n d visit sc he d ule  ............................................................................... 1 2  
3. 3.  
Ra n d o mizati o n  ............................................................................................................ 1 2  
4.  
C LI NI C A L A S S E S S M E N T S  ..................................................................................... 1 6  
4. 1.  
Baseli ne a n d Disease C haracteristics  ......................................................................... 1 6  
4. 2.  
Efficac y/ C o g niti ve Assess me nts  ................................................................................ 1 6  
4. 2. 1.  
Ne ur o ps yc h ol o gical Test Batter y ( N T B)  ................................................................... 1 6  
4. 2. 2.  
Cli nical De me ntia Rati n g Scale –  S u m of B o xes ( C D R -S B)  ..................................... 1 7  
4. 2. 3.  
Mi ni -Me ntal State E xa mi nati o n ( M M S E)  .................................................................. 1 8  
4. 2. 4.  
I nter nati o nal S h o p pi ng List Test  (I S L T) .................................................................... 1 8  
4. 2. 5.  
1 0 -ite m Ne ur o-Ps yc hiatric I n ve nt or y ( N PI -1 0)  ......................................................... 1 8  
4. 2. 6.  
Ti me d U p a n d G o Test  ( T U G) ................................................................................... 1 8  
4. 3.  
Ot her Cli nical Assess me nts  ........................................................................................ 1 9  
4. 3. 1.  
C ol u m bia -S uici de Se verit y Rati n g Scale  ................................................................... 1 9  
4. 3. 2.  
Electr oe nce p hal o gra p h y  ( E E G) .................................................................................. 1 9  
4. 4.  
P h ysical E xa mi nati o n a n d Vital Si g ns  ....................................................................... 1 9  
4. 5.  
1 2 -Lea d Electr ocar di o gra m  ........................................................................................ 1 9  
4. 6.  
Cli nical La b orat or y Assess me nt  ................................................................................. 1 9  
4. 7.  
P har mac o ki netics ( P K)  ............................................................................................... 2 1  
4. 8.  
Bi o mar ker Testi n g  ...................................................................................................... 2 1  
5.  
D E FI NI TI O N S, C O N V E N TI O N S A N D D E RI V E D V A RI A B L E S  ......................... 2 2  
5. 1.  
Defi niti o ns a n d c o n ve nti o ns  ....................................................................................... 2 2  
5. 2.  
Deri ve d Varia bles  ....................................................................................................... 2 3  
5. 2. 1.  
C ha n ge fr o m Baseli ne  ................................................................................................ 2 3  
5. 2. 2.  
Sta n dar dize d Sc ores Relati ve t o Baseli ne Sc ore  ........................................................ 2 3  


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5. 2. 3.  
C o m p osite O utc o me Meas ures Deri ve d fr o m t he I n di vi d ual Tests  ........................... 2 4  
6.  
A N A L Y SI S P O P U L A TI O N S  .................................................................................... 2 6  
6. 1.  
Safet y P o p ulati o n  ....................................................................................................... 2 6  
6. 2.  
E val u a ble Efficac y P o p ulati o n ( E E P) P o p ulati o n  ...................................................... 2 6  
6. 3.  
C o m pleter P o p ulati o n ( C P)  ........................................................................................ 2 6  
6. 4.  
P har mac o ki netics ( P K) P o p ulati o n  ............................................................................ 2 6  
7.  
D A T A M A N G E M E N T, R E VI E W A N D P R E E S E N T A TI O N  ................................. 2 7  
7. 1.  
Data Ma na ge me nt a n d Q ualit y Ass ura nce  C o nsi derati o ns  ........................................ 2 7  
7. 1. 1.  
Ge neral C o nsi derati o ns  .............................................................................................. 2 7  
7. 1. 2.  
Q ualit y Ass ura nce f or C o gstate C o m p uterize d Tests  ................................................. 2 7  
7. 2.  
Data Prese ntati o n  ........................................................................................................ 2 9  
7. 3.  
I nteri m Data Re vie w .................................................................................................. 2 9  
8.  
S T A TI S T SI C A L M E T H O D O L O G Y  ........................................................................ 3 0  
8. 1.  
Ge neral Statistical Met h o d ol o g y  ................................................................................ 3 0  
8. 2.  
Prese ntati o n of Efficac y Meas ures  ............................................................................. 3 0  
8. 3.  
S u bject Dis p ositi o n  ..................................................................................................... 3 1  
8. 4.  
Pr ot oc ol De viati o ns  .................................................................................................... 3 1  
8. 5.  
Missi n g Val ues  ........................................................................................................... 3 1  
8. 6.  
S u b gr o u ps  ................................................................................................................... 3 1  
8. 7.  
C o m plia nce  ................................................................................................................. 3 1  
8. 8.  
Baseli ne S u bject Data a n d Disease C haracteristics A nal yses  .................................... 3 2  
8. 9.  
Efficac y A nal yses  ....................................................................................................... 3 2  
8. 9. 1.  
Pri mar y Efficac y A nal ysis  .......................................................................................... 3 2  
8. 9. 2.  
A nal ysis of t he Sec o n dar y Efficac y E n d p oi nts  .......................................................... 3 3  
8. 9. 3.  
A nal ysis of t he e x pl orat or y Efficac y E n d p oi nts  ......................................................... 3 3  
8. 9. 4.  
A nal ysis of Plas ma Bi o mar kers  ................................................................................. 3 4  
8. 9. 5.  
S u m mar y of Reas o ns f or Efficac y N o n -e val ua bilit y/ E xcl usi o n fr o m E fficac y 
A nal yses  ..................................................................................................................... 3 4  
8. 1 0.  
P har mac o ki netic A nal ysis  .......................................................................................... 3 4  
8. 1 1.  
Safet y a n d T olera bilit y A nal yses  ............................................................................... 3 4  
8. 1 1. 1.  
Ge neral Safet y A nal ysis Met h o ds  .............................................................................. 3 4  
8. 1 1. 2.  
R o uti ne La b orat or y Data  ............................................................................................ 3 4  
8. 1 1. 3.  
Vital Si g ns a n d P h ysical E xa mi nati o n  ....................................................................... 3 4  


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8. 1 1. 4.  
Electr ocar di o gra m E val uati o ns  .................................................................................. 3 5  
8. 1 1. 5.  
C o nc o mita nt Me dicati o ns  ........................................................................................... 3 5  
8. 1 1. 6.  
St u d y Ter mi nati o n Stat us  ........................................................................................... 3 5  
9.  
R E F E R E N C E  ............................................................................................................. 3 6  
1 0.  
A P P E N DI X  ................................................................................................................ 3 7  
1 0. 1.  
Ta ble of C o nte nts f or Data Dis pla y S pecificati o ns  .................................................... 3 7  
1 0. 1. 1.  
List of Ta bles  .............................................................................................................. 3 7  
1 0. 1. 2.  
List of Fi g ures  ............................................................................................................ 3 9  
1 0. 1. 3.  
Listi n gs  ....................................................................................................................... 4 3  
1 0. 2.  
Sa m ple Ta ble Te m plate  .............................................................................................. 4 5  
1 0. 2. 1.  
Sa m ple Te m plate f or C o u nt Data  ............................................................................... 4 5  
1 0. 2. 2.  
Sa m ple Te m plate f or C o nti n u o us Data ( Efficac y/ Safet y/ La b)  .................................. 4 7  
 


EI P P har ma, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -5 0 1   
 
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
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LI S T O F T A B L E S  
Ta ble 1: Sc he d ule of Assess me nts  ................................................................................................. 1 3  
Ta ble 2: Cli nical La b orat or y A nal ytes  .......................................................................................... 2 0  
Ta ble 3: Ne ur o ps yc h ol o gical Test C o m p osites  ............................................................................. 2 4  
 
 
 


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Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -5 0 1   
 
 
 
 
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1.  
I N T R O D U C TI O N 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he pla n ne d a nal yses a n d data 
dis pla ys t o be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R) f or Pr ot oc ol EI P 1 9 -N F D -5 0 1 , 
Versi o n 1 . 0, 1 2 A pril  2 0 1 9 . 
T his S A P is a m ore detaile d c o m pa ni o n t o t he Statistical Met h o ds secti o n of t he st u d y pr ot oc ol 
a n d pr o vi des a c o m pre he nsi ve descri pti o n of t he a nal ysis  data  sets, efficac y e n d p oi nts, 
ass u m pti o ns, h o w missi n g data will be ha n dle d , as well as deta ils o n statistical met h o ds will be 
use d  t o a nal yze t he safet y a n d efficac y data.  W he n differe nces e xist i n descri pti o ns or 
e x pla nati o ns pr o vi de d i n t he pr ot oc ol a n d t his a nal ysis pla n, t he S A P pre vails. T h e d oc u me nt 
ma y e v ol ve o ver ti me;  f or e xa m ple, t o reflect t he re q uire me nts of pr ot oc ol a me n d me nts or 
re g ulat or y re q uests. T he fi nal S A P will  be fi nalize d, a p pr o ve d b y t he S p o ns or, a n d place d o n file 
bef ore data base is l oc ke d.   De viati o ns fr o m t he fi nal a p pr o ve d pla n will be n ote d i n t he cli nical 
st u d y re p ort.  
 


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Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -5 0 1   
 
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
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2.  
S T U D Y O B J E C TI V E S  
2. 1.  Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve is t o e val uate t he effect of nefla ma pi m o d o n c o g niti ve f u ncti o n as 
assesse d i n a st u d y -s pecific Ne ur o ps yc h ol o gical Test Batter y ( N T B) c o m prise d of: 
• 
C o gstate Detecti o n test ( D E T)  
• 
C o gstate I de ntificati o n test (I D N)  
• 
C o gstate O ne Car d Lear ni n g t est ( O C L) 
• 
C o gstate O ne Bac k test ( O N B)   
• 
Letter Fl ue nc y Test  ( L F T) 
• 
Cate g or y Fl ue nc y Test ( C F T)  
2. 2.  Sec o n d ar y O bjecti ve s 
•  E val uate t he effects of nefla ma pi m o d o n i nf or ma nt/careta ker e val uati o n of c o g niti o n 
a n d f u ncti o n, as assesse d b y t he Cli nical De me ntia Rati n g Scale -S u m of B o xes 
( C D R-S B).  
•  Assess t he effects of nefla ma pi m o d o n ge neral c o g niti o n, as assesse d b y t he Mi ni 
Me ntal State E xa mi nati o n ( M M S E).  
•  Assess t he effects of nefla ma pi m o d o n e pis o dic me m or y, as assesse d b y t he 
I nter nati o nal S h o p pi n g List Test (I S L T).  
•  Assess t he effects of nefla ma pi m o d o n select d o mai ns of t he 1 0 -ite m 
Ne ur o ps yc hiatric I n ve nt or y ( N PI -1 0), i ncl u di n g de pressi o n ( d ys p h oria), a n xiet y, 
hall uci nati o ns, a n d a gitati o n/a g gressi o n.  
•  E val uate t he effects of nefla ma pi m o d o n m ot or f u ncti o n as assesse d b y t he Ti me d U p 
a n d G o Test ( T U G).  
•  E val uate t he effects of nefla ma pi m o d o n q ua ntitati ve electr oe nce p hal o gra p h y ( E E G) 
para meters.   
2. 3.  E x pl or at or y Effic ac y  a n d S afet y  O bjecti ves  
I n a d diti o n, e x pl orat or y a nal yses of t he f ull set of para meters i n t he N T B  a n d ass ociate d 
c o m p osite sc ores  will be c o n d ucte d  a n d e x p os ure t o safet y relati o ns hi p will be i n vesti gate d if 
data all o w . 
 


EI P P har ma, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -5 0 1   
 
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
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3.  
S T U D Y D E SI G N  
T his is a P hase 2, m ulti -ce nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, pr o of -of - pri nci ple 
st u d y of nefla ma pi m o d vers us matc hi n g place b o (ra n d o mize d 1: 1) a d mi nistere d wit h f o o d f or 1 6 
wee ks i n s u bjects wit h d e me ntia wit h le w y b o dies (D L B ). S u bjects wei g hi n g < 8 0 k g will recei ve 
2 ca ps ules per da y (i n di vi de d d oses) a n d t h ose wei g hi n g ≥8 0 k g will recei ve 3 ca ps ules per da y 
(i n di vi de d d oses). S u bjects recei vi n g t w o ca ps ules per da y will be a d mi nistere d 1 ca ps ule, t wice 
dail y ( BI D) wit h f o o d (i.e., wit h t he m or ni n g a n d e ve ni n g meals), eit her  nefla ma pi m o d 4 0 m g or 
place b o. S u bjects recei vi n g 3 ca ps ules per da y  will be a d mi nistere d 1 ca ps ule t hree ti mes dail y 
( TI D) wit h f o o d (i.e., wit h t he m or ni n g, mi d-da y, a n d e ve ni n g meals), eit her nefla ma pi m o d 4 0 
m g or place b o. D oses s h o ul d be a d mi nistere d at least 3 h o urs a part.  
F oll o wi n g c o m pleti o n of i nf or me d c o nse nt pr oc e d ures, s u bjects will e nter t he Scree ni n g p hase of 
t he st u d y. 
O ne t o t w o Scree ni n g visits are pla n ne d, d uri n g w hic h safet y scree ni n g meas ures will be 
u n derta ke n, a practice N T B will be perf or me d, a n d t he re q uire d dia g n osis a n d c o g niti ve 
i m pair me nt will be c o nfir me d. Scree ni n g will be c o n d ucte d wit hi n 2 1 da ys bef ore Baseli ne ( Da y 
1). If a Da Tsca n ™ is re q uire d t o deter mi ne st u d y eli gi bilit y, Scree ni n g ma y be e xte n de d t o 3 5 
da ys.  
O nce eli gi bilit y is c o nfir me d a n d bef ore t he first d ose of st u d y dr u g, s u bjects w ill be ra n d o ml y 
assi g ne d o n a 1: 1 basis t o place b o or nefla ma pi m o d f or t he 1 6 -wee k treat me nt peri o d. 
I n vesti gat ors a n d s u bjects will be bli n de d t o t he treat me nt assi g n me nt. Ra n d o mize d s u bjects will 
be stratifie d b y I nter nati o nal S h o p pi n g List Test (I S L T) T otal Recall sc ore at Baseli ne ( < 2 1 vs. 
> 2 1), i.e. b y w het her  patie nts ha ve a n e pis o dic me m or y defect at baseli ne or n ot.  
S u bjects will recei ve st u d y dr u g f or 1 6 wee ks. D osi n g will start o n Da y 1 f oll o wi n g c o m pleti o n 
of all baseli ne pr oce d ures. D uri n g t he 1 6 -wee k treat me nt peri o d, s u bjects will ret ur n t o t he cli nic 
e ver y 2 wee ks f or t he first m o nt h a n d t he n e ver y 4 wee ks t hereafter. A Fi nal St u d y Visit (i.e. 
F oll o w -U p Visit) will be c o n d ucte d 2 wee ks ( +/ -3 da ys) after c o m pleti o n of st u d y dr u g or after 
t he Earl y Ter mi nati o n ( E T) visit.  
T he N T B, I S L T, a n d N PI -1 0 will be c o n d ucte d at Scree ni n g, Baseli ne ( Da y 1), Wee k 4 ( Da y 
2 8), Wee k 8 ( Da y 5 6), a n d Wee k 1 6 ( Da y 1 1 2) or E T if earl y ter mi nati o n. T he C D R -S B a n d 
T U G will be c o n d ucte d at Baseli ne ( Da y 1), Wee k 8 ( Da y 5 6), a n d Wee k 1 6 ( Da y 1 1 2) or E T. 
T he M M S E will be c o n d ucte d at Scree ni n g, Baseli ne ( Da y 1), Wee k 8 ( Da y 5 6), a n d Wee k 1 6 
( Da y 1 1 2) or E T. E E Gs will be c o n d ucte d at Baseli ne ( Da y 1) a n d Wee k 1 6 ( Da y 1 1 2) or E T. 
Sa m ples f or plas ma bi o mar kers will be o b tai ne d at Scree ni n g, Baseli ne ( Da y 1) a n d Wee k 1 6 
( Da y 1 1 2) or E T. 
  
3. 1.  S a m ple Size J ustific ati o n  
A t otal of a p pr o xi matel y 8 0 s u bjects are pla n ne d t o be e nr olle d, of w h o m 4 0 are pla n ne d t o 
recei ve nefla ma pi m o d a n d 4 0 are pla n ne d t o recei ve place b o. 
As t here is n o pri or e x perie nce wit h nefla ma pi m o d i n patie nts wit h D L B u p o n w hic h t o base 
ass u m pti o ns of treat me nt effect, n o f or mal sa m ple size calc ulati o n has bee n perf or me d. 
H o we ver, base d o n pri or e x perie nce wit h N T B i n cli nical st u dies, 4 0 s u bjects pe r treat me nt ar m 


EI P P har ma, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -5 0 1   
 
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
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s h o ul d pr o vi de a reas o na bl y r o b ust first assess me nt of w het her nefla ma pi m o d i m pr o ves 
c o g niti ve f u ncti o n i n patie nts wit h D L B.  
3. 2.  St u d y d ur ati o n a n d visit sc he d ule  
Scree ni n g wi n d o w of 2 1 da ys ( u nless Da Tsca n is re q uire d, i n w hic h case Scree ni n g  wi n d o w ma y 
be e xte n de d t o 3 5 da ys), 1 6 wee ks of treat me nt, a 2 -wee k f oll o w -u p visit f or a t otal of 2 1 wee ks 
st u d y d urati o n.  C o m plete descri pti o ns of t he assess me nts t o be perf or me d at eac h visit are  liste d 
i n Ta ble 1 . 
 
3. 3.  R a n d o miz ati o n  
After s u bjects ha ve c o m plete d t he Scree ni n g Visit a n d are dee me d eli gi ble,  t he y will be 
ra n d o mize d o n a 1: 1 basis i n a bli n de d ma n ner t o recei ve eit her place b o or 4 0 m g nefla ma pi m o d 
utili zi n g a n a ut o maticall y ge nerate d ra n d o m c o de. Ra n d o mizati o n will be stratifie d b y I S L T 
T otal Recall sc ore at Baseli ne ( <  2 1 vs.  > 2 1). Ra n d o mizati o n a n d stratificati o n will be 
a d mi nistere d via I nteracti ve Res p o nse Tec h n ol o g y (I R T). S u bjects will f oll o w t he BI D re gi me n 
if wei g hi n g < 8 0 k g or t he TI D re gi me n if wei g hi n g ≥8 0 k g. 


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T a ble 1 : Sc he d ule of Assess me nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess me nt  
St u d y Peri o d / W ee k / St u d y D a y  
 
Scree ni n g P  
 
 
Tre at m e nt Peri o d  
E arl y 
Ter mi n ati o n  
F oll o w - 
U p  
 
Scree ni n g 
V isitaP  
 
 
 
B aseli ne  
 
W ee k 
2  
 
W ee k 
4  
 
W ee k 
8  
 
W ee k 
1 2  
 
W ee k 
1 6  
 
 
E T Visit c 
 
F oll o w - 
U p V isitdP  
 
Wit hi n 2 1 - 
3 5 d a ys of 
D 1  
 
 
 
D 1 bP  
 
 
D 1 4 
( ± 3) 
 
 
D 2 8 
( ± 3) 
 
 
D 5 6 
( ± 5) 
 
 
D 8 4 
( ± 5) 
 
 
D 1 1 2 
( ± 5) 
Wit hi n  
3 d a ys after 
l ast d ose 
Wit hi n 
1 4  d a ys  
( ± 3) of  
l ast d ose 
I nf or me d C o nse nt 
X e 
P  
 
 
 
 
 
 
 
 
Me dical hist or y re vie w  
X  
 
 
 
 
 
 
 
 
Pre g na nc y testi n g  
X f 
P  
 
 
 
 
 
 
 
 
P h ysical e xa mi nati o n g  
P  
X  
 
 
 
 
 
X  
X  
X  
Vital si g ns h  
X  
X  
X  
X  
X  
X  
X  
X  
X  
He mat ol o g y a n d 
c he mistr y i 
P  
X  
X  
 
X  
X  
X  
X  
X  
 
C oa g ulati o n st u dies i 
P  
X  
 
 
 
X  
 
 
 
X  
1 2 -lea d 
electr ocar di o gra m j 
P  
X  
 
 
 
 
 
 
 
 
Da Tsca n ™, if nee de d 
X k  
 
 
 
 
 
 
 
 
C T/ M RI  
X l 
P  
 
 
 
 
 
 
 
 
C -S S R S  
X  
X  
 
X  
X  
X  
X  
X  
 
M M S E
m  
X  
X  
 
 
X  
 
X  
X  
 
N T B m , I nter nati o nal 
S h o p pi n g List Test  
(I S L T) 
X  
X  
 
X  
X  
 
X  
X  
 
C D R -S B  
 
X  
 
 
X  
 
X  
X  
 
N PI -1 0  
X  
X  
 
X  
X  
 
X  
X  
 
Ti me d U p a n d G o ( T U G)   
X  
 
 
X  
 
X  
X  
 
E E G n  
 
X  
 
 
 
 
X  
X  
 
Dis pe nse st u d y dr u g  
 
X  
X  
X  
X  
X  
 
 
 
P har mac o ki netic 
sa m pli n go  
 
 
X  
X  
X  
 
 
 
 
Plas ma sa m ple f or pr otei n 
bi o mar ker testi n g p  
X q  
X  
 
 
 
 
X  
X  
 


EI P P har ma, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -5 0 1   
 
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
1 4  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess me nt  
St u d y Peri o d / W ee k / St u d y D a y  
 
Scree ni n g P  
 
 
Tre at m e nt Peri o d  
E arl y 
Ter mi n ati o n  
F oll o w - 
U p  
 
Scree ni n g 
V isitaP  
 
 
 
B aseli ne  
 
W ee k 
2  
 
W ee k 
4  
 
W ee k 
8  
 
W ee k 
1 2  
 
W ee k 
1 6  
 
 
E T Visit c 
 
F oll o w - 
U p V isitdP  
 
Wit hi n 2 1 - 
3 5 d a ys of 
D 1  
 
 
 
D 1 bP  
 
 
D 1 4 
( ± 3) 
 
 
D 2 8 
( ± 3) 
 
 
D 5 6 
( ± 5) 
 
 
D 8 4 
( ± 5) 
 
 
D 1 1 2 
( ± 5) 
Wit hi n  
3 d a ys after 
l ast d ose 
Wit hi n 
1 4  d a ys  
( ± 3) of  
l ast d ose 
Pri or/c o nc o mita nt 
me dicati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse e ve nt rec or di n g  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Fi nal st u d y dr u g 
rec o nciliati o n 
 
 
 
 
 
 
X  
X  
 
 
C D R -S B: Cli nical De me ntia Rati n g Scale –  S u m of B o xes; C -S S R S: C ol u m bia -S uici de Rati n g Scale; C T: 
C o m p ute d t o m o gra p h y; D = da y; M M S E: Mi ni -Me ntal State E xa mi nati o n; M RI: Ma g netic res o na nce i ma gi n g; 
N PI -1 0: 1 0 -ite m Ne ur o ps yc hiatric I n ve nt or y; N T B: Ne ur o ps yc h ol o gical Test Batter y. 
 
 
a. 
O ne t o t w o Scree ni n g visits are pla n ne d d uri n g w hic h safet y scree ni n g pr oce d ures are t o be c o m plete d a n d 
re vie we d, i ncl u di n g a practice N T B a n d t he re q uire d dia g n ostic a n d c o g niti ve i m pair me nt pr oce d ures. 
Scree ni n g will be c o n d ucte d  wit hi n 2 1 da ys bef ore Baseli ne ( Da y 1); if a Da Tsca n a n d/ or M RI or C T sca n is 
re q uire d t o deter mi ne st u d y eli gi bilit y, Scree ni n g ma y be e xte n de d t o 3 5 da ys. (If necessar y, a sec o n d visit 
ma y be c o n d ucte d o n a differe nt da y t o all o w f or sc he d uli n g p ur p oses .) All scree ni n g assess me nts s h o ul d be 
c o n d ucte d wit hi n 2 1 -3 5 da ys of Da y 1 a n d ca n be c o n de nse d t o o ne  visit.  
b.  
O n Da y 1, all pr oce d ures s h o ul d be c o n d ucte d pri or t o first d ose of st u d y  dr u g.  
c. 
S u bjects w h o pre mat urel y disc o nti n ue st u d y dr u g f or a n y reas o n wi ll be as ke d t o ret ur n t o t he st u d y ce nter 
f or a n Earl y Ter mi nati o n visit wit hi n 3 da ys f oll o wi n g t he last st u d y dr u g d ose; if it is deter mi ne d t hat t he 
s u bject will disc o nti n ue st u d y dr u g w hile  at t he st u d y ce nter f or a sc he d ule d visit, t he n t he Earl y  Ter m i nati o n 
visit  s h o ul d be  c o n d ucte d at t hat  ti me. 
d.  
T he F oll o w -u p Visit s h o ul d be c o n d ucte d wit hi n 1 4 ( ± 3) da ys of t he last d ose of st u d y dr u g f or s u bjects 
w h o c o m plete t he st u d y or disc o nti n ue  earl y. 
e. 
I nf or me d c o nse nt pr oce d ures, i ncl u di n g si g ni n g of i nf or me d c o nse nt, m ust be c o m plete d bef ore a n y 
st u d y-s pecific pr oce d ures are perf or me d.  
f. 
Fe male s u bjects w h o ha ve reac he d me n o pa use i n t he pre vi o us year m ust ha ve a ser u m or uri ne pre g na nc y test 
perf or me d d uri n g Scree ni n g; s u bjects wit h p ositi ve res ults are n ot eli gi ble f or st u d y partici pati o n.  
g.  
Refer t o Secti o n  6. 2. 8 of Pr ot oc ol  f or details re gar di n g p h ysical e xa mi nati o n.  
h.  
Vital si g ns i ncl u de bl o o d press ure, p ulse, res pirat or y rate, a n d b o d y te m perat ure. Vital si g ns s h o ul d be 
meas ure d after t he s u bject has bee n i n sitti n g p ositi o n f or 5  mi n utes.  
i. 
Details of cli nical la b orat or y sa m pli n g f or c he mistr y, he mat ol o g y, a n d c oa g ulati o n st u dies are disc usse d i n Secti o n 6. 2. 1 0  
of Pr ot oc ol . 
j. 
Details of 1 2 -lea d E C G assess me nt are disc usse d i n Secti o n 6. 2. 9  of Pr ot oc ol . 
k.  
S u bjects are re q uire d t o ha ve a pri or Da Tsca n. If a Da Tsca n has n ot bee n perf or me d wit hi n t he pre vi o us 2 years, 
it  is  t o  be  perf or me d  d uri n g  Scree ni n g o nl y  after  s u bject  has  bee n  dee me d  eli gi ble  base d  o n  all  ot her 
i ncl usi o n/e xcl usi o n criteria (e. g., me dical hist or y,  la b orat or y testi n g) a n d pri or  t o ra n d o mizati o n. N ote  t hat if 


EI P P har ma, I nc. 
 
 
Statistical A nal ysis Pla n - Pr ot oc ol  # EI P 1 9 -N F D -5 0 1   
 
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
1 5  
 
 
  
 
Da Tsca n  res ults are ne gati ve  (i.e., n o  e vi de nce of  
re d uce d u pta ke i n t he basal ga n glia), t he s u bject is re q uire d t o ha ve hist orical P S G-verifie d R B D t o be eli gi ble 
f or st u d y partici pati o n.  
l. 
If M RI  or  C T  has  n ot  bee n  perf or me d wit hi n 3 years  bef ore  Scree ni n g  a n d/ or res ults are n ot  a vaila ble, M RI or  
C T  sca n m ust be perf or me d t o e xcl u de ot her disease as part of Scree ni n g o nl y after  s u bject has bee n dee me d 
eli gi ble base d o n all ot her i ncl usi o n/e xcl usi o n criteria (e. g., me dical hist or y, la b orat or y testi n g) a n d pri or t o 
ra n d o mizati o n (see Secti o n 6. 2. 2  of Pr ot oc o l). 
m.  Refer t o  Secti o n 6. 2. 4 of  Pr ot oc ol  f or details re gar di n g c o g niti ve f u ncti o n tests. 
n.  
E E G nee d n ot perf or me d at t he E T visit f or s u bjects w h o disc o nti n ue pri or t o Wee k 4 ( Da y  2 8).  
o.  
Refer t o Secti o n 6. 2. 1 1  of Pr ot oc ol  f or details re gar di n g P K sa m pli n g. 
p.  
Refer t o Secti o n 6. 2. 1 2  of Pr ot oc ol  f or details re gar di n g plas ma bi o mar ker sa m pli n g. 
q.  
O nl y plas ma A b 4 2/ 4 0 rati o is re q uire d at  Scree ni n g.  


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 1 6  of 5 0  
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C o nfi de nti al  
 
 
4.  
C LI NI C A L A S S E S S M E N T S  
All cli nical assess me nts will be c o n d ucte d b y t he I n vesti gat or or desi g nee at t he ti me p oi nts 
s pecifie d i n Ta ble 1 . 
4. 1.  B aseli ne a n d Dise ase C h ar acteristics  
Details re gar di n g D L B hist or y, i ncl u di n g met h o d(s) of dia g n osis will be c ollecte d d uri n g 
Scree ni n g, as s pecifie d i n t he e C R F. S u bjects wit h o ut d oc u me ntati o n of pri or dia g n ostic D L B 
tests ( Da Tsca n a n d/ or k n o w n a m yl oi d bi o mar ker stat us) are t o ha ve s uc h tests perf or me d duri n g 
Scree ni n g.  
4. 2.  Effic ac y / C o g niti ve Assess me nts  
C o g niti ve f u ncti o n tests i ncl u de a Ne ur o ps yc h ol o gical Test Batter y ( N T B) as well as t he Letter 
Fl ue nc y Test a n d Cate g or y Fl ue nc y Test ( C F T), w hic h are all c o m p o ne nts of t he pri mar y 
o bjecti ve/e n d p oi nt t o assess atte nti o n, e xec uti ve f u ncti o n, a n d vis u os patial f u ncti o n.  
C o g niti ve f u ncti o n tests t o be perf or me d as c o m p o ne nts of t he sec o n dar y o bjecti ve i ncl u de t he 
C D R -S B, M M S E, N PI -1 0, Ti me d U p a n d G o ( T U G), a n d I nter nati o nal S h o p pi n g Lis t Test 
(I S L T). 
At Baseli ne a n d o n a n y visits at w hic h b ot h N T B a n d ot her c o g niti ve tests are c o n d ucte d, t he 
N T B s h o ul d be perf or me d pri or t o t he ot her tests.    
4. 2. 1.  
Ne ur o ps yc h ol o gic al Test B atter y ( N T B)  
T he N T B i ncl u des:  
•  C o gstate Detecti o n test ( D E T ; Ps yc h o m otor F u ncti o n ) 
T he Detecti o n test is a meas ure of ps yc h o m ot or f u ncti o n a n d uses a well -vali date d si m ple 
reacti o n ti me para di g m wit h pla yi n g car d sti m uli. I n t his test, t he pla yi n g car ds all de pict 
t he sa me j o ker. T he s u bject is as ke d t o press t he Yes ke y as s o o n as t he car d i n t he ce nter 
of t he scree n t ur ns face u p. T he s oft ware rec or ds t he mea n reacti o n ti me (l o g 1 0 ms).  
D urati o n of Test: 2 mi n utes  
•  C o gstate I de ntificati o n test (I D N ; Atte nti o n ) 
T he I de ntificati o n test is a meas ure of vis ual atte nti o n a n d uses  a well-vali date d c h oice 
reacti o n ti me para di g m wit h pla yi n g car d sti m uli. I n t his test, t he pla yi n g car ds are all 
eit her re d or blac k j o kers. T he s u bject is as ke d w het her t he car d dis pla ye d i n t he ce nter of 
t he scree n is re d. T he s u bject res p o n ds b y pressi n g t he Yes ke y w he n t he j o ker car d is re d 
a n d N o w he n it is blac k. T he s oft ware rec or ds t he mea n reacti o n ti me (l o g 1 0 ms). 
D urati o n of Test: 2 mi n utes  
•  C o gstate O ne Car d Lear ni n g test ( O C L ; Vis ual Lear ni n g) 
T he O ne Car d Lear ni n g test is a meas ure of vis ual  lear ni n g a n d uses a well-vali date d 
patter n se parati o n para di g m wit h pla yi n g car d sti m uli. I n t his test, t he pla yi n g car ds are 
i de ntical t o t h ose f o u n d i n a sta n dar d dec k of 5 2 pla yi n g car ds ( wit h o ut t he j o ker car ds). 


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 1 7  of 5 0  
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C o nfi de nti al  
 
 
T he s u bject is as ke d w het her t he car d dis pla ye d i n t he ce nter of t he scree n was see n 
pre vi o usl y i n t his test. T he s u bject res p o n ds b y pressi n g t he Yes or N o ke y. T he s oft ware 
meas ures t he acc urac y acr oss all res p o nses (arcsi ne s qrt % c orrect). D urati o n of Test: 5 
mi n utes  
•  C o gstate O ne Bac k test  ( O N B; W or ki n g Me m or y) 
T he O ne Bac k test is a meas ure of w or ki n g me m or y a n d uses a well -vali date d n -bac k 
para di g m wit h pla yi n g car d sti m uli. I n t his test, t he pla yi n g car ds are i de ntical t o t h ose 
f o u n d i n a sta n dar d dec k of 5 2 pla yi n g car ds ( wit h o ut t he j oker car ds). T he s u bject is 
as ke d w het her t he car d dis pla ye d i n t he ce nter of t he scree n is t he sa me as t he car d 
prese nte d i m me diatel y pre vi o usl y. T he s u bject res p o n ds b y pressi n g t he Yes or N o ke y. 
Beca use n o car d has bee n prese nte d yet o n t he first trial,  a c orrect first res p o nse is al wa ys 
N o. T he s oft ware rec or ds t he mea n reacti o n ti me (l o g 1 0 ms) a n d t he acc urac y acr oss all 
res p o nses (arcsi ne s qrt % c orrect). D urati o n of Test: 3 mi n utes 
•  Letter Fl ue nc y Test: T he Letter Fl ue nc y Test is a meas ure of p h o ne mic  fl ue nc y a n d is a 
s u btest of t he M ultili n g ual A p hasia E xa mi nati o n (Be nt o n et al, 1 9 9 4 ). T he L F T uses t he 
3 - letter set of F, A, a n d S or C, F, a n d L t o assess p h o ne mic fl ue nc y. I n di vi d uals are 
gi ve n 1 mi n ute t o na me as ma n y w or ds as p ossi ble be gi n ni n g wit h  o ne of t he letters. T he 
pr oce d ure is t he n re peate d f or t he re mai ni n g t w o letters. T he a d mi nistrati o n of p h o ne mic 
a n d se ma ntic fl ue nc y ta kes a p pr o xi matel y 5 mi n utes. A d missi ble res p o nses are s u m me d 
a n d c o m pare d t o a n or mati ve sa m ple.  
•  Cate g or y Fl ue nc y Test ( C F T): T he C F T is a meas ure of ver bal fl ue nc y a n d is s o meti mes 
calle d se ma ntic fl ue nc y. I n t he sta n dar d versi o n of t he tas k, partici pa nts are gi ve n 1 
mi n ute t o pr o d uce as ma n y u ni q ue w or ds as p ossi ble wit hi n a cate g or y. T he s u bject's 
sc ore is t he n u m ber of u ni q ue c orrect w or ds.  
 
 
 
4. 2. 2.  
Cli nic al De me nti a R ati n g Sc ale –  S u m of B o xes ( C D R -S B ) 
T he Cli nical De me ntia Rati n g Scale ( C D R) ( H u g hes, 1 9 8 2 ) is a se mi-str uct ure d i nter vie w 
res ulti n g i n a se mi-q ua ntitati ve sc ori n g of c o g niti ve i m pair me nt i n mil der a n d m ore pr o gresse d 
f or ms of de me ntia. It is se nsiti ve i n b ot h A D de me ntia a n d Mil d C o g niti ve I m pair me nt, a n d is a n 
a p pr o ve d re g ulat or y e n d p oi nt rec o g nize d b y t he F D A. T he C D R yiel ds b ot h a gl o bal sc ore 
( C D R-G S) a n d S u m of B o xes sc ore ( C D R - S B). W hile t he C D R -G S is  t y picall y utilize d f or 
sta gi n g p ur p oses, t he C D R-S B sc ore is a m ore detaile d q ua ntitati ve ge neral i n de x t ha n t he C D R -
G S a n d it pr o vi des m ore i nf or mati o n t ha n t he C D R t otal sc ore i n cases of mil d de me ntia 
(O’ Br ya nt, et al, 2 0 1 0 ).  
 
 


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
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C o nfi de nti al  
 
 
 
4. 2. 3.  
Mi ni -Me nt al St ate E x a m i n ati o n ( M M S E) 
T he M M S E ( F olstei n et al, 1 9 7 5 ) c o nsists of 1 1 tests of orie ntati o n, me m or y (rece nt a n d 
i m me diate), c o nce ntrati o n, la n g ua ge, a n d pra xis. Sc ores ra n ge fr o m 0 t o 3 0, wit h l o wer sc ores 
i n dicati n g greater c o g niti ve i m pair me nt. It is base d o n t he perf or ma nce of t he s u bject a n d ta kes 
a p pr o xi matel y 5 t o 1 0 mi n utes t o a d mi nister.  
 
4. 2. 4.  
Inter n ati o n al S h o p pi n g List Test  (I S L T) 
W or d lear ni n g tests ha ve bee n c o m m o nl y utilize d t o assess e pis o dic me m or y. I n D L B, t he 
rec o g niti o n c o m p o ne nt is c o nsi dere d t o be of partic ular utilit y ( Wes nes et al, 2 0 1 5 ). T he I S L T is 
o ne s uc h w or d lear ni n g test t hat has bee n utilize d i n a n u m ber of pr o of -of -c o nce pt cli nical 
st u dies wit h n o vel t hera pe utics (Nat ha n et al, 2 0 1 3 ; Ma her -E d war ds et al, 2 0 1 5 ). I m me diate a n d 
Dela ye d Recal l (I S R L), as well as Rec o g niti o n (I S R N), will be assesse d. T he s oft ware meas ures 
t he n u m ber of c orrect res p o nses as rec or de d b y t he test s u per vis or. D urati o n of Test: 5 mi n utes. 
 
4. 2. 5.  
1 0 -ite m Ne ur o-Ps yc hi atric I n ve nt or y ( N PI -1 0 ) 
T he N PI -1 0 is desi g ne d t o assess  ps yc h o pat h ol o g y i n t he pers o n wit h de me ntia a n d t o hel p 
disti n g uis h bet wee n t he differe nt ca uses of de me ntia. T he N PI -1 0 e xa mi nes 1 0 s u b -d o mai ns of 
be ha vi oral f u ncti o ni n g: del usi o ns, hall uci nati o ns, a gitati o n/a g gressi o n, d ys p h oria, a n xiet y, 
e u p h oria, a pat h y,  disi n hi biti o n, irrita bilit y/la bilit y, a n d a berra nt m ot or acti vit y. F or t his st u d y, t he 
f oll o wi n g d o mai ns are of s pecific i nterest: de pressi o n ( d ys p h oria), a n xiet y, hall uci nati o ns, a n d 
a gitati o n/a g gressi o n. T he N PI -1 0 is a d mi nistrate d t o care gi vers of d e me ntia s u bjects. A 
scree ni n g q uesti o n is as ke d a b o ut eac h i ncl u de d s u b- d o mai n. If t he res p o nses t o t hese q uesti o ns 
i n dicate t hat t he s u bject has pr o ble ms wit h a partic ular s u b- d o mai n of be ha vi or, t he care gi ver is 
o nl y t he n as ke d all t he q uesti o ns a b o ut t hat d o mai n, rati n g t he fre q ue nc y of t he s y m pt o ms o n a 4-
p oi nt scale, t heir se verit y o n a 3 -p oi nt scale, a n d t he distress t he s y m pt o m ca uses t he m o n a 5 -
p oi nt scale ( C u m mi n gs, 1 9 9 7). T he N PI -1 0 ta kes a p pr o xi matel y 1 0 mi n utes t o c o m plete.  
 
 
4. 2. 6.  
T i me d U p a n d G o Test ( T U G) 
T he Ti me d U p a n d G o Test is desi g ne d t o assess m o bilit y. It meas ures t he ti me i n sec o n ds f or a 
pers o n t o rise fr o m sitti n g fr o m a sta n dar d ar mc hair, wal k 3 meters, t ur n, wal k bac k t o t he c hair, 
a n d sit d o w n. T he s u bject wears re g ular f o ot wear a n d  uses his/ her c ust o mar y wal ki n g ai d. A 
sc ore of > 1 5 sec o n ds i n dicates clie nt has i ncrease d ris k of falls. T he test ta kes 1 t o 2 mi n utes t o 
c o m plete. 
 


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4. 3.  Ot her Cli nic al  Assess me nts  
4. 3. 1.  
C ol u m bi a -S uici de Se verit y R ati n g Sc al e 
T he C -S S R S is a cli nicia n -a d mi nistere d i nstr u me nt t hat assesses s uici dal i deati o n a n d be ha vi or 
(P os ner et al, 2 0 1 1 ).  T he “ Baseli ne” versi o n of t he i nstr u me nt will be a d mi nistere d t o s u bjects 
d uri n g Scree ni n g a n d bef ore be gi n ni n g t he sec o n d treat me nt peri o d, a n d t he “ Si nce Last Visit” 
versi o n will be use d at all ot her ti me p oi nts s pecifie d i n  Ta ble 1 . 
4. 3. 2.  
E lectr oe nce p h al o gr a p h y ( E E G) 
Q ua ntitati ve electr oe nce p hal o gra p h y ( q E E G) will be perf or me d wit h t he s u bject a wa ke i n 
acc or da nce wit h t he 1 0 -2 0 I nter nati o nal S yste m of Electr o de place me nt at t he ti me p oi nts 
s pecifie d i n Ta ble 6-1 acc or di n g t o a sta n dar d pr ot oc ol t hat will be pr o vi de d i n a se parate E E G 
ma n ual. Sl o wi n g of t he d o mi na nt fre q ue nc y ba n d b y q E E G o ver p osteri or as pects of t he brai n 
has bee n rec o g nize d t o be pr o mi ne nt i n D L B ( Ol de D u b be li n k et al 2 0 1 3; Peraza et al, 2 0 1 8 ), 
a n d vari o us patter ns ha ve bee n i de ntifie d t o differe ntiate D L B fr o m A D. E E G has als o bee n 
rec o g nize d t o be p ote ntial bi o mar ker f or D L B i n t he m ost rece nt c o nse ns us re p ort of t he D L B 
c o ns orti u m ( Mc Keit h et al, 2 0 1 7 ). 
4. 4.  P h ysic al E x a mi n ati o n a n d Vit al Si g ns  
P h ysical e xa mi nati o n will i ncl u de a re vie w of all b o d y s yste ms a n d meas ure me nt of wei g ht, per 
eac h I n vesti gat ors sta n dar d practice. P h ysical e xa mi nati o n fi n di n gs will be d oc u me nte d i n t he 
s u bject’s s o urce d oc u me nts. 
Vital  si g ns i ncl u de meas ure me nt of bl o o d press ure, p ulse, res pirat or y rate, a n d b o d y te m perat ure. 
A n y p h ysical e xa mi nati o n fi n di n g or vital si g n meas ure me nt t hat re prese nts a w orse ni n g fr o m 
Baseli ne c o n diti o n a n d is c o nsi dere d b y t he I n vesti gat or t o be cli nical l y si g nifica nt will be 
rec or de d as a n A E.   T he ti mi n g of assess me nts ca n be f o u n d i n t he sc he d ule of assess me nts i n 
Ta ble 1 . 
4. 5.  1 2 -Le a d Electr oc ar di o gr a m  
A 1 2 -lea d E C G will be perf or me d d uri n g Scree ni n g usi n g vali date d mac hi ner y a vaila ble l ocall y 
t o eac h cli nical site. E C G para meters t o be ca pt ure d i ncl u de heart rate ( b p m), P R i nter val, Q R S 
d urati o n, Q T i nter val, c orrecte d Q T i nter val ( usi n g Fri dericia’s f or m ula), a n d R R  i nter val Eac h 
re p ort will be re vie we d b y t he I n vesti gat or or q ualifie d s u b -i n vesti gat or a n d assesse d as n or mal, 
a b n or mal –  n ot cli nicall y si g nifica nt, or a b n or mal –  cli nicall y si g nifica nt. A b n or mal, cli nicall y 
si g nifica nt fi n di n gs are t o be re p orte d as part of t he s u bject’s me dical hist or y. 
4. 6.  Cli nic al L a b or at or y Assess me nt  
Bl o o d sa m ples will be c ollecte d at t he ti me p oi nts s pecifie d i n Ta ble 1  f or assess me nt of r o uti ne 
c he mistr y a n d he mat ol o g y a nal ytes. A d diti o nal bl o o d sa m ples will be c ollecte d f or c oa g ulati o n 
st u dies at t he ti me p oi nts s pecifie d i n Ta ble 1 . Cli nical l a b orat or y fi n di n gs t hat re prese nt a 
w orse ni n g fr o m Baseli ne val ue a n d are c o nsi dere d b y t he i n vesti gat or t o be cli nicall y si g nifica nt 
will be rec or de d as a n a d verse e ve nt . Ta ble 2  lists t he a nal ytes fr o m r o uti ne c he mistr y, 


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he mat ol o g y a n d c oa g ulati o n st u dies. Cli nical la b orat or y fi n di n gs t hat re prese nt a w orse ni n g fr o m 
Baseli ne val ue a n d are c o nsi dere d b y t he i n vesti gat or t o be cli nicall y si g nifica nt will be rec or de d 
as a n a d verse e ve nt . 
 
T a ble 2 : Cli nic al L a b or at or y A n al ytes 
Ser u m C he mistr y  
He m at ol o g y  
Al b u mi n  
Differe ntial (a bs ol ute a n d perce nt):  
Al kali ne P h os p hatase  
Bas o p hils  
Ala ni ne A mi n otra nsferase ( A L T)  
E osi n o p hils  
As partate A mi n otra nsferase ( A S T)  
L y m p h oc ytes  
Bilir u bi n (t otal a n d direct)  
M o n oc ytes  
Gl uc ose  
Ne utr o p hils  
Bl o o d Urea Nitr o ge n  
Er yt hr oc ytes:  
Calci u m  
Mea n c or p usc ular he m o gl o bi n ( M C H)  
Bicar b o nate  
Mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n ( M C H C)  
C hl ori de  
Mea n c or p usc ular v ol u me ( M C V)  
T otal c h olester ol  
He m o gl o bi n  
Tri gl yceri des  
Le u k oc ytes  
Creati ni ne  
Platelets  
Ga m ma -Gl uta m yl Tra nsferase ( G G T)  C o a g ul ati o n St u dies  
  
Lactate de h y dr o ge nase ( L D H)  
P h os p hate  
 Pr ot hr o m bi n ti me  
P otassi u m  
 Partial t hr o m b o plasti n ti me 
S o di u m  
 I N R 
T otal pr otei n  
  
Uric aci d  
  
 
 
 


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4. 7.  P h ar m ac o ki netics ( P K ) 
Bl o o d sa m ples f or P K are t o be c ollecte d at t he ti me p oi nts s pecifie d i n Ta ble 1 . T he act ual 
sa m ple c ollecti o n ti me o n t he desi g nate d visit da ys is per st u d y ce nter / s u bject c o n ve nie nce. T he 
act ual sa m ple c ollecti o n date a n d ti me relati ve t o t he m ost rece nt st u d y dr u g d o se is t o be 
d oc u me nte d.  
4. 8.  B i o m ar ker Testi ng  
Plas ma sa m ples f or pr otei n bi o mar ker assess me nt are t o be c ollecte d at t he ti me p oi nts s pecifie d 
i n Ta ble 1 . S a m ples will be st ore d f or f ut ure pr otei n bi o mar ker testi n g o nce a p plica ble assa ys are 
i de ntifie d or de vel o pe d; n ote t hat s uc h sa m ples will be n ot be use d f or ge netic testi n g. 
F or p ur p oses of use d uri n g a nal ysis of t he cli nical res ults, bi o mar ker stat us ( p ositi ve/ ne gati ve ) 
will be deter mi ne d b y hist orical a m yl oi d P E T, if a vaila ble. If pri or a m yl oi d P E T is n ot a vaila ble, 
t he n bi o mar ker stat us is t o be deter mi ne d b y hist orical bi o mar ker testi n g i n C S F. If pri or C S F is 
n ot a vaila ble, t he n bi o mar ker stat us is t o be deter mi ne d b y Scree ni n g A β 4 2/ 4 0 plas ma rati o.  
 


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5.  
D E FI NI TI O N S , C O N V E N TI O N S  A N D D E RI V E D V A RI A B L E S  
5. 1.  
Defi niti o ns a n d c o n ve nti o ns  
 
A ge  
T he s u bject a ge ( years) is calc ulate d base d o n i nf or me d c o nse nt date a n d birt h date.  
 
B aseli ne  
Baseli ne is defi ne d as t he meas ure me nt pri or t o first d ose of st u d y me dicati o n at st u d y Da y 1 of 
eac h peri o d.  If f or a n y para meter t he st u d y Da y 1 pre-d ose val ue is n ot d o ne or missi n g, t he n t he 
val ue o btai ne d at a Scree ni n g visit is use d as Baseli ne.  M M S E Baseli ne is defi ne d as t he a vera ge  
val ue  of  t he S cree ni n g a n d Da y 1 visits.  
 
C o nc o mit a nt me dic ati o n  
C o nc o mita nt me dicati o ns are defi ne d as a n y me dicati o ns o n g oi n g at t he start of treat me nt or wit h 
a start date a n d ti me o n or after t he date of first st u d y me dicati o n d ose at st u d y Da y 1 t hr o u g h t he 
en d of st u d y.    A si n gle me dicati o n ma y be pri or, c o nc o mita nt a n d p ost -treat me nt.  ( See als o 
pri or me dicati o n a n d p ost -treat me nt me dicati o n i n t his secti o n.) 
 
I nf or me d c o nse nt d ate 
I nf or me d c o nse nt date is deter mi ne d b y t he c orres p o n di n g fiel d i n t he data base.  
 
Missi n g Me dic ati o n D ates  
Me dicati o ns wit h missi n g or partial start dates will be classifie d t o a n y me dicati o n assi g n me nt 
t hat t he a vaila ble i nf or mati o n all o ws.  S h o ul d a st o p date e xist, t he st o p date will be ta ke n i nt o 
acc o u nt.  F or e xa m ple, if a me dicati o n has a missi n g start da te, b ut t he st o p date is pri or t o first 
d ose date, t he me dicati o n will o nl y be classifie d as pri or.  H o we ver, if a me dicati o n has a 
missi n g start date a n d t he st o p date occ urs o n t he last da y of treat me nt, t he me dicati o n will be 
classifie d as pri or a n d c o n c o mita nt.  Si milarl y, partial starts will use t he a vaila ble data t o ai d i n 
t he classificati o n.   
If t he st o p date is missi n g or o n g oi n g, t he me dicati o n will be classifie d base d o n t he start date 
a n d t he n t o all s u bse q ue nt assi g n me nts.  If t here is partial st o p date i nf or mati o n, t he a vaila ble 
data will be use d t o ai d i n t he classificati o n.  
 
P ost -tre at me nt me dic ati o n 


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A p ost -treat me nt me dicati o n is defi ne d as a n y me dicati o n o n g oi n g or wit h a start date a n d ti me 
after t he last da y of treat me nt.   A si n gle me di cati o n ma y be pri or, c o nc o mita nt a n d p ost -
treat me nt.  ( See als o pri or me dicati o n a n d c o nc o mita nt me dicati o n i n t his secti o n) 
 
Pri or me dic ati o n  
Pri or me dicati o ns are defi ne d as a n y me dicati o ns ta ke n pri or t o first d ose of st u d y me dicati o n at 
t he be gi n ni n g of t he st u d y.    A si n gle me dicati o n ma y be pri or, c o nc o mita nt, a n d p ost-treat me nt.   
 
5. 2.  
Deri ve d V ari a bles  
5. 2. 1.  
C h a n ge fr o m B aseli ne  
C ha n ge fr o m baseli ne  is defi ne d as t he p ost-baseli ne val ue  mi n us t he baseli ne val ue. 
5. 2. 2.  
St a n d ar dize d Sc ores  Rel ati ve t o  B aseli ne Sc or e 
D ue t o t he vari o us scales a m o n g differe nt tests a n d t he nee d t o ha ve e q ual wei g hts f or deri vi n g 
c o m p osite sc ore metrics. Perf or ma nce o n eac h C o gstate test will be sta n dar dize d relati ve t o 
baseli ne data fr o m all ra n d o mize d s u bjects (i.e., t he sc ore will be c o n verte d t o a z -sc ore b y 
s u btracti n g t he st u d y sa m ple’s mea n at baseli ne fr o m t he sc ore a n d di vi di n g b y t he sta n dar d 
de viati o n ( S D) of t he st u d y sa m ple’s baseli ne).  
T he z -sc ore will be calc ulate d as f oll o ws: 
! −# $ % & '  (! ! "#) =
, - ! "# −- ̅.% # /
0 .% #
∗2 3456 746 $ 8 9  
W here:  
t = i s t h e C o g st at e t e st i n di c at or 
i = i n d e x e s s u bj e ct i 
j = i n d e x e s t h e jt h a s s e s s m e nt ( vi sit) 
x = c o g niti v e s c or e  
! ̅." #  = m e a n p erf or m a n c e s c or e of t h e st u d y s a m pl e’ s b a s eli n e f or t e st  t                     
# ." #  = St a n d ar d D e vi ati o n of t h e st u d y s a m pl e’ s b a s eli n e f or t e st t 
T he m ulti plica n d e q uals 1 f or tests f or w hic h a hi g her sc ore is i n dicati ve of better c o g niti ve 
perf or ma nce (i.e., I S L T, I S R L, I S R N, O C L , O N B acc urac y) a n d -1 f or tests w here a l o wer sc ore 
is i n dicati ve of better c o g niti ve perf or ma nce (i.e., D E T, I D N, O N B s pee d). 
 
 


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5. 2. 3.  
C o m p osite O utc o me Me as ures Deri ve d fr o m t he I n di vi d u al Tests   
T he st u d y pri mar y o utc o me is a n Atte nti o nal/ E xec uti ve / Vis u os patial C o m p osite ( N T B) sc ore 
w h ic h will c o nsist of t he D E T, I D N, O C L, O N B acc urac y, Cate g or y Fl ue nc y ( C F T) a n d Letter 
Fl ue nc y  ( L F T).  T he calc ulati o n C o m p osite sc ore is t he a vera ge of Z-sc ores fr o m t he c o m p o ne nt 
of t he c o m p osite tests.  
In a d diti o n t o t his N T B  c o m p osite sc ore, a series o f e n d p oi nts (e x pl orat or y  c o m p osite sc ores) 
will be c o m p ute d i n or der t o facilitate u n dersta n di n g of t he effects of t he st u d y dr u g o n differe nt 
as pects of c o g niti o n w he n c o m bi ne d.  
T hese pri mar y a n d e x pl orat or y c o m p osite sc ores are as defi ne d i n Ta ble 3 .  
 
T a ble 3 : Ne ur o ps yc h ol o gic al Test C o m p osites  
C o g niti v e 
C o m p o sit e N a m e  
T e st s I n cl u d e d  
N u m b er of 
T e st s wit h 
D at a t o 
C o m p o sit e  
T h e or eti c al r ati o n al e f or c o m p o sit e  
Pri m ar y  
D E T, I D N, O C L, 
L F T, C F T, O N B 
( a c c ur a c y) 
4 o ut of 6  
Pri m ar y e n d p oi nt f or t h e st u d y  
Att e nti o n  
D E T, I D N  
2 o ut of 2  
All o w s u n d er st a n di n g of t h e eff e ct of t h e 
dr u g o n att e nti o n al f u n cti o n s s p e cifi c all y  
E x e c uti v e F u n cti o n  
L F T, C F T, O N B 
( a c c ur a c y) 
3 o ut of 3  
All o w s u n d er st a n di n g of t h e eff e ct of t h e 
dr u g o n e x e c uti v e f u n cti o n s s p e cifi c all y  
L e ar ni n g a n d 
M e m or y  
O C L, I S L T, I S R L  
3 o ut of 3  
All o w s u n d er st a n di n g of t h e eff e ct of t h e 
dr u g o n m e m or y f u n cti o n s s p e cifi c all y  
G e n er al 
N e ur o p s y c h ol o gi c al  
D E T, I D N, L F T, 
C F T, O N B 
( a c c ur a c y), O C L, 
I S L T, I S R L 
6 o ut of 8  
C a n pr o vi d e a n i n d e x of t h e e xt e nt t o 
w hi c h a n y e x p eri m e nt al eff e ct s o b s er v e d 
o n t h e pri m ar y o ut c o m e, w o ul d b e 
i m pr o v e d b y t h e si m ult a n e o u s 
c o n si d er ati o n of m e m or y  
G e n er al O v er all  
D E T, I D N, L F T, 
C F T, O N B 
( a c c ur a c y), O C L, 
I S L T, I S R L, M M S E 
6 o ut of 9 a n d 
m u st i n cl u d e t h e 
M M S E  
All o w s a n u n d er st a n di n g of t h e e xt e nt t o 
si m ult a n e o u s c o n si d er ati o n of g e n er al 
c o g niti v e f u n cti o n m e a s ur e d u si n g t h e 
M M S E will eit h er i m pr o v e or r e d u c e a n y 
e x p eri m e nt al eff e ct s o b s er v e d  


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D L B -P A C C  
D E T, O N B 
( a c c ur a c y), L F T, 
M M S E  
3 o ut of 4   
T h e P A C C  s c or e h a s r e c ei v e d s o m e 
a p pr o v al f or u s e i n Al z h ei m er’ s di s e a s e 
cli ni c al tri al.  T h e P A C C s c or e d e v el o p e d 
f or A D i n cl u d e s t w o m e a s ur e s of 
m e m or y, o n e of e x e c uti v e f u n cti o n a n d 
M M S E.  H e n c e t hi s e x pl or ati o n i s ai m e d 
at a s ki n g w h et h er a si mil ar a p pr o a c h t o 
D L B, w h er e t h e a s s e s s m e nt of g e n er al 
c o g niti o n ( M M S E) i s c o m bi n e d wit h 
m e a s ur e s of att e nti o n a n d e x e c uti v e 
f u n cti o n, gi v e n t h eir c e ntr alit y t o 
n e ur o p s y c h ol o gi c al m o d el s of D L B.   
P A C C : Pr e cli ni c al Al z h ei m er C o g niti v e C o m p o sit e  
 
 


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6.  
A N A L Y SI S P O P U L A TI O N S  
6. 1.  
S afet y  P o p ul ati o n  
T he safet y p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve at least 1 d ose of st u d y 
dr u g.  
6. 2.  
E v al u a ble  Effic ac y P o p ul ati o n (E E P ) P o p ul ati o n  
T he E val ua ble Efficac y P o p ulati o n ( E E P) p o p ulati o n will be all s u bjects w h o ha ve a baseli ne a n d 
at least o ne o n -st u d y assess me nt of t he efficac y para meter.  
6. 3.  
C o m pleter  P o p ul ati o n  ( C P) 
T he C o m pleter P o p ulati o n will be s u bjects w h o ha ve c o m plete d 1 6 wee ks of trea t me nt.    
6. 4.  
P h ar m ac o ki netics ( P K) P o p ul ati o n  
T he P har ma c ok inetics ( P K) P o p ulati o n i ncl u des all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y dr u g i n nefla ma pi m o d treat me nt gr o u p a n d ha d at least o ne meas ura ble p ost -
d ose P K data assess me nt.  
 
 


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7.  
D A T A M A N G E M E N T , R E VI E W  A N D P R E E S E N T A TI O N  
7. 1.  D at a M a n a ge me nt  a n d Q u alit y Ass ur a nce  C o nsi der ati o ns  
7. 1. 1.  
Ge ner al C o nsi der ati o ns  
T his st u d y will e m pl o y  electr o nic case re p ort f or ms ( eC R Fs ). T he site will be trai ne d o n s pecific 
f or ms a n d pr oce d ures f or s o urce d oc u me ntati o n a n d mai nte na nce of a n a u dit trail of t he data t hat 
is e ntere d o n t he eC R F pri or t o st u d y i nitiati o n.  
St u d y pers o n nel at eac h site will e nter data fr o m s o urce d oc u me nts c or res p o n di n g t o a s u bject’s 
visit o nt o t he pr ot oc ol -s pecific eC R F  w he n t he i nf or mati o n c orres p o n di n g t o t hat visit is 
a vaila ble. 
T he I n vesti gat ors will pre pare a n d mai ntai n a de q uate a n d acc urate s o urce d oc u me nts desi g ne d t o 
rec or d all o bser vati o ns a n d ot her perti ne nt data f or eac h s u bject treate d wit h t he st u d y dr u g.  
T he I n vesti gat or is res p o nsi ble f or all i nf or mati o n c ollecte d o n s u bjects e nr olle d i n t his st u d y. All 
data c ollecte d d uri n g t he c o urse of t his st u d y m ust be re vie we d a n d verifie d f or c o m plete ness  
a n d acc urac y b y t he I n vesti gat or.  
S u bjects a n d site pers o n nel ass ociate d wit h st u d y c o n d uct will be bli n de d t o treat me nt 
assi g n me nt. Treat me nt c o des will be pr o vi de d i n seale d e n vel o pes t o t he site a n d will be st ore d 
b y t he p har macist or desi g nee.  
D uri n g t he c o n d uct of t he st u d y, t he bli n d s h o ul d be br o ke n o n a n i n di vi d ual s u bject basis i n t he 
e ve nt of a n e mer ge nc y w here it is necessar y f or t he I n vesti gat or t o k n o w w hic h treat me nt t he 
s u bject is recei vi n g bef ore t he s u bject ca n be treate d. T he c o de ma y als o be br o ke n if s o me o ne 
n ot i n t he st u d y uses st u d y dr u g (e. g., if a c hil d i n t he partici pa nt’s h o use h ol d ta kes st u d y dr u g, 
t he bli n d ma y be br o ke n t o deter mi ne treat me nt f or t he c hil d.) 
Q ueries will be iss ue d f or a n y i nc o nsiste ncies, o missi o ns, a n d discre pa ncies a n d will be res ol ve d 
b y t he a p pr o priate parties.  
Data base l oc k will occ ur o nce q ualit y ass ura nce pr oce d ures ha ve bee n c o m plete d.  
All A Es will be c o de d usi n g t he latest versi o n of t he Me dical Dicti o nar y f or Re g ulate d Acti vities 
( Me d D R A). C o nc omita nt me dicati o ns will be c o de d usi n g t he latest versi o n of t he W orl d Healt h 
Or ga nizati o n Dr u g Dicti o nar y.  
All pr oce d ures f or t he ha n dli n g a n d a nal ysis of data will be c o n d ucte d usi n g g o o d c o m p uti n g 
practices meeti n g U nite d States F o o d a n d Dr u g A d mi nistra ti o n ( F D A), E ur o pea n Me dici nes 
A ge nc y, a n d I C H g ui deli nes f or t he ha n dli n g a n d a nal ysis of data f or cli nical st u dies. Data 
ma na ge me nt details will be o utli ne d i n a se parate data ma na ge me nt pla n . 
7. 1. 2.  
 Q u alit y Ass ur a nce f or C o gst ate C o m p uterize d Tests   
Data fr o m  t he C o gstate Batter y will be c ollecte d o n c o m p uters at site(s) a n d u pl oa de d t o t he 
C o gstate data base f or pr ocessi n g. C o gstate data ma na ge me nt staff will q uer y a n y data 
discre pa ncies. Q ueries will be c o nfir me d a n d res ol ve d wit h t he s p o ns or.  
 


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F or eac h of t h e C o gstate tests, s u bjects m ust pr o vi de s ufficie nt res p o nses t o all o w c o m p utati o n 
of relia ble perf or ma nce meas ures. F or t he maj orit y of C o gstate tests, t he ter m “s ufficie nt” has 
bee n defi ne d as a Test C o m pleti o n criteri o n. T he n u m ber of trials re q uire d f or  Test C o m pleti o n 
is u ni q ue t o eac h test. T he y d o n ot var y f or differe nt patie nt gr o u ps or st u d y sa m ples. 
 
Test C o m pleti o n Criteri a  
T he c o m pleti o n criteria set f ort h a pri ori f or eac h test were as f oll o ws:  
•  D E T: T he s u bject pr o vi de d 1 0 0 % of t he c orrect res p o nses re q uire d f or t he test t o 
c o m plete 
•  I D N: T he s u bject pr o vi de d 1 0 0 % of t he c orrect res p o nses re q uire d f or t he test t o 
c o m plete 
•  O C L: T he s u bject perf or me d 1 0 0 % of t he trials  
•  O N B: T he s u bject pr o vi de d 1 0 0 % of t he c orrect res p o nses re q uire d f or t he test t o 
c o m plete 
•  I S L T: All w or ds were prese nte d t o t he s u bject o n eac h of t he lear ni n g trials a n d t he 
s u bject atte m pte d t o recall t he w or ds o n t he s h o p pi n g list 
•  I S R L: T he s u bject atte m pte d t o recall t he w or ds o n t he s h o p pi n g list prese nte d t o t he m 
pre vi o usl y A N D m et c o m pleti o n criteria o n t he I S L T  
•  I S R N: T he s u bject atte m pte d res p o nses t o t he w or ds prese nte d t o t he m d uri n g t he 
rec o g niti o n trial A N D met c o m pleti o n criteria o n t he I S L T 
 
Test perf or m a nce criteri a  
Test perf or ma nce criteria reflects t he e xte nt t o w hic h p erf or ma nce o n a test s u g gests t hat t he 
s u bject was res p o n di n g i n acc or da nce wit h t he test re q uire me nts. I n ot her w or ds, w he n a 
partic ular test a d mi nistrati o n d oes n ot meet criteria f or test perf or ma nce it s u g gests t hat t he 
o bser ve d sc ore ma y n ot be re prese ntati ve of t he st u d y p o p ulati o n or t he effect of a c o m p o u n d 
u n der i n vesti gati o n.  
T he criteria f or test perf or ma nce are deri ve d b y t he C o gstate Scie nce Tea m s uc h t hat w he n 
trai ne d a n d s u per vise d a p pr o priatel y, s u bjects fr o m t he rele va nt st u d y p o p ulati o n s ho ul d 
t y picall y ac hie ve t he criteria. 
T he perf or ma nce criteria set f ort h a pri ori f or eac h test were as f oll o ws:  
 
•  D E T: T he s u bject pr o vi de d > 3 0 % of t he c orrect res p o nses  
•  I D N: T he s u bject pr o vi de d > 3 0 % of t he c orrect res p o nses 
•  O C L: T he s u bject pr o vi de d > 3 0 % of t he c orrect res p o nses  
•  O N B: T he s u bject pr o vi de d > 3 0 % of t he c orrect res p o nses  


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7. 2.  D at a Prese nt ati o n  
T he data will be prese nte d i n sta n dar d i n di vi d ual s u bject data listi n gs. T he listi n gs will i ncl u de 
s u bject i de ntificati o n n u m ber, de m o gra p hics , a n d treat me nt. Selecte d listi n gs will be i ncl u de d i n 
t he Cli nical St u d y Re p ort. I n data s u m maries, descri pti ve statistics ( n, arit h metic mea n, sta n dar d 
de viati o n [ S D], me dia n, l o wer a n d u p per q uartiles, mi ni m u m a n d ma xi m u m val ues) will be 
pre se nte d f or c o nti n u o us varia bles. C o u nts a n d perce nta ges will be prese nte d f or cate g orical 
varia bles.  
 
 
7. 3.  I nteri m D at a Re vie w 
A n  i nteri m safet y a n d efficac y a nal ysis is n ot  pla n ne d.   After all patie nts ha ve c o m plete d t heir 
treat me nt a n d t heir data are e ntered, a n u n bli n de d a d mi nistrati ve a nal ysis  of t he pri mar y efficac y 
para meters as well as C D R -S B, I S L T a n d M M S E will be perf or me d f or  pla n ni n g  p ur p oses.  


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8.  
S T A TI S T SI C A L M E T H O D O L O G Y  
All statistical a nal yses will be perf or me d usi n g S -P L U S ( Versi o n 8. 2) , R ( Versi o n 3. 6. 3 or 
hi g her) or S A S ( Versi o n 9. 3 or hi g her) .   T he versi o n e m pl o ye d at t he st u d y start will be 
mai ntai ne d t hr o u g h o ut t he pr oject.  
8. 1.  Ge ner al St atistic al Met h o d ol o g y  
Data will be ta b ulate d b y treat me nt gr o u p  b y st u d y peri o d , wit h data listi n gs pr o vi ded f o r all data 
ca pt ure d i n t he eC R F i ncl u di n g la b ora t or y data.  O n-treat me nt data will be assesse d descri pti vel y 
as b ot h o bser ve d val ues a n d as c ha n ges fr o m  baseli ne .  W he n ta b ulate d, data will be prese nte d 
usi n g descri pti ve statistics .  M ost c o nti n u o us data will be s u m marize d wit h t he f oll o wi n g 
descri pti ve statistics u nless ot her wise n ote d: n u m ber of o bser vati o ns, mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m; i nter q uartile ra n ges will be pr o vi de d as a p pr o priate.  
Cate g orical data will be s u m marize d w it h fre q ue ncies a n d perce nta ges. 
Missi n g data will n ot be i m p ute d u nless ot her wise d oc u me nte d i n t his S A P. U nless state d 
ot her wise, statistical tests c o n d ucte d will be t w o-si de d at a le vel of 0. 0 5. N o a dj ust me nt f or 
m ulti plicit y will be ma de.  
T w o -sa m ple t-test will be use d t o test t he differe nce bet wee n treat me nts  if t he tar get metric is 
n or mall y distri b ute d ( s y m metrical distri b ut e d at t he mi ni mal), ot her wise, t he n o n para metric 
a p pr oac h -Wilc o x o n si g ne d ra n k test will be use d . 
S o me e x pl orat or y e n d p oi nts ma y als o be a nal yze d usi n g a nal ysis of c o varia nce, t -test, Wilc o x o n 
si g n ra n k test or as descri pti ve s u m maries. T here will be n o c orrecti o n t o be ma de f or m ulti ple 
c o m paris o ns beca use of t he e x pl orat or y nat ure of t he data.  A nal ysis of cate g orica l e x pl orat or y 
e n d p oi nts ma y be perf or me d usi n g c hi -s q uare tests.   
A d diti o nal e x pl orat or y a nal yses ma y be perf or me d t o f urt her st u d y t he effects of t he treat me nt, 
as data warra nte d.  S u b gr o u p a nal yses will be perf or me d if data per mit.  S u b gr o u p ca n be defi n e d 
b y disease se verit y, se x ( male/fe male), a ge ( dic h ot o mize d at pretreat me nt me dia n a ge), race 
( W hite vs. n o n-W hite, His pa nic vs. n o n -His pa nic), a n d/ or ot her gr o u pi n g c o variates.  
F or ma n y varia bles, b ot h a bs ol ute a n d perce nt c ha n ge fr o m pre -treat me nt assess me nts mi g ht  be 
perf or me d  if data per mitte d.  All data c ollecte d a n d ca pt ure d i n t he eC R F will be i ncl u de d i n data 
listi n gs s orte d b y treat me nt, patie nt, st u d y peri o d a n d ti me p oint, or as a p pr o priate.   
 
8. 2.  
Prese nt ati o n of Effic ac y Me as ures  
Gra p hical prese ntati o n : 
T he ti me -c o urse of efficac y meas ures will be pl otte d f or eac h s u bject  f or b ot h peri o ds. T he 
c ha n ge fr o m baseli ne of effica c y meas ures b y peri o d (treat me nt) will be pl otte d via  b o x pl ot . T he 
distri b uti o n of differe nce of c ha n ge fr o m baseli ne b y treat me nt (n efla ma pi m o d  –  place b o) will be 
pl otte d eit her via scatter pl ot or b o x pl ot . 
 
Ta b ular prese ntati o n : 


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T he i n di vi d ual val ues a n d descri pti ve statistics f or efficac y meas ures will be s u m marize d b y 
peri o d/ treat me nt a n d b y visit. 
8. 3.  S u bject  Dis p ositi o n  
A ta b ulati o n of s u bject dis p ositi o n will be prese nte d b y treat me nt a n d o verall, i ncl u di n g t he 
n u m ber i n eac h a na l ysis p o p ulati o n, t he n u m ber t hat c o m plete d t he st u d y, t he n u m ber l ost t o 
f oll o w-u p, t he n u m ber t hat wit h dre w pri or t o c o m pleti n g t he st u d y, a n d reas o n(s) f or wit h dra wal.  
8. 4.  Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns a n d vi olati o ns n ote d d uri n g cli nical m o nit ori n g are e ntere d i nt o a trial 
ma na ge me nt  data base.  I m p orta nt pr ot oc ol de viati o ns t hat c o ul d p ote ntiall y i nfl ue nce st u d y 
o utc o mes will be liste d.  T hese ma y i ncl u de de viati o ns fr o m i ncl usi o n a n d e xcl usi o n criteria, 
recreati o nal dr u g use, pr o hi bite d c o nc o mitant me dicati o ns, i nc orrect treat me nt d osi n g, visit 
wi n d o wi n g  de viati o ns.  S pecificall y, wi n d o wi n g de viati o ns be y o n d +/ - 7 da ys fr o m t he 
sc he d ule d (tar get) st u d y da y will be liste d i n t he pr ot oc ol de viati o n data listi n g.   
8. 5.  Missi n g V al ues  
S u bjects wit h i nc o m pl ete data will be i ncl u de d i n a nal yses, c o ntri b uti n g as m uc h as is a vaila ble 
f or a n y gi ve n e n d p oi nt. F or A E, missi n g dates will n ot be i m p ute d; h o we ver,  if partial dates are 
a vaila ble, t he y will be use d t o assess w het her t he A E occ urre d d uri n g t he treat me nt  peri o d. 
Missi n g se verities of A Es will be c o nsi dere d i n a n y ta b ulati o ns of A E se verit y.   
D ue t o t he i m pact of C O VI D -1 9 pa n de mic o n data c ollecti o n, t here are s o me s u bjects w h o ha d 
wee k 8 efficac y assess me nt b ut n o wee k 1 6 assess me nts w hile c o m pleti n g st u d y treat me nt. 
I m p utati o n strate g y f or t his sit uati o n is detaile d i n t he efficac y a nal ysis secti o n.  
8. 6.  S u b gr o u ps  
S u b gr o u ps ma y  be defi ne d b y baseli ne disease se verit y, ge n der ( male/fe male), a ge 
( dic h ot o mize d at pre-treat me nt me dia n a ge), a n d race ( W hite vs N on -W hite, His pa nic  vers us 
n o n -His pa nic ).  S o me e x pl orat or y  o utc o me a nal yses mi g ht be assesse d b y p ost -h oc s u b gr o u ps as 
dictate d b y data.    
8. 7.  C o m pli a nce   
St u d y dr u g co m plia nce will be assesse d via ta blet c o u nts.  A ta b ulati o n of perce nt c o m plia nce 
will be pr o vi de d, w here perce nt c o m plia nce will be deri ve d as:  
•  T otal n u m ber of ta blets dis pe nse d mi n us t otal n u m ber ta blets ret ur ne d, di vi de d b y t he 
E X P E C T E D n u m ber of ta blets ( base d o n t he n u m ber of da ys fr o m first d ose t o last 
d ose ).    
•  Patie nts w h o d o n ot ha ve t he last d ose date or ha ve missi n g ca ps ule c o u nts of st u d y 
me dicati o n will n ot be i ncl u de d i n t his calc ulati o n of c o m plia nce.  
•  Patie nts wit h a c o m plia nce t hat is calc ulate d t o be o ver 1 0 0 % will ha ve t heir 
c o m plia nce set t o 1 0 0 %.  


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T he n u m ber ( %) of patie nts wit h c o m plia nce wit hi n eac h of t he f oll o wi n g i nter vals will be 
deri ve d:  
• 
9 5 -1 0 0 %  
• 
9 0 -< 9 5 %  
• 
8 5 -< 9 0 %  
• 
8 0 -< 8 5 %  
• 
7 5 -< 8 0 %  
• 
7 0 -< 7 5 %  
• 
< 7 0 %  
  
8. 8.  B aseli ne S u bject D at a  a n d Dise ase C h ar acteristics A n al yses  
F or t h ose patie nts missi n g a pre -treat me nt val ue ( Da y 1) f or a partic ular para meter, t he scree ni n g 
val ue ma y be use d as t he baseli ne val ue f or t hat para meter.  
Scree ni n g data, de m o gra p hic c harac teristics, a n d baseli ne c o g niti ve assess me nts  will be 
prese nte d usi n g s u m mar y statistics b y treat me nt.  
Baseli ne cate g orical  varia bles will be i nfere ntiall y assesse d via a c hi s q uare test, w hile baseli ne 
c o nti n u o us o utc o mes will be i nfere ntiall y assesse d via Wilc o x o n ra n k s u m test bet wee n place b o 
a n d acti ve  treat me nts.   Me dical hist or y data will be ta b ulate d a n d liste d.  
 
8. 9.  
Effi c ac y A n al yses  
8. 9. 1.  
Pri m ar y Effic ac y A n al ysis  
T he pri mar y e n d p oi nt is t he st u d y-s pecific N T B ( Atte nti o nal/ E xec uti ve / Vis u os patial C o m p osite ) 
sc ore w hic h will c o nsist of t he D E T, I D N, O C L, O N B acc urac y, Cate g or y Fl ue nc y ( C F T) a n d 
Letter Fl ue nc y  (details i n Secti o n 5. 2. 3 ). T he pri mar y efficac y a nal ysis will be usi n g Mi xe d 
M o del f or Re peate d Meas ures ( M M R M) a nal ysis met h o d  wit h c ha n ge fr o m baseli ne of 
Atte nti o nal/ E xec uti ve / Vis u os patial C o m p osite  as t he de pe n de nt varia ble . T here is a fi xe d effect 
o n  treat me nt a n d ma y be e xte n de d t o ot her c o variates  (i.e. baseli ne c o m p osite sc ore , st u d y visit , 
patie nt c haracteristics ).  T he i nteracti o n ter m (i.e.  sc he d ule d visit b y treat me nt ) will be 
c o nsi dere d.  T he ra n d o m effect fact or is s u bject.   
D ue t o t he i m pact of C O VI D -1 9 pa n de mic o n data c ollecti o n, t here are s o me s u bjects w h o ha d 
wee k 8 assess me nt b ut n o wee k 1 6 assess me nts w hile c o m pleti n g st u d y treat me nt. I n or der t o 
e val uate t he i m pact of patie nts w h o c o m plete d treat me nt b ut di d n ot ha ve a wee k 1 6 N T B 
assess me nt, i m p utati o n tec h ni q ue will be use i n C o m pleter P o p ulati o n t o acc o m m o date 
de viati o ns occ urri n g d ue t o C O VI D -1 9 ill ness a n d/ or C O VI D -1 9 c o ntr ol meas ures . T he first will 
be a n A N C O V A a nal ysis at wee k 1 6 a n d t he sec o n d will be a tre n d a nal ysis at wee k 1 6 f or 
place b o vs. BI D patie nts vs. TI D patie nts usi n g t he J o nc kere -Ter pstra test. Si n gle a n d m ulti ple 


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i m p utati o n a p pr oac hes will be use d (i.e. t he last o bser vati o n will be carrie d f or war d ( L O C F) a n d 
m ulti ple i m p ute d val ues usi n g val ues deri ve d fr o m M M R M m o del ). 
T he a nal yses res ults f oll o wi n g t he i m p utati o n  a p pr oac hes  will be s u m marize d t o assess 
se nsiti vit y of t he esti mates of treat me nt effect . 
Descri pti ve statistics of t he o bser ve d val ues a n d c ha n ge fr o m baseli ne will be prese nte d b y 
treat me nt gr o u p a n d visit. 
 
8. 9. 2.  
A n al ysis of t he Sec o n d ar y  Effic ac y E n d p oi nts  
 
Sec o n dar y efficac y e n d p oi nts are:  
• 
C ha n ge i n C D R -S B i n nefla ma pi m o d -treate d s u bjects c o m pare d t o place b o -reci pie nts. 
• 
C ha n ge i n M M S E i n nefla ma pi m o d -treate d s u bjects c o m pare d t o place b o -reci pie nts. 
• 
C ha n ge i n N PI -1 0 d o mai ns i n nefla ma pi m o d -treate d s u bjects c o m pare d 
t o place b o- reci pie nts. 
•  
C ha n ge i n I S L T i n nefla ma pi m o d -treate d s u bjects c o m pare d t o place b o -reci pie nts. 
•  
C ha n ge i n Ti me d U p a n d G o  Test.  
•  
C ha n ge i n E E G  para meters.  
T he A N C O V A  a nal ysis will be a p plie d f or t he a nal yses of t he c ha n ge i n  t he sec o n dar y efficac y 
e n d p oi nts if t he tar get e n d p oi nt has at least 2 p ost -d ose meas ure me nts .  F or a n y e n d p oint t hat has 
o nl y o ne p ost -d ose meas ure me nts ( Wee k 1 6), t he n t w o-sa m ple t-test will be use d t o test t he 
mea n differe nce  bet wee n treat me nt if t he tar get metric is s y m metrical at mi ni mal.  Ot her wise, t he 
n o n para metric a p pr oac h -Wilc o x o n si g ne d ra n k test will be use d t o test t he me dia n differe nce  
bet wee n treat me nt . 
Data will be ta b ulate d b y visit  a n d b y treat me nt.  A d diti o nal e x pl orat or y a nal yses , as state d i n 
Secti o n 8. 1 , ma y be perf or me d t o f urt her st u d y t he effects of t he treat me nt  gi ve n  data warra nte d . 
 
8. 9. 3.  
A n al ysis of t he e x pl or at or y  Effic ac y E n d p oi nts  
T he e x pl orat or y efficac y c o m p osite meas ures are liste d i n Ta ble 3 .  2 -sa m ple t-test will be use d 
t o test t he mea n differe nce of eac h e x pl orat or y efficac y c o m p osite metric bet wee n treat me nt at 
eac h visit if t he tar get metric is s y m metrical at mi ni mal.  Ot her wise, t he n o n para metric a p pr oac h 
-Wilc o x o n si g ne d ra n k test will be use d t o test t he me dia n differe nce .  
Descri pti ve a nal yses will be perf or me d t o descri be t he f ull set of e x pl orat or y efficac y c o m p osite 
meas ures .  
A d diti o nal e x pl orat or y a n d s u b gr o u p a nal yse s, as state d i n Secti o n 8. 1 , ma y be perf or me d t o 
f urt her st u d y t he effects of t he treat me nt as dictate d b y data.  
 


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8. 9. 4.  
A n al ysis of Pl as m a Bi o m ar kers  
T here is n o bi o mar k er a nal ysis pla n ne d.  
 
8. 9. 5.  
S u m m ar y of Re as o ns f or Effic ac y N o n -e v al u a bilit y/ E xcl usi o n fr o m Effic ac y 
A n al yses  
All n o n -e val ua ble or e xcl usi o n val ues fr o m efficac y a nal yses will be liste d a n d ta b ulate d b y 
st u d y visit a n d b y treat me nt . 
 
8. 1 0.  
P h ar m ac o ki netic A n al ysis  
C o nce ntrati o n d ata will be ta b ulate d b y visit a n d b y d osi n g re gi me n ( TI D or BI D) .  
 
8. 1 1.  
S afet y a n d T oler a bilit y A n al yses  
8. 1 1. 1.  
Ge ner al S afet y A n al ysis Met h o ds  
Safet y a n d t olera b ilit y will be e val uate d usi n g descri pti ve sta tistics a n d listi n gs of a d verse e ve nts, 
cli nical safet y la b orat or y test val ues, vital si g ns, wei g ht, b o d y te m perat ure, E C Gs a n d ot her 
safet y para meters. Safet y o utc o mes will be prese nte d f or t he safet y p o p ulati o n.   
A nal yses of A Es will be perf or me d f or t h ose e ve nts t hat are  c o nsi dere d treat me nt e mer ge nt, 
w here treat me nt e mer ge nt is defi ne d as a n y A E wit h o nset ( or w orse ni n g of a pre -e xisti n g 
c o n diti o n) after t he first d ose of treat me nt.  A d verse e ve nts wit h partial dates will be assesse d 
usi n g t he a vaila ble date i nf or mati o n t o deter mi ne treat me nt-e mer ge nt stat us.  A d verse e ve nt s wit h 
c o m pletel y missi n g dates will be ass u me d t o be treat me nt e mer ge nt.  
A d verse e ve nts will b e s u m marize d b y visit  a n d treat me nt, usi n g s u bject i nci de nce rates; 
t heref ore, i n a n y ta b ulati o n, a s u bject c o ntri b utes o nl y o nce t o t he c o u nt f or a gi ve n A E 
( preferre d ter m) per treat me nt.  Se parate ta b ulati o ns will be pr o d uce d f or all T E A Es, treat me nt-
relate d A Es (t h ose c o nsi dere d b y t he i n vesti gat or as p ossi bl y st u d y dr u g relate d), S A Es, a n d 
disc o nti n uati o ns d ue t o A Es.  B y s u bject listi n gs will be pr o vi de d f or a n y deat hs, S A Es, a n d A Es 
lea di n g t o disc o nti n uati o n of treat me nt. 
N o f or mal h y p ot hesis testi n g of A E i nci de nce rates will be perf or me d.  
8. 1 1. 2.  
R o uti ne La b orat or y Data  
F or place b o a n d nefla ma pi m o d  treat me nt gr o u ps, t he act ual val ue a n d c ha n ge fr o m baseli ne t o 
eac h o n-st u d y e val uati o n will be s u m marize d f or eac h cli nical la b orat or y para meter.  Cli nicall y 
si g nifica nt la b orat or y val ues ma y be prese nte d i n a se parate data listi n g.   
8. 1 1. 3.  
Vital Si g ns  a n d P h ysical E xa mi nati o n 
Act ual val ues a n d c ha n ges fr o m baseli ne t o eac h o n -st u d y e val uati o n will be s u m marize d b y visit  
a n d treat me nt f or vital si g ns.  P h ysical e xa mi nati o n fi n di n gs will be ta b ulate d a n d s u m marize d 


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 3 5  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
b y visit a n d treat me nt.  T he n u m ber of s u bjects  wit h p ote ntiall y cli nicall y si g nifica nt ( P C S) 
c ha n ges i n vital si g ns will be ta b ulate d.  P ote ntiall y cli nicall y si g nifica nt t hres h ol ds will be 
defi ne d pri or t o brea ki n g t he st u d y bli n d.  
8. 1 1. 4.  
Electr ocar di o gra m E val uati o ns  
Electr ocar di o gra m o utc o mes will be s u m m arize d descri pti vel y b y visit a n d b y treat me nt.  
C orrecte d Q T will be calc ulate d usi n g Fri dericia’s c orrecti o n.  T he n u m ber of s u bjects wit h P C S 
c ha n ges i n E C G i nter vals will be ta b ulate d.  T he P C S t hres h ol ds will be defi ne d pri or t o 
brea ki n g t he st u d y bli n d.  
8. 1 1. 5.  
C o nc o mita nt Me dicati o ns  
C o nc o mita nt me dicati o ns will be s u m marize d b y W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y 
A nat o mical -T hera pe utic -C he mical classificati o n a n d preferre d ter m.  C o nc o mita nt me dicati o ns 
i nf or mati o n will be ta b ulate d a n d s u m marize d b y  visit a n d b y treat me nt.  
8. 1 1. 6.  
St u d y Ter mi nati o n Stat us  
St u d y ter mi nati o n stat us will be ta b ulate d a n d s u m marize d b y visit  a n d b y treat me nt . 
 


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 3 6  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
9.  
R E F E R E N C E  
Be nt o n A L et al. M ultili n g ual A p hasia E xa mi nati o n ( 3r d e d.). I o wa Cit y, I A: AJ A Ass ociates, 1 9 9 4.  
Da Tsca n ™ (I o fl u pa ne I 1 2 3 I njecti o n) prescri bi n g i nf or mati o n. G E Healt hcare, 2 0 1 5. 
F olstei n M F et al. " Mi ni -me ntal state". A practical met h o d f or gra di n g t he c o g niti ve state of 
patie nts f or t he cli nicia n. J Psyc hi atr Res . 1 9 7 5; 1 2( 3): 1 8 9-9 8.  
H u g hes C P et al. A ne w cli n ical scale f or t he sta gi n g of de me ntia. Br J Psyc hi atry . 1 9 8 2; 1 4 0: 5 6 6-7 2.  
Ma her -E d war ds G et al. A 2 4 -wee k st u d y t o e val uate t he effect of rila pla di b o n c o g niti o n 
a n d cere br os pi nal fl ui d bi o mar kers of Alz hei mer's disease. Alz hei mers De me nt ( N Y) 
2 0 1 5; 1( 2): 1 3 1 -1 4 0.  
Mc Keit h I G. Dia g n osis a n d ma na ge me nt of de me ntia wit h Le w y b o dies: F o urt h c o nse ns us 
re p ort of t he D L B C o ns orti u m. Ne ur ol o gy . 2 0 1 7; 8 9( 1): 8 8-1 0 0.  
Nat ha n PJ et al. T he safet y, t olera bilit y, p har mac o ki netics a n d c o g niti ve effects of 
G S K 2 3 9 5 1 2, a selecti ve hista mi ne H₃ rece pt or a nta g o nist i n patie nts wit h mil d t o 
m o derate Alz hei mer's disease: a preli mi nar y i n vesti gati o n. C urr  Alz hei mer Res 
2 0 1 3; 1 0( 3): 2 4 0 -5 1.  
O' Br ya nt S E et al. Sta gi n g De me ntia Usi n g Cli nical De me ntia Rati n g Scale S u m of B o xes 
Sc ores. Arc h Ne ur ol . 2 0 0 8; 6 5( 8): 1 0 9 1– 1 0 9 5.  
Ol de D u b beli n k K T et al. C o g niti ve decli ne i n Par ki ns o n's disease is ass ociate d wit h sl o wi n g 
of resti n g - state brai n acti vit y: a l o n git u di nal st u d y. Ne ur o bi ol A gi n g 2 0 1 3; 3 4( 2): 4 0 8 -1 8.  
Peraza L R et al. Electr oe nce p hal o gra p hic deri ve d net w or k differe nces i n Le w y b o d y de me ntia 
c o m pare d t o Alz hei mer's disease patie nts. Sci Re p 2 0 1 8; 8( 1): 4 6 3 7.  
P os ner  K et al. T he C ol u m bia -S uici de Se verit y Rati n g Scale: i nitial vali dit y a n d i nter nal 
c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h a d olesce nts a n d a d ults. A m J Psyc hi atry 
2 0 1 1; 1 6 8: 1 2 6 6 -1 2 7 7.  
Wes nes K A et al. Me ma nti ne i m pr o ves atte nti o n a n d e pis o di c me m or y i n Par ki ns o n's disease 
de me ntia a n d de me ntia wit h Le w y b o dies. I nt J Geri atr Psyc hi atry 2 0 1 5; 3 0( 1): 4 6 -5 4.  
 
 
 


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 3 7  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 0.  
A P P E N DI X  
 
1 0. 1.  
T a ble of C o nte nts f or D at a Dis pl a y S pecific ati o ns  
T he n u m beri n g of ta bles, data listi n gs, a n d fi g ures will be c o nsiste nt wit h t h e I C H E 3 g ui da nce . 
1 0. 1. 1.  
List of T a bles  
Ta bles are di vi de d i nt o 4 secti o ns:  St u d y c haracteristics, efficac y, safet y, a n d p har mac o ki netic 
prese ntati o ns.  
• 
Ta bles i n t he 1 4. 1. X series are st u d y c haracteristics, i.e., patie nt dis p ositi o n a n d 
baseli ne c haracteristics ta b ulati o ns.  
• 
Ta bles i n t he 1 4. 2. X series are efficac y -base d data.  
• 
Ta bles i n t he 1 4. 3. X series are safet y -base d data.  
 
 
Title  
P o p ul ati o n  
1 4. 1 St u d y P o p ul ati o n Secti o n  
1 4. 1. 1  
S u m mar y of S u bject Dis p ositi o n  
Ra n d o mize d  
1 4. 1. 2  
S u m mar y of A nal ysis P o p ulati o ns  
Safet y; E E P  
1 4. 1. 3  
De m o gra p hics a n d Baseli ne C haracteristics  
Safet y; E E P  
1 4. 1. 3. 1  
S u m mar y of De m o gra p hic C haracteristics  
Safet y; E E P  
1 4. 1. 3. 2  
S u m mar y of Baseli ne/ P h ysical E xa mi nati o ns C haracteristics  
Safet y; E E P  
1 4. 1. 4  
Me dical Hist or y a n d Pri or Me dicati o ns  
Safet y  
1 4. 1. 5  
Maj or De viati o ns  
Ra n d o mize d  
1 4. 2 Effic ac y Secti o n  
  
1 4. 2. 1 Pri m ary Effic acy E n d p oi nt   
  
1 4. 2. 1. 1  
S u m mar y of N T B b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 1. 2  
S u m mar y of C ha n ge i n N T B b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2 Sec o n d ary Effic acy E n d p oi nts   
  


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 3 8  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 2. 1  
S u m mar y of C D R -S B b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 2  
S u m mar y of C ha n ge i n C D R -S B b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 3  
S u m mar y of M M S E b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 4  
S u m mar y of C ha n ge i n M M S E b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 5  
S u m mar y of N PI -1 0 b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 6  
S u m mar y of C ha n ge i n N PI -1 0 b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 7  
S u m mar y of I S L T b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 8  
S u m mar y of C ha n ge i n I S L T b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 9  
S u m mar y of T U G b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 1 0  
S u m mar y of C ha n ge i n T U G b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 1 1  
S u m mar y of E E G b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 2. 1 2  
S u m mar y of C ha n ge i n E E G b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 3 E x pl or at ory Effic acy E n d p oi nts   
  
1 4. 2. 3. 1  
S u m mar y of Atte nti o n C o m p osite b y Visit a n d b y Treat me nt  
E E P  
1 4. 2. 3. 2  
S u m mar y of C ha n ge i n Atte nti o n C o m p osite b y Visit a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 3  
S u m mar y of E xec uti ve F u ncti o n C o m p osite b y Visit a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 4  
S u m mar y of C ha n ge i n E xec uti ve F u ncti o n C o m p osite b y Visit 
a n d b y Treat me nt  
E E P  
1 4. 2. 3. 5  
S u m mar y of Lear ni n g a n d Me m or y C o m p osite b y Visit a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 6  
S u m mar y of C ha n ge i n Lear ni n g a n d Me m or y C o m p osite b y Visit 
a n d b y Treat me nt  
E E P  
1 4. 2. 3. 7  
S u m mar y of Ge neral Ne ur o ps yc h ol o gical C o m p osite b y Visit a n d 
b y Treat me nt  
E E P  
1 4. 2. 3. 8  
S u m mar y of C ha n ge i n Ge neral Ne ur o ps yc h ol o gical C o m p osite b y 
Visit a n d b y Treat me nt  
E E P  
1 4. 2. 3. 9  
S u m mar y of Ge neral O verall C o m p osite b y Visit a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 1 0  
S u m mar y of C ha n ge i n Ge neral O verall C o m p osite b y Visit a n d 
b y Treat me nt  
E E P  


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 3 9  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 3 S afet y D at a  
1 4. 3. 1  
S u m mar y of E x p os ure t o nefla ma pi m o d b y Treat me nt a n d b y Visit  
Safet y  
1 4. 3. 2. 1  
S u m mar y of A d verse E ve nts b y Treat me nt a n d b y Visit  
Safet y  
1 4. 3. 2. 2  
S u m mar y of Deat h a n d Seri o us A d verse E ve nts b y Treat me nt a n d 
b y Visit  
Safet y  
1 4. 3. 2. 3  
S u m mar y of Dr u g -Relate d A d verse E ve nts b y Treat me nt Gr o u p  
Safet y  
1 4. 3. 3  
Listi n g of S u bjects W h o Beca me Pre g na nt D uri n g t he St u d y  
Safet y  
1 4. 3. 4  
S u m mar y of Act ual Val ues a n d C ha n ges fr o m Baseli ne i n Cli nical 
C he mistr y Data b y Treat me nt Gr o u p a n d b y Visit  
Safet y  
1 4. 3. 5  
S u m mar y of Act ual Val ues a n d C ha n ges fr o m Baseli ne i n 
He mat ol o g y Data b y Treat me nt Gr o u p a n d b y Visit  
Safet y  
1 4. 3. 6  
S u m mar y of Act ual Val ues a n d C ha n ges fr o m Baseli ne i n Vital 
Si g ns b y Treat me nt Gr o u p a n d b y Visit  
Safet y  
1 4. 3. 7  
S u m mar y of E C G Data  
Safet y  
1 4. 3. 8  
S u m mar y of C o nc o mita nt Me dicati o n  
Safet y  
1 4. 4 P h ar m ac o ki netic Secti o n  
  
1 4. 4. 1  
S u m mar y of nefla ma pi m o d plas ma c o nce ntrati o n b y Visit a n d b y 
Treat me nt  
P K  
 
1 0. 1. 2.  
List of Fi g ures  
 
Title  
P o p ul ati o n  
1 4. 2 Fi g ure f or Effic ac y D at a  
  
1 4. 2. 1  
Fi g ure Pri m ary Effic acy E n d p oi nt  
  
1 4. 2. 1. 1  
N T B Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 1. 2  
Mea n C ha n ge ( ± S D) of N T B fr o m Baseli nes b y Treat me nt a n d b y 
Visit  
E E P  


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 4 0  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 1. 3  
B o x pl ot of N T B C ha n ge fr o m Baseli nes b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 2  
Fi g ure f or Sec o n d ary Effic acy E n d p oi nt  
  
1 4. 2. 2. 1  
C D R -S B Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 2. 2  
Mea n C ha n ge ( ± S D) of C D R -S B fr o m Baseli nes b y Treat me nt a n d 
b y Visit  
E E P  
1 4. 2. 2. 3  
B o x pl ot of C D R -S B C ha n ge fr o m Baseli nes b y Treat me nt a n d b y 
Visit  
E E P  
1 4. 2. 2. 4  
M M S E Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 2. 5  
Mea n C ha n ge ( ± S D) of M M S E fr o m Baseli nes b y Treat me nt a n d 
b y Visit  
E E P  
1 4. 2. 2. 6  
B o x pl ot of M M S E C ha n ge fr o m Baseli nes b y Treat me nt a n d b y 
Visit  
E E P  
1 4. 2. 2. 7  
N PI -1 0 Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 2. 8  
Mea n C ha n ge ( ± S D) of N PI -1 0 fr o m Baseli nes b y Treat me nt a n d 
b y Visit  
E E P  
1 4. 2. 2. 9  
B o x pl ot of N PI -1 0 C ha n ge fr o m Baseli nes b y Treat me nt a n d b y 
Visit  
E E P  
1 4. 2. 2. 1 0  
I S L T Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 2. 1 1  
Mea n C ha n ge ( ± S D) of I S L T fr o m Baseli nes b y Treat me nt a n d b y 
Visit  
E E P  
1 4. 2. 2. 1 2  
B o x pl ot of I S L T C ha n ge fr o m Baseli nes b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 2. 1 3  
T U G Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y Treat me nt 
E E P  
1 4. 2. 2. 1 4  
Mea n C ha n ge ( ± S D) of T U G fr o m Baseli nes b y Treat me nt a n d b y 
Visit  
E E P  


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 4 1  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 2. 1 5  
B o x pl ot of T U G C ha n ge fr o m Baseli nes b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 2. 1 6  
E E G Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y Treat me nt  
E E P  
1 4. 2. 2. 1 7  
Mea n C ha n ge ( ± S D) of E E G fr o m Baseli nes b y Treat me nt a n d b y 
Visit  
E E P  
1 4. 2. 2. 1 8  
B o x pl ot of E E G C ha n ge fr o m Baseli nes b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3  
Fi g ure f or E x pl or at ory Effic acy E n d p oi nt  
  
1 4. 2. 3. 1  
Atte nti o n C o m p osite Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 2  
Mea n C ha n ge ( ± S D) of Atte nti o n C o m p osite fr o m Baseli nes b y 
Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3. 3  
B o x pl ot of Atte nti o n C o m p osite C ha n ge fr o m Baseli nes b y 
Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3. 4  
E xec uti ve F u ncti o n C o m p osite Ti me Pr ofile Pl ot b y i n di vi d ual a n d 
b y Treat me nt  
E E P  
1 4. 2. 3. 5  
Mea n C ha n ge ( ± S D) of E xec uti ve F u ncti o n C o m p osite fr o m 
Baseli nes b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3. 6  
B o x pl ot of E xec uti ve F u ncti o n C o m p osite C ha n ge fr o m Baseli nes 
b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3. 7  
Lear ni n g a n d Me m or y C o m p osite Ti me Pr ofile Pl ot b y i n di vi d ual 
a n d b y Treat me nt  
E E P  
1 4. 2. 3. 8  
Mea n C ha n ge ( ± S D) of Lear ni n g a n d Me m or y C o m p osite fr o m 
Baseli nes b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3. 9  
B o x pl ot of Lear ni n g a n d Me m or y C o m p osite C ha n ge fr o m 
Baseli nes b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3. 1 0  
Ge neral Ne ur o ps yc h ol o gical C o m p osite Ti me Pr ofile Pl ot b y 
i n di vi d ual a n d b y Treat me nt 
E E P  
1 4. 2. 3. 1 1  
Mea n C ha n ge ( ± S D) of Ge neral Ne ur o ps yc h ol o gical C o m p osite 
fr o m Baseli nes b y Treat me nt a n d b y Visit 
E E P  


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 4 2  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 4. 2. 3. 1 2  
B o x pl ot of Ge neral Ne ur o ps yc h ol o gical C o m p osite C ha n ge fr o m 
Baseli nes b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3. 1 3  
Ge neral O verall C o m p osite Ti me Pr ofile Pl ot b y i n di vi d ual a n d b y 
Treat me nt  
E E P  
1 4. 2. 3. 1 4  
Mea n C ha n ge ( ± S D) of Ge neral O verall C o m p osite fr o m Baseli nes 
b y Treat me nt a n d b y Visit  
E E P  
1 4. 2. 3. 1 5  
B o x pl ot of Ge neral O verall C o m p osite C ha n ge fr o m Baseli nes b y 
Treat me nt a n d b y Visit  
E E P  


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 4 3  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 0. 1. 3.  
Listi n gs  
 
Title  
P o p ul ati o n  C o m me nt  
1 6. 2. 1. 1  
S u bject E nr oll me nt I nf or mati o n  
E nr olle d  
  
1 6. 2. 1. 2  
S u bject Dis p ositi o n  
Safet y  
  
1 6. 2. 2. 1  
S u bjects w h o di d n ot Satisf y I ncl usi o n/ E xcl usi o n Criteria (if 
a p plica ble)  
Scree ni n g 
Fail ure  
  
1 6. 2. 2. 2  
Pr ot oc ol De viati o ns  
Safet y  
  
1 6. 2. 4. 1  
S u bject De m o gra p hic a n d Baseli ne C haracteristics  
Safet y  
  
1 6. 2. 4. 2  
Listi n g of Me dical Hist or y  
Safet y  
  
1 6. 2. 4. 3  
Listi n g of P h ysical E xa m  
Safet y  
  
1 6. 2. 4. 4  
Listi n g of C o nc o mita nt Me dicati o ns  
Safet y  
  
1 6. 2. 5. 1  
Listi n g of Dr u g A d mi nistrati o n  
Safet y  
  
1 6. 2. 6. 1  
N T B Listi n g  
E E P  
  
1 6. 2. 6. 2  
C D R -S B Listi n g  
E E P  
  
1 6. 2. 6. 3  
M M S E Listi n g  
E E P  
  
1 6. 2. 6. 4  
N PI -1 0 Listi n g  
E E P  
  
1 6. 2. 6. 5  
I S L T Listi n g 
E E P  
  


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 4 4  of 5 0  
EI P P h ar m a, I nc  
C o nfi de nti al  
 
 
1 6. 2. 6. 6  
T U G Listi n g  
E E P  
  
1 6. 2. 6. 7  
E E G Listi n g  
E E P  
  
1 6. 2. 6. 8  
Atte nti o n C o m p osite Listi n g  
E E P  
  
1 6. 2. 6. 9  
E xec uti ve F u ncti o n C o m p osite Listi n g  
E E P  
  
1 6. 2. 6. 1 0  Lear ni n g a n d Me m or y C o m p osite Listi n g  
E E P  
  
1 6. 2. 6. 1 1  Ge neral Ne ur o ps yc h ol o gical C o m p osite Listi n g  
E E P  
  
1 6. 2. 6. 1 2  Ge neral O verall C o m p osite Listi n g  
E E P  
  
1 6. 2. 7. 1  
Listi n g of Relati o ns hi p of A d verse E ve nt B o d y S yste ms, Gr o u p 
Ter ms, a n d Ver bati m Te xt  
Safet y  
  
1 6. 2. 7. 2  
Listi n g of All A d verse E ve nts  
Safet y  
  
1 6. 2. 7. 3  
Listi n g of S u bjects Wit h dra w n D ue t o A Es  
Safet y  
  
1 6. 2. 7. 4  
Listi n g of Deat hs or S A Es (if a n y)  
Safet y  
  
1 6. 2. 8. 1  
Listi n g of He mat ol o g y Data  
Safet y  
  
1 6. 2. 8. 2  
Listi n g of Cli nical C he mistr y Data  
 Safet y  
  
1 6. 2. 8. 3  
Listi n g of Uri nal ysis  
Safet y  
if 
a p plica ble 
1 6. 2. 9  
Listi n g of Vital Si g n Data  
Safet y  
  
1 6. 2. 1 0  
Listi n g of E C G Data  
Safet y  
  
 
 


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 4 5  of 5 0  
 
 
 
1 0. 2.  
S a m ple T a ble Te m pl ate  
1 0. 2. 1.  
S a m ple Te m pl ate f or C o u nt  D at a  
T a bl e 1 4. x. x. x: S u m m ar y of C o u nt s b y vi sit a n d b y Tr e at m e nt  
P o p ul ati o n  
n  
Tr e at m e nt  
Vi sit 1  
Vi sit 2  
Vi sit 3  
Vi sit 4  
Vi sit 5  
R a n d o mi z e d 
( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %) 
4 0  m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
  
S af et y ( N = x)  
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0  m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
  
E E P  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0  m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
  
C o m pl et er  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
N ot e: P er c e nt a g e s ar e b a s e d o n t h e t ot al n u m b er of s u bj e ct s i n e a c h tr e at m e nt gr o u p of t h e s a m e p o p ul ati o n 
 
 
 


EI P 1 9 -N F D -5 0 1, Versi o n 1 2 0 2 0  
P a ge 4 6  of 5 0  
 
 
 
T a bl e 1 4. x. x. x: S u m m ar y of Effi c a c y/ S af et y/ L a b C o u nt D at a b y vi sit a n d b y Tr e at m e nt  
  
  
  
F or E x a m pl e: Diff er e n c e of Effi c a c y  S c or e fr o m B a s eli n e  
Vi sit  
n  
Tr e at m e nt  
≤-2  
-1  
± 0  
+ 1  
+ 2  
≥ 3  
Vi sit 1  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %) 
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
 
  
Vi sit 2  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
 
  
Vi sit 3  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
  
 
 
 
 
 
 
 
  
Vi sit 4  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %) 
x ( x %)  
  
 
 
 
 
 
 
 
  
F oll o w -u p  ( N = x) 
x ( x %)  
Pl a c e b o  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
4 0 m g  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
x ( x %)  
N ot e: P er c e nt a g e s ar e b a s e d o n t h e t ot al n u m b er of s u bj e ct s i n e a c h tr e at m e nt gr o u p of t h e s a m e vi sit  


EI P 1 9 -N F D -4 0 1, Versi o n 1, 2 0 1 9  
P a ge 4 7  of 5 0  
 
 
 
C O N FI D E N TI A L & P R O P RI E T A R Y  
4 7  
 
 
  
 
1 0. 2. 2.  
S a m ple Te m pl ate f or C o nti n u o us D at a ( Effic ac y / S afet y/ L a b) 
 
T a bl e 1 4. x. x. x : S u m m ar y of E n d p oi nt b y V i sit a n d b y Tr e at m e nt 
Vi sit  
Tr e at m e nt  
Mi n.  
Q 1  
M e di a n  
M e a n  
Q 3  
M a x.  
N  
s d  
S cr e e ni n g  
Pl a c e b o  
  
  
  
  
  
  
  
  
4 0 m g  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
  
Vi sit 1  
Pl a c e b o  
  
  
  
  
  
  
  
  
 
4 0 m g  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Vi sit 2  
Pl a c e b o  
 
 
 
 
 
 
 
 
 
4 0 m g