Clinical trial NCT03402659
Conditions: Alzheimer Disease
Sponsor: EIP Pharma Inc
Start date: 2017-12-29; Completion date: 2019-07-31
Enrollment: 161 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2b, double-blind, placebo controlled proof-of-concept study of a an oral small molecule selective inhibitor of p38 alpha kinase, neflamapimod, administered for 24 weeks in subjects with mild Alzheimer's disease. The primary objective is to demonstrate significant improvement relative to placebo-treatment in episodic memory function, as assessed by the Hopkins Verbal Learning Test. Secondary endpoints include Clinical Dementia Rating scale (CDR), Wechsler Memory Scale (WMS), Mini-Mental-Status-Examination (MMSE) and Cerebrospinal fluid (CSF) biomarkers of AD disease activity and progression.

Detailed description:
Details provided elsewhere.

Arms: arm 1: 40 mg hard gelatin capsules, taken twice daily with food. arm 2: hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food.
Interventions: intervention 1: neflamapimod intervention 2: placebo
Intervention descriptions: intervention 1: 40 mg neflamapimod capsule intervention 2: matching placebo capsule

Protocol documents:
Prot_000.pdf: 
EIP-VX17-745-304, Version 2.0, 27 August, 2018 
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EIP PHARMA, INC. 
CLINICAL STUDY PROTOCOL 
Title 
A Double-Blind, Placebo-Controlled Proof-of-Concept Study of a 
Selective 
p38 
MAP 
Kinase 
Alpha 
Inhibitor, 
Neflamapimod, 
Administered for 24 Weeks in Subjects with Mild Alzheimer’s Disease 
Investigational 
Product 
Neflamapimod (VX-745) 
Development Phase 
2 
EIP Study Number 
EIP-VX17-745-304 
IND Number 
125198 
EudraCT Number 
2017-004388-11 
Date (Version) 
27 August, 2018 (Version 2.0) 
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. 
NCT03402659


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SPONSOR PROTOCOL APPROVAL PAGE 
Signature 
 
 
Sponsor Responsible Person 
 
 
Title 
 
 
Date 
John J. Alam, MD
President and CEO
27 August 2018


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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: +1 617-945-0794 
E-mail: 38Tjalam@eippharma.com38T  
Contract Research Organization: 
Worldwide Clinical Trials 
3800 Paramount Parkway 
Suite 400 
Morrisville, NC 27560 
USA 
Telephone: +1 919-674-2900 
Medical Monitor: 
Idil Çavuş, MD PhD 
Worldwide Clinical Trials 
1000 Continental Dr 
King of Prussia, PA 19406 
USA 
Mobile Telephone:  +1 203-623-2622 
Facsimile:  +1 203-779-5678 
E-mail:  38Tidil.cavus@worldwide.com38T 
Serious Adverse Event Reporting: 
E-mail:  drugsafety@worldwide.com 
Telephone:  +44 (0)115 922 0960 


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SYNOPSIS 
Title 
A Double-Blind, Placebo-Controlled Proof-of-Concept Study of a 
Selective p38 MAP Kinase Alpha Inhibitor, Neflamapimod, Administered 
for 24 Weeks in Subjects with Mild Alzheimer’s Disease 
Study Phase 
2 
Study centers: 
Multi-center study in United States and European Union. 
Study Objectives 
The primary objective is to evaluate the effects of administration of 
neflamapimod (VX-745) for 24-weeks on immediate and delayed recall 
aspects of episodic memory, as assessed by the Hopkins Verbal Learning 
Test – Revised (HVLT-R) in subjects with mild Alzheimer’s disease 
(AD). 
The secondary objectives are: 
• 
To evaluate effects of neflamapimod on immediate and delayed 
recall of Logical Memory (LM), Verbal Paired Associates (VPA) 
and Visual Reproduction (VR) components of the Wechsler 
Memory ScaleP®
P (WMS). 
• 
To evaluate effects of neflamapimod on the Clinical Dementia 
Rating Scale-Sum of Boxes (CDR-SB) and Mini-Mental State 
Examination (MMSE). 
• 
To evaluate the effects of neflamapimod on AD-related 
cerebrospinal fluid (CSF) biomarkers (total tau, phospho-tau, 
amyloid-beta peptides, neurogranin, and neurofilament light 
chain). 
Study Endpoints 
Primary efficacy endpoints: 
• 
Combined change in z-scores of total recall and delayed recall on 
the HVLT-R in neflamapimod-treated subjects compared to 
placebo-recipients. 
Secondary endpoints: 
• 
Change in WMS immediate and delayed recall composites in 
neflamapimod-treated subjects compared to placebo-recipients. 
• 
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 CSF biomarkers (total tau, p-tauR181
R, AβR1-40
R, AβR1-42, 
neurogranin, Rneurofilament light chain) in neflamapimod-treated 
subjects compared to placebo-recipients. 


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Number of Subjects 
Approximately 152 subjects (76 subjects per dose group).   
Subject Population 
Subjects aged 55 to 85 years with CSF biomarker confirmed AD, with a 
CDR global score of 0.5 or 1.0, a CDR memory subscore of at least 0.5, and 
MMSE scores between 20 and 28, inclusive. 
Inclusion Criteria: 
1. Men and women age 55 to 85 years, inclusive. 
2. Willing and able to provide informed consent. 
3. Must have mild cognitive impairment (MCI) or mild AD with 
evidence of progression (“Mild-AD”), as defined by the following: 
a. CDR-Global Score of 0.5 or 1.0, with CDR memory subscore of at 
least 0.5. 
b. MMSE score ranging from 20 to 28, inclusive. 
c. Positive biomarker for AD, as defined by a CSF Aβ1-42
R below the 
threshold and phospho-tau above the threshold for the assay 
utilized in the study and assessed by the central laboratory. 
4. Computed tomography (CT) or magnetic resonance imaging (MRI) 
findings within 2 years of Screening that are compatible with AD (i.e., 
no other pathologic processes that would account for the cognitive 
deficit). 
5. If the subject is taking a single drug for AD (e.g., donepezil or other 
cholinesterase inhibitors or memantine; dual therapy is excluded), 
he/she has been on a stable dose for at least 2 months prior to baseline, 
and the dose must remain unchanged during the study unless required 
for management of adverse events (AEs). 
6. Adequate visual and auditory abilities to perform all aspects of the 
cognitive and functional assessments. 
7. Must have reliable informant or caregiver.  In Czech Republic only, 
the caregiver must be either sharing the same household as the subject 
or be in personal contact with the subject at least 5 days per week. 
Exclusion criteria 
1. Evidence that the primary basis for cognitive impairment is 
neurodegenerative disease other than AD, including, but not limited 
to, vascular dementia, dementia with Lewy bodies, and Parkinson’s 
disease. 
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. 


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3. History of major and active psychiatric disorder, moderate to severe 
depressive symptoms, 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. History of cancer within the last 5 years, except basal cell carcinoma, 
squamous skin carcinoma, prostate cancer or carcinoma in situ with no 
significant progression over the past 2 years. 
6. 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 preclude 
treatment with p38 mitogen activated protein (MAP) kinase inhibitor 
and/or assessment of drug safety and efficacy. 
7. History of serum B12 abnormality, anemia with hemoglobin 
≤10 g/dL, thyroid function abnormality, electrolyte abnormality, or 
positive syphilis serology that have not been corrected and/or 
otherwise addressed. 
8. History of epilepsy or unexplained seizure within the past 5 years. 
9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5 × the upper limit of normal (ULN), total bilirubin >1.5 × ULN, 
and/or International Normalized Ratio (INR) >1.5 
10. Known human immunodeficiency virus or active hepatitis B or 
hepatitis C virus infection. 
11. Subject participated in a study of an investigational drug less than 
3 months or 5 half-lives of the investigation drug, whichever is longer, 
before enrollment in this study. 
12. Male subjects with female partners of child-bearing potential who are 
unwilling or unable to adhere to contraception requirements specified 
in the protocol. 
13. Female subjects who have not reached menopause or have not had a 
hysterectomy or bilateral oophorectomy/salpingo-oophorectomy. 
• 
If a female subject reached menopause within the previous year, 
a pregnancy test must be performed during Screening and the 
subject must be willing to adhere to the contraception 
requirements specified in the protocol. Such subjects with a 


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positive urine or serum pregnancy test are not eligible for study 
participation. 
14. Requires concomitant use of strong cytochrome P450 (CYP) 3A4 
inhibitors or anti-tumor necrosis factor-alpha therapies during study 
participation (see Section 5.7). 
Study Drug Details 
Neflamapimod 40 mg capsule or matching placebo capsule administered 
orally according to randomized treatment assignment.   
Study Design and 
Methods 
This is a Phase 2, multicenter, randomized, double-blind, placebo-
controlled, proof-of-concept study of neflamapimod 40 mg or matching 
placebo administered twice daily for 24 weeks in subjects with mild AD. 
Following completion of informed consent procedures, subjects will enter 
the Screening phase of the study. 
Two Screening visits are planned to allow most screening procedures to be 
completed and reviewed during the first visit before lumbar puncture to 
collect CSF is performed during Screening Visit 2. 
Once eligibility is confirmed and before the first dose of study drug, 
subjects will be randomly assigned on 1:1 basis to placebo or 
neflamapimod treatment.  Investigators and subjects will be blinded to the 
treatment assignment. 
Dosing will start on Day 1 following completion of all Baseline 
procedures. 
During the treatment period, subjects will return to the clinic on Days 21, 
42, 84, 126, and 168.  Telephone contacts will be conducted to determine 
subject status and assess compliance between Days 42 and 84 (Visits 5 and 
6); Days 84 to 126 (Visits 6 and 7); and Days 126 and 168 (Visits 7 and 
8).   
Episodic memory and other cognitive assessments will be performed at 
Baseline and Days 42, 84, and 168.  
Lumbar puncture will be performed, and CSF collected at Screening Visit 
2 and on Day 168. 
A Follow-up visit will be conducted 14 (±3) days following the last dose 
of study drug. 


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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 .............................................................................................. 16 
2. 
OBJECTIVES ............................................................................................................................. 20 
2.1. 
Primary Objective .......................................................................................................... 20 
2.2. 
Secondary Objectives .................................................................................................... 20 
3. 
INVESTIGATIONAL PLAN .................................................................................................... 21 
3.1. 
Overall Study Design and Plan ..................................................................................... 21 
3.1.1. 
Screening ......................................................................................................... 21 
3.1.2. 
Treatment Period ............................................................................................. 21 
3.1.3. 
Follow Up ........................................................................................................ 21 
3.1.4. 
Early Discontinuation ...................................................................................... 21 
3.2. 
Discussion of Study Design ............................................................................................ 21 
3.2.1. 
Rationale for Dose Selection ........................................................................... 22 
4. 
SELECTION OF STUDY POPULATION............................................................................... 24 
4.1. 
Inclusion Criteria ........................................................................................................... 24 
4.2. 
Exclusion Criteria .......................................................................................................... 24 
4.3. 
Removal of Subjects from Treatment .......................................................................... 25 
5. 
TREATMENTS ADMINISTERED .......................................................................................... 27 
5.1. 
Packaging and Labeling ................................................................................................ 27 
5.2. 
Study Drug Supply, Storage, and Handling ................................................................ 27 
5.3. 
Drug Accountability, Disposal, Return, or Retention of Unused Study 
Drug ................................................................................................................................ 27 
5.4. 
Method of Assigning Subjects to Treatment Group ................................................... 28 
5.5. 
Study Blinding and Breaking the Blind ....................................................................... 28 


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5.6. 
Dose Modification for Toxicity ..................................................................................... 28 
5.7. 
Prior and Concomitant Therapy .................................................................................. 28 
5.8. 
Contraception and Pregnancy ...................................................................................... 30 
5.9. 
Activity Restrictions ...................................................................................................... 31 
5.10. 
Treatment Compliance .................................................................................................. 31 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................... 32 
6.1. 
Schedule of Assessments ................................................................................................ 32 
6.2. 
Study Assessments ......................................................................................................... 34 
6.2.1. 
Baseline and Disease Characteristics .............................................................. 34 
6.2.2. 
Columbia-Suicide Severity Rating Scale ........................................................ 34 
6.2.3. 
Computed Tomography/Magnetic Resonance Imaging .................................. 34 
6.2.4. 
Lumbar Puncture ............................................................................................. 34 
6.2.5. 
Genotyping and Apolipoprotein E4 Testing .................................................... 35 
6.2.6. 
Mini-Mental State Examination/CDR ............................................................. 35 
6.2.7. 
Episodic Memory Tests - HVLT-R and WMS ................................................ 35 
6.2.8. 
Pharmacokinetic Sampling .............................................................................. 36 
6.2.9. 
Physical Examination and Vital Signs ............................................................ 36 
6.2.10. 
12-Lead Electrocardiogram ............................................................................. 36 
6.2.11. 
Clinical Laboratory Assessments .................................................................... 36 
6.2.12. 
Withdrawal of Subjects ................................................................................... 37 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS/SAFETY 
REPORTING .............................................................................................................................. 39 
7.1. 
Definitions and Criteria ................................................................................................. 39 
7.1.1. 
Adverse Events ................................................................................................ 39 
7.1.2. 
Serious Adverse Events ................................................................................... 39 
7.1.3. 
Unexpected Adverse Drug Reactions .............................................................. 40 
7.1.4. 
Abnormal Laboratory Values .......................................................................... 40 
7.1.5. 
Assessing Intensity and Relationship .............................................................. 40 
7.2. 
Reporting Procedures and Requirements ................................................................... 41 
7.2.1. 
Adverse Events ................................................................................................ 41 
7.2.2. 
Serious Adverse Events ................................................................................... 42 
8. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ................................................. 43 


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8.1. 
Data Management and Quality Assurance Considerations ....................................... 43 
8.2. 
Sample Size ..................................................................................................................... 43 
8.3. 
Analysis Sets ................................................................................................................... 43 
8.4. 
Pharmacokinetics (PK) .................................................................................................. 44 
8.5. 
Efficacy ........................................................................................................................... 44 
8.5.1. 
Primary Efficacy Variables ............................................................................. 44 
8.5.2. 
Secondary Efficacy Variables ......................................................................... 44 
8.6. 
Safety ............................................................................................................................... 44 
8.7. 
Interim Analysis ............................................................................................................. 44 
9. 
STUDY MANAGEMENT .......................................................................................................... 45 
9.1. 
Ethics and Consent ........................................................................................................ 45 
9.1.1. 
Regulations and Guidelines ............................................................................. 45 
9.1.2. 
Institutional Review Boards/Independent Ethics Committees ........................ 45 
9.1.3. 
Informed Consent ............................................................................................ 45 
9.2. 
Indemnification .............................................................................................................. 45 
9.3. 
Discontinuation of the Study by the Sponsor .............................................................. 45 
9.4. 
Study Documentation .................................................................................................... 46 
9.5. 
Study Monitoring and Auditing ................................................................................... 46 
9.6. 
Use of Study Findings .................................................................................................... 46 
9.7. 
Publications .................................................................................................................... 46 
9.8. 
Recording, Access and Retention of Source Data ....................................................... 46 
9.9. 
Protocol Violations ......................................................................................................... 47 
10. 
REFERENCES ............................................................................................................................ 48 


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LIST OF TABLES 
Table 5-1: 
CYP3A4 Inhibitors .......................................................................................................... 29 
Table 5-2: 
CYP3A4 Inducers ............................................................................................................ 30 
Table 6-1 
Schedule of Assessments ................................................................................................. 33 
Table 6-2 
Clinical Laboratory Analytes ........................................................................................... 37 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APP 
Amyloid-Precursor-Protein 
AST 
Aspartate aminotransferase 
AUC 
Area under the time concentration curve 
BID 
bis in die (twice a day) 
CDR 
Clinical Dementia Rating Scale 
CDR-SB 
Clinical Dementia Rating Scale-Sum of Boxes 
CRmax 
Maximum concentration 
CNS 
Central Nervous System 
CT 
Computed tomography 
CTrough 
Trough concentration 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EF 
Effect sizes 
FDA 
Food and Drug Administration 
HVLT-R 
Hopkins Verbal Learning Test – Revised 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IL-1beta 
Interleukin-1 beta 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LFT 
Liver function test 
LM 
Logical Memory 


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Abbreviation 
Definition 
LP 
Lumbar puncture 
MAP 
Mitogen activated protein 
MCI 
Mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
MRI 
Magnetic Resonance Imaging 
NFT 
Neurofibrillary Tangle 
p38 alpha 
p38 mitogen activated protein kinase alpha 
PD 
Pharmacodynamic 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RA 
Rheumatoid arthritis 
SAE 
Serious adverse event 
ULN 
Upper limit of normal 
VPA 
Verbal Paired Associates 
VR 
Visual Reproduction 
WMS 
Wechsler Memory Scale 
 


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1. 
INTRODUCTION 
1.1. 
Scientific Rationale 
The investigational drug neflamapimod is a highly specific inhibitor of the intra-cellular enzyme p38 
mitogen activated protein (MAP) kinase alpha (“p38 alpha”).  Neflamapimod (VX-745) was discovered 
through a proprietary structure-based drug discovery platform at Vertex Pharmaceuticals (38TDuffy et al, 
201138T), and was licensed by EIP Pharma for development for the treatment of central nervous system 
(CNS) disorders.  Neflamapimod readily enters the brain, with brain concentrations being approximately 
2-fold higher than in peripheral blood. 
In the brain, p38 alpha is a major regulator of inflammation through effects on microglia, the major 
immune cell in the brain.  P38 alpha is also expressed in neurons, where it is directly involved in cellular 
stress-induced inhibition of synaptic plasticity and resulting formation of memory deficits (38TLynch, 
201038T; 38TPrieto, 201538T; 38TSandersen et al, 201638T).   
Pathologically, Alzheimer’s disease (AD) is defined of two distinct abnormalities: amyloid plaques and 
neurofibrillary tangles (NFTs).  The major constituent of amyloid plaques is amyloid-beta, and of NFTs is 
tau.  These 2 proteins have long been considered important in the development of AD.  While much 
scientific controversy exists on the relative contribution of the various pathogenic drivers, there is general 
agreement that the disease is a result of interplay between those 2 proteins (amyloid-beta and tau), but 
also with inflammation.  In addition, increasingly it appears the convergence point for the three drivers is 
the synapse, with synaptic dysfunction and loss being the fundamental pathogenic event within the neuron 
that leads to the defining characteristic of AD, memory deficits (38TSpires-Jones & Hyman, 201438T). 
Extensive scientific literature indicates p38 alpha is a critical contributor in the toxicity of amyloid-beta, 
inflammation (particularly the cytokine interleukin-1 beta [IL-1beta]), and tau to neurons and synapses 
(38TLi et al, 200338T; 38TLi et al, 201138T; 38TLynch, 201038T; 38TWatterson et al, 201338T; 38TBirnbaum et al, 201538T; 38TKoppensteimer 
et al, 201638T).  The most direct evidence of the contribution of p38 alpha in the development of synaptic 
dysfunction and memory deficits is from distinct animal models in which memory deficits are induced by 
amyloid-beta, inflammation, or tau, respectively.  In these models, the memory deficits are fully reversed 
with 2 to 3 weeks of treatment (38TRoy et al, 201538T; 38TAlam, 201538T; 38TMaphis et al, 201638T).  These data are 
consistent with multiple mechanistic in vitro studies in which p38 alpha plays a significant role in 
amyloid-beta and IL-1beta induced impairment of synaptic plasticity (38TWatterson et al, 201338T; 38TTong et al, 
201238T; 38TPrieto et al, 201538T).  Synaptic plasticity otherwise is the basic biochemical process by which 
information is encoded in the brain and therefore a process that is critical to learning and memory 
formation. 
Three recent scientific publications, in which p38 alpha activity was genetically knocked down by 50% in 
mice, suggest that p38 alpha activation is involved in hippocampal synaptic dysfunction.  In a 
hypertension-induced cognitive impairment model, mice with reduced p38 alpha activity had improved 
hippocampal synaptic plasticity (38TDai et al, 201638T); in another model, similar mice were protected from 
developing age-related hippocampal dysfunction and decline in neurogenesis (38TCortez et al, 201738T).  In the 
third report, and perhaps most important, genetic reduction of neuronal p38 alpha in Amyloid-Precursor-
Protein (APP) overexpressing transgenic mice resulted in improved synaptic transmission and plasticity 
in addition to reduced memory loss and amyloid pathology (38TColié et al, 201738T). 


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1.2. 
Pre-Clinical Pharmacology Results 
To obtain preclinical proof-of-principle, neflamapimod was tested in the aged rat model of age-related 
cognitive decline.  When tested in a water maze test, rats show cognitive deficits starting at 20 to 
22 months of age.  This deficit has been shown to be a result of impaired synaptic plasticity that is 
primarily due to inflammation (38TKelly, 200338T; 38TLynch, 201038T); however, it also due to increased levels of 
amyloid beta in the brain due to aging (38TChurch, 201438T).  Thus, aged rats provided an ideal model system to 
test whether neflamapimod could reverse impaired synaptic plasticity due to inflammation and amyloid-
beta. 
The published results (38TAlam, 201538T) showed that neflamapimod administered for 3 weeks fully reversed 
the spatial learning deficits in the morris-water-maze-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 advance of the Phase 2a clinical studies neflamapimod was also tested in aged-transgenic mice that 
overproduce APP and develop amyloid plaque.  In this model, neflamapimod appeared to decrease 
amyloid plaque burden in the hippocampus, a finding that provided the rationale for utilizing positron 
emission tomography (PET) amyloid scanning as a biomarker of drug effect in one of the two phase 2a 
clinical studies. 
More recently, neflamapimod 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 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 p38 alpha (refer to Section 1.1), the demonstrated of positive pharmacological effects of 
neflamapimod may be due to reversing proteostasis defects within the neuron 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 
Phase 1 studies in healthy subjects and a Phase 2a clinical study in patients with rheumatoid arthritis (RA) 
were previously conducted by the company that discovered neflamapimod, Vertex Pharmaceuticals.  
Approximately 150 health volunteers or patients with RA for up to 3 months received neflamapimod in 
the studies conducted by Vertex. 


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EIP Pharma licensed neflamapimod from Vertex in 2014 and initiated two phase 2a studies in patients 
with mild AD in May 2015:  Study 302, a 12-week treatment study conducted at VU Medical Center in 
Amsterdam, Netherlands; and Study 303, a 6-week treatment study conducted at the Early Clinical Phase 
Unit - Los Angeles, part of Parexel International.  Both studies enrolled patients with early AD, defined as 
patients with either mild cognitive impairment (MCI) with biomarker evidence of AD (i.e., “MCI due to 
AD”) or mild Alzheimer’s disease.  The Mini-Mental State Examination (MMSE) scores at baseline were 
between 20 and 28.  Neflamapimod doses of 40 mg and 125 mg twice a day (BID) were utilized in Study 
302; and effectively only 40 mg was utilized in Study 303 (one subject received 125 mg, but their plasma 
drug levels were near the middle of the 40 mg recipients in that study).  
The major efficacy findings from the Phase 2a clinical studies were: 
• 
Statistically significant improvement in tests of the recall component of episodic memory, as 
assessed by Wechsler Memory ScaleP®
P (WMS) immediate and delayed recall composite measures 
in Study 302, and Hopkins Verbal Learning Test – Revised (HVLT-R) in Study 303.  Though 
there were no placebo-control in either study, the consistency and magnitude of improvement 
indicates that there is a true drug effect, particularly in this patient population where the literature 
indicates there is less practice effects than in a healthy elderly population (see further discussion 
below). 
• 
Reductions in brain amyloid plaque load at the 40 mg dose level, as assessed in Study 302 by 
quantitative dynamic amyloid PET scan.  As neuronal p38 alpha has been shown to play a 
“critical role” in amyloid beta generation and plaque production (38TSchnoder et al, 201638T), this result 
is likely due to inhibition of p38 alpha within the neuron leading to decreased amyloid plaque 
production; thus, providing evidence of target engagement of neflamapimod in the neuron at the 
40 mg dose level.  At the higher dose level, this effect is not seen due to anti-inflammatory effect 
due to inhibition of p38 in microglia that reduces amyloid plaque clearance.   
• 
Definition of 40 mg BID as the optimal dose for neflamapimod in the treatment of AD based on 
this does level having positive effects on both recall component of episodic memory and amyloid 
plaque load. 
• 
In addition, neflamapimod at a dose level up to 125 mg BID for 12 weeks was well tolerated in 
patients with AD.  In addition, neflamapimod was confirmed to be blood-brain-barrier penetrant 
in humans. 
Because the episodic memory tests inform directly on the design of the current study, the results are 
discussed in more detail in this section. 
In Study 302 (12-week study in Netherlands), episodic memory was evaluated using the Dutch version of 
the WMS scale utilizing both verbal and visual information:  Logical Memory test, in which subject is 
read a story; Verbal-Paired Associates, in which subject is given pairs of words and asked remember 
which words go together; and Visual Reproduction, in which subject is given drawings of specific shapes.  
Subjects were then asked to recall the information within each test both in an immediate (WMS-
Immediate Recall composite) and delayed (WMS-Delayed Recall composite) basis.  The WMS was 
administered at baseline (i.e., before first dose of neflamapimod), after 28 days of treatment, and at end of 
treatment on Day 84.   


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Mean WMS immediate recall composite scores increased from 48.4 (±3.8) at baseline to 58.4 (±4.3) at 
Day 84 (n=15; p=0.005 by Wilcoxon sign rank test for improvement).  Mean WMS delayed recall 
composite scores increased from 13.2 (±2.3) at baseline to 22.1 (±4.1) at Day 84 (p<0.001).  Seven of 
8 patients in 40 mg group and 6 of 7 in 125 mg group showed improvement from baseline in immediate 
recall composite score; 8 of 8 patients in 40 mg group and 6 of 7 in 125 mg group showed improvement 
from baseline in delayed recall composite score. 
To further understand the impact of neflamapimod on episodic memory as assessed by WMS, an analysis 
of the relationship between plasma drug (neflamapimod) concentrations and outcome on WMS immediate 
and delayed recall tests was conducted.  Using a standard linear pharmacokinetic-pharmacodynamic (PK-
PD) regression model, a highly significant positive correlation was established between plasma drug 
levels and level of improvement at Day 84 in combined WMS-immediate and delayed recall (p=0.001).  
Moreover, plasma drug levels explained 70% (i.e., rP2
P=.70) of the variance in change (improvement) from 
baseline to end-of-treatment.  These statistics strongly argue that the improvement seen in episodic 
memory in this study was primarily due to neflamapimod treatment, and not due to chance or practice 
effects.  In addition, the concentration dependency of the effects on episodic memory in the plasma drug 
levels achieved with the dose range of 40 mg to 125 mg that there is no rationale for going to lower doses, 
as they would simply lead to lower efficacy; while the difference in plasma drug concentrations achieved 
with the two doses, and therefore effect on episodic memory, were not substantial. 
In Study 303 (6-week study in Los Angeles), the HLVT-R was utilized to assess episodic memory.  In 
this test, 12 specific words from a list are provided verbally, and subject asked to recall ask many words 
as possible.  Two scores are calculated: 
• 
Total (Immediate) Recall Score (0-36):  combined score of 3 consecutive trials immediately 
following provision of words.   
• 
Delayed Recall Score (0-12): Number of words recalled when subject is asked 20-25 minutes 
after initial trials to recall as many of the words originally provided. 
A strength of the HVLT-R is that 5 different validated version exist that incorporate different set of 
words.  Due to the use of these different versions during the course of a clinical study, there is essentially 
no practice effect (Benedict,38T et al, 199838T) with repeated administration. 
Mean Total Recall improved from 19.1 (±1.5) at Baseline to 22.6 (±2.1) at week 6 (p=0.015 for 
improvement from baseline); Delayed Recall increased from 5.4 (±0.6) to 7.5 (±1.1) (p=0.028 for 
improvement from baseline).  Median increase in Total Recall score was 4.5 (range: -2.5 to +9.5), with 
only one subject with a decrease during treatment.  Particularly with the use of alternate versions that 
should minimize “placebo effects”, the consistency of improvement and statistics indicates that the 
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To further evaluate and compare the episodic memory results, treatment effect sizes (ES; called Cohen’s d 
in statistics) were calculated for each study/measure.  The results are shown in the following table: 
 
Study 303 (N=15) 
(Wechsler Memory Scale) 
Study 303 (N=8) 
(HLVT-R) 
Immediate Recall 
.59 
.69 
Delayed Recall 
.69 
.86 
 
The ES calculations show first that the results are very similar between the two studies, i.e., there is a high 
degree of consistency between the studies despite the use of different measures and tests being applied in 
different languages/cultures.  The magnitude of the ES ranging between 0.59 and 0.86 also argues for a 
true drug effect, as in MCI and Alzheimer’s patient population, ES for improvement in placebo groups are 
generally <0.2 (38TGoldberg et al, 201538T) in short-term studies, and often show either no change or worsening 
after 12 weeks or longer follow-up (38TScheltens et al, 201138T; 38THassenstab et al, 201538T).  In addition, as ES >0.5 
is generally taken as being clinically meaningful, ES calculations allows an assessment of whether the 
magnitude of treatment effect is clinically relevant; which in this case appears to be so.   
MMSE scores were evaluated in the 2 studies  Though the variability in MMSE results and the samples 
sizes did not allow one to do statistical analyses, the overall trends were encouraging as 11 of 14 subjects 
at the 40 mg dose level across the 2 studies that had baseline and end-of-treatment had at least a 1-point 
improvement in MMSE score. 
With the consistent effect on recall component of episodic memory across the 2 studies, and corroboration 
using 2 different assessment tools in distinct patient populations, the phase 2a clinical data provide 
preliminary evidence that neflamapimod is pharmacologically active in a manner that is consistent with 
the scientific rationale and preclinical data that indicate the potential to reverse synaptic dysfunction in 
the hippocampus.  The objective of the current study then is to demonstrate proof-of-concept for 
neflamapimod by replicating the phase 2a results of improving episodic memory function in a placebo-
controlled study.  In addition, a general clinical measure of cognition and function (Clinical Dementia 
Rating Scale [CDR]) will be assessed both to determine whether there is evidence of improvement and 
estimating potential treatment effects to support Phase 3 study design. 
From a mechanism standpoint the expected effect of neflamapimod on episodic memory through 
reversing synaptic dysfunction, possibly through reversing endolysosmal dysfunction within neurons.  In 
animals, the biomarker of inhibiting reversing synaptic dysfunction through inhibiting neuronal p38α is 
reduced amyloid beta generation and tau aggregation (38TColié et al, 201738T; 38TMaphis et al, 201638T), which in 
humans might be expected to lead to reduced CSF Aβ peptides levels and CSF total or phospho-tau.  
Therefore, to provide additional support of an objective drug effect and to support mechanistic 
understanding of drug effect, CSF will be collected at baseline and at end-of-treatment to assess effects of 
neflamapimod on CSF levels of total tau, p-tauR181
R, AβR1-40
R, AβR1-42, and neurogranin.  In addition, 
neurofilament light chain in CSF, recently identified as potential marker of neurodegenerative diseases 
associated with proteostasis defects (38TBacioglu, 201638T) will be evaluated.   


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2. 
OBJECTIVES 
2.1. 
Primary Objective 
• 
To evaluate the effect of administration of neflamapimod (VX-745) for 24-weeks on immediate 
and delayed recall aspects of episodic memory, as assessed by the HVLT-R in subjects with mild 
AD. 
2.2. 
Secondary Objectives 
• 
To evaluate effects of neflamapimod on immediate and delayed recall of Logical Memory (LM), 
Verbal Paired Associates (VPA) and Visual Reproduction (VR) components of the WMS. 
• 
To evaluate effects of neflamapimod on the CDR-Sum of Boxes (SB) and MMSE. 
• 
To evaluate the effects of neflamapimod on AD-related CSF biomarkers (total tau, p-tauR181
R, 
AβR1-40
R, AβR1-42
R, neurogranin, and neurofilament light chain).  


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study of 
neflamapimod 40 mg or matching placebo administered twice daily for 24 weeks in subjects aged 55 to 
85 years with CSF biomarker-confirmed AD; with global CDR score of 0.5 or 1.0, with CDR memory 
subscore of at least 0.5, and MMSE scores between 20 and 28, inclusive. 
A schedule of assessments is presented in Table 6-1.  
3.1.1. 
Screening 
Following completion of informed consent procedures, subjects will enter the Screening phase of the 
study. 
Two screening visits are planned to allow most screening procedures to be completed and reviewed 
during the first visit before lumbar puncture to collect CSF to be performed on Screening Visit 2.  
All screening assessments should be conducted within 42 days of Day 1 (first dose of study drug). 
3.1.2. 
Treatment Period 
Once eligibility is confirmed and before the first dose of study drug, subjects will be randomly assigned 
to receive neflamapimod or placebo; refer to Section 5.4 for details regarding assignment to treatment 
group. 
Dosing will start on Day 1, following completion of all Baseline procedures.  During the treatment period, 
subjects will return to the clinic on Days 21, 42, 84, 126, and 168.  Telephone contacts will be conducted 
to determine subject status and assess compliance between Days 42 and 84 (Visits 5 and 6); Days 84 to 
126 (Visits 6 and 7); and Days 126 and 168 (Visits 7 and 8). 
3.1.3. 
Follow Up 
A Follow-up Visit will be conducted 14 (±3) days following the last dose of study drug.  
3.1.4. 
Early Discontinuation 
Subjects who prematurely discontinue study drug for any reason will be asked to return to the clinical site 
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.  These subjects will also be asked to return to the 
clinical site for a Follow-up Visit 14 (±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 
The primary objective of assessing episodic memory was chosen to provide a robust assessment of the 
potential of neflamapimod to reverse hippocampal dysfunction in subjects with mild AD.  Defects in 
episodic memory are a defining characteristic of AD and is one of earliest manifestations of cognitive 


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dysfunction in the disease process (38TGold & Budson, 200838T; 38TTromp et al, 201538T).  In addition, neflamapimod 
demonstrated effects on episodic memory in the Phase 2a studies. 
The HVLT-R test was chosen as the assessment tool for the primary endpoint because it has alternative 
versions validated in multiple cultural and language contexts, has high test-retest reliability, and shows 
good short-term stability (i.e., no practice effects) in subjects with mild AD (38TPhillips et al, 201238T). 
3.2.1. 
Rationale for Dose Selection 
The dosing regimen of 40 twice daily for 24 weeks is based on available efficacy (pharmacological 
activity; Section 3.2.1.1) and safety (Section 3.2.1.2) data.   
3.2.1.1. 
Efficacy Considerations 
The 40 mg BID regimen was chosen because PK-PD modeling (plasma drug concentration response) 
correlations indicated a plasma drug concentration dependency on the effects on episodic memory that 
argues against going to lower doses and only modest further increase in efficacy with utilizing 125 mg 
dose level, while the loss of an amyloid plaque load effect at 125 mg dose level provides a specific reason 
not to increase the dose above 40 mg.  The PK-PD modeling was also consistent with the in vitro potency 
of the drug and predicted doses for optimal cognitive effects based on pre-clinical studies (38TAlam, 201538T).  
Moreover, the 40 mg dose level provides an appropriate safety margin relative to findings in chronic 
toxicology findings in the dog (Section 3.2.1.2). 
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 dose of 40 mg BID and lower is expected to be well tolerated and to have a low risk of 
drug toxicity.  
In the Phase 2a studies (Study 303) of 6- or 12-weeks neflamapimod dosing in patients with mild 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 neflamapimod 
administration, and 16 completing 12 weeks neflamapimod administration).  The one subject who 
discontinued early did so within the first week of study drug administration due to an adverse event (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-limited 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 liver function tests (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 different formulations in the RA studies, the plasma drug concentrations were 4- to 5-fold higher 
than in the Phase 2a mild AD studies. 
The 40 mg BID dose level provides a 5-fold margin based on plasma drug levels to no adverse effect 
level and 10-fold margin to minimal and/or equivocal findings for hematological, hepatic and 


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neuropathological changes in chronic (9- and 12-month) dog toxicology studies.  Further details are 
provided in the investigator brochure. 


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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 age 55 to 85 years, inclusive. 
2. Willing and able to provide informed consent. 
3.  Must have MCI or mild AD with evidence of progression (“Mild-AD”), as defined by the 
following: 
a. CDR-Global Score of 0.5 or 1.0, with CDR memory subscore of at least 0.5. 
b. MMSE score ranging from 20 to 28, inclusive. 
c. Positive biomarker for AD, as defined by a CSF Aβ1-42
R below the threshold and phospho-tau 
above the threshold for the assay utilized in the study and assessed by the central laboratory. 
4. Computed tomography (CT) or magnetic resonance imaging (MRI) findings within 2 years of 
Screening that are compatible with AD (i.e., no other pathologic processes that would account for 
the cognitive deficit). 
5. If the subject is taking a single drug for AD (e.g., donepezil or other cholinesterase inhibitors or 
memantine; dual therapy is excluded), he/she has been on a stable dose for at least 2 months prior 
to baseline, and the dose must remain unchanged during the study unless required for 
management of AEs. 
6. Adequate visual and auditory abilities to perform all aspects of the cognitive and functional 
assessments. 
7. Must have reliable informant or caregiver.  In Czech Republic only, the caregiver must be either 
sharing the same household as the subject or be in personal contact with the subject at least 5 days 
per week. 
4.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for enrollment in this study: 
1. Evidence that the primary basis for cognitive impairment is neurodegenerative disease other than 
AD, including, but not limited to, vascular dementia, dementia with Lewy bodies, and 
Parkinson’s disease. 
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. History of major and active psychiatric disorder, moderate to severe depressive symptoms, 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. History of cancer within the last 5 years, except basal cell carcinoma, squamous skin carcinoma, 
prostate cancer or carcinoma in situ with no significant progression over the past 2 years. 
6. 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 preclude treatment with p38 mitogen activated protein (MAP) kinase inhibitor and/or 
assessment of drug safety and efficacy. 
7. History of serum B12 abnormality, anemia with hemoglobin ≤10 g/dL, thyroid function 
abnormality, electrolyte abnormality, or positive syphilis serology that have not been corrected 
and/or otherwise addressed. 
8. History of epilepsy or unexplained seizure within the past 5 years. 
9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit of 
normal (ULN), total bilirubin >1.5 × ULN, and/or International Normalized Ratio (INR) >1.5. 
10. Known human immunodeficiency virus or active hepatitis B or hepatitis C virus infection.  
11. Subject participated in a study of an investigational drug less than 3 months or 5 half-lives of the 
investigation drug, whichever is longer, before enrollment in this study. 
12. Male subjects with female partners of child-bearing potential who are unwilling or unable to 
adhere to contraception requirements (Section 5.8)  
13. Female subjects who have not reached menopause or have not had a hysterectomy or bilateral 
oophorectomy/salpingo-oophorectomy.  
• 
If a female subject reached menopause within the previous year, a pregnancy test must be 
performed during Screening and the subject must be willing to adhere to the contraception 
requirements specified in the protocol.  Such subjects with a positive urine or serum pregnancy 
test are not eligible for study participation. 
14. Requires concomitant use of strong cytochrome P450 (CYP) 3A4 inhibitors or anti-tumor necrosis 
factor-alpha therapies during study participation (see Section 5.7). 
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 6.2.12). 
The subject must be discontinued from the study for the occurrence of an unacceptable toxicity, including 
any of the following: 
• 
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. 


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Refer to Section 3.1.4 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.   
Subjects who withdraw from the study treatment and/or study for a reason prior to Day 21 will be 
replaced.  


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5. 
TREATMENTS ADMINISTERED 
Neflamapimod 40 mg capsule(s) or matching placebo capsules will be administered orally, BID with a 
meal or snack for 24 weeks.  Doses should be taken within 30 minutes following a meal or snack (i.e., 
breakfast and dinner) no less than 8 hours apart and at approximately the same times each day throughout 
the study. 
All subjects will receive matched (by size and color) capsules that contain 40 mg neflamapimod or 
placebo, respectively. 
The first dose of study drug and the morning dose on Day 21 will be administered at the clinical site.  
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. 
5.1. 
Packaging and Labeling 
EIP Pharma will supply placebo or neflamapimod capsules 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 a per-subject basis.  
Capsules will be supplied in blister cards, which each blister card containing 16 capsules (i.e., 1-week 
supply of study, with two extra capsules).  The blister cards will be packaged in cartons containing a 
3-week supply of study drug (i.e., 3 blister cards per carton). 
Neflamapimod capsules should be stored at 59 to 86°F (15–30°C; controlled room temperature), and 
should not be exposed to heat in excess of 86°F (30°C) or to high humidity. 
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 site from subject on the drug accountability log(s).   
Subjects will be instructed to return all blister packs, 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.   


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5.4. 
Method of Assigning Subjects to Treatment Group 
After subjects have completed Screening Visit 2 and are deemed eligible, they will be randomized in a 
blinded manner to either placebo or neflamapimod treatment utilizing a central Interactive Web Response 
System (IWRS).  Study drug for the entire 24-week period will then be sent on a per subject basis to the 
site.  Randomization will be stratified by 1) background AD-specific therapy (cholinesterase inhibitor or 
memantine versus no cholinesterase inhibitor or memantine); and 2) CDR-Global Score of 0.5 versus 1.0. 
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 may 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 Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) and the Medical Monitor and/or Sponsor as 
soon as possible, preferably by telephone and then in writing, regarding the necessity of code breaking. 
When possible, the Medical Monitor should be contacted to discuss reasons for breaking the blind.  
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 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.  
At study entry, any subject taking a drug for AD (e.g., donepezil or other cholinesterase inhibitors or 
memantine) must have been on a stable dose for at least 2 months (refer to Section 4).  Furthermore, the 
dose must remain unchanged during the study, unless required for management of AEs. 
While drug-drug interaction studies have not been conducted, in vitro testing indicates that neflamapimod 
is metabolized by oxidation in the liver by the CYP system (combination of CYP3A4 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 in could impact neflamapimod metabolism in subjects who have 
an underlying CYP2C19 genotypic variant that impacts activity of that CYP2C19.  Subjects will be tested 
for CYP2C19 genotype at baseline to assess any differences in neflamapimod levels and effect (see 
Section 6.2.5).   


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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.  
• 
Any anti-tumor necrosis factor-alpha therapy. 
• 
Typical and atypical antipsychotics. 
The Medical Monitor should be contacted with any questions regarding concomitant use of medications 
that are thought to modulate CYP3A4 activity. 
Table 5-1: 
CYP3A4 Inhibitors 
Strong Inhibitors 
≥5-fold increase in AUC  
or >80% decrease in CL 
Moderate inhibitors 
≥2 but <5-fold increase in AUC 
or 50-80% decrease in CL 
Weak inhibitors 
≥1.25 but <2-fold increase in AUC 
or 20-50% decrease in CL 
boceprevir 
cobicstat 
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 
 
 


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Table 5-2: 
CYP3A4 Inducers 
Strong Inducers 
≥80% decrease in AUC 
Moderate Inducers 
50-80% decrease in AUC 
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: 
• 
Inclusion criterion #1 (Section 4.1) and Exclusion criteria #12 and #13 (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) are not eligible for the study.  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: complete abstinence, vasectomy, or barrier method of contraception. 
Pregnancy of a female partner of a male subject (and, although unlikely, in a female subject) 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.  In the unlikely event a female 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. 


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5.9. 
Activity Restrictions 
The Investigator is to advise subjects to take measures to minimize exposure to ultraviolet light during 
study participation through 2 weeks after the last study drug dose.   
5.10. 
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.  
Patients will be provided with identification cards on which they will record the date and time of study 
drug administration prior to each scheduled study center visit. 
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 / Visit Number / Study Day 
ScreeningPa 
Treatment Period 
ET VisitPc 
Follow- 
Up VisitPd 
1Pa 
2Pa 
3 
4 
5 
6 
7 
8 
Within 
42 days of D1 
1Pb 
21 
(±3) 
42 
(±3) 
84 
(±5) 
126 
(±5) 
168 
(±5) 
Within 
3 days 
after last 
dose 
14 (±3) of 
last dose 
Informed Consent 
XPe 
 
 
 
 
 
 
 
 
 
Medical history review 
X 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
XPf 
 
 
 
 
 
 
 
 
 
Physical examinationPg 
X 
 
 
 
 
 
 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
recordingPh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
chemistryPi 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Coagulation studiesPi 
X 
 
 
 
 
X 
 
 
 
X 
12-lead 
electrocardiogramPj 
X 
 
 
 
 
 
 
X 
X 
 
MMSEPk 
X 
 
X 
 
 
X 
 
 
 
X 
CT/MRIPl 
 
X 
 
 
 
 
 
 
 
 
HVLT-R and WMSPk 
 
 
X 
 
X 
X 
 
X 
X 
 
CDR 
X 
 
 
 
 
X 
 
X 
X 
 
Lumbar puncturePm 
 
X 
 
 
 
 
 
Xn 
Xn,o 
 
Dispense study drugPp 
 
 
X 
X 
X 
X 
X 
 
 
 
Pharmacokinetic 
samplingPq 
 
 
 
X 
X 
X 
 
 
 
 
CYP2C19 genotyping 
and optional ApoE4 
testingPr 
 
 
X 
 
 
 
 
 
 
 
Final study drug 
reconciliation 
 
 
 
 
 
 
 
X 
X 
 
CDR:  Clinical Dementia Rating Scale; C-SSRS:  Columbia-Suicide Rating Scale; CT:  Computed tomography; D=day; HVLT-
R:  Hopkins Verbal Learning Test – Revised; MMSE: Mini-Mental State Examination; MRI:  Magnetic resonance imaging; 
WMS: Wechsler Memory Scale. 
Note:  Telephone contacts will be conducted to determine subject status and assess compliance between Days 42 and 84 (Visits 5 
and 6); Days 84 to 126 (Visits 6 and 7); and Days 126 and 168 (Visits 7 and 8).   


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a. 
Two Screening visits are planned to allow most screening procedures to be completed and reviewed during the first visit 
before lumbar puncture is performed at Visit 2.  All screening assessments should be conducted within 42 days of Day 1. 
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 clinical site 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 6.2.9 for details regarding physical examination.  
h. 
Definitions and procedures for documenting and reporting AEs serious adverse events (SAEs) are provided in Section 7. 
i. 
Details of clinical laboratory sampling for chemistry, hematology, and coagulation studies are discussed in Section 6.2.11. 
j. 
Details of 12-lead ECG assessment are discussed in Section 6.2.10. 
k. 
Refer to the following sections for details of cognitive assessments Section 6.2.6 (MMSE, CDR), and Section 6.2.7 (NTB – 
HVLT-R/WMS. 
l. 
MRI/CT results should be available and reviewed before lumbar puncture is performed. 
m. Perform lumbar puncture (LP) only after subject has been deemed eligible based on all other inclusion/exclusion criteria, 
e.g. MRI, labs etc. Refer to Section 6.2.4 for details regarding LP. 
n. 
LP is to be performed within ±2 days of the last study drug dose.   
o. 
LP need not be performed at the ET visit for patients who discontinue prior to Visit 5 (Day 42). 
p. 
Study drug details including packaging, storage, accountability, and dosing are presented in Section 5. 
q. 
Refer to Section 6.2.8 for details regarding PK sampling. 
r. 
CYP2C19 genotyping is mandatory; testing for apolipoprotein E is optional. (Apoliprotein E results may be disclosed to 
subject at the end of the study.)  
6.2. 
Study Assessments 
6.2.1. 
Baseline and Disease Characteristics  
Details regarding AD history will be collected during Screening, as specified in the eCRF. 
6.2.2. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a clinician-administered instrument that assesses suicidal ideation and behavior (38TPosner, 
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. 
6.2.3. 
Computed Tomography/Magnetic Resonance Imaging 
The subject must have had MRI or CT scan within 2 years of Screening, with findings negative for 
evidence of other neurodegenerative or other brain disease that could account for their cognitive 
symptoms.  If MRI or CT has not been performed within 2 years before Screening and/or results are not 
available, MRI or CT scan must be performed as part of Screening to exclude other disease.  MRI/CT 
results should be available and reviewed before Screening lumbar puncture is performed (see Section 
6.2.4). 
6.2.4. 
Lumbar Puncture 
LP will be performed at Screening Visit 2 and at the End-of-Treatment (Day 168 or Early Termination 
visit in subjects who discontinue treatment early).  The End-of Treatment LP is to be performed within 


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±2 days after the last study drug dose.  There is no need to perform the LP for subjects who discontinue 
prior to Visit 5 (Day 42). 
Kits for collection of CSF samples will be provided.  CSF levels of total tau, p-tauR181
R, AβR1-40
R, AβR1-42
R, 
neurogranin, and neurofilament light chain will be determined by enzyme-linked immunosorbent assay at 
a designated central laboratory.  
6.2.5. 
Genotyping and Apolipoprotein E4 Testing 
A blood sample will be collected from all subjects at Visit 3 (Day 1) for CYP2C19 genotyping; such 
testing is mandatory.  The CYP2C19 gene encodes for a drug metabolizing enzyme that accounts for 
approximately half the metabolism of neflamapimod.  (The other is the CYP3A4 enzyme).  As there are 
known polymorphisms in CYP2C19, particularly in Asian populations, that reduce the function of this 
enzyme, the PK profiles in individual subjects may be impacted CYP2C19 genotype (38TFricke-Galindo et 
al, 201638T).  PK profiles will be obtained in all subjects and correlated against CYP2C19 genotype (see 
Section 6.2.8 and Section 8.4).  An aliquot of blood from this sample may also be used for measurement 
of apolipoprotein E4; such testing is optional.  Results will be available to study sites and may be 
discussed with the subjects only after the clinical study report has been completed.  
6.2.6. 
Mini-Mental State Examination/CDR 
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. 
The 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 (MCI), and is an approved regulatory endpoint recognized by 
the FDA.  The CDR interview is to be conducted with the subject and Caregiver by an experienced and 
certified clinician.  The CDR yields both a global and an SB score.  The global CDR rating, along with 
the memory box score, will be used to determine a subject’s eligibility for inclusion.  In addition, the 
CDR-SB score will utilized to evaluate cognitive and functional changes from baseline to Visit 6 and 
Visit 8.   
Standardized MMSE (Version 2.0) and CDR will be conducted by the Investigator or designee. 
6.2.7. 
Episodic Memory Tests - HVLT-R and WMS 
The HVLT-R is a verbal learning and memory test, with 6 validated alternate forms.  Each form contains 
12 nouns, 4 words each from 1 of 3 semantic categories (e.g., precious gems, articles of clothing, 
vegetables), to be learned, and repeated back to the evaluator over the course of 3 learning trials.  
Approximately 20–25 minutes later, a delayed recall trial and a recognition trial are completed.  The 
delayed recall requires free recall of any words remembered.  The recognition trial is composed of 
24 words, including the 12 target words and 12 false-positives, 6 semantically related, and 6 semantically 
unrelated.  The 3 learning trials are combined to calculate a total recall score; the delayed recall trial 
creates the delayed recall score. 
For WMS, Logical Memory I & II & II-(Recognition), VPA I & II & II-(Recognition), and Visual 
Reproduction I & II & II-(Recognition) will be applied. 


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The HVLT-R and WMS tests must be performed sequentially within the day; with the HVLT-R to be 
conducted first and completed (including delayed recall component), prior to commencing WMS test. 
6.2.8. 
Pharmacokinetic Sampling 
On Day 21, the subject must not take their morning dose of study drug; instead, the morning dose of the 
study drug will be administered with a meal or snack in the clinic, and blood samples will be collected for 
PK (drug concentration) testing immediately prior to and 2.5 hours after study drug administration (i.e., at 
predicted time point for peak drug concentration after dose administration).  On Day 42 and Day 84, 
blood samples will also be collected for PK sample concurrently with clinical laboratory test sampling 
during the time of their visit to the clinic.  Subjects should take their morning dose of study drug at home 
with a meal or snack on Day 42 and 84 on their regular schedule and record the time of their morning 
dose.  Day 42 and Day 84 PK samples will be collected together with the safety laboratory samples at the 
clinic, the time of the PK sampling must be recorded.  
Refer to the Laboratory Manual for details regarding PK sample collection, processing, and shipment.   
6.2.9. 
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.  
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). 
6.2.10. 
12-Lead Electrocardiogram 
A 12-lead ECG will be performed using validated machinery available locally to each clinical site.  Each 
report will be reviewed by the Investigator for qualified sub-investigator and assessed as normal, 
abnormal – not clinically significant, or abnormal – clinically significant.  Abnormal, clinically significant 
findings that represent a worsening from Baseline will be recorded as an AE. 
6.2.11. 
Clinical Laboratory Assessments 
Two blood samples will be collected at the time points specified in Table 6-1 for assessment of routine 
chemistry and hematology analytes.  One additional blood sample will be collected for coagulation 
studies at the time points specified in Table 6-1.  
Kits for clinical laboratory assessments will be provided by and samples will be analyzed at a designated 
central laboratory.  Additional details are provided in the Laboratory Manual. 


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Table 6-2 
Clinical Laboratory Analytes 
Serum Chemistry  
Hematology 
• 
Albumin 
• 
Alkaline phosphatase 
• 
ALT 
• 
AST 
• 
Bilirubin (total and direct) 
• 
Glucose 
• 
Blood urea nitrogen 
• 
Calcium 
• 
Bicarbonate 
• 
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 (PT) 
• 
Partial thromboplastin time (PTT) 
• 
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). 
6.2.12. 
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 assent) 
• 
Subject lacks ability to provide continued informed consent (or assent) and/or sound judgement 
as to whether to continue in the study 
• 
Subject develops active suicidal ideations or attempts suicide 
• 
Subject is not compliant with study procedures 


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• 
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.   
Subjects who withdraw from the study treatment and/or study for a reason prior to Day 21 will be 
replaced.  
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. 
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. 
• 
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. 


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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 
7.2. 
Reporting Procedures and Requirements 
7.2.1. 
Adverse Events 
AEs occurring from when the subject signs the informed consent form (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. 


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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, (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 
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 as outlined 
below and also to the IRB/IEC according to its standard operating procedures. 
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 Worldwide 
Clinical Trials. 
SAE Reporting: 
E-mail:  drugsafety@worldwide.com 
Telephone:  +44 (0)115 922 0960 
All information about SAEs will be collected and reported via the SAE form and sent by e-mail message 
or facsimile (contact information will be contained in the investigator site file).  The Investigator should 
send the initial report within 24 hours of becoming aware of the SAE.  At minimum, the initial report 
should include the following information: 
• 
Event 
• 
Study code 
• 
Subject number, initials, and date of birth 
• 
Investigational product 
• 
Reporter name and contact information 
In the case of a “minimum report” (one that solely comprises the information bulleted above), a more 
detailed follow-up report should be sent as soon as more information becomes available but no later than 
7 calendar days after the date of the initial report.  Each SAE should be followed up until resolution or 
stabilization and for reported deaths, the Investigator should supply Worldwide Clinical Trials and the 
IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports). 
The original SAE form should be kept at the study site.  The Sponsor or its designee will be responsible 
for determining and in turn, reporting SAEs to regulatory authorities according to the applicable 
regulatory requirements. 
SAEs that are ongoing at the Follow-up visit should be followed until resolved. 


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8. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
8.1. 
Data Management and Quality Assurance Considerations  
This study will employ eCRFs.  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 institution 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 recorded by the person updating eCRF 
data 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 these 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 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 
Up to 76 subjects per treatment arm provides 90% power to detect ES of 0.53 and 80% power to detect 
ES of 0.46.  This level of ES is the minimum amount considered clinically relevant treatment effect and is 
less than the effect size seen in the Phase 2a studies; therefore, provides a statistical buffer to achieve a 
positive outcome, if the magnitude of treatment effect by chance is lower in the present study. 
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 has at 
least 1 post-dose HVLT-R assessment. 


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8.4. 
Pharmacokinetics (PK) 
Trough and maximum concentrations (CTrough and Cmax, respectively) will be evaluated on Day 21 (i.e.; at 
steady-state) for each subject and descriptive statistics for the neflamapimod treatment group will be 
presented.  In addition area under the time concentration curve (AUC) will be derived utilizing population 
PK methods utilizing drug concentration data from Day 21 as well the sparse sampling on Days 42 and 
84.  CTrough, Cmax and AUC will be correlated to CYP2C19 genotype status.  In addition, a PK/PD model 
for neflamapimod and effects on HVLT-R, WMS, CDR-SB, and/or CSF biomarkers will be developed 
post hoc based on the available data. 
8.5. 
Efficacy 
8.5.1. 
Primary Efficacy Variables 
The primary efficacy variable is: 
• 
Combined change in z-scores of total recall and delayed recall on the HVLT-R in neflamapimod-
treated subjects compared to placebo-recipients. 
To obtain a single statistic, the total recall and delayed recall scores will be converted to z-scores and the 
combined change in z-scores will be compared for the two treatment groups.  Specific statistical analyses 
for efficacy variables will be identified in a prospective Statistical Analysis Plan. 
8.5.2. 
Secondary Efficacy Variables  
The secondary efficacy variables are: 
• 
Change from Baseline to Week 24 in recall and recognition of the WMS, CDR-SB, 
MMSE, and CSF biomarkers (total tau, p-tauR181
R, AβR1-40
R, AβR1-42
R, neurogranin, 
neurofilament light chains) comparing neflamapimod-treated subjects with placebo-
recipients. 
8.6. 
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.   
8.7. 
Interim Analysis 
No interim analysis is planned.  Only pharmacokinetic data will be monitored by an independent clinical 
pharmacologist on an every 3-month basis without any reference to other study data or subject 
identification, with the exception of baseline demographics (age, weight, race) and CYP2C19 genotype. 


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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, US Investigational New Drug 
Application regulations (21 CFR 312) or local national laws (as applicable) and ICH guidelines for 
Good Clinical Practice.  These guidelines are on file at Worldwide Clinical Trials. 
9.1.2. 
Institutional Review Boards/Independent Ethics Committees 
Conduct of the study must be approved by an appropriately constituted IRB or 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 
IRB/IEC authorization has been received by the Sponsor or its designee. 
9.1.3. 
Informed Consent 
For each study subject, a written ICF will be obtained before 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) appointed guardian 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 
IRB/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 30 weeks, including 24 weeks of 
treatment.  Once the subjects have ended his 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. 
• 
Failure of the Investigator to enter subjects at an acceptable rate. 


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• 
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 Food and Drug Administration (FDA) 1572 or other country-specific 
regulatory forms, the Investigator acknowledges that he/she has received a copy of the investigator’s 
brochure 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. 
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 CRF was derived. 


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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 
Alam & Scheper.  Targeting neuronal MAPK14/p38α activity to modulate autophagy in the Alzheimer 
disease brain.  Autophagy 2016;12(12):2516-2520. 
Alam J. Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and 
Improves Morris Water Maze Performance in Aged Rats.  J Alzheimers Dis 2015;48(1):219-27. 
Baciouglu M et al.  Neurofilament light chain in blood and CSF as marker of disease progression in 
mouse models and in neurodegenerative diseases.  Neuron 2016;91:56-66. 
Birnbaum et al.  Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced 
synaptic loss.  Cell Death Dis 2015;6:e1791. 
Chollet F.  Pharmacologic approaches to cerebral aging and neuroplasticity:  insights from the stroke 
model. Dialogues Clin Neurosci 2013;15:67-76. 
Church RM et al. Amyloid-beta accumulation, neurogenesis, behavior, and the age of rats. Behav 
Neurosci 2014;128(4):523-36. 
Colié S et al.  Neuronal p38alpha mediates synaptic and cognitive dysfunction in an Alzheimer's mouse 
model by controlling beta-amyloid production. Sci Rep 2017;7:45306.  
Cortez et al.  Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult 
neurogenesis and context discrimination fear conditioning. Behav Brain Res 2017;322(Pt B):212-222. 
Duffy et al.  The discovery of VX-745: a novel and selective p38α kinase inhibitor.  ACS Med Chem Lett 
2011;2:758-763. 
Dai et al. p38 MAPK inhibition improves synaptic plasticity and memory in angiotensin II-dependent 
hypertensive mice. Sci Rep 2016;6:27600. 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive 
state of patients for the clinician. J Psychiatr Res 1975;12(3):189-98. 
Fricke-Galindo I et al.  Interethnic variation of CYP2C19 alleles, 'predicted' phenotypes and 'measured' 
metabolic phenotypes across world populations. Pharmacogenomics J 2016;16(2):113-23.  
Gold CA & Budson AE.  Memory loss in Alzheimer’s disease: implications for development of 
therapeutics.  Expert Rev Neurother 2008;8:1879-1891. 
Goldberg et al.  Practice effects due to serial cognitive assessment: implications for preclinical 
Alzheimer’s disease randomized controlled trials.  Alzheimers Dement (Amst) 2015;1:103-111. 
Hassenstab et al.  Absence of practice effects in preclinical Alzheimer’s disease.  Neuropsychology 
2015;29:940-948. 
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of 
dementia. Br J Psychiatry 1982;140:566-72. 
Koppensteiner et al. Time-dependent reversal of synaptic plasticity induced by physiological 
concentrations of oligomeric Aβ42: an early index of Alzheimer's disease.  Sci Rep 2016;6:32553.  


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Li S et al. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive 
activation of extrasynaptic NR2B-containing NMDA receptors.  J Neurosci 2011;31:6627-38. 
Li Y et al.  Interleukin-1 mediates pathological effects of microglia on  tau phosphorylation and on 
synaptophysin synthesis in cortical neurons through a p38-MAPK pathway.  J Neurosci 2003;23:1605-11. 
Kelly et al. Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and 
interleukin-1 beta on long term potentiation in rat dentate gyrus, J Biol Chem 2003; 278:19453-62. 
Lynch MA.  Age-related neuroinflammatory changes negatively impact on neuronal function.  Front 
Aging Neurosci 2010;1:6. 
Maphis et al. Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology.  
Alzheimers Res Ther 2016;8(1):54. 
Phillips et al.  No effect of omega-3 fatty acid supplementation on cognition and mood in individuals with 
cognitive impairment and probable Alzheimer’s disease:  a randomized controlled trial.  Int J Mol Sci 
2015; 16:24600-13. 
Posner K et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. Am J Psychiatry 2011;168:1266-1277. 
Prieto et al.  Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the 
aged hippocampus.  Proc Natl Acad Sci U S A 2015;112(36):E5078-87. 
Roy et al.  Targeting human central nervous system protein kinases: An isoform selective p38αMAPK 
inhibitor that attenuates disease progression in Alzheimer's disease mouse models.  ACS Chem Neurosci 
2015;6(4):666-80. 
Sanderson et al.  Hippocampal metabotropic glutamate receptor long-term depression in health and 
disease: focus on mitogen-activated protein kinase pathways.  J Neurochem 2016;139 Suppl 2:200-214. 
Scheltens et al.  Efficacy of souvenaid in mild Alzheimer’s disease: results from a randomized controlled 
trial.  J. Alzheimers Dis 2012;31:224-236. 
Benedict et al.  Hopkins Verbal Learning Test – Revised:  Normative data and analysis of inter-form and 
test-retest reliability.  Clin Neurophsychol. 1998; 12:43-55. 
Schnöder et al.  Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer 
Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.  J Biol Chem 
2016;291(5):2067-79. 
Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer's disease. 
Neuron 2014;82(4):756-71.  
Tong et al.  Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-
1β via p38 mitogen-activated protein kinase.  J Neurosci 2012;32(49):17714-24. 
Tromp et al.  Episodic memory in normal aging and Alzheimer disease: insights from imaging and 
behavioral studies.  Ageing Res Rev 2015;24:232-62. 
Watterson et al.  Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase 
Involvement in Synaptic Dysfunction.  PLoS One 2013;8(6):e66226. 

SAP_001.pdf: 
EIP Pharma, LLC 
EIP-VX17-745-304 
Statistical Analysis Plan 
Version Final 1.2 
Issue Date 30-JUL-2019 
Template: WCT-TP-ST-005-005 
Page 1 of 47 
Effective Date: 15-Apr-2016 
Confidential 
Statistical Analysis Plan 
A Double-Blind, Placebo-Controlled Proof-of-Concept Study of a Selective p38 
MAP Kinase Alpha Inhibitor, Neflamapimod, Administered for 24 Weeks in 
Subjects with Mild Alzheimer’s Disease 
Protocol Number: EIP-VX17-745-304 
Version Final 1.2 
Issue Date: 30-JUL-2019 
Author: Shuhua, Qi, MS 
NCT03402659


 
 
EIP Pharma, LLC 
 
EIP-VX17-745-304 
 
Statistical Analysis Plan 
 
Version Final 1.2 
 
Issue Date 30-JUL-2019 
 
Template: WCT-TP-ST-005-005 
 
Page 2 of 47 
Effective Date: 15-Apr-2016 
 
Confidential 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APP 
Amyloid-Precursor-Protein 
AST 
Aspartate aminotransferase 
AUC 
Area under the time concentration curve 
BID 
bis in die (twice a day) 
CDR 
Clinical Dementia Rating Scale 
CRmax 
Maximum concentration 
CNS 
Central Nervous System 
CT 
Computed tomography 
CRTrough 
Trough concentration 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ES 
Effect sizes 
FDA 
Food and Drug Administration 
HVLT-R 
Hopkins Verbal Learning Test – Revised 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee 
IL-1beta 
Interleukin-1 beta 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LFT 
Liver function test 
LM 
Logical Memory 
MAP 
Mitogen activated protein 
MCI 
Mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
 
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Version Final 1.2 
 
Issue Date 30-JUL-2019 
 
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Abbreviation 
Definition 
MMSE 
Mini-Mental State Examination 
MRI 
Magnetic Resonance Imaging 
NFT 
Neurofibrillary Tangle 
p38 alpha 
p38 mitogen activated protein kinase alpha 
PD 
Pharmacodynamic 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RA 
Rheumatoid arthritis 
SAE 
Serious adverse event 
ULN 
Upper limit of normal 
VPA 
Verbal Paired Associates 
VR 
Visual Reproduction 
WMS 
Wechsler Memory Scale 
 
 
 


 
 
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Issue Date 30-JUL-2019 
 
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SAP Amendments before database lock 
Version  
Issue Date 
Section 
Revision/Addition 
Rationale 
Final 1.2 
17-Jul-2019 
6.2.2 
Add following wordings: 
Visit 3 (Day 1) date is definded as 
the date of the first dose.  
Agreed by 
sponsor 
Final 1.2 
17-Jul-2019 
6.10.2 
Remove log transformaion 
Required 
by sponsor 
Final 1.2 
17-Jul-2019 
6.10.3 
Revises as follow: 
Original 
… baseline sum of total recall and 
delayed recall on the HVLT-R as the 
covariate ...  
 
Change to 
… baseline z-score as the covariate 
… 
Required 
by sponsor 
Final 1.2 
26-Jul-2019 
6.10.5 
The main change is to the subgroup 
analyses which should include 
disease severity (CDR 0.5 vs 1.0) as 
this was sponsor stratification along 
with AD background therapy.   
The analysis come out of 
exploratory 
Required 
by sposnor 
Final 1.2 
26-Jul-2019 
6.10.6 
Add additional subgroup analyses 
for primary and secondary endpoints 
as below: 
baseline body weight <80kg and 
those baseline body weight ≥80k 
 
disease severity (CDR 0.5 vs 1.0)   
 
Required 
by sposnor 
Final 1.2 
17-Jul-2019 
6.12 
Revision of PK parameters. 
Original 
Additional PK-PD exploratory 
analyses may be performed to 
further study the effects of the 
treatment via PK parameters (i.e. 
PPK model derived CTrough and 
Required 
by sposnor 


 
 
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EIP-VX17-745-304 
 
Statistical Analysis Plan 
 
Version Final 1.2 
 
Issue Date 30-JUL-2019 
 
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Cmax,, AUC, etc.) on HVLT-R, 
WMS, CDR, and/or CSF 
biomarkers, as warranted by data.  
 
Change to 
Additional PK-PD exploratory 
analyses may be performed to 
further study the effects of the 
treatment via PK parameters (i.e. 
CTrough and Cmax) on HVLT-R, 
WMS, CDR, and/or CSF 
biomarkers, as warranted by data. 
Nominal CTrough and Cmax will be 
summarized based on concentration 
values by nominal hour at Day 21 
(i.e. 2.5 hour for Cmax and 0 hour for 
CTrough). 
   
Final 1.2 
17-Jul-2019 
11 
Revised TOC of Tables, Figures and 
Listings 
Required 
by sposnor 
 
 


 
 
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Issue Date 30-JUL-2019 
 
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Table of Contents 
1 
INTRODUCTION ............................................................................................... 8 
2 
STUDY OBJECTIVES ....................................................................................... 8 
3 
ENDPOINTS ....................................................................................................... 9 
3.1 
Primary Endpoint ............................................................................................................ 9 
3.2 
Secondary Endpoints ...................................................................................................... 9 
4 
SAMPLE SIZE .................................................................................................... 9 
5 
RANDOMIZATION ........................................................................................... 9 
6 
PLANNED ANALYSES ...................................................................................10 
6.1 
Analysis Populations ..................................................................................................... 10 
6.1.1 
Safety Population .................................................................................................... 10 
6.1.2 
Evaluable Efficacy Population ................................................................................ 10 
6.1.3 
Per-Protocol Population .......................................................................................... 10 
6.1.4 
Pharmacokinetics (PK) Population ......................................................................... 10 
6.2 
Derived Data and Clinical Assessments ....................................................................... 11 
6.2.1 
Screening................................................................................................................. 11 
6.2.2 
Baseline and Change from Baseline ....................................................................... 11 
6.2.3 
Duration/Study Day/Time ....................................................................................... 11 
6.2.4 
Conventions for Missing and Partial Dates ............................................................ 12 
6.2.5 
Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications 12 
6.2.6 
Missing Last Dates of Study Drug Dosing ............................................................. 13 
6.2.7 
Missing Diagnosis Dates......................................................................................... 13 
6.2.8 
Exposure to Study Drug .......................................................................................... 14 
6.2.9 
Inexact Values ......................................................................................................... 14 
6.2.10 
Electrocardiogram Data .......................................................................................... 14 
6.2.11 
HVLT-R and WMS................................................................................................. 14 
6.2.12 
Z-Score .................................................................................................................... 15 
6.2.13 
CDR ........................................................................................................................ 15 
6.2.14 
MMSE ..................................................................................................................... 15 
6.2.15 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................... 15 
6.2.16 
Early Termination Efficacy Assessments ............................................................... 16 
6.2.17 
Unscheduled Visits ................................................................................................. 16 
6.2.18 
Follow-Up Visit ...................................................................................................... 17 


 
 
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Issue Date 30-JUL-2019 
 
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6.3 
Conventions .................................................................................................................. 17 
6.3.1 
Decimal Places ........................................................................................................ 18 
6.4 
Subject Disposition ....................................................................................................... 18 
6.5 
Protocol Deviations ....................................................................................................... 18 
6.6 
Baseline Comparability ................................................................................................. 19 
6.7 
Medical History ............................................................................................................ 19 
6.8 
Prior and Concomitant Medications ............................................................................. 20 
6.9 
Exposure to Study Drug and Treatment Compliance ................................................... 20 
6.10 
Efficacy Analyses ......................................................................................................... 20 
6.10.1 
Primary Endpoint .................................................................................................... 21 
6.10.2 
Primary Efficacy Analysis ...................................................................................... 21 
6.10.3 
Sensitivity Analyses ................................................................................................ 21 
6.10.4 
Secondary Analyses ................................................................................................ 22 
6.10.5 
Exploratory Analyses .............................................................................................. 22 
6.10.6 
Subgroup Analyses ................................................................................................. 23 
6.10.7 
Multiplicity ............................................................................................................. 23 
6.11 
Pharmacokinetic Analysis ............................................................................................. 23 
6.12 
Pharmacokinetic-Pharmacodynamic Analyses ............................................................. 24 
6.13 
Safety Analyses ............................................................................................................. 24 
6.13.1 
Adverse Events ....................................................................................................... 24 
6.13.2 
Laboratory Data ...................................................................................................... 25 
6.13.3 
Vital Signs ............................................................................................................... 26 
6.13.4 
Electrocardiogram Data .......................................................................................... 26 
6.13.5 
Physical Examination.............................................................................................. 27 
7 
INTERIM ANALYSIS ......................................................................................27 
8 
DATA SAFETY MONITORING BOARD ANALYSIS .................................27 
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................27 
10 REFERENCES ..................................................................................................27 
11 LIST OF TABLES, FIGURES AND LISTINGS .............................................28 
 
 


 
 
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Issue Date 30-JUL-2019 
 
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1 
INTRODUCTION 
This document details the planned statistical analyses for the EIP Pharma, LLC, protocol “EIP-
VX17-745-304” study titled “A Double-Blind, Placebo-Controlled Proof-of-Concept Study of a 
Selective p38 MAP Kinase Alpha Inhibitor, Neflamapimod, Administered for 24 Weeks in 
Subjects with Mild Alzheimer’s Disease”. 
The proposed analyses are based on the contents of the final version 3.0 of the protocol (dated27-
AUG-2018). 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept 
study of neflamapimod 40 mg or matching placebo administered twice daily for 24 weeks in 
subjects aged 55 to 85 years with CSF biomarker-confirmed AD; with CDR-Global score of 0.5 
or 1.0, with CDR memory subscore of at least 0.5, and MMSE scores between 20 and 28, 
inclusive.   
All screening assessments should be conducted within 42 days of Day 1 (first dose of study 
drug). Once eligibility is confirmed and before the first dose of study drug, subjects are randomly 
assigned (1:1 basis) to receive placebo or neflamapimod treatment. Randomization is stratified 
by 1) background AD-specific therapy (cholinesterase inhibitor or memantine versus no 
cholinesterase inhibitor or memantine); and 2) CDR 0.5 versus 1.0. Dosing will start on Day 1 
following completion of all Baseline procedures.  
Subjects will return to the clinic on Days 21, 42, 84, 126, and 168. 
A Follow-up Visit will be conducted 14 (±3) days following the last dose of study drug. 
Trough and maximum concentrations for PK analysis will be collected for each patient and 
summarized.   An integrated population PK analysis including other study PK parameters will be 
completed and reported on outside of the standard reporting.  
2 
STUDY OBJECTIVES 
Primary Objective 
• To evaluate the effect of administration of neflamapimod (VX-745) for 24-weeks on 
immediate and delayed recall aspects of episodic memory, as assessed by the Hopkins 
Verbal Learning Test – Revised (HVLT-R) in subjects with mild Alzheimer’s disease 
(AD). 
 
Secondary Objectives 


 
 
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• To evaluate effects of neflamapimod on immediate and delayed recall of Logical 
Memory (LM), Verbal Paired Associates (VPA) and Visual Reproduction (VR) 
components of the Wechsler Memory Scale® (WMS). 
• To evaluate effects of neflamapimod on the Clinical Dementia Rating Scale-Sum of 
Boxes (CDR-SB) and (Mini-Mental State Examination) MMSE. 
• To evaluate the effects of neflamapimod on AD-related cerebrospinal fluid (CSF) 
biomarkers (total tau, phospho-tau, amyloid-beta peptides, neurogranin,  and 
neurofilament light chain). 
3 
ENDPOINTS 
3.1 Primary Endpoint 
The primary efficacy variable is:  
• Combined change in z-scores of total recall and delayed recall on the HVLT-R in 
neflamapimod-treated subjects compared to placebo-recipients at Week 24. 
 
The detailed calculation of combined change in z-scores is described in section 6.2.12. 
3.2 Secondary Endpoints 
The secondary efficacy variables at Week 24 and follow-up when applicable are: 
• Change in WMS immediate and delayed recall composites in neflamapimod-treated 
subjects compared to placebo-recipients. 
• 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 CSF biomarkers [total tau (T-tau), P-tau181, Aβ1-40, Aβ1-42, neurogranin, 
neurofilament light chain] in neflamapimod-treated subjects compared to placebo-
recipients at the end of treatment. 
4 SAMPLE SIZE 
Up to 76 subjects per treatment arm (152 total) provides 90% power to detect ES of 0.53 and 
80% power to detect ES of 0.46. This level of ES is the minimum treatment effect amount 
considered clinically relevant and is less than the effect size seen in the Phase 2a studies.  
5 RANDOMIZATION 


 
 
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Randomization was stratified by 1) background AD-specific therapy (cholinesterase inhibitor or 
memantine versus no cholinesterase inhibitor or memantine); and 2) CDR-Global Score of 0.5 
versus 1.0.  
Eligible subjects were randomized 1:1 to two treatment arms: Neflamapimod 40mg or placebo 
utilizing a central Interactive Web Response System (IWRS). 
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive 
and the final clinical study report (CSR) may contain additional tables or statistical tests if 
warranted by the data obtained.  The justification for any such additional analyses will be fully 
documented in the final CSR. 
6.1 Analysis Populations 
6.1.1 
Safety Population 
The Safety Population is defined as all randomized subjects who receive at least one dose of 
study drug (neflamapimod or placebo).  
6.1.2 
Evaluable Efficacy Population 
The Efficacy Population used for efficacy analyses, consistent with the intent-to-treat (ITT) 
principles includes all subjects who received at least one dose of study drug and had at least one 
post-dose efficacy assessment. 
6.1.3 
Per-Protocol Population 
The Per-Protocol Population (PP) will be a subset of the Efficacy Population.   
All protocol deviations will be assessed and documented on a case-by-case basis before the 
database lock, and deviations considered to have a significant impact on the efficacy results will 
lead to the relevant subject being excluded from the PP.  Before database lock, potential subject 
exclusions from the PP will be reviewed by the Sponsor and documented in a subject 
evaluability document (WCT-TP-ST-016).  
6.1.4 
Pharmacokinetics (PK) Population 
The Pharmakinetics (PK) Population includes all randomized subjects who received at least 
one dose of study drug in neflamapimod treatment group and had at least one post-dose PK data 
assessment. 


 
 
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6.2 
Derived Data and Clinical Assessments 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 
Screening 
For each variable where a subject is re-screened, his/her latest non-missing value from the 
original or re-screening assessment will be taken for tabulation purposes. 
6.2.2 
Baseline and Change from Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the subject receives first dose of study drug (Day 1). Visit 3 (Day 1) date is definded as the date 
of the first dose.  
Baseline score of MMSE for each subject is calculated using the average of Screen and Day 1 
measurements. 
Change from baseline CHG=AVAL-BASE where AVAL is the post-baseline value, BASE is the 
baseline value.  
Baseline z-score will be used as a covariate in the MMRM and ANCOVA analysis. It will be 
calculated as below: 
For baseline total recall, a z-score for each subject is defined by z=(x-m)/s where x is the 
subject's total recall at baseline, and m and s are the overall mean and overall standard deviation 
of total recall at baseline across all subjects. Similarly, a baseline z-score for each subject for 
delayed recall can be calculated. 
A composite baseline z-score for each subject is calculated using equal weighting in the 
following way:  
Z=0.5*z-score for total recall at baseline + 0.5*z-score for delayed recall at baseline. 
The calculation method can be referenced to Section 6.2.12. 
6.2.3 
Duration/Study Day/Time  
Study day will be calculated as the number of days from first dose of study drug.  
• date of event – date of first dose of study drug + 1, for events on or after first dose  
• date of event – date of first dose of study drug, for events before first dose.   


 
 
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• Duration (e.g., event duration/medication usage) = stop date-start date +1. 
6.2.4 
Conventions for Missing and Partial Dates 
All rules explained below for partial/missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual subject listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
6.2.5 
Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications 
Missing and partial start and stop date will be imputed for analysis purposes as follows: 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved or the subject has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the subject’s last 
clinic visit in the study. 
• If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the subject’s last clinic visit in the study if in the same year. 
• If the month and year are known, the stop date will be imputed as the last day of that 
month unless the stop date corresponds to the same month as the subject’s last clinic visit 
in which case the date of subject’s last clinic visit in the study will be used instead. 
 
Missing start date will be imputed as follows: 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
• If the stop date occurs before the start of study drug, the start date of the 
event/concomitant medication will be imputed as the subject’s screening date or the stop 
date of the event/concomitant medication whichever the earlier. 
 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date 
will be imputed as “01-Jan” of the same year or the date of the first dose of study drug 


 
 
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whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
• If the stop date occurs before the start of study drug, the start date of the 
event/concomitant medication will be imputed as the “01-Jan” of the same year. 
 
Partial start date (month and year present, but day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month 
and year unless this partial start date is in same month as the first dose of study drug in 
which case the date of first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
 
Missing start/stop time of adverse events: 
• If the start time of the adverse event (AE) is missing, it will imputed only in the case 
where the start date of the AE corresponds to the date of the first dose of study drug. The 
time will be imputed as the same time as the first dose of study drug. In all other cases the 
time will not be imputed. 
• If the stop time of the adverse event is missing, it will be imputed as 23:59 for stop time. 
6.2.6 
Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing then the date of last dose of study 
drug will be taken for analysis purposes as the date when the subject would have run out of study 
drug assuming full compliance from the date the study drug was last dispensed or the date of 
subject’s last clinic visit in the study or early withdrawal or death whichever the earlier 
If only the month and year of the last dose was recorded, then the date of last dosing will be 
taken for analysis purposes as the date the subject would have run out of study drug assuming 
full compliance from the date the study drug was last dispensed, the last day of the month of the 
recorded last dose or the date of subject’s last clinic visit in the study or early withdrawal or 
death whichever the earlier. 
6.2.7 
Missing Diagnosis Dates   


 
 
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If the month and year are present but the day is missing, the diagnosis date will be set to the first 
day of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” 
for that year.   
6.2.8 
Exposure to Study Drug  
Exposure to study drug will be calculated as follows from the date of last dosing minus the first 
day of dosing + 1. The exposure calculation will not take into account breaks in therapy. 
6.2.9 
Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes, Where a range of values is quoted the midpoint of the range will be taken.  
6.2.10 
Electrocardiogram Data 
For 12-lead ECG data recorded on continuous scales, if more than one value is recorded at a 
visit, the mean value rounded to the integer will be presented. For overall interpretation if more 
than one value is recorded, the most severe (worst case) of the respective readings will be taken.  
6.2.11 
HVLT-R and WMS 
The HVLT-R is a verbal learning and memory test, with 6 validated alternate forms. Each form 
contains 12 nouns, 4 words each from 1 of 3 semantic categories (e.g., precious gems, articles of 
clothing, vegetables), to be learned, and repeated back to the evaluator over the course of 3 
learning trials. Approximately 20–25 minutes later, a delayed recall trial and a recognition trial 
are completed. The delayed recall requires free recall of any words remembered. The recognition 
trial is composed of 24 words, including the 12 target words and 12 false-positives, 6 
semantically related, and 6 semantically unrelated. The 3 learning trials are combined to 
calculate a total recall score; the delayed recall trial creates the delayed recall score.  
For WMS, LM I & II & II-(Recognition), VPA I & II & II-(Recognition), and VR I & II & II-
(Recognition) will be applied. 
There are following tests in WMS: Logical Memory test, in which subject is read a story; 
Verbal-Paired Associates, in which subject is given pairs of words and asked remember which 
words go together; and Visual Reproduction, in which subject is given drawings of specific 
shapes.  Subjects were then asked to recall the information within each test both in an immediate 
(WMS-Immediate Recall composite) and delayed (WMS-Delayed Recall composite) basis.   
The WMS immediate recall composite score is the total of all of the immediate recall tasks 
combined and the delayed recall composite is the delayed recall tasks combined.   


 
 
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The HVLT-R and WMS tests must be performed sequentially within the day; with the HVLT-R 
to be conducted first and completed (including delayed recall component), prior to commencing 
WMS test. 
6.2.12 
Z-Score 
For post-baseline total recall, a z-score for each subject at a specific visit is defined by z=(x-m)/s 
where x is the subject's total recall at that visit, and m and s are the overall mean and overall 
standard deviation of total recall from baseline visit across all subjects. Similarly, a z-score for 
each subject for delayed recall can be calculated.  
A post-baseline composite z-score for each subject on the HVLT-R at that visit is calculated 
using equal weighting in the following way: Z = 0.5*z-score for total recall + 0.5*z-score for 
delayed recall. 
Combined change in z-scores = Z(post-baseline) – Z(baseline). 
Z(baseline) is described in Section 6.2.2. 
6.2.13 
CDR 
The 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. The overall CDR 
rating, along with the memory box score, will be used to determine a subject’s eligibility for 
inclusion.  The CDR score - SB will also be used in calculating treatment group means for 
change from baseline calculation.  Standardized CDR will be conducted by the Investigator or 
designee. 
CDR score (sum of boxes) is the sum of each domain score. 
6.2.14 
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 (Version 2.0) will be 
conducted by the Investigator or designee.  The MMSE score is used for eligibility as well as 
calculating treatment group means for change from baseline.  
6.2.15 
Columbia-Suicide Severity Rating Scale (C-SSRS) 


 
 
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The C-SSRS is a clinician-administered instrument that assesses suicidal ideation and behavior 
(38TPosner, 201138T).  
The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale to facilitate the definition of composite 
endpoints: 
Category 1  
Wish to be Dead 
Category 2  
Non-specific Active Suicidal Thoughts 
Category 3  
Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act 
Category 4 
Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
Category 5 
Active Suicidal Ideation with Specific Plan and Intent 
Category 6 
Preparatory Acts or Behavior 
Category 7  
Aborted Attempt 
Category 8 
Interrupted Attempt 
Category 9 
Actual Attempt (non fatal) 
Category 10 
Completed Suicide 
 
Suicidal Ideation since baseline – A “yes” answer at any time during double blind treatment to 
any one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS. 
Suicidal Behavior since baseline – A “yes” answer at any time during double blind treatment to 
any one of the 5 suicidal behavior questions (categories 6-10) on the C-SSRS. 
There will be no imputation of missing data for C-SSRS. 
6.2.16 
Early Termination Efficacy Assessments 
For analysis purposes, efficacy data collected from early termination (ET) visit will be assigned 
to the next scheduled visit.   
6.2.17 
Unscheduled Visits 


 
 
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In general, only scheduled post-baseline laboratory, ECG, and vital signs values will be 
tabulated. Post-baseline repeat/unscheduled assessments will be disregarded from table, although 
these post-baseline assessments will be listed in the relevant appendices to the CSR.    
6.2.18 
Follow-Up Visit 
A follow-up visit should be scheduled 14 (+/- 3) days after the last dose of study drug for all 
subjects that complete or are withdrawn from the study. 
6.3 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS version 
9.3 or higher1. 
Summaries will be presented by treatment group or overall. Treatment group labels will be 
displayed as follows:    
Neflamapimod  
(40 mg) 
  
  
 
Placebo 
Overall columns are to be included within the table shells as follows: 
Demography 
Treatment and overall 
Baseline 
Treatment and overall 
Disposition 
Treatment and overall 
Efficacy 
Treatment 
PD 
Treatment 
PK 
Treatment 
AEs 
Treatment 
Other safety 
Treatment 
 
Listings will be sorted in the following order treatment group, subject, parameter, and visit 
unless otherwise stated. All data will be listed, subjects who were not randomized will be 
displayed after the randomized treatment groups.  
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum. For all tabulations of changes from 
baseline data, the lower and upper 95% confidence limits for the mean for the individual 
treatments will be given.  


 
 
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Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
6.3.1 
Decimal Places 
Decimal places for derived data described in section 6.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal 
places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the 
minimum and maximum will be displayed to the same number of decimal places as reported in 
the raw data. Percentages will be displayed with one decimal place.  
P- Values will be quoted to 3 decimal places. P-values < 0.001 will be presented as p<0.001. 
Where this value is less than 0.05, 0.01 or 0.001, attention will be drawn to this fact using the 
conventional “*”, “**” or “***” annotation, respectively.   
6.4 Subject Disposition 
Subject disposition will be summarized as follows:   
• The number of subjects, who entered in the study, were randomized and are in each 
population will be summarized by treatment group and overall for Enrolled Subjects.  
• The number of subjects who failed screening and the reasons for failure will be tabulated 
for Enrolled Subjects. 
• The number of study completers, early withdrawals and the reasons for withdrawals will 
be tabulated by treatment group and overall for the Safety and Efficacy Analysis 
Population.  
6.5 Protocol Deviations 




 
 
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Separate tabulations of previous and ongoing conditions at screening will be presented by 
treatment group and overall for the Safety Population. Conditions will be presented by Medical 
Dictionary of Regulated Activities (MedDRA version 21.0) primary system organ class and 
preferred term. 
6.8 Prior and Concomitant Medications 
Separate tabulations will be produced for prior and concomitant medications presented by 
treatment group and overall for the Safety Population. Prior medications are defined as all 
medications starting before the date of first dose of study drug. Concomitant medications are 
defined as medications taken on or after the date of first dose of study drug. Concomitant 
medications will be summarized by Anatomical Therapeutic Chemical (ATC) level 2 and 
Preferred Name using the World Health Organization (WHO) dictionary (Version WHODrug 
Global B3 March 2018). In addition, CNS medications will be summarized similarly.  
6.9 Exposure to Study Drug and Treatment Compliance 
Extent of exposure will be presented by randomized treatment group for the Safety Population 
(see Section 6.1.1). 
Overall compliance (%) will be calculated as: [Total number of capsules dispensed minus total 
number capsules returned, divided by the expected number of tablets (based on the number of 
days from first dose to last dose)] multiplied by 100, as a percentage.  
Number and percentage of subjects who had at least 80% of the (cumulative) planned dose will 
be summarized by treatment group. In addition, the number (%) of subjects with compliance 
within each of the following intervals will be provided: 
• 95 - 100% 
• 90 - <95% 
• 85 - <90% 
• 80 - <85% 
• 75 - <80% 
• 70 - <75% 
• <70% 
6.10  Efficacy Analyses 
All efficacy analyses will be based on the Evaluable Efficacy Population by randomized 
treatment regardless of the treatment actually received. Descriptive statistics by treatment group 


 
 
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and visit will be reported for all efficacy endpoints. All statistical tests will be performed using a 
two-tailed 5% overall significance level, unless otherwise stated.  All comparisons between 
treatments will be reported with 95% confidence intervals for the difference. 
There will be no imputation of missing efficacy data. 
6.10.1 
Primary Endpoint 
The primary efficacy endpoint is: 
Combined change in z-scores of total recall and delayed recall on the HVLT-R in neflamapimod- 
treated subjects compared to placebo-recipients at Week 24.  
Neflamapimod 40 mg group will be compared to the placebo group.  
The hypothesis test is as follows: 
Ho: µneflamapimod = µplacebo 
H1: µneflamapimod ≠ µplacebo 
The null hypothesis will be rejected at a significance level of α (two-sided) = 0.05.  There will be 
no p-value adjustment for multiplicity.  
6.10.2 
Primary Efficacy Analysis 
The primary endpoint will be analyzed using Mixed Model for Repeated Measures (MMRM) 
with fixed effects for treatment, background AD-specific therapy (cholinesterase inhibitor or 
memantine versus no cholinesterase inhibitor or memantine), CDR-Global Score of 0.5 versus 
1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for 
subject and baseline z-score as a covariate. Least-square means (LSM) and 2-sided 95% 
confidence intervals (CI) will be provided for treatment group differences and estimated 
endpoint values by visit.  
The normally-distributed assumption for the combined change in z-scores of total recall and 
delayed recall on the HVLT-R will be examined (at 0.05 alpha level). In case the assumption is 
violated, rank transformed data will be applied to the MMRM model. Ranks will be determined 
separately within each time point, based on observed data only. 
In addition, Scale plot will be provided for combined change in z-scores of total recall and 
delayed recall on the HVLT-R at each post-baseline visit by treatment group. 
6.10.3 
Sensitivity Analyses 


 
 
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• Repeat the primary efficacy analysis with the Per Protocol Population 
• Use an analysis of covariance (ANCOVA) with treatment group, background AD-
specific therapy, CDR-Global Score as main effects and the baseline z-score as the 
covariate to compare Z-scores of total recall and delayed recall on the HVLT-R at Week 
24 in the neflamapimod and placebo groups 
The results of the ANCOVA will be summarized using the treatment groups’ least square means, 
the difference between the treatment groups’ least square means, the 95% confidence interval for 
the treatment group difference and the p-value. 
6.10.4 
Secondary Analyses 
The secondary efficacy endpoints at Week 24 and follow-up when applicable are: 
• Change in WMS immediate and delayed recall composites in neflamapimod-treated 
subjects compared to placebo-recipients. 
• 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 CSF biomarkers (T-tau, P-tau181, Aβ1-40, Aβ1-42, neurogranin, neurofilament 
light chain) in neflamapimod-treated subjects compared to placebo-recipients at the end 
of treatment. 
The same method used for the primary efficacy analysis will be applied for the analyses of the 
change in WMS and change in CDR-SB.  
Changes in MMSE and CSF biomarkers will be compared using an analysis of covariance 
(ANCOVA) with treatment group, background AD-specific therapy, CDR-Global Score as main 
effects and the baseline assessment as the covariate.  The results of the ANCOVA will be 
summarized using the treatment groups’ least square means, the difference between the treatment 
groups’ least square means, the 95% confidence interval for the treatment group difference and 
the p-value. Scale Plots of Mini-Mental State Examination (MMSE) Score by Visit and by 
Treatment; and Baseline and Change from Baseline to Day 84 MMSE Score.  
6.10.5 
Exploratory Analyses 
Additional exploratory analyses may be performed to further study the effects of treatment as 
data warranted.  Numerical exploratory endpoints will be analyzed using analysis of covariance, 
t-tests, or Wilcoxon sign rank test. Analysis of categorical exploratory endpoints will be 
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• Change of total recall on the HVLT-R  
• Change of delayed recall on the HVLT-R 
• Change of retention (%) on the HVLT-R 
• Change of recognition on the HVLT-R 
• Change of recognition on the WMS  
• Subgroups analyses by , sex (male/female), age (dichotomized at pretreatment median 
age), race (white vs. non-white, Hispanic vs. non-Hispanic), CYP2C19 genotype status 
and/or other grouping covariates, if data permit. 
• Outlier analyses to identify the impact of any extreme values on the analysis results.  
• Categorical exploratory endpoints (i.e. responder analysis), if data permit, will be 
performed using Pearson's chi-square test 
6.10.6 
Subgroup Analyses  
The results for the primary and secondary endpoints will be further analyzed on the patients 
with a background AD-specific therapy, and those not on a background AD-specific therapy as 
well as for disease severity (patients who have a CDR score of 0.5 versus 1.0).  Another 
subgroup analysis will be performed base on patient baseline body weight (<80 kg and ≥80kg).  
6.10.7 
Multiplicity 
All secondary endpoints and the supportive analyses will be considered as descriptive evidence 
of efficacy and will be analyzed without any procedures to account for multiple comparisons. 
6.11 Pharmacokinetic Analysis 
Neflamapimod concentration values will be reported for the PK population.  All PK data 
collected will be included in data listings sorted by treatment, patient and time point, as 
appropriate.   
Individual values and descriptive statistics for the plasma concentrations of neflamapimod will 
be summarized by neflamapimod treatment and by visit. Boxplots of the distributions of 
neflamapimod concentrations by visit will be used to present graphical summaries of 
neflamapimod concentration data. 
Trough and maximum concentrations (CTrough and Cmax, respectively) will be obtained on Day 21 
(i.e., at steady-state) for each subject by observation and descriptive statistics for the 
neflamapimod treatment group will be presented.   
In addition, the effect of CYP2C19 genotype status on PK parameters will be investigated. 


 
 
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The robust PK parameters (i.e. PPK model derived CTrough and Cmax, AUC and etc.) will be 
derived by an integrated population pharmacokinetic (PPK) analysis.  PPK analysis plan will be 
detailed in a separate Pharmacometrics Analysis Plan and reported separately from the study 
results.  
6.12 Pharmacokinetic-Pharmacodynamic Analyses 
Analyses of CSF biomarkers (T-tau, P-tau181, Aβ1-40, Aβ1-42, neurogranin, neurofilament light 
chain) will use observational Trough and maximum concentrations (CTrough and Cmax, 
respectively) on Day 21 as exposure parameters in the initial PK-PD analysis.  For numerical PD 
endpoints, both absolute and percent change from pre-treatment assessments will be performed, 
as appropriate. Number and percent will be provided for categorical PD parameters (e.g. 
CYP2C19). Overall, summary statistics and for each treatment group for biomarkers will be 
presented and a by-subject listing of plasma biomarker results will be provided as an appendix. 
Additional PK-PD exploratory analyses may be performed to further study the effects of the 
treatment via PK parameters (i.e. CTrough and Cmax) on HVLT-R, WMS, CDR, and/or CSF 
biomarkers, as warranted by data. Nominal CTrough and Cmax will be summarized based on 
concentration values by nominal hour at Day 21 (i.e. 2.5 hour for Cmax and 0 hour for CTrough). 
For many endpoints, both absolute and percent change from pre-treatment assessments will be 
performed.  All data collected and captured in the CRF will be included in data listings sorted by 
treatment, patient and time point, as appropriate.   
6.13 Safety Analyses 
The safety analyses will be presented by the treatment received for the Safety Population. 
6.13.1 
Adverse Events 
A treatment emergent adverse event (TEAE) is defined as:  
• Any AE with an onset on or after the first dose of study drug and through 30 days after 
the last dose of study drug in the double blind treatment period.  
• Any pre-existing AE that has worsened in severity on or after the first dose of study drug 
and through 30 days after the last dose of study drug in the double blind treatment period. 
A treatment-related AE is defined as an AE as being possibly related to the study drug. If an AE 
has a missing relationship, it is assumed to be related to the study drug for analysis purposes. 
Maximum severity will be assumed for an AE with missing severity.  
 
The following tables will be presented for AEs: 


 
 
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• Overall incidence and the number of AEs, SAEs, Treatment related TEAEs, TEAEs 
leading to withdrawal of study/study drug 
• TEAE by system organ class and preferred term, incidence and number of events 
• Treatment related TEAE by system organ class and preferred term, incidence and number 
of events 
• Serious TEAE by system organ class and preferred term, incidence and number of events 
• TEAEs leading to withdrawal of study drug by system organ class and preferred term, 
incidence and number of events 
• TEAE by system organ class, preferred term and maximum severity, incidence 
• Listing of serious TEAEs (presented in the Table section of the appendices) 
• Listing of deaths (presented in the Table section of the appendices) 
Adverse events will be coded using MedDRA version 21.0. 
A complete subject listing of all AEs will be provided. This listing will include treatment, AE 
verbatim term, primary system organ class and preferred term, the time of onset and cessation of 
event relative to the first dose of study drug, duration of AE (for ongoing AEs, no duration will 
be calculated), whether serious, severity, relationship to study drug, action taken and outcome.  
In counting the number of AEs reported, a continuous event (i.e. reported more than once and 
which did not cease), will be counted only once; non-continuous AE reported several times by 
the same subject will be counted as multiple events.  
6.13.2 
Laboratory Data 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each hematology, serum chemistry, and coagulation 
parameter. Each measurement (continuous data) will be classed as below, within, or above 
normal range, based on ranges supplied by the laboratory used. Shift tables in relation to the 
normal range from baseline to each follow-up visit will be presented.  
A listing of any clinically significant laboratory measurements recorded throughout the study 
will be presented. 
Liver Function Parameter  
The number and percentage of subjects meeting certain liver function abnormality categories will 
be summarized by visit: 
• Alanine Aminotransferase (ALT) assessment > 3 times upper limit of normal (ULN), 


 
 
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• Aspartate aminotransferase (AST) > 3xULN, 
• ALT or AST: > 3xULN;  > 10xULN; > 20xULN  
• Total Bilirubin: > 1.5xULN;  > 2xULN  
• Alkaline Phosphatase: > 1.5xULN; >2xULN 
• (ALT or AST > 3xULN) and total bilirubin>2xULN 
• (ALT or AST>3xULN) and total bilirubin>2xULN and alkaline phosphatase<2xULN 
Coagulation Parameter Abnormalities 
• International Normalized Ratio (INR) >1.5 
6.13.3 
Vital Signs 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm)  
• Respiration rate (breath/min) 
• Body temperature (degrees Celsius) 
• Body weight (kg) 
Box plots for the above vital signs will be provided for changes from Baseline by visit and 
maximal change.   
6.13.4 
Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following 12-lead 
ECG variables will be tabulated at each follow-up visit: 
• Heart rate (beats/min) 
• PR interval (msec) 
• RR interval (msec)  
• QRS complex (msec)   
• QT interval (msec)  
• QTc interval (msec)   
• QTcF interval (msec) [Fridericia’s formula - QTcF]  


 
 
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ECG Result Interpretation (Normal, Abnormal Not Clinically Significant [NCS], and Abnormal 
Clinically Significant [CS]) will be summarized by treatment group and visit. 
The incidence of ECG abnormalities for subjects with any abnormal CS ECG result will be 
presented by treatment group and visit.   
Additionally, the number and percentage of subjects in each treatment group who meet any of 
the following criteria for QT or QTcF will be tabulated by treatment group and visit. 
• Maximum value >450 to 480 msec  
• Maximum value >480 to 500 msec  
• Maximum value >500 msec 
• Maximum increase from baseline >30 to 60 msec 
• Maximum increase from baseline >60 msec 
Shift tables in relation to the overall interpretation (Normal, Abnormal NCS, and Abnormal CS) 
from baseline to each follow-up visit will be presented.  
Box plots for ECG data will be provided for changes from baseline by visit and maximal change. 
6.13.5 
Physical Examination 
The body systems within the physical examination data will be summarized by treatment group 
and visit (Abnormal NCS and Abnormal CS). Changes from baseline will also be tabulated. 
Details of clinically significant findings will be listed.  
Descriptive statistics for observed values and changes from baseline in weight will be presented 
by treatment group and visit.   
7 INTERIM ANALYSIS 
No formal interim analyses are planned.  
8 DATA SAFETY MONITORING BOARD ANALYSIS 
No data safety monitoring board (DSMB) analyses are planned. 
9 CHANGES TO PLANNED PROTOCOL ANALYSIS 
Not applicable. 
10 REFERENCES 


 
 
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1. SAS Institute Inc., Cary, NC, 27513, USA 
11 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The eCTD section is shown in bold. The following validation methods 
maybe used  
• Independent programming of numbers and manual review of format (IP) 
• Independent programming by statistician of numbers and manual review of format (Stat 
IP) 
• Manual review (MR) 
• Code review (CR) 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(If Repeat) 
14.1 
Demographics Data 
 
 
14.1.1 
Disposition 
 
 
14.1.1.1 
Subject Disposition, Analysis Population 
IP 
 
14.1.1.2 
Subject Disposition, Screen Failures Enrolled 
Subjects 
IP 
 
14.1.1.3 
Inclusion/Exclusion Criteria Not Met Enrolled 
Subjects 
IP 
 
14.1.1.4.1 
Subject Disposition, Early Withdrawals Safety 
Population 
IP 
 
14.1.1.4.2 
Subject Disposition, Early Withdrawals Efficacy 
Population 
IP 
14.1.1.4.1 
14.1.1.5.1 
Number of Subject by Site Safety Population 
IP 
 
14.1.1.5.2 
Number of Subject by Site Efficacy Population 
IP 
14.1.1.5.1 
14.1.1.6.1 
Number of Subject by Visits Safety Population 
IP 
 
14.1.2 
Demographics and Baseline Characteristics 
 
 
14.1.2.1.1 
Demographics Safety Population 
IP 
 
14.1.2.1.2 
Demographics Efficacy Population 
IP 
14.1.2.1.1 
14.1.2.2.1 
Baseline Characteristics Safety Population 
IP 
 
14.1.2.2.2 
Baseline Characteristics Efficacy Population 
IP 
14.1.2.2.1 
14.1.3 
Physical Examinations 
 
 


 
 
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14.1.3.1 
Physical Examinations at Screening Safety 
Population 
IP 
 
14.1.4 
Medical History and Prior Medications 
 
 
14.1.4.1.1 
Prior Medical History Safety Population 
IP 
 
14.1.4.2.1 
Ongoing Medical Conditions at Screening Safety 
Population 
IP 
 
14.1.4.3.1 
Prior Medications Safety Population 
IP 
 
14.1.5.1 
Major Deviations 
 
 
14.1.5.1 
Major Protocol Deviations Safety Population 
IP 
 
14.2  
Efficacy Data 
 
 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1 
Hopkins Verbal Learning Test – Revised 
(HVLT-R) Efficacy Population 
 IP 
 
14.2.1.2 
Combined Change from Baseline in Z-score of 
Total Recall and Delayed Recall on the Hopkins 
Verbal Learning Test – Revised (HVLT-R) 
Efficacy Population 
Stat IP 
 
14.2.1.3 
Mixed Models for Repeated Measures Analysis 
of Combined Change from Baseline in Z-score 
of Total Recall and Delayed Recall on the 
Hopkins Verbal Learning Test – Revised 
(HVLT-R) Efficacy Population 
Stat IP 
 
14.2.2 
Secondary Endpoints 
 
 
14.2.2.1 
Wechsler Memory Scale (WMS) Subscore 
Efficacy Population 
IP 
 
14.2.2.2 
Wechsler Memory Scale (WMS) Composite and 
Overall Score Efficacy Population 
IP 
 
14.2.2.3 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Wechsler Memory 
Scale (WMS) Immediate and Delayed Recall 
Composite Score (0-228) Efficacy Population 
 Stat IP 
14.2.1.3 
14.2.2.3.1 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Wechsler Memory 
Scale (WMS) Immediate Composite Score (0-
136) Efficacy Population 
IP 
 
14.2.2.3.2 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Wechsler Memory 
Stat IP 
14.2.1.3 


 
 
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Scale (WMS) Delayed Recall Composite Score 
(0-92) Efficacy Population 
14.2.2.4 
Clinical Dementia Rating (CDR) Efficacy 
Population 
IP 
 
14.2.2.5 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Clinical Dementia 
Rating Scale-Sum of Boxes (CDR-SB) Efficacy 
Population 
Stat IP 
 
14.2.2.6 
Mini-Mental State Examination (MMSE) 
Efficacy Population 
IP 
 
14.2.2.7 
Analysis of Covariance of Change from Baseline 
in Mini-Mental State Examination (MMSE) 
Score Efficacy Population 
IP 
 
14.2.2.8.1 
CSF Biomarkers (T-tau, P-tau181, Aβ1-40, Aβ1-
42, Neurogranin, Neurofilament Light Chain, 
pTau/Aβ1-42 Ratio) Efficacy Population 
IP 
 
14.2.2.8.2 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (T-tau) Efficacy Population 
IP 
 
14.2.2.8.3 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (P-tau181) Efficacy 
Population 
IP 
 
14.2.2.8.4 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (Aβ1-40) Efficacy Population 
IP 
 
14.2.2.8.5 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (Aβ1-42) Efficacy Population 
IP 
 
14.2.2.8.6 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (Neurogranin) Efficacy 
Population 
IP 
 
14.2.2.8.7 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (Neurofilament Light Chain) 
Efficacy Population 
IP 
 
14.2.2.8.8 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (pTau/Aβ1-42 Ratio) Efficacy 
Population 
IP 
 
14.2.3 
Sensitivity Analyses 
 
 
14.2.3.1 
Hopkins Verbal Learning Test – Revised 
(HVLT-R) Per-Protocol Population 
IP 
 


 
 
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14.2.3.2 
Combined Change from Baseline in Z-score of 
Total Recall and Delayed Recall on the Hopkins 
Verbal Learning Test – Revised (HVLT-R) Per-
Protocol Population 
Stat IP 
 
14.2.3.3 
Mixed Models for Repeated Measures Analysis 
of Combined Change from Baseline in Z-score 
of Total Recall and Delayed Recall on the 
Hopkins Verbal Learning Test – Revised 
(HVLT-R) Per-Protocol Population 
Stat IP 
14.2.1.3 
14.2.3.4 
Analysis of Covariance of Combined Change 
from Baseline in Z-score of Total Recall and 
Delayed Recall on the Hopkins Verbal Learning 
Test – Revised (HVLT-R) Efficacy Population 
Stat IP 
 
14.2.3.5 
Analysis of Covariance of Combined Change 
from Baseline in Z-score of Total Recall and 
Delayed Recall on the Hopkins Verbal Learning 
Test – Revised (HVLT-R) Per-Protocol 
Population 
Stat IP 
 
14.2.4 
Exploratory Endpoints 
 
 
14.2.4.1 
Analysis of Covariance of Change from Baseline 
in Total Recall on the Hopkins Verbal Learning 
Test – Revised (HVLT-R) Efficacy Population 
IP 
 
14.2.4.2 
Analysis of Covariance of Change from Baseline 
in Delayed Recall on the Hopkins Verbal 
Learning Test – Revised (HVLT-R) Efficacy 
Population 
IP 
14.2.4.1 
14.2.4.3 
Analysis of Covariance of Change from Baseline 
in Retention (%) on the Hopkins Verbal 
Learning Test – Revised (HVLT-R) Efficacy 
Population 
IP 
14.2.4.1 
14.2.4.4 
Analysis of Covariance of Change from Baseline 
in Recognition on the Hopkins Verbal Learning 
Test – Revised (HVLT-R) Efficacy Population 
IP 
14.2.4.1 
14.2.4.5 
Analysis of Covariance of Change from Baseline 
in Wechsler Memory Scale (WMS) Recognition 
Composite Tests of Logical Memory II, Verbal 
Paired Associates II and Visual Reproduction II 
(0-60)  Efficacy Population 
IP 
14.2.4.1 


 
 
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14.2.4.6.x 
Subgroup Analysis of Covariance of Combined 
Change from Baseline in Z-score of Total Recall 
and Delayed Recall on the HVLT-R Efficacy 
Population 
IP 
  
14.2.4.7 
Pearson's Chi-square Test for Responder 
Efficacy Population 
IP 
 
14.2.5-
14.2.6 
Subgroup Analyses 
 
 
14.2.5.1.1 
Hopkins Verbal Learning Test – Revised 
(HVLT-R), Cholinesterase Inhibitor or 
Memantine Efficacy Population 
IP 
 
14.2.5.1.2 
Hopkins Verbal Learning Test – Revised 
(HVLT-R), No Cholinesterase Inhibitor or 
Memantine Efficacy Population 
IP 
 
14.2.5.2.1 
Combined Change from Baseline in Z-score of 
Total Recall and Delayed Recall on the Hopkins 
Verbal Learning Test – Revised (HVLT-R), 
Cholinesterase Inhibitor or Memantine Efficacy 
Population 
IP 
 
14.2.5.2.2 
Combined Change from Baseline in Z-score of 
Total Recall and Delayed Recall on the Hopkins 
Verbal Learning Test – Revised (HVLT-R), No 
Cholinesterase Inhibitor or Memantine Efficacy 
Population 
IP 
 
14.2.5.3 
Mixed Models for Repeated Measures Analysis 
of Combined Change from Baseline in Z-score 
of Total Recall and Delayed Recall on the 
Hopkins Verbal Learning Test – Revised 
(HVLT-R) by Background AD-specific Therapy 
Efficacy Population 
IP 
 
14.2.6.1.1 
Wechsler Memory Scale (WMS) Subscore, 
Cholinesterase Inhibitor or Memantine Efficacy 
Population 
IP 
 
14.2.6.1.2 
Wechsler Memory Scale (WMS) Subscore, No 
Cholinesterase Inhibitor or Memantine Efficacy 
Population 
IP 
 


 
 
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14.2.6.2.1 
Wechsler Memory Scale (WMS) Composite and 
Overall Score, Cholinesterase Inhibitor or 
Memantine Efficacy Population 
IP 
 
14.2.6.2.2 
Wechsler Memory Scale (WMS) Composite and 
Overall Score, No Cholinesterase Inhibitor or 
Memantine Efficacy Population 
IP 
 
14.2.6.3 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Wechsler Memory 
Scale (WMS) Immediate and Delayed Recall 
Composite Score (0-228) by Background AD-
specific Therapy Efficacy Population 
IP 
14.2.5.3 
14.2.6.4.1 
Clinical Dementia Rating (CDR), Cholinesterase 
Inhibitor or Memantine Efficacy Population 
IP 
 
14.2.6.4.2 
Clinical Dementia Rating (CDR), No 
Cholinesterase Inhibitor or Memantine Efficacy 
Population 
IP 
 
14.2.6.5 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Clinical Dementia 
Rating Scale-Sum of Boxes (CDR-SB) by 
Background AD-specific Therapy Efficacy 
Population 
IP 
14.2.5.3 
14.2.6.6.1 
Mini-Mental State Examination (MMSE), 
Cholinesterase Inhibitor or Memantine Efficacy 
Population 
IP 
 
14.2.6.6.2 
Mini-Mental State Examination (MMSE), No 
Cholinesterase Inhibitor or Memantine Efficacy 
Population 
IP 
 
14.2.6.7 
Analysis of Covariance of Change from Baseline 
in Mini-Mental State Examination (MMSE) 
Score by Background AD-specific Therapy 
Efficacy Population 
IP 
 
14.2.6.8.1 
CSF Biomarkers (T-tau, P-tau181, Aβ1-40, Aβ1-
42, Neurogranin, Neurofilament Light Chain, 
pTau/Aβ1-42 Ratio), Cholinesterase Inhibitor or 
Memantine Efficacy Population 
IP 
 
14.2.6.8.1 
CSF Biomarkers (T-tau, P-tau181, Aβ1-40, Aβ1-
42, Neurogranin, Neurofilament Light Chain, 
IP 
 


 
 
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pTau/Aβ1-42 Ratio), No Cholinesterase 
Inhibitor or Memantine Efficacy Population 
14.2.6.9.1 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (T-tau) by Background AD-
specific Therapy Efficacy Population 
IP 
14.2.6.7 
14.2.6.9.2 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (P-tau181) by Background 
AD-specific Therapy Efficacy Population 
IP 
14.2.6.7 
14.2.6.9.3 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (Aβ1-40) by Background 
AD-specific Therapy Efficacy Population 
IP 
14.2.6.7 
14.2.6.9.4 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (Aβ1-42) by Background 
AD-specific Therapy Efficacy Population 
IP 
14.2.6.7 
14.2.6.9.5 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (Neurogranin) by Background 
AD-specific Therapy Efficacy Population 
IP 
14.2.6.7 
14.2.6.9.6 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (Neurofilament Light Chain) 
by Background AD-specific Therapy Efficacy 
Population 
IP 
14.2.6.7 
14.2.6.9.7 
Analysis of Covariance of Change from Baseline 
in CSF Biomarker (pTau/Aβ1-42 Ratio) by 
Background AD-specific Therapy Efficacy 
Population 
IP 
14.2.6.7 
14.2.6.10.1 
Hopkins Verbal Learning Test – Revised 
(HVLT-R), Baseline Body Weight <80 kg 
Efficacy Population 
IP 
 
14.2.6.10.2 
Hopkins Verbal Learning Test – Revised 
(HVLT-R), Baseline Body Weight ≥80 kg 
Efficacy Population 
IP 
 
14.2.6.10.3 
Combined Change from Baseline in Z-score of 
Total Recall and Delayed Recall on the Hopkins 
Verbal Learning Test – Revised (HVLT-R), 
Baseline Body Weight <80 kg Efficacy 
Population 
IP 
 
14.2.6.10.4 
Combined Change from Baseline in Z-score of 
Total Recall and Delayed Recall on the Hopkins 
IP 
 


 
 
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Verbal Learning Test – Revised (HVLT-R), 
Baseline Body Weight ≥80 kg Efficacy 
Population 
14.2.6.10.5 
Mixed Models for Repeated Measures Analysis 
of Combined Change from Baseline in Z-score 
of Total Recall and Delayed Recall on the 
Hopkins Verbal Learning Test – Revised 
(HVLT-R) by Baseline Weight Efficacy 
Population 
IP 
 
14.2.6.11.1 
Wechsler Memory Scale (WMS) Subscore, 
Baseline Body Weight <80 kg Efficacy 
Population 
IP 
 
14.2.6.11.2 
Wechsler Memory Scale (WMS) Subscore, 
Baseline Body Weight ≥80 kg Efficacy 
Population 
IP 
 
14.2.6.11.3 
Wechsler Memory Scale (WMS) Composite and 
Overall Score, Baseline Body Weight <80 kg 
Efficacy Population 
IP 
 
14.2.6.11.4 
Wechsler Memory Scale (WMS) Composite and 
Overall Score, Baseline Body Weight ≥80 kg 
Efficacy Population 
IP 
 
14.2.6.11.5 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Wechsler Memory 
Scale (WMS) Immediate and Delayed Recall 
Composite Score (0-228) by Baseline Body 
Weight Efficacy Population 
IP 
 
14.2.6.12.1 
Clinical Dementia Rating (CDR), Baseline Body 
Weight <80 kg Efficacy Population 
IP 
 
14.2.6.12.2 
Clinical Dementia Rating (CDR), Baseline Body 
Weight ≥80 kg Efficacy Population 
IP 
 
14.2.6.12.3 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Clinical Dementia 
Rating Scale-Sum of Boxes (CDR-SB) by 
Baseline Body Weight Efficacy Population 
IP 
 
14.2.6.13.1 
Mini-Mental State Examination (MMSE), 
Baseline Body Weight <80 kg Efficacy 
Population 
IP 
 


 
 
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Effective Date: 15-Apr-2016 
 
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14.2.6.13.2 
Mini-Mental State Examination (MMSE), 
Baseline Body Weight ≥80 kg Efficacy 
Population 
IP 
 
14.2.6.13.3 
Analysis of Covariance of Change from Baseline 
in Mini-Mental State Examination (MMSE) 
Score by Baseline Body Weight Efficacy 
Population 
IP 
 
14.2.6.14.1 
Hopkins Verbal Learning Test – Revised 
(HVLT-R), CDR 0.5 Efficacy Population 
IP 
 
14.2.6.14.2 
Hopkins Verbal Learning Test – Revised 
(HVLT-R), CDR 1.0 Efficacy Population 
IP 
 
14.2.6.14.3 
Combined Change from Baseline in Z-score of 
Total Recall and Delayed Recall on the Hopkins 
Verbal Learning Test – Revised (HVLT-R), 
CDR 0.5 Efficacy Population 
IP 
 
14.2.6.14.4 
Combined Change from Baseline in Z-score of 
Total Recall and Delayed Recall on the Hopkins 
Verbal Learning Test – Revised (HVLT-R), 
CDR 1.0 Efficacy Population 
IP 
 
14.2.6.14.5 
Mixed Models for Repeated Measures Analysis 
of Combined Change from Baseline in Z-score 
of Total Recall and Delayed Recall on the 
Hopkins Verbal Learning Test – Revised 
(HVLT-R) by  
Disease Severity Efficacy Population 
IP 
 
14.2.6.15.1 
Wechsler Memory Scale (WMS) Subscore, CDR 
0.5 Efficacy Population 
IP 
 
14.2.6.15.2 
Wechsler Memory Scale (WMS) Subscore, CDR 
1.0 Efficacy Population 
IP 
 
14.2.6.15.3 
Wechsler Memory Scale (WMS) Composite and 
Overall Score, CDR 0.5 Efficacy Population 
IP 
 
14.2.6.15.4 
Wechsler Memory Scale (WMS) Composite and 
Overall Score, CDR 1.0 Efficacy Population 
IP 
 
14.2.6.15.5 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Wechsler Memory 
Scale (WMS) Immediate and Delayed Recall 
Composite Score (0-228) by Disease Severity 
Efficacy Population 
IP 
 


 
 
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14.2.6.16.1 
Clinical Dementia Rating (CDR), CDR 0.5 
Efficacy Population 
IP 
 
14.2.6.16.2 
Clinical Dementia Rating (CDR), CDR 1.0 
Efficacy Population 
IP 
 
14.2.6.16.3 
Mixed Models for Repeated Measures Analysis 
of Change from Baseline in Clinical Dementia 
Rating Scale-Sum of Boxes (CDR-SB) by 
Disease Severity Efficacy Population 
IP 
 
14.2.6.17.1 
Mini-Mental State Examination (MMSE), CDR 
0.5 Efficacy Population 
IP 
 
14.2.6.17.2 
Mini-Mental State Examination (MMSE), CDR 
1.0 Efficacy Population 
IP 
 
14.2.6.17.3 
Analysis of Covariance of Change from Baseline 
in Mini-Mental State Examination (MMSE) 
Score by Disease Severity Efficacy Population 
IP 
 
14.3 
Safety Data 
 
 
14.3.1 
Displays of Adverse Events 
 
 
14.3.1.1 
Adverse Events, Overview of Treatment-
Emergent Adverse Events (TEAE) Safety 
Population 
IP 
 
14.3.1.2 
Adverse Events, TEAEs by Primary System 
Organ Class and Preferred Term Safety 
Population 
IP 
 
14.3.1.3 
Adverse Events, TEAEs by Preferred Term 
Safety Population 
IP 
 
14.3.1.4 
Adverse Events, Treatment-Related TEAEs by 
Primary System Organ Class and Preferred Term 
Safety Population 
IP 
 
14.3.1.4.1 
Adverse Events, TEAEs by Primary System 
Organ Clas, Preferred Term and Causality Safety 
Population 
IP 
14.2.4.1 
14.3.1.5 
Adverse Events, TEAEs Leading to 
Discontinuation of Study by Primary System 
Organ Class and Preferred Term Safety 
Population 
IP 
14.2.4.1 
14.3.1.6 
Adverse Events, Serious TEAEs by Primary 
System Organ Class and Preferred Term Safety 
Population 
IP 
14.2.4.1 


 
 
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14.3.1.7 
Adverse Events, Treatment-Related Serious 
TEAEs by Primary System Organ Class and 
Preferred Term Safety Population 
IP 
 
14.3.1.8 
Adverse Events, TEAEs by Primary System 
Organ Class, Preferred Term and Maximum 
Severity Safety Population 
IP 
 
14.3.1.9 
Adverse Events, TEAEs [>=2%] by Primary 
System Organ Class and Preferred Term Safety 
Population 
IP 
 
14.3.2  
Listings Of Deaths, Other Serious And 
Significant Adverse Events 
 
 
14.3.2.1 
Death, Listing Safety Population 
IP 
 
14.3.2.2 
Serious TEAEs, Listing Safety Population 
IP 
14.3.2.1 
14.3.2.3 
Treatment-Related TEAEs, Listing Safety 
Population 
IP 
14.3.2.1 
14.3.2.4 
TEAEs Leading to Discontinuation of Study, 
Listing Safety Population 
IP 
14.3.2.1 
14.3.3  
Narratives of Deaths, Other Serious and 
Certain Other Significant Adverse Events ( 
This is usually not created by stats but this 
placeholder ) 
 
 
14.3.4  
Abnormal Laboratory Values 
 
 
14.3.4.1 
Hematology Safety Population 
IP 
 
14.3.4.2 
Shift Table - Hematology Safety Population 
IP 
 
14.3.4.3 
Chemistry Safety Population 
IP 
 
14.3.4.4 
Shift Table – Chemistry Safety Population 
IP 
14.3.4.2 
14.3.4.5 
Coagulation Safety Population 
IP 
 
14.3.4.6 
Shift Table – Coagulation Safety Population 
IP 
14.3.4.2 
14.3.4.7 
Liver Function Parameter and Coagulation 
Parameter Abnormalities Safety Population 
IP 
 
14.3.5  
Extent Of Exposure, Dosage Information, 
And Compliance 
 
 
14.3.5.1 
Study Drug Exposure and Compliance Safety 
Population 
IP 
 
14.3.6  
Vital Signs And Physical Examination 
 
 
14.3.6.1 
Vital Signs Safety Population 
IP 
 


 
 
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14.3.6.2 
Physical Examinations at Post-baseline Visits 
Safety Population 
IP 
 
14.3.6.3 
Body Weight Safety Population 
IP 
 
14.3.7  
Other Safety 
 
 
14.3.7.1 
12-lead ECG Safety Population 
IP 
 
14.3.7.2 
12-lead ECG Result Interpretations Safety 
Population 
IP 
 
14.3.7.3 
12-lead ECG Abnormalities for Subjects with 
Any Abnormal Clinically Significant ECG 
Interpretation Safety Population 
IP 
 
14.3.7.4 
12-lead ECG – QT, QTc, and QTcF Categories 
QTcF Categories Safety Population 
IP 
 
14.3.8  
Concomitant Medication 
 
 
14.3.8.1 
Concomitant Medications Safety Population 
IP 
 
14.4 
PK Data 
 
 
14.4.1.1 
Neflamapimod Concentrations by Visit PK 
Population 
IP 
 
14.4.1.2 
Pharmacokinetic Parameters of Neflamapimod 
PK Population 
IP 
 
14.4.1.3.x 
Pharmacokinetic Parameters of Neflamapimod 
by CYP2C19 Genotype Status PK Population 
IP 
 
14.4.2 
Correlation Analysis of PK Parameters and 
Efficacy Data (Combined Change in Z-score, 
Change in WMS, CDR-SB) Efficacy Population 
IP 
 
14.4.3 
Correlation Analysis of PK Parameters and 
Change from Baseline in CSF Biomarkers 
Efficacy Population 
IP 
 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number 
(If Repeat) 
14.2 
Figure 
Figure for Efficacy Data 
 
 
14.2.1.1 
Mean (±SE) Combined Change from Baseline in 
Z-score of Total Recall and Delayed Recall on 
the HVLT-R by Visit and by Treatment Efficacy 
Population 
IP 
 


 
 
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14.2.1.2 
Mean (±SE) Change from Baseline in Total 
Recall on the HVLT-R by Visit and by 
Treatment Efficacy Population 
IP 
14.2.1.1 
14.2.1.3 
Mean (±SE) Change from Baseline in Delayed 
Recall on the HVLT-R by Visit and by 
Treatment Efficacy Population 
IP 
14.2.1.1 
14.2.2 
Mean (±SE) Change from Baseline in Wechsler 
Memory Scale (WMS) Immediate and Delayed 
Recall Composite Score by Visit and by 
Treatment Efficacy Population 
IP 
14.2.1.1 
14.2.3 
Mean (±SE) Change from Baseline Clinical 
Dementia Rating Scale-Sum of Boxes (CDR-
SB) by Visit and by Treatment Efficacy 
Population 
IP 
14.2.1.1 
14.2.4 
Mean (±SE) Change from Baseline in Mini-
Mental State Examination (MMSE) Score by 
Visit and by Treatment Efficacy Population 
IP 
14.2.1.1 
14.2.5.1 
Box Plot of CSF Biomarker (T-tau) Efficacy 
Population 
IP 
  
14.2.5.2 
Box Plot of CSF Biomarker (P-tau181) Efficacy 
Population 
IP 
14.2.5.1 
14.2.5.3 
Box Plot of CSF Biomarker (Aβ1-40) Efficacy 
Population 
IP 
14.2.5.1 
14.2.5.4 
Box Plot of CSF Biomarker (Aβ1-42) Efficacy 
Population 
IP 
14.2.5.1 
14.2.5.5 
Box Plot of CSF Biomarker (Neurofilament 
Light Chain) Efficacy Population 
IP 
14.2.5.1 
14.2.5.6 
Box Plot of CSF Biomarker (pTau/Aβ1-42 
Ratio)  Efficacy Population 
IP 
14.2.5.1 
14.2.5.7 
Box Plot of CSF Biomarker (Brain derived 
neurotrophic factor (BDNF))  Efficacy 
Population 
IP 
 
14.3 
Figure 
 Figure for Safety Data 
  
 
 
14.3.1.1 
Box Plot of Change from Baseline in Heart Rate 
(beats/min) Safety Population 
IP 
  
14.3.1.2 
Box Plot of Change from Baseline in PR (msec) 
Safety Population 
IP 
14.3.1.1 


 
 
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14.3.1.3 
Box Plot of Change from Baseline in RR (msec) 
Safety Population 
IP 
14.3.1.1 
14.3.1.4 
Box Plot of Change from Baseline in QT (msec) 
Safety Population 
IP 
14.3.1.1 
14.3.1.5 
Box Plot of Change from Baseline in QRS 
(msec) Safety Population 
IP 
14.3.1.1 
14.3.1.6 
Box Plot of Change from Baseline in QTcF 
(msec) Safety Population 
IP 
14.3.1.1 
14.3.1.7 
Box Plot of Change from Baseline in QTc 
(msec) Safety Population 
IP 
14.3.1.1 
14.3.2.1 
Box Plot of Change from Baseline in Systolic 
Blood Pressure (mmHg) Safety Population 
IP 
  
14.3.2.2 
Box Plot of Change from Baseline in Diastolic 
Blood Pressure (mmHg) Safety Population 
IP 
14.3.2.1 
14.3.2.3 
Box Plot of Change from Baseline in Pulse Rate 
(beats/min) Safety Population 
IP 
14.3.2.1 
14.3.2.4 
Box Plot of Change from Baseline in Respiration 
(breaths/min) Safety Population 
IP 
14.3.2.1 
14.3.2.5 
Box Plot of Change from Baseline in Weight 
(kg) Safety Population 
IP 
14.3.2.1 
14.3.2.6 
Box Plot of Change from Baseline in in 
Temperature (C) Safety Population 
IP 
14.3.2.1 
14.4 
Figure 
Figure for PK and PD Data 
 
 
14.4.1 
Box Plot of Neflamapimod Concentrations by 
Visit Safety Population 
IP 
 
14.4.2.1.1 
Scatter Plot: CTrough vs. Change from Baseline 
in CSF Biomarker (T-tau) Efficacy Population 
IP 
  
14.4.2.1.2 
Scatter Plot: CTrough vs. Change from Baseline 
in CSF Biomarker (P-tau181) Efficacy 
Population 
IP 
14.4.2.1.1 
14.4.2.1.3 
Scatter Plot: CTrough vs. Change from Baseline 
in CSF Biomarker (Aβ1-40) Efficacy Population 
IP 
14.4.2.1.1 
14.4.2.1.4 
Scatter Plot: CTrough vs. Change from Baseline 
in CSF Biomarker (Aβ1-42) Efficacy Population 
IP 
14.4.2.1.1 
14.4.2.1.5 
Scatter Plot: CTrough vs. Change from Baseline 
in CSF Biomarker (Neurofilament light chain) 
Efficacy Population 
IP 
14.4.2.1.1 


 
 
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Statistical Analysis Plan 
 
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14.4.2.1.6 
Scatter Plot: CTrough vs. Change from Baseline 
in CSF Biomarker (pTau/Aβ1-42 Ratio) Efficacy 
Population 
IP 
14.4.2.1.1 
14.4.2.1.7 
Scatter Plot: CTrough vs. Change from Baseline 
in CSF Biomarker (Brain derived neurotrophic 
factor (BDNF))  Efficacy Population 
IP 
14.4.2.1.1 
14.4.2.2.1 
Scatter Plot: CTrough vs. Combined Change 
from Baseline in Z-score of Total Recall and 
Delayed Recall on the HVLT-R Efficacy 
Population 
IP 
14.4.2.1.1 
14.4.2.2.2 
Scatter Plot: CTrough vs. Change from Baseline 
in Wechsler Memory Scale (WMS) Immediate 
and Delayed Recall Composite Score Efficacy 
Population 
IP 
14.4.2.1.1 
14.4.2.2.3 
Scatter Plot: CTrough vs. Change from Baseline 
in Clinical Dementia Rating Scale-Sum of Boxes 
(CDR-SB) Efficacy Population 
IP 
14.4.2.1.1 
14.4.2.2.4 
Scatter Plot: CTrough vs. Change from Baseline 
in Mini-Mental State Examination (MMSE) 
Score Efficacy Population 
IP 
14.4.2.1.1 
14.4.3.1.1 
Scatter Plot: Cmax vs. Change from Baseline in 
CSF Biomarker (T-tau) Efficacy Population 
IP 
14.4.2.1.1 
14.4.3.1.2 
Scatter Plot: Cmax vs. Change from Baseline in 
CSF Biomarker (P-tau181) Efficacy Population 
IP 
14.4.2.1.1 
14.4.3.1.3 
Scatter Plot: Cmas vs. Change from Baseline in 
CSF Biomarker (Aβ1-40) Efficacy Population 
IP 
14.4.2.1.1 
14.4.3.1.4 
Scatter Plot: Cmax vs. Change from Baseline in 
CSF Biomarker (Aβ1-42) Efficacy Population 
IP 
14.4.2.1.1 
14.4.3.1.5 
Scatter Plot: Cmax vs. Change from Baseline in 
CSF Biomarker (Neurofilament light chain) 
Efficacy Population 
IP 
14.4.2.1.1 
14.4.3.1.6 
Scatter Plot: Cmax vs. Change from Baseline in 
CSF Biomarker (pTau/Aβ1-42 Ratio) Efficacy 
Population 
IP 
14.4.2.1.1 
14.4.3.1.7 
Scatter Plot: Cmax vs. Change from Baseline in 
CSF Biomarker (Brain derived neurotrophic 
factor (BDNF))  Efficacy Population 
IP 
14.4.2.1.1 


 
 
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14.4.3.2.1 
Scatter Plot: Cmax vs. Combined Change from 
Baseline in Z-score of Total Recall and Delayed 
Recall on the HVLT-R Efficacy Population 
IP 
14.4.2.1.1 
14.4.3.2.2 
Scatter Plot: Cmax vs. Change from Baseline in 
Wechsler Memory Scale (WMS) Immediate and 
Delayed Recall Composite Score Efficacy 
Population 
IP 
14.4.2.1.1 
14.4.3.2.3 
Scatter Plot: Cmax vs. Change from Baseline in 
Clinical Dementia Rating Scale-Sum of Boxes 
(CDR-SB) Efficacy Population 
IP 
14.4.2.1.1 
14.4.3.2.4 
Scatter Plot: Cmax vs. Change from Baseline in 
Mini-Mental State Examination (MMSE) Score 
Efficacy Population 
IP 
14.4.2.1.1 
 
 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2  
Subject Data Listings 
 
 
16.2.1  
Discontinued Subjects 
 
 
16.2.1.1 
Subject Disposition  (Enrolled Subjects) 
IP 
 
16.2.1.2 
Screen Failures 
IP 
 
16.2.1.3 
Early Withdrawals  (Enrolled Subjects) 
IP 
 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations (Protocol Deviations) 
IP 
 
16.2.3 
Subjects Excluded From The Efficacy Analyses 
 
 
16.2.3.1 
Analysis Sets (Enrolled Subjects) 
IP 
 
16.2.4  
Demographic Data, Medical History and 
Medications 
 
 
16.2.4.1 
Subject Randomization  (Randomized Subjects) 
IP 
 
16.2.4.2 
Demographic Data (Enrolled Subjects) 
IP 
 
16.2.4.3 
Computed tomography (CT)/Magnetic Resonance 
Imaging (MRI) Data (Enrolled Subjects) 
IP 
 
16.2.4.4.1 
Prior Medical History (Enrolled Subjects) 
IP 
 
16.2.4.4.2 
Ongoing Medical History (Enrolled Subjects) 
IP 
 


 
 
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Statistical Analysis Plan 
 
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Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.4.4.3 
Medical History-Probable Alzheimer’s Diagnosis 
(Enrolled Subjects) 
IP 
 
16.2.4.5.1 
Inclusion Criteria Not Met (Enrolled Subjects) 
IP 
 
16.2.4.5.2 
Exclusion Criteria Met (Enrolled Subjects) 
IP 
 
16.2.4.6.1 
Prior and Concomitant Medications (Enrolled 
Subjects) 
IP 
 
16.2.4.6.2 
Prior and Concomitant Alzheimer’s Medications 
(Enrolled Subjects) 
IP 
 
16.2.5  
Compliance And/Or Drug Concentration Data 
IP 
 
16.2.5.1 
Study Drug Exposure and Compliance (Enrolled 
Subjects) 
IP 
 
16.2.5.2 
Plasma Pharmacokinetic Parameters of 
Neflamapimod Concentrations Over Time (Enrolled 
Subjects) 
IP 
 
16.2.5.3 
Individual Pharmacokinetic Parameters of 
Neflamapimod (Enrolled Subjects) 
IP 
 
16.2.6  
Individual Efficacy Response Data and PD data 
 
 
16.2.6.1.1 
Hopkins Verbal Learning Test – Revised (HVLT-R) 
(Enrolled Subjects) 
IP 
 
16.2.6.1.2 
Combined Change from Baseline in Z-score of Total 
Recall and Delayed Recall on the HVLT-R (Enrolled 
Subjects) 
IP 
 
16.2.6.2 
Wechsler Memory Scale (WMS) (Enrolled Subjects) 
IP 
 
16.2.6.3 
Clinical Dementia Rating (CDR) (Enrolled Subjects) 
IP 
 
16.2.6.4 
Mini-Mental State Examination (MMSE) (Enrolled 
Subjects) 
IP 
 
16.2.6.5 
Cerebrospinal Fluid (CSF) Biomarkers (Enrolled 
Subjects) 
IP 
 
16.2.7  
Adverse Event Listings  
IP 
 
16.2.7.1 
Adverse Events (Enrolled Subjects) 
IP 
 
16.2.7.2 
All Serious Adverse Events (Enrolled Subjects) 
IP 
 
16.2.8  
Individual Laboratory Measurements And Other 
Safety and PD data 
 
 
16.2.8.1.1 
Hematology Results (Enrolled Subjects) 
IP 
 


 
 
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Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.8.1.2 
Chemistry Results (Enrolled Subjects) 
IP 
 
16.2.8.1.3 
Coagulation Results (Enrolled Subjects) 
IP 
 
16.2.8.1.4 
Clinically Significant Laboratory Results (Enrolled 
Subjects) 
IP 
 
16.2.8.1.5 
Laboratory Liver Function and Coagulation 
Parameter Abnormalities (Enrolled Subjects) 
IP 
 
16.2.8.2 
Vital Signs (Enrolled Subjects) 
IP 
 
16.2.8.3 
12-lead ECG Parameters (Enrolled Subjects) 
IP 
 
16.2.8.4 
Physical Examination, Abnormal Results (Enrolled 
Subjects) 
IP 
 
16.2.8.5 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Questionnaire (Enrolled Subjects) 
IP 
 
 
 


 
 
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Statistical Analysis Plan 
 
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Confidential 
 
Approval for implementation of Statistical Analysis Plan 
 
Title: 
A Double-Blind, Placebo-Controlled Proof-of-Concept Study of a 
Selective p38 MAP Kinase Alpha Inhibitor, Neflamapimod, 
Administered for 24 Weeks in Subjects with Mild Alzheimer’s 
Disease 
 
Protocol Reference: 
EIP-VX17-745-304 Protocol V1.0 Final 17-NOV-2017 
 
 
 
 
Sponsor: 
EIP Pharma, LLC. 
 
 
 
 
Author: 
Shuhua Qi:  Senior Biostatistician 
 
 
 
 
WCT reviewer: 
Jonathan White:  Director, Biostatistics 
 
 
 
 
 
  
 
Author’s signature: 
 
 Date:  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
Reviewer’s signature: 
 
 Date: 
 
 
 
 
 


 
 
EIP Pharma, LLC 
 
EIP-VX17-745-304 
 
Statistical Analysis Plan 
 
Version Final 1.2 
 
Issue Date 30-JUL-2019 
 
Template: WCT-TP-ST-005-005 
 
Page 47 of 47 
Effective Date: 15-Apr-2016 
 
Confidential 
 
 
The above Statistical Analysis Plan has been reviewed and approved by the Sponsor: 
 
 
  
 
Name of Approver: 
Kelly Blackburn, MHA, MeD 
 
Position: 
Head of Clinical Development, EIP Pharma  
 
 
 
 
 
 
 
 
 
 
  
 
Signature: 
 
 Date: 
 
 
 
  
 
 
 
 
 
 
Name of Approver: 
Hui-May Chu, PhD, MBA 
 
 
 
Position: 
Senior Director of Statistics, Anoixis Corporation 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
Signature: 
 
 Date: 
 
 
 
 
 
 
 
 
 
 
 
Name of Approver: 
John Alam, MD 
 
 
 
Position: 
CEO, EIP Pharma 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
Signature: 
 
 Date: