Conditions: Alzheimer Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
This study seeks to measure changes in cognition through verbal and visual test procedures and changes in biomarkers of Alzheimer's disease and inflammatory and metabolic parameters that can be measure in the central nervous system (CNS) with advanced neuroimaging techniques in patients treated with NE3107 (17a-ethynyl-androst-5-3b,7b,17b-triol).

Detailed description:
Considering how many people are in a state of mild cognitive impairment (MCI) and frank dementia, there is a substantial cost to society in terms of financial burden and suffering. Degenerative conditions that result in cognitive change in middle and late life are frequently associated with abnormal deposits of protein material (e.g., amyloid, phospho-tau) which interfere with neuronal function and viability. Inflammation and insulin resistance in the CNS and abnormal protein deposition and resultant physiological impairment characterize conditions of the Alzheimer's dementia (AD) type.

Neuroinflammation prompts AD progression, impaired cholesterol efflux and reduced insulin signaling (insulin resistance). Insulin resistance has been considered a risk factor as well as a feature of AD, and has also been associated with increased aß-42 secretion, neuritic plaque burden, abnormal insulin receptor performance, decreased glucose metabolism, and consequently decreased cognitive performance.

No therapy exists that has been proven to halt or reverse the progressive deposition of abnormal proteins or the attendant neurophysiological deterioration. Various investigational therapies aim to target the pathophysiological processes of AD; from combating abnormal protein deposition, to targeting sources of systemic and neuroinflammation, to providing cholinergic, hormonal, and metabolic support. A promising area of research is the ongoing use of insulin synthesizers as a therapeutic option for AD.

Several Phase 3 studies have been initiated and/or completed with compounds such as Semaglutide, a hormone that stimulates insulin signaling, Metformin, an insulin synthesizer, and NE3107, an anti-inflammatory insulin-sensitizing agent.

This study seeks to measure changes in cognition through verbal and visual test procedures and changes in biomarkers of Alzheimer's disease and inflammatory and metabolic parameters that can be measured in the CNS with advanced neuroimaging techniques in patients treated with NE3107 (17a-ethynyl-androst-5-ene-3b,7b,17b-triol).

Investigational Product

The drug under investigation is NE3107 (17a-ethynyl-androst-5-ene-3b,7b,17b-triol). NE3107 is formulated with common excipients used in oral medications in #2 hard gelatin capsules. The capsules are designed for oral administration. NE3107 capsules are stable at room temperature for at least 18 months. Stability of the capsules used in this study will be monitored by a concurrent stability study conducted by the capsule manufacturer and the holder of the primary IND, Biovie, Inc (Santa Monica, CA).

Arms:
arm 1: All participants will take 200mg BID (12 hours apart) of NE3107 for 3 months.

Interventions: intervention 1: NE3107
Intervention descriptions: intervention 1: Participants will take 20mg twice daily (BID) approximately 12 hours apart. The dose will be stable the duration of the study intervention (3 months)

Protocol document:
Prot_SAP_000.pdf: 
CLINICAL TRIAL PROTOCOL: NE3107-TRP-001 
Study Title: 
A Phase II Open-Label Study for the Use of Anti-Inflammatory, 
Insulin-Sensitizing NE3107 for Treatment of Cognitive Decline Due to 
Degenerative Dementias 
Study Number: 
NE3107-TRP-001 
Study Phase: 
2 
Product Name: 
NE3107 (17a-ethynyl-androst-5-ene-3b,7b,17b-triol) 
IND Number: 
159271 
Indication: 
Degenerative Dementias 
Investigators: 
Principal Investigator: Dr. Sheldon E. Jordan, M.D., F.A.A.N. 
Sub-Investigator: Dr. Bijan Pourat, M.D. 
 
 
 
Sponsor: 
The Regenesis Project 
Sponsor Contact: 
Sheldon Jordan, MD 
Sponsor’s Legal 
Representative: 
Stephanie Berg, ND, JD 
3019 Wilshire Blvd., #242 
Santa Monica, CA 90403 
Medical Monitor: 
Sheldon Jordan, MD 
 
 
 
Original Protocol: 
11/04/2021 
Amendment 1: 
Version 2, dated 12/17/2021 
 
Confidentiality Statement 
This document and its contents are the property of and confidential to Sheldon Jordan, MD Inc. dba 
The Regenesis Project. Any unauthorized copying or use of this document is prohibited. 


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SYNOPSIS 
Sponsor:  Sheldon Jordan MD Inc., dba The Regenesis Project 
Name of Finished Product:  NE3107 
Name of Active Ingredient:  17a-ethynyl-androst-5-ene-3b,7b,17b-triol 
Study Title:  A Phase II Open-Label Study for the Use of Anti-Inflammatory, Insulin-Sensitizing 
NE3107 for Treatment of Cognitive Decline Due to Degenerative Dementias 
Study Number:  NE3107-TRP-001 
Study Phase: 2  
Primary Objective(s):  
Primary endpoints will involve a comparison of neurophysiological health as evaluated by multi-
modal brain MRIs obtained at baseline and post-intervention termination (3 months). 
Secondary Objective(s): 
Secondary endpoints will include a longitudinal comparison of cognitive functioning as well as 
serological inflammatory markers and glucose and insulin homeostasis. 
Study Design: 
The present open label study is designed to evaluate the potential efficacy of NE3107 among 
patients with degenerative dementias through neuroimaging, cognitive performance testing, and 
serological measures of insulin resistance. 
Study Population:  
Approximately 25 participants are planned to be enrolled in this study. 
Diagnosis and Main Criteria for Inclusion 
Inclusion criterion are a diagnosis of cognitive decline due to degenerative dementia and a clinical 
dementia rating (CDR) score of 0.5 or 1. 
Test Product; Dose; and Mode of Administration:  
NE3107 20mg BID 
Duration of Treatment:  
The duration of active intervention will be three (3) months. 
Pharmacokinetic Variables: 
The terminal plasma t1/2 for NE3107 is 6-8 hours. The estimated time to reach steady-state drug 
concentrations is 3 days using BID daily dosing. 
Safety Assessments: 
Safety and tolerability will be assessed using incidence reports, vital sign measurements, physical 
examinations, and clinical laboratory assessments. 
Statistical Methods:  
Statistical analyses will be run to compare change from baseline at the post-intervention 
termination follow-up (three months after baseline) using a level of significance of 0.05.  
Date of Original Protocol: 4 November 2021 
Date of Most Recent Protocol Amendment (if applicable): Version 2, dated 17 December 2021 
Prepared in: Microsoft Word version 16  


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF APPENDICES ............................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................7 
1 
INTRODUCTION .................................................................................................11 
2 
STUDY OBJECTIVES ..........................................................................................13 
2.1 
Primary Objective(s) ........................................................................................13 
2.2 
Secondary Objective(s) ....................................................................................13 
3 
INVESTIGATIONAL PLAN ................................................................................14 
3.1 
Overall Study Design and Plan ........................................................................14 
3.2 
Rationale for Study Design and Control Group ...............................................14 
3.3 
Study Duration and Dates ................................................................................14 
4 
STUDY POPULATION SELECTION .................................................................15 
4.1 
Study Population ..............................................................................................16 
4.2 
Inclusion Criteria .............................................................................................16 
4.3 
Exclusion Criteria ............................................................................................16 
5 
STUDY TREATMENT(S) ....................................................................................18 
5.1 
Description of Treatment(s) .............................................................................18 
5.1.1 
Study Drug ...........................................................................................18 
5.1.2 
Placebo or Control ...............................................................................18 
5.2 
Treatment(s) Administered ..............................................................................18 
5.3 
Selection and Timing of Dose for Each Participant.........................................18 
5.4 
Method of Assigning Participants to Treatment Groups .................................18 
5.5 
Blinding............................................................................................................18 
5.6 
Concomitant Therapy.......................................................................................18 
5.7 
Restrictions ......................................................................................................19 
5.7.1 
Prior Therapy .......................................................................................19 
5.7.2 
Fluid and Food Intake ..........................................................................19 
5.7.3 
Participant Activity Restrictions ..........................................................19 
5.8 
Treatment Compliance .....................................................................................19 
5.9 
Packaging and Labeling ...................................................................................19 
5.10 
Storage and Accountability ..............................................................................19 
5.11 
Investigational Product Retention at Study Site ..............................................20 
6 
STUDY PROCEDURES .......................................................................................21 
6.1 
Informed Consent.............................................................................................22 
6.2 
Medical History ...............................................................................................22 
6.3 
Physical Examination.......................................................................................23 
6.4 
Vital Signs ........................................................................................................23 


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6.5 
Electrocardiography and Continuous Telemetry Monitoring ..........................23 
6.5.1 
12-Lead Electrocardiograms ................................................................23 
6.5.2 
Continuous Holter Monitoring .............................................................23 
6.6 
Clinical Laboratory Tests .................................................................................23 
6.6.1 
Laboratory Parameters .........................................................................23 
6.6.2 
Sample Collection, Storage, and Shipping ..........................................26 
6.7 
Dispensing Study Drug ....................................................................................26 
6.8 
Pharmacokinetic Assessments .........................................................................27 
6.9 
Adverse Events Assessments ...........................................................................27 
6.9.1 
Timing ..................................................................................................28 
6.9.2 
Severity ................................................................................................28 
6.9.3 
Relationship .........................................................................................28 
6.9.4 
Expectedness ........................................................................................29 
6.9.5 
Clinical Significance ............................................................................29 
6.9.7 
Serious Adverse Events .......................................................................29 
 
Definition ....................................................................................29 
 
Reporting Serious Adverse Events .............................................29 
6.10 
Concomitant Medication Assessments ............................................................29 
6.11 
Removal of Participants from the Trial or Study Drug....................................29 
7 
STUDY ACTIVITIES ...........................................................................................31 
7.1 
Screening Visit (Days –10 to -1) .....................................................................31 
7.2 
Clinic Admission (Day 0) ................................................................................32 
7.3 
Treatment Period (Day 1 to Day 90)................................................................32 
7.4 
Early Termination Procedures .........................................................................33 
7.5 
Follow-up Visit (Day 91 ± 15).........................................................................33 
8 
QUALITY CONTROL AND ASSURANCE .......................................................31 
9 
PLANNED STATISTICAL METHODS ..............................................................36 
9.1 
General Considerations ....................................................................................36 
9.2 
Determination of Sample Size .........................................................................36 
9.3 
Analysis Populations ........................................................................................36 
9.4 
Demographics and Baseline Characteristics ....................................................37 
9.5 
Statistical Analysis of Endpoints .....................................................................37 
 
     9.5.1 
       Statistical Analysis of Primary Imaging Endpoints……………..37 
 
     9.5.2 
       Statistical Considerations for Secondary Endpoints………...…..41 
9.6 
Safety Analysis ................................................................................................42 
10 
ADMINISTRATIVE CONSIDERATIONS ..........................................................44 
10.1 
Investigators and Study Administrative Structure ...........................................44 
10.2 
Institutional Review Board (IRB) Approval ....................................................44 


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10.3 
Ethical Conduct of the Study ...........................................................................44 
10.4 
Participant Information and Consent ...............................................................44 
10.5 
Participant Confidentiality ...............................................................................45 
10.6 
Study Monitoring .............................................................................................46 
10.7 
Case Report Forms and Study Records ...........................................................46 
10.8 
Protocol Violations/Deviations ........................................................................46 
10.9 
Access to Source Documentation ....................................................................46 
10.10 
Data Generation and Analysis .........................................................................47 
10.11 
Retention of Data .............................................................................................47 
10.12 
Financial Disclosure.........................................................................................47 
10.13 
Publication and Disclosure Policy ...................................................................47 
11 
REFERENCE LIST ...............................................................................................49 
 
 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................55 
Appendix 4 
Sponsor Signatures.....................................................................................56 
Appendix 5 
Investigator’s Signature .............................................................................57 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
A 
Amyloid beta 
Abin2 
A20 binding inhibitor of NFappaB activation 2 
AChEI 
Acetylcholine esterase inhibitor 
AD 
Alzheimer’s disease 
ADAS-Cog 11 
Alzheimer’s Disease assessment Scale-Cognitive Subscale 11 
ADCOMS 
Alzheimer’s disease composite score 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study-Clinical Global Impression of 
Change 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse event 
API 
Active pharmaceutical ingredient  
ApoE(1-4) 
Apolipoprotein E 
APP 
amyloid precursor protein 
Arrestin 
adaptor/scaffold proteins involved in inhibition of GPCR-mediated & 
intracellular signaling pathways 
AUC 
Time integrated drug exposure area under the curve  
BACE1 
beta secretase (cleaves APP) 
BBB 
Blood-brain barrier 
BDNF 
brain-derived neurotrophic factor 
BID 
twice daily 
BMI 
Body mass index 
CCR2 
C-C motif chemokine receptor 2 (binds MCP1) 
CDR 
Clinical Dementia Rating Scale 
CHO 
Chinese hamster ovarary (cell line) 
Cmax 
Maximum concentration of drug in plasma or serum 
CNS 
Central nervous system 
cPLA2 
phospholipase A2 
CRP 
C-reactive protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CXCL 
C-X-C motif chemokine ligand 
CYP 
Cytochrome P450 
EAE 
experimental autoimmune encephalomyelitis  
EC50 
half maximal effective concentration 
ECG(EKG) 
Electrocardiogram  
eGFR 
Estimated glomerular filtration rate 
ERK1, ERK2 
extracellular signal regulated kinase 1 and 2 
F(%) 
Percent absolute oral bioavailability  


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Abbreviation 
Definition 
GABA 
gamma amino butyric acid 
GD 
Gestation day 
GDS-SF 
Geriatric Depression Scale Short Form 
GLP 
Good laboratory practice  
GRK 
G protein-coupled receptor kinase 
HbA1c 
hemoglobin A1c 
HDL 
High-density lipoprotein 
HE3129 
3,7-dihydroxy-androst-5-en-17-one 
HE3291 
17-ethynyl-androst-5-ene-3,7,17-triol 
HE3393 
17-ethynyl-3,17-dihydroxy-androst-5-en-7-one 
HE3892 
17-ethynyl-androst-5-ene-2,3,7,17-tetrol 
HE3545 
17-ethynyl-androst-5-ene-3,7,17-triol 
HE3633 
17-ethynyl-17-hydroxy-androst-4,6-diene-3-one 
hERG 
Human-ether a-go-go related gene, Kv11.11 alpha subunit of 
potassium ion channel 
HIS 
Hachinski Ischemic Scale 
HOMA 
Homeostatic model assessment  
HPA 
hypothalamus-pituitary-adrenal 
HPLC 
High-performance liquid chromatography 
Hsd17b4 
17-hydroxysteroid dehydrogenase 4 
IFN 
interferons 
IB 
inhibitor of NFB 
IKK 
IB kinase 
IL 
interleukin cytokines 
IGT 
impaired glucose tolerance 
IQGAP1 
IQ Motif Containing GTPase Activating Protein 1 scaffold 
IQR 
inter-quartile range 
IR 
Insulin resistance 
iv 
intravenous 
JNK 
c-Jun N-terminal kinases 
B 
promoter NFB transcription site 
KO 
Knock out 
KSR 
kinase suppressor of Ras (scaffold) 
LC-MS-MS 
Liquid chromatography–tandem mass spectrometry 
LDL 
Low-density lipoprotein 
LID 
L-dopa induced dyskinesia 
LPS 
lipopolysaccharide 
Lrp1 
low density lipoprotein receptor related protein 


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Abbreviation 
Definition 
MEK 
mitogen-activated protein kinase kinase (phosphorylates ERK) 
MAP3K8 
mitogen-activated kinase kinase kinase (phosphorylates MEK; Tpl2 in 
mouse, COT1 in human) 
MAPK 
mitogen-activated protein kinases 
MAPK1 
p42 ERK2 
MAPK3 
p44 ERK1 
MCI 
Mild cognitive impairment 
MCP1 
monocyte chemoattractant protein 1 
mITT 
Modified Intent-to-Treat 
MPK1 
mitogen-activated protein kinase phosphatase 1 
MMP 
matrix metallopeptidases 
MMSE 
Mini mental state exam 
MNK 
MAP kinase signal-integrating kinase 
MP1 
Mitogen-activated protein kinase scaffold protein 1 
MORG 
WD-repeat protein family scaffold 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
MRI 
Magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MSK 
stress-activated protein kinase 
MTD 
Maximum tolerated dose 
M value 
mean glucose infusion rate 
MW 
Molecular weight 
NE3107 
17-ethynyl-androst-5-ene-3,7,17-triol 
NOAEL 
No-observed-adverse-effect-level 
NEMO 
NF-kappa-B essential modulator (aka IKK) 
NFB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
NMT 
Not more than 
Nos 
Nitric oxide synthase 
NPI-12 
Neuropsychiatric Inventory 12-Domain 
p- 
phospho substituent (e.g. p-ERK) 
p38 
p38 MAPK 
p65 
NFB3 
p105 
NFB subunit 
Paxillin 
scaffold encoded by the PXN gene 
PBMC 
Peripheral blood mononuclear cells 
PD 
Parkinson’s disease 
PD98059 
MEK inhibitor 
PEA-15 
proliferation and apoptosis adaptor protein-15 


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Abbreviation 
Definition 
PgP 
P-glycoprotein 
PK 
pharmacokinetics 
PK-PD 
Pharmacokinetics-pharmacodynamics 
po 
Oral route of drug administration 
PPAR 
peroxisome proliferator activated receptors 
QD 
Once daily 
QSAR 
Quantitative structure-activity relationship 
QT interval 
Length of time from the start of the Q wave to the end of the T wave, 
the time taken for ventricular depolarization and repolarization 
Raf 
serine/threonine-specific protein kinases 
Ras 
small GTPase proteins involved in signal transduction 
RAW264.7 
mouse macrophage cell line 
RH 
Relative humidity  
Rsp6ka3 
p90 ribosomal S6 kinases 
SAE 
Severe adverse event 
Sef 
similar expression to fgf genes scaffold 
SIRT2 
sirtuin-2 
SP1 
specificity protein 1 (transcription factor) 
t1/2 
Half-life 
T2D 
Type 2 diabetes 
TG 
Triglycerides  
Tmax 
Length of time after drug administration to Cmax 
TLR 
toll-like receptor 
TNF 
tumor necrosis factor 
UC 
Ulcerative colitis 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia  
Vcam 
vascular cell adhesion molecules  
Vd 
Volume of distribution 
 
 


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1 
INTRODUCTION 
Considering how many people are in a state of mild cognitive impairment (MCI) and frank 
dementia, there is a substantial cost to society in terms of financial burden and suffering 
(Connolly, 2018). Degenerative conditions that result in cognitive change in middle and late 
life are frequently associated with abnormal deposits of protein material (e.g., amyloid, 
phospho-tau) which interfere with neuronal function and viability (Lacor, Buniel, Furlow, 
Clemente, Velasco, Wood, et a., 2007; Khan, 2016). Inflammation and insulin resistance in 
the CNS and abnormal protein deposition and resultant physiological impairment 
characterize conditions of the Alzheimer’s dementia (AD) type (Kinney, Bemiller, 
Murtishaw, Leisgang, Salazar & Lamb, 2018; Rorbach-Dolata & Piwowar, 2019).  
Neuroinflammation prompts AD progression, impaired cholesterol efflux and reduced insulin 
signaling (insulin resistance) (Hølscher, 2020; Kinney et al., 2018; Rorbach-Dolata & 
Piwowar, 2019; Chow, Shi & Cheng, 2019. Insulin resistance has been considered a risk 
factor as well as a feature of AD, and has also been associated with increased aß-42 
secretion, neuritic plaque burden, abnormal insulin receptor performance, decreased glucose 
metabolism, and consequently decreased cognitive performance (Holscher, 2020; Chow et 
al., 2019; Reading & Ahlem, 2021). 
No therapy exists that has been proven to halt or reverse the progressive deposition of 
abnormal proteins or the attendant neurophysiological deterioration. Various investigational 
therapies aim to target the pathophysiological processes of AD; from combating abnormal 
protein deposition, to targeting sources of systemic and neuroinflammation, to providing 
cholinergic, hormonal, and metabolic support. A promising area of research is the ongoing 
use of insulin synthesizers as a therapeutic option for AD. Several Phase 3 studies have been 
initiated and/or completed with compounds such as Semaglutide, a hormone that stimulates 
insulin signaling (Nauck, Quast, Wefers, & Meier, 2020), Metformin, an insulin synthesizer 
(Koenig, Mechanic-Hamilton, Xie, Combs, Cappola, Xie, et al., 2017; Lin, Wang, Ma, 
Wang, Gong, Zhang, et al., 2018), and NE3107, an anti-inflammatory insulin-sensitizing 
agent (Reading & Ahlem, 2021).  
In this study, the drug under investigation is NE3107 (17a-ethynyl0androst-5-ene-3b, 7b, 
17b-triol). NE3107 is a small, blood-brain permeable molecule with anti-inflammatory and 
insulin-sensitizing properties. The mechanism of action for NE3107 involves selective 
inhibition of inflammatory mediators.  
This study seeks to measure changes in advanced neuroimaging, CNS biomarkers of 
Alzheimer’s disease, inflammatory serological and metabolic parameters, and cognitive 
performance measures among participants treated with NE3107. 
The dose of NE3107 administered in this study will be 20 mg BID. Nonclinical safety studies 
and prior clinical trials have not identified a toxicity indicating the need for exploration of 
dose response. NE3107 dose response for anti-inflammatory and insulin sensitizing activity 
was not statistically resolved between 2, 5 and 10 mg BID in impaired glucose tolerance 
subjects in trial HE3286-0102. Neither preclinical data, nor available clinical information 
suggest an ordered dose response relationship across exposure on key indices of glycemic 


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control and insulin sensitivity. There has been no indication that NE3107’s anti-inflammatory 
activity could be increased with higher exposures. The dose duration will be 3 months. The 
rationale for 3-month administration is to allow sufficient time for detectable change to 
occur. The route of administration for NE3107 will be orally. NE3107 is formulated with 
common excipients used in oral medications in #2 hard gelatin capsules. NE3107 capsules 
are stable at room temperature for at least 18 months.  
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s)  
Primary endpoints will involve a comparison of neurophysiological health as evaluated by 
multi-modal brain MRIs obtained at baseline and post-intervention termination (3 months). 
Specifically, multi-modal MRI endpoints will include: (1) An increase or stabilization in 
glutathione levels (as measured by magnetic resonance spectroscopy, MRS) compared to 
baseline. Patients with cognitive decline often show characteristic change in MRS or 
volumetric evaluation compared to age-matched controls (Kuhn et al. 2021); (2) Stabilized 
and/or improved dendritic density compared to baseline (as measured by diffusion tensor 
imaging, DTI-NODDI); (3) Enhancement of arterial signal compared to baseline (as 
quantified by arterial spin labeling, ASL). Patients with cognitive decline often have 
decreased perfusion in temporal parietal or frontal regions of the brain with ASL perfusion 
(Kuhn et al. 2021); (4) increased functional connectivity of the nucleus basalis of Meynert 
(NBM) with both hippocampi as well as between both hippocampi compared to baseline, as 
visualized by seed analysis of blood-oxygen level dependent (BOLD) imaging as well as (5) 
increased neurovascular coupling as visualized by BOLD compared to baseline.  
 
2.2 
Secondary Objective(s)  
Secondary endpoints will include a longitudinal comparison of metabolic and serological 
analysis (specifically measures of glucose and insulin homeostasis); the level of cognitive 
impairment as defined by neuropsychological testing. Neuropsychological testing measures 
will include the Quick Dementia Rating Scale (QDRS), Clinical Dementia Rating (CDR) 
score as estimated by the QDRS, the Alzheimer’s Disease Assessment Scale (ADAS-Cog12), 
the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment 
(MoCA).  


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
The present study is designed as a Phase II, open-label study of patients with dementia to 
evaluate potential efficacy of NE3107 using serological measures of insulin resistance, 
cognitive performance testing, AD biomarkers, and neuroimaging endpoints. Baseline and 
outcome measures in this study utilize validated tests that are appropriate for repeated 
measures which are not affected by practice effects. Advantages of this study include the fact 
that the neuropsychological testing instruments and advanced MRI imaging protocols that 
have been in routine clinical deployment provide for a high degree of availability and 
reliability for diagnosis and for monitoring change of status.  The study population is 
sufficiently broad and the conditions of interest are sufficiently prevalent so that recruitment 
of the projected numbers of participants is not a limiting factor. 
 
The duration of treatment is 3 months. The rationale for 3-month administration is to 
allow sufficient time for detectable change to occur. To minimize risk, participants will 
be called within 24 hours following initiation of the drug and weekly thereafter, as well 
as attend monthly visits the principal investigator to evaluate for safety and tolerability 
of the study intervention. Mild, moderate, and severe adverse reactions will be reported 
on an ongoing basis.  Previously observed adverse reactions are listed in Table 22 of 
the Investigator’s Brochure. Participants will be discontinued if they have moderate or 
severe adverse reaction ratings according to the ICH SAE E2A. 
 
(See Appendix 1, Study Events Table.) 
3.2 
Rationale for Study Design and Control Group 
The dose of NE3107 to be used in this study is 20 mg BID. Nonclinical safety studies and 
prior clinical trials have not identified a toxicity that supports the need for exploration of 
dose response.  In vitro data indicate NE3107 is active at low nanomolar concentrations.  
NE3107 dose response for anti-inflammatory and insulin sensitizing activity was not 
statistically resolved between 2, 5 and 10 mg BID in impaired glucose tolerance subjects 
in trial HE3286-0102, and neither preclinical data, nor available clinical information 
suggest an ordered dose response relationship across exposure on key indices of glycemic 
control and insulin sensitivity. There has been no indication that NE3107’s anti-
inflammatory activity could be increased with higher exposures.   NE3107 
pharmacokinetics have high standard deviations for maximum serum concentration 
(Cmax) and daily area under curve (AUC), which raise the concern for drug holiday or 
suboptimal trough plasma concentrations in participants with the lowest exposure.  The 
dose of 20 mg BID is expected to increase the lowest expected Cmax and AUC values to 
within 1 standard deviation below the average values for 10 mg BID, with trough values 
greater than 1 ng/mL.   
 


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3.3 
Study Duration and Dates 
The proposed participant recruitment start date will begin on 15 January 2022 and end on 31 
January 2022. The recruitment period of 2 weeks, active treatment intervention period of 3 
months, and final follow-up period of 2 weeks yields an expected 4-month study duration. 
The actual overall study duration, start date and end date may vary depending on participant 
recruitment.  


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Number of Participants 
 
Approximately 25 participants are expected to be enrolled in this Phase II trial to 
evaluate longitudinal findings from multimodal MRI among the population that is 
being studied. 
 
Gender of Participants 
 
The gender distribution for this study will aim for a ratio of 50:50 men to women. This 
is to ensure that both men and women benefit equally from any potential efficacy of 
NE3107 in treating dementia and that neither men nor women are disproportionately 
burdened by any tolerability issues. Women who are pregnant, who may become 
pregnant, or who are breastfeeding will not be included in the study. 
 
Age of Participants 
 
The ages for the participants in this study will range from 50-89 years old. This age range 
was selected based on the fact that degenerative conditions that result in cognitive change 
occur in middle and late life. 
 
 
4.2 
Inclusion Criteria 
In order for a subject to be considered for this study, the following criterion is required: 
 
• Diagnosis of cognitive decline due to degenerative dementia 
• Age within range of 50-89 years old 
• QDRS score ranging from 1.5-12.5, with a converted Clinical Dementia Rating 
(CDR) score of 0.5 (mild cognitive impairment) to 1(mild dementia) 
 
The QDRS scale will be given to all patients; a cutoff range for QDRS scores has been 
specified as 1.5-12.5 to qualify patients with a clinical dementia score (CDR) of 0.5 to 1. 
4.3 
Exclusion Criteria 
In order for a subject to be considered for this study, he/she may NOT have any of the 
following: 
  
• Subjects with contraindications for lumbar puncture, such as bleeding 
abnormalities, use of anticoagulant medications, and local skin or spine 
abnormalities. See Section 6.6.1 “Laboratory Parameters,” page 26.  


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• Subjects with contraindications to magnetic resonance imaging (MRI) 
acquisition, including patients with non MRI-compatible pacemakers, 
defibrillators, or other implanted electronic devices. 
• Women who are pregnant, who may become pregnant, or who are 
breastfeeding 
• Reversible causes of cognitive impairment that explains the clinical status 
entirely, such as hypothyroidism, depression 
• Advanced stages of any terminal illness or any active cancer that requires 
chemotherapy 
• History of breast cancer   
• Women with child-bearing potential who are not willing to use a double-barrier birth 
control method 
• Males not willing to use a double-barrier birth control method with female sex 
partners with child-bearing potential 
• Individuals with hepatic impairment as defined by: 
o Alanine aminotransferase (ALT) lab values >3x the upper normal limit (UNL) 
o Aspartate aminotransferase (AST) lab values >3x UNL 
OR 
o History of clinically significant liver disease in the Principal Investigator’s 
medical judgment 
• Individuals with renal impairment as defined by Creatinine clearance (Cockcroft-
Gault formula) of <45 mL/min. 
 
 


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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Study Drug 
NE3107 is an investigational orally bioavailable, blood-brain barrier permeable anti-
inflammatory agent with a new mechanism of action targeting multiple mechanisms of 
pathology in Alzheimer's disease. NE3107 is an uncharged, low molecular weight molecule, 
poly-hydroxylated synthetic derivative of the C-19 adrenal steroid series.  In vitro studies 
have been conducted to measure membrane transport, active efflux/P-gp interaction, hepatic 
stability, CYP inhibition, and CYP induction.  
5.1.2 
Placebo or Control 
All participants will receive the study drug; this study will utilize no placebo group. 
5.2 
Treatment(s) Administered 
The drug under investigation is NE3107 (17a-ethynyl-androst-5-ene-3b,7b,17b-triol).  
NE3107 is formulated with common excipients used in oral medications in #2 hard gelatin 
capsules. The capsules are designed for oral administration. The dose of NE3107 (Biovie, 
inc.) is 20 mg twice daily (BID) approximately 12 hours apart, for the duration of 3 months. 
Study drug will be dispensed and monitored by the Sponsor. 
5.3 
Selection and Timing of Dose for Each Participant 
The dose of NE3107 (Biovie, inc.) is 20 mg twice daily (BID) approximately 12 hours apart. 
The dose will be stable for the duration of the study intervention, and will be the same for all 
participants. 
 
5.4 
Method of Assigning Participants to Treatment Groups 
All participants will receive active study drug at the same dosage.  
5.5 
Blinding 
No blinding procedures will be utilized. 
5.6 
Concomitant Therapy 
Concomitant medications will be considered any therapies that the patient begins/continues 
taking from the time point of 30 days prior to first dose of NE3107. Concomitant medications 
will be stabilized for 30 days prior to entry in the study protocol. There are no 
pharmacologically or toxicologically important NE3107 metabolites for consideration in 
drug exposure rationale, but memantine and acetylcholine esterase inhibitors, galantamine, 
donepezil and rivastigmine, are permitted as co-medications in the proposed study.  
Memantine and rivastigmine do not have appreciable interactions with hepatic CYP 


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enzymes, so they do not factor into drug-drug PK interactions.  Donepezil is predominately 
metabolized by CYP2D6, but is also metabolized by CYP3A4.  NE3107 is also metabolized 
primarily by CYP3A4.  In conclusion, no drug-drug PK interactions with co-medications 
memantine, donepezil, galantamine and rivastigmine are expected with the proposed dose of 
20 mg BID. As noted in the exclusion criteria, patients with contraindications for lumbar 
puncture (such as bleeding abnormalities requiring the use of anticoagulant medications) will 
not be permitted into the study. Additionally, participants with any active cancer requiring 
chemotherapy will not be permitted to take part in the study. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
There are no restrictions of entry to the study based on prior therapy. 
5.7.2 
Fluid and Food Intake  
Patients will be required to obtain bloodwork having fasted for a period of time no less than 8 
hours. There are no other fluid or food intake restrictions during the course of the study. 
5.7.3 
Participant Activity Restrictions 
The participant will have no activity restrictions related to study involvement. 
5.8 
Treatment Compliance 
Participants / primary caregiver / study partner will be instructed to bring their unused 
investigational product (IP) to every visit. Compliance will be assessed by capsule counts. 
Details will be recorded in the case report form. All unused IP will be collected from the 
participant at V10/ET. Noncompliance is defined as taking less than 80% or more than 120% 
of the assigned dose during any outpatient evaluation period (visit to visit). Discontinuation 
for noncompliance is at the Investigator’s discretion. 
5.9 
Packaging and Labeling 
Each investigational study drug will be labeled (in English) with a statement indicating that 
the drug is an investigational drug to be used only by a Qualified Investigator and will 
include but not limited to: Drug Name, Strength, Protocol Number, Sponsor’s Name and 
Address, the recommended storage conditions for the drug, Expiry/Retest Date (when 
available) and Lot/Batch Number. 
5.10 
Storage and Accountability 
Records will be made of receipt and dispensing of NE3107 supplied. It is the responsibility 
of the Sponsor to ensure that storage of study drug is within guidelines of the Investigator’s 
Brochure.  It is the responsibility of the Manufacturer to ensure that all drug supplies 
provided for the study are manufactured under current Good Manufacturing Practices 
(cGMP) and are suitable for human use.  


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5.11 
Investigational Product Retention at Study Site 
Upon completion or termination of the study, all remaining study supplies will be retained 
according to applicable regulations. Once the retention period has elapsed, any remaining 
unused drug will be returned to the Manufacturer in the original containers, or destroyed, as 
directed in writing by the Manufacturer.  
 


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6 
STUDY PROCEDURES 
For this Phase II open label study, all participants will be screened following acquisition of a 
signed, written informed consent form.  
Screening will involve confirmation that all inclusion criteria and none of the exclusion 
criterion are met. Following confirmation of inclusion and exclusion criterion, participants 
will undergo baseline testing to include the following: Advanced magnetic resonance 
imaging (MRI) of the brain, lumbar puncture, APoE genotyping, cognitive testing, and 
serological analysis.  
All patients will have an advanced MRI of the brain to include T1 and T2-weighted structural 
images, susceptibility-weighted imaging, neuromelanin, arterial spin labeling (ASL) 
perfusion, blood oxygen level-dependent (BOLD) at rest, diffusion tensor imaging with 
neurite orientation density and dispersion (DTI-NODDI), and magnetic resonance 
spectroscopy (MRS) of the precuneus. MRI will demonstrate if patients have tumors, 
hydrocephalus, subdural hematomas and other structural etiologies of cognitive decline. 
Having the scan completed will be required for inclusion, but no specific imaging parameters 
will determine inclusion. The advanced MRI of the brain will be repeated upon completion 
of the 3-month study intervention period. 
 
All patients will have APoE swab testing and a lumbar puncture for Aß42 and Tau proteins 
for Alzheimer’s Spectrum. This spinal fluid examination has been shown to be both 
sensitive and specific for Alzheimer’s disease. Cerebrospinal fluid (CSF) studies have 
demonstrated good sensitivity and specificity for mild cognitive impairment (MCI) and 
dementia of the Alzheimer’s type. MRI volumetrics, perfusion scans and MR spectroscopy 
have shown to be responsive to change as patients progress from MCI to dementia. The 
lumbar puncture is performed at entry and after completion of the study protocol. The APoE 
testing will only be performed at baseline. 
 
Baseline and completion (3-month) cognitive testing will include the Quick Dementia Rating 
System (QDRS), estimated clinical dementia rating (CDR) scale level, Mini-Mental Status 
Evaluation (MMSE), Montreal Cognitive Examination (MoCA), and Alzheimer’s Disease 
Assessment Scale (ADAS-Cog12). Upon completion of the protocol intervention, 
participants will also be asked to report a Global Rating of Change (GRC) score in addition 
to the neuropsychological testing battery. 
 
All participants will be administered the NE3107 and instructed to maintain a consistent 
daily dosage of 20 mg BID for the three-month active intervention period. Primary endpoints 
will involve a comparison of neurophysiological health as evaluated by multi-modal brain 
MRIs and neuropsychological testing obtained at baseline and post-intervention termination 
(3 months) (See 2.1: Primary Outcomes and 2.2: Secondary Outcomes for detailed 
descriptions of the MRI modalities and neuropsychological tests, respectively). Additional 
procedures include blood and serum samples to be collected at baseline and completion to 
ensure participant safety and effect of NE3107 on laboratory values (See 6.6.1 Laboratory 
Parameters). 


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6.1 
Informed Consent 
Prior to administration of NE3107, informed consent must be obtained by the participant. 
The principal investigator, all sub-investigators, and the research coordinator may obtain 
consent from the subject. All consenting will be done behind closed doors in the privacy of a 
medical exam room. The participant will be allowed to take home the consent form if he/she 
needs more time to review the document. The participant will be read the consent form out 
loud by the member of the study staff obtaining consent. As part of the study criteria, the 
participant will be required to be cognitively aware and understand the English language. 
Therefore, the participant’s consent should be viewed as their own, and without any undue 
influence or coercion. If the participant feels uncomfortable, he/she may have an impartial 
witness of their choice enter the room for the consenting process. 
Before signing the consent form, the member of the study staff obtaining consent will 
verbally ask the participant if he/she has any questions regarding the consent form. If the 
participant says no, the member of the study staff will ask if all information in the consent 
form was understood. If the participant says yes, then a member of the study staff will ask if 
the participant consents to being in this study. If the participant says yes, he/she is ready to 
sign the consent form. 
The principal investigator, all sub-investigators, and the research coordinator may obtain 
consent from the participant. Once the participant has agreed to be in the study and has 
signed the consent form, the documentation will exist both physically and electronically. The 
consent form will be scanned into a computer in which it will be stored under the appropriate 
folders designated for this research study. The computer will be locked under username, 
password, and firewall, and will only be accessible by the study staff. The physical version of 
the consent form will be stored behind lock and key in a drawer or cabinet designated for this 
research study. The key will also only be accessible by the study staff. 
 
6.2 
Medical History 
Participants for the present study will be primarily recruited through the primary 
investigator’s medical practice. As patients, participants will have completed intake forms 
including medical history and any relevant neurological evaluations previously completed. 
All participants will be required to report on all previous medications for 30 days prior to the 
study, as well as for the duration of the study. Memantine and acetylcholine esterase 
inhibitors, donepezil and rivastigmine, are permitted as co-medications in the proposed study. 
Per the Investigator’s Brochure, no drug-drug PK interactions with co-medications 
memantine, donepezil, galantamine and rivastigmine are expected with the proposed dose of 
20 mg BID. As noted in the exclusion criteria, patients with contraindications for lumbar 
puncture (such as bleeding abnormalities requiring the use of anticoagulant medications) will 
not be permitted into the study. Additionally, participants with any active cancer requiring 
chemotherapy will not be permitted to take part in the study.  


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6.3 
Physical Examination 
The Principal Investigator (PI) and study doctor will be responsible for performing physical 
examinations of the participants prior to study participation. As routine practice in the clinic, 
patients will have filled out a complete demographic questionnaire, undergone a physical 
examination at first visit, and have had their vital signs recorded. The nervous system is the 
primary body system to be included in the examination and routine demographics including 
height and weight will be noted. 
6.4 
Vital Signs 
The PI will be responsible for performing the physical examination of the participant. During 
in-person study visits, resting heart rate, blood pressure, and temperature will be measured. 
Blood pressure and heart rate will be monitored using the same machine and same arm upon 
each visit. The physical exam will not include a pelvic, rectal, or breast exam. Additionally, 
participants will answer a health and medication questionnaire, disclosing relevant medical 
history and past or present medications.   
 
6.5 
Electrocardiography and Continuous Telemetry Monitoring 
6.5.1 
12-Lead Electrocardiograms 
ECG monitoring is not required during this study but may be requested by the study doctor. 
6.5.2 
Continuous Holter Monitoring 
A continuous Holter monitor is not required during this study but may be requested by the 
study doctor. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
Participants will be in a seated or supine position during blood collection. Clinical laboratory 
tests (to be collected at baseline, 2 weeks, 4 weeks, 8 weeks, and completion) include the 
following: 


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Collected at Baseline and Completion: 
 
Hematology: 
- 
Complete Blood Count with 
Differential 
- 
Hematocrit (Hct) 
- 
Hemoglobin (Hgb) 
- 
Hemoglobin A1c 
- 
Mean corpuscular hemoglobin 
(MCH) 
- 
Mean corpuscular hemoglobin 
concentration (MCHC) 
- 
Mean corpuscular volume (MCV) 
- 
Platelet count 
- 
Red blood cell (RBC) count  
- 
White blood cell (WBC) count with 
differential  
 
Inflammatory Markers:  
- 
Appearance 
- 
Chlamydia pneumoniae serology 
(IgG/IgM)   
- 
TNF (tumor necrosis factor)  
- 
Cytokine Panel 13   
- 
hsCRP (highly sensitive c-reactive 
protein)  
- 
ESR (erythrocyte sedimentation 
rate)  
- 
HSV (herpes simplex virus 
serology, IgG/IgM)  
- 
CMV (cytomegalovirus serology, 
IgG/IgM)  
- 
Helicobacter pylori - breath test  
- 
Lymphocyte Subset Panel 4: CD4 
& CD8  
- 
Vasoactive intestinal peptide   
 
 
 
 
Serum Chemistry: 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (ALK-P) 
- 
Alanine aminotransferase (ALT; 
SGPT) 
- 
Amylase 
- 
Aspartate aminotransferase (AST; 
SGOT) 
- 
Blood urea nitrogen (BUN) 
- 
Calcium (Ca) 
- 
Carbon dioxide (CO2) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Creatine kinase and subtypes 
- 
Gamma-glutamyl transferase (GGT) 
- 
Globulin 
- 
Glucose 
- 
Lactate dehydrogenase (LDH) 
- 
Lipase 
- 
Phosphorus 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total bilirubin 
- 
Direct bilirubin 
- 
Total protein 
- 
Triglycerides 
- 
Troponins 
- 
Uric acid 
- 
Zinc 
- 
Ethanolamine phospholipids 


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- 
TGF -b1  
- 
Alpha Melanocyte stimulating 
hormone  
- 
Beta Melanocyte Stimulating 
Hormone   
- 
C4A  
- 
ACTH, 
Plasma (Adrenocorticotropic 
hormone)  
- 
Anti-gliadin antibodies 
- 
VEGF  
- 
Gastrointestinal tract acids (GTAs) 
- 
MMP-9  
- 
Quantitative immunoglobulins  
- 
Lyme Antibody  
- 
Bartonella quintana antibodies 
 
Urinalysis, complete 
- 
Glucose 
- 
pH 
- 
Bilirubin 
- 
Ketones 
- 
Nitrite 
- 
Uric acid 
- 
WBC, RBC, epithelial cell count 
 
Collected at Weeks 2, 4, and 8: 
- 
Amylase 
- 
Lipase 
- 
Potassium 
- 
Calcium 
- 
Complete Blood Count (CBC) with 
Differential 
- 
Ethanolamine plasmalogens 
- 
DHA ethanolamine phospholipids 
- 
Choline phospholipids 
- 
Choline plasmalogens 
- 
DHA choline phospholipids 
- 
Dietary fatty acids (omega-3, omega-
6, omega-9, OA, LA, AA) 
- 
Iron 
- 
Methyltransferase/choline system 
- 
Phosphatidylethanolamines 
- 
Phosphatidylcholine 
- 
Sphingomyelins 
- 
Ceramides 
- 
Homocysteine 
- 
Elongase 5 activity 
- 
Peroxisomal function 
- 
DHA, EPA 
- 
Triacylglycerols 
- 
Cholesterol total (Fasting) 
- 
HDL (Fasting) 
- 
LDL (Fasting) 
- 
 
 
 


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- 
Hemoglobin A1c 
- 
Glucose 
- 
Alanine aminotransferase (ALT; 
SGPT) 
- 
Aspartate aminotransferase (AST; 
SGOT) 
- 
Creatine Phosphokinase 
- 
Cholesterol total (Fasting) 
- 
HDL (Fasting) 
- 
LDL (Fasting) 
- 
Triglycerides (Fasting) 
 
Collected Prior to Lumbar Puncture 
Procedure: 
- 
Prothrombin time 
- 
International Normalized Ratio 
- 
Partial thromboplastin time 
- 
Platelet count 
 
 
6.6.2 
Sample Collection, Storage, and Shipping 
After screening, laboratory orders will be written by the study physician which can be taken 
to any Quest Diagnostics, LabCorp, or any other clinical laboratory. Additional serum will be 
drawn at the primary study site and sent for analysis to Prodrome Sciences (40880 County 
Center Drive, Suite R, Temecula, CA 92591, USA). Samples will be shipped on ice and 
labeled adhering to federal biological substance shipping regulations.  
6.7 
Dispensing Study Drug 
The Manufacturer will supply sufficient quantities of the study formulation for the following: 
(1) completion of this study and (2) retention, as per applicable regulations. All drug supplies 
provided for this study will be stored in a secure area with restricted access, under controlled 
storage conditions described in the product package labelling, unless otherwise instructed per 
protocol.  


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Records will be made of receipt and dispensing of NE3107 supplied. It is the responsibility 
of the Manufacturer to ensure that all drug supplies provided for the study are manufactured 
under current Good Manufacturing Practices (cGMP) and are suitable for human use.  
 
6.8 
Pharmacokinetic Assessments 
NE3107 is an orally bioavailable, blood-brain barrier permeable, uncharged, low molecular 
weight molecule (MW 330.46, LogD = 2), poly-hydroxylated synthetic derivative of the 
C-19 adrenal steroid series.  In vitro studies have been conducted to measure membrane 
transport, active efflux/P-gp interaction, hepatic stability, CYP inhibition, and CYP 
induction.  Numerous pharmacokinetics (PK) studies of NE3107 have been performed in 
various animal species using single and multiple doses exploring different routes of 
administration.  Oral NE3107 PK studies have been performed in mice, rats, rabbits, dogs, 
and monkeys.  PK following parenteral administration in support of absolute oral availability 
measurements has also been studied in mice and monkeys.  Numerous non-GLP PK studies 
have been conducted in mice to support formulation development, but only a few that are 
most relevant to the clinical drug product are summarized below.  GLP PK studies have been 
conducted in rats (Sprague Dawley) and dogs (beagles) concurrent with toxicology studies.  
No stand-alone single dose GLP PK studies were conducted.  All GLP PK studies in rats and 
dogs have been conducted as part of multiple dose toxicology studies.  PK studies have been 
conducted in rat toxicology studies with oral gavage of NE3107 formulated as an aqueous 
solution in 30% sulfobutyl ether-cyclodextrin (formulation code HERF202) and as an 
aqueous suspension of micronized NE3107 (vehicle contained 1 mg/mL sodium 
carboxymethyl cellulose [CMC], 9 mg/mL sodium chloride, and 20 mg/mL polysorbate-80, 
0.5 mg/mL phenol (formulation code HERF405).  PK studies have been conducted in dogs 
with soluble NE3107 (HERF202) and with micronized NE3107 formulated in hard gelatin 
capsules containing sodium lauryl sulfate, polyplasdone XL 10, microcrystalline cellulose, 
and magnesium stearate in proportions similar to the NE3107 clinical capsule formulation 
used for all human studies.  NE3107 exists as a single polymorph in all lots of drug 
substance.  All PK studies of crystalline NE3107 used the same polymorph, which is the 
same polymorph used in human studies. 
6.9 
Adverse Events Assessments 
Following all of the inclusion/exclusion criteria may help to reduce the occurrence of severe 
adverse reactions. Both the principal investigator and sub-investigators are medical doctors, 
and are licensed in the state of California, and are in close communication the primary IND 
holder (BioVie, Inc.) regarding safety monitoring. We will be performing routine patient 
calls and standard monitoring of side effects due to these medications, as discussed 
elsewhere in this report. Following these guidelines, side effects can be identified early 
enough to mitigate any significant or permanent side effects.  
 


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6.9.1 
Timing 
NE3107 has no specific dose-limiting toxicity to guide stopping criteria for laboratory 
values for safety monitoring. Abnormal lab values will be reviewed in the context of patient 
safety and potential relationship with NE3107 treatment and NE3107 prior safety data. The 
investigator may terminate a patient’s participation in the trial due to abnormal lab values 
irrespective the lab values potential relationship with NE3107 treatment.  
 
6.9.2 
Severity 
The term "severe" describes the intensity (severity) of a specific event; the event itself, 
however, may be of relatively minor medical significance (such as severe headache). This 
means it is not the same as "serious", which is based on patient/event outcome or action 
criteria usually associated with events that pose a threat to a patient's life or functioning.  
The severity of all AEs will be graded by the PI/Sub-Investigator or a medical qualified 
delegate according to the following 
definitions:
 
Mild: Adverse event resulting in discomfort, but not sufficient to cause interference in 
normal daily activities.  
Moderate: Adverse event resulting in discomfort that is sufficient to cause interference in 
daily activities.  
Severe: Adverse event resulting in discomfort causing an inability to carry out daily 
activities. 
6.9.3 
Relationship 
The PI/Sub-Investigator will assess the relationship of all adverse reactions to NE3107 using 
the following scale:  
Probable: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to drug administration, unlikely to be attributed to concurrent disease or other drugs 
or chemicals, and which follows a clinically reasonable response on withdrawal.  
Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to drug administration, but which could also be explained by concurrent disease or 
other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
Unlikely: A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship improbable, and which 
other drugs, chemicals or underlying disease provide plausible explanation.  


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Unrelated: This category is applicable to AEs which are judged to be clearly and 
incontrovertibly due to extraneous causes (diseases, environment, etc.) and do not meet the 
criteria for drug relationship listed for the above-mentioned conditions.  
All AEs will be evaluated by the PI/Sub-Investigator, who must approve the subject for 
subsequent dosing.  
Any AEs, whether serious or non-serious, will be monitored throughout the study and 
followed to resolution, when possible, regardless of whether the subject is still participating 
in the study.  
6.9.4 
Expectedness 
The principal investigator and study doctor will be responsible for determining whether an 
SAE is expected or unexpected as per drug labels. An adverse event will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the intervention.  
6.9.5 
Clinical Significance 
Clinical laboratory data collected during the course of the study, which exceeds or drops 
below the acceptable limits for the participant population and which, based on baseline 
values, are considered by the Investigator to be clinically significant, will be reported as an 
AE. If clinically significant abnormal laboratory values lead to, or are associated with clinical 
symptom(s), they will be reported as an AE.  
6.9.6 
Serious Adverse Events 
6.9.6.1 
Definition 
A serious adverse event (SAE) is defined by federal regulation as any AE occurring at any 
dose that results in any of the following outcomes: death, life-threatening AE, hospitalization 
or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
6.9.6.2 
Reporting Serious Adverse Events 
All serious adverse events (SAEs), whether or not the event is deemed study drug- related, 
will be reported to the Sponsor by telephone within 24 hours of becoming aware of SAE, 
followed by a written report within five business days.  


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Reports of all SAEs will be communicated as soon as possible to the appropriate Institutional 
Review Board (IRB) and/or reported in accordance with local laws and regulations.  
6.10 
Concomitant Medication Assessments 
Participant medications will be assessed by PI and study staff upon initial screening for the 
study. Participants will be admitted as a patient under the PI and will fill out a comprehensive 
demographics form (including past and present medications), which will be subsequently 
stored in the patient’s chart. Concomitant medications will be stabilized for 30 days prior to 
enrollment in the study protocol. 
6.11 
Removal of Participants from the Trial or Study Drug 
The investigator may withdraw a subject from trial participation for any of the following 
reasons: 
• A protocol violation occurs, 
• A serious or intolerable adverse event occurs, 
• A clinically significant change in a laboratory parameter occurs, 
• The sponsor or investigator terminates the study, or 
• The subject requests to be discontinued from the study. 


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7 
STUDY ACTIVITIES 
7.1 
Screening Visit & Baseline Measure Collection (Days –10 to -1) 
Study Screening may take place during an initial visit with study staff to obtain the following 
assessments, which will be recorded in participant’s source documentation/medical record 
and on the Case Report Form (CRF): 
• Participant ID number generation 
• Demographic information 
• Medical history 
• Vital signs 
• Height, weight, and calculation of BMI 
• Prior/concomitant medications (must be stabilized for 30 days prior to study entry) 
• Quick Dementia Rating Scale (QDRS) 
• Clinical Dementia Rating (CDR) score, derived from QDRS 
• Confirming eligibility (no exclusionary criteria are met) 
Baseline measure acquisition may take place over the subsequent 9 days prior to starting the 
active study intervention, which will include the following: 
• Lumbar puncture to test for AB42 and Tau protein levels 
• APoE genotyping 
• Advanced brain MRI  
o T1, T2, SWI, Neuromelanin, BOLD, ASL perfusion, DTI-NODDI, MRS of 
the precuneus 
• Cognitive examination including: 
o Montreal Cognitive Assessment (MoCA) 
o Mini-mental Status Examination (MMSE) 
o Alzheimer’s Disease Assessment Scale (ADAS-Cog12) 
• Blood tests for: 
o Complete blood count + diff 
o Creatinine clearance 
o Thyroid hormone panel 
o Electrolytes 
o Inflammatory markers (hsCRP, TNFα, CD4, CD8, absolute neutrophils) 


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o Quantitative immunoglobulins 
o Total and direct bilirubin 
o Hemoglobin 
• ProdromeScan blood test for: 
o Phosphatidylethanolamines 
o Choline 
o Mitochondrial function 
 
7.2 
Clinic Admission (Day 0) 
On Day 0, each study participant will be provided with enough NE3107 capsules to maintain 
a 20mg bid dosage for the three-month active intervention period.  Participants will be 
instructed to take each dosage spaced approximately 12 hours apart. 
 
7.3 
Treatment Period (Day 1 to Day 90) 
The drug under investigation is NE3107 (17a-ethynyl-androst-5-ene-3b,7b,17b-triol).  
NE3107 is formulated with common excipients used in oral medications in #2 hard gelatin 
capsules. The capsules are designed for oral administration. NE3107 capsules are stable at 
room temperature for at least 18 months. Stability of the capsules used in this study will be 
monitored by a concurrent stability study conducted by the capsule manufacturer and the 
holder of the primary IND, Biovie, Inc (Santa Monica, CA). 
The rationale for 3-month administration is to allow sufficient time for detectable 
change to occur. To minimize risk, participants will be called within 24 hours following 
initiation of the drug and weekly thereafter, as well as meet with the study doctor 1 
week after starting the NE3107 regimen and attending once-monthly visits thereafter 
with the principal investigator to evaluate for safety and tolerability of the study 
intervention for the duration of the study protocol. These visits will include evaluations 
of the following: 
 
• Vital signs 
• Height, weight, and calculation of BMI 
• Documenting changes in concomitant medications 
• Participant reports of tolerability 
• Evaluation for AEs  
• Assessing compliance with the study drug 
 
Additionally, specific laboratory tests will be repeated at weeks 2, 4, and 8 to ensure 
safety (6.6.1 Laboratory Parameters). Mild, moderate, and severe adverse reactions 
will be reported on an ongoing basis.  Previously observed adverse reactions are listed 


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in Table 22 of the Investigator’s Brochure. Participants will be discontinued if they 
have moderate or severe adverse reaction ratings according to the ICH SAE E2A.  
 
7.4 
Early Termination Procedures 
Early termination assessments will include the full battery of neuropsychological testing, 
advanced MRI, and lumbar puncture to the extent that a participant is willing to undergo 
these follow-up assessments. The minimum assessment required for early termination is a 
clinical evaluation by the study physician to assess for patient safety and provide instructions 
to return the study drug.  
 
7.5 
Follow-up Visit (Day 90 ± 15) 
At the 3-month follow-up visit, the following assessments will be performed and recorded in 
the participant’s source documentation/medical record and on the CRF:  
• 
Vital signs  
• 
Weight  
• 
Concomitant medications  
• 
AEs  
• 
Quick Dementia Rating Scale (QDRS) 
• 
Clinical Dementia Rating (CDR) score, derived from QDRS 
• 
Lumbar puncture to test for AB42 and Tau protein levels 
• 
Advanced brain MRI  
• 
T1, T2, SWI, Neuromelanin, BOLD, ASL perfusion, DTI-NODDI, MRS of 
the precuneus 
• 
Cognitive examination including: 
• 
Montreal Cognitive Assessment (MoCA) 
• 
Mini-mental Status Examination (MMSE) 
• 
Alzheimer’s Disease Assessment Scale (ADAS-Cog12) 
• 
Blood tests for: 
• 
Complete blood count + diff 
• 
Creatinine clearance 
• 
Thyroid hormone panel 
• 
Electrolytes 
• 
Inflammatory markers (hsCRP, TNFα, CD4, CD8, absolute neutrophils) 


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• 
Quantitative immunoglobulins 
• 
Total and direct bilirubin 
• 
Hemoglobin 
• 
ProdromeScan blood test for: 
• 
Phosphatidylethanolamines 
• 
Choline 
• 
Mitochondrial function 
Note: NE3107 was not teratogenic in rat and rabbit safety studies. Sexually active male and 
female patients on study should continue using barrier method contraception for 72 hours 
(three days) after the last dose of NE3107 (terminal plasma t1/2 6-8 hours). The outcome of 
any pregnancy conceived by a patient on study will be followed to term and the results 
(normal or detailed description of abnormalities) will be collected as part of the study data 
and reported to the primary IND holder (Biovie, Inc,). 


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8 
QUALITY CONTROL AND ASSURANCE 
BioVie Inc. is encouraged to visit The Regenesis Project at their convenience. The Principal 
Investigator (PI) and study staff will provide upon request source documents and/or other 
study-related documents. The PI will maintain regular written and telephone communication 
with BioVie Inc. In addition, to ensure quality data and standardization, The Regenesis 
Project will send monthly status reports to BioVie Inc. 
All data will be recorded in accordance with good clinical practice (GCP) to ensure accuracy, 
completeness, legibility, and timeliness of the data reported. All data will be recorded 
directly on the source documents and will be considered source data. This data will be 
transferred to Case Report Forms (CRFs). Source data and CRFs will be kept on site at The 
Regenesis Project. All records and documents pertaining to the study will be retained by The 
Regenesis Project for at least five (5) years from the completion of the study and will be 
available for inspection by the Sponsor and Regulatory Agencies. 
All source documents and laboratory reports will be Quality Control reviewed to ensure 
accuracy and completeness. Adverse events will be reviewed and assessed for severity 
according to the ICH SAE E2A, dated 27 October 1994, by the PI. Specific processes of the 
study, source documentation and case report forms, and any reports will be audited internally 
within The Regenesis Project and may be subject to audit by BioVie Inc.  


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
Statistical analyses will be performed by the statistician on staff with The Regenesis Project. 
Software for statistical analyses will include Microsoft Excel (version 14 or newer) and IBM 
SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, N.Y., USA). Statistical 
analyses will be run to compare change from baseline at the post-intervention termination 
follow-up (three months after baseline) using a level of significance of 0.05. 
A single unblinded interim analysis may be performed when 30% to 50% of the participants 
have completed the final follow-up timepoint. The purposes of this interim analysis are to 
declare futility, study discontinuation for overwhelming efficacy, or sample size re-
estimation. The sample size will not be reduced based on interim data.  
The primary analysis model for the efficacy endpoints will be an MMRM analysis. All 
available data will be included in these models with no imputation for missing data. 
Supportive analyses of efficacy data may be conducted to evaluate different methods of 
handling missing data (i.e., Last Observation Carried Forward, Baseline Observation Carried 
Forward, multiple imputation for missing data, etc.). These supportive analyses will be 
detailed in the SAP. Each endpoint within the neuropsychological testing family will be 
analyzed using MMRM analysis methods in a similar manner as to how the primary 
endpoints will be analyzed. Formal significance for a given hypothesis will only be declared 
if that hypothesis is significant and all hypotheses within the family preceding it are 
significant. This approach will ensure strong type 1 error control is present for all statistical 
tests conducted. 
9.2 
Determination of Sample Size 
Approximately 25 participants are expected to be enrolled in this Phase II trial to evaluate 
longitudinal findings from multimodal MRI among the population that is being studied. 
The study population is sufficiently broad and the conditions of interest are sufficiently 
prevalent so that recruitment of participants is not a limiting factor for the trial site. 
 
The sample size was chosen according to a power analysis calculated with 80% power 
and a significance level of 0.05. To achieve completion data for at least 20 participants, 
enrollment of 25 participants will allow for 20% attrition while maintaining statistical 
integrity. 
 
9.3 
Analysis Populations 
Approximately 25 older adults (aged 50-89 years) are expected to be enrolled in this Phase II 
trial to evaluate longitudinal findings from multimodal MRI. 
Populations to be analyzed in the study include the Full Analysis Population (all 
participants who received any study drug and who participated in at least one post-
baseline assessment), Per Protocol Population (all participants who adhere to the major 


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criteria in the protocol and who did not substantially deviate from the protocol), Safety 
Population (all participants who received any study drug, excluding participants who 
drop out prior to receiving any study drug). Evaluable participants (those with baseline 
and completed follow-up data) will be included in final statistical analyses. 
 
Data may be excluded from analysis on the basis of participant non-compliance with the 
protocol. Outliers will be identified by testing including Pierce’s Criterion, Chauvenet’s 
Criterion, Grubb’s test for outliers, and Dixon Q’s test. If necessary to address outliers, 
the statistician will employ standard Winsorization techniques. 
 
The primary analysis model for the efficacy endpoints will be an MMRM analysis. All 
available data will be included in these models with no imputation for missing data. 
Supportive analyses of efficacy data may be conducted to evaluate different methods of 
handling missing data (i.e., Last Observation Carried Forward, Baseline Observation 
Carried Forward, multiple imputation for missing data, etc.).  
 
9.4 
Demographics and Baseline Characteristics 
Demographic data to be collected will include age, gender, and number of years from onset 
of memory complaints in addition to CDR level (as derived from QDRS score) gathered at 
baseline and final follow-up (three months post-baseline). Results may be stratified by CDR 
at baseline to see if there is a correlation between baseline CDR and strength of clinical 
response. 
9.5 
Statistical Analysis of Endpoints 
Based on published annual progression rates ranging from 15-35%, the investigative team 
determined that this study subset could yield a proportional expected progression rate of 4-
9% among study participants over the 3-month study duration. (Maioli et al., 2007; McKann 
et al., 2011; Amieva et al., 2009; Mitchell & Shiri-Feshki, 2009; Schmidtke & Hermeneit, 
2008; Albert  et al., 2011; Mashour et al., 2019). Statistical analysis for primary and 
secondary endpoints will utilize standard evaluations for categorical data. 
Primary endpoints will involve a comparison of neurophysiological health as evaluated by 
multi-modal brain MRIs obtained at baseline and post-intervention termination (3 months). 
Specifically, multi-modal MRI endpoints will include: An increase or stabilization in 
glutathione levels (as measured by magnetic resonance spectroscopy, MRS) compared to 
baseline. Patients with cognitive decline often show characteristic change in MRS or 
volumetric evaluation compared to age-matched controls (Kuhn et al. 2021); Stabilized 
and/or improved dendritic density compared to baseline (as measured by diffusion tensor 
imaging, DTI-NODDI); Enhancement of arterial signal compared to baseline (as quantified 
by arterial spin labeling, ASL). Patients with cognitive decline often have decreased 
perfusion in temporal parietal or frontal regions of the brain with ASL perfusion (Kuhn et al. 
2021); Increased functional connectivity of the nucleus basalis of Meynert (NBM) with both 
hippocampi as well as between both hippocampi compared to baseline, as visualized by seed 
analysis of blood-oxygen level dependent (BOLD) imaging as well as increased 
neurovascular coupling compared to baseline.  


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9.5.1 Statistical Analysis for Primary Imaging Endpoints 
 
Repeated Measures ANOVAs (RMANOVAs) will be employed to evaluate whether the 
participants who successfully complete the treatment protocol demonstrate differential 
improvement in cognition over time with global and domain level mean T-scores as the 
outcome variable of interest. The same ANOVA-based statistical analysis paradigms will be 
applied to the neuroimaging data after it is preprocessed. RMANOVAs will be run to 
determine whether the treatment group demonstrated improvements in the below imaging 
modalities, from baseline to study completion. Age, sex, and education, as statistically 
indicated, will be included as additional regressors. Correlation analyses will then be 
conducted to determine whether absolute change in domain level as measured by 
neuropsychological evaluation and global cognitive performance is associated with absolute 
change in the following imaging parameters. To compare individuals from the study 
population with a “normal” population, Z-score will be calculated for each individual for 
each component of the toolbox as well as compute a global-cognitive Z-score metric. This 
will allow the comparison of individual participants to a large population of normal derived 
from the published literature (e.g. Human Connectome Project).  
 
Global volumetric loss and regional atrophy is a common radiological finding related to AD 
progression. A disproportionate loss is expected in the temporal-parietal regions and 
hippocampal structures compared to age-matched controls in the study 
population (Rabinovici et al., 2007; Whitwell et al., 2011). T1 images will be corrected for 
field biasing. Then, using FMRIB’s Automated Segmentation Tool (FAST), T1 images will 
be skull-stripped and linearly registered to standard MNI space. Each patient’s T1 image will 
be segmented into 100 cortical and 15 subcortical areas using the Harvard-Oxford Cortical 
and Subcortical structural atlas in conjunction with fslmaths. Mean volume will be computed 
for each of these regions for each patient with fslstats (Smith 2002; Manera 2020). The 
investigative team will use Freesurfer version 6.0 (longitudinal recon-all function) to obtain 
volumetric measures of 68 segmented cortical volumes and 70 cortical thicknesses. Global 
volumetric loss and regional atrophy is a common radiological finding related to AD 
progression. Regional volumes will be analyzed (statistically corrected for intracranial 
volume) from baseline – 3 months compared to age-matched controls; significant volumetric 
change is not expected to be seen over the course of treatment with NE3107. Nevertheless, 
additional analyses will be conducted to determine if demographic or treatment variables 
predict change in regional volume. Correlation will assess the relationship between 
neuromelanin change and functional outcomes.  
 
Magnetic resonance spectroscopy (MRS) can detect biochemical changes in the brain related 
to loss of neuronal interactivity and other neurodegenerative pathology underlying dementia 
of the Alzheimer’s type (Graff-Radford & Kantaci, 2013). MRS data will be processed using 
Osirix (https://www.osirix-viewer.com/osirix/osirix-md/) and Tarquin 
(http://tarquin.sourceforge.net/) to calculate neurotransmitter specific peak heights from 
which neurotransmitter comparison ratios (e.g. NAA/Gl) can be computed.  MRS values will 
be creatine adjusted to improve the likelihood that data was derived from tissue and not CSF. 
Literature consistently reports on a ratio of decline between the NAA and Creatine (Cr) peaks 


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among patients with AD (Modrego & Fayed, 2011). A Wilcoxon Signed-rank test will be 
performed in R (https://www.rstudio.com/) to statistically analyze the changes in the 
NAA:Cr ratio from baseline to completion of NE3107 protocol. In addition, glutathione 
levels decrease with redox stress, and declines in glutathione levels have been reported on 
among patients with AD (Mandal, Saharan, Tripathi & Murari, 2015b). It is anticipated that 
participants will demonstrate improvement (elevation) of glutathione levels compared to 
baseline as a signal of overall improvement in bioenergetics. Glutathione levels after NE3107 
intervention will be compared to baseline levels with a Wilcoxon Signed rank test in R. 
Correlation will assess the relationship between neuromelanin change and functional 
outcomes. 
 
Noradrenergic dysfunction has been associated with the cognitive decline seen 
in Alzheimer’s disease (Peterson & Li, 2018).  Pathological alteration to the locus coeruleus, 
a major source of noradrenaline in the brain, has been implicated in neurodegenerative 
processes (Betts, Kirilina, Otaduy, Ivanov, Acosta-Cabronero, Callaghan, et al., 2019). Locus 
coeruleus integrity can be assessed by looking at signal intensity on a Neuromelanin-
sensitive MRI. Decreased signal intensity in the locus coeruleus is expected as dementia 
progresses (Olivieri, Lagarde, Lehericy, Valabrègue, Michel, Macé et al., 
2019). Longitudinal changes in locus coeruleus signal will be evaluated visually by 
a blinded neurologist. Participant change will be analyzed relative to expected rates of 
dropout/loss. Correlation will assess the relationship between neuromelanin change and 
functional outcomes.  
  
By measuring free-water changes and the integrity of white matter tracts, DTI can indirectly 
measure changes caused by amyloid plaque deposition (Wen, Risacher, Xie, Li, Harezlak, 
Farlow et al., 2021; Alexander, Lee, Lazar & Field, 2007; Smith, Johansen-Berg, Jenkinson, 
Rueckert, Nichols, Miller et al., 2007). The post-NE3107 DTI metric [fractional anisotropy 
(FA) and mean, axial and radial diffusivity (MD, AD, RD)] image will be subtracted from 
the baseline image to produce change images (Fu, Shrestha, Sun, Wu, Luo, Zhang, et al., 
2019). Neurite orientation dispersion and density imaging (NODDI) uses a three-
compartment model to probe brain tissue microstructure: (1) Free Water Fraction (FWF) 
which estimates the extent of CSF contamination, (2) Neurite Density index (NDI) which 
quantifies the packing density of axons/dendrites, and (3) Orientation Dispersion index (ODI) 
which assesses the coherence of neurites (Fu et al., 2019; Zarei, Patenaude, Damoiseaux, 
Morgese, Smith, Matthews et al., 2010).  
 
Limited literature using NODDI has been produced in-vivo in mild-cognitive impairment 
subjects, but the current results show it to be more sensitive/robust than traditional FA 
values (Fu et al., 2019). Similar to ASL, the three indexes will be compared between 
baseline/follow-up values. It would be expected that an increase in NDI and a decrease in 
ODI/FWF to correspond with an improvement in brain health (Fu et al., 2019). Here, an 
established tract-based spatial statistics (tbss) approach will be used to assess the relationship 
between voxel-wise changes in white matter integrity (Fu et al., 2019). Additionally, graph 
theory will be applied to quantify the effect of NE3107 on hippocampal connectivity and 
associate this effect with cross-sectional and longitudinal cognitive performance (Wen et al., 
2021). Lastly, probabilistic tractography will be used to simulate white matter connectivity 


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between the hippocampus formations (Zarei et al., 2010) and Nucleus Basalis of Meynert. 
The baseline and follow-up will similarly be compared. Again, RMANOVA will 
compare pre-and post-NE3107 treatment and within group analyses will assess network 
predictors of response to NE3107 treatment. All imaging analyses will be corrected for 
multiple comparisons, both across voxel and between analyses.  
 
Arterial Spin Labeling (ASL) data will be processed and analyzed using FSLs Bayesian 
Inference for ASL MRI (BASIL; Chappell, Groves, Whitcher & Woolrich, 
2009; Woolrich, Chiarelli, Gallichan, Perthen & Lie, 2006).  ASL scans yield a perfusion 
image with voxel values representing local perfusion rates; perfusion difference will be 
calculated (subtracting tagged/control pairs) and averaged to create a mean perfusion-
weighted image (Chen, Wolk & Reddin, 2011). Quantification to cerebral blood flow (CBF) 
values (milliliters of blood per 100 g of tissue per minute) will be implemented using an 
estimate of the equilibrium magnetization of arterial blood and the mean perfusion values 
(Ahlgren, Wirestam, Knutsson & Petersen, 2018; Hernandez-Garcia & Jahanian, 2010). 
Given the variability of ASL across patients, CBF data will be examined as a ratio to mean 
grey matter signal.  
 
Each participant’s ASL data will be linearly to each his or her T1-weighted image; images 
will then be transferred to MNI space using non-linear registration in FSL. Within FSL, a 
voxel-wise between groups (normal vs MRI) comparison of perfusion, corrected for multiple 
comparisons, will be performed. A repeated measures comparison within subject for pre-vs 
post intervention ASL as well as between groups will be used to compare effects of NE3107 
to normals.  Demographic covariates will be included in the model as indicated.  All imaging 
analyses will be corrected for multiple comparisons, both across voxel and between analyses. 
 
Existing literature consistently demonstrates a dropout of signal seen in the temporal parietal 
lobes among individuals with dementia of the probable Alzheimer’s type (Zhang, Gordon & 
Goldberg, 2017). The  mean perfusion values per voxel in the temporal parietal regions will 
be measured and used to generate a statistical output of participant values relative to a 
normative, age-matched database. This will test the hypothesis that there will be either 
stabilization or improvement of voxel signal among participant scans compared with the 
normative database associated with NE3107. 
 
Reported trends in BOLD imaging follow dementia progression from earlier stages of decline 
(e.g., CDR = 0.5, characterized by initial hippocampal hyper connectivity) to progressive 
stages of dementia (CDR > 1) and ultimate loss of hippocampal connectivity (Wang, Zang, 
He, Liang, Zhang, Tian et al., 2006; Sperling, 2011). Processing of resting state (rs) fMRI 
will include correcting for motion artifacts (using framewise displacement calculations, and 
within-subject independent component analysis), scrubbing, unwarping and spatial 
smoothing (FWHM = 5mm). rsFMRI data will be linearly registered to stereotaxic MNI 
space and co-registered with anatomic, T1 data for each participant.  
 
Two approaches will be used to test rs-network differences. First, the hub of the default mode 
network atlas will be used as a seed region for each subject, and multivariate exploratory 
linear optimized decomposition into independence components (MELODIC) will be used to 


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identify the brain regions whose time series correlate significantly with the hub (Erhardt, 
Rachakonda, Bedrick, Allen, Adali & Calhoun, 2011). Between-groups comparison of these 
correlation maps will identify differences in default and salience network integrity. A matrix 
for each subject will then be made from correlations of time series between each node.  
 
 
Subsequently, ANOVA will be used to assess group comparisons of the connection strength 
between nodes, within networks and between networks. All of these analyses will be 
conducted both within diagnostic group (e.g. within healthy control group only) and between 
diagnostic groups (i.e. compare effects in cognitive impairment and control groups). Finally, 
time series correlations will be assessed between multiple regions of interest implicated in 
the literature in Alzheimer’s disease (hippocampal formation, Nucleus Basalis of Meynert 
(NBM), and other seeds) and the rest of the brain to generate functional connectivity maps 
(Salami, Pudas & Nyberg, 2014; Li, Jia, Qi, Fan, Ma, Ni et al., 2017; Miao, Wu, Li, Chen & 
Yao, 2011). Then, between-group comparison will identify differences in the 
connectivity/network integrity of these regions. Finally, within-group regressions will be 
used to determine which neural network factors predict response to NE3107 treatment.  Age, 
sex, education, and neuropsychological assessment, as needed, will be included as additional 
regressors. All imaging analyses will be corrected for multiple comparisons, both across 
voxel and between analyses. 
 
For the seed-based analysis, after spatial normalization of the images, a standard ROI of the 
bilateral hippocampi will be drawn on the images using a priori anatomic segmentation. A 
seed reference time course will be obtained by averaging the survived time courses within the 
ROI. Correlation analyses will be carried out between the seed reference and the whole brain 
in a voxel-wise manner. The percent signal change will be extracted from within the same 
ROI across multiple scan acquisitions and compare an individual’s change relative to 
expected levels of change. Existing literature suggests that a relatively higher activation of 
hippocampal activity precedes a steeper slope of cognitive decline. Individuals with a 
baseline CDR of 0.5 will typically demonstrate a decrease in fMRI activity in the 
hippocampus, and individuals with more rapid decline in their neuropsychological testing 
scores will have higher hippocampal activation at baseline, and the greatest loss of 
hippocampal activation over time (O’Brien, O’Keefe, LaViolette, DeLuca, Blacker, 
Dickerson, & Sperling, 2010). We will compare between baseline, pre-NE3107 and post-
NE3107. 
 
Further, BOLD-activity changes will be assessed within a standard ROI (e.g., hippocampus; 
conventionally defined using a priori anatomic segmentation).  To do so, the percent signal 
change within the same ROI across multiple scan acquisitions will be extracted to compare 
an individual participant’s change relative to expected levels of change. The degree of this 
change will be correlated with NE3107 treatment and other neural network and behavioral 
changes to further elucidate the intricacies of the NE3107 treatment. A decrease in 
neurovascular coupling is expected (as shown and evaluated voxel-wise) globally and 
regionally in the locus coeruleus and temporal parietal lobes compared to age-matched 
controls. With NE3107 intervention, it is hypothesized that participants will yield 
improvement in neurovascular response from baseline. This will be analyzed relative to the 
normative database and expected decline. 


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9.5.2 Statistical Considerations for Secondary Endpoints 
Secondary endpoints will include a longitudinal comparison of metabolic and serological 
analysis (specifically measures of glucose and insulin homeostasis); the level of cognitive 
impairment as defined by neuropsychological testing (QDRS/CDR, MMSE, ADAS-Cog, and 
MoCA scores). Thresholds for reporting clinically meaningful change will include references 
to published minimal clinically important differences (MCIDs) for each measure. Paired 
samples t-tests will be used to statistically analyze each secondary endpoint, including the 
cognitive measures described below as well as changes in serological markers.  
The ADAS-Cog evaluates participants’ cognitive abilities. It is composed of 11 parts that 
measure word recall, object/figure naming, command following, constructional praxis, 
ideational praxis, orientation, word recognition, test direction recall, spoken language, 
comprehension, and word-finding difficulty. The ASAS-COG is scored from 0-70 by 
measuring the errors made in each task, with a score of 70 representing the most severe 
impairment. A point reduction of 3.1 to 3.8 has been found to be the minimal clinically 
important difference (Schrag & Schott, 2012). 
The MMSE is a 30-point questionnaire that evaluates cognition. The MMSE includes 
specific tasks that assess orientation, attention, memory, language and visual-spatial skills. 
MMSE scores range from 0 – 30 possible points; 0-17: severe cognitive impairment, 18-23: 
mild cognitive impairment, 24-30: no cognitive impairment. A point decrease >/= to 3 on the 
MMSE has been identified as the minimally clinically important difference (Andres, 2019). 
The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental 
calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., 
person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure 
copy), divided visual attention, and immediate and delayed memory of unstructured 
information (Nasreddine, Phillips, Bédoran, Charbonneau, Whitehead, Collin, et al., 2005). 
MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal 
cognitive status. 
The Quick Dementia Rating Scale (QDRS) is an interview-based tool administered by study 
officials to participants' caregivers used to obtain observations from a consistent source 
(Berman, Koscik, Clark, Mueller, Bluder, Galvin et al., 2017) . The QDRS form consists of 
10 categorical questions (5 cognitive, 5 functional), each with 5 detailed options depicting 
the level of impairment as either 0 (normal), 0.5 (mild/inconsistent impairment), 1 
(mild/consistent impairment), 2 (moderate impairment), or 3 (severe impairment). Based on 
the conversion table outlined in Dr. James Galvin's research (2015), total QDRS scores were 
converted to Clinical Dementia Rating (CDR) scale levels ranging from 0 (normal aging), 0.5 
(mild cognitive impairment), 1 (mild dementia), 2 (moderate dementia), and 3 (severe 
dementia). 
9.6 
Safety Analysis 
Mild, moderate and severe adverse effects/reactions and mortality will be monitored to 
confirm the safety and tolerability of NE3107 in the study population. Blood tests and 


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clinical monitoring will be performed according to standard practice for these agents. 
Participants will be discontinued if they have moderate or severe adverse reaction ratings 
according to the ICH SAE E2A. Unexpected or excess serious adverse reaction and excess 
mortality will result in early termination of the study. Suspected unexpected serious adverse 
reactions, life threatening reactions and mortality will be reported to the FDA by way of the 
primary IND holder (Biovie, Inc.) as required under 21 CFR 312.32(c)(1)(v). These reports 
will be recorded in a lab notebook that will be locked away in a cabinet requiring a key that 
only the study staff will have access to. This information will also be transcribed to a 
computer file that will be kept behind username and password. 


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10 
ADMINISTRATIVE CONSIDERATIONS 
10.1 
Investigators and Study Administrative Structure 
Principal Investigator: Sheldon E. Jordan, MD 
Sheldon Jordan MD, Inc. dba The Regenesis Project 
2811 Wilshire Blvd., Suites #690 & 790, Santa Monica, CA 90403 
Phone number: (310) 829-5968 
 
10.2   
Institutional Review Board (IRB) Approval 
Prior to study initiation, institutional review board (IRB) approval shall be obtained and 
proof shall be provided to all regulatory agencies. The IRB submission for NE3107-TRP-001 
“A Phase II Open Label Study for the Use of Anti-Inflammatory, Insulin Sensitizing NE3107 
for the Treatment of Cognitive Decline Due to Degenerative Dementias” is awaiting final 
review and approval from Advarra IRB (Pr#00058626). All reviews and approval by the IRB 
will be in accordance with Good Clinical Practice (GCP).  
In the event of any serious adverse events, the IRB will be notified by the study sponsor. 
10.3 
Ethical Conduct of the Study 
All aspects of this trial shall be conducted in compliance with all applicable federal, state, 
and local laws and regulations. In particular, the study protocol will be conducted in 
accordance with generally accepted standards of good clinical practice, informed consent for 
human participants, and conflict of interest policies related to conduct in clinical research. 
The Principal Investigator will be responsible for the conduct of the study and oversight of 
the clinical research staff, all of whom will remain in full compliance with the protocol. 
10.4 
Participant Information and Consent 
The clinical research staff shall obtain from each participant, prior to screening or official 
entry in the study protocol, a signed informed consent and necessary authorization to disclose 
health information to BioVie in a form approved in writing by the IRB. The principal 
investigator, all sub-investigators, and the research coordinator may obtain consent from the 
participant. In obtaining and documenting informed consent, the investigator will comply 
with the applicable regulatory requirements and will adhere to good clinical practice and the 
ethical principles that have their origin in the Declaration of Helsinki. The written informed 
consent form and any other written information provided to participants will be revised 
whenever new information becomes available that may be relevant to the participant’s 
consent. Any revised written informed consent form and written information will receive 
IRB approval in advance of use. Neither the investigator, nor the study staff, will coerce or 
unduly influence a patient to participate or continue participation in a trial. All consenting 
will be done behind closed doors in the privacy of a medical exam room. The participant will 
be allowed to take home the consent form if he/she needs more time to review the document. 
The participant will be read the consent form out loud by the member of the study staff 


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obtaining consent. As part of the study criteria, the participant will be required to be 
cognitively aware and understand the English language. Therefore, the participant’s consent 
should be viewed as their own, and without any undue influence or coercion. If the 
participant feels uncomfortable, he/she may have an impartial witness of their choice enter 
the room for the consenting process. 
 
Before signing the consent form, the member of the study staff obtaining consent will 
verbally ask the participant if he/she has any questions regarding the consent form. If the 
participant says no, the member of the study staff will ask if all information in the consent 
form was understood. If the participant says yes, then a member of the study staff will ask if 
the participant consents to being in this study. If the participant says yes, he/she is ready to 
sign the consent form. 
As stated in the Process of Consent section, all consent by the participant will be done behind 
closed doors in a private medical exam office. Once the participant has agreed to be in the 
study and has signed the consent form, the documentation will exist both physically and 
electronically. The consent form will be scanned into a computer in which it will be stored 
under the appropriate folders designated for this research study. The computer will be locked 
under username, password, and firewall, and will only be accessible by the study staff. The 
physical version of the consent form will be stored behind lock and key in a drawer or 
cabinet designated for this research study. The key will also only be accessible by the study 
staff. 
10.5 
Participant Confidentiality 
All participant data will be protected and kept private during the study in compliance with 
federal, state, and local regulations. All documentation collected by the study staff and 
Sponsor will be kept confidential. The name and identity of the participants will remain 
confidential. Any physical data, such as a lab notebook used to record data during the 
study, will be kept under lock and key. Any digital data will be kept under username and 
password. Both physical and digital data will only be accessible by the research staff.  
 
The study staff and sponsor shall comply with applicable laws and regulations, as amended 
from time to time, including without limitation, the Health Insurance Portability and 
Accountability Act of 1996 and its implementing regulations (HIPAA) with respect to the 
collection, use, storage, and disclosure of Protected Health Information (PHI) as defined in 
HIPAA. All study-related PHI shall be collected, stored, used, accessed, and disclosed only 
as permitted by the IRB-approved informed consent form or HIPAA authorization form 
obtained from a study participant. BioVie’s ability to review participants’ study-related 
information contained in the study participants’ medical records shall be subject to 
reasonable safeguards for the protection of study participant confidentiality and the study 
participants’ informed consent forms or HIPAA authorization forms. BioVie shall not 
attempt to identify, or contact, any Study participant unless permitted by the informed 
consent form or HIPAA authorization form. 


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10.6 
Study Monitoring 
The primary investigator, Dr. Sheldon E. Jordan, is responsible for monitoring the study site 
and study activities. Dr. Jordan is on staff at Providence Saint John’s Medical Center which 
is within one to two miles of the clinical site of Sheldon Jordan MD, Inc. dba The Regenesis 
Project at 2811 Wilshire Blvd, Santa Monica, 90403. The clinical site has five on-campus 
physicians with Advanced Cardiovascular Support certification and a crash cart, resuscitation 
equipment and a nursing staff including an RN which are all on site.  
All participant data will be recorded on-site at The Regenesis Project. All participant data 
will be kept private, and all post-processing will be done internally. 
The Principal Investigator will assign internal audits to be performed at least twice per month 
for the duration of the study protocol. 
 
10.7 
Case Report Forms and Study Records 
Source documents used for this study include neurocognitive examination packets, lab 
results, raw and post-processed neuroimaging data, and screening forms. Data from source 
documents will be transferred to case report forms (CRFs) using anonymized participation 
identification numbers. CRF forms are created and modified by The Regenesis Project staff. 
The Principal Investigator and clinical research staff will provide BioVie with any and all 
CRFs and safety-monitoring reports related to the study; all of which will be submitted to the 
IRB as required. During the study and for at least two years following the completion of the 
study at all sites, the study staff and Principal Investigator shall promptly provide BioVie 
with the written report of any findings, including study results and any routine monitoring 
findings, monitoring reports, and data safety monitoring committee reports including, but not 
limited to, data and safety analyses, and any study information that may (a) affect the safety 
and welfare of current or former study participants, or (b) influence the conduct of the study.  
10.8 
Protocol Violations/Deviations 
Deviations from the protocol which will be considered protocol violations include late “out-
of-window” follow-up telephone and in-person visits and missed testing appointments. These 
deviations will be reported in the final clinical study report. 
10.9 
Access to Source Documentation 
Study participants will be able to access copies of source documents upon request following 
completion of the study protocol.  
The study site acknowledges that trial-related monitoring audits, regulatory inspection(s), and 
regular IRB review are expected, and will make direct access to source data and documents 
available for review by the proper regulatory agencies. 


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10.10 
Data Generation and Analysis 
All study data will be processed on site at Sheldon Jordan MD, Inc. dba The Regenesis 
Project. All participant data will be protected and kept private during the study in 
compliance with federal, state, and local regulations. Any physical data, such as a lab 
notebook used to record data during the study, will be kept under lock and key. Any digital 
data will be kept under username and password. Both physical and digital data will only be 
accessible by the research staff.  
 
The clinical database will be generated using Microsoft Excel (version 14 or newer) and 
analyzed using IBM SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, N.Y., 
USA). 
Data will be entered by authorized clinical research staff on a weekly basis. Database entries 
will be checked for accuracy and completion at the time of internal audits, to be performed at 
a minimum of twice per month throughout the study.  
10.11 
Retention of Data 
The study staff shall retain and preserve a copy of the study records for the longer of (a) five 
(5) years following the termination of the study protocol. 
10.12 
Financial Disclosure 
The investigative team and the Sponsor understand that the amount of any payment made on 
behalf of research conduct may be disclosed and made public by either party as required by 
law or regulation, including the Patient Protection and Affordable Care Act of 2010, 
provided that the disclosure clearly designates the payment as having been made to the 
Sponsor Institution (The Regenesis Project) and not to the Principal Investigator or 
physician. 
10.13 
Publication and Disclosure Policy 
The investigative team shall have the right to publish, present, or use any study data for its 
teaching, research, education, clinical and commercial purposes without the payment of 
royalties or other fees. However, the investigative team, including the Principal Investigator, 
will not use or provide any drug performance data to any third party for commercial benefit. 
With respect to publications of any study data, the contents (including scientific conclusions 
and professional judgments) of any paper submitted shall be determined by the Principal 
Investigator in the exercise of reasonable judgment. The Principal Investigator shall provide 
the Sponsor with a copy of papers prepared for publication at the earliest practicable time, 
but in any event not less than sixty (60) days prior to the submission to a scientific journal or 
presentation at scientific meetings and a reasonably detailed summary or abstract of any 
other oral or written publication not less than sixty (60) days prior to their submission or 
presentation. The investigative team shall consider any and all comments made by BioVie in 
good faith; BioVie personnel shall be acknowledged in accordance with customary scientific 
practice; authorship shall be determined in accordance with the standards of the International 


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Committee of Medical Journal Editors (ICMJE). If during BioVie’s review, BioVie finds that 
any publication contains BioVie Confidential Information, BioVie shall have thirty (30) days 
from the date of receipt from the investigative team to respond with a request to remove such 
Confidential Information. The Principal Investigator agrees that any publication or other 
public disclosure shall include an acknowledgement of BioVie’s support of the study, and if 
applicable, support of the development of the publication or disclosure. BioVie shall be 
entitled to make and use copies of the publication made by the Principal Investigator in 
relation to the study. The sixty (60) day minimum lead time for publication or disclosure may 
be shortened by mutual consent by both Parties in writing. 


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11 
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(2015) Alzheimers Dement (Amst). 1(2):249-259. doi:10.1016/j.dadm.2015.03.003.    
 


NE3107 
 
The Regenesis Project 
Clinical Trial Protocol: NE3107-TRP-001 
 
Page 55  
 
 
Appendix 1 
Schedule of Events 
Evaluation 
Screening Days 
-10 to -1 
Clinic Visit 
Day 0 
Treatment Period 
Day 1 - 90 
Follow-
up (Days 
91 ± 15)  
Day 1 
Day 7 
Day 15 
Day 30 
Day 45 
Day 60 
Day 75 
Day 90 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Advanced MRI of the Brain 
X 
 
 
 
 
 
 
 
 
 
X 
Lumbar Puncture 
X 
 
 
 
 
 
 
 
 
 
X 
Cognitive Testing 
X 
 
 
 
 
 
 
 
 
X 
X 
APoE Genotyping 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Laboratory Tests 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
Participant ID Assignment 
X 
 
 
 
 
 
 
 
 
 
 
AE Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conmed Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge From Clinic 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


NE3107 
 
The Regenesis Project 
Clinical Trial Protocol: NE3107-TRP-001 
 
Page 56  
 
 
Appendix 2 
Sponsor Signatures 
Study Title: 
A Phase II, Open-Label Study for the Use of Anti-Inflammatory, 
Insulin-Sensitizing NE3107 for Treatment of Cognitive Decline Due to 
Degenerative Dementia 
Study Number: 
NE3107-TRP-001 
Final Date: 
Final V1.0 (4 November 2021) 
Amendment 1 Date: 
 
 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor. The following personnel contributed to writing and/or approving this protocol: 
 
Signed: 
 
 
Date:  
 
Sheldon E. Jordan, MD Inc. 
Principal Investigator 
Sheldon Jordan MD Inc., dba The Regenesis Project 
2811 Wilshire Blvd., Suite #790, Santa Monica, CA 90403 
(310) 829-5968 
 
 
 


NE3107 
 
The Regenesis Project 
Clinical Trial Protocol: NE3107-TRP-001 
 
Page 57  
 
 
Appendix 3 
Investigator’s Signature 
Study Title: 
A Phase II, Open-Label Study for the Use of Anti-Inflammatory, Insulin-
Sensitizing NE3107 for Treatment of Cognitive Decline Due to 
Degenerative Dementia 
Study Number: 
NE3107-TRP-001 
Final Date: 
Final V1.0 (4 November 2021) 
Amendment 1 Date: 
{revision date} 
The information contained in this protocol and all other information relevant to NE3107 are 
the confidential and proprietary information of Sheldon E. Jordan, MD Inc., dba The 
Regenesis Project, and except as may be required by federal, state, or local laws or 
regulation, may not be disclosed to others without prior written permission of Sheldon Jordan 
MD Inc.  
 I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I agree to 
comply with all applicable regulations and to conduct the study as described herein, in 
accordance with applicable national, state, and local regulations, and will make a reasonable 
effort to complete the study within the time designated.  
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Sheldon Jordan MD, Inc., or 
specified designees. I will discuss the material with them to ensure that they are fully 
informed about NE3107 and the study. 
 
 
Signed: 
 
 
Date:  
 
Sheldon E. Jordan, MD 
Principal Investigator 
Sheldon Jordan MD Inc., dba The Regenesis Project 
2811 Wilshire Blvd., Suite #790, Santa Monica, CA 90403 
(310) 829-5968