Clinical trial NCT04650555
Conditions: Acute Radiation Syndrome
Sponsor: Humanetics Corporation
Start date: 2020-12-08; Completion date: 2021-07-06
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Open-label, single ascending dose and multiple single dose study in healthy volunteers to evaluate the safety and pharmacokinetics of BIO 300 Oral Powder (BIO 300). The single ascending dose study consists of 4 ascending dose cohorts and the multiple single dose study consists of a single dose given daily for 6 consecutive days.

Detailed description:

Arms: arm 1: 500 mg BIO 300 Oral Powder administered as a single dose arm 2: 1000 mg BIO 300 Oral Powder, if dose escalation criteria met, administered as a single dose arm 3: 2000 mg BIO 300 Oral Powder, if dose escalation criteria met, administered as a single dose arm 4: Single dose to be determined based on the safety and pharmacokinetic profiles in cohorts 1-3 arm 5: Highest dose or maximum tolerated dose from the Single Ascending Dose study administered as a single dose given daily for 6 consecutive days
Interventions: intervention 1: BIO 300 Oral Powder
Intervention descriptions: intervention 1: Amorphous solid dispersion of genistein milled into a powder

Protocol documents:
Prot_SAP_000.pdf: 
   
A Phase 1 Dose Escalation Trial Evaluating the Safety 
and Pharmacokinetic Profile of BIO 300 Oral Powder in 
Healthy Volunteers 
 
 
 
 Short title: Phase 1 BIO 300 Oral Powder 
 
 
 
 
Protocol Number: CL0106-01 
National Clinical Trial (NCT) Identified Number:  NCT04650555 
Principal Investigator: Amy R. Eastenson, MD 
IND Sponsor: Humanetics Corporation 
Version Number:  v3.0 
07 June 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
Phase 1 BIO 300 Oral Powder – v3.0 07 June 2021 
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Background and Study Rationale ...................................................................................................... 8 
2.2 
Risk/Benefit Assessment .................................................................................................................... 8 
2.2.1 
Known Potential Risks ..................................................................................................... 8 
2.2.2 
Known Potential Benefits .............................................................................................. 10 
2.2.3 
Assessment of Potential Risks and Benefits .............................................................. 10 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 10 
4 
STUDY DESIGN ........................................................................................................................................... 11 
4.1 
Overall Design .................................................................................................................................... 11 
4.2 
Scientific Rationale for Study Design.............................................................................................. 11 
4.3 
Justification for Dose ......................................................................................................................... 11 
4.4 
End of Study Definition ..................................................................................................................... 11 
5 
STUDY POPULATION ................................................................................................................................ 12 
5.1 
Inclusion Criteria ................................................................................................................................ 12 
5.2 
Exclusion Criteria ............................................................................................................................... 12 
5.3 
Lifestyle Considerations .................................................................................................................... 14 
5.4 
Screen Failures .................................................................................................................................. 15 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 15 
6 
STUDY INTERVENTION ............................................................................................................................ 15 
6.1 
Study Intervention(s) Administration ............................................................................................... 15 
6.1.1 
Study Intervention Description ..................................................................................... 15 
6.1.2 
Dosing and Administration ............................................................................................ 15 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 16 
6.2.1 
Acquisition and accountability ...................................................................................... 16 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 16 
6.2.3 
Product Storage and Stability ....................................................................................... 17 
6.2.4 
Preparation ...................................................................................................................... 17 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 18 
6.4 
Study Intervention Compliance ........................................................................................................ 18 
6.5 
Concomitant Therapy ........................................................................................................................ 18 
6.5.1 
Permitted Surpportive Therapy .................................................................................... 18 
6.5.2 
Non-Permitted Surpportive Therapy ........................................................................... 18 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 18 
7.1 
STOPPING CRITERIA FOR DISCONTINUATION OF THE STUDY INTERVENTION ......... 18 
7.2 
Discontinuation of Study Intervention ............................................................................................. 19 
7.3 
Participant Discontinuation/Withdrawal from the Study ............................................................... 19 
7.4 
Lost to Follow-Up ............................................................................................................................... 19 
7.5 
Dose Escalation Criteria ................................................................................................................... 20 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 20 
8.1 
Criteria for evaluation ........................................................................................................................ 20 


  
Phase 1 BIO 300 Oral Powder – v3.0 07 June 2021 
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8.2 
Safety and Other Assessments ....................................................................................................... 20 
8.3 
Blood Sampling for Pharmacokinetics, Safety and Biomarkers ................................................. 22 
8.3.1 
Single ascending dose subject blood volume requirements ................................... 24 
8.3.2 
Multiple single dose subject blood volume requirements ......................................... 24 
8.4 
Adverse Events and Serious Adverse Events ............................................................................... 25 
8.4.1 
Definition of Adverse Events (AE) ............................................................................... 25 
8.4.2 
Definition of Serious Adverse Events (SAE) .............................................................. 25 
8.4.3 
Classification of an Adverse Event .............................................................................. 25 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 26 
8.4.5 
Adverse Event Reporting .............................................................................................. 27 
8.4.6 
Serious Adverse Event Reporting ............................................................................... 27 
8.4.7 
Events of Special Interest ............................................................................................. 27 
8.4.8 
Reporting of Pregnancy ................................................................................................ 27 
8.5 
Unanticipated Problems .................................................................................................................... 28 
8.5.1 
Definition of Unanticipated Problems (UP) ................................................................. 28 
8.5.2 
Unanticipated Problem Reporting ................................................................................ 28 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 29 
9.1 
Statistical Hypotheses ....................................................................................................................... 29 
9.2 
Sample Size Determination .............................................................................................................. 29 
9.3 
Populations for Analyses .................................................................................................................. 29 
9.4 
Statistical Analyses............................................................................................................................ 29 
9.4.1 
General Approach .......................................................................................................... 29 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 30 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 30 
9.4.4 
Safety Analyses .............................................................................................................. 30 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 31 
9.4.6 
Planned Interim Analyses ............................................................................................. 31 
9.4.7 
Sub-Group Analyses ..................................................................................................... 31 
9.4.8 
Tabulation of Individual participant Data .................................................................... 31 
9.4.9 
Exploratory Analyses ..................................................................................................... 31 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 31 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 31 
10.1.1 
Informed Consent Process ........................................................................................... 31 
10.1.2 
Study Discontinuation and Closure ............................................................................. 32 
10.1.3 
Confidentiality and Privacy ........................................................................................... 32 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 33 
10.1.5 
Key Roles and Study Governance .............................................................................. 33 
10.1.6 
Safety Oversight ............................................................................................................. 34 
10.1.7 
Clinical Monitoring .......................................................................................................... 34 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 34 
10.1.9 
Data Handling and Record Keeping ............................................................................ 35 
10.1.10 
Protocol Deviations ........................................................................................................ 35 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 36 
10.1.12 
Conflict of Interest Policy .............................................................................................. 36 
10.2 
Abbreviations ...................................................................................................................................... 36 
10.3 
Protocol Amendment History ........................................................................................................... 38 
11 
REFERENCES ............................................................................................................................................. 40 


  
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12 
Appendices .................................................................................................................................................... 40 
Appendix 1: Soy Rich Foods ............................................................................................................................... 40 
 


Phase 1 BIO 300 Oral Powder 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
•
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
A Phase 1 Dose Escalation Trial Evaluating the Safety and Pharmacokinetic 
Profile of BIO 300 Oral Powder in Healthy Volunteers  
Study Description: 
Single Ascending Dose: 
Open-label, single-dose escalation in healthy volunteers. Each cohort will 
enroll 8 subjects of which 2 will be backups (1M/1F), so that at least 6 
subjects (3M/3F) complete the protocol procedures. The pertinent safety 
data will be reviewed for each cohort before the next dose level cohort is 
started.  Subjects will follow a diet low in soy isoflavones for 7 days before 
and 7 days after treatment and will fast at least 8 h before dosing. The test 
article will be administered on day 1 and the initial dose will be one BIO 
300 Oral Powder sachet, 500 mg genistein. Subsequent doses will be 2x 
the previous cohort. The fourth, and final cohort, dose level will be TBD 
based on the safety and pharmacokinetic (PK) results from the previous 3 
cohorts. Subjects will remain in the clinic 12 hours after dosing for 
observations and blood sample collection for clinical lab assessment, PK, 
and pharmacodynamics (PD).  Subjects will remain fasted for 4 hours after 
the test article administration. Subjects will be provided a standardized 
low soy meal after the 4-hour blood draw and after the 8-hour blood 
draw.  Subjects will return to the clinic on day 2, 3 and 8 after dosing for 
blood sampling and/or observations as detailed in the schedule of events. 
Subjects may not miss any clinic visits. At the conclusion of the study, data 
will be analyzed from all cohorts to determine safety and PK.  PD samples 
will be stored until the completion of all phase 1 studies, and then sent for 
RNA sequencing and data analysis. 


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Multiple Single Dose: 
Open-label, single dose given daily for 6 days in healthy volunteers. A 
single cohort will enroll 14 subjects (7M/7F) of which 4 will be backups 
(2M/2F), so that at least 8 subjects (4M/4F) complete the protocol 
procedures. Subjects will follow a diet low in soy isoflavones for 7 days 
before treatment, during the 6 days of treatment and 7 days after 
treatment. Subjects will fast at least 8 h before the first dose, 3rd dose and 
the 6th dose. The test article will be administered starting on day 1 and 
the dose used in this study will be determined based on safety and PK 
analysis from the single ascending dose study. Subjects will be 
administered test article daily during their schedule clinic visits.  Subjects 
will remain in the clinic 4 hours after the first dose and 12 hours after the 
6th dose for observations and blood sample collection for clinical lab 
assessment, PK and PD.  Subjects will remain fasted for 4 hours after the 
test article administration on days 1 and 6. On the 6th day, subjects will be 
provided a standardized low soy meal after the 4-hour blood draw and 
after the 8-hour blood draw.  Blood sampling and/or observations will be 
performed on dosing days 1-6 as described in the schedule of events. 
Subjects will return to the clinic on days 7, 8 and 13 after initial dosing for 
blood sampling and/or observations as detailed in the schedule of events. 
Subjects may not miss any clinic visits. At the conclusion of the study, data 
will be analyzed to determine safety and PK, and data will be analyzed 
from all cohorts to determine PD. 
Objectives: 
Primary Objectives: 
•
Determine the overall adverse event and PK profiles of single
ascending doses of BIO 300 Oral Powder in healthy volunteers
•
Determine the overall adverse event and PK profile of multiple
doses of BIO 300 Oral Powder in healthy volunteers
Secondary Objectives: 
•
Determine the effects of single and multiple doses of BIO 300 Oral
Powder on blood-based biomarkers
•
Use a combination of the PK and PD profiles from the single and
multiple doses of BIO 300 Oral powder to identify the putative BIO
300 Oral Powder human efficacious dose
Endpoints: 
Primary 
Evaluate the safety and pharmacokinetics of BIO 300 Oral Powder in 
Healthy Volunteers 
Secondary 
Characterize the expression of blood-based biomarkers 
Study Population: 
•
6 subjects/cohort (3M/3F) will be recruited for the single
ascending dose study, and at least 6 (3M/3F) subjects/cohort will
complete all aspects of the study.  2 additional subjects (1M/1F),


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will be screened, consented and available as backups for each 
cohort. 
•
10 (5M/5F) subjects will be recruited for the multiple single dose
study, and at least 8 (4M/4F) subjects will complete all aspects of
the study. 4 additional subjects (2M/2F) will be screened,
consented and available as backups.
•
In total, at least 32 healthy volunteers who will complete all
aspects of the trial.
Phase: 
1 
Description of 
Sites/Facilities Enrolling 
Participants: 
Nucleus Network (formally Prism Clinical Research) 
1000 Westgate Drive, #149 
Saint Paul, MN 55114 
Description of Study 
Intervention: 
BIO 300 Oral Powder will be provided by Humanetics Corporation, 
Minneapolis, Minnesota.
 
 
 The inactive ingredients 
include povidone K12 and sucralose powder.  The vials are labeled with 
clinical study information including the lot number, storage instructions to 
store at controlled room temperature 15-30°C (59-86°F) and the 
statement “CAUTION: New Drug, limited by Federal law to investigational 
use.” 
Study Duration: 
Approximately 8 months 
Participant Duration: 
The duration of study participation will be 35 days for Cohorts 1 – 4 (28-
day screening period; Dosing on day 1; final follow-up visit on Day 8). 
The duration of study participation will be 41 days for Cohort 5 (28-day 
screening period; Dosing on days 1 - 6; final follow-up visit on day 13) 


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1.2 
SCHEMA 


Phase 1 BIO 300 Oral Powder 
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Phase 1 BIO 300 Oral Powder 
Protocol CL0106-01 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Schedule of Events and Assessments 
Visit Number· 
Day 
hlfom1ed Consent 
Medical Histo1y 
Concomitant Medication 
Contraception Check 
Vital Sicms1 
Calculation ofBMI 
Phvsical Exam2 
Dmg Screen/Alcohol Testine. 
Pre=ancv test3 
Hepatitis and HIV testing 
CBC with differential4 
PT/INR,PTT 
Semm chemistries and fasting lipid panels 
Urinalvsis6 
ECG7 
Low isoflavone dietary counseling 
Administer BIO 300 Oral Powder 
PK 
PD 
Adverse Event Monitoring 
Notes 
Single Ascending Dose Cohorts 
1 
2 
3 
4 
-28 to -8
1 
2 
3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x9 
X 
X 
X 
X 
X 
X 
X 
xio
xu
x12 
x14
xis
X 
X 
X 
5 
1 
8 
-28 to
-8
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Version 3.0 
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Multiple Single Dose Cohort 
2 
3 
4 
5-6
7 
1 
2 
3 
4-5
6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xn
X 
X 
X 
xs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x13
xio
x14
x16
X 
X 
X 
X 
X 
8 
9 
10 
7 
8 
13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xu
x12 
xis
X 
X 
X 
1.
Vital signs include height, weight, BMI, resting pulse, blood pressure, respiratory rate, and temperature. Subjects should be rested semi-recumbent for at least 5 min prior to collection.
2. 
Physical exams will assess the HEENT, lymphatic, cardiovascular, pulmonary, gastrointestinal, musculoskeletal, and neurological systems, and anything else deemed necessary by
the Investigator.
3. 
Pregnancy test may be performed on urine or serum
4. 
CBC to include white blood cell count with differential, platelet count, red blood cell count, hemoglobin, and hematocrit
5.
Serum cliemistries to include total protein, albUlllin, sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, alkaline phosphatase, ALT, AST, uric acid, LDH, total and 
direct bilirubin, phosphorous, calcium, magnesium, amylase, lipase, total cholesterol, triglycerides, HDL. Subjects should fast at least 8 h prior to collection and blood will be drawn
prior to test article administration.
6. 
Urinalysis to include pH, specific gravity, dipstick determinations of protein, glucose, ketones, blood and bilirubin and reflex microscopic exan1 (reflex only if any qualitative
measurements or appearance return abnormal)
7. 
ECGs to be oerformed in triolicate with 5-minute inteivals. Subiects should be rested suoine for at least 5 minutes orior to collection.
6 


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8.
Vital signs to be obtained within 1 hour prior to administration of BIO 300 Oral Powder and then approximately 30 minutes, 1, 2, 4, 6, 8, and 12 h following administration of BIO
300 Oral Powder
9.
ECGs to be obtained within 1 h prior to BIO 300 Oral Powder administration and then approximately 1, 2, and 4 h following BIO 300 Oral Powder administration
10.
Samples for PK assessment to be obtained just prior to BIO 300 Oral Powder administration and then 30 minutes, 1, 2, 4, 6, 8, and 12 h following BIO 300 Oral Powder administration. 
The time of the blood draw will be ±10 minutes of the nominal time.
11.
Samples for PK assessment to be obtained 24 + 2 h following administration of BIO 300 Oral Powder
12.
Samples for PK assessment to be obtained 48 + 4 h following administration of BIO 300 Oral Powder
13.
Samples for PK assessment to be obtained just prior to administration of BIO 300 Oral Powder and then 30 minutes, 1, 2, and 4 h following BIO 300 Oral Powder administration. 
The time of the blood draw will be ±10 minutes of the nominal time.
14.
Samples for PD assessment to be obtained -2 to 0 h before BIO 300 Oral Powder administration, and 1, 2, and 4 h following BIO 300 Oral Powder administration. The time of the
blood draw will be ±10 minutes of the nominal time.
15. Samples for PD assessment to be obtained 24 + 2 h following administration of BIO 300 Oral Powder
16.
Samples for PD assessment to be -2 to 0 h before BIO 300 Oral Powder administration, and 4, 8, and 12 h following BIO 300 Oral Powder administration. The time of the blood draw 
will be ±10 minutes of the nominal time.
17.
Vital signs to be obtained within 1 hour prior to administration of BIO 300 Oral Powder and then approximately 30 minutes, 1, 2, and 4 h following administration of BIO 300 Oral
Powder


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2 
INTRODUCTION 
2.1 
BACKGROUND AND STUDY RATIONALE 
The active ingredient in BIO 300 Oral Powder is genistein, a selective agonist of estrogen receptor beta 
(ERβ). ERβ activation promotes DNA repair, cell cycle regulation, and importantly, anti-inflammatory 
effects. This pleiotropic mechanism can partly be explained by ERβ’s ability to repress expression and 
activation of nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB), which is a master 
regulator that controls transcription of genes involved in the immune response and cell survival 1-3. NF-
κB is activated in response to radiation, infection or other immune stimuli, and in turn promotes 
expression of pro-inflammatory cytokines [reviewed in 4]. 
Humanetics is developing BIO 300 for multiple clinical indications related to DNA damage and 
inflammation.  The primary indication for BIO 300 Oral Powder is as a prophylactic medical 
countermeasure to increase survival in individuals exposed to myelosuppressive doses of ionizing 
radiation. 
BIO 300 has been studied in a previous clinical trial (NCT02567799) as an aqueous oral nanosuspension 
(BIO 300 Oral Suspension).  BIO 300 Oral Powder has been developed to facilitate a solid dosage form of 
BIO 300.  The pharmacokinetics of BIO 300 Oral Powder are not fully known in humans, and the safety 
and maximum tolerated dose of this formulation is unknown.  This phase 1 study is intended to 
methodically explore both safety and PK of this formulation in healthy human volunteers.  In addition, 
blood-based biomarkers will be examined as part of an effort to develop a human dose conversion 
strategy under the FDA Animal Rule. 
Refer to the Investigator’s Brochure (IB) for more detail. 
2.2 
RISK/BENEFIT ASSESSMENT 
2.2.1 KNOWN POTENTIAL RISKS  
All study participants in this clinical trial will receive identical care and health assessments.  This will be 
explained in detail at the time of consent to participate. Patient alternatives include the choice not to 
participate in this study, a decision that may mean no specific follow-up care.  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Subjects with documented soy allergies should carefully consider taking BIO 300. Because BIO 300 is 
manufactured with synthetic genistein the risk of a soy-based allergic reaction is minimal. Although 
teratology studies were negative, it is not known if BIO 300 will cause harm when administered to 
pregnant women. If a patient becomes pregnant while taking BIO 300, the patient should be informed of 
potential hazards to the unborn fetus. For these reasons mothers who are nursing their children should 
be informed of potential hazards of taking BIO 300. 
 
 
 
  
The following list summarizes the potential physical risks associated with participation in the proposed 
clinical study based upon known adverse events in previous clinical studies of BIO 300 at the proposed 
dose and dosing duration: 
Less Likely 
•
Fatigue
•
Constipation
•
Diarrhea
•
Dyspepsia
•
Flatulence
•
Anorexia
•
Dysgeusia
•
Increase in serum amylase
•
Increase is serum lipase
•
Decrease in the number of red blood cells
•
Increase in blood pressure
•
Lowering of the heart rate
•
Increase in breathing rate
•
Pain such as headaches, aches in muscles and joints and abdominal pain
•
Change in appetite






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Section 9 and prepare a final study report that will be submitted to the Investigational New Drug 
Application (IND). 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1)
Healthy adult non-smokers, 18-64 years old.
2)
BMI 18-32 kg/m2
3)
No ingestion of prescription or over-the-counter medications (including dietary and herbal
supplements) for 7 days prior to first dose of study drug and no planned use during study
participation.  Acetaminophen of up to 3 g/day and ibuprofen up to 1 g/day will be allowed at
discretion of the Investigator.
4)
At the discretion of the Investigator, blood routine, liver and kidney functions are within the
controllable range.
a.
Adequate hepatic function as evidenced by ALT, AST or LDH < 1.25X ULN and bilirubin <
1.5X ULN for the reference lab.
b.
Adequate renal function as evidenced by a serum creatinine ≤ 1.5 X ULN for the
reference laboratory OR a calculated creatinine clearance of ≥ 60 mL/min by the
Cockcroft-Gault Equation.
c.
Adequate hematopoietic function as evidenced by white blood cells ≥ 3x109 / L and
platelets ≥ 100x109 / L.
5)
Female subjects of childbearing potential must have a negative pregnancy test within 72 hours
of the start of treatment.
6)
Subjects must agree to abstain from heterosexual intercourse or use a reliable method of
contraception for 7 days after their last dose. Subjects using hormonal contraception are
required to utilize condom/spermicide + additional barrier method for 7 days after their last
dose.
7)
Ability to read and provide written informed consent.
8)
Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory
tests, dietary restrictions, and other study procedures.
9)
No clinically significant abnormalities identified by medical history, physical examination, vital
signs, ECG, and clinical laboratory tests in the opinion of the Investigator.
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1)
Any prior use of the study test article.
2)
Any clinically significant weight loss any time in prior 4 weeks at discretion of Investigator based
on medical history interview.
3)
Subjects with any of the following are not eligible;
a.
Previous history of QTc prolongation resulting from “known-risk” medications
(www.Crediblemeds.org) that required discontinuation of that medication;


Phase 1 BIO 300 Oral Powder 
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b.
Congenital long QT syndrome, or 1st degree relative with unexplained sudden death
under 40 years of age;
c.
Presence of left bundle branch block (LBBB);
d.
QTc with Fridericia’s correction (QTcF) that is unmeasurable, or ≥ 480 msec on screening
ECG. The average QTcF from the screening ECG (completed in triplicate) must be < 480
msec in order for the subject to be eligible for the study.
4)
Subjects must not have had a clinically significant cardiac event such as myocardial infarction
(within 6 months prior to the first dose of the study treatment); uncontrolled/symptomatic
congestive heart failure (New York Heart Association (NYHA) classification of heart disease, Class
III or IV, see Appendix 3) within 6 months before entry; or the presence of any other
uncontrolled cardiovascular conditions [unstable hypertension at discretion of Investigator or
arrhythmia, unstable angina pectoris, or severe valvular heart disease, etc.] that, in the opinion
of the Investigator, increases the risk of ventricular arrhythmia.
5)
Subjects with a history of arrhythmia (multifocal premature ventricular contractions (PVCs),
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is
symptomatic or requires treatment (CTCAE Grade 3) or asymptomatic sustained ventricular
tachycardia are not eligible.  Subjects with atrial fibrillation with well-controlled ventricular rate
are eligible at the discretion of the Investigator.
6)
Psychiatric conditions, social situations or substance abuse that precludes the ability of the
subject to cooperate with the requirements of the trial and protocol therapy at Investigator
discretion.
7)
Inability to refrain from alcohol consumption for 48 hours prior to day 1 and for the duration of
the study.  Illicit drugs, including THC, must be avoided from screen through the duration of the
study.
8)
Grade 2 or higher peripheral neuropathy.
9)
Positive results for Hep B surface antigen, Hep C antibody, or HIV 1/2 antibody at screening visit.
10) Clinically significant immunodeficiency disorder in the opinion of the Investigator.
11) Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception.
12) Women who are breastfeeding are not eligible for this study.
13) Subjects that are vegan, vegetarian or consume a soy-rich diet.
14) Any history of systemic infection requiring hospitalization, systemic antibiotics, or as judged
clinically significant by the investigator in the 3 months prior to day 1.
15) Any condition possibly affecting drug absorption (e.g., prior bariatric surgery, gastrectomy,
intestinal resection).  Participants who have undergone appendectomy or cholecystectomy are
allowed so long as the surgery occurred more than 6 months prior to day 1.
16) Treatment with another investigational drug within 30 days or 5 half-lives (whichever is longer)
proceeding Day 1.
17) Positive drug screen or alcohol test at screen and day 1 predose.
18) Blood donation of approximately 1 pint (500 ml) or more within 60 days of day 1; plasma
donations within 14 days of day 1.  Subjects must agree not to donate blood or plasma for the
duration of the study and for 30 days following end of study procedures.
19) Inability to swallow powdered medication followed with water.
20) History of sensitivity to heparin or heparin-induced thrombocytopenia.
21) Considered by the Investigator to be unsuitable to participate in the study for any other reason.


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5.3 
LIFESTYLE CONSIDERATIONS 
Participants will be counseled to adhere to a low isoflavone diet, such as those listed in Appendix 1, 
during the dosing and PK/PD assessment period. It is important for study participants to maintain a low 
isoflavone diet (e.g., low soy-diet) in order to accurately quantify study drug pharmacokinetics and drug 
exposure. 
Contraception: 
1)
Women who are not able to get pregnant are not required to use birth control. To be
considered not able to get pregnant, you must be
a)
postmenopausal for at least 12 months confirmed by hormone testing; or
b)
surgically sterile
-
hysterectomy (surgical removal of uterus)
-
bilateral tubal ligation (tubes “tied”)
-
removal of both ovaries and/or fallopian tubes
2)
Women who are able to get pregnant must
a)
have a negative urine pregnancy test at screening and on admission to CRU; and
b)
must be using, and agree to continue using, an effective method of contraception for at least
4 weeks prior to first study drug administration until 7 days after the last dose of study drug.
Effective methods of contraception include the following: 
1)
Total abstinence from sexual intercourse with a partner that may result in pregnancy
2)
Sexual intercourse with a partner who has had a vasectomy
3)
Non-Hormonal Intrauterine device
4)
Double barrier contraception, i.e., condom and diaphragm, or condom or diaphragm with
spermicidal gel or foam.
5)
Women using hormonal contraception below must agree to use a barrier or other effective
method of contraception during the study
a)
Combined (estrogen and progestogen containing) hormonal contraception
-
oral
-
intravaginal
-
transdermal
b)
Progestogen-only hormonal contraception
-
oral
-
injectable
-
implantable
Women must not donate ova (eggs) during the study and for at least 30 days after the last dose of study 
drug. 
Male subjects who have not had a vasectomy and/or subjects who have had a vasectomy but have not 
had 2 post-surgery negative tests for sperm whose partners are not on a highly effective method of 
contraception (hormonal contraception is sufficient for female partners) must agree to use an acceptable 
method of contraception from time of first dose of study drug until 30 days after the last dose of the study 
drug, and must not donate sperm during the study and for at least 30 days after the last dose of study 
drug. 


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5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study due to their inability to meet inclusion or exclusion criteria or their 
decision to not consent to enrollment. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment of subjects will be performed by the clinical site who maintains a robust database of 
healthy volunteers.  The site will outreach to potential participants to encourage screening. 
For optimal recruitment and retention, subject contact and convenience will be prioritized. Examples 
include providing effective subject information on the study, providing face-to-face meetings for 
discussing the study and questions, and ensuring the study design places no significant burden to being 
involved in the research study.  
Subjects will be in contact with the study through clinical visits.  Subject outreach will occur to 
encourage continued compliance and participation in clinic visits during the repeat dose study period. 
6 
STUDY INTERVENTION 
The study intervention being investigated under this protocol is BIO 300 Oral Powder, an amorphous 
solid dispersion of synthetic genistein.  
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
BIO 300 Oral Powder will be provided by Humanetics Corporation, Minneapolis, Minnesota.  BIO 300 
Oral Powder is an amorphous solid dispersion of genistein.  It is packaged in single use foil sachets 
containing 500 mg genistein.  It is a free-flowing pale orange to slightly tan powder. 
6.1.2 DOSING AND ADMINISTRATION 
Single Ascending Dose Cohorts: 
Cohort 1 dose: one BIO 300 Oral Powder sachet, 500 mg genistein  
Cohort 2 dose: two BIO 300 Oral Powder sachets, 1000 mg genistein (2X the dose of Cohort 1 in the 
absence of dose-limiting toxicity [DLT])  
Cohort 3 dose: four BIO 300 Oral Powder sachets, 2000 mg genistein (2X the dose of Cohort 2 in the 
absence of DLT) 
Cohort 4 dose: TBD based on the observed PK and AE profiles in the first 3 dose cohorts 
All single dose cohorts will be administered the drug at the clinic under the supervision of the study 
personnel. Subjects will follow a diet low in soy isoflavones for 7 days before and 7 days after treatment 
and will fast at least 8 h before dosing. Subjects will remain fasted for 4 hours after the test article 


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administration. Subjects will remain in the clinic 12 hours after dosing. Subjects will be provided a 
standardized low soy meal after the 4-hour blood draw and after the 8-hour blood draw. The purpose of 
fasting is to standardize the effect of food on PK and PD markers. 
Multiple Single Dose Cohort: 
The cohort 5 dose will be dosed daily for 6 consecutive days at the highest dose or the maximum 
tolerated dose from the Single Ascending Dose cohorts.  Subjects will consume the test article each day 
within +/- 2 hours of time when the first dose was administered and not within 1 hour before or after 
eating.  The Day 6 dose will be administered during clinic visit 7 so that PK and PD blood draws can be 
timed after the dose. 
Drinking of room temperature water only, (up to 240 mL) will be encouraged following administration of 
each BIO 300 Oral Powder sachet.  
Subjects will follow a diet low in soy isoflavones for 7 days before treatment, during the 6 days of 
treatment and 7 days after treatment. Subjects will fast at least 8 h before the first dose, 3rd dose and 
the 6th dose. Subjects will remain in the clinic 4 h after the first dose and 12 hours after the 6th dose. 
Subjects will remain fasted for 4 hours after the test article administration on days 1 and 6. On the 6th 
day, subjects will be provided a standardized low soy meal after the 4-hour blood draw and after the 8-
hour blood draw.  The purpose of fasting is to standardize the effect of food on PK and PD markers. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
BIO 300 Oral Powder will be supplied to the investigational site pharmacy in foil sachets, each containing 
500 mg of genistein.  Sachets will be bulk packed in cardboard boxes and will be labeled as a new drug 
for investigational use only.  All dosing cohorts will be administered whole sachets for dosing (e.g., 1 
sachet for the 500 mg cohort). 
Study drug used during the trial will be on an ICH compliant stability study with appropriate retest 
intervals.  Any expired or out-of-spec drug product will be quarantined by the pharmacy and will be 
disposed upon full drug accountability monitoring and instruction by the Sponsor.   
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Description and Composition  
The drug product, BIO 300 Oral Powder, is an amorphous solid dispersion (ASD) 
 
 
The 
composition of BIO 300 Oral Powder is shown in Table 6.2.2.1.  
Table 6.2.2.1 BIO 300 Oral Powder quantitative composition 
Component 
Function 
Reference to 
Quality 
Standard 
Amount 
(mg/g) 


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Genistein (Bonistein®) 
Active Ingredient 
(API) 
In-house 
 
Polyvinylpyrrolidone K12 
Carrier/Stabilizer 
USP 
 
Sucralose 
Sweetener 
NF 
 
The ASD/sucralose mixture is filled into 1.5”x2.5” high barrier, multi-layer low-density polyethylene 
(LDPE)/foil, individual dosing sachets. The drug product contact surface of the sachet is comprised of linear 
low-density polyethylene (LLDPE). 
 
  
The drug product is labelled for investigational use only. 
6.2.3 PRODUCT STORAGE AND STABILITY 
BIO 300 Oral Powder is to be stored at 15-30°C, at ambient relative humidity by the study site 
pharmacy.  The sachets should be stored in their original packaging until dispensed.  Protection from 
light is not required. The sachets will be stored at the study facility and will be dispensed according to 
the study protocol.  An extra supply of the BIO 300 Oral Powder study drug will be available in the event 
additional sachets are needed once the study is underway. 
6.2.4 PREPARATION 
The steps for preparing and dispensing BIO 300 Oral Powder are as follows: 
1)
Prepare the subject identifier label to each sachet.
2)
Holding the sachet from the top (end with V grooves), gently swing back and forth to force all
powder to the bottom of sachet.
3)
Tear the top off the sachet being careful not to spill any powder.
4)
Pour entire contents of sachet into mouth.
5)
Immediately consume up to 8 oz. of water.
6)
Inspect sachet to ensure all powder was dispensed.  If not, take any residual powder
immediately.
7)
Follow steps 3 and 4 if more than 1 sachet is required.  You may space the time between sachets
but consume all within a 5 minute period.


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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
This is an open label, non-randomized phase 1 trial. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Adherence to the protocol will be assessed by documenting study visits. Study intervention compliance 
will be assessed by accounting for the number of returned empty sachets.  
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications, and supplements. 
6.5.1 PERMITTED SURPPORTIVE THERAPY 
All supportive therapy for optimal medical care will be given during the study period at the discretion of 
the subject’s attending physician(s) within the parameters of the protocol and documented on the site’s 
source documents as concomitant medication. 
6.5.2 NON-PERMITTED SURPPORTIVE THERAPY 
Though no data have shown that any concomitant medications will interfere with BIO 300 Oral Powder, 
it is advisable that subjects do not take any other medication(s) 1 hour before or after a dose of BIO 300 
Oral Powder. Concomitant medications will be collected for all subjects from the screening visit through 
the end of the study.  
The following drugs are not permitted during the study protocol: 
Anti-pulmonary fibrosis therapeutics, (e.g., imatinib, nintedanib, pirfenidone, penicillamine, colchicine, 
and tumor necrosis factor alpha blocker), anti-cytokine release syndrome therapeutics (e.g., anakinra, 
sarilumab, siltuximab, tocilizumab and/or lenzilumab), biologics used to treat asthma (e.g., omalizumab, 
mepolizumab, reslizumab, benralizumab and dupilumab), and all systemic corticosteroids. 
If a subject receives any of the listed non-permitted supportive therapies, this will constitute as a major 
protocol deviation.  
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
STOPPING CRITERIA FOR DISCONTINUATION OF THE STUDY INTERVENTION 
Discontinuation of a subject and early stopping of the study intervention will be based on the following 
unacceptable adverse events (AEs) and must be attributable to the investigational drug BIO 300 Oral 
Powder (i.e., possibly, probably or definitely related to the study drug) to constitute a Dose-Limiting 
Toxicity (DLT).   
•
Non-hematologic toxicities of Grade 3 or higher, with the following exceptions:
o
anorexia
o
fatigue
o
infection without neutropenia


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o
Grade 3 AST/ALT elevations ≤ 7 days
o
Grade 3 or 4 electrolyte abnormalities that are corrected to Grade 2 or less in less than
48 hours.
•
Occurrence of a VTE (DVT or pulmonary embolism).
7.2 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from BIO 300 Oral Powder does not mean discontinuation from the study, and the 
remaining study procedures should be completed as indicated by the study protocol. If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
Principal Investigator or qualified designee will determine if any change in participant management is 
needed. Any new clinically relevant finding will be reported as an adverse event (AE). 
7.3 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Subjects are free to withdraw from participation in the study at any time upon request. The Principal 
Investigator may discontinue or withdraw a subject from the study for the following reasons: 
•
Pregnancy (see Section 8.4.8). Women of childbearing potential must perform a pregnancy test
in case of delayed menstruation and stop treatment immediately in case of positive result.
•
Significant study intervention non-compliance.
•
Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness that, in the
opinion of the Principal Investigator, indicates that continued participation in the study is not in
the best interest of the participant.
•
If the participant meets an exclusion criterion (either newly developed or not previously
recognized) that precludes further study participation.
•
If the participant withdraws their informed consent.
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.   
7.4 
LOST TO FOLLOW-UP 
For both the Single Ascending Dose and the Multiple Single Dose studies a subject will be considered lost 
to follow-up if he or she fails to return for a single visit and is unable to be contacted by the study site 
staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
•
The site will attempt to contact the participant and reschedule the missed visit as soon as
possible that same day and counsel the participant on the importance of maintaining the
assigned visit schedule and ascertain if the participant wishes to and/or should continue in the
study.
•
If the missed visit consists of timed blood draws for PK and PD, that subject will be immediately
considered lost to follow up and may be replaced.
•
Should the subject be unreachable, he or she will be considered to have withdrawn from the
study with a primary reason of lost to follow-up.


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For both the Single Ascending Dose and Multiple Single Dose studies, subjects that are lost to follow up 
may be replaced.  For the Single Ascending Dose study, and at least 6 (3M/3F) subjects/cohort will 
complete all aspects of the study.  For the Multiple Single Dose study at least 8 (4M/4F) subjects will 
complete all aspects of the study. 
7.5 
DOSE ESCALATION CRITERIA 
A Safety Monitoring Committee (SMC) consisting of a Humanetics representative, the Medical Monitor 
and Principal Investigator, or their recognized delegates will review all available data. The determination 
for escalation to the next Cohort will require, at a minimum, a review of all safety data of 6 subjects in 
the previous SAD Cohort through at least Day 3.  Decisions to proceed with dose escalations, adding 
additional subjects to the current Cohort, and possible dose adjustments will be made following this 
review with the Medical Monitor and Principal Investigator agreeing with the decision. Whether 
additional information such as PK or PD data may be needed before a decision to escalate can also be 
determined by the SMC. The primary responsibility of the SMC is to regularly monitor the overall safety 
of patients enrolled in the study, while protecting the scientific integrity of the study data. Dose 
escalation criteria will be the following: 
•
Dose escalation may occur if no more than 2 subjects in a 6-subject cohort experiences a dose-limiting
toxicity (DLT, as defined below).
•
If 3 DLTs occur (3/6 subjects), an additional 2 subjects will be treated with the same dose.
•
If no additional DLTs occur (3/8 subjects), dose escalation may proceed.
•
The study sponsor will temporarily cease enrollment for evaluation if in any given cohort 4/8 subjects
experience DLTs attributable to BIO 300 Oral Powder as the MTD (maximum tolerated dose) will have
been exceeded and no further dose escalation will occur.
DLT is any grade 3 or grade 4 adverse event listed in the draft FDA document entitled “Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.” 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
CRITERIA FOR EVALUATION 
Safety: 
The safety profile of BIO 300 Oral Powder will be based on the results of CBC with differential, coagulation 
parameters, serum chemistries, urinalysis, ECGs, and vital signs the reporting of adverse events.  
Pharmacokinetics: 
Blood samples will be collected at multiple timepoints after BIO 300 Oral Powder administration and 
processed for serum isolation. Serum concentrations of genistein aglycone will be measured from PK 
parameters (Cmax, Tmax, clearance, AUC(0-24;0-48;0-INF), volume of distribution, T1/2 and drug accumulation 
index) which will be calculated using standard procedures and statistical analyses. 
Pharmacodynamics: 
Blood samples will be collected at multiple timepoints in PAXgene tubes after BIO 300 Oral Powder 
administration.  It will be subjected to RNA sequencing to explore biomarkers which may be predictive of 
BIO 300 Oral Powder effectiveness. 
8.2 
SAFETY AND OTHER ASSESSMENTS 


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Physical Exam – Examination of the participant’s cardiovascular, HEENT, lymphatic, pulmonary, 
gastrointestinal, musculoskeletal, and neurological systems. 
Vital Signs – Vital signs will record the patient’s height, weight and BMI. They will also measure heart 
rate, blood pressure (systolic and diastolic), respiratory rate, and body temperature. 
Electrocardiogram – ECGs occur during the screening visit, on visit 2 (1 hr before, 1hr after, 2 hrs after 
and 4 hrs after BIO 300 Oral Powder dose), and visits 3-5 for the SAD phase. ECGs will occur during the 
screening visit, visit 2 (1 hr before, 1hr after, 2 hrs after and 4 hrs after BIO 300 Oral Powder dose), visits 
3-4, visit 7 and visit 10 for the multiple single dose phase. ECGs will be digitally read locally at the study
site. ECGs will be completed in triplicate and the average will be used to determine if the study subject
has an abnormal reading.
QTc Interval Prolongation – Fridericia-corrected QTc (QTcF) interval from all subjects in both the SAD 
and the multiple single dose studies will be used to evaluate QTcF interval prolongation. QTcF 
prolongation will be determined by evaluating ECG at baseline (pre-dose) and at multiple time points 
around the predicted Cmax of BIO 300 Oral Powder (ECG timepoints listed above). QTcF intervals will be 
reported for each dosing cohort as a mean and standard deviation. The upper limit for QTcF interval 
prolongation will be >480 ms or absolute QTcF change from baseline of >30 ms with a 95% confidence 
interval. The relationship between drug exposure and mean QTcF interval change will be evaluated in 
the SAD study using both Cmax and AUC. Any adverse events that may signal a potential proarrhythmic 
effect will be carefully monitored (e.g., Torsade de pointes, sudden death, ventricular tachycardia, 
seizures, etc.). 
Complete Blood Count – Blood sampling for the laboratory parameters will be performed during the 
screening and BIO 300 Oral Powder treatment period according to the study schedule (Section 1.3). A 
complete blood count with differential will evaluate hemoglobin, hematocrit, red blood cells (RBCs), 
white blood cells (WBCs), neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet 
count. 
Serum Chemistry and Fasting Lipid Panel – Blood serum will be used to evaluate the blood chemistry 
parameters. Serum chemistries to include total protein, albumin, sodium, potassium, chloride, 
bicarbonate, glucose, BUN, creatinine, alkaline phosphatase, ALT, AST, uric acid, LDH, total and direct 
bilirubin, phosphorous, calcium, magnesium, amylase, lipase, total cholesterol, triglycerides, HDL. 
Subjects will fast at least 8 h prior to blood collection for serum chemistries. 
PTT/INR – Prothrombin Time (PTT) is a test that evaluates a subject’s ability to appropriately form blood 
clots. The International Normalized Ratio (INR) is a calculation based on results of the PTT that is used to 
monitor individuals who are being treated with the blood-thinning medication. 
Pregnancy Test – Tests will occur at screening, day 1 and during the final visit (SAD, day 8, visit 5; 
Multiple Single Dose, day 13, visit 10). Tests will use urine or serum for determination of β-HCG.  
Viral Testing – Test will occur at screening for both studies. Tests will utilize blood for analysis of the 
Hepatitis B surface antigen, Hepatitis C antibody, and HIV1 and HIV2 antibody. 
Urinalysis – To include pH, specific gravity, dipstick determinations of protein, glucose, ketones and 
bilirubin, blood and reflex microscopic exam (reflex only if any qualitative measurements or appearance 
return abnormal) 
Concomitant Medications – A record of concomitant medications will be collected for all subjects from 
the screening visit through BIO 300 Oral Powder treatment and the one-week follow-up phase. 


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Assessment of Adverse Events – All adverse events (AEs) will be collected from the time the subject 
takes their first dose of BIO 300 Oral Powder until 7 days after their last dose of BIO 300 Oral Powder. 
AEs will be documented and submitted to the Sponsor. Any serious AEs (SAEs) will be documented and 
reported to the Sponsor within 24 hours of awareness (see Section 8.3). 
Blood-Based Biomarkers – Whole blood will be collected for biomarker analysis. Blood will be collected 
pre-dose, at several time points around the predicted Cmax of BIO 300 Oral Powder. The collected 
samples will be subject to RNA extraction and next-generation RNA sequencing on the Illumina HiSeq 
platform with paired-end sequencing. 
8.3 
BLOOD SAMPLING FOR PHARMACOKINETICS, SAFETY AND BIOMARKERS 
Blood will be collected from all subjects to monitor BIO 300 Oral Powder pharmacokinetics, safety, and 
biomarkers. At each visit where blood sampling occurs, whole blood and serum may be collected for 
pharmacokinetics, complete blood counts (CBC) with differential, serum chemistry, clotting (PT/INR, 
PTT) and RNA extraction. A summary of blood draws for safety and biomarkers can be found in Section 
1.3 Schedule of Activities. Below is an overview of the details of the blood collection summarized by 
visit. 
For blood draws, whole blood will be collected in one 3 cc lavender top blood collection tubes for CBC 
analysis and two PAXgene blood RNA tubes for RNA isolation. The PAXgene tubes will be stored at -70°C 
until they are shipped to a Sponsor-designated laboratory for RNA extraction and processing. Blood will 
also be collected in one 3.5 mL SST collection tube for serum isolation to be used for serum chemistry 
and 1x 3cc red top blood collection tube for serum isolation to be used for BIO 300 Oral Powder PK 
analysis. Blood used for serum will be allowed to clot 20-30 minutes and then centrifuged at room 
temperature for 10-15 minutes. Collected serum will be frozen at -70°C. All blood and serum will be 
shipped to the sponsor-designated bioanalytical lab for analysis. Additionally, at screening, blood will be 
collected into another 3.5 mL SST collection tube, and a 3 mL EDTA collection tube to be used for viral 
testing. Specific blood draw volume requirements for the procedures listed below are detailed in 
Section 8.3.1 and Section 8.3.2. 
Single Ascending Dose 
Visit 1 (Screening) 
At the screening visit, blood will be collected to acquire the subject’s baseline blood counts and serum 
chemistries, and for viral testing. If a pregnancy test is required for the subject, either a serum or urine 
test will be done at this time. These test results will assist in determining the subject’s ability to be 
included in the trial (see Section 5.1 Inclusion Criteria). 
Visit 2 (Day 1) 
All subjects will have their blood collected for serum as described above. Serum samples will be 
collected for pharmacokinetics just prior to and following administration of a single dose of BIO 300 Oral 
Powder at 30 minutes, 1, 2, 4, 6, 8, and 12 hours. The time of the blood draw will be ±10 minutes of the 
nominal time. Subjects will be given a standardized low-soy meal after the 4 h blood draw and 2 h after 
the 6 h blood draw. Whole blood will be collected as described above for RNA isolation prior to a single 
dose BIO 300 Oral Powder administration, and at 1, 2 and 4 hours after administration. 


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Visit 3 (Day 2) 
All subjects will have blood serum collected for PK 24 ± 2 hrs after BIO 300 Oral Powder dosing. Whole 
blood will also be collected for RNA isolation 24 ± 2 hrs after BIO 300 Oral Powder dosing.  
Visit 4 (Day 3) 
All subjects will have a whole blood and serum collected for CBC, PT/INR, PTT, 48 ± 4 hrs PK and serum 
chemistry as described above.  
Visit 5 (Day 8) 
All subjects will have a whole blood and serum collected for CBC, PT/INR, PTT and serum chemistry as 
described above. 
Multiple Single Dose 
Visit 1 (Screening) 
At the screening visit, blood will be collected to acquire the subject’s baseline blood counts, serum 
chemistries, PT/INR, PPT, and viral testing. If a pregnancy test is required for the subject, either a serum 
or urine test will be done at this time. These test results will assist in determining the subject’s ability to 
be included in the trial (see Section 5.1 Inclusion Criteria). 
Visit 2 (Day 1) 
All subjects will have their blood collected for serum as described above. Serum samples will be 
collected for pharmacokinetics just prior to and following administration of a single dose of BIO 300 Oral 
Powder at 30 minutes, 1, 2 and 4 hours. The time of the blood draw will be ±10 minutes of the nominal 
time.  Whole blood will be collected as described above for RNA extraction prior to a single dose BIO 300 
Oral Powder administration, and at 1, 2 and 4 hours after administration. 
Visit 4 (Day 3) 
All subjects will have a whole blood and serum collected for CBC, serum chemistry, and PT/INR, PPT as 
described above. 
Visit 5 and 6 (Days 4 and 5) 
All volunteers will have their vital signs performed and will be administer a single dose of BIO 300 Oral 
Powder at the research unit. 
Visit 7 (Day 6) 
All subjects will have their blood collected for serum as described above. Serum samples will be 
collected for pharmacokinetics just prior to and following administration of a single dose of BIO 300 Oral 
Powder at 30 minutes, 1, 2, 4, 6, 8, and 12 hours. The time of the blood draw will be ±10 minutes of the 
nominal time.  Subjects will be given a standardized low-soy meal after the 4 hr blood draw and 2 hours 
after the 6-hour blood draw. Serum will also be used for serum chemistry analysis. Whole blood will be 
collected as described above for RNA extraction prior to a single dose BIO 300 Oral Powder 
administration, and at 4, 8 and 12 hours after administration. Whole blood will also be collected for CBC 
analysis. 
Visit 8 (Day 7) 
All subjects will have blood serum collected for PK 24 ± 2 hrs after BIO 300 Oral Powder dosing. Whole 
blood will also be collected for RNA extraction 24 ± 2 hrs after BIO 300 Oral Powder dosing.  
Visit 9 (Day 8) 
All subjects will have blood serum collected for PK 48 ± 4 hrs after BIO 300 Oral Powder dosing. 


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All subjects will have a whole blood and serum collected for CBC, serum chemistry, and PT/INR, PPT as 
described above. 
j s.3.1 
SINGLE ASCENDING DOSE SUBJECT BLOOD VOLUME REQUIREMENTS
Blood volume (mL) required 
Visit Numbe1· 
1 
2 
3 
4 
s 
·2
Day 1 
Day2 
Day3 
Days 
TOTAL 
...." 
CBC 
(Lavender top 
3 
3 
3 
9 
whole blood) 
Serum Chemistry 
3.5 
3.5 
3.5 
10.5 
(SST) 
PT/INRPTT 
2.7 
2.7 
2.7 
8.1 
,ssn 
Viral Testing 
6.5 
6.5 
(SST and EDTA) 
BIO 300 Oral 
24 
Powder PK 
(3cc x 8 draws) 
3 
3 
30 
<Red top serum) 
BIO 300 Oral 
20 
Powder PD 
(5mLx4 
5 
25 
(RNA) 
(PAX2ene tube) 
draws) 
Waste associated 
with use of 
8 
8 
heoarin lock 
Subtotals 
9.2 
52 
8 
12.2 
9.2 
STIJDY TOTAL 
97.1 
j s.3.2 
MULTIPLE SINGLE DOSE SUBJECT BLOOD VOLUME REQUIREMENTS
Blood volume (mL) required 
Visit Number 
1 
2 
3 
4 
s 
6 
7 
8 
9 
·2
Dayl 
Day 
Day 
Day 
Day 
Day6 
Day 
Day 
....
2 
3 
4 
s 
7 
8 
" 
CBC 
(Lavender top whole 
3 
3 
3 
blood) 
Serum Chemistry 
3.5 
3.5 
3.5 
SST) 
PT/INRPTT 
2.7 
2.7 
2.7 
(SST) 
Viral Testing 
6.5 
(SST and EDTA) 
10 
Day 
TOTAL 
13 
3 
12 
3.5 
14 
2.7 
10.8 
6.5 
24 


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BIO 300 Oral Powder 
15 
PK 
(3cc x 5
ffied top sernm) 
draws) 
BIO 300 Oral Powder 
20 
PD(RNA) 
(5mLx 
(PAX2ene tube) 
4 draws) 
Waste associated with 
5 
use of heparin lock 
Subtotals 
11 
40 
11 
STUDYTOTAL 
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
18.4.1 
DEFINITION OF ADVERSE EVENTS (AE) 
24 
(3cc x 8 
3 
3 
45 
draws) 
20 
(5mLx 
5 
45 
4 draws) 
8 
13 
63 
8 
3 
11 
146.3 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of unrelated, unlikely, possible, probable, or definite) (ICH, E2A, 
E6). 
18.4.2 
DEFINITION OF SER1ous ADVERSE EVENTS (SAE) 
SAEs that fit any one of the criteria in the SAE definition below must be reported to the Sponsor 
within 24 hours of awareness of the event. 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
Principal Investigator or Sponsor, it results in any of the following outcomes: 
•
Death;
•
A life-threatening adverse event;
•
Inpatient hospitalization or prolongation of existing hospitalization;
•
A persistent or significant incapacity or substantial disruption of the ability to conduct normal
life functions;
•
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. 
18.4.3 
CLASSIFICATION OF AN ADVERSE EVENT 
8.4.3.1 SEVERITY OF EVENT 
For adverse events (AEs), guidelines based on the FDA Guidance for Industry Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials will be used to 
describe severity. The guidance provides a toxicity grading scale (grade 1, mild; grade 2, moderate; 
grade 3, severe; grade 4, potentially life threatening) for clinical and laboratory abnormalities. For AE 
25 


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terminology, the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be used, 
and AE system organ classification will follow the Medical Dictatory for Regulatory Activities (MedDRA). 
8.4.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. 
•
Definite – There is clear evidence to suggest a causal relationship, and other possible
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test
result, occurs in a plausible time relationship to study intervention administration and cannot be
explained by concurrent disease or other drugs or chemicals. The event must be
pharmacologically or phenomenologically definitive.
•
Probable – There is evidence to suggest a causal relationship, and the influence of other factors
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a
reasonable time after administration of the study intervention, is unlikely to be attributed to
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on
withdrawal.
•
Possible – There is some evidence to suggest a causal relationship (e.g., the event occurred
within a reasonable time after administration of the study intervention). However, other factors
may have contributed to the event (e.g., the participant’s clinical condition, other concomitant
events). Although an AE may rate only as “possibly related” soon after discovery, it can be
flagged as requiring more information and later be upgraded to “probably related” or “definitely
related”, as appropriate.
•
Unlikely – A clinical event, including an abnormal laboratory test result, whose temporal
relationship to study intervention administration makes a causal relationship improbable (e.g.,
the event did not occur within a reasonable time after administration of the study intervention)
and in which other drugs or chemicals or underlying disease provides plausible explanations
(e.g., the participant’s clinical condition, other concomitant treatments).
•
Unrelated – The AE is completely independent of study intervention administration, and/or
evidence exists that the event is definitely related to another etiology.
8.4.3.3 EXPECTEDNESS  
The Principal Investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention.  The final 
determination of expectedness will be determined by the Medical Monitor in consultation with the 
Principal Investigator. 
8.4.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 


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training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened, or after they are 
screened, but before they are administered the first dose of study drug, will be considered as baseline 
and not reported as an AE. However, if the study participant’s condition deteriorates at any time during 
the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
Delegated study personnel will record AEs with start dates occurring any time after the first dose of 
study intervention is administered through the end of the study. SAEs will be recorded with start dates 
occurring any time after informed consent is obtained through the end of the study. At each study visit, 
the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed 
for outcome information until resolution or stabilization. Documentation of the serious event will be 
reported on the Serious Adverse Event CRF and submitted to the Sponsor within 24 hours of awareness. 
8.4.5 ADVERSE EVENT REPORTING  
The notification process to the study Sponsor of all safety data begins with the completion and 
submission of the appropriate CRFs or in the case of an initial serious event reporting, by phone. 
Investigators are required to report promptly to the Sponsor any adverse events that may reasonably be 
regarded as caused by, or probably caused by, the drug. If the Adverse Event (AE) meets the Serious 
Adverse Event (SAE) criteria, the investigator is required to report the event to the Sponsor within 24 
hours of awareness.   
8.4.6 SERIOUS ADVERSE EVENT REPORTING  
The Sponsor will notify the FDA, all participating investigators in a written IND safety report of any 
adverse experience associated with the use of the drug that is both serious and unexpected and any 
finding from tests in laboratory animals that suggests a significant risk for human subjects. The Sponsor 
will submit an IND safety report to the FDA and all participating investigators no later than 15 calendar 
days after the Sponsor determines that the suspected adverse reaction or other information qualifies for 
reporting. Unexpected fatal or life-threatening suspected adverse reactions will be reported to the FDA 
no later than 7 calendar days after the Sponsor’s initial receipt of the information. If the FDA requests 
any additional data or information, the Sponsor will submit it to FDA as soon as possible, but no later 
than 15 calendar days after receiving the request. 
8.4.7 EVENTS OF SPECIAL INTEREST  
Subjects that experience any cardiovascular-related events, overdose on the study intervention, have 
any clinically significant laboratory test abnormalities, or become COVID-19 positive should be reported 
to the study Sponsor. 
8.4.8 REPORTING OF PREGNANCY  
Should a participant become pregnant during the study, the Principal Investigator will report this event 
to the study Sponsor and will create a plan to stop the study intervention as soon as possible. The 
Principal Investigator will communicate with the physician managing the pregnancy and the subject and 
pregnancy will be followed to term. 


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8.5 
UNANTICIPATED PROBLEMS 
8.5.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all the 
following criteria: 
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are
described in the protocol-related documents, such as the IRB-approved research protocol and
informed consent document; and (b) the characteristics of the participant population being
studied;
•
Related or possibly related to participation in the research (“possibly related” means there is a
reasonable possibility that the incident, experience, or outcome may have been caused by the
procedures involved in the research); and
•
Suggests that the research places participants or others at a greater risk of harm (including
physical, psychological, economic, or social harm) than was previously known or recognized.
8.5.2  UNANTICIPATED PROBLEM REPORTING 
The Principal Investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the Sponsor. The UP report will include the following information: 
•
Protocol identifying information: protocol title and number, PI’s name, and the IRB project
number;
•
A detailed description of the event, incident, experience, or outcome;
•
An explanation of the basis for determining that the event, incident, experience, or outcome
represents an UP;
•
A description of any changes to the protocol or other corrective actions that have been taken or
are proposed in response to the UP.
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
•
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the study Sponsor
in accordance with the sites policies and procedures and within 24 hours of the investigator
becoming aware of the event.
•
Any other UP will be reported to the IRB and to the study Sponsor within one week of the
investigator becoming aware of the problem.
All UPs should be reported to appropriate institutional officials (as required by an institution’s
written reporting procedures), the supporting agency head (or designee), and the Office for
Human Research Protections (OHRP) within 7 business days of the IRB’s receipt of the report of
the problem from the investigator.


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9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
Data analysis of the primary endpoints will be based on measurements of genistein aglycone (free 
genistein) serum concentrations (0-48 h). They will also be based on safety assessments which include 
blood counts, serum chemistries, urinalysis, ECGs, vital signs, and PTT/INR at the timepoints listed in the 
SoA, Section 1.3.  “Baseline” will refer to measurements taken during the screening visit. If no “baseline” 
data exists from a parameter, then changes in the parameter time regression will be compared. 
As this is a single dose escalation and multiple single dose trial evaluating the safety and pharmacokinetic 
profile of BIO 300 Oral Powder, the statistical hypotheses for the safety measurements is that there will 
be no change in safety measurements during BIO 300 Oral Powder dosing, and 7 days after the last BIO 
300 Oral Powder dose.  
For the secondary endpoint, the statistical hypothesis is that there will be a significant change in the level 
of expression of one or more genes that is attributable to BIO 300 Oral Powder dose.   
9.2 
SAMPLE SIZE DETERMINATION 
The single ascending dose study consists of 4 cohorts, each with at least 6 subjects completing all 
aspects of the study, split evenly to include at least 3 females and 3 males. As such, 12 
 females and 12 males will participate for a total of 24 subjects. The multiple single dose study will 
include at least 8 subjects completing all aspects of the study, split evenly to include at least 4 females 
and 4 males. This is a sufficient number of subjects in each study to characterize the PK and PD of BIO 
300 Oral Powder and to identify DLTs.   
9.3 
POPULATIONS FOR ANALYSES 
All participants will be analyzed. The ITT dataset is the primary dataset for analysis. As a guide, analyses 
may include, but are not limited to, any or all of the following: 
•
Intention-to-Treat (ITT) Analysis Dataset: all participants
•
Safety Analysis Dataset: participants who took at least one dose of BIO 300 Oral Powder
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
An independent statistician using standard statistical techniques will determine statistically significant 
differences in the trial measurement data. Statistical significance will be set at the nominal level of 
p<0.05. Plasma concentrations (genistein aglycone; free genistein) will be measured (AUC, Cmax, Tmax, 
T1/2) and plasma kinetic rate will be calculated using standard procedures and statistical analyses (e.g., 
AUC using the linear trapezoidal formula and T1/2 using linear regression). Data will be summarized by 
descriptive statistics (mean/medians and standard errors/confidence intervals for continuous response 
variables and distribution tables or histograms for discrete response variables). 
Baseline characteristics will be compared using matched-pair t-tests. The computed change from 
baseline will be calculated for all measured variables and expressed as the mean change from baseline 


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and accompanying standard deviation (SD) of the change from baseline. Repeated measures ANOVA 
tests will be used to compare changes in scores for each variable between each treatment group. 
Matched pair t-tests will be used to compare the change scores within each treatment group. All data 
analyses will be conducted on the subjects who completed the study treatment periods and statistical 
significance will be set at p<0.05. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Blood counts, serum chemistry, urinalysis, ECGs, vital signs, and PTT/INR for the study cohorts will be 
reported as a mean ± SD at each of the timepoints listed in the SoA, Section 1.3. An analysis of 
covariance (ANCOVA) to compare the cohorts after adjusting for "baseline" (the adjustment covariate) 
will be completed.  Analysis will be performed in individual subjects to identity changes in safety 
measurements relative to baseline, and between cohorts at the timepoints listed in the SoA, Section 1.3 
to identify any potential dose-response relationships.  
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
For the secondary endpoint of RNA sequencing, statistical analysis will be used to detect differential 
expressed genes (DEGs). Analysis will be performed in individual subjects to identity DEGs relative to 
baseline, and between cohorts at the timepoints listed in the SoA, Section 1.3 to identify dose-response 
relationships.  
RNA samples will be sequenced using an Illumina HiSeq approach that will produce 20-30 million paired 
end reads per sample. Raw reads will be mapped to the human genome. Reads will be normalized as 
fragments per kilobase million (FPKM) and used to identify DEGs for biomarker evaluation. 
9.4.4 SAFETY ANALYSES 
All adverse events (AEs), including clinically significant laboratory abnormalities, will be collected in the 
site’s source document, and reported on the AE case report form (CRF). Documentation of the serious 
event will be reported on the Serious Adverse Event (SAE) CRF and submitted to the Sponsor within 24 
hours of awareness.  
AEs will be identified using the FDA Guidance for Industry Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. The following information regarding 
each adverse event will be recorded: 
•
Assessment period
•
Severity Grade (0-4)
•
Attribution to study agent (relatedness)
•
Date AE occurred
•
Date AE resolved
•
Whether or not the event was reported as an SAE
•
Whether or not the participant dropped due to the event
•
Action taken with study agent
•
Outcome of the event
•
Additional investigator comments
AEs will be summarized by study group and system organ class. Tables will include summaries of all AEs, 
all SAEs, all BIO 300 Oral Powder related AEs, all BIO 300 Oral Powder related SAEs, all Grade 3 or 4 AEs, 
and all AEs leading to death or study discontinuation. 


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9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline characteristics, such as subject age, vital signs, laboratory results, and BMI will be compared 
between the dosing cohorts using descriptive statistics. ANOVA analysis will be used to compare each 
parameter between the study cohorts at baseline. 
9.4.6 PLANNED INTERIM ANALYSES 
Following the 2000 mg single ascending dose cohort, safety and PK analysis will be completed to 
determine the dose for the final cohort of the single ascending dose study. 
9.4.7 SUB-GROUP ANALYSES 
No sub-group analysis is planned. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
All individual participant data will be listed by measure and timepoint. 
9.4.9 EXPLORATORY ANALYSES 
There are no exploratory analyses planned for this study. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The informed consent form (ICF) is submitted with this 
protocol.  
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
The environment where the process of consent is conducted will be private, confidential, and safe in 
order to facilitate a constructive dialogue between the prospective subject and the person(s) involved in 
obtaining consent. All prospective subjects must have the cognitive ability to provide legally effective 
informed consent. Individuals who do not have such ability (i.e., decisionally impaired persons) can only 
be enrolled in research through consent of their legally authorized representative (LAR). If there is any 
concern about an individual’s cognitive ability an appropriate assessment should be performed by a 
qualified individual. 
The informed consent will be presented and discussed with the prospective subject in a sequential 
manner utilizing the approved ICF as a guide. The presentation should be structured to facilitate a 
dialogue with reinforcement and elaboration of important information (e.g., the risks of the research). 
The person(s) involved in obtaining the subject’s consent will constantly evaluate whether the process is 


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achieving the goal which is obtainment of legally effective informed consent from the subject. In 
addition to paying attention to general signs of information receptivity, the person obtaining consent 
may ask open-ended questions in order to identify points of confusion which require clarification. 
A delayed consent procedure will be used in order to afford the subject the opportunity to discuss 
participation in the research with family, friends, counselors, or other confidants before they sign the 
ICF. If the individual is uncomfortable or anxious about participating in the research, they will be 
instructed to take the ICF home for further review and consideration before deciding whether or not to 
participate in the research. 
The informed consent process will be documented by personnel qualified to attest the that the subject 
has provided legally effective informed consent. The individual documenting the process and the 
consenting subject will sign and date the ICF and indicate the time at which the ICF was signed. It is 
unacceptable for the person documenting consent to sign the ICF in advance of obtaining the subject’s 
signature.  
The informed consent document must be reviewed and approved by the IRB, any changes to the 
informed consent must be submitted to the IRB for approval prior to initiation.   
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending, or terminating party to study participants, Principal Investigator, funding 
agency, the Investigational New Drug (IND) Sponsor and regulatory authorities.  If the study is 
prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and Sponsor and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the Sponsor, IRB and/or Food and Drug Administration (FDA). 
10.1.3 CONFIDENTIALITY AND PRIVACY  
In order to maintain subject confidentiality, a subject number and initials will identify all study subjects 
on CRFs and other documentation submitted to the Sponsor.   
Participant confidentiality and privacy is strictly held in trust by the Principal Investigator, their staff, and 
the Sponsor(s) and their interventions. This confidentiality is extended to cover all aspects of the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, and all other 




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10.1.6 SAFETY OVERSIGHT 
Safety oversight will be the responsibility of the Principal Investigator and the Medical Monitor. 
10.1.7 CLINICAL MONITORING 
Site monitoring will be conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with ICH GCP, and 
with applicable regulatory requirement(s). 
Sponsor will monitor the progress of all clinical investigations being conducted under its IND based on 
the study specific Monitoring Plan, which shall be prepared by the Sponsor. If Sponsor discovers that 
a participating investigator is not complying with the signed agreement (Form FDA-1572), the general 
investigational plan, or other requirements the study Sponsor shall promptly either secure 
compliance or discontinue the investigator’s participation in the investigation.  
The Sponsor will review and evaluate the evidence relating to the safety and effectiveness of the drug as 
it is obtained from the participating investigator. The notification process to the study Sponsor begins 
with the completion and submission of the appropriate CRFs. Investigators are required to report 
promptly to the Sponsor any adverse events that may reasonably be regarded as caused by, or probably 
caused by, the drug. If the adverse event meets the serious adverse event criteria, the investigator is 
required to report the event to the Sponsor within 24 hours of discovery. 
Prompt review of the AE by the study Sponsor will be completed to determine if the AE meets any of the 
criteria for an AE to be reported to the FDA, Investigators, and/or Institutional Review Boards (IRB).  
Should an AE be determined by the study Sponsor to meet the criteria for a 7- or 15-day reportable 
event, the medical monitor will be notified promptly. The medical monitor will assist in writing the IND 
safety report with the study Sponsor. The Sponsor will submit all necessary reports to FDA regarding 
information relevant to the safety of the drug. 
The study Sponsor will promptly investigate all safety information it receives.  Should the Sponsor, in 
consultation with the Medical Monitor, determine that the investigational drug presents an 
unreasonable and significant risk to subjects, the study shall be discontinued. In this case, the study 
Sponsor will notify the FDA, all institutional review boards, and all investigators who have at any time 
participated in the investigation of the discontinuance and assure the disposition of all stocks of the 
drug outstanding and furnish FDA with a full report of the Sponsor’s actions.  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion per its Standard Operating Procedures (SOPs).  
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written SOPs, the monitor(s) will verify that the clinical trial is conducted and data are 
generated and biological specimens are collected, documented (recorded), and reported in compliance 
with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 


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applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the Sponsor, and inspection by local and 
regulatory authorities as appropriate and necessary. 
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
Principal Investigator. The Principal Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into a study specific data capture system, a 21 CFR Part 
11-compliant data capture system utilized by the Sponsor. The data system includes password
protection and internal quality checks, such as automatic range checks, to identify data that appear
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source
documents.
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the Sponsor, if applicable. It is the responsibility of the Sponsor to inform 
the investigator when these documents no longer need to be retained. 
10.1.10 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP: 
•
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3
•
5.1 Quality Assurance and Quality Control, section 5.1.1
•
5.20 Noncompliance, sections 5.20.1, and 5.20.2.


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Compliance with the study protocol and all study procedures will be assessed during each monitoring 
visit.  A protocol deviation for this study is defined as any departure from the protocol whether pre-
approved by the Sponsor or unplanned. Protocol deviations may be identified during monitoring visits or 
by the site either in anticipation of a deviation or upon discovery. The research site should complete a 
Protocol Deviation CRF and submit it to the Sponsor after review and signature by the investigator. 
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The 
site investigator is responsible for knowing and adhering to the reviewing IRB requirements. Further 
details about the handling of protocol deviations will be included in the MOP. 
As specified in the Study Monitoring Plan, the Sponsor will review protocol deviations by site and overall 
to determine if there are any trends identified that may affect subject safety, data integrity and the 
impact on analysis and to determine if any actions need to be taken prevent continued deviations.  
10.1.11 PUBLICATION AND DATA SHARING POLICY 
Publication of clinical trial results will be consistent with the Sponsor’s Publication Policy. The first 
publication in journal, or presentation at a congress, will be based on the consolidated data, analyzed as 
stipulated by the protocol and agreed upon by investigators. 
The Sponsor intends to share all applicable data collected as part of this project with the DoD and the 
general scientific community. The data will be made as widely and freely available as possible through 
presentation at scientific conferences and publication of primary data in a peer-reviewed journal.  
10.1.12 CONFLICT OF INTEREST POLICY 
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or 
any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial.   
10.2 ABBREVIATIONS 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ASD 
Amorphous Spray Dried Dispersion 
AST 
Aspartate Aminotransferase 
AUC 
Area-Under-The-Curve 
β-HCG 
Human Chorionic Gonadotropin 
BMI 
Body mass Index 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CC 
Cubic Centimeter 
 
 
CFR 
Code of Federal Regulations 
Cmax 
Maximum (Peak) Concentration 
CONSORT 
Consolidated Standards of Reporting Trials 


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Confidential Information of Humanetics Corporation 
 
37 
 
COVID-19 
 
Coronavirus Disease 2019 
CRF 
 
 
 
Case Report Form 
CTCAE 
 
 
Common Terminology Criteria for Adverse Events 
CTPA  
 
 
Computed Tomography Pulmonary Angiogram 
DEG  
 
 
Differentially Expressed Gene 
DLT 
 
 
 
Dose Limiting Toxicity 
DVT  
 
 
Deep Vein Thrombosis 
ECG  
 
 
Electrocardiogram 
eCRF  
 
 
Electronic Case Report Form 
ERβ  
 
 
Estrogen Receptor Beta 
FDA  
 
 
US Food and Drug Administration 
FPKM  
 
 
Fragments Per Kilobase Million 
 
 
 
GCP  
 
 
Good Clinical Practice 
GLP 
 
 
 
Good Laboratory Practice 
GMP  
 
 
Good Manufacturing Practice 
g  
 
 
 
Gram 
HDL  
 
 
High-Density Lipoprotein 
HEENT 
 
 
Head, Eyes, Ears, Nose and Throat  
H/Hr  
 
 
Hours 
IB  
 
 
 
Investigator’s Brochure 
ICF 
 
 
 
Informed Consent Form 
ICH 
 
 
 
International Conference on Harmonisation 
  
 
 
  
 
 
 
  
 
 
 
 
IND 
 
 
 
Investigational New Drug Application 
INR 
 
 
 
International Normalized Ratio Based On PTT 
IRB 
 
 
 
Institutional Review Board 
ITT 
 
 
 
Intention-to-Treat 
Kg  
 
 
 
Kilogram 
LAR 
 
 
 
Legally Authorized Representative 
LBBB  
 
 
Left Bundle Branch Block 
LDPE  
 
 
Low-Density Polyethylene 
LLDPE  
 
 
Linear Low-Density Polyethylene 
M2  
 
 
 
Square Meters 
MedDRA  
 
Medical Dictionary for Regulatory Activities 
M/F  
 
 
Male/Female 
mg 
 
 
 
Milligram 
min 
 
 
 
Minute 
mL 
 
 
 
Milliliter 
msec  
 
 
Millisecond 
MOP  
 
 
Manual of Procedures 
MTD  
 
 
Maximum Tolerated Dose 
N  
 
 
 
Number 
NCT  
 
 
National Clinical Trial 


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38 
NF-κB  
Nuclear Factor Kappa Light-Chain-Enhancer of Activated B Cells 
 
 
NIH 
National Institutes of Health 
NF 
National Formulary and Drug Standards Laboratory 
NYHA 
New York Heart Association 
OHRP 
Office for Human Research Protections 
oz 
Fluid Ounce 
PD  
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PTT 
Prothrombin Time 
PVC 
Premature Ventricular Contractions 
QC 
Quality Control 
QTc 
Corrected QT Interval 
QTcF 
QTc with Fridericia’s Correction 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SoA 
Schedule of Assessments 
SOP 
Standard Operating Procedure 
T1/2 
Half-life 
TBD 
To Be Determined 
Tmax 
Time to Reach Cmax 
 
 
 
 
UP  
Unanticipated Problems 
USP 
United States Pharmacopeia 
VTE 
Venous Thromboembolism 
w 
Weight 
WBC 
White Blood Cells 
Yrs 
Years 
10.3 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
Version 
Date 
Description of Change 
Brief Rationale 
0.5 
17Sep2020 
Initial Release 
Initial Release 
1.0 
16Nov2020 
Changed the biomarkers of interest, 
time period and frequency of AE 
reporting and reporting of pregnancy 
Revised to include acute 
radiation syndrome relevant 
biomarkers, provide consistency 
with the Schedule Activities, 


Phase 1 BIO 300 Oral Powder 
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and remove unnecessary 
language. 
2.0 
16Mar2021 
Changed the blood draw times for 
PD (biomarkers) on day 6 of the 
multiple single dose study 
Added a pregnancy test to day 1 of 
the Multiple Single Dose Study 
Cohort 
The original blood draw times 
were based on the predicted 
Cmax of BIO 300 Oral Powder 
from animal studies. The 
updated blood draw times are 
based on the actual Cmax from 
all 4 cohorts in the SAD study 
conducted under this protocol. 
Pregnancy test added to day 1 of 
the Multiple Single Dose Study 
Cohort to align with inclusion 
criteria requiring a negative 
pregnancy test within 72 hours 
of day 1.  


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40 
11 REFERENCES 
1. Hamalainen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E. Anti-inflammatory effects of flavonoids:
genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone,
isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on
iNOS expression and NO production in activated macrophages. Mediators of inflammation 2007;2007:45673.
2. Pons DG, Vilanova-Llompart J, Gaya-Bover A, et al. The phytoestrogen genistein affects inflammatory-related
genes expression depending on the ERalpha/ERbeta ratio in breast cancer cells. Int J Food Sci Nutr 2019:1-9.
3. Liu J, Viswanadhapalli S, Garcia L, et al. Therapeutic utility of natural estrogen receptor beta agonists on ovarian
cancer. Oncotarget 2017;8:50002-14.
4. Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2017;2.
5. Chen Y, Xiao CQ, He YJ, et al. Genistein alters caffeine exposure in healthy female volunteers. European journal
of clinical pharmacology 2011;67:347-53.
12 APPENDICES 
APPENDIX 1: SOY RICH FOODS 
The following is a list of soy rich foods that study participants should be counseled to avoid while participating in 
the study: 
•
Edamame
•
Meat Alternatives containing soy protein or tofu, e.g.no meat hot dogs
•
Miso
•
Natto
•
Nutritional drinks and bars with added soy protein
•
Soymilk
•
Soy cheese
•
Soy ice cream
•
Soy yogurt
•
Soy Nuts
•
Tempeh
•
Textured Soy Protein
•
Tofu
•
Whole Soybeans
Use to the following links for additional information on soy rich foods: 
http://www.ucsfhealth.org/education/a_guide_to_foods_rich_in_soy/ 
http://www.ars.usda.gov/SP2UserFiles/Place/80400525/Data/isoflav/Isoflav_R2.pdf 


 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 1 Dose Escalation Trial Evaluating the Safety and 
Pharmacokinetic Profile of BIO 300 Oral Powder in Healthy 
Volunteers 
Protocol Number: 
CL0106-01 
 
 
Investigational Agent: 
BIO 300 Oral Powder 
Phase of Development: 
Phase 1 
Sponsor: 
Humanetics Corporation 
7650 Edinborough Way, Suite 620 
Edina, Minnesota 55435 
Date of SAP: 
December 28, 2020 (version 1.0) 
Amendment History: 
Original Version 


CL0106-01 
Statistical Analysis Plan 
December 28, 2020 
 
 
1 
 
Table of Contents 
1. 
INTRODUCTION ............................................................................................................................ 2 
2. 
STUDY OBJECTIVES........................................................................................................................ 2 
2.1. 
PRIMARY OBJECTIVES ...................................................................................................................... 2 
2.2 SECONDARY OBJECTIVES ...................................................................................................................... 2 
3. 
STUDY ENDPOINTS ........................................................................................................................ 2 
3.1. 
PRIMARY ENDPOINT ....................................................................................................................... 2 
3.2. 
SECONDARY ENDPOINT .................................................................................................................... 3 
4. 
SAMPLE SIZE ................................................................................................................................. 3 
5. 
ANALYSIS POPULATIONS ............................................................................................................... 3 
5.1. 
INTENTION-TO-TREAT ANALYSIS DATASET ........................................................................................... 3 
5.2. 
SAFETY ANALYSIS DATASET .............................................................................................................. 3 
5.3. 
PHARMACOKINETIC (PK) POPULATION ............................................................................................... 3 
5.4. 
PHARMACODYNAMICS (PD) POPULATION ........................................................................................... 3 
6. 
SAFETY MONITORING COMMITTEE ............................................................................................... 3 
7. 
STATISTICAL METHODS ................................................................................................................. 4 
7.1. 
DEFINITIONS ................................................................................................................................. 4 
7.2. 
MISSING VALUES ........................................................................................................................... 4 
7.3. 
VISIT WINDOWS ............................................................................................................................ 4 
7.4. 
INTERIM ANALYSIS ......................................................................................................................... 5 
7.5. 
SIGNIFICANCE LEVEL ........................................................................................................................ 5 
8. 
GENERAL DATA ANALYSES ............................................................................................................ 5 
8.1. 
SUBJECT DISPOSITION ..................................................................................................................... 5 
8.2. 
PROTOCOL DEVIATIONS ................................................................................................................... 5 
8.3. 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS .................................................................................. 5 
9. 
ENDPOINT ANALYSES .................................................................................................................... 5 
9.1. 
ANALYSIS FOR SAFETY ENDPOINTS ..................................................................................................... 5 
9.2. 
ANALYSIS FOR THE PHARMACOKINETIC PROFILE .................................................................................... 5 
9.3. 
ANALYSIS FOR BLOOD-BASED BIOMARKERS ......................................................................................... 6 
10. 
SAFETY ANALYSES ....................................................................................................................... 6 
10.1. 
EXPOSURE TO BIO 300 ORAL POWDER ............................................................................................. 6 
10.2. 
ADVERSE EVENTS ......................................................................................................................... 6 
10.3. 
CLINICAL LABORATORY TEST RESULTS ............................................................................................... 7 
10.4. 
VITAL SIGNS ................................................................................................................................ 7 
10.5. 
ELECTROCARDIOGRAMS ................................................................................................................. 7 
11. 
SYMBOLS AND ABBREVIATIONS .................................................................................................. 8 
 
 
 


CL0106-01 
Statistical Analysis Plan 
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2 
1. Introduction 
Protocol Title: A Phase 1 Dose Escalation Trial Evaluating the Safety and Pharmacokinetic Profile of BIO 
300 Oral Powder in Healthy Volunteers 
Protocol Number: CL0106-01 
 
Investigational Agent: BIO 300 Oral Powder 
Phase of Development: Phase 1 
Sponsor: Humanetics Corporation 
Design: Open label, single site phase 1 study in healthy volunteers who are equally distributed by sex. The 
study will include a single ascending dose (SAD) study in four cohorts and will be followed by a six-day 
multiple single dose (MSD) study at either the highest dose or the maximum tolerated dose. There are no 
planned stratifications or sub-studies. 
This Statistical Analysis Plan (SAP) details the planned methods for summarizing data collected in the 
clinical study conducted under Humanetics Corporation protocol CL0106-01. The current study protocol 
is identified as version 1.0 dated 16-Nov-2020. 
Future protocol amendments (if any) will be reviewed to assess whether the changes necessitate 
modification of this SAP. 
Since the study protocol is a companion document to this SAP, aspects in the protocol unrelated to 
statistical issues (e.g., patient eligibility criteria and detailed BIO 300 Oral Powder information) are not 
repeated here. 
2. Study Objectives 
2.1. Primary Objectives 
• 
Determine the overall adverse event and pharmacokinetic (PK) profiles of single ascending 
doses of BIO 300 Oral Powder in healthy volunteers 
• 
Determine the overall adverse event and PK profile of multiple doses of BIO 300 Oral Powder in 
healthy volunteers 
2.2 Secondary Objectives 
• 
Determine the effects of single and multiple doses of BIO 300 Oral Powder on blood-based 
biomarkers 
• 
Use a combination of the PK and pharmacodynamic (PD) profiles from the single and multiple 
doses of BIO 300 Oral powder to identify the putative BIO 300 Oral Powder human efficacious 
dose  
3. Study Endpoints 
3.1. Primary Endpoint 
• 
Evaluate the safety and pharmacokinetics of BIO 300 Oral Powder in Healthy Volunteers 


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Statistical Analysis Plan 
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3 
3.2. Secondary Endpoint  
• 
Characterize the expression of blood-based biomarkers 
4. Sample Size 
• 
6 subjects/cohort (3M/3F) will be recruited for the single ascending dose study, and at least 6 
(3M/3F) subjects/cohort will complete all aspects of the study.  2 additional subjects (1M/1F), will 
be screened, consented and available as backups for each cohort. 
• 
10 (5M/5F) subjects will be recruited for the multiple single dose study, and at least 8 (4M/4F) 
subjects will complete all aspects of the study. 4 additional subjects (2M/2F) will be screened, 
consented and available as backups. 
• 
In total, at least 32 healthy volunteers who will complete all aspects of the trial. 
The single ascending dose study consists of 4 cohorts, each with at least 6 subjects completing all aspects 
of the study, split evenly to include at least 3 females and 3 males. As such, 12 females and 12 males will 
participate for a total of 24 subjects. The multiple single dose study will include at least 8 subjects 
completing all aspects of the study, split evenly to include at least 4 females and 4 males. This is a sufficient 
number of subjects in each study to characterize the PK and PD of BIO 300 Oral Powder and to identify 
dose limiting toxicities (DLTs).   
5. Analysis Populations 
5.1. Intention-to-Treat Analysis Dataset 
The Intention-to-Treat (ITT) analysis dataset will include all study participants 
5.2. Safety Analysis Dataset 
All study participants who receive at least one dose of BIO 300 Oral Powder. This analysis set will be used 
to summarize all safety endpoints. 
5.3. Pharmacokinetic (PK) Population 
The PK Population will include all subjects who receive at least 1 dose of BIO 300 Oral Powder and have 
sufficient, valid serum samples to estimate key parameters for at least 1 of the days of sampling. PK 
summaries will be based on the PK population. 
5.4. Pharmacodynamics (PD) Population 
The PD Population will include all subjects who receive at least 1 dose of BIO 300 Oral Powder and have 
sufficient, valid serum samples to estimate key parameters for at least 1 of the days of sampling. PD 
summaries will be based on the PD population. 
6. Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) will review safety and PK data (when available) during the conduct 
of the study. After each cohort in the SAD study, the SMC will make decisions on proceeding with dose 
escalation, adding additional subjects to the current cohort, and possible dose adjustments. The SMC may 
also recommend stopping the study, suspending enrollment or significant changes to the dosing regimen 
and/or enrollment if warranted by safety data. The SMC will immediately communicate this 
recommendation to Humanetics for review and determination of a final decision. SMC data reviews are 


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4 
not considered interim analyses and do not necessitate adjusting of the alpha level for multiple statistical 
hypothesis tests. 
7. Statistical Methods 
Unless stated otherwise, the term “descriptive statistics” refers to the number of subjects (n), mean, 
median, standard deviation (STD), minimum (min), and maximum (max) and standard errors/confidence 
intervals for continuous response variables and distribution tables or histograms for discrete response 
variables. Min and max values will be rounded to the precision of the original value, means and medians 
will be rounded to 1 decimal place greater than the precision of the original value, and STDs will be 
rounded to 2 decimal places greater than the precision of the original value. Percentages will be rounded 
to the nearest whole number (zeros are not displayed) with values of “< 1%” and “> 99%” shown as 
necessary for values falling near the boundaries. 
The computed change from baseline will be calculated for all measured variables and expressed as the 
mean change from baseline + STD of the change from baseline. Analysis of covariance will be used to 
compare dosage groups on “change from baseline” measures (with baseline measurement considered as 
an adjustment covariate).  
Unless otherwise note, all data collected during the study will be included in data listings and will be sorted 
by study cohort, subject number and then by visit for each subject number. 
7.1. Definitions 
• 
Baseline is synonymous with screening, and the baseline value (or baseline result) is that 
measured during the screening visit prior to the first administration of BIO 300 Oral Powder. 
• 
Day 1 is the first day of dosing with BIO 300 Oral Powder. 
• 
Estimand is the estimated value for a parameter or, alternatively, a formula and/or description 
for how a parameter is estimated. 
• 
Proportional months, defined for durations of time reported in months, are given by the formula 
months =
12
365.25 × days 
• 
Shift table is a two-way frequency table pairing baseline value with the most extreme post-
baseline result. 
7.2. Missing Values 
Given the small sample size, descriptive statistics and other analyses will be completed without replacing 
or imputing missing values. 
7.3. Visit Windows 
The study protocol defines a visit schedule based on the number of days since the first dose of BIO 300 
Oral Powder (Day 1). All study participants will be instructed on when they need to return to the clinic in 
order to meet all scheduled assessments. Assessments outside of the scheduled visit window will be 
analyzed (by visit according to the clinical database) as if they occur within the visit window; that is, no 
data will be excluded if it is measured outside the visit window. 


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7.4. Interim Analysis 
Following the third SAD cohort, PK analysis will be completed for all subjects (cohorts 1-3) and analyzed 
along with all safety data to determine the dose for the final cohort of the SAD study. No other interim 
analyses are planned. SMC data reviews are not considered interim analyses (see Section 6). 
7.5. Significance level 
An independent statistician using standard statistical techniques will determine statistically significant 
differences in the trial measurement data at the nominal 0.05 level of significance.      
8. General Data Analyses 
8.1. Subject Disposition 
The numbers of subjects who were enrolled and dosed with BIO 300 Oral Powder will be summarized by 
frequency counts. Reasons for discontinuing BIO 300 Oral Powder and study completion status will be 
summarized as categorical variables (number and percentage of subjects in each category). Relevant data 
supporting these summaries will be listed by subject. 
8.2. Protocol Deviations 
Study inclusion/exclusion criteria violations and protocol deviations recorded in the clinical database, if 
any, will be summarized as categorical variables (number and percentage of subjects in each category). 
Relevant data supporting this summary will be listed by subject. 
8.3. Baseline and Demographic Characteristics 
Demographic and baseline characteristic data will be summarized with descriptive statistics for age, 
gender, race, ethnicity, height, weight, BMI, vital signs and laboratory results. ANOVA analysis will be used 
to compare each parameter between the study cohorts at baseline. 
9. Endpoint Analyses 
All observations available in the study database will be included in endpoint analysis regardless of 
subjects’ aggregate exposure to BIO 300 Oral Powder, use of concomitant medications, or violations of 
the protocol. Relevant data supporting efficacy analyses will be listed by subject.  
9.1. Analysis for Safety Endpoints 
Safety data will include adverse events (AEs), safety laboratory (CBC/hematology, serum chemistry and 
urinalysis), pregnancy (if applicable), drug and alcohol tests test, physical exam, ECG, and vital signs. The 
proportion of subjects experiencing adverse events, serious adverse events, and DLTs will be 
summarized for each dosing cohort. See Section 10 for more information on safety analysis. 
9.2. Analysis for the Pharmacokinetic Profile 
PK parameters will be estimated using nominal sampling times relative to each dose administration and 
nominal doses unless otherwise specified. Serum concentration values obtained at the predose time point 
will be used to estimate the concentration at time zero (baseline).  Concentration values reported as not 
quantifiable (BLQ, <1.0 ng/mL) will be assigned a value of zero.   
The area under the concentration vs. time curve (AUC) will be calculated using the linear trapezoidal 
method with linear interpolation. The AUC will not be calculated for PK profiles with less than 3 
quantifiable concentrations of BIO 300 Oral Powder at separate time points. When practical, the terminal 


CL0106-01 
Statistical Analysis Plan 
December 28, 2020 
 
 
6 
elimination phase of each concentration versus time curve will be identified using at least three observed 
concentration values after Cmax, but not including Cmax. The slope of the terminal elimination phase will 
be determined using log linear regression on the unweighted concentration data. Parameters relying on 
the determination of the terminal elimination phase will not be reported if the coefficient of 
determination is less than 0.800, or if the extrapolation of the AUC to infinity represented more than 20% 
of the total area. The parameters Tmax, Cmax, AUC(0-t), AUC(0-inf) and T1/2 will be reported for each 
SAD cohort and for the MSD cohort on after the Day 6 dose of BIO 300 Oral Powder. 
9.3. Analysis for Blood-Based Biomarkers 
Blood-based biomarkers will be identified by extracting RNA from whole blood samples and performing 
transcriptome analysis to determine differential gene expression. Transcriptome analysis will be 
conducted by paired-end RNA sequencing. After investigating the quality of the raw sequencing data, 
sequence reads will be trimmed to remove possible adapter sequences and nucleotides with poor quality 
using Trimmomatic v.0.36. The trimmed reads will be mapped to the Homo sapiens reference genome 
available on ENSEMBL using the STAR aligner v.2.5.2b. The STAR aligner is a splice aligner that detects 
splice junctions and incorporates them to help align the entire read sequences. Binary Alignment Map 
(BAM) files will be generated as a result of this step. Unique gene hit counts will be calculated by using 
feature counts from the Subread package v.1.5.2. Only unique reads that fell within exon regions will be 
counted. 
After extraction of gene hit counts, the gene hit counts table will be used for downstream differential 
expression analysis. Using DESeq2, a comparison of gene expression between the groups of samples will 
be performed. The Wald test will be used to generate p-values and Log2 fold changes. Genes with adjusted 
p-values < 0.05 and absolute log2 fold changes > 1 will be called as differentially expressed genes for each 
comparison. A gene ontology analysis will be performed on the statistically significant set of genes by 
implementing the software GeneSCF. The goa_human GO list will be used to cluster the set of genes based 
on their biological process and determine their statistical significance. A principal component analysis 
(PCA) will be performed using the "plotPCA" function within the DESeq2 R package. This plot will show 
the samples in a 2D plane spanned by their first two principal components. The top 500 genes, selected 
by highest row variance, will be used to generate the plot. 
10. Safety Analyses 
Summaries of safety endpoints will include data collected from the safety analysis dataset. Relevant data 
supporting safety analyses will be listed by subject. 
10.1. Exposure to BIO 300 Oral Powder 
For the SAD study, safety data will also be listed by cohort in order to analyze safety endpoints by dose 
level. For the MSD study, the number of BIO 300 Oral Powder doses will be calculated and summarized 
by the mean, standard deviation, median, minimum and maximum values. 
10.2. Adverse Events 
The FDA guidance entitled “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials” will be used to grade all AEs. All reported terms and descriptions for 
AEs will be coded using this FDA guidance and summarized with frequencies and percentages by 
treatment group, system organ classification (SOC) and preferred term. 


CL0106-01 
Statistical Analysis Plan 
December 28, 2020 
 
 
7 
All AEs will be included in comprehensive and cohort separated data listings. Additionally, AE summaries 
will be provided for the following: 
• 
DLT 
• 
Serious AEs (SAEs) 
• 
All Grade 3 or 4 AEs 
• 
AEs leading to discontinuation from the study 
• 
AEs by severity using Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials grades 
• 
AEs with 10% or higher incidence rates 
For all AE summaries, events will be counted only once per subject by primary SOC and preferred term. 
When an AE occurs more than once for a subject, the maximum severity and causality will be used. 
Partial start and end dates for adverse events will be replaced by calendar dates that maximize the 
duration of the adverse event. The following steps will be followed. 
For a partial start date: 
1. Replace a missing month with January 
2. Replace a missing calendar day with the first of the month 
For a partial end date: 
1. Replace a missing month with December 
2. Replace a missing calendar day with the last day of the month 
An end date will not be estimated for adverse events marked continuing at the end of the study. 
10.3. Clinical Laboratory Test Results 
Subject minimum and maximum post-baseline laboratory values (and changes from baseline) for analytes 
measured on a continuous scale will be summarized by the mean, standard deviation, median, minimum 
and maximum values. The same statistics will be calculated to summarize laboratory test results by visit. 
Ordinal categorical test results with a corresponding Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials severity scale will be summarized 
using shift tables. 
Urinalysis tests such as specific gravity and pH were collected only to assess a subjects’ eligibility to 
participate in the study. No analyses are planned for urinalysis test results. 
10.4. Vital Signs 
Subject minimum and maximum post-baseline systolic and diastolic blood pressures, respiratory rate, 
pulse rate, temperature and body weight (and changes from baseline) will be summarized by the mean, 
standard deviation, median, minimum and maximum values. The same statistics will be calculated to 
summarize vital signs by visit. 
10.5. Electrocardiograms 
ECG QTc measurements will be summarized with descriptive statistics and time point with respect to BIO 
300 Oral Powder administration. All ECG data will be displayed in a data listing. 


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Statistical Analysis Plan 
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8 
11. Symbols and Abbreviations 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Curve 
BAM 
Binary Alignment Map 
BLQ 
Below the Limit of Quantitation 
BMI 
Body-Mass Index 
CBC 
Complete Blood Count 
Cmax 
Maximum (Peak) Serum Concentration 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
F 
Female 
FDA 
U.S. Food and Drug Administration 
ITT 
Intent to Treat 
Inf 
Infinity 
M 
Male 
Max 
Maximum 
Min 
Minimum 
mL 
Milliliter 
MSD 
Multiple Single Dose 
ng 
Nanogram 
PCA 
Principal component analysis 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
QTc 
Corrected QT Interval 
RNA 
Ribonucleic Acid 
SAD 
Single Ascending Dose 
SAE 
Serios Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Classification 
STD 
Standard Deviation 
t 
time 
T1/2 
Half-Life 
Tmax 
Time to Reach Maximum (Peak) Serum Concentration