Clinical trial NCT05677893
Conditions: Disease Caused by Severe Acute Respiratory Syndrome Coronavirus 2 (Disorder)
Sponsor: Oneness Biotech Co., Ltd.
Start date: 2022-11-07; Completion date: 2023-03-30
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of Inhaled MBS-COV in Healthy Participants

Detailed description:

Arms: arm 1: Eligible participants will be assigned to receive 0.3-1.2 mg/kg single or multiple doses of the investigational drug. arm 2: Eligible participants will be assigned to single or multiple doses of the placebo.
Interventions: intervention 1: MBS-COV intervention 2: Placebo
Intervention descriptions: intervention 1: MBS-COV is a potent siRNA treatment for mild to moderate COVID-19. intervention 2: Normal saline

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL 
 
  
 
Page 1 of 94 
 
 
 
A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of Single and Multiple 
Ascending Doses of Inhaled MBS-COV (SNS812) in Healthy Participants 
 
Protocol Number: 
SNS812CLCT01 
Version: 
 
V4.1 
Date: 
19-Jan-2023 
ClinicalTrials.gov ID: 
NCT05677893 
 
 
Sponsor: 
Oneness Biotech Co., Ltd.  
11F, No. 236, Sec. 4, Xinyi Rd., Da’an Dist., 
Taipei City 106, Taiwan 
TEL: 886-2-2655-8098 
 
Confidentiality Statement 
 
This document is a confidential communication of Oneness Biotech Co., Ltd. It is provided 
for the conduct of a clinical research study. The information contained in this document is 
confidential and, except to the extent necessary to obtain informed consent or IEC/IRB 
approval, cannot be disclosed unless required by governmental regulation. Persons to whom 
any portion of the contents of this document is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


 
 
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SPONSOR  SIGNATURE PAGE 
 
 
 
 
 
Protocol Title 
A Phase I, Randomized, Double-Blind, Placebo-Controlled 
Study 
to 
Evaluate 
the 
Safety, 
Tolerability, 
and 
Pharmacokinetics of Single and Multiple Ascending Doses of 
Inhaled MBS-COV(SNS812) in Healthy Participants 
Protocol Number 
SNS812CLCT01 
Protocol Date 
19-Jan-2023 
 
Protocol (v4.1) accepted and approved by:  
Oneness  
Director/ Department of Pharmaceutical Development 
 
Oneness Biotech Co., Ltd. (Oneness) 
11F, No. 236, Sec. 4, Xinyi Rd., Da’an Dist., 
Taipei City 106, Taiwan 
TEL: 886-2-2655-8098 
 
Signature 
 
 
 
 
 
Date 
 
 
 
 
 
                
 


 
 
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INVESTIGATOR  SIGNATURE PAGE 
 
 
 
Protocol Number:  
SNS812CLCT01 
 
Version: 
 
V4.1 
 
Date: 
 
19-Jan-2023 
 
I have read the protocol specified above and agree to participate in and comply with the 
procedures, as outlined herein for the conduct of this clinical study. I also agree to comply 
with US Food and Drug Administration (FDA) regulations and Investigational Review 
Board/Institutional Ethics (IRB/IEC) requirements for testing on human participants. I agree 
to ensure that the requirements for obtaining informed consent are met.  
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
 
Date 
Print Name 
 
 
 
 
 
 
Site Number 
 
 
 


 
 
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company:  
Oneness Biotech Co., Ltd. 
Name of Study Product: MBS-COV(SNS812) 
Comparator Product: Placebo (Normal Saline) 
Protocol Number:  
SNS812CLCT01 
Indication:  
Coronavirus Disease 2019 (COVID-19) 
Title of Study: A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of Inhaled MBS-COV 
(SNS812) in Healthy Participants 
Study Center: One center in the United States (US) 
Planned Number of Participants: 44 participants  
Study Development Phase: Phase I 
Indication for Use: MBS-COV is indicated for patients with mild to moderate COVID-19 
Study Objectives  
Primary Objective: 
 
To determine the safety and tolerability of MBS-COV after single and multiple doses in healthy 
participants. 
Secondary Objective: 
 
To evaluate the pharmacokinetics (PK) of MBS-COV after single dose administration (Part A) 
and multiple dose administrations in healthy participants (Part B). 
 
To evaluate the immunogenicity of MBS-COV. 
Study Outcome Measures  
Primary Outcome Measures: 
The primary outcome measures in this study are:  
o 
Evaluation of the safety and tolerability of MBS-COV after a single and multiple dose 
administrations in healthy participants. The safety and overall tolerability assessments will be 
evaluated based on:   
- 
Incidence and severity of Treatment-Emergent Adverse Events (TEAEs)  
- 
Incidence of withdrawals due to Adverse Events (AEs) 
- 
Incidence of Treatment-Related Adverse Events 
- 
Incidence of Serious Adverse Events (SAEs) 
- 
Change/shifts in laboratory values from baseline 
- 
Change in vital signs including blood pressure, pulse, respiratory rate, and temperature 
from baseline  
- 
Change in spirometry from baseline to assess the acute bronchospasm 


 
 
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Name of Sponsor/Company:  
Oneness Biotech Co., Ltd. 
Name of Study Product: MBS-COV(SNS812) 
Comparator Product: Placebo (Normal Saline) 
Protocol Number:  
SNS812CLCT01 
Indication:  
Coronavirus Disease 2019 (COVID-19) 
- 
Change in other safety examination parameters from baseline 
Secondary Outcome Measures: 
The secondary outcome measures in this study are: 
Pharmacokinetic Outcome Measures: 
 
Maximum observed plasma drug concentration (Cmax) 
 
Apparent terminal elimination half-life (t1/2) 
 
Time to maximum observed plasma drug concentration (Tmax) 
 
Area under the plasma drug concentration-time curve (AUC) from time 0 to the time of the last 
quantifiable concentration (Tlast) (AUC0-t) 
 
AUC from time 0 to infinity (AUC0-∞) 
 
Apparent plasma clearance (CL/F) 
 
Estimate of steady state Pharmacokinetic Parameters such as AUC0-τ, and Cmax,ss, Cmin,ss, 
Cavg,Tmax, t1/2, AUCtau, λz, CLss/F, Vss/F, DF, ARAUC/ARCmax (accumulation ratio) for 
multiple dose administration of MBS-COV 
Immunogenicity Outcome Measure: 
 
Occurrence of anti MBS-COV antibody (ADA) after administration of MBS-COV 


 
 
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Study Design:  
This is a Phase I, randomized, double-blind study designed to evaluate the safety, tolerability and 
pharmacokinetics (PK) of inhaled MBS-COV in healthy adult participants in the part A and part B of the 
study.  A total of 44 male and female healthy participants will be enrolled. All participants, after signing 
the Informed Consent Form (ICF), will be assessed during the screening phase. Only those participants 
who successfully complete the screening phase and meet the study eligibility criteria will be enrolled. 
MBS-COV will administered via inhalation through a portable mesh nebulizer.  
Part A (SAD phase) 
Part A is randomized, blinded study of a single ascending dose (SAD) phase to evaluate the safety, 
tolerability and PK of inhaled MBS-COV in healthy participants.  
All participants will have a screening visit within 28 days of check-in (Day -1) to determine eligibility. 
Eligible participants will be admitted to the study center on study Day -1 at which point their eligibility to 
participate in the study will be confirmed. Only those participants who successfully complete the screening 
phase and meet the study eligibility criteria will proceed to be randomized to receive a single dose of 
MBS-COV or placebo in the morning of Day 1 at the assigned dose. 
Participants will be assigned to one of up to three doses of MBS-COV (0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg) 
and treated sequentially with increasing doses. Each cohort will include eight (8) participants (6 active and 
2 placebo) per below table: 
Table 0-1: SAD Phase Cohorts 
Cohort 
Number of Participants 
MBS-COV Dose 
(mg/kg) 
Frequency of Dose 
SAD 
Phase 
A1 
6 (MBS-COV) +2 
(placebo) 
0.3  
Single Administration 
A2 
6 (MBS-COV) +2 
(placebo) 
0.6  
Single Administration 
A3 
6 (MBS-COV) +2 
(placebo) 
1.2  
Single Administration 
SAD phase will include a sentinel design in which 2 participants at the given cohort dose be initially 
enrolled. If the dose can be well tolerated for 48 hours after full administration per site Principle 
Investigator’s judgement, the remaining 6 participants will be enrolled to receive a single dose of MBS-
COV at the same dose. 
The decision for the escalation to the higher dose levels will be made by the study SRC after safety review 
of available information 7-day post treatment period. The data from SAD phase will be reviewed for safety 
trends to start MAD phase. 
Part B (MAD Phase)  
This is a randomized, double-blind, placebo-controlled study in approximately 20 healthy participants. 
Doses will be selected based on a comprehensive review of the SAD data and estimates of the clinically 
efficacious dose.  
The MAD Phase of the study consists of a screening period followed by multiple dose administrations of 
MBS-COV or placebo through a portable nebulizer once daily for 7 consecutive days (Day 1 to Day 7). 
Participants will be followed up for 21 days to assess post-treatment safety. 
The decision for the escalation to the higher dose levels will be made by the study SRC after safety review 


 
 
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of available information 7-day post treatment period. Each cohort will include ten participants (8 active 
and 2 placebo) per table below: 
Table 0-2: MAD Phase Cohorts 
Cohort 
Number of Participants 
MBS-COV Dose 
(mg/kg) 
Dose 
MAD 
Phase 
B1 
8 (MBS-COV) +2 
(placebo) 
0.6 
Once daily for 7 days 
B2 
8 (MBS-COV) +2 
(placebo) 
1.2 
Once daily for 7 days 
 
Study Visits:  
 
Screening Visit (SV: Up to 28 Days prior to Day 1): Consists of signing the ICF and study 
qualification based on evaluation of inclusion/exclusion criteria.  
 
Treatment Visit 0 (T0: Day -1): All participants continuing to meet eligibility criteria will be 
enrolled into the study and confined to research clinic until Day 2 for cohort A1 to A3 (SAD 
phase) and Day 9 for cohort B1 to B2 (MAD phase). 
 
Treatment Visit 1: Baseline Visit (T1: Day 1): The first assigned study treatment dose will be 
administered after completion of all study evaluations. Adverse events and changes in 
concomitant medications will be collected. Participants in Cohorts A1 to A3 will inhaled a single 
dose of MBS-COV or placebo through a portable nebulizer on Day 1. Participants in cohort B1 
and B2 will receive doses of MBS-COV or placebo by through a portable nebulizer once daily for 
7 consecutive days from Day 1 to Day 7.  
Part A (SAD Phase) 
o 
Treatment Visit 2 (T2: Day 2) 
o 
Treatment Visit 3 (T3: Day 3) 
o 
Treatment Visit 4 (T4: Day 4) 
o 
Treatment Visit 5 (End of Treatment) (T5: Day 7) 
 
Follow-Up Visit 1 (FU1: Day 14) 
 
Follow-Up Visit 2 (FU2: Day 28) 
Part B (MAD Phase) 
o 
Treatment Visit 2 (T2: Day 2) 
o 
Treatment Visit 3 (T3: Day 3) 
o 
Treatment Visit 4 (T4: Day 4) 
o 
Treatment Visit 5 (T5: Day 5) 
o 
Treatment Visit 6 (T6: Day 6) 
o 
Treatment Visit 7 (T7: Day 7) 
o 
Treatment Visit 8 (T8: Day 8) 
o 
Treatment Visit 9 (End of Treatment) (T9: Day 9) 
 
Follow-Up Visit 1 (FU1: Day 14) 


 
 
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 
Follow-Up Visit 2 (FU2: Day 28) 
If any of the dose escalation stopping criteria have occurred in Part A or Part B, the SRC will make a final 
recommendation for dose escalation to the next cohort. 
NOTE: The dose escalation decision through the study will not be made until the following: 
(1) All study participants in a given cohort have been enrolled, 
(2) All such participants have completed Treatment Visit 5 (Day 7) (for SAD-Part A) and Treatment 
Visit 9 (Day 9) (for MAD-Part B) of the study or withdrawn from the study, whichever occurs 
first. 
(3) The SRC will review the available safety data and recommend further dose escalation.  
Additionally, dose escalation stopping criteria are defined per the below: 
a. Death in any participant in which the cause of death is judged to be possibly, probably or 
definitely related to MBS-COV. 
b. The occurrence in any participant of a severe local application site reaction (Grade 3 
which doesn’t resolve or recurs; or Grade 4) that is judged to be possibly, probably or 
definitely related to MBS-COV. 
c. The occurrence in any participant of a SAE whose causal relationship to MBS-COV is 
judged to be probably, possibly, or definitely related to MBS-COV. 
d. The occurrence, in two or more participants of Grade 3 AE or laboratory abnormalities, 
judged to be probably, possibly, or definitely related to MBS-COV. 
e. The occurrence of two of the same AE or laboratory abnormality ≥ Grade 3 judged to be 
probably, possibly, or definitely related to MBS-COV. 
f. 
The occurrence, in one or more participants of Grade 4 AE or laboratory abnormalities, 
judged to be probably, possibly, or definitely related to MBS-COV. 
g. Any pattern of significant symptoms, physical findings, or laboratory abnormalities that, 
although individually minor, collectively represent a safety concern in the opinion of the 
investigator and are judged by the SRC to be at least possibly related to MBS-COV. 
h. PK exposure limits of mean AUC of 385.6 h*ng/mL or Cmax of 141.8 ng/mL for one 
cohort, whichever comes first.(Single dose: AUC of 386.9 h*ng/mL or Cmax of 91.7 
ng/mL) 
The SRC will review the PK data (if applicable) and safety trends of available information 7-day post 
treatment period of Cohort A1 and A2 (or if study stops prematurely due to safety reasons), to start part B 
of the study. The starting dose of Part B will be determined by SRC. 
 
 
 
 
 
 
 


 
 
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Figure 0-1: Dose Escalation Schematic  
 
 
Blood Sample Collection for the PK study: 
 
SAD cohorts A1 to A3: For the single dose on day 1, blood samples will be collected before 
dosing, and afterwards at 5 min (± 1 min), 15 min (± 2 min), 0.5 h (± 5 min), 1 h (± 5 min), 2 h (± 
5 min), 4 h (± 5 min), 8 h (± 10 min), 10 h (± 10 min), 24 h (± 10 min) and 48 h (± 10 min) (Total 
11 samples) after dosing. 
 
MAD cohort B1 and B2: Blood samples will be collected on Day 1 and Day 7 before dosing, and 
afterwards at 5 min (± 1 min), 15min (± 2 min), 0.5 h (± 5 min), 1 h (± 5 min), 2 h (± 5 min), 4 h 
(± 5 min), 8 h (± 10 min), 10 h (± 10 min) on Day 1; and at 5 min (± 1 min), 15min (± 2 min), 0.5 
h (± 5 min), 1 h (± 5 min), 2 h (± 5 min), 4 h (± 5 min), 8 h (± 10 min), 10 h (± 10 min) , 24 h (± 
10 min) and 48 h (± 10 min) after dosing on Day 7; and before dosing on Day 2 to Day 6 (Total 25 
samples). The detailed study schedule and assessments in each visit are provided in Section 4 of 
the protocol. 
Blood Sample Collection for the immunogenicity study: 
 
Blood Sample will be collected on Day 1 before dosing, Day 14 and Day 28 for SAD and MAD 
cohorts, and the analysis will be performed when analytic method is well-established. 
 
 
Study Duration:  
Part A 
SAD Phase: 
 
Screening Period (For SAD Phase Only): Up to 28 days 
 
Treatment Period: 7 days 
o 
In-unit: 3 day 
 
Follow-Up Period: Up to 21 days 
 
Total Study Duration: Up to 56 days 
Part B 
MAD Phase:  
 
Screening Period: Up to 28 days 


 
 
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 
Treatment Period: 9 days 
o 
In-unit: 9 days 
 
Follow-Up Period: Up to 19 days after EOT 
 
Total Study Duration: Up to 56 days 
Eligibility Criteria  
Inclusion Criteria:  
Participants will be eligible for enrollment in the study only if they meet ALL the following criteria at time 
of Screening: 
1. Male or female adults who are between 18 and 55 years old (inclusive). 
2. Body mass index (BMI) between 18.0 and 32.0 kg/m2 (inclusive). 
3. No serious or chronic underlying disease which would adversely affect the study conduct and data 
interpretation per the investigator. 
4. Female participants should have negative results in serum pregnancy test at screening and 
negative urine pregnancy test at admission (Day -1).  
5. Participants with normal spirometry (FEV1 %: 80 % or greater) results at screening or day -1.  
6. Both male and female participants and their partners of childbearing potential must agree to use 
two medically accepted methods of contraception (e.g., barrier contraceptives [male condom, 
female condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, 
injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], or one 
of the following methods of birth control (intrauterine devices, tubal sterilization or vasectomy) or 
must practice complete abstinence from intercourse of reproductive potential from study entry to 3 
months after the last day of treatment (excluding women who are not of childbearing potential and 
men who have been sterilized). 
7. Participants should have normal (or abnormal but not clinically significant) laboratory results per 
the PI’s judgement including the hematology, biochemistry, coagulation indices and urinalysis  
8. Participants should have a normal (or abnormal but not clinically significant) 12-lead ECG at 
screening and day -1 and chest X-ray at screening 
9. Participants should be willing to cooperate and able to participate in this study, comply with all 
protocol requirements, and sign an informed consent. 
10. Current non-smokers and those who have not smoked within the last 3 months. This includes the 
use of cigarettes, e-cigarettes, and nicotine replacement products. 
11. Nasopharyngeal or nasal swab sample of Participants collected for COVID-19 antigen rapid test at 
screening and qRT-PCR test on Day -1 should be negative. 
Eligibility Criteria  
Exclusion Criteria:  
Participants meeting ANY of the following criteria at time of Screening will be excluded from enrollment: 
1. The participant has a known history of, or a positive test result for, hepatitis B surface antigen 
(HBsAg), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) at screening. 
2. As reported by the participant has severe cardiovascular disease, neurological disease, 
hematological disease, infectious disease, mental disorder, liver disease, gastrointestinal disease, 
lung disease, endocrine disease, immune disease or kidney disease, or has a history of the above 
diseases, or other symptoms known to interfere with the absorption, distribution, metabolism, or 
excretion of the medicine, or other conditions that the investigator believes will increase the risk 


 
 
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of the participant and might interfere with the study conduct and results interpretation 
3. The participant has history or presence of active lung disease (i.e., asthma, chronic obstructive 
pulmonary disease [COPD], pulmonary fibrosis, hemoptysis, bronchiectasis) or prior intubation 
due to respiratory failure conditions. 
4. The participant has upper respiratory infection within the 3 months prior to the first dose of study 
drug. 
5. Consumed more than 14 units of alcohol per week in the 6 months before screening (1 unit of 
alcohol = 360 mL of beer or 45 mL of spirits with 40% alcohol content or 150 mL of wine) or 
have taken alcohol products in the 48 hours prior to administration, or those who have a positive 
alcohol breath test result at screening and day -1. 
6. Unwillingness to abstain from the consumption of any caffeine or alcohol-containing food or 
drinks that may influence the drug metabolism from 48 hours before administration. 
7. History of drug abuse or a positive drug abuse (barbiturates, methamphetamine, benzodiazepines, 
morphine/opiates, 
phencyclidine 
(PCP), 
amphetamines, 
tetrahydrocannabinol 
(THC), 
methylenedioxymethamphetamine (MDMA), cocaine, methadone, and cotinine) test result at 
screening and day -1. 
8. Female participants who are lactating. 
9. Use of prescription or non-prescription drugs, including vaccine within 14 days or 5 half-lives 
(whichever is longer) prior to the first dose of study drug.  
10. The subject has received an experimental agent (vaccine, drug, biologic, device, blood product or 
medication) within 1 month prior to the first dose of study drug and will receive another 
experimental agent during the duration of this study. 
11. The participant has a history of frequent nose bleeding. 
12. Participants with known allergic reactions to the study drug or its excipients. 
13. The participant has an acute sinusitis or history of chronic sinusitis, a history of active allergic 
rhinitis (AR), history of perennial allergic rhinitis (PAR), or current seasonal allergic rhinitis 
(SAR), or recent viral rhinitis within 2 weeks prior to administration. 
14. The participant has Any nasopharyngeal abnormality that may have interfered with nasal 
absorption, distribution, or study-related evaluations of signs or symptoms (e.g., polyps, septal 
deviation). 
15. Blood donation of more than 400 mL within 3 months before screening or more than 200 mL 
within 4 weeks before screening or plan to donate blood during study period. 
16. Any other clinical condition that, in the Investigator's judgment, would potentially compromise 
study compliance or the ability to evaluate safety/efficacy.  
Statistical Considerations:  
Sample Size Determination and Rationale 
The sample size of 44 participants (24 healthy participants in part A and 20 healthy participants in part B) 
will be used in this study. This sample size is selected based on clinical judgment and not based on 
statistical power calculation; it is deemed adequate to provide clinically meaningful descriptive results 
consistent with study objectives. 
Randomization and Blinding: 


 
 
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All eligible participants will proceed to be randomized and will be assigned the IP kit. A detailed 
Randomization plan the block size and all the relevant considerations will be detailed in the randomization 
plan. The participants will be randomized using a web-based randomization system at Treatment Visit 1 
(Baseline) and site personnel will be trained on this system. Only those participants who successfully 
complete the screening phase and meet the study eligibility criteria will proceed to randomization. 
Statistical Analysis Populations  
Full Analysis Set (FAS): FAS includes all randomized participants. This analysis set will be used to 
analyze the disposition, demographic and baseline characteristics of the subjects. 
Safety Set (SS): SS includes all the participants who receive the study drug at least once. This population 
will be used for the analysis of safety parameters.  
PK concentration analysis set (PKCS): PKCS includes all randomized participants who receive at least 
one dose of the study drug and have at least plasma concentration. The PKCS will be used for PK 
concentration analysis. 
PK parameters analysis set (PKPS): PKPS includes all randomized participants who receive at least one 
dose of the study drug with no major protocol violations or protocol deviations that have a significant 
impact on PK parameters (Cmax, AUC, etc.), and have at least one analyzable PK parameter. The PKPS 
will be used for PK parameters analysis. 
Immunogenicity Set (IS): The IS includes all randomized participants who receive at least one dose of the 
study drug, and have at least one ADA concentration. The IS will be used for immunogenicity analysis. 
Statistical Analysis  
All collected study data will be presented in participant data listings. All report outputs will be produced 
using SAS® version 9.4 or a later version in a secure and validated environment. 
All data collected will be summarized and analyzed according to the variable type:  
o 
Continuous data summaries will include:  
 
Number of observations, mean, standard deviation, median, and minimum and maximum 
values.   
o 
Categorical data summaries will include: 
 
Frequency counts and percentages.  
No inferential statistics are planned. 
The pharmacokinetic analyses will be performed using Phoenix® WinNonlin 8.3.1 or above. 
A Statistical Analysis Plan (SAP) will be developed and approved before the database is locked. The SAP 
will present the detailed statistical methodology to be used in analyzing the pharmacokinetic and safety 
data from this study. 


 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..............................................................................................................4 
TABLE OF CONTENTS ............................................................................................................13 
List of Tables .................................................................................................................................18 
List of Figures ...............................................................................................................................19 
List of Abbreviations .....................................................................................................................20 
1 INTRODUCTION AND BACKGROUND .........................................................................22 
1.1. Statement of Intent ..............................................................................................................22 
1.2. Background of the Disease ..................................................................................................22 
1.3. Name and Description of the Investigational Product .........................................................23 
1.4. Summary of Prior Non-Clinical and Clinical Studies .........................................................24 
1.4.1. 
Non-Clinical Studies .........................................................................................24 
1.4.2. 
Clinical Studies..................................................................................................29 
1.5. Risks / Benefits Assessment ................................................................................................29 
1.5.1. 
Systemic Anaphylaxis .......................................................................................29 
1.5.2. 
Pregnancy ..........................................................................................................29 
1.5.3. 
Venipuncture for Blood Sampling ....................................................................29 
1.5.4. 
Unknown Risks .................................................................................................29 
1.6. Rationale for Study Dose ....................................................................................................29 
2. STUDY OBJECTIVES AND ENDPOINTS/OUTCOME MEASURES ..........................31 
2.1. Study Objectives ..................................................................................................................31 
2.1.1. 
Primary Objective..............................................................................................31 
2.1.2. 
Secondary Objective..........................................................................................31 
2.2. Study Outcome Measures ....................................................................................................31 
2.2.1. 
Primary Outcome Measures ..............................................................................31 
2.2.2. 
Secondary Outcome Measures ..........................................................................31 
3. STUDY DESIGN ....................................................................................................................33 
3.1. General Schema ...................................................................................................................33 
3.2. Study Center ........................................................................................................................37 
3.3. Study Population .................................................................................................................37 
3.4. Eligibility Criteria ................................................................................................................37 


 
 
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3.4.1. 
Inclusion Criteria ...............................................................................................37 
3.4.2. 
Exclusion Criteria ..............................................................................................38 
4. STUDY SCHEDULE .............................................................................................................40 
4.1. Overview .............................................................................................................................40 
4.2. Part A ...................................................................................................................................47 
4.2.1. 
Part A (SAD) - Screening Visit (SV: Up to 28 Days prior to Day 1): ..............47 
4.2.2. 
Part A (SAD) - Treatment Visit 0 (T0: Day -1) ................................................47 
4.2.3. 
Part A (SAD) - Treatment Visit 1: Baseline Visit (T1: Day 1) .........................48 
4.2.4. 
Part A (SAD) – Treatment Visit 2 to Treatment Visit 5/End of Treatment 
(T2: Day 2 to T5: Day 7) ...................................................................................49 
4.2.5. 
Part A (SAD) – Follow-Up Visit 1 (FU1: Day 14) ...........................................49 
4.2.6. 
Part A (SAD) – Follow-Up Visit 2 (FU2: Day 28) ...........................................50 
4.3. PART B  Study Visits .........................................................................................................50 
4.3.1. 
Part B (MAD) - Screening Visit (SV: Up to 28 Days prior to Day 1) ..............50 
4.3.2. 
Part B (MAD) - Treatment Visit 0 (T0: Day -1) ...............................................51 
4.3.3. 
Part B (MAD) - Treatment Visit 1: Baseline Visit (T1: Day 1): .......................51 
4.3.4. 
Part B (MAD) – Treatment Visit 2 to Treatment Visit 7 (T2: Day 2 to T7: 
Day 7) ................................................................................................................52 
4.3.5. 
Part B (MAD) - Treatment Visit 8 (T8: Day 8) ................................................53 
4.3.6. 
Part B (MAD) - Treatment Visit 9 (End of Treatment) (T9: Day 9).................53 
4.3.7. 
Part B (MAD) - Follow-Up Visit 1 (FU1: Day 14) ...........................................54 
4.3.8. 
Part B (MAD) - Follow-Up Visit 2 (FU2: Day 28) ...........................................54 
4.5. Missed Visits .......................................................................................................................55 
5. PARTICIPANT 
COMPLETION, 
WITHDRAWAL 
AND 
CRITERIA 
FOR 
STOPPING THE STUDY .....................................................................................................56 
5.1. Participant Completion ........................................................................................................56 
5.1.1. 
Definition of Study Treatment Completion.......................................................56 
5.2. Participant Withdrawal ........................................................................................................56 
5.2.1. 
Participant Discontinuation ...............................................................................56 
6. STUDY TREATMENT .........................................................................................................58 
6.1. MBS-COV ...........................................................................................................................58 


 
 
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6.1.1. 
Packaging and Labeling ....................................................................................58 
6.1.2. 
Storage and Handling ........................................................................................59 
6.1.3. 
Study Treatment Administration .......................................................................60 
6.1.4. 
Study Treatment Dispensation ..........................................................................60 
6.1.5. 
Study Treatment Accountability .......................................................................60 
6.2. Concomitant Medications ....................................................................................................61 
7. DESCRIPTION OF PROTOCOL ASSESSMENTS AND PROCEDURES ...................62 
7.1. Informed Consent ................................................................................................................62 
7.2. Assessment of Eligibility .....................................................................................................62 
7.2.1. 
Re-screening ......................................................................................................62 
7.3. Demographic Information ...................................................................................................63 
7.4. Medical History ...................................................................................................................63 
7.5. Physical Examination ..........................................................................................................63 
7.6. Vital Signs, Height and Weight ...........................................................................................64 
7.7. Concomitant Medication .....................................................................................................64 
7.8. Clinical Laboratory Assessments ........................................................................................65 
7.9. 12-Lead Electrocardiogram .................................................................................................66 
7.10. Nasopharyngeal Swab or nasal swab for Covid-19 .............................................................67 
7.11. Spirometry Assessment .......................................................................................................67 
7.12. Randomization .....................................................................................................................67 
8. STATISTICAL CONSIDERATIONS .................................................................................68 
8.1. Cohorts/Treatment Groups ..................................................................................................68 
8.2. Study Endpoints/ Outcome Measures .................................................................................68 
8.3. Sample Size Determination and Rationale ..........................................................................68 
8.4. Randomization .....................................................................................................................68 
8.5. Blinding and Prevention of Bias .........................................................................................69 
8.6. Interim Analysis ..................................................................................................................69 
8.7. General Statistical Considerations .......................................................................................69 


 
 
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8.7.1. 
Statistical Analysis Populations ........................................................................69 
8.7.2. 
Missing Data......................................................................................................69 
8.7.3. 
Statistical Methods ............................................................................................70 
8.7.4. 
Participant Disposition ......................................................................................70 
8.7.5. 
Demographics And Baseline Characteristics Analysis .....................................70 
8.7.6. 
Concomitant Medications/Therapies .................................................................70 
8.7.7. 
Pharmacokinetic (PK) Analysis ........................................................................70 
8.7.8. 
Safety Analyses .................................................................................................70 
9. SAFETY REPORTING.........................................................................................................72 
9.1. Adverse event (AE) Definition ............................................................................................72 
9.2. Reporting of Adverse Events (AEs) ....................................................................................72 
9.2.1. 
Impact on Study Treatment ...............................................................................72 
9.2.2. 
Toxicity Grading Scale (Intensity) Assessment ................................................72 
9.2.3. 
Event Causality Assessment ..............................................................................73 
9.2.4. 
Treatment Given as a Result of the Event .........................................................74 
9.2.5. 
Event Outcome Assessment ..............................................................................74 
9.3. Serious Adverse Event (SAE) Definition ............................................................................74 
9.4. Reporting of Serious Adverse Events (SAEs) .....................................................................74 
9.4.1. 
SAE Follow-Up .................................................................................................75 
9.5. Pregnancy Reporting ...........................................................................................................75 
9.5.1. 
AE and SAE Reporting .....................................................................................75 
9.5.2. 
Informed Consent ..............................................................................................75 
9.5.3. 
Pregnancy Follow-Up........................................................................................76 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ......................................77 
11. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................78 
11.1. Monitoring Requirements ....................................................................................................78 
11.2. Acceptability of Case Report Forms (CRFs) ......................................................................78 
11.3. Modification of Protocol .....................................................................................................78 
11.4. Reporting Protocol Deviations ............................................................................................79 
11.4.1. 
Major Protocol Deviation or Violation .............................................................79 
11.4.2. 
Minor Protocol Deviation or Violation .............................................................79 
12. ETHICS AND REGULATORY REQUIREMENTS .........................................................81 
12.1. Institutional Review Board/Independent Ethics Committee (IRB/IEC) .............................81 
12.2. Investigator’s Responsibilities ............................................................................................81 


 
 
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12.3. Participant Informed Consent Requirements ......................................................................82 
13. DATA HANDLING AND RECORD KEEPING ................................................................83 
13.1. Recording and Collection of Data .......................................................................................83 
13.2. Clinical Data Management ..................................................................................................83 
13.3. Archiving .............................................................................................................................84 
14. PUBLICATION PLAN .........................................................................................................86 
15. REFERENCES .......................................................................................................................87 
16. APPENDIX .............................................................................................................................88 
16.1. Appendix 1: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials .............................................................................88 


 
 
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LIST OF TABLES 
Table 0-1: SAD Phase Cohorts ........................................................................................................6 
Table 1-1:  Overview of Pre-Clinical Studies ................................................................................24 
Table 3-1: SAD Phase Cohorts ......................................................................................................33 
Table 3-2: MAD Phase Cohorts ....................................................................................................34 
Table 4-1: Schedule of Assessments – Part A (SAD Phase) ........................................................41 
Table 4-2: Schedule of Assessments – Part B (MAD Phase) .......................................................44 
Table 7-1: Lab Parameters ............................................................................................................66 


 
 
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LIST OF FIGURES 
Figure 0-1: Dose Escalation Schematic ...........................................................................................9 
Figure 1-1: Genetic Map and Locations of MBS-COV .................................................................23 
Figure 1-2: Sequence and Modification of MBS-COV(C6G25S) .................................................24 
Figure 3-1: Dose Escalation Scheme .............................................................................................36 
Figure 6-1: Example Part A and Part B Study Treatment Vial Label ............................................59 
Figure 6-2: Box label for Clinical Study Treatment ......................................................................59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AI 
Aerosol Inhalation 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FDA 
U.S. Food and Drug Administration 
FUV 
Follow-up Visit 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HEENT 
Head, Ears, Eyes, Nose, and Throat 
HIPAA 
Health Insurance Portability Accountability Act 
IA 
Interim Analysis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IN 
Intranasal Instillation  
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IS 
Immunogenicity Set 
LAR 
Legally Authorized Representative 
LDH 
Lactate Dehydrogenase 


 
 
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Abbreviation 
Term 
LTF 
Lost to Follow-up 
PI 
Principal Investigator 
PKCS 
PK concentration analysis set 
PKPS 
PK parameters analysis set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
SS 
Safety Set 
SV 
Screening Visit 
TEAE 
Treatment Emergent Adverse Event 
TV 
Treatment Visit 
WFI 
Water For Injection 


 
 
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1 INTRODUCTION AND BACKGROUND 
1.1. STATEMENT OF INTENT 
The design, conduct, and reporting of this study shall be conducted in compliance with the 
protocol, International Council for Harmonisation/Good Clinical Practice (ICH/GCP), and all 
appropriate regulatory requirements. Investigator(s) participating in this study will have 
documented training in GCP. Independent monitoring of the study will be accomplished utilizing 
a Contract Research Organization (CRO). 
1.2. BACKGROUND OF THE DISEASE 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 500 million 
people and caused more than 6.2 million deaths worldwide as of April 26, 2022, according to the 
John Hopkins coronavirus resource center. Despite the availability of vaccines, breakthrough 
infections caused by the variant appear to be driving a new wave of pandemic (Dyer 2021, 
Kupferschmidt 2021). The SARS-CoV-2 vaccines initially achieved great success in reducing 
viral infection and severe illness. The effectiveness of ChAdOx1 nCoV-19, BNT162b2 and 
mRNA-1273 vaccine reached 70.4%, 95% and 94.1%, respectively (Baden 2021, Knoll 2021, 
Wang 2021). Nevertheless, the emergence of new variants has raised great concerns, since 
reduced sensitivity of SARS-CoV-2 variants to therapeutic neutralizing antibodies, serum from 
convalescent patients and vaccinated individuals have been reported (Planas 2021). A report 
from the UK indicates that the effectiveness of two doses of ChAdOx1 nCoV-19 vaccine against 
delta infection reduces to 67% while BNT162b2 reduces to 88% (Lopez 2021). Another report 
from Qatar showed that two doses of BNT162b2 only present 51.9% of effectiveness while 
mRNA-1273 presents 73.1% (Tang 2021). These reports implicate those viral mutations has 
influenced vaccine effectiveness.  
Recently, a novel variant called Omicron, is spreading rapidly across the globe. The unusual, 
clustered mutations and extensive transmission of this variant led the World Health Organization 
to designate it as a variant of concern on November 26, 2021. In total, 32 mutations were 
identified in Omicron’s spike protein and 15 in the receptor-binding domain, which are 
responsible for interacting with the angiotensin-converting enzyme 2 receptor. The highly 
mutated features of Omicron have allowed it to escape most of the existing SARS-CoV-2 
neutralizing antibodies (Cao 2021). A more than 22-fold reduction of neutralizing titers against 
the Omicron strain as compared to the wild-type strain was observed in individuals receiving 2-
dose of mRNA vaccine, and a third dose of mRNA vaccine was suggested (Muik 2022). 
Moreover, an artificial intelligence model trained with tens of thousands of experimental data 
and extensively validated based on experimental results for SARS-CoV-2 indicated that Omicron 
may be over 10 times more contagious than the original virus and about 2.8 times more 
infectious than the Delta variant (Chen 2022). The emergence of Omicron variant indicates how 
fast the SARS-CoV-2 evolves, and its potential impact on the current protein-based intervention 


 
 
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(i.e., vaccines, antibodies, or convalescent plasma) that primarily target the highly-mutated spike 
protein (Van 2020) cannot be neglected.  
One therapeutic with great potential is short-interfering (si)RNA, which is an artificially 
synthesized double-stranded RNA of 19–23 nucleotides (Zamore 2000). Upon entering the 
cytosol, siRNA interacts with several proteins to form an RNA-induced silencing complex 
(RISC) and subsequently knocks down the expression of target genes based on sequence 
complementarity. 
1.3. NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT 
Oneness Biotech Co., Ltd is developing MBS-COV for the treatment of mild to moderage 
COVID-19. MBS-COV is a potent siRNA targeting a highly conserved region of RdRP gene of 
SARS-CoV-2. It consists of double-stranded RNA with each of 21 nucleotides in length and is 
fully-modified with 2’-O-methyl, 2′-fluoro or phosphonothioate (PS) substitution (Figure 1-1) 
shows the sequence and target site of MBS-COV. MBS-COV is a double-stranded, small 
interfering RNA (siRNA) targeting a highly conserved RNA-dependent RNA polymerase region 
of SARS-CoV-2 RNA to induce the degradation effect against the virus RNA. 
Figure 1-1: 
Genetic Map and Locations of MBS-COV 
 


 
 
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MBS-COV (also named MBS-COV C6G25S) drug substance is the sodium salt of a chemically 
synthesized double-stranded oligonucleotide, with a 19-base (19-mer) sense strand and a 21 base 
(21-mer) antisense strand. The sequence and modification of MBS-COV is shown in Figure 1-2. 
Figure 1-2: 
Sequence and Modification of MBS-COV(C6G25S) 
 
1.4. SUMMARY OF PRIOR NON-CLINICAL AND CLINICAL STUDIES 
1.4.1. Non-Clinical Studies 
There have been multiple non-clinical studies conducted with MBS-COV to evaluate its 
toxicological and pharmacokinetic profile. Table 1-1 provides a summary of pre-clinical studies. 
Table 1-1:  
Overview of Pre-Clinical Studies 
Study 
Summary 
Primary Pharmacology 
 MBS-COV inhibit viral RNA amplification with 
pico-molar IC50 (IC50 = 0.17 nM) 
 MBS-COV inhibit different variants and human 
coronavirus 229E with pico-molar IC50 (IC50 = 0.09 
~ 0.73 nM). 
 The concentration (detected via OD260) and 
integrity (assayed via HPLC) of MBS-COV were 
the same before and after nebulization 
 The 
effectiveness 
of 
the 
MBS-COV 
after 
nebulization 
was 
the 
same 
as 
that 
before 
nebulization, evaluated by the inhibition of viral 
envelope gene expression in Vero E6 cells. 
 The nebulization rate was maintained unaffected 
when the concentration of C6G25S was ≦30 mg/mL 
and reduced significantly at higher concentrations. 
 The C6G25S concentration in the inhalation 
chamber reached a maximum within 2 min and was 
maintained at 1.48 mg/L. 
 The particle size of the siRNA aerosol generated by 
the nebulizer had a mass median aerodynamic 
diameter (MMAD) of 4.845 m, a geometric 


 
 
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Study 
Summary 
standard deviation (GSD) of 2.402 m with a fine 
particle fraction (FPF; <5 m) of 50.22%. 
 MBS-COV was distributed throughout the lung in 
the AI group, whereas uneven distribution in the IN 
group. There are twice as many MBS-COV+ cells in 
the 
AI 
group 
compared 
with 
MBS-COV 
significantly suppresses the production of viral RNA 
and infectious virions in both prophylactic treatment 
and co-treatment of both SARS-CoV-2-and Delta- 
infected K18-hACE2 mice. 
 MBS-COV inhibits spike protein expression and 
prevents 
SARS-CoV-2-induced 
pathological 
features in lungs of K18-hACE2 transgenic mice.  
 MBS-COV reduces the expression of inflammatory 
cytokines induced by SARS-CoV-2 in lungs of K18-
hACE2 transgenic mice. 
Secondary Pharmacology 
 Modification of MBS-COV significantly reduced 
off-targets. None of the off-target genes are essential 
for cell viability. 
Safety Pharmacology 
 No cytotoxicity was observed in the treatment up to 
40M of MBS-COV. 
 No 
inflammation-associated 
cytokines 
were 
significantly induced in MBS-COV treated-human 
PBMCs. 
 MBS-COV does not activate non-specific immune 
response against SASR-CoV-2 in mice treated with 
efficacy dose of MBS-COV.  MBS-COV inhibits 
viral RNA amplification and infectious virion 
production, while control siRNA does not. The virus 
inhibition of MBS-COV is not evoked through 
nonspecific immune responses. 
 No significant immune stimulation was observed in 
mice treated with high dose (up to 75 mg/kg) of 
MBS-COV. 
 No MBS-COV-related changes in cardiovascular 
functions, respiratory functions, blood pressure, 
body temperature and clinical observation after 
administration up to the highest dose of 16+30 


 
 
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Study 
Summary 
mg/kg (AI+SC). 
 
Pharmacokinetics 
 
Lung distribution and pharmacokinetics of MBS-COV 
in lungs of golden hamsters 
 In a single inhalation of MBS-COV at delivered 
doses of 15.7 and 52.7 mg/kg, MBS-COV level in 
lungs of golden hamsters peaked at 0.5-1 hr 
postdose. 
 The elimination T1/2 ranged 60.95 -74.16 hours in 
low dose group and 152.20 - 182.59 hours in high 
dose group. 
 The Cmax were within 28.98 -30.79 μg/g lung in low 
dose group and 64.30 - 108.77 μg/g lung in high 
dose group. 
 No significant gender difference was found. 
 The maximum concentrations in lung tissue and the 
systemic exposures to MBS-COV were positively 
correlated with the administrated doses. 
Toxicokinetics of MBS-COV in the blood of golden 
hamsters 
 In the 7-day repeat-dose toxicokinetic study, the 
actual delivered doses were 30 and 90.4 mg/kg for 
medium and high dose group. The elimination T1/2 
values ranged from 1.97 to 17.42 hours for sense 
and antisense strand of MBS-COV in medium and 
high dose group on Day 1. On Day 7, T1/2 values 
ranged from 1.88 to 6.06 hours. Mean Cmax and 
AUClast values increased with the increasing 
administered doses. MBS-COV did not accumulate 
in golden hamsters, and there was no significant 
gender difference. 
 In the 14-day repeat-dose toxicokinetic study, the 
actual delivered doses were 57 and 87.9 mg/kg for 
medium and high dose group. The elimination T1/2 


 
 
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Study 
Summary 
values ranged from 1.18 to 36.67 hours on day 1 for 
sense and antisense strand of MBS-COV in medium 
and high dose group. On day 14, T1/2 values ranged 
from 3.47 to 9.02 hours. Mean Cmax and AUClast 
values increased with increasing administered doses 
in both females and males. There was no significant 
gender difference. No accumulation was observed in 
male animals; in female animals, a tendency of 
accumulation was observed in the medium group. 
No accumulation was observed in the high dose 
group. 
Toxicology 
Single Dose 
 MBS-COV was well-tolerated in SD rat at intranasal 
instillation of 20, 40, and 75 mg/kg and the NOAEL 
was considered to be 75 mg/kg. 
Repeat Dose 
 MBS-COV was well-tolerated in CD-1 (ICR) mice 
at intranasal instillation of 2, 10, and 50 mg/kg and 
the NOAEL was considered to be 50 mg/kg. 
 MBS-COV was well-tolerated in Golden hamster at 
inhalation of 10, 30, and 90 mg/kg and the NOAEL 
was considered to be 90 mg/kg. 
 MBS-COV was well-tolerated in Golden hamster at 
inhalation of 18, 57, and 87.9 mg/kg. Minimal to 
slight alveolar macrophage aggregation in the lung 
with bronchi was observed in medium- and high-
dose group, and could be completely recovered after 
a 1-week recovery period. no obvious systemic 
toxicity and toxic target organs were found at doses 
of ≤ 87.925±21.984 mg/kg. The NOAEL was 
considered to be 87.9 mg/kg.   
Genotoxicity 
 The bone marrow micronucleus analysis showed 
that the incidence of micronucleus in the positive 
control group increased significantly compared with 
the vehicle control group, while the incidence of 


 
 
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Study 
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micronucleus in all MBS-COV treatment groups did 
not. No genotoxicity was observed for MBS-COV 
to 
damage 
chromosome 
in 
bone 
marrow 
erythrocytes 
when 
CD-1 
(ICR) 
mice 
were 
administered with MBS-COV at doses up to 2000 
mg/kg by intravenous injection for 2 consecutive 
days. 
 The potential of MBS-COV to cause chromosome 
aberration was evaluated by using Chinese Hamster 
Lung (CHL) Fibroblast continuously exposed (for 
either 4 or 24 hours) to different concentrations of 
MBS-COV with or without S9 metabolic activation. 
The chromosomal aberration rates in CHL cells 
treated with MBS-COV at all tested concentrations 
for 4 hours with or without S9 and 24 hours without 
S9 showed no significant difference (P>0.05) when 
compared with the vehicle control group. The results 
indicate that MBS-COV at doses ≤500 µg/mL, 
regardless of the presence or absence of the 
metabolic activation enzyme system, has no 
genotoxic 
potential 
to 
induce 
chromosome 
aberration. 
 The mutagenicity study was conducted at dose 
levels of 50, 150, 500, 1500 and 5000 µg/plate of 
MBS-COV in both the absence and presence of S9 
activation incubated with Salmonella typhimurium 
tester strains for 65.5 hours. Compared with the 
spontaneous control group, the revertant colony 
counts of TA97a, TA98, TA100, TA102 and 
TA1535 strains in all the dose groups when treated 
with or without S9 were within the negative 
historical 
background 
range. 
MBS-COV 
at 
concentrations ≤5000 µg/plate is not mutagenic in 
the presence or absence of metabolic activation. 
Systemic Anaphylaxis Study 
 MBS-COV did not exert any systemic anaphylaxis 
response in Guinea Pigs, and therefore is not 
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1.4.2. Clinical Studies 
The current proposed study is a first-in-human study to evaluate the safety, tolerability, and PK 
of inhaled MBS-COV. 
1.5. RISKS / BENEFITS ASSESSMENT 
1.5.1. Systemic Anaphylaxis 
The potential of MBS-COV to provoke respiratory sensitization reactions was evaluated in 
Hartley guinea pigs (n = 9 per groups). Three sensitization inductions with either MBS-COV 
(actual delivered doses of 3.8 and 15.1 mg/kg) or vehicle control (saline) were performed by 
inhalation every other days (Day 1, 3 and 5), followed by a challenge of MBS-COV (actual 
delivered doses of 8.1 and 32.6 mg/kg) by inhalation at two or three weeks after the last 
induction (Day 19 or 26). After challenged, the animals were observed for multiple symptoms 
for 3 hours. In conclusion, MBS-COV did not exert any systemic anaphylaxis response in 
Hartley guinea pigs, and therefore is not considered as a sensitizer. 
1.5.2. Pregnancy 
To date, no carcinogenicity and reproductive studies have been conducted with MBS-COV. 
Risks to unborn babies are unknown at this time, thus pregnant females will be excluded from 
this study. Females of childbearing potential must have a negative pregnancy test prior to 
enrollment and must agree to use appropriate birth control methods throughout the study 
duration (excluding women who are not of childbearing potential). 
1.5.3. Venipuncture for Blood Sampling 
Venipuncture for blood sample collection carries a minimal risk of minor discomfort and the 
possibility of minor bruising at the site of the needle puncture and, rarely, the possibility of 
infection at the needle puncture site. 
1.5.4. Unknown Risks 
As with all research there is the remote possibility of risks that are unknown or that cannot be 
foreseen based on current information. 
1.6. RATIONALE FOR STUDY DOSE  
Golden hamster was well-tolerated at inhalation doses of 10, 30, and 90 mg/kg of MBS-COV 
once daily for 7 days in the dose ranging finding (DRF) study and 18, 57, and 87.9 mg/kg for 14 
days in the GLP compliance study. There were no MBS-COV-related clinical observations or 
toxicology effects on body weights, food intake, hematology, serum biochemistry, urinalysis and 
histopathology. No obvious systemic toxicity and toxic target organs were found at doses of ≤ 
87.9 mg/kg. The NOAEL was considered to be 87.9 mg/kg. 


 
 
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For inhaled drug, clinical doses will need to be supported by both local and systemic safety 
margins. The pulmonary deposition factor (10% for hamster) was considered in the calculations 
for systemic safety. Based on the calculation (based on 1.2 mg/kg as human dose) shown as 
below, for the first in human starting dose (0.3 mg/kg) and maximum dose (1.2 mg/kg), the 
safety margin of systemic toxicity is 3.809 and 0.952, respectively. And the safety margin of 
local toxicity is 83.89 and 20.97, respectively. As no evidence of unmonitorable systemic 
toxicity in preclinical studies, proposed clinical doses up to 1.2 mg/kg would have adequate 
nonclinical support.  
Determining PDDs in rats and humans： 
Assuming the NOAEL for local is the same with the NOAEL for systemic effects in the 
hamster study, 87.9 mg/kg/d.  
PDD hamster local = 87.9 mg/kg/d *0.1(DF)=8.79 mg/kg/d 
PDD hamster system= 87.9 mg/kg/d *0.1(DF)=8.79 mg/kg/d 
PDD human=1.2 mg/kg subject/d* 1 (DF)= 1.2 mg/kg/d  
 Determining lung doses in rats and humans 
PDD hamster, lung=8.79 mg/kg/d* 0.12 BWT/0.7g (lung hamster) =1.51 mg/g lung 
PDD human, lung=72 mg/d /1000 g lung hamster=0.072 mg/g lung 
 Calculating SM for systemic effects:  
SM system=8.79 mg/kg/d (hamster)*0.13（HED）/ 1.2 mg/kg/d (human) =0.952 
 Calculating SM for local effects  
On a mg/g lung/day basis: SM local=1.51mg/g /0.072 mg/g =20.97 
Since the safety profile of MBS-COV in humans is unknown and this is the first clinical study to 
assess MBS-COV in humans, phase I clinical study for MBS-COV will be divided into two parts. 
Part A is a randomized, double-blind, and placebo-controlled study with single ascending dose 
(SAD) design of inhaled MBS-COV in healthy participants for determining safety, tolerability, 
and pharmacokinetics of MBS-COV. Part B will be performed after review of sufficient result of 
Part A. Part B is a randomized, double-blind and placebo-controlled study with multiple 
ascending doses (MAD) of inhaled MBS-COV in healthy participants to evaluate safety, 
tolerability, and pharmacokinetics.  
 


 
 
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2. 
STUDY OBJECTIVES AND ENDPOINTS/OUTCOME MEASURES 
2.1. STUDY OBJECTIVES 
2.1.1. Primary Objective 
The primary objective of this study is: 
 
To determine the safety and tolerability of MBS-COV after single and multiple doses in 
healthy participants.  
2.1.2. Secondary Objective 
The secondary objectives of this study are:  
 
To evaluate the pharmacokinetics (PK) of MBS-COV after single dose administration in 
healthy participants (Part A) and multiple dose administrations in healthy participants 
(Part B).  
 
To evaluate the immunogenicity of MBS-COV. 
2.2. STUDY OUTCOME MEASURES 
2.2.1. Primary Outcome Measures 
The primary outcome measures in this study are: 
 
Evaluation of the safety and tolerability of MBS-COV after a single and multiple dose 
administrations in healthy participants. The following parameters will be used to assess 
safety: 
- Incidence and severity of Treatment-Emergent Adverse Events (TEAEs)  
- Incidence of withdrawals due to Adverse Events (AEs) 
- Incidence of Treatment-Related Adverse Events 
- Incidence of Serious Adverse Events (SAEs) 
- Change/shifts in laboratory values from baseline 
- Change in vital signs including blood pressure, pulse, respiratory rate, and 
temperature from baseline  
- Change in spirometry from baseline to assess the acute bronchospasm 
- Change in other safety examination parameters from baseline 
2.2.2. Secondary Outcome Measures 
The secondary outcome measures in this study are: 
Pharmacokinetic Outcome Measures: 
 
Maximum observed plasma drug concentration (Cmax) 


 
 
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 
Apparent terminal elimination half-life (t1/2) 
 
Time to maximum observed plasma drug concentration (Tmax) 
 
Area under the plasma drug concentration-time curve (AUC) from time 0 to the time of 
the last quantifiable concentration (Tlast) (AUC0-t) 
 
AUC from time 0 to infinity (AUC0-∞) 
 
Apparent plasma clearance (CL/F) 
 
Estimate of steady state Pharmacokinetic Parameters such as AUC0-τ, and Cmax,ss, Cmin,ss, 
Cavg, Tmax, t1/2, AUCtau, λz, CLss/F, Vss/F, DF, ARAUC/ARCmax (accumulation ratio) 
for multiple dose administration of MBS-COV 
immunogenicity Outcome Measure: 
 
Occurrence of anti MBS-COV antibody after administration of MBS-COV 


 
 
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3. 
STUDY DESIGN  
3.1. GENERAL SCHEMA 
This is a Phase I, randomized, double-blind study designed to evaluate the safety, tolerability, 
and PK of inhaled MBS-COV in healthy adult participants in the part A and part B of the study.  
A total of 44 male and female healthy participants will be enrolled. All participants, after signing 
the Informed Consent Form (ICF), will be assessed during the screening phase. Only those 
participants who successfully complete the screening phase and meet the study eligibility criteria 
will be enrolled. MBS-COV will administered via inhalation through a portable nebulizer.  
Part A (SAD phase) 
Part A is randomized, blinded study of a single ascending dose (SAD) phase to evaluate the 
safety, tolerability and PK of inhaled MBS-COV in healthy participants.  
All participants will have a screening visit within 28 days of check-in (Day -1) to determine 
eligibility. Eligible participants will be admitted to the study center on study Day -1 at which 
point their eligibility to participate in the study will be confirmed. Only those participants who 
successfully complete the screening phase and meet the study eligibility criteria will proceed to 
be randomized to receive a single dose of MBS-COV or placebo in the morning of Day 1 at the 
assigned dose. 
Participants will be assigned to one of up to three doses of MBS-COV (0.3 mg/kg, 0.6 mg/kg, 
1.2 mg/kg) to be treated sequentially with increasing doses. Each cohort will include eight (8) 
participants (6 active and 2 placebo) per below table: 
Table 3-1: SAD Phase Cohorts 
Cohort 
Number of Participants 
MBS-COV Dose 
(mg/kg) 
Frequency of Dose 
SAD 
Phase 
A1 
6 (MBS-COV) +2 (placebo) 
0.3  
Single Administration 
A2 
6 (MBS-COV) +2 (placebo) 
0.6  
Single Administration 
A3 
6 (MBS-COV) +2 (placebo) 
1.2  
Single Administration 
SAD phase will include a sentinel design in which two (2) participants at the given cohort dose 
be initially enrolled. If the dose can be well tolerated for 48 hours after full administration per 
site Principle Investigator’s judgement, the remaining 6 participants will be enrolled to receive a 
single dose of MBS-COV at the same dose. 
The decision for cohort (dose level) escalation to the higher dose levels will be made by the 
study SRC after safety review of available information 7-day post treatment period. The data 
from SAD phase will be reviewed for safety trends to start MAD phase. 
 
Part B (MAD Phase)  


 
 
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This is a randomized, double-blind, placebo-controlled study in approximately 20 healthy 
participants. Doses will be selected based on a comprehensive review of SAD data and estimates 
of the clinically efficacious dose.  
The MAD Phase of the study consists of a screening period followed by multiple dose 
administrations of MBS-COV or placebo through a portable nebulizer once daily for 7 
consecutive days (Day 1 to Day 7). Participants will be followed up for 21 days to assess post-
treatment safety. 
The decision for the escalation to the higher dose levels will be made by the study SRC after 
safety review of available information 7-day post treatment period. Each cohort will include ten 
participants (8 active and 2 placebo) per table below: 
Table 3-2: 
MAD Phase Cohorts 
Cohort 
Number of 
Participants 
MBS-COV Dose 
(mg/kg) 
Dose 
MAD 
Phase 
B1 
8 (MBS-COV) +2 
(placebo) 
0.6 
Once daily for 7 days 
B2 
8 (MBS-COV) +2 
(placebo) 
1.2 
Once daily for 7 days 
 
Study Visits:  
 Screening Visit (SV: Up to 28 Days prior to Day 1): Consists of signing the ICF and 
study qualification based on evaluation of inclusion/exclusion criteria.  
 Treatment Visit 0 (T0: Day -1): All participants continuing to meet eligibility criteria 
will be enrolled into the study and confined to research clinic until Day 2 for cohort A1 to 
A3 (SAD phase) and Day 9 for cohort B1 to B2 (MAD phase). 
 Treatment Visit 1: Baseline Visit (T1: Day 1): The first assigned study treatment dose 
will be administered after completion of all study evaluations. Adverse events and 
changes in concomitant medications will be collected. Participants in Cohorts A1 to A3 
will inhaled a single dose of MBS-COV or placebo through a portable nebulizer on Day 1. 
Participants in cohort B1 and B2 will receive doses of MBS-COV or placebo by through 
a portable nebulizer once daily for 7 consecutive days from Day 1 to Day 7.  
Part A (SAD Phase) 
o Treatment Visit 2 (T2: Day 2) 
o Treatment Visit 3 (T3: Day 3) 
o Treatment Visit 4 (T4: Day 4) 
o Treatment Visit 5 (End of Treatment) (T5: Day 7) 


 
 
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 Follow-Up Visit 1 (FU1: Day 14) 
 Follow-Up Visit 2 (FU2: Day 28) 
Part B (MAD Phase) 
o Treatment Visit 2 (T2: Day 2) 
o Treatment Visit 3 (T3: Day 3) 
o Treatment Visit 4 (T4: Day 4) 
o Treatment Visit 5 (T5: Day 5) 
o Treatment Visit 6 (T6: Day 6) 
o Treatment Visit 7 (T7: Day 7) 
o Treatment Visit 8 (T8: Day 8) 
o Treatment Visit 8 (End of Treatment) (T9: Day 9) 
 Follow-Up Visit 1 (FU1: Day 14) 
 Follow-Up Visit 2 (FU2: Day 28) 
If any of the dose escalation stopping criteria have occurred in Part A or Part B, the SRC will 
make a final recommendation for dose escalation to the next cohort. 
 NOTE: The dose escalation decision through the study will not be made until the 
following: 
(1) All study participants in a given cohort have been enrolled,  
(2) All such participants have completed Treatment Visit 5 (Day 7) (for SAD-Part A) and 
Treatment Visit 9 (Day 9) (for MAD-Part B) of the study or withdrawn from the study, 
whichever occurs first, 
(3) The SRC will review the available safety data and recommend further dose escalation.  
Additionally, dose escalation stopping criteria are defined per the below: 
a. Death in any participant in which the cause of death is judged to be possibly, 
probably or definitely related to MBS-COV. 
b. The occurrence in any participant of a severe local application site reaction 
(Grade 3 which doesn’t resolve or recurs, or Grade 4) that is judged to be possibly, 
probably or definitely related to MBS-COV. 
c. The occurrence in any participant of a SAE whose causal relationship to MBS-
COV is judged to be probably, possibly, or definitely related to MBS-COV. 
d. The occurrence, in two or more participants of Grade 3 AE or laboratory 
abnormalities, judged to be probably, possibly, or definitely related to MBS-COV. 


 
 
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e. The occurrence of two of the same AE or laboratory abnormality ≥ Grade 3 
judged to be probably, possibly, or definitely related to receipt of MBS-COV 
f. The occurrence, in one or more participants of Grade 4 AE or laboratory 
abnormalities, judged to be probably, possibly, or definitely related to receipt of 
MBS-COV. 
g. Any pattern of significant symptoms, physical findings, or laboratory 
abnormalities that, although individually minor, collectively represent a safety 
concern in the opinion of the investigator and are judged by the SRC to be at least 
possibly related to MBS-COV. 
h. PK exposure limits of mean AUC of 385.6 h*ng/mL or Cmax of 141.8 ng/mL for 
one cohort, whichever comes first.(Single dose: AUC of 386.9 h*ng/mL or Cmax 
of 91.7 ng/mL). 
The SRC will review the PK data (if applicable) and safety trends of available information 7-day 
post treatment period of Cohort A1 and A2 (or if study stops prematurely due to safety reasons), 
to start part B of the study. The starting dose of Part B will be determined by SRC. 
Figure 3-1: 
Dose Escalation Scheme  
 
Blood Sample Collection for the PK study: 
 SAD cohorts A1 to A3: For the single dose on day 1, blood samples will be collected 
before dosing, and afterwards at 5 min (± 1 min), 15 min (± 2 min),0.5 h (± 5 min), 1 h (± 
5 min), 2 h (± 5 min), 4 h (± 5 min), 8 h (± 10 min), 10 h (± 10 min), 24 h (± 10 min) and 
48 h (± 10 min) (Total 11 samples) after dosing. 
 MAD cohort B1 and B2: Blood samples will be collected on Day 1 and Day 7 before 
dosing, and afterwards at 5 min (± 1 min), 15min (± 2 min), 0.5 h (± 5 min), 1 h (± 5 min), 
2 h (± 5 min), 4 h (± 5 min), 8 h (± 10 min), 10 h (± 10 min) on Day 1; and at 5 min (± 1 
min), 15min (± 2 min), 0.5 h (± 5 min), 1 h (± 5 min), 2 h (± 5 min), 4 h (± 5 min), 8 h (± 


 
 
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10 min), 10 h (± 10 min) , 24 h (± 10 min) and 48 h (± 10 min) after dosing on Day 7; 
and before dosing on Day 2 to Day 6 (Total 25 samples). The detailed study schedule and 
assessments in each visit are provided in Section 4 of the protocol. 
Blood Sample Collection for the immunogenicity study: 
 Blood Sample will be collected on Day 1 before dosing, Day 14 and Day 28 for SAD and 
MAD cohorts, and the analysis will be performed when analytic method is well-
established. 
3.2. STUDY CENTER 
One study center in the United States (US). 
3.3. STUDY POPULATION 
The target population for this study will be healthy participants. 
3.4. ELIGIBILITY CRITERIA 
3.4.1. Inclusion Criteria  
Participants will be eligible for enrollment in the study only if they meet ALL the following 
criteria at time of Screening: 
1. Male or female adults who are between 18 and 55 years old (inclusive). 
2. Body mass index (BMI) between 18.0 and 32.0 kg/m2 (inclusive). 
3. No serious or chronic underlying disease which would adversely affect the study conduct 
and data interpretation per the Investigator. 
4. Female participants should have negative results in serum pregnancy test at screening and 
negative urine pregnancy test at admission (Day -1).  
5. Participants with normal spirometry (FEV1 %: 80 % or greater) results at screening or 
day -1.  
6. Both male and female participants and their partners of childbearing potential must agree 
to use two medically accepted methods of contraception (e.g., barrier contraceptives 
[male condom, female condom, or diaphragm with a spermicidal gel], hormonal 
contraceptives [implants, injectables, combination oral contraceptives, transdermal 
patches, or contraceptive rings], or one of the following methods of birth control 
(intrauterine devices, tubal sterilization or vasectomy) or must practice complete 
abstinence from intercourse of reproductive potential from study entry to 3 months after 
the last day of treatment (excluding women who are not of childbearing potential and 
men who have been sterilized). 


 
 
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7. Participants should have normal (or abnormal but not clinically significant) laboratory 
results per the PI’s judgement including the hematology, biochemistry, coagulation 
indices and urinalysis. 
8. Participants should have a normal (or abnormal but not clinically significant) 12-lead 
ECG at screening and day -1 and chest X-ray at screening. 
9. Participants should be willing to cooperate and able to participate in this study, comply 
with all protocol requirements, and sign an informed consent. 
10. Current non-smokers and those who have not smoked within the last 3 months. This 
includes the use of cigarettes, e-cigarettes, and nicotine replacement products. 
11. Nasopharyngeal or nasal swab sample of Participants collected for COVID-19 antigen 
rapid test at screening and qRT-PCR test on Day -1 should be negative. 
3.4.2. Exclusion Criteria  
Participants meeting ANY of the following criteria at time of Screening will be excluded from 
enrollment: 
1. The participant has a known history of, or a positive test result for, hepatitis B surface 
antigen (HBsAg), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) at 
screening. 
2. As reported by the participant has severe cardiovascular disease, neurological disease, 
hematological disease, infectious disease, mental disorder, liver disease, gastrointestinal 
disease, lung disease, endocrine disease, immune disease or kidney disease, or has a 
history of the above diseases, or other symptoms known to interfere with the absorption, 
distribution, metabolism, or excretion of the medicine, or other conditions that the 
Investigator believes will increase the risk of the participant and might interfere with the 
study conduct and results interpretation. 
3. The participant has history or presence of active lung disease (i.e., asthma, chronic 
obstructive pulmonary disease [COPD], pulmonary fibrosis, hemoptysis, bronchiectasis) 
or prior intubation due to respiratory failure conditions. 
4. The participant has upper respiratory infection within the 3 months prior to the first dose 
of study drug. 
5. Consumed more than 14 units of alcohol per week in the 6 months before screening (1 
unit of alcohol = 360 mL of beer or 45 mL of spirits with 40% alcohol content or 150 mL 
of wine) or have taken alcohol products in the 48 hours prior to administration, or those 
who have a positive alcohol breath test result at screening and day -1. 
6. Unwillingness to abstain from the consumption of any caffeine or alcohol-containing 
food or drinks that may influence the drug metabolism from 48 hours before 
administration. 


 
 
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7. History of drug abuse or a positive drug abuse (barbiturates, methamphetamine, 
benzodiazepines, 
morphine/opiates, 
phencyclidine 
(PCP), 
amphetamines, 
tetrahydrocannabinol (THC), methylenedioxymethamphetamine (MDMA), cocaine, 
methadone, and cotinine) test result at screening and day -1. 
8. Female participants who are lactating. 
9. Use of prescription or non-prescription drugs, including vaccine within 14 days or 5 half-
lives (whichever is longer) prior to the first dose of study drug.  
10. The participant has received an experimental agent (vaccine, drug, biologic, device, 
blood product or medication) within 1 month prior to the first dose of study drug and will 
receive another experimental agent during the duration of this study. 
11. The participant has a history of frequent nose bleeding. 
12. Participants with known allergic reactions to the study drug or its excipients. 
13. The participant has an acute sinusitis or history of chronic sinusitis, a history of active 
allergic rhinitis (AR), history of perennial allergic rhinitis (PAR), or current seasonal 
allergic rhinitis (SAR), or recent viral rhinitis within 2 weeks prior to administration. 
14. The participant has Any nasopharyngeal abnormality that may have interfered with nasal 
absorption, distribution, or study-related evaluations of signs or symptoms (e.g., polyps, 
septal deviation). 
15. Blood donation of more than 400 mL within 3 months before screening or more than 200 
mL within 4 weeks before screening or plan to donate blood during study period. 
16. Any other clinical condition that, in the Investigator's judgment, would potentially 
compromise study compliance or the ability to evaluate safety/efficacy. 


 
 
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4. 
STUDY SCHEDULE 
4.1. OVERVIEW 
The study Schedule of Assessments in presented in Table 4-1 (Part A) and Table 4-2 (Part B). 
See Section 7 for a detailed description of each protocol assessment and procedure.  
The study is divided into three phases: Screening Phase, Treatment Phase, and Follow-Up Phase.  
 


 
 
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Table 4-1: 
Schedule of Assessments – Part A (SAD Phase) 
Procedure/Assessments 
Screening 
Phase 
Treatment Phase 
Follow-Up Phase 
Inpatient Visit 
 
Outpatient Visits 
Visit 
SV 
T0 
T1 (Baseline) 
T2 
T3 
T4 
T5 
(EOT/ET) 
FU1 
FU2[19] 
(Pre-Rx) 
(Post-Rx) 
Day 
Up to -28 
Day -1 
Day 1 
Day 2 
Day 3 (48 
hours after 
dosing) 
Day 4 
Day 7 
Day 14 
Day 28 
Window Period 
 
 
Within 28 days of the 
Screening Visit 
NA 
NA 
NA 
±1 
±1 
±1 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
Informed Consent [1] 
X 
 
 
 
 
 
 
 
 
 
Eligibility Evaluation [2] 
X 
X 
 
 
 
 
 
 
 
 
Participant Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical History [3] 
X 
X 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
X 
X[4] 
X[4] 
X[4] 
X[4] 
X[4] 
X 
 
Height, Weight and BMI 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X[5] 
X 
X 
X 
 X 
X 
 
12-lead ECG 
X 
X 
X 
X[6] 
X 
X 
X 
X  
X 
 
Chest X-ray 
X 
 
 
 
 
 
 
X 
 
 
Spirometry assessments [7] 
X 
X 
 
X 
 
 
 
 
 
 
Participant Confined to Research Clinic 
 
X 
X 
X 
X 
 
 
 
 
 
Participant Discharge from Research Clinic (if 
applicable) [8]  
 
 
 
 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
LABORATORY TESTS[9]: 
 
 
 
 
 
 
 
 
 
 
Hematology [10] 
X 
X 
 
 
X 
X 
 
 X 
X 
 
Biochemistry [11] 
X 
X  
 
 
X 
X 
 
 X 
X 
 
Coagulation Indices [12] 
X 
X 
 
 
X 
X 
 
X  
X 
 
Serum/Urine Pregnancy Test [13] 
X 
X 
 
 
 
 
 
X 
X 
 
Urinalysis [14] 
X 
X 
 
 
X 
X 
 
 X 
X 
 


 
 
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Procedure/Assessments 
Screening 
Phase 
Treatment Phase 
Follow-Up Phase 
Inpatient Visit 
 
Outpatient Visits 
Visit 
SV 
T0 
T1 (Baseline) 
T2 
T3 
T4 
T5 
(EOT/ET) 
FU1 
FU2[19] 
(Pre-Rx) 
(Post-Rx) 
Day 
Up to -28 
Day -1 
Day 1 
Day 2 
Day 3 (48 
hours after 
dosing) 
Day 4 
Day 7 
Day 14 
Day 28 
Window Period 
 
 
Within 28 days of the 
Screening Visit 
NA 
NA 
NA 
±1 
±1 
±1 
Nasopharyngeal or nasal swab for COVID-19 
[15] 
X 
X 
 
 
 
X 
X 
X 
 X 
X 
Urine Drug and Alcohol Screening 
X 
X 
 
 
 
 
 
 
 
 
PK evaluations [16] 
 
 
X 
X 
X 
X 
 
 
 
 
ADA[17] 
 
 
X 
 
 
 
 
 
X 
X 
Screening 
for 
infectious 
diseases 
(HIV 
antibody; HbsAg; HCV antibody) 
X 
 
 
 
 
 
 
 
 
 
INTERVENTION(s): 
 
 
 
 
 
 
 
 
 
MBS-COV Administration [18] 
 
 
X 
  
 
 
 
 
 
[1] Informed consent must be obtained prior to participation in any protocol-related activities that are not part of routine care. 
[2] Initial evaluation of participant eligibility will be performed by Investigator. 
[3] Medical history and current therapies (medications and non-medications). 
[4] Symptom-directed physical examination.   
[5] Vital signs will include blood pressure, pulse, respiration rate, and temperature. On treatment visits will be conducted three times a day, within 120 minutes before 
administration, within 1 hour after administration, and 4-6 hours after administration, respectively. On other visits will be conducted once during the visit. 
[6] 12-lead ECG on treatment visits will be conducted three times a day, within 120 minutes before administration, within 1 hour after administration, and 4-6 hours after 
administration, respectively. On other visits will be conducted once during the visit. 
[7] Spirometry assessments will be started 5 minutes after the dosing with frequent spirometry measurements at 5 (± 1 min), 15 (± 1 min), 30 (± 5 min), 60 minutes (± 5 
min). On other visits will be conducted once during the visit. If spirometry is completed within 7 days prior to dosing, this assessment does not need to be repeated on 
Day-1. 
[8] Participants will be discharge from the clinic when all required assessments for T3 Day (3) are performed. 
[9] If hematology, biochemistry, coagulation and urinalysis are completed within 7 days prior to dosing, this assessment does not need to be repeated on Day-1. 
[10] Hematology  
Hemoglobin, Hematocrit (HCT), Red Blood Cells (RBC), White Blood Cells (WBC) with total and differential count, Absolute Neutrophil Count (ANC) and platelets. 
[11] Biochemistry  
Hepatic function indicators: total bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin, Lactate 
dehydrogenase (LDH), amylase and lipase 


 
 
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Renal function indicators: Serum creatinine, eGFR  
Electrolytes: sodium, potassium, chloride, calcium and bicarbonate 
Other: glucose (random), triglyceride (TG), cholesterol (total), Creatine kinase. 
[12] Coagulation 
Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB) 
[13] Serum pregnancy test in screening visit (Will include FSH and estradiol levels at screening for post-menopausal women only) and EOT, and Urine pregnancy test in 
other visits. 
[14] Urine samples will be tested for color, appearance, specific gravity, pH, protein, glucose, occult blood, ketones, leukocyte esterase, nitrite, bilirubin, and urobilinogen. 
[15] Nasopharyngeal or nasal swab sample will be collected for COVID-19 antigen rapid test at screening and qRT-PCR test on Day -1, Day 3, Day 4, Day 7, Day 14 and 
Day 28. 
[16] PK timepoints: Cohorts A1 to A3: For the single dose on day 1, blood samples will be collected before dosing, and afterwards at 5 min (± 1 min), 15 min (± 2 min), 
0.5h (± 5 min), 1h (± 5 min), 2h (± 5 min), 4h (± 5 min), 8h (± 10 min), 10 h (± 10 min), 24 h (± 10 min) and 48 h (± 10 min) after dosing. 
[17] ADA timepoints: Blood samples will be collected on Day 1 before dosing, Day 14, and Day 28. 
[18] IP administration: SAD cohorts A1-A3: Single MBS-COV treatment administration through a portable nebulizer (0.3 - 1.2 mg/kg).   
[19] Adverse events and concomitant medications will be followed up on Day 28. 
 


 
 
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Table 4-2: 
Schedule of Assessments – Part B (MAD Phase) 
Procedure/Assessments 
Screening 
Phase 
Treatment Phase 
Follow-Up Phase 
Inpatient Visits 
Visit 
SV 
T0 
T1 (Baseline) 
T2-T7 
T8 
T9(EOT/ET) 
FU1 
FU2[19] 
(Pre-
Rx) 
(Post-
Rx) 
Day 
Up to -28 
Day -1 
Day 1 
Day 2-Day 7 
Day 8 
Day 9 
(48 hours after 
last dosing) 
Day 14 Day 28 
Window Period 
 
 
Within 28 days 
of the 
Screening Visit 
NA 
NA 
±1 
±1 
±1 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Informed Consent [1] 
 
X 
 
 
 
 
 
 
 
 
Eligibility Evaluation [2] 
X 
X 
 
 
 
 
 
 
 
Participant Demographics  
X 
 
 
 
 
 
 
 
 
Medical History [3] 
X 
X 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
X 
X[4] 
X[4] 
X[4] 
X[4] 
X 
 
Height, Weight and BMI 
X 
 
 
 
 
 
 
 
 
Vital Signs  
X 
X 
X 
X[5] 
X[5] 
X 
X 
X 
 
12-lead ECG 
X 
X 
X 
X[6] 
X[6] 
X  
X 
X 
 
Chest X-ray 
X 
 
 
 
 
 
X 
 
 
Spirometry assessments [7] 
X 
X 
 
X 
X 
 
 
 
 
Participant Confined to Research Clinic 
 
X 
X 
X 
X 
X 
 
 
 
Participant Discharge from research clinic 
(if applicable) [8] 
 
 
 
 
 
 
X 
 
 
Randomization  
 
 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X 
LABAROTORY ASSESSMENTS[9] 
 
 
 
 
 
 
 
 
 
Hematology [10] 
X 
X 
 
 
X 
X 
X 
X 
 
Biochemistry [11] 
X 
X  
 
 
X 
X 
X 
X 
 
Coagulation Indices [12] 
X 
X 
 
 
X 
X 
X 
X 
 
Serum/Urine Pregnancy Test [13] 
X 
X 
 
 
 
 
X 
X 
 


 
 
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Procedure/Assessments 
Screening 
Phase 
Treatment Phase 
Follow-Up Phase 
Inpatient Visits 
Visit 
SV 
T0 
T1 (Baseline) 
T2-T7 
T8 
T9(EOT/ET) 
FU1 
FU2[19] 
(Pre-
Rx) 
(Post-
Rx) 
Day 
Up to -28 
Day -1 
Day 1 
Day 2-Day 7 
Day 8 
Day 9 
(48 hours after 
last dosing) 
Day 14 Day 28 
Window Period 
 
 
Within 28 days 
of the 
Screening Visit 
NA 
NA 
±1 
±1 
±1 
Urinalysis [14] 
X 
X 
 
 
X 
X 
X 
X 
 
Nasopharyngeal or Nasal Swab for 
COVID-19 [15] 
X 
X 
 
 
 
 
X 
X 
X 
Urine Drug and Alcohol Screening 
X 
X 
 
 
 
 
 
 
 
PK evaluations [16] 
 
 
X 
X 
X 
X 
X 
 
 
ADA [17] 
 
 
X 
 
 
 
 
X 
X 
Screening for infectious diseases (HIV 
antibody; HbsAg; HCV antibody ) 
X 
 
 
 
 
 
 
 
 
INTERVENTON(s) 
 
 
 
 
 
 
 
 
MBS-COV Administration [18] 
 
 
X 
X  
 
 
 
 
[1] Informed consent must be obtained prior to participation in any protocol-related activities that are not part of routine care. 
[2] Initial evaluation of participant eligibility will be performed by Investigator. 
[3] Medical history and current therapies (medications and non-medications). 
[4] Symptom-directed physical examination.   
[5] Vital signs will include blood pressure, pulse, respiration rate, and temperature. On treatment visits will be conducted three times a day, within 120 minutes before 
administration, within 1 hour after administration, and 4-6 hours after administration, respectively. On other visits will be conducted once during the visit. 
[6] 12-lead ECG on treatment visits will be conducted three times a day, within 120 minutes before administration, within 1 hour after administration, and 4-6 hours after 
administration, respectively. On other visits will be conducted once during the visit. 
[7] Spirometry assessments will be started 5 minutes after the dosing with frequent spirometry measurements at 5 (± 1 min), 15 (± 1 min), 30 (± 5 min) 60 (± 5 min) minutes. On 
other visits will be conducted once during the visit. 
[8] Participant will be discharge from the clinic when all required assessments for V9 are performed. 
[9] If hematology, biochemistry, coagulation and urinalysis are completed within 7 days prior to dosing, this assessment does not need to be repeated on Day-1. 
[10] Hematology 
Hemoglobin, Hematocrit (HCT), Red Blood Cells (RBC), White Blood Cells (WBC) with total and differential count, Absolute Neutrophil Count (ANC) and platelets. 
[11] Biochemistry  


 
 
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Hepatic function indicators: total bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin Lactate 
dehydrogenase (LDH), amylase and lipase 
Renal function indicators: Serum creatinine, eGFR  
Electrolytes: sodium, potassium, chloride, calcium and bicarbonate 
Other: glucose (random) , triglyceride (TG), cholesterol (total), Creatine kinase. 
[12] Coagulation 
Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB) 
[13] Serum pregnancy test in screening visit (Will include FSH and estradiol levels at screening for post-menopausal women only) and EOT, and Urine pregnancy test in other visits. 
[14] Urine samples will be tested for color, appearance, specific gravity, pH, protein, glucose, occult blood, ketones, leukocyte esterase, nitrite, bilirubin, and urobilinogen. 
[15] Nasopharyngeal or nasal swab sample will be collected for COVID-19 antigen rapid test at screening and qRT-PCR test on Day -1, Day 9, Day 14 and Day 28. 
[16] PK timepoints: Cohorts B1 to B2: Blood samples will be collected on Day 1 and Day 7 before dosing, and afterwards at 5 min (± 1 min), 15min (± 2 min), 0.5 h (± 5 min), 1 h 
(± 5 min), 2 h (± 5 min), 4 h (± 5 min), 8 h (± 10 min), 10 h (± 10 min) on Day 1; and at 5 min (± 1 min), 15min (± 2 min), 0.5 h (± 5 min), 1 h (± 5 min), 2 h (± 5 min), 4 h (± 
5 min), 8 h (± 10 min), 10 h (± 10 min), 24 h (± 10 min) and 48 h (± 10 min) after dosing on Day 7; and before dosing on Day 2 to Day 6 (Total 25 samples). 
[17] ADA timepoints: Blood samples will be collected on Day 1 before dosing,  Day 14, and Day 28. 
[18] IP administration: MAD cohorts B1-B2: MBS-COV treatment administration through a portable mesh nebulizer for 7 consecutive days, once daily, according to the cohort 
dosing schedule   
[19] Adverse events and concomitant medications will be followed up on Day 28. 


 
 
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4.2. PART A 
4.2.1. Part A (SAD) - Screening Visit (SV: Up to 28 Days prior to Day 1): 
The participant will sign and date the ICF, and screening visit procedures of Part A of the study 
are per below: 
 Informed consent will be obtained prior to any study-related procedures 
 Eligibility assessment per the inclusion and exclusion criteria  
 Participant demographics  
 Medical history  
 Vital signs 
 Height, Weight, BMI  
 Physical examination  
 12-lead electrocardiogram (12-lead ECG) 
 Chest X-ray 
 List concomitant medications  
 Spirometry assessment 
 Laboratory assessments (hematology, chemistry, coagulation and urine analysis, urine 
drug screening and alcohol screen) 
 Screening for infectious diseases (HIV antibody; HbsAg antigen; HCV antibody positive)  
 Serum pregnancy test  
 Nasopharyngeal or nasal swab for COVID-19  
If spirometry, hematology, chemistry, coagulation, and urine analysis, are completed within 
7 days prior to dosing, this assessment does not need to be repeated on Day-1. 
4.2.2. Part A (SAD) - Treatment Visit 0 (T0: Day -1) 
If continued to be eligible for the study at Treatment Visit 0 per below, the participant will 
proceed to be enrolled into Part A (SAD) of the study in next visit.  
 Assessment of continued eligibility  
 Medical history  
 Vital signs 
 12-lead ECG  


 
 
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 List concomitant medications  
 Spirometry assessment 
 Participant confined to research clinic 
 Laboratory assessments (hematology, chemistry, coagulation and urine analysis, urine 
drug screening and alcohol screen)  
 Urine pregnancy test  
 Nasopharyngeal or nasal swab for COVID-19 
4.2.3. Part A (SAD) - Treatment Visit 1: Baseline Visit (T1: Day 1) 
The first assigned study treatment dose will be administered after completion of all study 
evaluations. Adverse events and changes in concomitant medications will be collected. 
Participants in Cohorts A1 to A3 will be inhaled a single dose of MBS-COV or placebo through 
a portable nebulizer on Day 1.  
The following assessments will be performed: 
 Medical history (pre dose) 
 Vital signs (pre and post dose) (Vital signs will include blood pressure, pulse, respiration 
rate, and temperature. On treatment visits will be conducted three times a day, within 120 
minutes before administration, within 1 hour after administration, and 4-6 hours after 
administration, respectively.) 
 Randomization (pre dose) 
 Physical examination (pre and post dose) 
 12-lead ECG (pre and post dose) (12-lead ECG on treatment visits will be conducted 
three times a day, within 120 minutes before administration, within 1 hour after 
administration, and 4-6 hours after administration, respectively.) 
 List concomitant medications  
 PK timepoints: Cohorts A1 to A3: For the single dose on day 1, blood samples will be 
collected before dosing, and afterwards at 5 min (± 1 min), 15 min (± 2 min), 0.5 h (± 2 
min), 1 h (± 5 min), 2 h (± 5 min), 4 h (± 5 min), 8 h (± 10 min), 10 h (± 10 min) after 
dosing. 
 ADA timepoints: Blood samples will be collected on Day 1 before dosing 
 Spirometry Assessment (Spirometry assessments will be started 5 minutes after the 
dosing with frequent spirometry measurements at 5 (± 1 min), 15 (± 1 min), 30 (± 5 min), 
60 minutes (± 5 min).) 


 
 
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 Adverse events evaluation after first dose 
 Participants will be confined till 24 hours pharmacokinetic samples are obtained 
following study drug administration. 
4.2.4. Part A (SAD) – Treatment Visit 2 to Treatment Visit 5/End of Treatment (T2: Day 2 
to T5: Day 7) 
The following assessments will be performed (refer to the schedule of events Table 4-1) 
 Vital signs 
 Physical examination, including dermatologic examination 
 12-lead ECG 
 List concomitant medications  
 Laboratory assessments (hematology, chemistry, coagulation and urine analysis) (T2, T3, 
and T5 only) 
 Chest X-ray (T5 only) 
 PK timepoints: Cohorts A1 to A3: For the single dose on day 1, blood samples will be 
collected at 24 h (± 10 min) and 48h (± 10 min) after dosing. 
 Serum pregnancy test only on T5 (EOT) 
 Adverse events evaluation  
 Nasopharyngeal or nasal swab for COVID-19 (T3, T4 and T5) 
 Participants will be discharged from the clinic on Day 3. if applicable. 
4.2.5. Part A (SAD) – Follow-Up Visit 1 (FU1: Day 14) 
A Follow-Up visit will be conducted to evaluate safety and study evaluations. Adverse events 
and changes in concomitant medications will be collected. The following assessments will be 
performed: 
 Vital signs  
 Physical examination  
 12-lead ECG  
 List concomitant medications  
 Laboratory assessments (hematology, chemistry, coagulation, and urine analysis) 
 ADA timepoints: Cohorts A1 to A3: For the single dose on day 1, blood samples will be 
collected at day 14 after dosing. 


 
 
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 Urine pregnancy test  
 Adverse events evaluation  
 Nasopharyngeal or nasal swab for COVID-19 
4.2.6. Part A (SAD) – Follow-Up Visit 2 (FU2: Day 28) 
The following assessments will be performed: 
 ADA sampling 
 Nasopharyngeal or nasal swab for COVID-19 
 Adverse events evaluation 
 Changes in concomitant medications  
4.3. PART B  STUDY VISITS 
4.3.1. Part B (MAD) - Screening Visit (SV: Up to 28 Days prior to Day 1) 
The participant will sign and date the ICF, and screening visit procedures of Part B of the study 
are per below: 
 Informed consent will be obtained prior to any study-related procedures  
 Eligibility assessment per the inclusion and exclusion criteria  
 Participant demographics  
 Medical history  
 Vital signs  
 Height, Weight, and BMI  
 Physical examination  
 12-lead ECG  
 Chest X-ray 
 List concomitant medications  
 Spirometry assessment  
 Laboratory assessments (hematology, chemistry, Coagulation, and urine analysis), Urine 
Drug Screening, and alcohol screen, Screening for infectious diseases (HIV antibody; 
HbsAg; HCV antibody)   
 Serum pregnancy test  
 Nasopharyngeal or nasal swab for COVID-19  


 
 
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These assessments must be conducted within 28 days of the First Treatment Visit (T1). 
Screening information will be fully documented in the participant’s medical records (i.e., source 
documents).  
For consented participants who do not meet eligibility criteria, a Screen Failure Case Report 
Form (CRF) will be completed. The Screen Failure CRF will contain the following details: the 
participant identification number, the date of ICF signature, demographic information, and the 
reason for screen failure. No additional information will be required for participants who fail 
screening.  
For consented participants who meet eligibility criteria, all required screening information will 
be transcribed onto the appropriate page of the CRF. 
4.3.2. Part B (MAD) - Treatment Visit 0 (T0: Day -1) 
Participants who meet the eligibility criteria will have completed the following evaluations and 
assessments at T0:  
 Assessment of continued eligibility 
 Review of any changes in medical and medical history  
 List concomitant medications  
 Vital signs  
 Spirometry assessment  
 Participant confined to research clinic 
 Laboratory assessments (hematology, chemistry, coagulation, and urine analysis), Urine 
Drug Screening, and alcohol screen  
 Urine pregnancy test  
 12-lead ECG  
 Nasopharyngeal or nasal swab for COVID-19  
If spirometry, hematology, chemistry, coagulation, and urine analysis, are completed within 7 
days prior to dosing, this assessment does not need to be repeated on Day-1. 
4.3.3. Part B (MAD) - Treatment Visit 1: Baseline Visit (T1: Day 1): 
At T1, participants will be enrolled to receive the assigned study treatment which will be 
administered daily at Treatment Visits 1 to 7 by a qualified medical professional at clinic.  
 Review of any changes in medical and medical history (pre dose) 
 Vital signs (pre and post dose) (Vital signs will include blood pressure, pulse, respiration 
rate, and temperature. On treatment visits will be conducted three times a day, within 120 


 
 
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minutes before administration, within 1 hour after administration, and 4-6 hours after 
administration, respectively.) 
 Physical examination (pre and post dose) 
 Randomization (pre dose) 
 12-lead ECG (12-lead ECG on treatment visits will be conducted three times a day, 
within 120 minutes before administration, within 1 hour after administration, and 4-6 
hours after administration, respectively.) 
 PK timepoints: Blood samples will be collected on Day 1 before dosing, and afterwards 
at 5 min (± 1 min), 15min (± 2 min), 0.5 h (± 5 min), 1 h (± 5 min), 2 h (± 5 min), 4 h (± 
5 min), 8 h (± 10 min), 10 h (± 10 min) after dosing. 
 ADA timepoints: Blood samples will be collected on Day 1 before dosing 
 Spirometry Assessment (Spirometry assessments will be started 5 minutes after the 
dosing with frequent spirometry measurements at 5 (± 1 min), 15 (± 1 min), 30 (± 5 min), 
60 minutes (± 5 min).) 
 List concomitant medications  
 Adverse events evaluation after first dose  
 Study drug administration  
IP administration: MBS-COV treatment administration through a portable nebulizer (0.6 and 1.2 
mg/kg) for 7 consecutive days, once daily, according to the cohort dosing schedule   
In part B participants will be randomized 8:2 to MBS-COV or placebo in the assigned cohort. 
4.3.4. Part B (MAD) – Treatment Visit 2 to Treatment Visit 7 (T2: Day 2 to T7: Day 7)  
During Treatment Visit 2 to Treatment Visit 7, the following assessments will be performed per 
the study schedule of assessments Table 4-2. 
 Vital signs (Vital signs will include blood pressure, pulse, respiration rate, and 
temperature. On treatment visits will be conducted three times a day, within 120 minutes 
before administration, within 1 hour after administration, and 4-6 hours after 
administration, respectively.) 
 Physical examination  
 Laboratory assessments (hematology, chemistry, coagulation, and urine analysis)   
 PK timepoints:  Blood samples will be collected before dosing on Day 2 to Day 6, and on 
Day 7 before dosing, and afterwards at 5 min (± 1 min), 15min (± 2 min), 0.5 h (± 5 min), 
1 h (± 5 min), 2 h (± 5 min), 4 h (± 5 min), 8 h (± 10 min), and 10 h (± 10 min) after 
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 12-lead ECG (12-lead ECG on treatment visits will be conducted three times a day, 
within 120 minutes before administration, within 1 hour after administration, and 4-6 
hours after administration, respectively.) 
 Study drug administration 
 Spirometry Assessment (Spirometry assessments will be started 5 minutes after the 
dosing with frequent spirometry measurements at 5 (± 1 min), 15 (± 1 min), 30 (± 5 min), 
60 (± 5 min) minutes). 
 List concomitant medications  
 Adverse events evaluation  
Participants will be discharged from the clinic on Day 9 if applicable. 
4.3.5. Part B (MAD) - Treatment Visit 8 (T8: Day 8) 
The following assessments will be performed: 
 Vital signs  
 Physical examination  
 12-lead ECG  
 Laboratory assessments (hematology, chemistry, coagulation and urine analysis)  
 PK timepoints:  Blood samples will be collected on Day 8 
 List concomitant medications  
 Adverse events evaluation 
4.3.6. Part B (MAD) - Treatment Visit 9 (End of Treatment) (T9: Day 9) 
The following assessments will be performed: 
 Vital signs  
 Physical examination  
 12-lead ECG  
 Chest X-ray 
 Laboratory assessments (hematology, chemistry, coagulation and urine analysis)  
 PK timepoints:  Blood samples will be collected on Day 9 
 Serum pregnancy test  
 Nasopharyngeal or nasal swab for COVID-19 


 
 
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 List concomitant medications  
 Adverse events evaluation 
 Participants will be discharged from the clinic on Day 9. if applicable. 
4.3.7. Part B (MAD) - Follow-Up Visit 1 (FU1: Day 14) 
A Follow-up visit will be performed 1 week (FU1) after last day of study drug administration. To 
ensure the safety of participants and site staff. The following assessments will be performed: 
 Vital signs  
 Physical examination  
 12-lead ECG 
 Nasopharyngeal or nasal swab for COVID-19  
 Laboratory assessments (hematology, chemistry, coagulation and urine analysis)  
 ADA timepoints: Blood samples will be collected on Day 14  
 Urine pregnancy test  
 List concomitant medications  
 Adverse events evaluation  
4.3.8. Part B (MAD) - Follow-Up Visit 2 (FU2: Day 28) 
The following assessments will be performed: 
 ADA sampling 
 Nasopharyngeal or nasal swab for COVID-19 
 Adverse events evaluation 
 Changes in concomitant medications   
4.4. UNSCHEDULED VISITS 
In the event that the participant will return to clinic at a time other than a regularly scheduled 
study visit, the visit will be regarded as an unscheduled visit. This includes when participants 
require rescue therapy or need interim care due to chronic illness. Assessments at unscheduled 
visits are at the discretion of the Investigator. All pertinent findings, including adverse events or 
changes in medications, will be noted in the CRF. 


 
 
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4.5. MISSED VISITS 
If a participant misses a visit, the site is to make every effort to have the participant return as 
soon as possible to make up the visit.  
  


 
 
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5. 
PARTICIPANT COMPLETION, WITHDRAWAL AND CRITERIA 
FOR STOPPING THE STUDY 
5.1. PARTICIPANT COMPLETION 
5.1.1. Definition of Study Treatment Completion 
5.1.1.1. 
End of Treatment (EOT) Completion 
A participant is considered to have completed the treatment phase if all scheduled treatment 
visits have been completed. 
5.1.1.2. 
End of Follow-Up (EOFU) Completion 
A participant is considered to have completed the follow-up phase if all scheduled follow-up 
visits have been completed. 
5.2. PARTICIPANT WITHDRAWAL 
At any point during the study all participants have the right to withdraw without prejudice to 
future care. Documentation to whether or not each participant completed the clinical study will 
be recorded. If study treatment is discontinued for any participant, the reason(s) will be 
documented.  
5.2.1. Participant Discontinuation 
The Investigator can discontinue a participant at any time if in their clinical judgment considers 
to be medically necessary. Investigators considering discontinuing study treatment should 
contact the medical monitor prior to such discontinuation. Participants who have study 
treatment discontinued will continue to be followed, per protocol, whenever possible. 
Participants who have study treatment discontinued due to a serious adverse event will be 
followed until resolution or stabilization of the event as described in Section 9.4.1 (SAE Follow-
Up). 
In addition, participants will be discontinued from the study in the following conditions: 
 
Withdrawal of consent. 
 
The participant has an AE and is unsuitable for the study as judged by the Investigator. 
 
The participant experiences events which significantly affect safety, tolerability, or PK 
profile of the drug, and is unsuitable for the study as judged by the Investigator. 
 
Participants have poor compliance or major protocol deviations occur is unsuitable for the 
study as judged by the investigator. 
 
The Investigator no longer believes participation is in the best interest of the participant. 


 
 
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5.2.2. Data Collected from Withdrawn Participants 
In the case of early termination, assessments listed in Section 4.2.4 and Section 4.3.6 will be 
completed when possible.  
Every attempt should be made to collect follow-up information. The reason for withdrawal from 
the study will be recorded in the source documents and on the appropriate page of the CRF. 
Before a participant is identified as lost-to-follow up, the site should make all reasonable efforts 
to contact the participant. These attempts must be documented and should include at a minimum 
one phone call and one certified letter.  
In the event that a participant is withdrawn from the study at any time due to an AE or SAE, the 
procedures stated in Section 9.2 (AE) or Section 9.4 (SAE) must be followed. 
5.3. STUDY STOPPING CRITERIA 
Upon occurrence of any of the following events, data will be reviewed by the Medical Monitor 
and the Lead Principal Investigator. 
1. A significant unexpected AE occurs during the study, and the Investigator considers that 
the study should be terminated. 
2. The study shall be terminated due to major violations of the clinical study protocol, GCP, 
or relevant regulations during the study. 
3. The Sponsor requests termination under the premise of fully protecting the rights and safety 
of the participants (for financial reasons, management reasons, etc.). 
4. The regulatory authority or Ethics Committee elects to terminate the study for certain 
reason. 
In case the above listed event(s) occurred, participant accrual will be suspended pending further 
review and the FDA and other global regulatory authority will be notified. The study will be 
stopped if any of these stopping criteria are met unless, after reviewing the safety events of 
interest, the medical monitor and Sponsor, agree to allow the study to proceed. The FDA and 
other global regulatory authority will be consulted for any protocol amendment before restarting 
the study if a stopping rule is met. 
 


 
 
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6. 
STUDY TREATMENT 
6.1. MBS-COV 
The investigational product (IP) in this study is MBS-COV. MBS-COV is a sterile, excipient-
free lyophilized powder with 50 mg of siRNA in a single dose 2-mL vial, to be reconstituted 
with normal saline before use for inhalation only at a to-be-determined dose level in 
milligram/kilogram per day, once daily, for 1 day or 7 consecutive days during this study. MBS-
COV drug substance were manufactured at CCI                   . The study drug is only formulated 
with water for injection (WFI), then sterile filtration and lyophilization. 
To administer the IP in all cohorts, MBS-COV powder is reconstituted with normal saline (0.9% 
Sodium Choloride Injection) before use and administered through a portable nebulizer, Vibrating 
mesh nebulizer Air Pro 3, for single dose groups and multi-dose groups.  
6.1.1. Packaging and Labeling 
Study drug will be prepared, packaged, and labeled by   CCI              , and will be shipped by 
sponsor-designated CRO. 
Study treatment will be labeled, according to the regulatory guidelines, as an investigational 
product to ensure that it will not be used outside of the clinical investigation. The Sponsor, 
protocol number, expiry date and time, and any additional relevant information will appear on 
the pack label. 
Example study treatment labels for both Part A and Part B is presented in Figure 6-1 and Figure 
6-2. 


 
 
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Figure 6-1: 
Example Part A and Part B Study Treatment Vial Label 
 
 
Figure 6-2: 
Box label for Clinical Study Treatment  
 
 
 
 
6.1.2. Storage and Handling 


 
 
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All study treatment vials, MBS-COV and placebo must be stored in a secure area (e.g., a locked 
cabinet), protected from light, and be stored at refrigerated condition 2-8°C. Access to study 
treatments will be restricted to authorized personnel only.  
The investigator must maintain an accurate record of the shipment, storage, and dispensing of the 
study drug in a drug accountability log. An accurate record including the date and amount of 
study drug dispensed to each participant must be available for inspection at any time. A study 
CRA assigned to monitor the investigational site will review these documents once study drug 
has been received by the investigational site. Study drug will be accounted for on an ongoing 
basis during the study. 
6.1.3. Study Treatment Administration   
Detailed guidelines for dose of formulation, administration technique and administration 
direction can be found in the study pharmacy manual.  
All participants, after signing the Informed Consent Form (ICF), will be assessed during the 
screening phase. Eligible participants who have completed the screening phase will proceed with 
treatment phase of the study. Based on the phase of the study and randomization/Enrolment, 
study pharmacist will prepare the study drug for each participant and participants will be dosed 
individually at the pharmacy (or) designated space in the study site. Please refer to the study 
pharmacy manual for preparation of study drug prior to administration to each participant. 
6.1.4. Study Treatment Dispensation 
In both part of the study, the participants will be enrolled /randomized using a web-based 
randomization system (IWRS) and each participant enrolled into the study will receive assigned 
kit number including vials to be used via IWRS per the study enrolment/randomization scheme.  
6.1.5. Study Treatment Accountability 
Study treatments must be used in accordance with this protocol and only under the direction of 
the responsible investigator. The investigational site must maintain complete and accurate 
records showing receipt and disposition of all study treatments, including master records listing 
the date of receipt, the number of the kits received, and a dispensing record which includes each 
quantity dispensed, identification of the staff member to whom dispensed, the date of dispensing, 
the intended study participant number, and the identification of the preparer. All used and unused 
study kits will be retained by the investigational site until study treatment accountability can be 
confirmed by study CRA during the monitoring visits. Instructions will be provided by Sponsor 
regarding final disposition of all study drug in compliance with applicable regulations. 
A study treatment accountability log will be provided to the site for use by the Investigator to 
maintain current and accurate inventory records (batch, expiry, and quantity) covering the receipt, 
dispensing and the return/destruction of all the study treatments.  


 
 
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At the conclusion of the study, the Investigator must agree to return or destroy all study materials 
as instructed by the Sponsor.  
6.2. CONCOMITANT MEDICATIONS 
Unless medication is necessary for safety reasons and approved by the Sponsor and the 
Investigator, participants must abstain from taking any prescription or non-prescription drugs, 
within 14 days or 5 times the half-life (whichever is longer) prior to the first dose of IP until 
completion of the study. 
During the entire study period, participants must adhere to the following prohibitions: 
● Able to abstain from the use of nicotine/tobacco containing products during the study. 
● Able to abstain from the consumption of alcohol and any alcohol-containing products 
from 48 hours before dosing to the end of the study. 
● Able to abstain from the consumption of coffee and any caffeine-containing products 
from 48 hours before dosing to the end of study. 
 


 
 
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7. 
DESCRIPTION 
OF 
PROTOCOL 
ASSESSMENTS 
AND 
PROCEDURES 
7.1. INFORMED CONSENT 
A written informed consent will be obtained for this study by the Investigator or designee from 
all participants prior to performance of any protocol-specific procedure. This study will be 
conducted in accordance with the provisions of the Declaration of Helsinki.  
The Investigator must comply with applicable regulatory requirements and must adhere to the 
Good Clinical Practice (GCP) in the process of obtaining and documenting the informed consent. 
The Investigator, or designee, must also inform participants of all pertinent aspects of the study. 
Before written informed consent is obtained from the participant, the Investigator or a person 
designated by the Investigator, must provide the participant enough time and opportunity to 
inquire about the details of the study and to decide whether or not to participate in the study. All 
questions addressed by the participant about the study must be answered to the satisfaction of the 
participant. Prior to the participant’s participation in the study, the written informed consent must 
be signed and personally dated by the participant and by the person who conducted the informed 
consent discussion. Authorization for release of protected health information must also be 
obtained, as per local policies.  
7.2. ASSESSMENT OF ELIGIBILITY 
The Investigator must assess participant’ continued eligibility for the study as per the Inclusion 
and Exclusion criteria, during the Screening Phase. The eligibility criteria are described in 
Section 3.4.1 (Inclusion Criteria) and Section 3.4.2 (Exclusion Criteria). In the event that the 
participant is not suitable or eligible for the study, the participant will be considered “screen 
failure”.  
7.2.1. Re-screening 
A participant who signed a consent form but did not meet the inclusion/exclusion criteria is 
classified as a screen failure.  
Note: If a participant initially fails to meet inclusion/exclusion criteria and is later reconsidered 
for participation, the participant will be re-consented and assigned a new unique identification 
number at the time of re-screening. Participants who fail their first screening attempt may be re-
screened a maximum of once and may be enrolled if they are found to meet all inclusion and no 
exclusion criteria when re-screened. 
For consented participants who do not meet eligibility criteria, a Screen Failure Case Report 
Form (CRF) will be completed. The Screen Failure CRF will contain the following details: the 
participant identification number, the date of ICF signature, demographic information (see 


 
 
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Section 7.3), and the reason for screen failure. No additional information will be required for 
participants who fail screening. 
7.3. DEMOGRAPHIC INFORMATION 
In this study the demographic information will include: 
 Dates of ICF signature  
 Date of birth 
 Gender 
 Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Reported, or Unknown) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, or Unknown) 
 Use of tobacco or nicotine replacement products and e-cigarettes 
7.4. MEDICAL HISTORY 
A medical history will be recorded during the Screening Phase and will include: 
 All ongoing medical conditions 
 All previously resolved medical conditions that are relevant in the judgment of the 
Investigator  
 Any prior medical conditions that have resolved within the last year  
Events that emerge prior to the first treatment will be recorded in the medical history and not as 
AEs. Aside from being used to determine participant eligibility, this information will permit the 
Investigator to record the nature, duration, and severity of any ongoing baseline medical 
conditions prior to the participant’s receiving investigational product treatment.  
 
For each relevant history, the following will be documented:  
 Disease/disorder/condition 
 Date of diagnosis 
 History status (resolved or ongoing). 
7.5. PHYSICAL EXAMINATION 
The physical examination will include routine examinations for the following: 


 
 
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 Constitutional/General Appearance 
 Head, Ears, Eyes, Nose, Throat (HEENT) 
 Neurologic  
 Chest (including heart and lung) 
 Abdomen 
 Musculoskeletal and Extremities 
 Dermatologic 
 Lymphatic  
 Psychiatric  
Each abnormality will be recorded and the Investigator will record an assessment of its clinical 
significance.  
7.6. VITAL SIGNS, HEIGHT AND WEIGHT 
The following vital signs will be collected:  
 Systolic and Diastolic Blood Pressure 
 Pulse 
 Respiratory Rate  
 Oral Temperature 
Blood pressure and pulse will be obtained in the supine position after participant has been resting 
for 5 minutes. 
In addition, the following will be recorded: 
 Height (Only performed at Screening visit) 
 Weight 
 Body Mass Index  
7.7. CONCOMITANT MEDICATION 
 
All medications and therapies administered or taken by the participant beginning 14 days prior to 
Screening Visit and throughout the study will be recorded in the source documents and on the 
appropriate page of the Case Report Form (CRF). Participants must be questioned at each study 


 
 
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visit concerning any new medications or changes in current medications including over-the-
counter medication and topical medication. 
For each medication and non-study treatment, the following will be documented: 
 Medication/treatment name (generic name may be used if trade name is unknown) 
 Dose, unit, and frequency of dosing (individual dosages, not total daily dose).  
o Note: Each new dose of medication should be recorded as a separate entry, with 
the exception of medications that are given on a sliding scale. For these, it is 
acceptable to enter the range of the dosage, including the start and stop dates for 
which the specified dosage range was used. 
 Route of dosing  
 Indication for use 
 The start date  
 The stop date (if medication/therapy is not ongoing).  
7.8. CLINICAL LABORATORY ASSESSMENTS 
All laboratory assessments will be reviewed by the Investigator. If clinically significant findings, 
as determined by the Investigator, are recorded for a particular symptom, sign or abnormal 
measurement, that measurement will be repeated at medically appropriate intervals until the 
value returns to an acceptable range, a specific diagnosis is established, or the condition is 
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Table 7-1: 
Lab Parameters  
CBC Parameters 
Biochemistry Parameters 
Urinalysis 
Hemoglobin (g/dL) 
Hematocrit (%) 
RBC/Erythrocytes (10^12/L) 
WBC/Leukocytes (10^6/L) 
Absolute 
Neutrophil 
Count 
(10^6/L) 
Platelets (10^9/L) 
Differential WBC: 
- 
Neutrophils (%) 
- 
Lymphocytes (%) 
- 
Monocytes (%) 
- 
Eosinophils (%) 
- 
Basophils (%)  
Liver Function Tests 
Total bilirubin (mg/dL) 
Alkaline 
Phosphatase 
(ALP) 
(U/L) 
Aspartate 
Aminotransferase 
(AST) (or SGOT) (U/L) 
Alanine Aminotransferase (ALT) 
(or SGPT) (U/L) 
Total Protein (g/dL) 
Albumin (g/dL) 
Lactate Dehydrogenase (LDH) 
(U/L) 
Amylase (U/L) 
Lipase (U/L) 
Renal Function Tests 
Serum creatinine (mg/dL) 
eGFR(ml/min/1.73 m2) 
Electrolytes 
Sodium (mEq/L) 
Potassium (mEq/L) 
Chloride (mEq/L) 
Calcium (mg/dL) 
Bicarbonate (mEq/L) 
Other: 
Glucose, Random (mg/dL) 
Creatine kinase (U/L)  
Triglyceride (TG) (mg/dL) 
Total Cholesteriol (TC) (mg/dL) 
Coagulation Parameters 
Prothrombin time (PT) 
Activated partial thromboplastin 
time (APTT) 
Thrombin time (TT) 
Fibrinogen (FIB) 
pH  
Specimen Appearance  
Color  
Specific Gravity 
Ketones  
Bilirubin  
Occult Blood  
Glucose 
Protein 
Nitrite 
Urobilinogen (mg/dL) 
Leukocyte Esterase 
 
Miscellaneous 
Serum pregnancy test 
Urine pregnancy test 
(for 
female 
participants 
of 
childbearing potential) 
Drug in Urine  
Alcohol breath test 
Chest X-ray 
PK Evaluation 
ADA 
COVID-19 antigen rapid test at 
screening and qRT-PCR test 
Serology 
HBs Ag, HCV Ab and HCV RNA 
(if required), HIV Ab 
7.9. 12-LEAD ELECTROCARDIOGRAM 
12-Lead ECG will be performed per the site standard procedures. The following parameters will 
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the CRF: ventricular rate (beats per minute), PR interval (msec), QRS interval (msec), QT 
interval (msec), and QTc interval (msec). Additionally, the Investigator will record the overall 
results of the 12-lead ECG reading as either normal or abnormal, and if abnormal, as either “not 
clinically significant” or “clinically significant.” If abnormalities are observed, each will be 
recorded. Each treatment-emergent abnormality that is clinically significant will be recorded as 
an AE. Each 12-lead ECG should be signed by a physician. Clinically significant abnormal 12-
lead ECG’s may be repeated at the discretion of the Investigator. 
7.10. NASOPHARYNGEAL SWAB OR NASAL SWAB FOR COVID-19 
Nasopharyngeal or nasal swab sample will be collected for COVID-19 antigen rapid test at 
screening and qRT-PCR test according to Table 4-1 and Table 4-2. The participant will be 
followed, and samples will be collected for the entire duration of the study.  
7.11. SPIROMETRY ASSESSMENT 
It is to be used as a validation method to ensure participants don’t have a former yet undiagnosed 
respiratory disease and to validate the presence of abnormal Forced Expiratory Volume1(FEV1) 
values. 
Spirometry will evaluate the respiratory functions of acute bronchospasm. Spirometric parameter 
including FEV1% (the percent of predicted FEV1), FEV1/FVC, and peak expiratory flow (PEF). 
Extra spirometry assessments may be repeated at the discretion of the investigator. 
7.12. RANDOMIZATION 
Healthy participants who are eligible to participate in the study will be randomized to one of the 
treatment groups via IWRS in assigned cohort (Interactive Web Based Randomization System) 
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8. 
STATISTICAL CONSIDERATIONS  
This section presents general information about statistical considerations and concepts such as 
randomization, sample size, and a brief discussion on analysis methodology, as well as some 
data conventions. Detailed descriptions of the statistical analysis methods and data conventions 
will be included in a separate document; i.e., the Statistical Analysis Plan (SAP). 
8.1. COHORTS/TREATMENT GROUPS  
Refer to Table 3-1, and Table 3-2 for description of cohorts/treatment groups.  
8.2. STUDY ENDPOINTS/ OUTCOME MEASURES 
Refer to Section 
 for list of study endpoints/outcome measures.  
8.3. SAMPLE SIZE DETERMINATION AND RATIONALE 
The sample size of at least 44 participants (24 healthy participants in part A and 20 healthy 
participants in part B) will be used in this study. This sample size is selected based on clinical 
judgment and not based on statistical power calculation; it is deemed adequate to provide 
clinically meaningful descriptive results consistent with study objectives. 
8.4. RANDOMIZATION  
In Part A (SAD Phase), 24 participants (8 per group) will be randomized in a 6:2 ratio (MBS-
COV: placebo). In Part B (MAD Phase), a total of 20 participants (10 per group) will be 
randomized in a 8:2 ratio (MBS-COV: placebo)  
 
An individual, independent of the clinical study team, will develop the randomization schedules. 
The actual randomization assignment will be made through a web based system. Participants 
who have provided written informed consent and have met all the inclusion criteria and none of 
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8.5. BLINDING AND PREVENTION OF BIAS 
8.6. INTERIM ANALYSIS 
There is no efficacy interim analysis planned for this study; however, the safety data from all 
participants of each completed cohort will be reviewed by the SRC prior to enrolment of further 
participants or dose escalation.  
8.7. GENERAL STATISTICAL CONSIDERATIONS 
All collected study data will be presented in participant data listings and/or will be summarized. 
Statistical analyses will be performed using SAS® for Windows, version 9.4 or later.  
A Statistical Analysis Plan (SAP) will be developed and approved before the database is locked. 
The SAP will present the detailed statistical methodology to be used in analyzing the efficacy 
and safety data from this study.  
8.7.1. Statistical Analysis Populations  
8.7.1.1. 
Full Analysis Set (FAS) 
FAS includes all randomized participants. This analysis set will be used to analyze the 
disposition, demographic and baseline characteristics of the subjects. 
8.7.1.2. 
Safety Set (SS) 
SS includes all the participants who receive the study drug at least once. This population will be 
used for the analysis of safety parameters.  
8.7.1.3. 
PK concentration analysis set (PKCS) 
PKCS includes all randomized participants who receive at least one dose of the study drug and 
have at least one plasma concentration. The PKCS will be used for PK concentration analysis. 
8.7.1.4. 
PK parameters analysis set (PKPS) 
PKPS includes all randomized participants who receive at least one dose of the study drug with 
no major protocol violations or protocol deviations that have a significant impact on PK 
parameters (Cmax, AUC, etc.), and have at least one analyzable PK parameter. The PKPS will be 
used for PK parameters analysis. 
8.7.1.5. 
Immunogenicity Set (IS)  
IS includes all randomized participants who receive at least one dose of the study drug, and have 
at least one ADA concentration. The IS will be used for immunogenicity analysis. 
8.7.2. Missing Data 


 
 
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All efforts will be made to minimize the amount of missing data for the study. The methods of 
handling missing data will be detailed in the SAP.  
8.7.3. Statistical Methods  
All safety analyses will be conducted using the Safety population.  
For continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum 
and maximum) will be presented by treatment group. For categorical variables both frequencies 
and percentages will be presented by treatment group. 
8.7.4. Participant Disposition  
The disposition of all participants who signed an ICF will be provided. The numbers of 
participants screened, randomized (if applicable), received treatment, completed, and 
discontinued during the study, as well as the reasons for discontinuation will be summarized. 
Disposition and reason for study discontinuation will also be provided as a by-participant listing.  
8.7.5. Demographics And Baseline Characteristics Analysis  
Demographics and baseline characteristics will be summarized using appropriate descriptive 
statistics. 
8.7.6. Concomitant Medications/Therapies 
All prior and concomitant medications recorded in the case report form will be coded to all 
matching Anatomic Therapeutic Classification codes using the most recent version of the WHO 
Drug Dictionary. Descriptive summaries will be prepared using the coded term. All concomitant 
medications recorded in the case report form will be listed. 
8.7.7. Pharmacokinetic (PK) Analysis 
The pharmacokinetic analyses and estimation of PK parameters will be performed using  non 
compartmental methods using Phoenix® WinNonlin 8.3.1 or above. 
8.7.8. Safety Analyses  
8.7.8.1. 
Adverse Events  
Adverse events will be classified by system organ class (SOC) and preferred term (PT) according 
to the most recent version of MedDRA dictionary.     
TEAE are defined as adverse events with onset date on or after the first treatment. TEAEs will be 
summarized by treatment group, System Organ Class, and preferred term. The following TEAE 
summaries will be provided: 
a) Overall (i.e., regardless of severity or relationship to treatment) 
b) Adverse events by severity 
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d) Adverse events leading to treatment discontinuation by severity 
e) Adverse events leading to death by severity 
8.7.8.2. 
Clinical Laboratory Data 
Tabulations of raw data and change from baseline values will be presented by time point for each 
lab parameter. Tabulations will include the number of observations, mean, standard deviation, 
median, and minimum and maximum values. Abnormal laboratory results will be listed and 
summarized. 
8.7.8.3. 
Vital signs  
Tabulations of raw data and change from baseline values will be presented by time point for each 
vital sign parameter. Tabulations will include the number of observations, mean, standard 
deviation, median, and minimum and maximum values. 
8.7.8.4. 
Physical Examination  
Physical Examination findings will be presented as by-participant listing.  
8.7.8.5. 
12-lead ECG  
Tabulations of raw data and change from baseline values will be presented by time point for each 
12-lead ECG parameter. Tabulations will include the number of observations, mean, standard 
deviation, median, and minimum and maximum values. 
8.7.8.6. 
Other Safety Data 
All data from other tests such as unscheduled tests will be presented as a by-participant listing 
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9. 
SAFETY REPORTING 
The Investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE, as provided in this protocol. During the study when there is a 
safety evaluation, the Investigator or site staff will be responsible for detecting, documenting, 
and reporting AEs and SAEs as detailed in this Section of the protocol.  
9.1. ADVERSE EVENT (AE) DEFINITION  
An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, or disease 
that occurs or is reported by the participant to have occurred, or a worsening of a pre-existing 
condition. An adverse event may or may not be related to the study treatment.  
AEs will be elicited through direct questioning and participant reports. Any abnormality in 
physical examination findings or laboratory results that the investigator believes is clinically 
significant (CS) to the research participant and that occurred after initiation of the first study 
treatment will be reported as AEs. Abnormal findings that are NOT clinically significant should 
not be recorded as an AE. 
9.2. REPORTING OF ADVERSE EVENTS (AES) 
 The Investigator will then record all relevant AE/SAE information in the eCRF. All AEs will be 
collected from the time of dose administration until the safety follow-up visit. Medical 
occurrences that occur before the start of the study treatment, but after obtaining the ICF will be 
recorded in the Medical History section of the eCRF and not in the AE section, unless considered 
related to the study procedures.  All events will be followed to resolution or until the participant 
completes the study. A final assessment of outcome will be made at that time.  
All AEs must be recorded in the participant’s medical records and on the CRF. AEs will be 
reported using customary medical terminology along with the following information: the onset 
and end dates,  whether the event is considered to be a SAE (see Section 9.3), the impact the 
event had on study treatment (see Section 9.2.1), the Toxicity Grading Scale (intensity) of the 
event (see Section 9.2.2), the causality of the event (see Section 9.2.3), whether treatment is 
given as a result of the event (see Section 9.2.4), and the outcome of the event (see Section 9.2.5). 
9.2.1. Impact on Study Treatment 
The impact the event had on the study treatment will be assessed as either: dose increased, dose 
not changed, dose rate reduced, dose reduced, drug interrupted, drug withdrawn, not applicable, 
or unknown. The “not applicable” assessment will be used only when the participant is no longer 
in the Treatment Phase of the protocol. 
9.2.2. Toxicity Grading Scale (Intensity) Assessment 


 
 
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According to the guideline of “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” issued by FDA, the severity of 
adverse events occurred in this study will be graded. The general guidelines for assessing the AE 
grade refer to appendix 1. 
9.2.3. Event Causality Assessment  
AEs will be assigned a relationship (causality) to the study treatment. The Investigator will be 
responsible for determining the relationship between an AE and the study treatment. The type of 
event, organ system affected, and timing of onset of the event will be factors in assessing the 
likelihood that an AE is related to the study treatment. Relationship of AEs to study treatment 
will be classified as follows: 
1. Definitely related: This category applies to those AEs that the Investigator feels are 
incontrovertibly related to the study treatment. An AE may be assigned an attribution of 
definitely related if or when it meets all of the following criteria: (1) it follows a reasonable 
temporal sequence from administration of the study treatment; (2) it could not be reasonably 
explained by the known characteristics of the participant’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the participant; (3) it follows a 
known response pattern to treatment with the study treatment. 
2. Probably related: This category applies to those AEs which, after careful medical 
consideration at the time they are evaluated, are felt with a high degree of certainty to be 
related to the study treatment. An AE may be considered probable if or when (must have 
three): (1) it follows a reasonable temporal sequence from administration of the study 
treatment. (2) It could not readily have been produced by participant’s clinical state, 
environmental or toxic factors, or other therapies administered to the participant. (3) 
Disappears or is decreased upon discontinuation of the study treatment. (4) It follows a 
known response pattern to treatment with the study treatment.  
3. Possibly related: This category applies to those AEs which, after careful medical 
consideration at the time they are evaluated, are judged unlikely but cannot be ruled out with 
certainty to the study treatment. An AE may be considered possible if or when (must have 
two): (1) it follows a reasonable temporal sequence from administration of the study 
treatment. (2) It could not readily have been produced by participant’s clinical state, 
environmental or toxic factors, or other therapies administered to the participant. (3) 
Disappears or is decreased upon discontinuation of the study treatment. (4) It follows a 
known response pattern to treatment with the study treatment.  
4. Unlikely related: In general, this category can be considered applicable to those AEs which, 
after careful medical consideration at the time they are evaluated, are judged likely to be 
unrelated to the study treatment. An AE may be considered unlikely if or when (must have 
two): (1) it does not follow a reasonable temporal sequence from administration of the study 
treatment. (2) It could not readily have been produced by participant’s clinical state, 


 
 
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environmental or toxic factors, or other therapies administered to the participant. (3) 
Disappears or is decreased upon discontinuation of the study treatment. (4) It does not follow 
a known response pattern to treatment with the study treatment.  
5. Unrelated: This category applies to those AEs which, after careful consideration at the time 
they are evaluated, are clearly and incontrovertibly due to extraneous causes (disease, 
environment, etc.) and determined with certainty to have no relationship to the study 
treatment.  
9.2.4. Treatment Given as a Result of the Event 
The event impact in terms of treatment provided will be as either: none, medication administered, 
non-drug therapy administered, surgery performed, hospitalization, or other (with a 
specification). 
9.2.5. Event Outcome Assessment 
The outcome of the event will be assessed as either: fatal, not recovered/not resolved, 
recovered/resolved, recovered/resolved with sequelae, recovering/resolving, or unknown. Only 
one AE per participant is allowed to have an outcome assessment as “death.” If there are 
multiple causes of death for a given participant, only the primary cause of death will have an 
outcome of death.  
9.3. SERIOUS ADVERSE EVENT (SAE) DEFINITION  
A SAE is defined as any AE that: 
 Results in death 
 Is life threatening (the participant is at immediate risk of dying from the adverse 
experience) 
 Requires participant hospitalization or prolongs existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse effect when, based upon appropriate 
medical judgment, they may jeopardize the participant or participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
9.4. REPORTING OF SERIOUS ADVERSE EVENTS (SAES)  
The Investigator is required to report all SAEs that occur during the time period specified in 
Section 9.2. Once the Investigator becomes aware of an SAE, he/she must report the SAE to 
Safety Contact/Sponsor within 24 hours. The fax number or email address for reporting SAEs 
can be found in the protocol-specific Safety Management Plan. 


 
 
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The Safety Contact/Sponsor may request additional supporting documentation as it becomes 
available, such as lab reports, 12-lead ECG reports, discharge summary, hospital notes, etc., if 
applicable. Additional follow-up information as it becomes available must be reported to the 
Medical Monitor. 
The Investigator is also responsible for reporting all SAEs to the appropriate Institutional Review 
Board (IRB) in accordance with local laws and regulations. The Investigator is responsible for 
maintaining documentation in the study file that indicates the IRB has been properly notified.  
9.4.1. SAE Follow-Up 
All participants experiencing an SAE, including the discontinued participants, must be closely 
followed until sufficient information is obtained to indicate a return to normal status or until the 
event stabilizes at a level acceptable to the Investigator or the last study visit, whichever occurs 
first (i.e., recovery, return to baseline status, no further improvement expected, or death). 
For each SAE indicated as an unresolved event on the initial report, regardless of whether the 
participant completed the study or withdrew, the site should submit a follow-up report with 
updated information. 
9.5. PREGNANCY REPORTING 
To ensure participant safety, any pregnancy that occurs while participant is taking study drug 
should be recorded using a Pregnancy Notification Form and reported immediately to Sponsor 
within 24 hours of learning of the pregnancy. 
If a participant becomes pregnant during the study before the end of treatment period, they will 
be a discontinued participant. If a participant becomes pregnant during the study after the end of 
treatment during the follow up portion, they can complete the remaining scheduled follow up 
unless there is a medical contraindication. 
9.5.1. AE and SAE Reporting  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP may have 
interfered with the effectiveness of a contraceptive medication. Congenital abnormalities/birth 
defects and spontaneous miscarriages should be reported and handled as SAEs. 
9.5.1.1. 
Abortions 
An induced elective abortion to terminate a pregnancy without medical reason is not regarded as 
an AE. However, an induced therapeutic abortion to terminate a pregnancy because of 
complications or medical reasons must be reported as an SAE. The underlying medical diagnosis 
for this procedure should be reported as the SAE term. A spontaneous abortion in a study 
participant is always considered an SAE.  
9.5.2. Informed Consent  


 
 
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The ICF will include information regarding reporting of pregnancy to the Sponsor and collection 
of information through the end of pregnancy that occurs in a female participant. If a female 
partner becomes pregnant, the Investigator will request consent from the partner to collect this 
information. 
9.5.3. Pregnancy Follow-Up 
The pregnancy will be followed-up to determine the outcome (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) and should include an 
assessment of the possible relationship to the study treatment of any pregnancy outcome. This 
information should also be documented on the Pregnancy Outcome Form and reported to the 
Sponsor.  
. 


 
 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Participants will be identified on CRFs by a unique participant identification number and on 
source documents by name and date of birth. No personal identifier will be used in any 
publication or communication used to support this research study. The participant identification 
number will be used if it becomes necessary to identify data specific to a single participant.  
The local IRB, FDA, the monitors, auditors and personnel authorized by the Sponsor are eligible 
to review the medical and research records related to this study as part of their responsibility to 
protect human participants in clinical research. They will be given direct access to source data 
and documentation (e.g., medical charts/records, printouts etc.) for source data verification, 
provided that participant confidentiality is maintained in accordance with local requirements. 
Access to electronic medical records may be governed by institution policy. Each site will be 
required to ensure access while remaining compliant with institutional requirements. 
 
 


 
 
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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. MONITORING REQUIREMENTS 
The specific obligations outlined in 21 Code of Federal Regulations (CFR) and ICH guidelines 
require the Sponsor to maintain current personal knowledge of the progress of a study. Therefore, 
the Sponsor's designated monitor will visit the site during the study as well as maintain frequent 
telephone and written communication. The Investigator will permit the Sponsor to monitor the 
study as frequently as is deemed necessary and provide access to medical records to ensure that 
data are being recorded adequately, that data are verifiable and that protocol adherence is 
satisfactory.  
As delineated above, the Investigator will permit representatives of the Sponsor and/or 
designated CRO to inspect all CRFs and corresponding study participant original medical 
records (source documents) at regular intervals throughout the study. Participant original medical 
records and other relevant data must be available to support all data recorded in the CRF. In 
addition to the original medical records, these data may include but are not limited to study, 
laboratory reports, etc.  
In accordance with federal regulations, site inspections will serve to verify strict adherence to the 
protocol and the accuracy of the data that is being entered on the case report forms. A 
Monitoring Log will be maintained at each study site. The Monitoring Log will be signed by the 
monitor, dated and stated the type of visit. The Investigator should be aware that the study site 
and participant records may be inspected by the Sponsor and or representatives of the designated 
CRO, FDA or other regional regulatory authority. 
11.2. ACCEPTABILITY OF CASE REPORT FORMS (CRFS) 
For each participant who has signed an informed consent form, a CRF must be completed. For 
participants who are screen failures, this would be limited to the screen failure CRF page. All 
source documents and CRFs will be completed as soon as possible after the participant's visit and 
corrections to data on the CRFs will be documented, if applicable. The Investigator will review 
the CRFs to indicate that, to his/her knowledge, they are complete and accurate. CRFs will be 
reviewed by the Sponsor’s or designated CRO’s monitor, who will make a decision as to their 
acceptability.  
11.3. MODIFICATION OF PROTOCOL 
The Investigator will not modify or alter this protocol without first obtaining the concurrence of 
the Sponsor. Approval by the Investigator’s IRB must also be obtained prior to implementation 
of the change, with two exceptions: 
1. When necessary to eliminate apparent immediate hazard to the participant; or 


 
 
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2. When the modification does not involve the participant’s participation in the study. 
An amendment may also require modification of the informed consent form. The Investigator 
will provide an approval letter for the amendment and revised informed consent form, if 
applicable, to the Sponsor. An amendment must be provided in writing and it must be dated by 
both the Sponsor and the Investigator. If necessary, the Sponsor will submit protocol 
amendments to FDA and other appropriate regulatory authorities and notify other Investigators 
using this protocol. 
11.4. REPORTING PROTOCOL DEVIATIONS 
The Investigator is obligated to follow the protocol without departure from the requirements 
written in the protocol. If the Investigator deviates from the protocol requirements, the Sponsor 
will make the determination as to whether the participant will continue in the study. The Sponsor 
also has the right to discontinue the participant for protocol violations. The IRB may also have to 
be contacted if safety to the participant or if the scientific soundness of the study is involved. All 
protocol deviations must be documented in the CRFs. 
11.4.1. Major Protocol Deviation or Violation 
A major protocol deviation or violation is a deviation from the IRB approved protocol that may 
affect the participant's rights, safety, or well-being and/or the completeness, accuracy, and 
reliability of the study data. Examples of this include: 
 Failure to obtain informed consent prior to initiation of study-related procedures  
 A research participant does not meet the protocol's eligibility criteria but was enrolled 
without prior approval from the sponsor. 
 A research participant received the wrong treatment or incorrect dose. 
 A research participant met withdrawal criteria during the study but was not withdrawn. 
 A research participant received a prohibited concomitant medication. 
 Failure to treat research participants per protocol procedures that specifically relate to 
primary efficacy outcomes. 
 Changing the protocol without prior sponsor and IRB approval. 
 Multiple minor violations of the same nature after multiple warnings. 
11.4.2.  Minor Protocol Deviation or Violation 
A minor protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that has not been approved by the IRB and which DOES NOT 
have a major impact on the participant's rights, safety or well-being, or the completeness, 
accuracy and reliability of the study data.  Examples of this include: 


 
 
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 Follow-up visits that occurred outside the protocol required time frame because of the 
participant’s schedule. 
 Blood samples obtained at times close to but not precisely at the time points specified in 
the protocol. 
 
 


 
 
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12. 
ETHICS AND REGULATORY REQUIREMENTS 
This study is to be conducted in accordance with the specifications of this protocol and in 
accordance with principles consistent with Declaration of Helsinki, GCP, 21 CFR, ICH E6, 
HIPAA regulations in 45 CFR Part 164 (US only), and the Belmont Principles of respect for 
persons, beneficence, and justice. No protocol changes will be implemented without the prior 
review and approval of the IRB, except when the modification does not involve the participant’s 
participation in the study or where it may be necessary to eliminate an immediate hazard to 
research participant. In the latter case, the change will be reported to the IRB as soon as possible, 
according to IRB regulations.  
Additionally, the study product used in this study is manufactured, handled and stored in 
accordance with applicable GMP. The study product provided for this study will be used only in 
accordance with this protocol. 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
The Principal Investigator (PI) at each site will provide the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) with all appropriate materials as required by 
their IRB/IEC, including but not limited to the clinical study protocol, informed consent form, 
and any advertising materials. The study will not be initiated until the IRB/IEC provides written 
approval of the aforementioned documents and until approval documents have been obtained by 
the Principal Investigator and Sponsor or Sponsor designee. The Investigator will not participate 
in the decision. If the Investigator is an IRB or IEC member, documentation must be provided 
indicating recusal from the approval process. Appropriate reports on the progress of this study by 
the Principal Investigator will be made to the IRB/IEC as required by local and applicable 
government regulations and in agreement with policy established by the Sponsor. The 
Investigator is required to maintain an accurate and complete record of all written 
correspondence to and received from the IRB/IEC and must agree to share all such documents 
and reports with the Sponsor. 
No changes from the final approved protocol will be initiated without the IRB/IEC’s prior 
written approval or favorable opinion of a written amendment, except when necessary to 
eliminate immediate hazards to the participants or when the modification does not involve the 
participant’s participation in the study.  
12.2. INVESTIGATOR’S RESPONSIBILITIES 
The Investigators are responsible for performing the study in full accordance with the protocol 
and the current revision of the Declaration of Helsinki, the Good Clinical Practice: Consolidated 
Guideline, approved by the ICH, and any applicable national and local laws and regulations.  


 
 
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12.3. PARTICIPANT INFORMED CONSENT REQUIREMENTS 
All participants participating in this study will be given to by the Investigator and/or designee, 
written and oral information about the study in a language understandable by the participant. 
Written informed consent will be obtained from each participant prior any procedures or 
assessments that would not otherwise be required for the care of the participant are done and 
after the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in 
force are explained and the participant has been given sufficient time to ask questions and 
consider participation in the study. It will also be explained to the participants that they are free 
to refuse entry into the study and free to withdraw from the study at any time without prejudice 
to future treatment. It is permissible for a third person (e.g., a family member) to be present 
during the explanation of the study. 
The written Informed Consent Form (ICF) will be in compliance with CFR 21 Part 50.27 and 
GCP guidelines. The Sponsor and/or designated CRO will approve the ICF and all amendments 
to the ICF prior to submission to the IRB/IEC. A copy of the ICF to be used will be submitted by 
the Investigator to the IRB/IEC for review and approval prior to the start of the study. The study 
site must provide the Sponsor with an unsigned copy of IRB/IEC-approved ICF along with 
applicable documentation to support this approval. The original signed ICF is retained in the 
participant's study records, and a copy is provided to the participant. A second copy may be filed 
in the participant’s medical record, if allowed by institutional policy.  
 


 
 
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13. 
DATA HANDLING AND RECORD KEEPING 
13.1. RECORDING AND COLLECTION OF DATA 
The primary source document for this study will be the participant's medical record. If separate 
research records are maintained by the Investigator(s), the medical record and the research 
records will be considered the source documents for the purposes of auditing the study.  
Applicable source data will be manually transcribed to approve case report forms (CRF). The 
Investigator is ultimately responsible for the accuracy of the data transcribed on the forms. All 
source documents and CRFs will be completed as soon as possible after the participant's visit. 
The Investigator will review the CRFs to indicate that, to his/her knowledge, they are complete 
and accurate. Designated source documents will be signed and dated by the appropriate study 
personnel. The Investigator must agree to complete and maintain source documents and CRFs 
for each participant participating in the study. 
All research data will be entered, either electronically or manually, into a computerized database. 
The clinical database will be designed by the clinical data manager in accordance with 21 CFR 
Part 11 and based on protocol requirements defined by the Sponsor in association with the Lead 
Investigator.  
The Investigator will maintain a confidential list of study participants that will include each 
participant’s study number, name, date of birth, and unique hospital identification number if 
applicable. This list will be kept by the Investigator and will not be collected by the Sponsor. A 
notation will be made in the participant’s case history/medical chart that he/she is participating in 
a clinical study and has provided a signed and dated ICF as well as a release for protected health 
information as required by local policies. The Investigator must also maintain a separate 
screening log of all the participants screened for participation in the study; it should include 
gender, age, eligibility status, reason for ineligibility, if applicable; and study allocated 
participant number, if applicable.  
13.2. CLINICAL DATA MANAGEMENT 
The Sponsor and/or designated CRO will be responsible for the processing and quality control of 
the data. Data management will be carried out as described in the Sponsor’s or CRO’s standard 
operating procedures (SOPs) for clinical studies. 
The handling of data, including data quality control, will comply with regulatory guidelines 
(e.g., ICH E6 GCP, and local regulations where applicable) and the Sponsor’s or the CRO’s 
SOPs as well as provisions of the study-specific Data Management Plan. 


 
 
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13.3. ARCHIVING 
All study documentation at the Investigator site and Sponsor site will be archived in accordance 
with ICH GCP E6 and the Sponsor’s quality standards and SOPs. 
The Investigator will maintain all research records, reports, and case history reports for a period 
of two (2) years after regulatory approval of the investigational product. If no application is filed 
or if the application is not approved, records must be maintained for two (2) years after all 
investigations have been completed, terminated or discontinued and the FDA has been notified.  
These documents should be retained for a longer period however, if required by the applicable 
regulatory requirements or if needed by Sponsor or its authorized representative (as per 
GCP 5.5.11). 
At the completion of the study, details of the archival process must be provided to the Sponsor. 
Study records are participant to inspection by applicable health and regulatory agencies at any 
time.  
Records to be retained by the Investigator include, but are not restricted to: 
 Source data and the primary records upon which they are based (e.g., participant’s 
progress notes, adverse event data, test results, and any other diagnostic procedures 
required to evaluate the progress of the study) 
 Completed CRFs 
 Signed protocols and protocol amendments 
 Laboratory results, ranges, and certifications 
 IP and accountability records 
 Study personnel signature log 
 Monitoring logs 
 Correspondence to and from the Sponsor, designee and IRB 
 Principle Investigator and sub-investigator CVs 
 Signed informed consent and protected health information consent forms 
 Participant screening  
 SAE reports 
 IRB approval and re-approval letters 
 Other documents pertaining to the conduct of the study 
These documents must be maintained and kept on file by the Investigator so that the conduct of 
the study can be fully documented and monitored. 


 
 
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Study records should not be transferred from site or destroyed without prior written agreement 
between the Sponsor and the study Investigator. Study records are participant to inspection by 
applicable health and regulatory agencies at any time.  


 
 
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14. 
PUBLICATION PLAN 
All information supplied by Oneness Biotech Co., Ltd. in connection with this study and not 
previously published, is considered confidential information. This information includes, but 
is not limited to, the Investigator’s Brochure, clinical protocol, case report forms and other 
scientific data. Any data collected during the study are also considered confidential. This 
confidential information shall remain the sole property of Oneness Biotech Co., Ltd., shall 
not be disclosed to others without the written consent of Oneness Biotech Co., Ltd., and shall 
not be used except in the performance of this study. 
It is understood by the Investigator that the Sponsor will use the information collected in this 
clinical study in connection with the development of the investigational product. Therefore, this 
information may be disclosed as required to other Investigators or appropriate regulatory 
authorities. By agreeing to participate in this clinical study, the Investigator understands that 
he/she has an obligation to provide the Sponsor with complete test results and all data developed 
during this study. 
Publication and Disclosure: The site and Investigator agree to submit any proposed manuscript, 
presentation or other public disclosure regarding the study to Sponsor for review at least thirty 
(30) days prior to submitting such proposed manuscript to a publisher or delivering or making 
such presentation or other public disclosure to any third party. Within thirty (30) days of its 
receipt, Sponsor shall advise the site and/or Investigator, as the case may be, in writing of any 
information contained therein that is confidential information (other than research results 
included in a proposed manuscript) or that may impair Sponsor’s ability to obtain patent 
protection. Sponsor shall have the right to require the site and/or Investigator, as applicable, to 
remove specifically identified confidential information (but may not require removal of research 
results from a proposed manuscript) and/or to delay the proposed submission or delivery of the 
proposed manuscript or presentation, or other public disclosure, for an additional sixty (60) days 
to enable Sponsor to seek patent protection. The site and Investigator shall not publish, publicly 
disclose, present or discuss any results of or information pertaining to the site’s and 
Investigator’s activities prior to completion of the study, even if the study is terminated before its 
completion and the final clinical study report is signed off, or with respect to any endpoints or 
analyses other than those specified in this protocol. 


 
 
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15. 
REFERENCES 
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, 
Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz 
H, Neuzil K, Corey L, Gilbert P et al. (2021) Efficacy and Safety of the mRNA-1273 SARS-
CoV-2 Vaccine. N Engl J Med 384: 403-416 
Cao Y, Wang J, Jian F, Xiao T, Song W, Yisimayi A, Huang W, Li Q, Wang P, An R et al (2021) 
Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies. Nature 
https://doi.org/10.1038/s41586-021-04385-3   
Chen J, Wang R, Gilby NB, Wei GW (2022) Omicron variant (B.1.1.529): Infectivity, vaccine 
breakthrough, and antibody resistance. J Chem Inf Model 62: 412–422 
Dyer O (2021) Covid-19: Delta infections threaten herd immunity vaccine strategy. BMJ 374: 
n1933 
Knoll MD, Wonodi C (2021) Oxford-AstraZeneca COVID-19 vaccine efficacy. Lancet 397: 72-
74  
Kupferschmidt K, Wadman M (2021) Delta variant triggers new phase in the pandemic. Science 
372: 1375-1376 
Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, Stowe J, Tessier E, 
Groves N, Dabrera G, Myers R, Campbell CNJ, Amirthalingam G, Edmunds M, Zambon M, 
Brown KE, Hopkins S, Chand M, Ramsay M (2021) Effectiveness of Covid-19 Vaccines against 
the B.1.617.2 (Delta) Variant. N Engl J Med 385: 585-594 
Muik A, Lui BG, Wallisch AK, Bacher M, Muhl J, Reinholz J, Ozhelvaci O, Beckmann N, 
Guimil Garcia RC, Poran A et al (2022) Neutralization of SARS-CoV-2 Omicron by BNT162b2 
mRNA vaccine-elicited human sera. Science 375: 678–680 
Planas D, Veyer D, Baidaliuk A, Staropoli I, Guivel-Benhassine F, Rajah MM, Planchais C, 
Porrot F, Robillard N, Puech J, Prot M, Gallais F, Gantner P, Velay A, Le Guen J, Kassis-
Chikhani N, Edriss D, Belec L, Seve A, Courtellemont L et al. (2021) Reduced sensitivity of 
SARS-CoV-2 variant Delta to antibody neutralization. Nature 596: 276-280 
Tang P, Hasan MR, Chemaitelly H, Yassine HM, Benslimane FM, Al Khatib HA, AlMukdad S, 
Coyle P, Ayoub HH, Al Kanaani Z, Al Kuwari E, Jeremijenko A, Kaleeckal AH, Latif AN, 
Shaik RM, Abdul Rahim HF, Nasrallah GK, Al Kuwari MG, Al Romaihi HE, Butt AA et al. 
(2021) BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 
Delta variant in Qatar. Nat Med .DOI: 10.1038/s41591-021-01583-4 
Van Dorp L, Acman M, Richard D, Shaw LP, Ford CE, Ormond L, Owen CJ, Pang J, Tan CCS, 
Boshier FAT, Ortiz AT, Balloux F (2020) Emergence of genomic diversity and recurrent 
mutations in SARS-CoV-2. Infect Genet Evol 83: 104351 
Zamore PD, Tuschl T, Sharp PA, Bartel DP (2000) RNAi: double-stranded RNA directs the 
ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101: 25-33 
 
 


 
 
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16. 
APPENDIX 
16.1. APPENDIX 1: TOXICITY GRADING SCALE FOR HEALTHY ADULT AND ADOLESCENT 
VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE CLINICAL TRIALS 
For complete detailed information please refer to the link below: 
https://www.fda.gov/media/73679/download 
A. Tables for Clinical Abnormalities 
Local Reaction to 
Injectable Product 
Mild (Grade 1)  
Moderate (Grade 
2)  
Severe (Grade 
3)  
Potentially Life 
Threatening 
(Grade 4) 
Pain  
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness  
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness *  
2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling **  
2.5 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the 
actual measurement. 
Vital Signs *  
Mild (Grade 
1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Potentially 
Life 
Threatening (Grade 4) 
Fever (°C) **  
(°F) ** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40  
> 104 
Tachycardia - beats 
per minute 
101 – 115  
116 – 130  
> 130  
ER visit or hospitalization 
for arrhythmia 
Bradycardia - beats 
per minute*** 
50 – 54  
45 – 49  
< 45  
ER visit or hospitalization 
for arrhythmia 
Hypertension 
(systolic) - mm Hg 
141 – 150  
151 – 155  
> 155  
ER visit or hospitalization 
for malignant hypertension 
Hypertension 
(diastolic) - mm Hg 
91 – 95  
96 – 100  
> 100  
ER visit or hospitalization 
for malignant hypertension 


 
 
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Hypotension 
(systolic) – mm Hg 
85 – 89  
80 – 84  
< 80  
ER visit or hospitalization 
for hypotensive shock 
Respiratory Rate – 
breaths per minute 
17 – 20  
21 – 25  
> 25  
Intubation 
* Subject should be at rest for all vital sign measurements. 
 ** Oral temperature; no recent hot or cold beverages or smoking.  
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when 
characterizing bradycardia among some healthy subject populations, for example, conditioned 
athletes. 
 
Systemic (General)  
Mild (Grade 1)  
Moderate (Grade 
2)  
Severe (Grade 3)  
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting  
No interference 
with activity or 
1 – 2 
episodes/24 
hours 
Some interference 
with activity or > 
2 episodes/24 
hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive 
shock 
Diarrhea  
2 – 3 loose 
stools or < 400 
gms/24 hours 
4 – 5 stools or 
400 – 800 gms/24 
hours 
6 or more watery 
stools or > 
800gms/24 hours 
or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache  
No interference 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 
hours or some 
interference with 
activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue  
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia  
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
ER visit or 
hospitalization 


 
 
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activity 
Illness or clinical 
adverse event (as 
defined according to 
applicable 
regulations) 
No interference 
with activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
B. Tables for Laboratory Abnormalities 
The laboratory values provided in the tables below serve as guidelines and are 
dependent upon institutional normal parameters. Institutional normal reference 
ranges should be provided to demonstrate that they are appropriate. 
Serum *  
Mild (Grade 
1)  
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life 
Threatening 
(Grade 4)** 
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125 
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150 
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6 
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1 
Glucose – Hypoglycemia 
mg/dL  
65 – 69  
55 – 64  
45 – 54  
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL Random – 
mg/dL 
 
100 – 110  
110 – 125 
111 – 125  
126 – 200 
>125 
>200 
Insulin 
requirements 
or 
hyperosmolar 
coma 


 
 
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Serum *  
Mild (Grade 
1)  
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life 
Threatening 
(Grade 4)** 
Blood Urea Nitrogen BUN 
mg/dL 
23 – 26  
27 – 31  
> 31  
Requires 
dialysis 
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or 
requires 
dialysis 
Calcium – Hypocalcemia 
mg/dL  
8.0 – 8.4  
7.5 – 7.9  
7.0 – 7.4  
< 7.0 
Calcium – hypercalcemIa 
mg/dL  
10.5 – 11.0  
11.1 – 11.5  
11.6 – 12.0  
> 12.0 
Magnesium – 
hypomagnesemia mg/dL  
1.3 – 1.5  
1.1 – 1.2  
0.9 – 1.0  
< 0.9 
Phosphorous – 
hypophosphatemia mg/dL 
2.3 – 2.5  
2.0 – 2.2  
1.6 – 1.9  
< 1.6 
CPK – mg/dL  
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x 
ULN  
3.1 –10 x 
ULN  
> 10 x ULN 
Albumin – Hypoalbuminemia 
g/dL  
2.8 – 3.1  
2.5 – 2.7  
< 2.5  
-- 
Total Protein – 
Hypoproteinemia g/dL  
5.5 – 6.0  
5.0 – 5.4  
< 5.0  
-- 
Alkaline phosphate – increase 
by factor 
1.1 – 2.0 x 
ULN  
2.1 – 3.0 x 
ULN  
3.1 – 10 x 
ULN  
> 10 x ULN 
Liver Function Tests –ALT, 
AST increase by factor 
1.1 – 2.5 x 
ULN  
2.6 – 5.0 x 
ULN  
5.1 – 10 x 
ULN  
> 10 x ULN 
Bilirubin – when accompanied 
by any increase in Liver 
Function Test increase by 
factor 
1.1 – 1.25 x 
ULN  
1.26 – 1.5 x 
ULN  
1.51 – 1.75 x 
ULN  
> 1.75 x ULN 
Bilirubin – when Liver 
Function Test is normal; 
increase by factor 
1.1 – 1.5 x 
ULN  
1.6 – 2.0 x 
ULN  
2.0 – 3.0 x 
ULN  
> 3.0 x ULN 
Cholesterol  
201 – 210  
211 – 225  
> 226  
--- 
Pancreatic enzymes – 
1.1 – 1.5 x 
1.6 – 2.0 x 
2.1 – 5.0 x 
> 5.0 x ULN 


 
 
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Serum *  
Mild (Grade 
1)  
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life 
Threatening 
(Grade 4)** 
amylase, lipase  
ULN  
ULN  
ULN  
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate.  
** The clinical signs or symptoms associated with laboratory abnormalities might result in 
characterization of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For 
example. a low sodium value that falls within a grade 3 parameter (125-129 mE/L) should be 
recorded as a grade 4 hyponatremia event if the subject had a new seizure associated with the low 
sodium value. 
***ULN” is the upper limit of the normal range.   


 
 
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Hematology *  
Mild (Grade 1)  
Moderate 
(Grade 2) 
Severe 
(Grade 3)  
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (Female) - 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0 
Hemoglobin (Female) 
change from baseline 
value - gm/dL 
Any decrease – 
1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0 
Hemoglobin (Male) - 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5 
Hemoglobin (Male) change 
from baseline value – 
gm/dL 
Any decrease – 
1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0 
WBC Increase - cell/mm3  
10,800 – 
15,000  
15,001 – 
20,000  
20,001 – 
25,000  
> 25,000 
WBC Decrease - cell/mm3  2,500 – 3,500  
1,500 – 
2,499  
1,000 – 1,499  
< 1,000 
Lymphocytes Decrease - 
cell/mm3  
750 – 1,000  
500 – 749  
250 – 499  
< 250 
Neutrophils Decrease - 
cell/mm3  
1,500 – 2,000  
1,000 – 
1,499  
500 – 999  
< 500 
Eosinophils - cell/mm3  
650 – 1500  
1501 - 5000  > 5000  
Hypereosinophilic 
Platelets Decreased - 
cell/mm3  
125,000–
140,000  
100,000–
124,000  
25,000–99,000  < 25,000 
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 x 
ULN** 
1.11 – 1.20 x 
ULN  
1.21 – 1.25 x 
ULN  
> 1.25 ULN 
PTT – increase by factor 
(partial thromboplastin 
time) 
1.0 – 1.2 x ULN  
1.21 – 1.4 x 
ULN  
1.41 – 1.5 x 
ULN  
> 1.5 x ULN 
Fibrinogen increase - 
mg/dL  
400 – 500  
501 – 600  
> 600  
-- 
Fibrinogen decrease - 
mg/dL  
150 – 200  
125 – 149  
100 – 124  
< 100 or 
associated with 
gross bleeding or 
disseminated 


 
 
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intravascular 
coagulation (DIC) 
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
** “ULN” is the upper limit of the normal range. 
Urine *  
Mild 
(Grade 
1)  
Moderate 
(Grade 2) 
Severe 
(Grade 3)  
Potentially Life 
Threatening (Grade 4) 
Protein  
Trace  
1+  
2+  
Hospitalization or dialysis 
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia 
Blood (microscopic) – red 
blood cells per high power 
field (rbc/hpf) 
1 - 10  
11 – 50  
> 50 
and/or 
gross 
blood 
Hospitalization or packed 
red blood cells (PRBC) 
transfusion 
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
 

SAP_001.pdf: 
 
 
SNS812CLCT01 
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                                            Statistical Analysis Plan   
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Page 1 of 22 
 
 
 
 
Oneness Biotech Co., Ltd. 
 
 
 
 
A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending 
Doses of Inhaled MBS-COV (SNS812) in Healthy Participants 
 
SNS812CLCT01 
 
Statistical Analysis Plan -Safety Part 
 
 
 
Version: 1.0 
 
Date:13 APR 2023 
 
ClinicalTrials.gov ID: NCT05677893


 
 
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Page 2 of 22 
 
 
Sponsor Approval Page  
 
A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending 
Doses of Inhaled MBS-COV (SNS812) in Healthy Participants 
 
SNS812CLCT01 
 
Statistical Analysis Plan-Safety Part 
Version: 1.0 
Project Statistician: 
Joey Yu 
Company Name: 
Hangzhou Tigermed Consulting Co., Ltd 
 
 
 
Signature: 
 
Date: 
 
 
Review Statistician: 
Elaine Chen 
Company Name: 
Hangzhou Tigermed Consulting Co., Ltd 
 
 
Signature: 
 
Date: 
 
 
 
Approved by: 
 
Yi-Chung Chang, Ph.D. 
Company Name: 
Oneness Biotech Co., Ltd. 
 
 
Signature: 
 
Date: 
 
 
 
 
Oneness
Oneness
Oneness
Oneness
Oneness
Oneness


 
 
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Modification History  
Version 
Version Date 
Author 
Description 
V1.0 
13APR2023 
JOEY YU 
FINALIZED  
 
 
 
 
 
 
 
 
 
Oneness


 
 
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Table of Contents  
Abbreviations .................................................................................................................................. 6
1.
Introduction ........................................................................................................................... 8
2.
Study Objectives ................................................................................................................... 8
2.1.
Part A: SAD phase.......................................................................................................... 8
2.1.1.
Primary Objectives ................................................................................................... 8
2.1.2.
Secondary Objectives................................................................................................ 8
2.2.
Part B: MAD phase ........................................................................................................ 8
2.2.1.
Primary Objectives ................................................................................................... 8
2.2.2.
Secondary Objectives................................................................................................ 8
3.
Study Design ......................................................................................................................... 8
3.1.
Part A: SAD phase.......................................................................................................... 9
3.2.
Part B: MAD ................................................................................................................ 10
4.
Study Outcomes Measures .................................................................................................. 10
4.1.
Part A: SAD Phase ....................................................................................................... 10
4.1.1.
Primary Outcomes Measures ................................................................................. 10
4.1.2.
Secondary Outcome Measures ............................................................................... 11
4.2.
Part B: MAD Phase ...................................................................................................... 11
4.2.1.
Primary Outcomes Measures ................................................................................. 11
4.2.2.
Secondary Outcome Measures ............................................................................... 11
4.3.
Study Safety Outcome Measures ................................................................................. 12
4.3.1.
Adverse Events ........................................................................................................ 12
4.3.2.
Other Safety Endpoints .......................................................................................... 14
4.3.3.
Demographics and Baseline Characteristics ........................................................ 15
4.3.4.
Concomitant Medication and Procedure .............................................................. 16
4.3.5.
Protocol Deviations ................................................................................................. 16
4.4.
Study PK Endpoint ....................................................................................................... 16
5.
Statistical hypothesis ........................................................................................................... 16
6.
Analysis Datasets ................................................................................................................ 16
7.
Statistical Methods .............................................................................................................. 17
7.1.
General Statistical Consideration ................................................................................. 17


 
 
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7.2.
Data Handling .............................................................................................................. 17
7.2.1.
Missing Data ............................................................................................................ 17
7.2.2.
Derivation and Transformation on Data .............................................................. 18
7.2.3.
Handling PK data ................................................................................................... 19
7.3.
Study Subjects .............................................................................................................. 19
7.3.1.
Subjects Disposition ................................................................................................ 19
7.3.2.
Protocol Deviations ................................................................................................. 19
7.3.3.
Demographics and Baseline Characteristics ........................................................ 19
7.3.4.
Prior/Concomitant Medication and Procedures .................................................. 19
7.4.
Safety Analysis ............................................................................................................. 20
7.4.1.
Drug Exposure ........................................................................................................ 20
7.4.2.
Adverse Events ........................................................................................................ 20
7.4.3.
Laboratory Evaluations.......................................................................................... 21
7.4.4.
Physical Examination ............................................................................................. 21
7.4.5.
12-Lead ECG ........................................................................................................... 21
7.4.6.
Vital Signs ................................................................................................................ 21
7.4.7.
Spirometry Assessment ........................................................................................... 21
7.5.
PK analysis ................................................................................................................... 21
8.
Reference ............................................................................................................................ 22


 
 
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Abbreviations 
Abbreviation  
Term  
ADL  
Activities of Daily Living  
AE  
Adverse Event  
AI  
Aerosol Inhalation  
ALP  
Alkaline Phosphatase  
ALT  
Alanine Transaminase  
ANC  
Absolute Neutrophil Count  
AST  
Aspartate Aminotransferase  
BUN  
Blood Urea Nitrogen  
CFR  
Code of Federal Regulations  
CRF  
Case Report Form  
CRO  
Contract Research Organization  
CS  
Clinically Significant  
ECG  
Electrocardiogram  
EOT  
End of Treatment  
FAS  
Full Analysis Set  
FDA  
U.S. Food and Drug Administration  
FUV  
Follow-up Visit  
GCP  
Good Clinical Practice  
GMP  
Good Manufacturing Practice  
HEENT  
Head, Ears, Eyes, Nose, and Throat  
HIPAA  
Health Insurance Portability Accountability Act  
IA  
Interim Analysis  
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonization  
IEC  
Independent Ethics Committee  
IN  
Intranasal Instillation  
IND  
Investigational New Drug  
IP  
Investigational Product  
IRB  
Institutional Review Board  
IS  
Immunogenicity Set  
LAR  
Legally Authorized Representative  
LDH  
Lactate Dehydrogenase  
LTF  
Lost to Follow-up  
PI  
Principal Investigator  
PKCS  
PK concentration analysis set  
PKPS  
PK parameters analysis set  
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SOP  
Standard Operating Procedure  
SRC  
Safety Review Committee  
SS  
Safety Set  
SV  
Screening Visit  
TEAE  
Treatment Emergent Adverse Event  


 
 
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TV  
Treatment Visit  
WFI  
Water For Injection  


 
 
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1. 
Introduction 
This statistical analysis plan is prepared for the A Phase I, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single and 
Multiple Ascending Doses of Inhaled MBS-COV (SNS812) in Healthy Participants  (Protocol 
No.: SNS812CLCT01) of Oneness Biotech Co., Ltd. In this document, the contents and methods 
of statistical analysis will be described in detail. 
This statistical analysis plan is drafted based on protocol of SNS812CLCT01 (version 4.1, 
19Jan2023) and Case Report Form (CRF, version 2.0, 09Jan2023). 
 
2. 
Study Objectives  
2.1. Part A: SAD phase 
2.1.1. Primary Objectives 
 To determine the safety and tolerability of MBS-COV after single doses in healthy 
participants.  
2.1.2. Secondary Objectives 
 To evaluate the pharmacokinetics (PK) of MBS-COV after single dose administration in 
healthy participants. 
   To evaluate the immunogenicity of MBS-COV. 
2.2. Part B: MAD phase 
2.2.1. Primary Objectives  
 To determine the safety and tolerability of MBS-COV after multiple doses in healthy 
participants.  
2.2.2. Secondary Objectives 
 To evaluate the pharmacokinetics (PK) of MBS-COV after multiple dose administrations 
in healthy participants.  
   To evaluate the immunogenicity of MBS-COV. 
3. 
Study Design 
This is a Phase I, randomized, double-blind study designed to evaluate the safety, tolerability and 
pharmacokinetics (PK) of inhaled MBS-COV in healthy adult participants in the part A and part 


 
 
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B of the study. A total of 44 male and female healthy participants will be enrolled. All 
participants, after signing the Informed Consent Form (ICF), will be assessed during the 
screening phase. Only those participants who successfully complete the screening phase and 
meet the study eligibility criteria will be enrolled. MBS-COV will administered via inhalation 
through a portable mesh nebulizer. 
3.1. Part A: SAD phase 
Part A includes 3 dose-escalation cohorts (0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg MBS-COV or 
placebo). Each cohort will include 8 participants (6 active and 2 placebo) per below table: 
Cohort 
MBS-COV Does 
Active:placebo 
Frequency of Does 
A1 
0.3 mg/kg (6:2) 
Single Administration 
A2 
0.6 mg/kg (6:2) 
Single Administration 
A3 
1.2 mg/kg (6:2) 
Single Administration 
From the perspective of safety, sentinel dosing will be used in each cohort, and the first 2 
subjects in each cohort will be randomized 1:1 to MBS-COV or placebo. If the dose can be well 
tolerated for 48 hours after full administration per the study Safety Review Committee (SRC) 
consisting of the sponsor (designee), site Principle Investigator, and medical monitor, the 
remaining 6 subjects in the cohort may be randomized 5:1 to MBS-COV or placebo. 
All participants will have a screening visit within 28 days of check-in (Day -1) to determine 
eligibility. Eligible participants will be admitted to the study center on study Day -1 at which 
point their eligibility to participate in the study will be confirmed. Only those participants who 
successfully complete the screening phase and meet the study eligibility criteria will proceed to 
be randomized to receive a single dose of MBS-COV or placebo in the morning of Day 1 at the 
assigned dose. 
The decision for cohort (dose level) escalation to the higher dose levels will be made by the 
study SRC after safety review of available information 7-day post treatment period. The data 
from SAD phase will be reviewed for safety trends to start MAD phase. 


 
 
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3.2. Part B: MAD 
This is a randomized, double-blind, placebo-controlled study in approximately 20 healthy 
participants. Doses will be selected based on a comprehensive review of the SAD data and 
estimates of the clinically efficacious dose.  
The MAD Phase of the study consists of a screening period followed by multiple dose 
administrations of MBS-COV or placebo through a portable nebulizer once daily for 7 
consecutive days (Day 1 to Day 7). Participants will be followed up for 21 days to assess post-
treatment safety. 
The decision for the escalation to the higher dose levels will be made by the study SRC after 
safety review of available information 7-day post treatment period. Each cohort will include ten 
participants (8 active and 2 placebo) per table below: 
Cohort 
MBS-COV Does 
Active:placebo 
Frequency of Does 
B1 
0.6 mg/kg (8:2) 
Once daily for 7 days 
B2 
1.2 mg/kg (8:2) 
Once daily for 7 days 
 
4. 
Study Outcomes Measures 
4.1. Part A: SAD Phase 
4.1.1. Primary Outcomes Measures 
The primary outcome measures in this study are: 
 Evaluation of the safety and tolerability of MBS-COV after a single administration in 
healthy participants. The following parameters will be used to assess safety: 
 Incidence and severity of Treatment-Emergent Adverse Events (TEAEs)  
 Incidence of withdrawals due to Adverse Events (AEs) 
 Incidence of Treatment-Related Adverse Events 
 Incidence of Serious Adverse Events (SAEs) 
 Change/shifts in laboratory values from baseline 
 Change in vital signs including blood pressure, pulse, respiratory rate, and 
temperature from baseline  
 Change in spirometry from baseline to assess the acute bronchospasm 


 
 
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 Change in other safety examination parameters from baseline 
4.1.2. Secondary Outcome Measures  
The secondary outcome measures in this study are: 
Pharmacokinetic Outcome Measures: 
 Maximum observed plasma drug concentration (Cmax) 
 Apparent terminal elimination half-life (t1/2) 
 Time to maximum observed plasma drug concentration (Tmax) 
 Area under the plasma drug concentration-time curve (AUC) from time 0 to the time of 
the last quantifiable concentration (Tlast) (AUC0-t) 
 AUC from time 0 to infinity (AUC0-  
 Apparent plasma clearance (CL/F) 
Immunogenicity Outcome Measure: 
 Occurrence of anti MBS-COV antibody after administration of MBS-COV  
4.2. Part B: MAD Phase 
4.2.1. 
Primary Outcomes Measures 
The primary outcome measures in this study are: 
 Evaluation of the safety and tolerability of MBS-COV after multiple dose administrations 
in healthy participants. The following parameters will be used to assess safety: 
 Incidence and severity of Treatment-Emergent Adverse Events (TEAEs)  
 Incidence of withdrawals due to Adverse Events (AEs) 
 Incidence of Treatment-Related Adverse Events 
 Incidence of Serious Adverse Events (SAEs) 
 Change/shifts in laboratory values from baseline 
 Change in vital signs including blood pressure, pulse, respiratory rate, and 
temperature from baseline  
 Change in spirometry from baseline to assess the acute bronchospasm 
 Change in other safety examination parameters from baseline 
4.2.2. 
Secondary Outcome Measures  
The secondary outcome measures in this study are: 
Pharmacokinetic Outcome Measures: 


 
 
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 Maximum observed plasma drug concentration (Cmax) 
 Apparent terminal elimination half-life (t1/2) 
 Time to maximum observed plasma drug concentration (Tmax) 
 Area under the plasma drug concentration-time curve (AUC) from time 0 to the time of 
the last quantifiable concentration (Tlast) (AUC0-t) 
 AUC from time 0 to infinity (AUC0-  
 Apparent plasma clearance (CL/F) 
 Estimate of steady state Pharmacokinetic Parameters such as AUC0- , and Cmax,ss, Cmin,ss, 
Cavg, Tmax, t1/2, AUCtau
z, CLss/F, Vss/F, DF, ARAUC/ARCmax (accumulation ratio) for 
multiple dose administration of MBS-COV 
Immunogenicity Outcome Measure: 
 Occurrence of anti MBS-COV antibody after administration of MBS-COV 
 
4.3. Study Safety Outcome Measures 
4.3.1. Adverse Events 
Adverse Events (AE) 
An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, or disease  
that occurs or is reported by the participant to have occurred, or a worsening of a pre-existing  
condition. An adverse event may or may not be related to the study treatment.  
AEs will be elicited through direct questioning and participant reports. Any abnormality in  
physical examination findings or laboratory results that the investigator believes is clinically  
significant (CS) to the research participant and that occurred after initiation of the first study  
treatment will be reported as AEs. Abnormal findings that are NOT clinically significant should  
not be recorded as an AE. 
Serious Adverse Events (SAE) 
A SAE is defined as any AE that: 
 Results in death 
 Is life threatening (the participant is at immediate risk of dying from the adverse 
experience) 
 Requires participant hospitalization or prolongs existing hospitalization 


 
 
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 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse effect when, based upon appropriate 
medical judgment, they may jeopardize the participant or participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Treatment - Emergent Adverse Event (TEAE) 
Any adverse event which occurs on or after the first administration of study drug are defined as 
TEAE, namely if date/time of AE occurrence is greater or equal to the date/time of first dose, 
those AEs will be judged as TEAE (rising grade in severity will be recorded as a new AE in 
CRF). For this study, AE will be collected start from the first study drug administration. 
Therefore, all AEs will be TEAEs. 
AE Leading to Treatment Discontinuation 
In this study, these AEs caused subject treatment discontinuation. 
AE Leading to Death 
In this study, these AEs caused subject death. 
Treatment Related Adverse Event 
onship to study drug is part of the 
documentation process
The evaluation of relationship is based on the following 5 levels: 
Definitely related, Probably related, Possibly related, Unlikely related, Unrelated and will be 
recorded on CRF. The adverse events been evaluated the relationship to drug as Definitely 
related, Probably related, Possibly related will be referred to treatment related adverse event. The 
detailed definition and guidelines of 5 level relationship (Definitely related, Probably related, 
Possibly related, Unlikely related, Unrelated) of adverse event to study drug can be referred on 
protocol section 9.2.3. 
Grading AE by Severity 
 
Volunteers Enrolled in Preventive Vaccine Clinical Tria
 
adverse events occurred in this study will be graded. The general guidelines for assessing the AE  


 
 
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grade refer on protocol appendix 1.  
 
4.3.2. Other Safety Endpoints 
Clinical laboratory test, physical examination, 12-lead ECG, vital sign assessments will be 
collected and analyzed to evaluate the safety of MBS-COV. 
Laboratory evaluation  
Clinical Laboratory Assessments are listed below: 
Biochemistry 
 
 
 
 
 
Total bilirubin (mg/dL), Alkaline Phosphatase (ALP) (U/L), Aspartate 
Aminotransferase (AST) (or SGOT) (U/L), Alanine Aminotransferase (ALT)  
(or SGPT) (U/L),  Total Protein (g/dL),  Albumin (g/dL), Lactate 
Dehydrogenase (LDH) (U/L), Amylase (U/L), Lipase (U/L), Serum 
creatinine (mg/dL), eGFR(ml/min/1.73 m2), Sodium (mEq/L), Potassium 
(mEq/L), Chloride (mEq/L), Calcium (mg/dL), Bicarbonate (mEq/L), 
Glucose, Random (mg/dL), Creatine kinase (U/L), Triglyceride (TG) 
(mg/dL), Total Cholesteriol (TC) (mg/dL) 
Hematology 
 
 
Hemoglobin (g/dL), Hematocrit (%), RBC/Erythrocytes (10^12/L), 
WBC/Leukocytes (10^6/L), Absolute Neutrophil Count  
(10^6/L), Platelets (10^9/L), Neutrophils (%), Lymphocytes (%), Monocytes 
(%), Eosinophils (%), Basophils (%) 
Coagulation test 
Prothrombin time (PT), Activated partial thromboplastin time (APTT), 
Thrombin time (TT), Fibrinogen (FIB) 
Urinalysis 
 
pH, Specimen Appearance, Color, Specific Gravity, Ketones, Bilirubin, 
Occult Blood, Glucose, Protein, Nitrite, Urobilinogen (mg/dL), Leukocyte, 
Esterase 
Besides, pregnancy test will be conducted in serum. A positive urine pregnancy test will be 
confirmed with a serum pregnancy test.  
Results of Clinical Laboratory Assessments at each scheduled visit will be recorded on the CRF. 
Physical examination 
The physical examination will include routine examinations for the following: 
 Constitutional/General Appearance 
 Head, Ears, Eyes, Nose, Throat (HEENT) 
 Neurologic  


 
 
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 Chest (including heart and lung) 
 Abdomen 
 Musculoskeletal and Extremities 
 Dermatologic 
 Lymphatic 
 Psychiatric 
Any findings made during the physical examination must be noted regardless of whether they are 
 history.  
Results at each scheduled visit will be recorded on the CRF. 
12-lead ECG 
12-lead ECG will include ventricular rate, PR interval, QRS interval, QT interval, and QTc 
interval and clinical overall evaluation. 
Results at each scheduled visit will be recorded on the CRF. 
Vital sign 
The following vital signs will include Systolic and Diastolic Blood Pressure, Pulse, Respiratory 
Rate, Oral Temperature and clinical overall evaluation.  
Results at each scheduled visit will be recorded on the CRF. 
Spirometry assessment  
Spirometry assessment will include FEV1%, FEV1/FVC, PEF. 
Results at each scheduled visit will be recorded on the CRF. 
 
4.3.3. Demographics and Baseline Characteristics 
 age (in years, at time of signing informed consent), gender, race, ethnicity, height, 
weight, and BMI will be recorded on CRF. 
A medical history will be recorded on the CRF and will include: 
 All ongoing medical conditions 
 All previously resolved medical conditions that are relevant in the judgment of the 
Investigator  
 Any prior medical conditions that have resolved within the last year  
Events that emerge prior to the first treatment will be recorded in the medical history. Medical 
history term, duration, and status will be recorded on the CRF  


 
 
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4.3.4. Concomitant Medication and Procedure 
All medications and therapies administered or taken by the participant beginning 14 days prior to 
Screening Visit and throughout the study will be recorded on the CRF. Participants must be 
questioned at each study visit concerning any new medications or changes in current medications 
including over-the-counter medication and topical medication. 
For each medication and non-study treatment, the following will be documented: 
 Medication/treatment name (generic name may be used if trade name is unknown) 
 Dose, unit, and frequency of dosing (individual dosages, not total daily dose).  
 Route of dosing 
 Indication for use 
 The start date  
 The stop date (if medication/therapy is not ongoing). 
4.3.5. Protocol Deviations 
A protocol deviation is any noncompliance with the protocol or study procedures detailed in the 
laboratory or pharmacy manuals. The noncompliance may have been the result of action by the 
PI, site staff, or subject. 
4.4. Study PK Endpoint 
Refer to separate PK statistical analysis plan. 
 
5. 
Statistical hypothesis 
No formal statistical hypothesis for this Phase I study. 
 
6. 
Analysis Datasets 
The following datasets for analysis will be used in this study: 
 Full Analysis Set (FAS): FAS includes all randomized participants. This analysis set 
will be used to analyze the disposition, demographic and baseline characteristics of the 
subjects. 
 Safety Analysis Set (SS): SS includes all the participants who receive the study drug at 
least once. This population will be used for the analysis of safety parameters. 


 
 
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 Pharmacokinetic Concentration Analysis Set (PKCS): PKCS includes all randomized 
participants who receive at least one dose of the study drug and have at least plasma 
concentration. The PKCS will be used for PK concentration analysis. 
 Pharmacokinetic Parameter Analysis Set (PKPS): PKPS includes all randomized 
participants who receive at least one dose of the study drug with no major protocol 
violations or protocol deviations that have a significant impact on PK parameters (Cmax, 
AUC, etc.), and have at least one analyzable PK parameter. The PKPS will be used for 
PK parameters analysis. 
 Immunogenicity Set (IS): The IS includes all randomized participants who receive at 
least one dose of the study drug, and have at least one ADA concentration. The IS will be 
used for immunogenicity analysis. 
Safety analysis will be based on the safety analysis set. The division of the analysis population 
will be determined before database lock. 
 
7. 
Statistical Methods 
7.1. General Statistical Consideration  
If no other specified, SAS® (Version 9.4 or above) statistical software will be used for all 
statistical calculation and all analyses of safety part. 
All summaries will be provided by treatment group for both study parts. Continuous variables 
will be summarized using descriptive statistics including number of observations (n), mean, 
standard deviation, median (med), minimum (min) and maximum (max). Categorical variables 
will be summarized using frequency and percentages. 
For laboratory examination, keep 2 decimal places for mean, minimum, median, and maximum, 
3 decimals for standard deviation. For percentage, keep 1 decimal place. 
If no other specified, baseline of safety analysis is defined as the last effective assessment record 
before first treatment dosing. 
7.2. Data Handling 
7.2.1. Missing Data 
Data evaluation will be based on the data collected by CRF without any imputation for safety 
part
 


 
 
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The missing date of AE will be imputed as follows. The imputation of missing date of AE is only 
used to classify AEs, and the original missing date record will still be presented when generating 
the listing of AE related data. 
 If the start date of AE was missing 
 
1) If year and month were known and earlier than that of the first treatment dose, then 
impute with the last day of the known month. 
 
2) If the year and month were known as same as that of the first treatment dose, then 
impute the start date with the date of first treatment dosing (date in form of 
 
 
3) If year and month were known and later than that of the first treatment dosing, then 
impute with the first day of the known month. 
 
4) If year only was known and earlier than that of the first treatment dosing, then impute 
 
 
5) If year only was known and equal to that of the first treatment dosing, then impute the 
 
 
6) If year only was known and later than that of the first treatment dosing, then impute 
 
 
7) If year, month and day were all missing, use the first treatment dosing date as the start 
date of AE. 
 
8) Other conditions will be regarded as missing. 
 If the end data of AE was missing 
 
1) If year and month were known, then impute with the last day of the known month. 
 
2) 
 
 
3) the start date was later than the end date after imputation, then use the start date 
directly as the end date. 
 
4) Other condition will be regarded as missing. 
7.2.2. Derivation and Transformation on Data  
Apart from the calculation of study endpoints mentioned in section 4, which are based on data 
collected via CRF, no derivation or transformation will be done for data. Outliers will be reported 
to data management function as data issue to be resolved or confirmed before database lock. No 
other special data handling will be done. 


 
 
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7.2.3. Handling PK data 
For PK data handling, please refer to separate PK statistical analysis plan. 
7.3. Study Subjects 
7.3.1. Subjects Disposition 
The frequency counts of subjects who signed the informed consent will be calculated, 
distinguishing those screen failures. Listing will be provided for subjects who were failed to 
screen with detail reasons. 
Based on all subjects receiving randomization, the frequency counts and percentage of subjects 
who dosed, completed the study and withdrew early, as well as the frequency counts and 
percentage of subjects who withdrew early for various reasons, will be calculated and 
summarized.  
Based on full analysis set, the frequency counts and percentage of subjects included in the full 
analysis set, safety analysis set will be calculated and summarized. 
7.3.2. Protocol Deviations 
Based on full analysis set, by-subject listing of all protocol deviation will be produced.  
7.3.3. Demographics and Baseline Characteristics 
All demographics and baseline characteristics analysis will be performed based on the full 
analysis set. 
Descriptive statistical summary will be performed by treatment group on demographic data 
collected including age (in years, at time of signing informed consent), gender, race, ethnicity, 
height, weight, BMI, and smoking history. 
Listing by subjects will be produced regarding to baseline demographic information collected. 
Medical history collected will be coded by MedDRA (version refer to DMP). 
Listing will be produced by subject for recording medical history, start data, end data of 
treatment, and current medication. 
7.3.4. Prior/Concomitant Medication and Procedures 
Analysis will be performed based on safety analysis set. 
Prior/concomitant medications will be coded using the latest available WHO Drug Reference 
Dictionary (version refer to DMP). 


 
 
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All prior/concomitant medication data will be provided in listing by subject in detail, as well as 
prior/concomitant procedure.  
7.4. Safety Analysis 
All safety analysis will be performed based on the safety analysis set. 
Safety endpoint includes adverse events, clinical laboratory evaluations, physical examination, 
12-Lead ECG, and vital signs. 
7.4.1. Drug Exposure  
Exposure to treatment will be summarized descriptively, and compliance on treatments for both 
active and placebo will be evaluated. 
Listing by-subject will be produced for recording drug administration, including the date and 
time of administration. 
7.4.2. Adverse Events  
All AEs will be coded and classified according to the MedDRA (version refer to DMP) with 
System organ class (SOC) and Preferred Term (PT). 
Frequencies and percentages of subjects and frequencies of events by treatment group for all 
adverse events will be summary as following: 
 Summaries of all AE 
 Summaries of all AE by SOC and PT 
 Summaries of all SAE by SOC and PT 
 Summaries of all Treatment related Adverse Event by SOC and PT 
 Summaries of all AE leading to early discontinuation by SOC and PT 
 Summaries of all SAE leading to early discontinuation by SOC and PT 
 Summaries of all Treatment related Adverse Event leading to early discontinuation by 
SOC and PT 
 Summaries of all AE by SOC and PT and the Worst Severity 
 Summaries of all Treatment related Adverse Event by SOC and PT and the Worst 
Severity 
Listing by subjects will be provided for all AEs, SAE, Treatment related Adverse Event. 


 
 
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7.4.3. Laboratory Evaluations 
Clinical laboratory evaluations include Hematology, Blood chemistry, Urinalysis, Coagulation 
test. 
Laboratory evaluation results of each visit and their changes from baseline will be calculated and 
summarized in descriptive statistics by treatment group. 
Listing by subjects and evaluations will be produced for results from visits and timepoints. 
Any abnormal with clinical significance results will be tabulated. 
The results of pregnancy test of female subjects will be tabulated. 
7.4.4. Physical Examination 
Listing by subjects will be produced for all the physical examination results at baseline and each 
post-baseline visit timepoint. 
7.4.5. 12-Lead ECG 
12-lead ECG assessment results of each visit and their changes from baseline will be calculated 
and summarized in descriptive statistics by treatment group. 
Listing by subjects will be produced for all 12-lead ECG result. Abnormal with clinical 
significance results of 12-lead ECG will be provided by listing separately. 
7.4.6. Vital Signs 
Vital signs results of each visit and their changes from baseline will be calculated and 
summarized by treatment group. 
Listing by subject will be provided for all vital signs results. Abnormal with clinical significance 
results of vital signs will be provided by listing separately. 
7.4.7. Spirometry Assessment 
Spirometry results of each visit and their changes from baseline will be calculated and 
summarized by treatment group. 
Listing by subject will be provided for all spirometry assessment results. Abnormal with clinical 
significance results of spirometry assessment will be provided by listing separately. 
 
7.5. PK analysis 
For study PK analysis, please refer to separate PK statistical analysis plan. 


 
 
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8. 
Reference  
[1] 
National Medical Products Administration, Guidance of Data Management and Statistical 
Analysis Plan for Clinal Trials, 2021. 
[2] 
National Medical Products Administration, Guidance of Biostatistics for Clinical Trials, 
2016.