Conditions: Covid-19
Keywords: Antroquinonol COVID 19 pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 124
Healthy volunteers: no

Brief summary:
To evaluate the safety and efficacy of antroquinonol treatment of mild to moderate pneumonia due to COVID-19, as measured by the proportion of patients alive and free of respiratory failure.

Detailed description:
This is a randomized, double blind, placebo controlled, Phase 2, proof of concept study in hospitalized patients with mild to moderate pneumonia due to COVID 19. Written informed consent must be obtained from all patients during screening. Following completion of all screening assessments and meeting of eligibility criteria, patients will either receive antroquinonol or placebo for 14 days in combination with SoC therapy per local SoC policies.

Arms:
arm 1: Antroquinonol in a dose of 100 mg (1 capsule) administered twice daily (BID) orally, for 14 days. arm 2: Placebo (1 capsule) administered twice daily (BID) orally, for 14 days.

Interventions: intervention 1: Antroquinonol intervention 2: Placebo
Intervention descriptions: intervention 1: double-blind for antroquinonol and Placebo with same out-look and same frequency. intervention 2: Capsule without active compound

Protocol document:
Prot_000.pdf: 
09 July 2021 
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CONFIDENTIAL 
TITLE PAGE 
Protocol 
A Phase 2 Randomized, Double-blind, Placebo-controlled, Proof of Concept Study to 
Evaluate the Safety and Efficacy of Antroquinonol in Hospitalized Patients with Mild to 
Moderate Pneumonia due to COVID-19 
Protocol Status: Final 
Protocol Version: 4.0, Date: 09 July 2021 
Protocol Version: 3.1, Date: 29 March 2021 
Protocol Version 3.0, Date: 11 March 2021 
Protocol Version: 2.0, Date: 02 September 2020 (submitted to FDA) 
Protocol Version 1.1: 01 June 2020 (submitted to FDA) 
Original Protocol Version 1.0: 14 May 2020 (submitted to FDA) 
 
Investigational Product: Antroquinonol (Hocena®) 
Protocol Reference Number: GHCovid-2-001 
Investigational New Drug: 149841 
 
 
Sponsor: 
Golden Biotechnology Corporation 
15F, No. 27-6, Sec. 2, Zhong-Zheng E. Rd., 
Tamsui Dist., New Taipei City 251, Taiwan 
 
 
 
Sponsor Signatory: 
Howard Cheng, PhD 
VP, Clinical Medicine Research Department 
Golden Biotechnology Corporation 
15F, No. 27-6, Sec. 2, Zhong-Zheng E. Rd., 
Tamsui Dist., New Taipei City 251, Taiwan 
Medical Monitor: 
Norberto Soto, MD 
Senior Medical Director 
LabCorp Drug Development 
E-mail: Norberto.Soto@labcorp.com 
Tel: + 1 609-212-7892 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
 


Protocol Version 4.0 
LabCmp Drug Development Study: 8427146 
CONFIDENTIAL 
Protocol Reference Number: GHCovid-2-001 
SPONSOR APPROVAL 
Title: 
A Phase 2 Randomized, Double-blind, Placebo-controlled, 
Proof of Concept Study to Evaluate the Safety and Efficacy of 
Antroquinonol in Hospitalized Patients with Mild to Moderate 
Pneumonia due to COVID-19 
Protocol Reference Number: GHCovid-2-001 
I agree to the content of the Clinical Study Protocol as presented. 
Sponsor Signature: 
Howard Cheng, PhD 
Date 
VP, Clinical Medicine Research Department 
Golden Biotechnology Corporation 
09 July 2021 
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Protocol Reference Number: GHCovid-2-001 
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INVESTIGATOR AGREEMENT 
Title:  
A Phase 2 Randomized, Double-blind, Placebo-controlled, 
Proof of Concept Study to Evaluate the Safety and Efficacy of 
Antroquinonol in Hospitalized Patients with Mild to Moderate 
Pneumonia due to COVID-19 
Protocol Reference Number: GHCovid-2-001 
 
 
I have read the following protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
Name:  
 
Date 
Qualification:  
 
 
 
Principal Investigator 


 
 
 
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SYNOPSIS 
 
Title of study: 
A Phase 2 Randomized, Double-blind, Placebo-controlled, Proof of Concept Study to Evaluate the Safety and 
Efficacy of Antroquinonol in Hospitalized Patients with Mild to Moderate Pneumonia due to COVID-19 
Indication: 
Mild to moderate pneumonia due to COronaVIrus Disease 2019 (COVID-19) 
Number of investigators and study centers: 
Approximately 15 to 20 sites in the United States, and other countries based on the pandemic situation. 
Development phase: 
Phase 2 
Objectives: 
The primary objective of this study is: 
• 
To evaluate the efficacy of antroquinonol treatment of mild to moderate pneumonia due to COVID-19, 
as measured by the proportion of patients alive and free of respiratory failure (ie, no need for invasive 
mechanical ventilation, non-invasive ventilation, high-flow oxygen, or extracorporeal membrane 
oxygenation [ECMO]) on Day 14 
The secondary objectives are: 
• 
To further evaluate the efficacy of antroquinonol compared with placebo in this patient population as 
measured by: 
o 
World Health Organization (WHO) COVID-19 Clinical Improvement Ordinal Scale score on 
Days 7, 14, and 28 
o 
Duration of hospitalization up to Day 28 
o 
Virological clearance on Days 5, 14, and 28 
o 
Vital status (death) on Days 7, 14, and 28 
o 
Duration of intensive care unit (ICU) stay up to Day 28 
o 
Proportion of patients alive and free of respiratory failure on Days 7 and 28 
o 
COVID-19 symptoms on Days 7, 14, and 28 
• 
To evaluate the safety of antroquinonol treatment in patients with mild to moderate pneumonia due to 
COVID-19. 
• 
To assess the pharmacokinetics (PK) of antroquinonol in a subset of 20 patients (first 10 patients 
randomized to antroquinonol and first 10 patients to placebo) 
The exploratory objective is to further evaluate efficacy via supportive analyses of: 
• 
To further evaluate efficacy via supportive analyses of: 
o 
Subgroup analyses of selected covariates 
o 
Impact on efficacy of any new authorized treatments recommended as standard of care (SoC) for 
COVID-19 during the course of the study. 
Methodology/study design: 
This is a randomized, double-blind, placebo-controlled, Phase 2, proof of concept study in hospitalized patients 
with mild to moderate pneumonia due to COVID-19. Written informed consent must be obtained from all 
patients during screening (Days -2 to 0). Following completion of all screening assessments and meeting of 
eligibility criteria, patients will either receive antroquinonol or placebo for 14 days in combination with SoC 
therapy per local SoC policies. 
A total of 174 patients are planned to be randomized in a 1:1 ratio to antroquinonol or placebo. 


 
 
 
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The study will consist of a sentinel cohort of 20 patients (10 patients randomized to antroquinonol and 10 patients 
to placebo), and an expansion cohort of 154 patients (77 patients in each treatment group). Enrollment will pause 
after the 20th patient in the sentinel cohort has been enrolled and started treatment, until the results of the interim 
analysis 1 are known. Once the 20th patient in the sentinel cohort has completed 14 days of treatment, an 
unblinded Data Monitoring Committee (DMC) will assess the safety, tolerability, efficacy, and PK of 100 mg 
twice daily (BID) antroquinonol in COVID-19 patients in the sentinel cohort (interim analysis 1). The DMC will 
issue a recommendation to enroll patients for the expansion cohort, or to stop the study depending on the safety 
and futility assessment. Once the 80th patient has been enrolled, and completed 14 days of treatment, the DMC 
will review the safety, tolerability, and efficacy data (interim analysis 2). Enrollment may be restricted at the 
100th patient until the DMC has completed the assessment to prevent excessive enrollment. The DMC will 
continue to review safety and assess the risk/benefit profile on an ongoing basis. A DMC Charter, which includes 
detailed processes, will be prepared. 
Patients will undergo assessment during hospitalization or could be discharged after start of study treatment any 
time after Day 2 if judged to be ready for discharge. If discharged, patients will then be requested to take study 
treatment at home (as prescribed) up to Day 14. End of Treatment assessments at Day 14 (+2 days) (at home or 
site visit) will be performed. A Day 5 (+/- 1 day) visit (at home or site visit) will be performed if the patient is 
discharged prior to Day 5. If the patient is discharged after completion of treatment and before the follow-up 
visit, he/she will be followed up on Day 28 (±2 days) for study assessments (a telephone or telemedicine visit). 
Post discharge, assessments will be done by telephone or telemedicine, except for Day 5, Day 14, and Early 
Termination (ET) of Study Treatment. If the discharge, ET, or Early Withdrawal visit falls within the window of 
a schedule Day visit, the assessments for the visits can be combined as one visit. On days of laboratory 
assessments, discharged patients will have a home visit. On days of no laboratory assessments, discharged 
patients will complete their assessments via telephone, telemedicine, or other means of remote communication. 
Additionally, patients will receive a diary to capture all doses after a discharge.  
Number of patients: 
A total of 174 patients are planned to be randomized into the study: 
• 
20 patients in the sentinel cohort (10 patients in each treatment group) 
• 
154 patients in the expansion cohort (77 patients in each treatment group). 
This enrollment level ensures 80% power to demonstrate proof of concept efficacy with one-sided alpha of 0.2. 
The sample size is based on the following assumptions: 
• 
The randomized allocation ratio is 1:1 between the antroquinonol group and the placebo group 
• 
The proportion of patients alive and free of respiratory failure is approximately 78% on placebo vs 89% 
on antroquinonol 
• 
The following nonbinding rules will be considered by the DMC for futility, and the DMC will not make 
any recommendations to stop for early efficacy: 
o 
Interim analysis 1 (sentinel cohort): An odds ratio of 3.5 on the primary endpoint in favor of 
placebo. 
o 
Interim analysis 2: An odds ratio of 1.2 on the primary endpoint in favor of placebo. This 
analysis will be conducted on all data collected up to the 80th randomized patient completing 14 
days of treatment. Enrollment may be restricted at the 100th patient until the DMC has 
completed the assessment to prevent excessive enrolment. 
Diagnosis and criteria for inclusion and exclusion: 
Patients must satisfy all of the following inclusion criteria at the Screening visit unless otherwise stated: 
1. Willing and able to provide informed consent. 
2. Male or female patients between 18 and 80 years of age. 
3. Oxygen Saturation <94% in room air at screening. 
4. Hospitalized with mild COVID-19 disease (not requiring oxygen therapy [WHO COVID-19 Clinical 
Improvement Ordinal Scale, score of 3] or requiring oxygen therapy by mask or nasal prong [WHO 


 
 
 
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COVID-19 Clinical Improvement Ordinal Scale, score of 4]). Requirement of oxygen therapy by mask 
with reservoir to treat severe COVID-19 pneumonia is not allowed for enrollment.  
Note: Hospitalized patients can also include patients admitted to centers conditioned as hospitals to 
treat COVID-19 patients. 
5. Chest x- ray or computerized tomography (CT) scan consistent with pneumonia. 
6. Onset of COVID-19 symptoms within 2 weeks prior to randomization. 
7. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection confirmed by a polymerase 
chain reaction (PCR) test, antigen, or any authorized commercial or public health assay 
(nasopharyngeal, oropharyngeal, or respiratory samples, not serology testing). 
8. Male patients and female patients of childbearing potential must agree to use protocol-specified methods 
of contraception. 
9. Female patients of childbearing potential must have a negative pregnancy test at Screening or 
pretreatment on Day 1. 
10. Male patients must agree not to donate sperm from the first dose through 90 days after the last dose of 
study treatment; female patients of childbearing potential should refrain from donation of ova from 
Day 1 until 90 days after the last dose of study treatment. 
11. Patient is, in the opinion of the investigator, willing and able to comply with the study treatment regimen 
and all other study requirements. 
Patients will be excluded from the study if they satisfy any of the following exclusion criteria at the Screening 
visit unless otherwise stated: 
1. Female patient is pregnant or breastfeeding. 
2. Any patient’s concomitant life-threatening condition, including but not limited to: requiring mechanical 
ventilation, acute respiratory distress syndrome, shock, or cardiac failure. 
3. Evidence of multi-lobar consolidation pneumonia or cavities on chest x-ray or CT scan. 
4. Severe COVID-19 disease as defined by the WHO COVID-19 Clinical Improvement Ordinal Scale, 
scores of 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation), or 
7 (ventilation + additional organ support-pressors, renal replacement therapy, ECMO). 
5. Medical history significant for the following pulmonary diseases: lung cancer, cystic fibrosis, empyema. 
6. Respiratory rate >30 respirations per minute. 
7. History of abuse of drugs or alcohol that could interfere with adherence to study requirements, as judged 
by the investigator. 
8. Treatment with other drugs thought to possibly have activity against COVID-19 within 7 days prior to 
enrollment or concurrently. Note: remdesivir or other authorized treatments for COVID-19 is allowed if 
considered SoC, if started prior to randomization or during the study.  
9. Use of Antrodia camphorata -containing products within 2 weeks prior to the first administration of 
study drug.  
10. Use of other investigational drugs within 30 days of dosing, or plans to enroll in another clinical trial of 
an investigational agent while participating in the present study. Note: authorized COVID-19 vaccines 
are not considered investigational and are not exclusionary.  
11. Clinically significant abnormal electrocardiogram (ECG) at Screening, as determined by the 
investigator. 
12. Patient requires frequent or prolonged use of systemic corticosteroids (≥20 mg of prednisone/day or 
equivalent for >4 weeks) or other immunosuppressive drugs (eg, for organ transplantation or 
autoimmune conditions).  
13. Abnormal laboratory values at Screening: 
a. 
Estimated glomerular filtration rate <50 mL/min. 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal 
(ULN), or ALT/AST >3 × ULN plus total bilirubin >2 × ULN. 


 
 
 
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c. 
Total bilirubin >1.5 × ULN, unless the patient has known Gilbert’s syndrome. 
d. Hemoglobin <9 g/dL for females or <11 g/dL for males. 
e. 
Absolute neutrophil count <1,500/mm3. 
f. 
Thrombocytopenia (platelets count <100 × 109/L). 
14. Treatment with any antiviral drugs (except remdesivir or other authorized treatments for COVID-19), or 
with any drugs known to be strong inducers or inhibitors of cytochrome P450 isoform (CYP) 2C19, 
CYP3A4, CYP2C8, and CYP2E1 within 14 days or 5 half-lives prior to the start of study treatment. 
Drugs with a narrow therapeutic index that are substrates of 1A2, 2B6, 2C8, 2C9, 2C19, 3A, and 2D6 
are also prohibited. 
15. Inability to swallow oral medications or a gastrointestinal disorder with diarrhea (eg, Crohn’s disease), 
malabsorption, or diarrhea of any etiology at baseline. 
16. Any other clinically significant medical condition or laboratory abnormality that, in the opinion of the 
investigator, would jeopardize the safety of the patient or potentially impact patient compliance or the 
safety/efficacy observations in the study. 
Test product, dose, and mode of administration: 
Antroquinonol in a dose of 100 mg (1 capsule) administered BID orally, for 14 days. 
Reference therapy, dose, and mode of administration: 
Placebo (1 capsule) administered BID orally, for 14 days. 
Duration of patient participation in study: 
Total duration of patient participation is planned to be a maximum of 33 days. 
The screening period is planned to be up to 3 days. The planned study treatment duration is 14 days. 
Follow-up/EOS assessments will be performed on Day 28 (±2 days). 
Study populations: 
Intention-to-treat (ITT): All randomized patients. Patients will be analyzed according to the treatment to which 
they were randomized. 
modified ITT (mITT): All randomized patients who received at least 1 dose of study drug. 
Per Protocol Set (PPS): All patients from the ITT set who have no important protocol deviations during the study. 
Patients with any important protocol deviations shall be excluded from the PPS prior to database lock. 
Safety Set (SS): All patients who have received at least 1 dose of the study treatment. Patients will be analyzed 
according to the study treatment they actually received. 
Pharmacokinetic Set (PKS): Patients in the sentinel cohort who have received at least 1 dose of the study 
treatment and have at least 1 evaluable plasma concentration without important protocol deviations or events 
thought to significantly affect the PK. 
The ITT set will be the primary analysis population for efficacy and the mITT and PPS will be the supportive 
analysis populations for efficacy analysis. Safety endpoints will be analyzed using the SS. The PKS will be used 
for PK assessment. 
Endpoints: 
The primary efficacy endpoint is: 
• 
The proportion of patients who are alive and free of respiratory failure (eg, no need for invasive 
mechanical ventilation, non-invasive ventilation, high-flow oxygen, or ECMO) on Day 14. 
The secondary efficacy endpoints are: 
• 
Clinical improvement score as measured by the WHO COVID-19 Clinical Improvement Ordinal Scale, 
as follows: 
o 
Time to 2-point improvement from baseline. 
o 
Supportive analysis, time to score 2 or lower. 


 
 
 
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o 
Supportive analysis, time to score 0. 
• 
Duration of hospitalization (days) up to Day 28 
• 
Virological clearance evaluated using PCR testing from nasopharyngeal or mid-turbinate samples on 
Days 5, 14, and 28: 
o 
Time to virological clearance, measured as study days from start of treatment to first negative 
SARS-CoV-2 PCR test 
o 
Rate of change in viral load will be evaluated depending on availability of quantitative assays. 
• 
Vital status (death) on Days 7, 14, and 28 
• 
Duration of ICU stay up to Day 28 
• 
Proportion of patients alive and free of respiratory failure on Days 7 and 28 
• 
COVID-19 symptoms on Days 7, 14, and 28. Assessment will evaluate: presence or absence of dry 
cough, dyspnea (shortness of breath/ difficulty in breathing), or chills/rigors, myalgia (muscle pain), 
headache, sore throat, and loss of taste or smell; other symptoms that could be related to COVID-19 will 
also be recorded. 
The exploratory efficacy endpoints include: 
• 
Age, sex, and remdesivir or other authorized treatments for COVID-19 use at baseline. 
• 
Use of any new authorized treatments recommended as SoC for COVID-19 during the course of the 
study 
The safety endpoints include the following variables: 
• 
Adverse events (AEs) 
• 
Standard safety laboratory tests (hematology, clinical chemistry, and urinalysis) 
• 
Vital signs: respiratory rate, body temperature, blood pressure, pulse rate 
• 
Complete physical examination: general appearance; head, eyes, ear/nose/throat, and neck; and 
lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, and 
dermatological systems 
• 
12-lead ECG 
• 
Chest imaging (x-ray or CT scan) findings 
The PK parameters to be assessed from plasma samples (sentinel cohort only) are:  
• 
Trough (predose) plasma concentration (Ctrough) 
• 
Maximum plasma concentration (Cmax) 
• 
Time to Cmax (tmax) 
Area under the plasma concentration versus time curve (AUC) from time zero to the time of last quantifiable 
concentration (AUC0-last), AUC within a dosing interval (AUCtau, where tau = 12 hours). On Day 14, if patients 
are still hospitalized, a predose and a 2-hours postdose sample will also be collected. 
Statistical methods: 
General Principles: 
Continuous variables will be summarized by the standard descriptive statistics: number of patients (n), mean, 
standard deviation, median, minimum, and maximum. Frequency of patients or events and percentages will be 
summarized in categorical variables. 
Results will be considered statistically significant at one-sided alpha of 0.025, and considered to indicate 
promising trend at one-sided alpha of 0.2. 
Efficacy Analysis: 
Primary Efficacy Analysis 
The proportion of patients from each treatment group who are alive and free of respiratory failure on Day 14 will 
be compared using logistic regression. The p-value will be based on the Wald test. The primary model will be 


 
 
 
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stratified by remdesivir or other authorized treatments for COVID-19 use at baseline and by age at baseline 
(≤65 years vs >65 years). 
Secondary Efficacy Analysis 
• 
Clinical improvement measured as a score on the WHO COVID-19 Clinical Improvement Ordinal Scale 
will be analyzed at each timepoint, adjusted for the clinical improvement score at baseline, age at 
baseline, and remdesivir or other authorized treatments for COVID-19 use at baseline, using an ordinal 
logistic regression on Days 7, 14, and 28. In addition, descriptive statistics will be provided for average 
score, and the proportion of patients at or below each score, at each timepoint. Time to 2-point 
improvement from baseline in WHO COVID-19 Clinical Improvement score, time to score of 2 or 
lower, and time to score of 0, will also be analyzed. 
• The hazard ratio and its 95% confidence interval for time to event outcomes will be estimated by the Cox 
proportional hazard model, with patients censored at the time they are provided any antiviral therapy not 
prescribed at baseline, or on Day 28 if they have not yet recovered. Patients who die at any time will be 
considered not yet recovered by Day 28. Median time to 2-point improvement, time to score of 2 or 
lower, and time to score of 0 will be estimated by Kaplan-Meier (KM) method, and the KM curve will 
be provided. The p-value for comparison between groups will be obtained based on proportional hazards 
modeling stratified by the same covariates as the primary model. 
• 
Duration of hospitalization and ICU stay up to Day 28 will be analyzed using normal regression, using 
the same covariates as for the primary endpoint. Patients who have died will be considered as continuing 
to require hospitalization or ICU up to Day 28 for the purposes of this analysis. 
• 
Time to virological clearance, measured as study days from start of treatment to first negative 
SARS-CoV-2 PCR test, will be evaluated using similar statistical methods as clinical improvement. All 
patients who have died will be considered as not having cleared the virus by Day 28. 
• 
Rate of change in viral load will be summarized descriptively and estimated using a Mixed Model for 
Repeated Measurements model. The model will include the treatment group, age, remdesivir or other 
authorized treatments for COVID-19 use at baseline, visit, and the interaction between visit and the 
treatment group as fixed factors, and will include the baseline value as a covariate. 
• 
Proportion of patients with vital status of death in both groups on Days 7, 14, and 28 will be analyzed 
using logistic regression stratified by the same covariates as the primary model. 
• 
Proportion of patients alive and free of respiratory failure on Days 7 and 28 will be compared using the 
same analysis as the primary endpoint. 
• 
COVID-19 symptoms at screening and on Days 7, 14, and 28 will be summarized, and compared using 
logistic regression following the same method as the primary endpoint. 
Exploratory Analyses 
Subgroup analyses will be provided for the parameters of age, sex, and remdesivir or other authorized treatments 
for COVID-19 use at baseline. Investigation of the interaction between these parameters and the treatment effect 
will be provided. The impact on efficacy of any new authorized treatments recommended as SoC for COVID-19 
during the course of the study will also be evaluated. 
Safety Analysis: 
Adverse events will be coded according to Medical Dictionary for Regulatory Activities version 23.0 dated 
19 April 2020 (exclusively meant for COVID-19), or later. 
The number and percentage of patients with treatment-emergent AEs (TEAEs), serious AEs (SAEs), TEAEs 
related to study treatment, SAEs related to study treatment, TEAEs leading to treatment discontinuation, and 
TEAEs leading to death will be summarized by system organ class (SOC), preferred term (PT), and treatment 
group. In addition, the severity of TEAEs and relationship to study treatment will be summarized by SOC, PT, 
and treatment group. 
Test values and change from baseline will be summarized descriptively for specific laboratory test results, vital 
signs, and complete physical examination, ECG, and chest imaging (x‑ray or CT scan) findings. Where 
applicable, shift tabulations by treatment group will be presented. 


 
 
 
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Pharmacokinetic Analysis: 
Descriptive statistics will be provided for antroquinonol plasma concentrations at prespecified timepoints and 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................................1 
SPONSOR APPROVAL .................................................................................................................................2 
INVESTIGATOR AGREEMENT ..................................................................................................................3 
SYNOPSIS ......................................................................................................................................................4 
TABLE OF CONTENTS .............................................................................................................................. 11 
LIST OF TABLES AND FIGURES ............................................................................................................. 13 
LIST OF ABBREVIATIONS ........................................................................................................................ 14 
1.
INTRODUCTION ........................................................................................................................ 16 
1.1. 
Study Rationale ......................................................................................................................... 16 
1.2. 
Background ................................................................................................................................ 16 
1.2.1. 
Investigational product .............................................................................................................. 17 
1.2.2. 
Nonclinical and preclinical data ................................................................................................ 17 
1.2.3. 
Clinical data ............................................................................................................................... 17 
1.3. 
Benefit-risk Assessment ............................................................................................................ 19 
2.
OBJECTIVES AND ENDPOINTS .............................................................................................. 20 
2.1. 
Objectives .................................................................................................................................. 20 
2.2. 
Endpoints ................................................................................................................................... 20 
3.
INVESTIGATION PLAN ............................................................................................................ 23 
3.1. 
Overall study design and plan description ................................................................................. 23 
3.2. 
Discussion of study design, including the choice of control groups .......................................... 24 
3.3. 
End of study definition .............................................................................................................. 25 
3.4. 
Selection of doses in the study ................................................................................................... 25 
4.
SELECTION OF STUDY POPULATION .................................................................................. 27 
4.1. 
Inclusion Criteria ....................................................................................................................... 27 
4.2. 
Exclusion Criteria ...................................................................................................................... 27 
4.3. 
Disease Diagnostic Criteria ....................................................................................................... 29 
4.4. 
Discontinuation Criteria ............................................................................................................ 29 
4.4.1. 
Screen failures ........................................................................................................................... 29 
4.4.2. 
Hepatic injury or renal impairment ............................................................................................ 29 
4.4.3. 
Discontinuation of study treatment ............................................................................................ 30 
4.4.4. 
Study withdrawal ....................................................................................................................... 31 
4.4.5. 
Lost to Follow-up ...................................................................................................................... 31 
4.4.6. 
Replacement procedures ............................................................................................................ 32 
4.4.7. 
Follow-up of patients who withdraw from the study ................................................................. 32 
4.5. 
Stopping Rules ........................................................................................................................... 32 
4.6. 
Study Termination ..................................................................................................................... 33 
5.
STUDY TREATMENTS ............................................................................................................. 34 
5.1. 
Treatments Administered........................................................................................................... 34 
5.1.1. 
Antroquinonol ............................................................................................................................ 34 
5.1.2. 
Placebo ...................................................................................................................................... 35 
5.2. 
Preparation, storage, handling, and accountability .................................................................... 35 
5.3. 
Method of treatment assignment ............................................................................................... 35 
5.4. 
Dose Modification ..................................................................................................................... 36 
5.5. 
Blinding ..................................................................................................................................... 36 
5.6. 
Treatment Compliance .............................................................................................................. 36 
6.
PRIOR AND CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ....................... 38 
6.1. 
Permitted medications ............................................................................................................... 38 
6.2. 
Prohibited medications .............................................................................................................. 38 
6.3. 
Other restrictions and contraindications .................................................................................... 39 
7.
STUDY ASSESSMENTS AND PROCEDURES ........................................................................ 40 
7.1. 
Efficacy Assessments ................................................................................................................ 40 
7.1.1. 
Primary efficacy endpoint.......................................................................................................... 40 
7.1.2. 
Secondary efficacy endpoints .................................................................................................... 40 
7.1.3. 
Exploratory efficacy endpoints .................................................................................................. 42 


 
 
 
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7.2. 
Safety Assessments.................................................................................................................... 42 
7.2.1. 
Adverse events ........................................................................................................................... 42 
7.2.2. 
Pregnancy .................................................................................................................................. 43 
7.2.3. 
Clinical laboratory evaluations .................................................................................................. 43 
7.2.4. 
Vital signs, physical examination, and other safety evaluations ................................................ 44 
7.3. 
Pharmacokinetic Assessment ..................................................................................................... 45 
8. 
SAMPLE SIZE AND DATA ANALYSES ................................................................................. 46 
8.1. 
Determination of sample size .................................................................................................... 46 
8.2. 
Analysis Populations ................................................................................................................. 47 
8.3. 
General Considerations .............................................................................................................. 47 
8.4. 
Efficacy Analysis ....................................................................................................................... 48 
8.4.1. 
Primary efficacy outcome measures .......................................................................................... 48 
8.4.2. 
Secondary efficacy outcome measures ...................................................................................... 48 
8.4.3. 
Exploratory outcome measures .................................................................................................. 49 
8.5. 
Safety Analysis .......................................................................................................................... 49 
8.6. 
Pharmacokinetic Analysis ......................................................................................................... 50 
8.7. 
Interim Analysis ........................................................................................................................ 50 
9. 
REFERENCES ............................................................................................................................. 51 
10. 
APPENDICES .............................................................................................................................. 53 
APPENDIX 1. 
ADVERSE EVENT DEFINITIONS ................................................................................ 54 
APPENDIX 2. 
CLINICAL LABORATORY EVALUATIONS ............................................................... 59 
APPENDIX 3. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ......... 60 
APPENDIX 4. 
CONTRACEPTIVE GUIDANCE .................................................................................... 64 
APPENDIX 5. 
SCHEDULE OF ASSESSMENTS ................................................................................... 66 
APPENDIX 6. 
REFERENCE LIST OF KNOWN INDUCERS, INHIBITORS, AND SUBSTRATES 
OF SELECTED CYTOCHROME P450 ENZYMES .................................................................. 69 
APPENDIX 7. 
WORLD HEALTH ORGANIZATION COVID-19 CLINICAL IMPROVEMENT 
ORDINAL SCALE ...................................................................................................................... 75 
 


 
 
 
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LIST OF TABLES AND FIGURES 
Table 1: Treatment Details .......................................................................................................................................... 34 
Table 2: Clinical Laboratory Evaluations .................................................................................................................... 59 
Table 3: Schedule of Assessments ............................................................................................................................... 66 
Table 4: Classification of In Vivo Inhibitors of CYP Enzymes................................................................................... 69 
Table 5: Classification of In Vivo Inducers of CYP Enzymes .................................................................................... 72 
Table 6: Examples of Sensitive In Vivo CYP Substrates and CYP Substrates with Narrow Therapeutic Range ....... 73 
 
Figure 1: Study Design ................................................................................................................................................ 24 
Figure 2: Stopping Criteria for Liver Injury ................................................................................................................ 30 
 


 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-last 
area under the plasma concentration versus time curve from 
time zero to the time of last quantifiable concentration 
AUCtau 
area under the plasma concentration versus time curve 
within a dosing interval 
BID 
twice daily 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration  
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization 
CSA 
clinical study agreement 
CT 
computerized tomography 
Ctrough 
trough (predose) plasma concentration 
CYP 
cytochrome P450 isoform 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HEENT 
head, eyes, ear/nose/throat, and neck 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IMP 
investigational medicinal product 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IWRS 
Interactive Web Response System 
KM 
Kaplan-Meier 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention-to-treat 


 
 
 
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Abbreviation 
Definition 
NOAEL 
no-observed-adverse-effect-level 
NSCLC 
nonsmall cell lung cancer 
PaO2 
partial pressure of oxygen 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic(s) 
PKS 
Pharmacokinetic Set 
PPS 
Per Protocol Set 
PSS 
Patient Safety Services 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SoC 
standard of care 
SOC 
system organ class 
SpO2 
peripheral capillary oxygen saturation; oxygen saturation 
SS 
Safety Set 
T1/2 
half-maximum concentration C1/2 
TEAE 
treatment-emergent adverse event 
TID 
3 times daily 
tmax 
time to Cmax 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 


 
 
 
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1. INTRODUCTION 
In 2019, an outbreak of respiratory disease caused by a novel coronavirus was first detected in 
Wuhan City, Hubei Province, China.1 The virus has been named Severe Acute Respiratory 
Syndrome COronaVirus 2 (SARS-CoV-2), and the disease it causes has been named 
COronaVIrus Disease 2019 (COVID-19). This virus has now been detected in many locations 
internationally, and COVID-19 was characterized as a pandemic by the World Health 
Organization (WHO) on 11 March 2020.2 
1.1. 
Study Rationale 
This is a Phase 2 clinical trial to evaluate the safety and efficacy of antroquinonol in patients 
hospitalized with mild to moderate pneumonia due to COVID-19. 
Currently, there is no approved treatment for COVID-19. An effective therapeutic is urgently 
needed. 
COVID-19 infection is characterized by the presence of systemic symptoms followed by a 
cytokine storm with elevated IL-6 leading to lung injury and requirement of mechanic 
ventilation, multi organ failure, and death.3 Antroquinonol modulates systemic immune 
responses by suppression of T-cell proliferation / activation and suppression of serum 
inflammatory cytokines expression including IL-6, MCP-1, IL-12, IFN-γ, TNF-α, and IL-10 
without affecting B cell activation.4 Examination of the antiviral activity of antroquinonol 
against hepatitis B virus (HBV) replication showed significantly suppressed HBV protein 
expression, including surface antigen and e antigen at 1 to 5 µM in HepG2.2.15 cells (human 
hepatoblastoma cell line HepG2 and characterized by having stable HBV expression) and 
suppressed expression of HBV DNA as shown by significantly suppressed HBV replicative 
intermediates (relaxed-circular, linear, and single-stranded DNA) at 5 µM in Qs5 cells 
(HBV-producing rat hepatoma cell line) (sponsor data). 
Preclinical data shows increased distribution of antroquinonol to the lungs compared to other 
organs.5 Antroquinonol has been studied in human trials for the treatment of pancreatic and lung 
cancer and has been shown to be well tolerated and without revealing safety concerns. This 
clinical trial represents the first time that antroquinonol will be administered to humans for 
treatment of mild to moderate pneumonia caused by COVID-19. 
Considering the antiviral and anti-inflammatory activity of antroquinonol and known safety 
profile to date, this study will assess the safety and efficacy of antroquinonol for the treatment of 
mild to moderate pneumonia due to COVID-19, with the goal to assess suppression of the virus, 
improvement of symptoms and prevention of disease progression. 
1.2. 
Background 
Antroquinonol (Hocena®) is currently being investigated for the treatment of patients with 
pancreatic cancer, and nonsmall cell lung cancer (NSCLC), under investigational new drug 
(IND) 133158 and IND 105226, respectively. Preclinical pharmacology and toxicology studies 
indicated that antroquinonol has a relatively low-toxicity profile, and has shown acceptable 
tolerability in the clinical trial setting, with no fatal serious adverse drug reactions (ADRs) 


 
 
 
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reported thus far. Cumulatively, 161 study subjects have been exposed to antroquinonol. 
Previous research has found antroquinonol to have a high concentration in the lung and have an 
anti-inflammatory effect. Therefore, Golden Biotechnology Corporation plans to investigate the 
use of antroquinonol for the treatment of mild to moderate pneumonia due to COVID-19. 
1.2.1. 
Investigational product 
Antroquinonol, a novel cyclohexenone compound, is a purified compound from extract of 
Antrodia camphorata. A. camphorata is an endemic species in Taiwan, and has been 
traditionally used for food and drug intoxication, and the treatment of diarrhea, abdominal pain, 
hypertension, itching of the skin, and liver cancer.6 Other research has shown A. camphorata to 
have detoxification,7, 8 anti-inflammatory,9, 10 immuno-modulatory,11 liver protection,12 and 
anticancer effects.13, 14, 15, 16, 17, 18 
The mycelium of A. camphorata has been marketed as a food supplement by Golden 
Biotechnology Corporation since 2005. The supplement “Antrodia camphorata” has been tested 
to be safe and approved by Department of Health, Taiwan. The extract of A. camphorata has 
been approved to be marketed by Golden Biotechnology Corporation as health supplement for 
promoting liver health since 2008. No fatal or severe/serious ADR has been reported by the 
marketed product of A. camphorata. 
1.2.2. 
Nonclinical and preclinical data 
For nonclinical data, refer to the investigator’s brochure (IB).5 
1.2.3. 
Clinical data 
Antroquinonol is currently being investigated for the treatment of patients with pancreatic 
cancer, and nonsmall cell lung cancer (NSCLC), under investigational new drug (IND) 133158 
and IND 105226, respectively. Additional investigations for the indications of acute myeloid 
leukemia, hyperlipidemia, chronic hepatitis B, and atopic dermatitis are underway. 
Phase 1 study (Study GOLANTA20090911) 
A first-in-human Phase 1 study was performed to determine the maximum tolerated dose and to 
evaluate pharmacokinetics (PK), safety and tolerability, and efficacy profiles of antroquinonol in 
NSCLC patients who are refractory to conventional treatment modalities. This open-label, 
nonrandomized, dose-escalation study enrolled a total of 13 patients, all of whom were Asian. A 
total of 5 patients were enrolled in an accelerated titration phase (1 patient each in the 50-, 100-, 
200-, 300-, and 450-mg dose groups), and 8 patients were enrolled in a standard titration phase 
(3 patients in the 450-mg dose group and 5 patients in the 600-mg dose group). No dose-limiting 
toxicities were reported in any patient for any of the doses in the intention-to-treat (ITT) 
population. Safety results indicated that antroquinonol doses up to 600 mg were generally safe 
and well tolerated when given daily for 4 weeks. 
Under single dose conditions, the maximum antroquinonol concentration was generally observed 
between 1.00 and 3.70 hours, with the exception of the 200-mg dose group where a median time 


 
 
 
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to maximum plasma concentration (tmax) of 10.00 hours was observed. Under multiple dose 
conditions, the results were similar, with the median tmax ranging from 1.92 to 4.05 hours. 
Antroquinonol was rapidly eliminated following single and multiple administrations of 
antroquinonol with the mean half-life (time between maximum plasma concentration [Cmax] to 
half-maximum concentration C1/2 [T1/2]) ranging from 1.30 to 4.33 hours, independent of the 
treatment dose. The rate and extent of absorption of antroquinonol increased in a dose-
proportional manner over the dosing range of 50 to 600 mg after multiple administrations of 
antroquinonol. However, under single-dose conditions, the rate and extent of antroquinonol 
absorption increased in a nondose proportional and a dose-proportional manner, respectively, 
over the dosing range of 50 to 600 mg. No clear trend was observed when comparing the PK 
parameters under single dose conditions to those under multiple dose conditions. 
Phase 2 study (GHNSCLC-2-001) in NSCLC 
A single-arm, open-label, Phase 2 study was conducted to determine the efficacy, safety, and PK 
of antroquinonol in patients with stage IV (including pleural effusion) NSCLC who had failed 
2 lines of anticancer therapy. Thirty-one patients with NSCLC received antroquinonol at 200 mg 
3 times daily (TID) (at 8-hour intervals) for 12 weeks with option for extension. A total of 
15 patients were Kirsten rat sarcoma viral oncogene homolog (KRAS)-positive and 16 patients 
were KRAS-negative. After the first 12-week treatment cycle, 5 patients who were progression 
free received further (12-week) treatment cycles with 200 mg TID antroquinonol (extension 
phase). 
Of the 52 patients screened, 31 patients were enrolled and treated during the Treatment Phase. 
Overall, 30 (96.8%) patients experienced 268 treatment-emergent adverse events (TEAEs); 
28 (90.3%) patients experienced 111 treatment-related TEAEs; 12 (38.7%) patients experienced 
at least one serious adverse event (SAE). 
Average concentrations of antroquinonol in plasma with 200 mg TID antroquinonol treatment 
were uniformly higher on Day 28 than on Day 1. The mean Cmax was 276.87 and 393.55 ng/mL 
for Days 1 and 28, respectively, and the mean area under the plasma concentration versus time 
curve (AUC) within a dosing interval (AUCtau) was 790.9 and 1224.3 h*ng/mL. The average oral 
clearance for antroquinonol was higher on Day 1 (254.31 L/h) than on Day 28 (197.82 L/h). The 
mean values of T1/2 on Day 1 and T1/2,eff on Day 28 were 1.617 and 7.643 h, respectively. The 
mean antroquinonol trough plasma concentration (Ctrough) were 44.99 and 74.71 ng/mL on Days 
1 and 28, respectively. Accumulation of antroquinonol following 28 days of 200 mg TID dosing 
was estimated to be 1.892-fold. 
Phase 2 study (GHLIP-2-001) Hyperlipidemia 
A total of 180 subjects were screened and 120 of them were eligible. Of the 120 enrolled 
subjects, 30 each were randomly assigned to the placebo, antroquinonol 50 mg, antroquinonol 
100 mg, and antroquinonol 150 mg groups. One hundred subjects completed the 12-week study 
treatment period. The main reason of discontinuation was the occurrence of adverse events (AEs) 
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Antroquinonol was generally well tolerated when administered at 50 mg, 100 mg, and 150 mg 
once daily for 12 weeks. During the study, 55.6% in the antroquinonol group and 46.7% in the 
placebo group reported at least 1 AE. All AEs, except one, were mild or moderate in severity. 
The most common AE occurring in the antroquinonol group and placebo group by system organ 
class (SOC) were gastrointestinal disorders, in which, diarrhoea was the most frequent AE 
reported in both antroquinonol and placebo groups. The AEs most frequently associated with 
antroquinonol treatment by preferred terms (PTs) were diarrhoea (32.2%), nausea (6.7%), and 
vomiting (4.4%). There was an increasing trend in the incidence of diarrhoea as the dose of 
antroquinonol increased. 
Two SAEs were reported in one subject receiving antroquinonol. The SAEs were not related to 
antroquinonol and did not cause study discontinuation. 
There were no clinically meaningful findings in vital signs, physical examination, 
electrocardiogram (ECG), and laboratory assessments. 
Overall, the results of this study showed a positive benefit-risk profile in favor of antroquinonol 
100 mg in terms of lipid profile and arterial stiffness. The dosages of antroquinonol were 
generally well tolerated. 
1.3. 
Benefit-risk Assessment 
There remains a significant unmet medical need for treatment options for patients with mild to 
moderate pneumonia due to COVID-19. Antroquinonol has been observed as a drug with a 
relatively low-toxicity profile in preclinical pharmacology and toxicology studies and clinical 
studies. To date, no fatal or severe/serious ADRs have occurred in the clinical studies of 
antroquinonol. Based on previous studies, antroquinonol has no hepatotoxicity and no cardiac 
toxicities. Safety of antroquinonol has not been assessed in a patient population hospitalized with 
mild to moderate pneumonia due to COVID-19. More detailed information about the known and 
expected benefits and risks and reasonably expected AEs of antroquinonol in other patient 
populations may be found in the current IB.5 
The results of PK studies, including absolute bioavailability determination, organ distribution, 
metabolism related to cytochrome P450 isoform (CYP450), main metabolites in rat urine, and 
cross-species metabolite comparisons indicated fast absorption, substantial organ distribution 
(especially in lung, heart, and kidney), and CYP450-involved metabolism profiles of 
antroquinonol. 
No other proven therapeutic options exist for the patient population hospitalized with mild to 
moderate pneumonia due to COVID-19. If proved effective, use of antroquinonol in mild to 
moderate pneumonia due to COVID-19 would fulfil an urgent unmet medical need in the context 
of a global pandemic and a novel coronavirus. 
As the design of this study is considered conservative and acceptable, and the study subjects 
targeted are patients with limited treatment options, the overall benefit/risk assessment supports 
further investigation of antroquinonol in hospitalized patients with mild to moderate pneumonia 
due to COVID-19 in a Phase 2 setting.  


 
 
 
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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of this study is: 
• To evaluate the efficacy of antroquinonol treatment of mild to moderate pneumonia due to 
COVID-19, as measured by the proportion of patients alive and free of respiratory failure 
(ie, no need for invasive mechanical ventilation, non-invasive ventilation, high-flow 
oxygen, or extracorporeal membrane oxygenation [ECMO]) on Day 14 
The secondary objectives are: 
• To further evaluate the efficacy of antroquinonol compared with placebo in this patient 
population as measured by: 
• WHO COVID-19 Clinical Improvement Ordinal Scale score on Days 7, 14, and 28 
• Duration of hospitalization up to Day 28 
• Virological clearance on Days 5, 14, and 28 
• Vital status (death) on Days 7, 14, and 28 
• Duration of intensive care unit (ICU) stay up to Day 28 
• Proportion of patients alive and free of respiratory failure on Days 7 and 28 
• COVID-19 symptoms on Days 7, 14, and 28 
• To evaluate the safety of antroquinonol treatment in patients with mild to moderate 
pneumonia due to COVID-19 
• To assess the PK of antroquinonol in a subset of 20 patients (first 10 patients randomized 
to antroquinonol and first 10 patients to placebo). 
The exploratory objective is to further evaluate efficacy via supportive analyses of: 
• Subgroup analyses of selected covariates 
• Impact on efficacy of any new authorized treatments recommended as standard of care 
(SoC) for COVID-19 during the course of the study. 
2.2. 
Endpoints 
The primary efficacy endpoint is: 
• The proportion of patients who are alive and free of respiratory failure (eg, no need for 
invasive mechanical ventilation, non-invasive ventilation, high-flow oxygen, or ECMO) 
on Day 14 
The secondary efficacy endpoints are: 
• Clinical improvement score as measured by the WHO COVID-19 Clinical Improvement 
Ordinal Scale (Appendix 7), as follows: 
• Time to 2-point improvement from baseline. 


 
 
 
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• Supportive analysis, time to score 2 or lower. 
• Supportive analysis, time to score 0. 
• Duration of hospitalization (days) up to Day 28 
• Virological clearance evaluated using polymerase chain reaction (PCR) testing from 
nasopharyngeal or mid-turbinate samples on Days 5, 14, and 28: 
• Time to virological clearance, measured as study days from start of treatment to first 
negative SARS-CoV-2 PCR test 
• Rate of change in viral load will be evaluated depending on availability of quantitative 
assays. 
• Vital status (death) on Days 7, 14, and 28 
• Duration of ICU stay up to Day 28 
• Proportion of patients alive and free of respiratory failure on Days 7 and 28 
• COVID-19 symptoms on Days 7, 14, and 28. Assessment will evaluate: presence or 
absence of dry cough, dyspnea (shortness of breath/ difficulty in breathing), or 
chills/rigors, myalgia (muscle pain), headache, sore throat, and loss of taste or smell; 
other symptoms that could be related to COVID-19 will also be recorded. 
The exploratory efficacy endpoints include: 
• Age, sex, and remdesivir or other authorized treatments for COVID-19 use at baseline. 
• Use of any new authorized treatments recommended as SoC for COVID-19 during the 
course of the study. 
The safety endpoints include the following variables: 
• AEs 
• Standard safety laboratory tests (hematology, clinical chemistry, and urinalysis) 
• Vital signs: respiratory rate, body temperature, blood pressure, pulse rate 
• Complete physical examination: general appearance; HEENT (head, eyes, ear/nose/throat, 
and neck); and lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, 
neurological, and dermatological systems 
• 12-lead ECG 
• Chest imaging (x-ray or computerized tomography [CT] scan) findings 
The PK parameters to be assessed from plasma samples (sentinel cohort only) are: 
• Trough (predose) plasma concentration (Ctrough) 
• Maximum plasma concentration (Cmax) 
• Time to Cmax (tmax) 
• AUC from time zero to the time of last quantifiable concentration (AUC0-last) 
• AUC within a dosing interval (AUCtau, where tau = 12 hours). 


 
 
 
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On Day 14, if patients are still hospitalized, a predose and 2-hours postdose sample will be 
collected. 


 
 
 
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3. INVESTIGATION PLAN 
3.1. 
Overall study design and plan description 
This is a randomized, double-blind, placebo-controlled, Phase 2, proof of concept study in 
hospitalized patients with mild to moderate pneumonia due to COVID-19. As antroquinonol has 
shown antiviral and anti-inflammatory activity in preclinical studies, it is being planned to use 
for treatment in patients with COVID-19 infection. 
Approximately 15 to 20 sites in the United States, and other countries based on the pandemic 
situation, are planned to enroll patients. 
The main characteristics of hospitalized patients to be included in this study are: adult patients 
with onset of COVID-19 symptoms within 2 weeks prior to randomization.  
The planned treatment duration is 14 days of administration of antroquinonol or placebo in 
combination with SoC therapy per local SoC policies. The total study duration is planned to be a 
maximum of 33 days (screening period up to 3 days, planned study treatment duration up to 
14 days, follow-up/End of Study (EOS) assessments up to 28±2 days after start of treatment). 
A total of 174 patients are planned to be randomized in a 1:1 ratio to antroquinonol or placebo. 
The study will consist of a sentinel cohort of 20 patients (10 patients randomized to 
antroquinonol and 10 patients to placebo), and an expansion cohort of 154 patients (77 patients 
in each treatment group). Enrollment will pause after the 20th patient in the sentinel cohort has 
started treatment, until the results of the interim analysis are known. Once the 20th patient in the 
sentinel cohort has completed 14 days of treatment, an unblinded Data Monitoring Committee 
(DMC) will assess the safety, tolerability, efficacy, and PK of 100 mg twice daily (BID) 
antroquinonol in COVID-19 patients in the sentinel cohort (interim analysis 1). The DMC will 
issue a recommendation to enroll patients for the expansion cohort, or to stop the study 
depending on the safety and futility assessment. Once the 80th patient has been enrolled and 
completed 14 days of treatment, the DMC will review safety, tolerability, and, efficacy data 
(interim analysis 2). Enrollment may be restricted at the 100th patient until the DMC has 
completed the assessment to prevent excessive enrollment. The DMC will continue to review 
safety and assess the risk/benefit profile on an ongoing basis. 
Patients will undergo assessment during hospitalization or could be discharged after start of 
study treatment any time after Day 2 if judged to be ready for discharge. If discharged, patients 
will then be requested to take study treatment at home (as prescribed) up to Day 14. End of 
Treatment (EOT) assessments will be performed at Day 14 (+2 days) (at home or site visit). A 
Day 5 (+/-1 day) visit (at home or site visit) will be performed if the patient is discharged prior to 
Day 5. If the patient is discharged after completion of treatment and before the follow up visit, 
he/she will be followed up on Day 28 (±2 days) for study assessments (a telephone or 
telemedicine visit). Post discharge, assessments will be done by telephone or telemedicine, 
except for Day 5, Day 14, and Early Termination (ET) of Study Treatment. If the discharge, ET, 
or Early Withdrawal visit falls within the window of a schedule Day visit, the assessments for 
the visits can be combined as one visit. The study design is summarized in Figure 1. 


 
 
 
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Figure 1: Study Design 
 
 
 
Abbreviations: BID = twice daily; DMC = Data Monitoring Committee; EOS = end of study; EOT = end of treatment; PK = 
pharmacokinetics; SoC = standard of care. 
a Sentinel cohort of 20 patients and an expansion cohort of 154 patients. The sentinel cohort will be treated with 100 mg 
antroquinonol or placebo BID. Enrollment will pause after the 20th patient in the sentinel cohort has started treatment. Once the 
20th patient in the sentinel cohort has completed 14 days of treatment, an unblinded DMC will assess the data for safety, 
tolerability, efficacy, and PK in the sentinel cohort (interim analysis 1). The DMC will issue a recommendation to enroll patients 
for the expansion cohort, or to stop the study depending on the safety and futility assessment. Once the 80th patient has been 
enrolled, and completed 14 days of treatment, the DMC will review the safety, efficacy, and tolerability data (interim analysis 2). 
Enrollment may be restricted at the 100th patient until the DMC has completed the assessment to prevent excessive enrollment. 
b Patients could be discharged after start of treatment any time after Day 2 if judged to be ready for discharge. If discharged, 
patients will then be requested to take study treatment at home (as prescribed) up to Day 14. End of Treatment assessments at 
Day 14 (+2 days) (at home or site visit) will be performed. A Day 5 (+/-1 day) visit (at home or site visit) will be performed if the 
patient is discharged prior to Day 5. If the patient is discharged after completion of treatment and before follow up visit, he/she 
will be followed up on Day 28 (±2 days) for study assessments (a telephone or telemedicine visit). Post discharge, assessments 
will be done by telephone, except for Day 5, Day 14, and Early Termination of Study Treatment. If the discharge, Early 
Termination, or Early Withdrawal visit falls within the window of a schedule Day visit, the assessments for the visits can be 
combined as one visit. 
3.2. 
Discussion of study design, including the choice of control groups 
This is a randomized, double-blind, placebo-controlled, Phase 2, proof of concept study in 
hospitalized patients with mild to moderate pneumonia due to COVID-19 infection. The 
rationale for this study is outlined in Section 1.1 and described in detail below. 
The study is designed to obtain initial safety, efficacy, tolerability, and PK of antroquinonol in 
patients in a sentinel cohort. Once the DMC assesses safety, efficacy, tolerability, and PK of a 
sentinel cohort, patient enrollment will resume. The study will assess the efficacy and safety in 
all of the patients (174 patients). 
Antroquinonol has been studied for NSCLC and pancreatic cancer. Preclinical studies showed 
that antroquinonol appeared to distribute to the lungs more than any other organ, followed by 
heart, kidneys, and small intestine (Section 5.2.3 of the IB5). Hence, the sponsor has planned use 
to assess the safety and efficacy of antroquinonol in the COVID-19 patient population. 


 
 
 
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The variability of individual clinical courses in COVID-19 and the incomplete understanding of 
this newly recognized disease can seriously affect the reliability of any conclusions based on 
uncontrolled data. Therefore, per the FDA’s recommendation, this is a randomized, 
placebo-controlled study. 
There are safety concerns in this patient population, both because of risks associated with the 
disease and because of the potential for adverse effects from the treatment that might be difficult 
to recognize.  
In addition, altering the immune response during an acute infection could theoretically have either 
beneficial or harmful consequences that cannot be precisely predicted. For this reason, the DMC 
will review safety data in 2 interim analyses, and will continuously monitor for safety until 
completion. 
The safety endpoints in this study are standard. Assessment of AEs, vital signs, complete 
physical examination, 12-lead ECGs, chest imaging, and safety laboratory tests are planned to be 
conducted and provide a robust approach to assess the safety of this patient population. 
Efficacy endpoints have been chosen to assess virological and clinical parameters to evaluate 
clinical improvement including measures that maximize objectivity such as, requirement of ICU 
care, and vital status, and also include the WHO COVID-19 Clinical Improvement Ordinal 
Scale. 
The PK of antroquinonol will be assessed from blood samples taken after the first study drug 
dose of the day on Day 3 and Day 14 (if patients are still hospitalized), in the sentinel cohort. 
Although PK has been well characterized in earlier studies, this is an acute patient population 
which may experience third-spacing and may be hemodynamically unstable. For this reason, 
intensive serial plasma PK samples (7-8 samples per patient) are being collected on Day 3 from 
hospitalized patients to characterize the PK of antroquinonol in the COVID-19 patient 
population. Every effort will be made to have PK samples taken close to the times as other blood 
sampling for serum to reduce the number of contacts between hospital staff and the patient. The 
PK samples will not be collected for the expansion cohort. 
3.3. 
End of study definition 
The end of the study is defined as the date of the last visit of the last patient in the study. 
3.4. 
Selection of doses in the study 
Antroquinonol is already in clinical development, albeit in cancer patients, and shown to be well 
tolerated. Levels have included oral single doses of 50-600 mg and 200 mg BID (BID use has 
occurred due to a short plasma half-life of 1.30 to 4.33 hours). For the proposed clinical work, a 
starting dose of 100mg (given BID due to short half-life) is proposed based around anti-
inflammatory activity in mouse efficacy work and the rat no-observed-adverse-effect-level 
(NOAEL) from toxicology testing. In the former, a 15-50 mg/kg/12.3 body surface factor was 
calculated to correspond to a 1.22-4.07 mg/kg human equivalent dose, or 85-285 mg for a 70 kg 
person. Therefore, a dose of 100 mg BID is within the animal efficacy range. The proposed dose 
is also supported by the rat study NOAEL on a mg/m² basis with an approximate 2-fold safety 


 
 
 
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margin [NOAEL in rat (30 mg/kg) x 6 (to convert dose in mg/kg to dose in mg/m²) = 180 mg/m² 
vs human 200 mg daily dose = 2.9 mg/kg x 37 (dose in mg/kg to dose in mg/m²) which converts 
to 108 mg/m² for a 70 kg person]. 
The safety of antroquinonol in patients with mild to moderate pneumonia caused by COVID-19 
will be confirmed at 100 mg BID in the sentinel and expansion cohorts, which is within the 
animal efficacy range. 
Treatment duration was selected based on the clinical presentation of the disease. Patients with 
COVID-19 experience systemic symptoms for approximately 7 to 10 days, and patients with 
disease progression but without ventilator use are typically hospitalized for 5 to 7 days. In a 
subset of patients, a cytokine storm can emerge resulting in complications. A treatment duration 
of 14 days should be adequate to treat the infection and prevent the immune response 
complications. 


 
 
 
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4. SELECTION OF STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
4.1. 
Inclusion Criteria 
Patients must satisfy all of the following criteria at the screening visit unless otherwise stated: 
1. Willing and able to provide informed consent. 
2. Male or female patients between 18 and 80 years of age. 
3. Oxygen saturation <94% in room air at screening. 
4. Hospitalized with mild COVID-19 disease (not requiring oxygen therapy [WHO 
COVID-19 Clinical Improvement Ordinal Scale, score of 3] or requiring oxygen therapy 
by mask or nasal prong [WHO COVID-19 Clinical Improvement Ordinal Scale, score of 
4]). Requirement of oxygen therapy by mask with reservoir to treat severe COVID-19 
pneumonia is not allowed for enrollment.  
Note: Hospitalized patients can also include patients admitted to centers conditioned as 
hospitals to treat COVID-19 patients. 
5. Chest x-ray or CT scan consistent with pneumonia. 
6. Onset of COVID-19 symptoms within 2 weeks prior to randomization. 
7. SARS-CoV-2 infection confirmed by a PCR test, antigen, or any authorized commercial 
or public health assay (nasopharyngeal, oropharyngeal, or respiratory samples, not 
serology testing). 
8. Male patients and female patients of childbearing potential must agree to use protocol-
specified methods of contraception (Appendix 4). 
9. Female patients of childbearing potential must have a negative pregnancy test at 
screening or pretreatment on Day 1. 
10. Male patients must agree not to donate sperm from the first dose through 90 days after 
the last dose of study treatment; female patients of childbearing potential should refrain 
from donation of ova from Day 1 until 90 days after the last dose of study treatment. 
11. Patient is, in the opinion of the investigator, willing and able to comply with the study 
treatment regimen and all other study requirements. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study if they satisfy any of the following criteria at the 
screening visit unless otherwise stated: 


 
 
 
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1. Female patient is pregnant or breastfeeding. 
2. Any patient’s concomitant life-threatening condition, including but not limited to: 
requiring mechanical ventilation, acute respiratory distress syndrome, shock, or cardiac 
failure. 
3. Evidence of multi-lobar consolidation pneumonia or cavities on chest x-ray or CT scan. 
4. Severe COVID-19 disease as defined by the WHO COVID-19 Clinical Improvement 
Ordinal Scale, scores of 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation 
and mechanical ventilation), or 7 (ventilation + additional organ support-pressors, renal 
replacement therapy, ECMO). 
5. Medical history significant for the following pulmonary diseases: lung cancer, cystic 
fibrosis, empyema. 
6. Respiratory rate >30 respirations per minute. 
7. History of abuse of drugs or alcohol that could interfere with adherence to study 
requirements as judged by the investigator. 
8. Treatment with other drugs thought to possibly have activity against COVID-19 within 
7 days prior to enrollment or concurrently. Note: remdesivir or other authorized 
treatments for COVID-19 is allowed if considered SoC, if started prior to randomization 
or during the study.  
9. Use of A. camphorata-containing products within 2 weeks prior to the first administration 
of study drug. 
10. Use of other investigational drugs within 30 days of dosing, or plans to enroll in another 
clinical trial of an investigational agent while participating in the present study. 
Note: authorized COVID-19 vaccines are not considered investigational and are not 
exclusionary.  
11. Clinically significant abnormal ECG at screening, as determined by the investigator. 
12. Patient requires frequent or prolonged use of systemic corticosteroids (≥20 mg of 
prednisone/day or equivalent for >4 weeks) or other immunosuppressive drugs (eg, for 
organ transplantation or autoimmune conditions). 
13. Abnormal laboratory values at screening: 
a. Estimated glomerular filtration rate <50 mL/min. 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper 
limit of normal (ULN), or ALT/AST >3 × ULN plus total bilirubin >2 × ULN. 
c. Total bilirubin >1.5 × ULN, unless the patient has known Gilbert’s syndrome. 
d. Hemoglobin <9 g/dL for females or <11 g/dL for males. 


 
 
 
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e. Absolute neutrophil count <1,500/mm3. 
f. Thrombocytopenia (platelets count <100 × 109/L). 
14. Treatment with any antiviral drugs (except remdesivir or other authorized treatments for 
COVID-19), or with any drugs known to be strong inducers or inhibitors of CYP2C19, 
CYP3A4, CYP2C8, and CYP2E1 within 14 days or 5 half-lives prior to the start of study 
treatment. Drugs with a narrow therapeutic index that are substrates of 1A2, 2B6, 2C8, 
2C9, 2C19, 3A, and 2D6 are also prohibited. 
15. Inability to swallow oral medications or a gastrointestinal disorder with diarrhea 
(eg, Crohn’s disease), malabsorption, or diarrhea of any etiology at baseline. 
16. Any other clinically significant medical condition or laboratory abnormality that, in the 
opinion of the investigator, would jeopardize the safety of the patient or potentially 
impact patient compliance or the safety/efficacy observations in the study. 
4.3. 
Disease Diagnostic Criteria 
Patients with SARS-CoV-2 infection confirmed by a PCR test, antigen, or any authorized 
commercial or public health assay (nasopharyngeal, oropharyngeal, or respiratory samples, not 
serology testing) and any symptoms of mild to moderate COVID-19 as defined by the WHO 
Clinical Improvement Ordinal Scale are required for enrollment (see Section 4.1). 
4.4. 
Discontinuation Criteria 
4.4.1. 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently enrolled in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAEs. 
Patients who do not meet the criteria for participation in this study may not be rescreened. 
4.4.2. 
Hepatic injury or renal impairment 
 
Hepatic injury 
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a patient meets one of the conditions outlined in Figure 2 or if the investigator 
believes that it is in the best interest of the patient.  


 
 
 
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Figure 2: Stopping Criteria for Liver Injury 
 
 
Abbreviations: ALT = alanine aminotransferase; INR = international normalized ratio; ULN = upper limit of normal 
 Note: INR value is not applicable to patients on anticoagulants. 
 
 
Renal impairment 
If a patient has renal impairment (creatinine clearance <50 mL/min), treatment should be 
discontinued. 
4.4.3. 
Discontinuation of study treatment 
A patient may be discontinued early from study drug treatment (ET of study treatment) for the 
following reasons: 
• Lack of efficacy (e.g. patients who require nonstudy antiviral or anticytokine therapy due 
to progression of COVID-19), and the investigator’s decision. Note: remdesivir or other 
authorized treatments for COVID-19 is allowed if considered SoC, if started prior to 
randomization or during the study. Initiation of remdesivir or other authorized treatments 
for COVID-19 during the study will be considered a treatment failure if started due to 
progression of disease. 
• Adverse event 
• Withdrawal by patient (specify reason in the eCRF) 
• Lost to follow-up 
• Death 


 
 
 
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• Physician decision (i.e. investigator decision based on protocol deviation, assessment that 
it is not in the patient’s best interest to continue, or other reason [specify reason in the 
eCRF]). 
• Sponsor decision (specify reason in the electronic case report form [eCRF]) 
No temporary treatment discontinuation is permitted. 
Patients who discontinue study treatment prematurely will be asked about the reason(s) for 
discontinuation and will be asked to continue all assessments up to Day 28. Patients will be 
educated about the continued scientific importance of their data and encouraged to complete the 
Day 28 Follow-up/EOS assessments even if they discontinue study treatment prematurely. 
4.4.4. 
Study withdrawal 
A patient may be discontinued early from the study for the following reasons: 
• Withdrawal by patient (specify reason in the eCRF) 
• Lost to follow-up 
• Death 
• Physician decision (i.e. investigator decision based on protocol deviation, assessment that 
it is not in the patient’s best interest to continue, or other reason [specify reason in the 
eCRF]). 
• Sponsor decision (specify reason in the eCRF) 
If the patient withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. Additionally, patients 
may request destruction of any samples taken and not tested, and the investigator must document 
this in the site study records. Refer to the Schedule of Assessments (Appendix 5) for data to be 
collected at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. Patients will be asked to complete Follow-up/EOS evaluations. 
4.4.5. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly is unable to be contacted by 
the study site after hospital discharge. 
The following actions must be taken if a patient repeatedly is unable to be contacted: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible, counsel the patient on the importance of maintaining the assigned visit schedule, 
and ascertain whether or not the patient wishes to and/or should continue in the study. 


 
 
 
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• In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4.4.6. 
Replacement procedures 
Patients who discontinue from the study will not be replaced. 
4.4.7. 
Follow-up of patients who withdraw from the study 
Due to the continued scientific importance of patient data even if study treatment is discontinued 
early, patients who withdraw from the study will be asked to complete final study procedures 
(Follow-up/EOS visit), as described in the Schedule of Assessments (Appendix 5). Patients who 
are no longer hospitalized may complete their assessments by telephone or via telemedicine or 
other means of remote communication. 
All SAEs that are ongoing at the time of discontinuation, or that develop prior to the final 
Follow-up/EOS visit, will be followed until resolution or stabilization, or up to 30 days following 
the last dose of study treatment, by Covance Patient Safety Services (PSS) group 
(Section 7.2.1.2). 
Steps will be taken by the sites to ascertain vital status in all randomized patients (eg, with a vital 
records search) up to Day 28. 
4.5. 
Stopping Rules 
The study will consist of a sentinel cohort of 20 patients (10 patients randomized to 
antroquinonol and 10 patients to placebo), and an expansion cohort of 154 patients (77 patients 
in each treatment group). Enrollment will pause after the 20th patient in the sentinel cohort has 
started treatment. Once the 20th patient in the sentinel cohort has completed 14 days of treatment, 
the unblinded DMC will assess the safety, efficacy, tolerability, and PK of study medication 
(interim analysis 1). The DMC will issue a recommendation to enroll patients for the expansion 
cohort, or to stop the study depending on the safety and futility assessment. 
Once the 80th patient has been enrolled, and completed 14 days of treatment, the DMC will 
review the safety, tolerability and efficacy data (interim analysis 2). Enrollment may be restricted 
at the 100th patient until the DMC has completed the assessment to prevent excessive enrolment. 
The DMC will continue to review safety and assess the risk/benefit profile on an ongoing basis. 
The following nonbinding rules will be considered by the DMC for futility, and the DMC will 
not make any recommendations to stop for early efficacy: 


 
 
 
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• Interim analysis 1 (sentinel cohort): An odds ratio of 3.5 or higher on the primary 
endpoint (proportion of patients who are alive and free of respiratory failure on Day 14) 
in favor of placebo. 
• Interim analysis 2: An odds ratio of 1.2 or higher on the primary endpoint (proportion of 
patients who are alive and free of respiratory failure on Day 14) in favor of placebo. 
Enrollment will pause pending unscheduled DMC review of safety data when any of the 
following criteria is met: 
• ≥ 2 patients experience treatment-related SAE, or 
• ≥ 2 patients experience treatment-related severe AEs that are of a similar nature. 
Enrollment and dosing may restart following review of relevant safety data by the DMC. 
A DMC Charter, which includes detailed processes, will be prepared. 
4.6. 
Study Termination 
The sponsor reserves the right to close a study site or terminate the study (ET of study) at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. Reasons for study 
termination may include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable treatment-emergent safety 
risk to the patients 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• Cancellation of drug development. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for the early 
closure of a study site by the sponsor or investigator may include, but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
Institutional Review Board/Ethics Committee or local health authorities, the sponsor's 
procedures, or Good Clinical Practice guidelines 
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5. STUDY TREATMENTS
5.1. 
Treatments Administered 
Details on the active treatment and placebo provided to patients are summarized in Table 1. 
Table 1: Treatment Details 
Study Treatment Name: 
Antroquinonol (Hocena®) 
Placebo 
Dosage Formulation: 
Antroquinonol in corn oil, 
encapsulated volume 212 μL, 
in a gelatin capsule 
Corn oil, encapsulated 
volume 212 μL, in a gelatin 
capsule 
Unit Dose Strength(s) 
100 mg 
N/A 
Dosage Level(s): 
One capsule BID  
(200 mg total daily dose) 
One capsule BID 
Route of Administration: 
Oral 
Oral 
Dosing Instructions: 
To be taken every 12 hours 
approximately within 
15 minutes after a meal or 
refreshment to reduce 
gastrointestinal adverse 
effect 
To be taken every 12 hours 
approximately within 
15 minutes after a meal or 
refreshment for consistency 
with active treatment 
Packaging and Labeling: 
Antroquinonol will be 
provided in a polyethylene 
bottle. Each bottle will be 
labeled as required per 
country regulations. 
Placebo will be provided in a 
polyethylene bottle. Each 
bottle will be labeled as 
required per country 
regulations. 
Manufacturer: 
Golden Biotechnology 
Corporation 
Golden Biotechnology 
Corporation 
Abbreviations: BID = twice daily. 
5.1.1. 
Antroquinonol 
The physicochemical properties and the pharmaceutical specifications of antroquinonol are 
provided in the IB.5 
Antroquinonol is supplied by Golden Biotechnology Corporation. Antroquinonol (100 mg in 
corn oil, encapsulated volume 212 μL) will be filled in #2 gelatin capsules and then packed in a 
light-protected polyethylene bottle and closed with a piece of polyethylene cap liner fitted in the 
cap for dispensation at each visit. The study treatment will be labeled in accordance with 
country-specific requirements. 
Beginning on Day 1, patients in the sentinel cohort who are randomized to receive active 
treatment will receive 1 capsule of study treatment (100 mg antroquinonol) orally BID. 
Antroquinonol should be taken approximately within 15 minutes after a meal or refreshment to 
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5.1.2. 
Placebo 
Placebo is supplied by Golden Biotechnology Corporation and will be in similar packaging as 
described for antroquinonol in Section 5.1.1. 
Placebo (corn oil, encapsulated volume 212 μL) will be filled in #2 gelatin capsules and then 
packed in a light-protected polyethylene bottle and closed with a piece of polyethylene cap liner 
fitted in the cap for dispensation at each visit. The study treatment will be labeled in accordance 
with country-specific requirements. 
Beginning on Day 1, patients who are randomized to receive placebo treatment will receive 
1 capsule of placebo orally BID. Placebo capsules should be taken approximately within 
15 minutes after a meal or refreshment to reduce any gastrointestinal adverse effect. Dosage of 
placebo will match dosage of antroquinonol. 
5.2. 
Preparation, storage, handling, and accountability 
Antroquinonol and placebo will be supplied by Golden Biotechnology Corporation for final 
formulation and packaging; along with the batch/lot numbers and Certificates of Analysis. The 
study treatment will be provided as individual patient kits consisting of 1 bottle with 30 capsules 
(supply for dosing 1 capsule BID for 14 days, plus 2 extra capsules). The sponsor is responsible 
for shipping both the treatments to the study site and for implementing strict inventory control 
for drug accountability. During shipping, antroquinonol will be packaged to maintain a 
temperature below 27ºC/80.6°F. 
The study investigator and/or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment. Drug accountability and inventory 
(capsule counts) will be recorded in the eCRF and the relevant study log. 
All study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. 
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. The investigator, institution, or the head of the 
medical institution (where applicable) is responsible for study treatment accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are provided 
in a separate document. 
5.3. 
Method of treatment assignment 
All patients will either receive antroquinonol or placebo after randomizing in a 1:1 ratio using an 
Interactive Web Response System (IWRS). Before the study is initiated, the log in information 
and directions for the IWRS will be provided to each site. 


 
 
 
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Randomization will be stratified by remdesivir or other authorized treatments for COVID-19 use 
at baseline and age at baseline (≤ 65 years vs > 65 years). 
Patients confirmed eligible at screening will be assigned a patient identifier prior to the 
administration of study treatment. The patient identifier will consist of the country number, site 
number, and patient number. The country number will comprise the first 2 digits, the site number 
will comprise the next 3 digits, and the patient number will comprise the final 3 digits 
eg, 01002003 is Country 1, Site 2, Patient 3. 
Study treatment will be dispensed at the Day 1 visit (see Schedule of Assessments, Appendix 5). 
5.4. 
Dose Modification 
No modification of study treatment dosage for patient management will be permitted. 
5.5. 
Blinding 
This is a double-blind study. 
The IWRS will be programmed with blind-breaking instructions. The study blind may be broken 
if, in the opinion of the investigator, it is in the patient’s best interest to know the study treatment 
assignment. The sponsor and the Contract Research Organization (CRO) must be notified before 
the blind is broken unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the patient’s condition (eg, antidote is available). In this case, sponsor 
and the CRO must be notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation and eCRF, as applicable. 
5.6. 
Treatment Compliance 
Records shall be maintained of the delivery of study treatment to the study sites, the inventory at 
the study sites, the use for each patient, and the return to the sponsor. 
These records shall include dates, quantities, batch/lot information, expiry dates, and the unique 
code numbers assigned to the study treatment and study patients. 
The investigator shall be responsible for ensuring that the records adequately document that the 
patients were provided the doses specified in the protocol and that all study treatment received 
from the sponsor is reconciled. 
Site staff will monitor compliance of patients with their assigned randomized treatment 
(antroquinonol or placebo) by recording the number of capsules actually used. 
Patients will be administered treatment by the site staff during hospitalization. On discharge, all 
patients are to be reminded of the importance of compliance with the treatment with an emphasis 
on taking their study treatment on schedule and contacting the study site for an appointment as 
soon as possible if they think they are experiencing worsening of condition. Compliance 


 
 
 
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information will be captured via eSource (if a patient version is used) or telemedicine. Patients 
will return unused supply at the EOT visit. 


 
 
 
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6. PRIOR AND CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Permitted medications 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study must be recorded in the eCRF along with: 
• reason for use 
• dates of administration including start and end dates, and 
• dosage information including dose and frequency. 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. The Medical Monitor should be contacted if there 
are any questions regarding concomitant or prior therapy. 
Medications, other than that those listed as prohibited medications and other restrictions, which 
are considered necessary for the patient’s safety and well-being, may be given at the discretion of 
the investigator and must be recorded in the appropriate sections of the eCRF. 
6.2. 
Prohibited medications 
Simultaneous participation in other clinical treatment study protocols is not allowed. 
Treatment with any antiviral drugs (except remdesivir or other authorized treatments for 
COVID-19), or with any drugs known to be strong inhibitors or inducers of CYP2C19, 3A4, 
2C8, and 2E1 are prohibited within 14 days or 5 half-lives prior to the start of study treatment. 
Drugs with a narrow therapeutic index that are substrates of 1A2, 2B6, 2C8, 2C9, 2C19, 3A, and 
2D6 are also prohibited. 
A list of commonly known CYP inducers and inhibitors is given in Appendix 6 for reference use. 
Antroquinonol is a purified compound from an extract of A. camphorata. For this reason, the use 
of A. camphorata-containing products is prohibited within 2 weeks prior to the first 
administration of study drug, and the use of A. camphorata-containing products other than 
antroquinonol is prohibited throughout the study. 
Patients who begin to receive nonstudy antiviral medication after the start of study treatment will 
be discontinued from study treatment. Note: remdesivir or other authorized treatments for 
COVID-19 is allowed if considered SoC, if started prior to randomization or during the study. 
Initiation of remdesivir or other authorized treatments for COVID-19 during the study will be 
considered a treatment failure if started due to progression of disease. 
Administration of an authorized COVID-19 vaccines is permitted as per the local health 
authority recommendation.  


 
 
 
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6.3. 
Other restrictions and contraindications 
Antroquinonol is contraindicated in patients who are hypersensitive to components of this 
product. Since antroquinonol primarily inhibits CYP3A4, some foods that are known to inhibit, 
induce, or serve as a substrate of CYP3A4 are potential contraindications to administration and 
should be avoided. These foods include charbroiled food, star fruit, and grapefruit juice. In 
addition, cruciferous vegetables should not be consumed within an appropriate time interval of 
study treatment dosing (at least 30 minutes). Alcohol or drug abuse is prohibited during the 
study. Social drinking is allowed; however, excessive alcohol use or binge drinking is 
discouraged during the study. In addition, smoking or vaping use is discouraged at least to 
Day 14, which is the primary endpoint. 


 
 
 
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7. STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Assessments (Appendix 5). 
As protocol waivers or exemptions are not allowed, with the exception of immediate safety 
concerns, deviations should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the patient should continue or discontinue the study treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Assessments, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure 
(Section 4.4.1), as applicable. Procedures conducted as part of the patient’s routine clinical 
management (eg, blood count) and obtained before signing the informed consent form (ICF) may 
be utilized for screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the timeframe defined in the Schedule of Assessments 
(Appendix 5). Additionally, patients will receive instructions for home administration of study 
treatment and a diary to capture all doses after a discharge.  
Results of the confirmatory COVID-19 test already done as SoC can be used to determine 
eligibility. The test does not need to be repeated at screening if already confirmed and 
documented. A confirmatory test may be done at screening if the COVID-19 test is not 
documented as SoC. 
At screening, laboratory tests and ECGs will be performed locally, as applicable, to assess 
eligibility and do not need to be repeated if already done as SoC (eg, within 24 to 48 hours of 
screening and patient is clinically stable). Chest x-ray or CT scan will be performed, as 
applicable, to assess eligibility and does not need to be repeated if done within 48 hours of 
screening. In addition, baseline central laboratory test samples can be taken after confirming 
eligibility. Baseline laboratory samples can be obtained at screening or on Day 1 (predose). 
Postbaseline laboratory samples do not need to be taken predose.  
7.1. 
Efficacy Assessments 
Efficacy assessment will be based on the clinical status of the patient during the study. 
7.1.1. 
Primary efficacy endpoint 
The primary efficacy endpoint is related to the proportion of patients alive and free of respiratory 
failure (ie, no need for invasive mechanical ventilation, non-invasive ventilation, high-flow 
oxygen, or ECMO) on Day 14. 
7.1.2. 
Secondary efficacy endpoints 
 
Clinical improvement 
The WHO COVID-19 Clinical Improvement Ordinal Scale will be used to assess a clinical 
improvement score on Days 7, 14, and 28. See Appendix 7 for details on the scale. 


 
 
 
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Duration of hospitalization 
The number of days a patient has been hospitalized prior to study entry will be recorded in the 
eCRF. 
Duration of hospitalization is the total number of days the patient is hospitalized during their 
participation in the study, up to Day 28. 
 
Virological clearance 
PCR testing for SARS-CoV-2 will be performed at a local or central laboratory at screening. 
Results of a confirmatory COVID-19 test already done as SoC can be used to determine 
eligibility. All subsequent tests (Day 1 and later) will be performed by a central laboratory. The 
PCR testing for SARS-CoV-2 will be collected during hospitalization as noted in the Schedule of 
Assessments (Appendix 5) and evaluated by the central laboratory. 
Virological clearance will be measured by: 
• Time to viral clearance: This endpoint will measure the time (days) to the first negative 
test for COVID-19. 
• Rate of change in viral load: if quantitative PCR results are performed, the level of 
virus will be measured over time (days). 
 
Vital status 
Patient mortality will be recorded up to Day 28 and summarized in the analysis on Days 7, 14, 
and 28. Every effort will be made to ascertain vital status in all randomized patients (eg, with a 
vital records search) up to Day 28. 
 
Duration of ICU stay 
Duration of ICU stay is defined as the total number of days the patient is managed in the ICU 
during their participation in the study, up to Day 28. The date of the start and stop of the ICU 
stay must be recorded in the eCRF; no daily assessment is needed. 
 
Respiratory failure free 
The proportion of patients alive and respiratory failure free will be evaluated on Days 7 and 28. 
Respiratory failure is defined as the need for invasive mechanical ventilation, non-invasive 
ventilation, high-flow oxygen, or ECMO. The date of the start of the respiratory intervention 
must be recorded in the eCRF; no daily assessment is needed. 
 
COVID-19 symptoms 
COVID-19 symptoms assessment at the times indicated in the Schedule of Assessments in 
Appendix 5 will evaluate: presence or absence of dry cough, dyspnea (shortness of breath/ 


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difficulty in breathing), or chills/rigors, myalgia (muscle pain), headache, sore throat, and loss of 
taste or smell; other symptoms that could be related to COVID-19 will also be recorded. 
7.1.3. 
Exploratory efficacy endpoints 
The exploratory efficacy endpoints include: 
•
Covariates of age, sex, and remdesivir or other authorized treatments for COVID-19 use at baseline
•
Use of any new authorized treatments recommended as SoC for COVID-19 during the course of the study
The final list of covariates for subgroup analyses are as detailed in the final statistical analysis 
plan. 
New authorized treatments to be analyzed will be identified post hoc and will be collected from 
the concomitant medications eCRF page. 
7.2. 
Safety Assessments 
7.2.1. 
Adverse events 
Definitions 
Adverse event definitions and assignment of severity and causality are detailed in Appendix 1. 
Adverse events will be elicited from the patient (or, when appropriate, from a caregiver, 
surrogate, or the patient’s legally authorized representative) by the study site staff using a 
nonleading question such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?” 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the patient 
to discontinue the study treatment. 
Adverse events will be assessed from signing the ICF until 2 weeks after the last dose of study 
treatment (Day 28 ± 2 days) as noted in the Schedule of Assessments table (Appendix 5). 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.0 dated 19 April 2020 (exclusively meant for COVID-19) or later. 
Reporting serious adverse events 
Serious AE reporting will be carried out as per local/country regulations, and will be described in 
the Safety Management Plan. 
All SAEs occurring after the signing of the ICF until 30 days following last dose of the study 
treatment and regardless of study treatment relationship, must be reported to Covance within 
24 hours of obtaining knowledge of the event. The report should include all available 
information requested on the SAE form.  


 
 
 
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Serious AEs - Covance PSS 
 
E-mail: SAEintake@covance.com (standard) 
The SAE form will collect data surrounding the event (eg, the nature of the symptom[s], time of 
onset in relation to initiation of therapy, duration, intensity, and whether or not therapy was 
discontinued). The investigator’s assessment of the probable cause of the event will also be 
included. In addition, relevant medical history, concomitant medications, laboratory and 
diagnostic tests reports, and procedures as well as all pertinent medical information related to the 
event will also be collected. 
Covance PSS will forward SAE queries requesting incomplete or missing information directly to 
the investigator. It is the investigator’s responsibility to be diligent in providing this information 
back to Covance PSS as soon as it is available.  
7.2.2. 
Pregnancy 
Female patients of childbearing potential will take a pregnancy test during screening (or 
pretreatment on Day 1), discharge, ET/EOT, and at the Day 28 Follow-up/EOS visit. 
Additionally, local/country regulations will be followed as applicable (eg., a pregnancy test one 
month following the last dose of study treatment in female patients of childbearing potential). 
A urine pregnancy test may be performed but must be confirmed with a serum pregnancy test 
(screening only). The Follow-up/EOS visit test will be a urine pregnancy test only (pregnancy 
test kit will be provided to the patient when discharged). 
Following administration of study treatment, pregnancy cases in any patient who is a female of 
childbearing potential or female partner of a male patient will be reported if known until the 
patient completes or withdraws from the study. The pregnancy will be reported immediately by 
telephone and by faxing a completed pregnancy report to the sponsor (or designee) within 
24 hours of knowledge of the event. The pregnancy will not be processed as an SAE; however, 
the investigator will follow the patient until completion of the pregnancy and must assess the 
outcome in the shortest possible time. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. 
The investigator should notify the sponsor (or designee) of the pregnancy outcome by submitting 
a follow-up pregnancy report. If the outcome of the pregnancy meets the criteria for immediate 
classification of an SAE (eg, spontaneous or therapeutic abortion [any congenital anomaly 
detected in an aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the investigator will report the event by telephone and by faxing a completed SAE 
form to the sponsor (or designee) within 24 hours of knowledge of the event. 
7.2.3. 
Clinical laboratory evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations at the times 
indicated in the Schedule of Assessments in Appendix 5. Clinical laboratory evaluations are 
listed in Appendix 2. Additional clinical laboratory evaluations will be performed at other times 


 
 
 
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if judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Serum pregnancy test is to be performed in female patients of child bearing potential at a local 
(site) laboratory, during screening or Day 1, discharge, and ET/EOT. A urine pregnancy test may 
be performed but must be confirmed with a serum pregnancy test (screening only). The 
Follow-up/EOS visit test will be a urine pregnancy test only (no serum pregnancy test 
confirmation). Additionally, local/country regulations will be followed as applicable (eg., a 
pregnancy test one month following the last dose of study treatment in female patients of 
childbearing potential). 
Screening laboratory test will be assessed by a local laboratory, and baseline and postbaseline 
laboratory tests will be assessed by a central laboratory. If delays in transportation of the samples 
are encountered, then local safety laboratory samples can be obtained instead for samples that 
can’t be frozen for shipment (e.g. hematology and urine). Baseline laboratory tests can be done 
once patients eligibility is confirmed The investigator will perform a clinical assessment of all 
clinical laboratory data. 
All screening laboratory results must be available and reviewed before the patient receives the 
first dose of study treatment on Day 1. After the test results are evaluated, the investigator should 
judge whether the patient is still eligible to stay in the study. Significant abnormal values 
occurring during the study will be followed until repeat test results return to normal, stabilize, or 
are no longer clinically significant. 
In this study, clinical laboratory tests will be performed predose on Days 1, 5, and 14 (+2 days). 
7.2.4. 
Vital signs, physical examination, and other safety evaluations 
 
Physical examinations 
Patients will be examined at the times indicated in the Schedule of Assessments in Appendix 5. 
A complete physical examination including general appearance, HEENT, lymphatic, 
cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, and dermatological 
systems will be performed at screening. 
 
Vital signs 
Seated blood pressure, seated pulse rate, respiratory rate, and body temperature will be assessed 
for safety and efficacy endpoints at the times indicated in the Schedule of Assessments in 
Appendix 5. Vital signs may also be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of vital 
signs is required. 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. Patients must be seated for at least 5 minutes before blood pressure and pulse 
rate measurements. Body temperature will be measured according to site’s local practices and 
may include oral, tympanic, rectal, axillary, or frontal.  


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Pulse oximetry to measure the peripheral capillary oxygen saturation (SpO2) will be collected in 
the eCRF during the study. SpO2 measurements should be collected at Screening, Day 1, Day 3, 
Day 5, Day 7, Day 14/EOT or Discharge/ET, and Day 28 visits if patient is in hospital (refer to 
Appendix 5). For discharged patients, SpO2 should be collected at Day 5 and Day 14 if visits 
completed in clinic/hospital. SpO2 may be collected if the visit is conducted at home by a home 
health service professional, but is not required.  
Fraction of inspired oxygen (FiO2) data will be collected and partial pressure of oxygen (PaO2) 
will also be collected if done as standard of care as per Appendix 5.  
12-lead Electrocardiogram Parameters 
Single 12-lead ECGs will be recorded after the patient has been supine and at rest for at least 
5 minutes at screening and after screening as per Appendix 5. The evaluation items for all ECGs 
will include heart rate, QRS complex, QT interval, QT interval corrected for heart rate, and RR 
interval. At screening, the investigator should examine the ECG for signs of cardiac disease that 
could exclude the patient from the study. An assessment of normal, abnormal and not clinically 
significant, or abnormal and clinically significant will be performed by the investigator. If the 
ECG is considered abnormal, the abnormality will be documented on the eCRF. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically appropriate 
or if the ongoing review of the data suggests a more detailed assessment of ECGs is required. 
Chest imaging 
A chest x-ray or CT scan will be performed at the times indicated in the Schedule of 
Assessments in Appendix 5. 
7.3. 
Pharmacokinetic Assessment 
The PK evaluation of antroquinonol in patients in the sentinel cohort includes Ctrough, Cmax, tmax, 
AUC0-1ast, and AUCtau. 
Blood samples for PK evaluations will be on Day 3 at predose and 1, 2, 3, 4, 6, 8, and 12 hours 
postdose (after the first study drug dose of the day), for hospitalized patients only. For 
discharged patients/outpatient visits, the 12-hour sample can be omitted for scheduling purposes. 
On Day 14 if patients are still hospitalized, predose and 2 hours postdose samples (after the first 
study drug dose of the day) will also be collected. 
Patients who are discharged from the hospital on Day 2 prior to PK sampling will not need to 
return to the clinic for sample collection. 
The PK samples will not be collected for the expansion cohort. 


 
 
 
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8. SAMPLE SIZE AND DATA ANALYSES 
8.1. 
Determination of sample size 
The decision to include 20 patients in the sentinel cohort was chosen arbitrarily.  
The sample size for the expansion group has been determined to provide evidence of proof of 
concept efficacy should the treatment prove effective. The primary endpoint and futility rules are 
based on assessments at Day 14 to enable rapid decision making, and the assessment at Day 28 
will also be presented as a secondary endpoint. 
The detailed assumptions are as follows, and the calculations include the patients from the 
sentinel cohort that were treated with the same dose used for the expansion cohort: 
Alpha 
0.2 (one-sided) 
Power 
80% 
Drop-Outs assumed 
2% 
Endpoint 
Odds of patient alive and respiratory failure free by Day 14 
Effect Size 
78% Placebo 
89% Antroquinonol 
Futility boundary shape 
Manually chosen. 
Odds Ratio of 3.5 at interim analysis 1 in favor of placebo, 
and 1.2 at interim analysis 2 in favor of placebo. 
Equivalent to 4 patients not in respiratory failure on 
antroquinonol vs 7 on placebo at interim analysis 1, or 
26 patients not in respiratory failure on antroquinonol vs 
28 on placebo at interim analysis 2. 
Nonbinding 
Efficacy boundary shape 
None 
 
In addition, the performance of the study under the following scenarios for the efficacy of 
antroquinonol were also considered: 
Antroquinonol harmful 
78% Placebo 
67% Antroquinonol 
Antroquinonol no effect 
78% Placebo 
78% Antroquinonol 
 
The nonbinding decision rules of the interim analysis and stopping probabilities under: 
 
 
 
Cumulative Futility  
Stopping Probability 
Look # 
Sample  
Size 
Futility 
Stopping 
Boundary 
Odds Ratio 
Drug 
harmful 
No 
effect 
Drug 
effective 
Interim analysis 1 
20 
3.5 
25% 
17% 
5% 
Interim analysis 2 
80 
1.2 
79% 
44% 
9% 
Final 
174 
 0.697 
 
 
 
 


 
 
 
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The decision rules may be modified pending discussion with the DMC, but any modifications 
will still be considered nonbinding; therefore, no adjustment for the final alpha will be made. 
The estimates of the probabilities of response are supported by recently published analysis by 
Richardson et al 19, which reported 21% mortality of hospitalized patients, and 320 patients 
requiring ventilation. The authors reported 88.1% mortality for patients requiring ventilation, 
implying that 282 patients died after receiving ventilation. Since 553 patients died overall, this 
means that 271 patients died without receiving mechanical ventilation, and therefore 320+271 = 
591 patients either died or received mechanical ventilation. This leads to the conclusion that 
591/2634 (22.4%) patients, either died or received mechanical ventilation at some point. 
It is anticipated that at least 50% of patients will need to benefit from antroquinonol to be 
considered a clinical breakthrough, hence an improvement from 22% to 11% is considered 
appropriate for the alternative hypothesis. 
8.2. 
Analysis Populations 
The following analysis populations will be included for this study: 
Intention-to-treat (ITT): All randomized patients. Patients will be analyzed according to the 
treatment to which they were randomized. 
modified ITT (mITT): All randomized patients who received at least 1 dose of study drug.  
Per Protocol Set (PPS): All patients from the ITT set who have no important protocol deviations 
during the study. Patients with any important protocol deviations shall be excluded from the PPS 
prior to database lock. 
Safety Set (SS): All patients who have received at least 1 dose of the study treatment. Patients 
will be analyzed according to the study treatment they actually received. 
Pharmacokinetic Set (PKS): Patients in the sentinel cohort who have received at least 1 dose of 
the study treatment and have at least 1 evaluable plasma concentration without important 
protocol deviations or events thought to significantly affect the PK. 
The ITT set will be the primary analysis population for efficacy and the mITT and PPS will be 
the supportive analysis populations for efficacy analysis. Safety endpoints will be analyzed using 
the SS. The PKS will be used for PK assessment. 
8.3. 
General Considerations 
Continuous variables will be summarized by the standard descriptive statistics: number of 
patients (n), mean, standard deviation, median, minimum, and maximum. Frequency of patients 
or events and percentages will be summarized in categorical variables. 
Missing values on clinical improvement score will be imputed using Last Observation Carried 
Forward for a maximum of 1 day at Day 7, 2 days at Day 14, and 4 days at Day 28. For 


 
 
 
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respiratory failure status, where a patient has died, their status will not be considered missing but 
will be treated as an observation at each timepoint. 
Unless otherwise stated, all regression models will be adjusted for age and remdesivir or other 
authorized treatments for COVID-19 use at baseline. 
Results will be considered statistically significant at one-sided alpha of 0.025, and considered to 
indicate promising trend at one-sided alpha of 0.2. 
Additional information is available in the statistical analysis plan (SAP). 
8.4. 
Efficacy Analysis 
The efficacy analysis will be based on the final SAP.  
8.4.1. 
Primary efficacy outcome measures 
The proportion of patients from each treatment group who are alive and free of respiratory 
failure on Day 14 will be compared using logistic regression. The p-value will be based on the 
Wald test. The primary model will be stratified by remdesivir or other authorized treatments for 
COVID-19 use at baseline and by age at baseline (> 65 years vs ≤ 65 years). 
8.4.2. 
Secondary efficacy outcome measures 
Clinical improvement measured as a score on the WHO COVID-19 Clinical Improvement 
Ordinal Scale will be analyzed at each timepoint, adjusted for the clinical improvement score at 
baseline, age at baseline, and remdesivir or other authorized treatments for COVID-19 use at 
baseline, using an ordinal logistic regression on Days 7, 14, and 28. In addition, descriptive 
statistics will be provided for average score, and the proportion of patients at or below each 
score, at each timepoint. Time to 2-point improvement from baseline in WHO COVID-19 
Clinical Improvement score, time to score of 2 or lower, and time to score of 0, will also be 
analyzed. 
The hazard ratio and its 95% confidence interval for time to event outcomes will be estimated by 
Cox proportional hazard model, with patients censored at the time they are provided any antiviral 
therapy not prescribed at baseline, or on Day 28 if they have not yet recovered. Patients who die 
at any time will be considered not yet recovered by Day 28. Median time to 2-point 
improvement, time to score of 2 or lower, and time to score of 0 will be estimated by 
Kaplan-Meier (KM) method, and the KM curve will be provided. The p-value for comparison 
between groups will be obtained based on proportional hazards modeling stratified by the same 
covariates as the primary model. 
Duration of hospitalization and ICU stay up to Day 28 will be analyzed using normal regression, 
using the same covariates as for the primary endpoint. Patients who die will be considered as 
continuing to require hospitalization or ICU stay up to Day 28 for the purposes of this analysis. 
Time to virological clearance, measured as study days from start of treatment to first negative 
SARS-CoV-2 PCR test, will be evaluated using similar statistical methods as clinical 


 
 
 
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improvement. All patients who have died will be considered as not having cleared the virus by 
Day 28 
Rate of change in viral load will be summarized descriptively and estimated using a Mixed 
Model for Repeated Measurements model. The model will include the treatment group, age, 
remdesivir or other authorized treatments for COVID-19 use at baseline, visit, and the interaction 
between visit and the treatment group as fixed factors, and will include the baseline value as a 
covariate. If a patient has tested negative, they are assumed to be negative until they are tested 
again.  
Proportion of patients with vital status of death in both groups on Days 7, 14, and 28 will be 
compared using logistic regression stratified by the same covariates as the primary model. 
Proportion of patients alive and free of respiratory failure on Days 7 and 28 will be compared 
using the same analysis as the primary endpoint. 
COVID-19 symptoms at screening and on Days 7, 14, and 28 will be summarized, and compared 
using logistic regression following the same method as the primary endpoint. 
8.4.3. 
Exploratory outcome measures 
Subgroup analyses will be provided for the parameters of age, sex, and remdesivir or other 
authorized treatments for COVID-19 use at baseline. Investigation of the interaction between 
these parameters and the treatment effect will be provided. 
The impact on efficacy of any new authorized treatments recommended as SoC for COVID-19 
during the course of the study will also be evaluated.  
8.5. 
Safety Analysis 
Safety variables include incidence of AEs (or TEAEs), laboratory test results, vital signs, and 
complete physical examination, ECG, and chest imaging (x‑ray or CT scan) findings. All safety 
analyses will be based on the SS. No formal statistical analysis of the safety data will be 
performed. 
Adverse events will be coded according to MedDRA, version 23.0 dated 19 April 2020 
(exclusively meant for COVID-19) or later. 
The number and percentage of patients with TEAEs, SAEs, TEAEs related to study treatment, 
SAEs related to study treatment, TEAEs leading to treatment discontinuation, TEAEs leading to 
study discontinuation, and TEAEs leading to death will be summarized by SOC, PT, and 
treatment group. In addition, the severity of TEAEs and relationship to study treatment will be 
summarized by SOC, PT, and treatment group. 
The AE summary tables will include counts of patients. Therefore, if a patient experiences more 
than 1 episode of a particular AE, the patient will be counted only once for that event. If a patient 
has more than one AE that is coded to the same PT, the patient will be counted only once for that 


 
 
 
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PT. Similarly, if a patient has more than 1 AE within an SOC, the patient will be counted only 
once in that SOC. 
Test values and change from baseline will be summarized descriptively for specific laboratory 
test results, vital signs, complete physical examination results, ECG findings, and chest imaging 
(x‑ray or CT scan) findings. Where applicable, shift tabulations by treatment group will be 
presented. 
Pregnancy test results and patients with confirmed positive pregnancy test result will be listed. 
8.6. 
Pharmacokinetic Analysis 
Descriptive statistics will be provided for antroquinonol plasma concentrations at prespecified 
timepoints and derived PK parameters (listed in Section 7.3). 
8.7. 
Interim Analysis 
The following interim analyses will be conducted: 
• Interim analysis 1, for safety and futility, will be conducted when the sentinel cohort has 
completed at least 14 days of treatment. Enrollment will be paused once the 20th patient 
in the sentinel cohort has been enrolled and started treatment until the results of the 
interim analysis are known. 
• Interim analysis 2, for safety and futility, will be conducted on all data collected up to the 
80th randomized patient completing 14 days of treatment. Enrollment may be restricted at 
the 100th patient until the DMC has completed the assessment to prevent excessive 
enrollment.  
All interim analyses will be reviewed by the unblinded DMC. The DMC will not make 
recommendations to stop the study early for efficacy. Futility rules provided to the DMC will be 
nonbinding, and therefore no adjustment of the final analysis will be made. Should either ≥ 2 
patients experience treatment related SAEs or severe AEs that are of a similar nature at any time, 
enrollment will be paused while the DMC reviews safety data. 
A DMC Charter, which includes detailed processes, will be prepared. 


 
 
 
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9. REFERENCES 
1. Food and Drug Administration. Guidance for Industry, Investigators, and Institutional 
Review Boards: FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency [Internet]. Food and Drug Administration; 2020. 
Available at: https://www.fda.gov/media/136238/download. 
2. World Health Organization. WHO Director-General's opening remarks at the media 
briefing on COVID-19 - 11 March 2020. Available at: 
https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-
media-briefing-on-covid-19---11-march-2020. Accessed 31 March 2020. 
3. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes 
and immunosuppression. Lancet. 2020;395(10229):P1033-1034. 
https://doi.org/10.1016/S0140-6736(20)30628-0. 
4. Tsai PY, Ka SM, Chang JM, et al. Antroquinonol Differentially Modulates T Cell 
Activity and Reduces Interleukin-18 Production, but Enhances Nrf2 Activation, in 
Murine Accelerated Severe Lupus Nephritis. Arthritis & Rheumatism. Jan 
2012;64(1):232-242. doi 10.1002/art.33328. 
5. Golden Biotechnology Corporation. Antroquinonol – Investigator’s Brochure. 
(Version 20200401 01). 01 April 2020. 
6. Chen CC, Shiao YJ, Lin RD, et al. Neuroprotective diterpenes from the fruiting body of 
Antrodia camphorata. J Nat Prod. 2006;69(4):689-691. 
7. Lee TH, Lee CK, Tsou WL, Liu SY, Kuo MT, Wen WC. A new cytotoxic agent from 
solid-state fermented mycelium of Antrodia camphorata. Planta Med. 2007;73(13):1412-
1415. 
8. Hseu YC, Chang WC, Hseu YT, et al. Protection of oxidative damage by aqueous extract 
from Antrodia camphorata mycelia in normal human erythrocytes. Life Sci. 
2002;71(4):469-482. 
9. Chang JM, Lee YR, Hung LM, et al. An extract of Antrodia camphorata mycelia 
attenuates the progression of nephritis in systemic lupus erythematosus–Prone NZB/W 
F1 Mice. Evid Based Complement Alternat Med. 2011;2011:465894. 
doi:10.1093/ecam/nen057. 
10. Shen YC, Wang YH, Chou YC, et al. Evaluation of the anti-inflammatory activity of 
Zhankuic acids isolated from the fruiting bodies of Antrodia camphorata. Planta Med. 
2004;70(4):310-314. 
11. Chou CJ, Shen YC, Chang TT, Chen CF. Evaluation of the immuno-modulating activity 
of some active principles isolated from the fruiting bodies of Antrodia camphorata. The 
12th International Congress of Oriental Medicine 2003. 


 
 
 
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12. Song TY, Yen GC. Protective effects of fermented filtrate from Antrodia camphorata in 
submerged culture against CCl4-induced hepatic toxicity in rats. J Agric Food Chem. 
2003;51(6):1571-1577. 
13. Chen KC, Peng CC, Peng RY, et al. Unique Formosan mushroom Antrodia camphorate 
differentially inhibits androgen-responsive LNCaP and –independent PC-3 prostate 
cancer cells. Nutr Cancer. 2007;57(1):111-121. 
14. Peng CC, Chen KC, Peng RY, Chyau CC, Su CH, Hsieh-Li HM. Antrodia camphorata 
extract induces replicative senescence in superficial TCC, and inhibits the absolute 
migration capability in invasive bladder carcinoma cells. J Ethnopharmacol. 
2007;109(1):93-103. 
15. Yang HL, Chen CS, Chang WH, et al. Growth inhibition and induction of apoptosis in 
MCF-7 breast cancer cells by Antrodia camphorata. Cancer Lett. 2006;231(2):215-227. 
16. Ao ZH, Xu ZH, Lu HY, Xu XY, Zhang XM, Dou WF. Niuchangchih (Antrodia 
camphorata) and its potential in treating liver diseases. J Ethnopharmacol. 
2009;121(2):194-212. 
17. Chen YS, Pan JH, Chiang BH, Lu FJ, Sheen LY. Ethanolic extracts of Antrodia 
cinnamomea myceliam fermented at varied times and scales have differential effects on 
hepatoma cells and normal primary hepatocytes. J Food Sci. 2008;73(7):H179-85. 
18. Ho CM, Huang CC, Huang CJ, et al. Effects of Antrodia camphorata on viability, 
apoptosis, and [Ca2+]i in PC3 human prostate cancer cells. Chin J Physiol. 
2008;51(2):78-84. 
19. Richardson S, Hirsch JS, Narasimhan M, et al., on behalf of the Northwell COVID-19 
Research Consortium. Presenting Characteristics, Comorbidities, and Outcomes Among 
5700 Patients Hospitalized with COVID-19 in the New York City Area. JAMA. 2020; 
May 26;323(20):2052-2059. doi: 10.1001/jama.2020.6775. 
20. Department of Health and Human Services, Food and Drug Administration. Guidance for 
Industry: Drug Interaction Studies - Study Design, Data Analysis, Implications for 
Dosing, and Labeling Recommendations. Draft, 2012. 
21. World Health Organization. WHO R&D Blueprint. Novel Coronavirus COVID-19 
Therapeutic Trial Synopsis. Draft February 18, 2020. Available at: 
https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf 
 


 
 
 
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10. APPENDICES 
 


 
 
 
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Appendix 1. Adverse Event Definitions 
Definitions 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. This includes the following: 
• Any clinically significant worsening of a pre-existing condition. 
• Any recurrence of a pre-existing condition. 
• An AE occurring from overdose of a sponsor study drug whether accidental or intentional (ie, a dose higher 
than that prescribed by a health care professional for clinical reasons). 
• An AE occurring from abuse of a sponsor study drug (ie, use for nonclinical reasons). 
• An AE that has been associated with the discontinuation of the use of a sponsor study drug. 
• Clinically significant laboratory abnormalities (i.e. the laboratory abnormality is associated with symptoms, 
requires medical intervention, or requires changes to study drug treatment).  
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the patient signs the informed consent form and that is documented as part of 
the patient’s medical history. 
The questions concerning whether the condition existed before the start of the active phase of the 
study and whether it has increased in severity and/or frequency will be used to determine 
whether an event is a treatment-emergent AE. An AE is considered to be treatment-emergent if 
(1) it is not present when the active phase of the study begins and is not a chronic condition that 
is part of the patient’s medical history, or (2) it is present at the start of the active phase of the 
study or as part of the patient’s medical history, but the severity or frequency increases during 
the active phase. The active phase of the study begins at the time of the first dose of the study 
drug. The active phase of the study ends at the Day 28 Follow-up/End of Study (EOS) visit. 
Disease-specific signs and symptoms that were ongoing prior to study entry will not be 
considered AEs unless they worsen (eg, increase in frequency or severity) unexpectedly during 
the course of the trial. 
Reporting of Adverse Events 
At each visit the investigator, or delegate, will determine whether or not any AEs have occurred. 
Nonleading questions such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?” should be used to elicit the patient to report any possible AEs. If 
any AEs have occurred, they will be recorded in the AE section of the electronic case report form 
(eCRF) and in the patient’s source documents. If known, the diagnosis should be recorded, in 
preference to listing the individual signs and symptoms. 
Adverse event reporting begins from the time of informed consent and ends 2 weeks after the last 
dose of study treatment (Day 28 ± 2 days). 


 
 
 
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Assessment of Severity 
The investigator will be asked to provide an assessment of the severity of the AE using the 
following categories: 
• Mild: Usually transient and may require only minimal treatment or therapeutic intervention. The event does 
not generally interfere with usual activities of daily living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The event interferes with 
usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the 
patient. 
• Severe: Interrupts usual activities of daily living, significantly affects clinical status, or may require 
intensive therapeutic intervention. 
Relationship to Study Treatment 
The investigator will make a determination of the relationship of the AE to the study drug using 
a 4-category system according to the following guidelines: 
• Not related: When the AE is definitely caused by the patient’s clinical state, or the study 
procedure/conditions. 
• Unlikely Related: When the temporal association between the AE and the drug is such that the drug is not 
likely to have any reasonable association with the AE. 
• Possibly Related: When the AE follows a reasonable temporal sequence from the time of drug 
administration but could have been produced by the patient’s clinical state or the study 
procedures/conditions. 
• Related: When the AE follows a reasonable temporal sequence from administration of the drug, abates upon 
discontinuation of the drug, and follows a known or hypothesized cause-effect relationship. 
• If causality is assessed as Related or Possibly Related, the event will be considered as related for regulatory 
reporting purposes. 
Action Taken for Adverse Events 
The investigator or designee will record the action taken for the AE in the eCRF. Actions taken 
will include: 
• Dose not changed: The medication schedule was not changed. 
• Drug withdrawn: The medication schedule was modified through termination of the prescribed regimen of 
medication. 
• Not applicable 
• Unknown. 
Follow-up of Adverse Events 
All (S)AEs that are ongoing at the time of discontinuation, or that develop prior to the final 
Follow-up/EOS visit, will be followed for up to 30 days following the last dose of study 
treatment, or until resolution or stabilization. 
Adverse Drug Reactions 


 
 
 
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All noxious and unintended responses to an investigational medicinal product (IMP; ie, where a 
causal relationship between an IMP and an AE is at least a reasonable possibility) related to any 
dose should be considered adverse drug reactions (ADRs). 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or 
for modification of physiological function, is to be considered an ADR. 
An unexpected ADR is defined as an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, investigator’s brochure for an unapproved 
IMP). 
Serious Adverse Events 
An SAE is any AE occurring at any dose that meets 1 or more of the following criteria: 
• Results in death 
• Is life-threatening (see below) 
• Requires patient hospitalization or prolongation of an existing hospitalization (see below) 
• Results in a persistent or significant disability or incapacity (see below) 
• Results in a congenital anomaly or birth defect. 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not require hospitalization, or development of drug dependency or drug abuse. 
A life-threatening adverse event is any AE that places the patient at immediate risk of death 
from the event as it occurred. A life-threatening event does not include an event that might have 
caused death had it occurred in a more severe form but that did not create an immediate risk of 
death as it actually occurred. For example, drug-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life-threatening, even though drug-induced hepatitis 
of a more severe nature can be fatal. 
Hospitalization or prolongation of a hospitalization is a criterion for considering an AE to be 
serious. Hospitalization is to be considered only as an overnight admission. In the absence of an 
AE, the participating investigator should not report hospitalization or prolongation of 
hospitalization. This is the case in the following situations: 
• Hospitalization or prolongation of hospitalization is needed for a procedure required by the protocol 
(excluding hospitalization required by the index case). Day or night survey visits for biopsy or surgery 
required by the protocol are not considered serious. 
• Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the study center 
(eg, stent removal after surgery). This should be recorded in the study file. 
• Hospitalization for survey visits or annual physicals fall in the same category. 


 
 
 
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In addition, a hospitalization planned before the start of the study for a pre-existing condition that 
has not worsened does not constitute an SAE (eg, elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the study).  
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions (ie, the AE resulted in a significant, persistent, or permanent change, impairment, 
damage, or disruption in the patient’s bodily function/structure, physical activities, or quality of 
life).  
If there is any doubt as to whether a case constitutes an AE or SAE based on the information 
available, the case should be treated as an SAE. 
Pregnancy 
The investigator will collect pregnancy information on any female patient who becomes pregnant 
while participating in this study. Information will be recorded on the appropriate form and 
submitted to the sponsor (or designee) within 24 hours of learning of a patient’s pregnancy. The 
patient will be followed to determine the outcome of the pregnancy. 
The investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study. After obtaining the 
necessary signed informed consent from the pregnant female partner directly, the investigator 
will record pregnancy information on the appropriate form and submit it to the sponsor (or 
designee) within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor (or designee). 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is 
always considered to be an SAE and will be reported as such. Any poststudy pregnancy-related 
SAE considered reasonably related to the IMP by the investigator will be reported to the sponsor. 
While the investigator is not obligated to actively seek this information in former study patients, 
he or she may learn of an SAE through spontaneous reporting. 
Events not to be reported as adverse events  
A lack of drug effect is not an AE in this study because the purpose of the clinical study is to 
establish treatment effect. 
The following study-specific clinical events related to Coronavirus Disease 2019 (COVID-19) 
are exempt from AE reporting unless the investigator judges the event to be related to study 
drug: 


 
 
 
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• Hypoxemia due to COVID-19 requiring non-invasive ventilation or high flow oxygen; 
• Respiratory failure due to COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane 
oxygenation 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease under study, unless judged by the investigator 
to be more severe than expected for the participant’s condition. 
The disease being studied or expected progression, signs, or symptoms of the disease being 
studied, unless more severe than expected for the participant’s condition. 


 
 
 
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Appendix 2. Clinical Laboratory Evaluations 
The following clinical laboratory analytes will be assessed: 
Table 2: Clinical Laboratory Evaluations 
Clinical Chemistry: 
Hematology (complete blood count): 
Albumin 
Hematocrit 
ALP 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
BUN 
MCV 
Calcium 
Platelet count  
Chloride 
Red blood cell (RBC) count 
Cholesterol 
White blood cell (WBC) count 
Creatinine 
WBC differential 
GGT 
(% and absolute values): 
Glucose 
Basophils 
eGFR 
Eosinophils 
LDH 
Lymphocytes 
Phosphorus 
Monocytes 
Potassium 
Neutrophils 
Sodium 
 
Total Bilirubin 
 
Total CO2 (measured as bicarbonate) 
For female patients of child bearing potential: 
Total Protein 
Pregnancy test (urine, serum) 
Triglycerides 
 
Uric acid 
 
 
 
Complete Urinalysis: 
 
Color and appearance  
 
pH and specific gravity 
 
Bilirubin 
 
Glucose 
 
Ketones  
 
Leukocytes  
 
Nitrite  
 
Occult blood  
 
Protein  
 
Microscopic (including RBCs and WBCs) 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CBC = complete blood count; CO2 = carbon dioxide; eGFR = estimated glomerular 
filtration rate; GGT = gamma glutamyl transferase; LDH = lactate dehydrogenase; MCH = mean corpuscular 
hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; 
RBC = red blood cell; WBC = white blood cell. 
 


 
 
 
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Appendix 3. Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and 
Council for International Organizations of Medical Sciences International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines 
• Applicable local/country laws and regulations 
• The protocol, protocol amendments, informed consent form (ICF), investigator’s brochure, and other 
relevant documents (eg, advertisements) must be submitted to an Institutional Review Board (IRB)/ Ethics 
Committee (EC) by the investigator and reviewed and approved by the IRB/EC before the study is initiated. 
• Any amendments to the protocol will require IRB/EC approval before implementation of changes made to 
the study design, except for changes necessary to eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/EC 
• Notifying the IRB/EC of serious adverse events or other significant safety findings as required by IRB/EC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 21 Code of 
Federal Regulations (CFR), ICH guidelines, the IRB/EC, European regulation 536/2014 for clinical studies 
(if applicable), and all other applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each patient will be provided with a study-specific ICF 
giving details of the study drugs, procedures, and potential risks of the study. Patients will be 
instructed that they are free to obtain further information from the investigator (or designee) and 
that their participation is voluntary and they are free to withdraw from the study at any time. 
Patients will be given an opportunity to ask questions about the study prior to providing consent 
for participation.  
Patients or their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of local regulations, ICH guidelines, and the IRB/EC or 
study center, where applicable. If using a legally authorized representative, informed consent 
should be obtained from the patient once he/she has regained the cognitive ability to understand 
the study. The patient or their legally authorized representative will be given a copy of the signed 
ICF, and the original will be maintained with the patient’s records. 
Patients must be reconsented to the most current version of the ICF(s) during their participation 
in the study. 


 
 
 
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Patient Data Protection 
Patients will be assigned a unique identifier and will not be identified by name in electronic case 
report forms (eCRFs), study-related forms, study reports, or any related publications. Patient and 
investigator personal data will be treated in compliance with all applicable laws and regulations. 
In the event the study protocol, study report, or study data are included in a public registry, all 
identifiable information from individual patients or investigators will be redacted according to 
applicable laws and regulations. 
The patient must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. The patient must also be informed that his/her medical records may be examined by 
sponsor or Contract Research Organization (CRO) auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB/EC members, and by inspectors from regulatory 
authorities. 
Data Monitoring Committee (DMC) 
The unblinded DMC will assess the safety, efficacy, tolerability, and pharmacokinetics (PK) of 
study medication. The DMC will assess data in the sentinel cohort (interim analysis 1) and will 
issue a recommendation to enroll patients for the expansion cohort, or to stop the study 
depending on the safety assessment. Once the 80th patient has been enrolled, and completed 
14 days of treatment, the DMC will review the safety, tolerability and efficacy data (interim 
analysis 2). Enrollment may be restricted at the 100th patient until the DMC has completed the 
assessment to prevent excessive enrolment. The DMC will continue to review safety and assess 
the risk/benefit profile on an ongoing basis. 
The DMC members (independent of the sponsor) will be selected on the basis of relevant 
experience and understanding of clinical research and the issues specific to the therapeutic area, 
as well as previous DMC experience. 
A DMC charter, which includes detailed processes, will be prepared. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All patient data relating to the study will be recorded on eCRFs unless directly transmitted to the sponsor or 
designee electronically (eg, laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by electronically signing the eCRF. 


 
 
 
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• The investigator must maintain accurate documentation (source data) that supports the information entered 
in the eCRF. 
• The investigator must permit study-related monitoring, audits, IRB/EC review, and regulatory agency 
inspections and provide direct access to source data documents. 
• The sponsor or designee is responsible for the data management of this study including quality checking of 
the data. Predefined, agreed risks, monitoring thresholds, quality tolerance thresholds, controls, and 
mitigation plans will be documented in a risk management register. Additional details of quality checking 
to be performed on the data may be included in a Data Management Plan. 
• Study monitors will perform ongoing source data verification to confirm that data entered into the eCRF by 
authorized site personnel are accurate, complete, and verifiable from source documents; that the safety and 
rights of patients are being protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must be retained by 
the investigator in accordance with 21 CFR 312.62(c) unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. 
Investigator Documentation Responsibilities 
All individual, patient-specific study data will be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. All data generated from 
external sources (eg, central laboratory, pharmacokinetics, pharmacodynamics, 
electrocardiogram central readers) and transmitted to the sponsor or designee electronically will 
be integrated with the patient’s eCRF data in accordance with the Data Management Plan. 
An eCRF must be completed for each patient who signs an ICF and undergoes any prescreening 
or screening procedures, according to the eCRF completion instructions. The sponsor, or CRO, 
will review the supporting source documentation against the data entered into the eCRFs to 
verify the accuracy of the electronic data. The investigator will ensure that corrections are made 
to the eCRFs and that data queries are resolved in a timely fashion by the study staff.  
The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the data on 
the eCRF, the data queries, and the site notifications. 
Publications 
If on completion of the study the data warrant publication, the investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical study 
agreement (CSA). Unless otherwise specified in the CSA, the following process shall occur: 
The institution and investigator shall not publish or present data from an individual study center 
until the complete multicenter study has been presented in full or for 2 years after the termination 
of the multicenter study, whichever occurs first. Subsequent publications must refer to the 
multicenter findings. Thereafter, if the investigator expects to participate in the publication of 
data generated from this site, the institution and investigator shall submit reports, abstracts, 
manuscripts, and/or other presentation materials to the sponsor for review before submission for 
publication or presentation. The sponsor shall have 60 days to respond with any requested 
revisions, including (without limitation) the deletion of confidential information. The 


 
 
 
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investigator shall act in good faith upon requested revisions, except the investigator shall delete 
any confidential information from such proposed publications. The investigator shall delay 
submission of such publication or presentation materials for up to an additional 90 days in order 
to have a patent application(s) filed. 


 
 
 
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Appendix 4. Contraceptive Guidance 
Definitions 
Female Patients of Childbearing Potential: Premenopausal female study patients who are 
anatomically and physiologically capable of becoming pregnant following menarche. 
Female Patients of Nonchildbearing Potential: 
1. Surgically sterile: Female study patients who are permanently sterile via 
hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy by reported 
medical history and/or medical records. Surgical sterilization to have occurred a 
minimum of 6 weeks, or at the investigator’s discretion, prior to screening. 
2. Postmenopausal: Female study patients at least 45 years of age with amenorrhea for 
at least 24 months without an alternative medical reason. 
Fertile male: A male that is considered fertile after puberty. 
Infertile male: Permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Patients 
Female patients who are of nonchildbearing potential will not be required to use contraception. 
Female patients of childbearing potential must be confirmed as not being pregnant at screening 
or pretreatment on Day 1 and be willing to use an acceptable highly-effective method of birth 
control from the time of signing the informed consent form (ICF) until 90 days after the last dose 
of study treatment. Additionally, local/country regulations will be followed as applicable (eg., 
monthly pregnancy test after the last dose of study treatment in female subjects of childbearing 
potential). Acceptable methods of contraception include: 
• hormonal injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 90 days prior to the screening visit: 
o bilateral tubal ligation 
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of occlusion 
of the fallopian tubes 
• hormonal implant 


 
 
 
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• hormonal or nonhormonal intrauterine device 
• vasectomized male partner (sterilization performed at least 90 days prior to the screening 
visit) with verbal confirmation of surgical success, and the sole partner for the female 
patient. 
Female patients of childbearing potential should refrain from donation of ova from the first dose 
through 90 days after the last dose of study treatment. 
Male Patients 
Male patients (even with a history of vasectomy) with partners of childbearing potential must use 
a male barrier method of contraception (ie, male condom with spermicide) in addition to a 
second highly effective method of acceptable contraception from the first dose through 90 days 
after the last dose of study treatment. Acceptable methods of contraception for female partners 
include: 
• 
hormonal injection 
• 
combined oral contraceptive pill or progestin/progestogen-only pill 
• 
combined hormonal patch 
• 
combined hormonal vaginal ring 
• 
surgical method (bilateral tubal ligation or Essure [hysteroscopic bilateral tubal occlusion]) 
• 
hormonal implant 
• 
hormonal or nonhormonal intrauterine device. 
An acceptable second method of contraception for male patients is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male patients (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the first dose 
until 90 days after the last dose of study treatment. Male patients are required to refrain from 
donation of sperm from the first dose through 90 days after the last dose of study treatment. 
Sexual Abstinence and Same-sex Relationships 
Patients who practice true abstinence, because of the patient’s lifestyle choice (ie, the patient 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a patient 
who is abstinent at the time of signing the ICF becomes sexually active, he or she must agree to 
use contraception as described previously. 
For patients who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a patient who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, he or she must agree to use contraception as described 
previously. 


 
 
 
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Appendix 5. Schedule of Assessments 
Table 3: Schedule of Assessments 
Study Period 
Screening 
Treatment 
Discharge 
Follow-up 
Visit name 
Screening 
Baseline 
 
 
 
EOTa 
Discharge/ 
ET of Study 
Treatment/ 
EOTa 
EOSa/ Early 
Withdrawal/ 
ET of Study  
Study Day(s) 
-2 to 0 
1 
3  
5 (+/-1 
day) 
7 (+1 
day) 
14 (+2) 
2-28 
28 (±2) 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteriac 
X 
X 
 
 
 
 
 
 
Daily study treatment administrationd 
 
 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examinatione 
X 
X 
 
 
 
X 
X 
X 
Height, body weighte 
X 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-ray or CT scanf 
X 
 
 
 
 
X 
Pregnancy testg 
X 
X 
 
 
 
X 
X 
X 
Oxygenatione 
X 
X 
X 
X 
X 
X 
X 
X 
Return unused study treatment 
 
 
 
 
 
X 
X 
 
Efficacyh 
[1] Confirm setting (outpatient, in hospital, in 
ICU) 
X 
 
X 
X 
X 
X 
X 
X 
[2] SARS-CoV-2 PCR test 
X 
X 
 
X 
 
X 
 
X 
[3] WHO COVID-19 Clinical Improvement 
Ordinal Scale 
X 
X 
X 
X 
X 
X 
X 
X 
[4] Vital status 
 
X 
X 
X 
X 
X 
X 
X 
[5] Respiratory failure status 
 
X 
X 
X 
X 
X 
X 
X 
[6] COVID-19 symptoms assessment 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
 
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Study Period 
Screening 
Treatment 
Discharge 
Follow-up 
Visit name 
Screening 
Baseline 
 
 
 
EOTa 
Discharge/ 
ET of Study 
Treatment/ 
EOTa 
EOSa/ Early 
Withdrawal/ 
ET of Study  
Study Day(s) 
-2 to 0 
1 
3  
5 (+/-1 
day) 
7 (+1 
day) 
14 (+2) 
2-28 
28 (±2) 
Safetyi  
[1] Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
[2] Laboratory assessments 
X 
X 
 
X 
 
X 
X 
 
[3] Electrocardiogram 
X 
 
 
 
 
X 
X 
 
[4] Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokineticsj 
PK parametersk 
 
 
X 
 
 
X 
 
 
Abbreviations: AE = adverse event; AUC = area under the plasma concentration versus time siurve;AUC0-last = AUC from time zero the time of last quantifiable concentration; 
AUCtau = AUC within a dosing interval, tau = 12 hours; BID = twice daily; Cmax = maximum plasma concentration; Ctrough = trough (predose) plasma concentration; COVID-19 = 
COronaVIrus Disease 2019; CT = computerized tomography; CRF = case report form; DMC = Data Monitoring Committee; ECG = electrocardiogram; ECMO = extracorporeal 
membrane oxygenation; EOS = End of Study; EOT = End of Treatment; ET = early termination; FiO2 = fraction of inspired oxygen; HEENT = head, eyes, ear, nose and throat; 
ICF = informed consent form; ICU = intensive care unit; PaO2 = partial pressure of oxygen; PCR = polymerase chain reaction; PK = pharmacokinetic; SpO2 = peripheral capillary 
oxygen saturation; SARS-CoV-2 = Severe Acute Respiratory Syndrome Coronavirus 2; tmax = time to Cmax; WHO = World Health Organization. 
Notes: 
General note: on days of laboratory assessments, discharged patients will have a home visit. On days of no laboratory assessments, discharged patients will complete all 
assessments via telephone or telemedicine visits. Patients will receive instructions for home administration of study treatment and a diary to capture all doses after a discharge.  
a 
Patients will undergo assessment during hospitalization or could be discharged after start of study treatment any time after Day 2 if judged to be ready for discharge. If 
discharged, patients will then be requested to take study treatment at home (as prescribed) up to Day 14. End of Treatment assessments at Day 14 (+2 days) (at home or site 
visit) will be performed. A Day 5 (+/- 1 day) visit (at home or site visit) will be performed if the patient is discharged prior to Day 5. If the patient is discharged after 
completion of treatment and before the follow up visit, he/she will be followed up on Day 28 (±2 days) for study assessments (a telephone or telemedicine visit). Post 
discharge, assessments will be done by telephone or via telemedicine or other means of remote communication, except for Day 5 (+/- 1 day), Day 14 (+2 days), and Early 
Termination (ET) of Study Treatment, which would be a home or site visit. If the discharge, ET or Early Withdrawal visit falls within the window of a schedule Day visit, the 
assessments for the visits can be combined as one visit.  
b 
Initial sentinel cohort of 20 patients to be enrolled to assess safety, tolerability, efficacy, and PK. Enrollment will pause after the 20th patient in the sentinel cohort has started 
treatment, until the results of the interim analysis are known. Once the 20th patient in the sentinel cohort has completed 14 days of treatment, an unblinded DMC will assess 
the safety, tolerability, efficacy, and PK of 100 mg BID antroquinonol in COVID-19 patients in the sentinel cohort (interim analysis 1). The DMC will issue a 
recommendation to enroll patients for the expansion cohort, or to stop the study depending on the safety and futility assessment. Once the 80th patient has been enrolled and 
completed 14 days of treatment, the DMC will review the safety, tolerability and efficacy data (interim analysis 2). Enrollment may be restricted at the 100th patient until the 
DMC has completed the assessment to prevent excessive enrollment. 
c 
Patients must satisfy all of the criteria at the screening visit unless otherwise stated (e.g. some criteria can be evaluated at Day 1 if needed). 
d 
Daily study treatment administration from Day 1 to Day 14. 
e 
A complete physical examination (general appearance, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, and dermatological 
systems) will be performed at screening. Vital signs (respiratory rate, temperature, blood pressure, and pulse rate) to be assessed during hospitalization, on discharge, ET/EOT 
and Follow-up/EOS visit (for site or in-person visits only). Pulse oximetry to measure SpO2 will be collected in the eCRF at screening (room air) after screening with vital 


 
 
 
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signs (Day 1; Day 3, Day 5, Day 7, Day 14/EOT and/or Discharge/ET visits, Day 28 if patient is in hospital). FiO2 data will be collected the same days as vital signs. PaO2 
will be collected if done as part of the standard of care. Height and body weight will be measured only at screening. After patient is discharged from hospital, SpO2 should be 
collected at Day 5 and Day 14 if visits completed in clinic/hospital. Values collected by a home health provider may be utilized, but are not required(refer to Section 7.2.4.2). 
Body temperature will be measured according to site’s local practices and may include oral, tympanic, rectal, axillary, or frontal. 
f 
Chest x-ray or CT scan should show findings consistent with pneumonia due to COVID-19 and will be performed at screening and either at hospital discharge, at ET of Study 
Treatment, or at ET of Study, whichever comes first (Note: only 1 scan must be done for hospital discharge, ET of Study Treatment, or ET of Study). Chest x-ray or CT scan 
does not need to be repeated at screening if performed as standard of care and done within 48 hours of screening. Chest x-ray or CT scan is not required post discharge. 
g 
Serum pregnancy test is to be performed in female patients of child-bearing potential at a local (site) laboratory, during screening or pretreatment Day 1, discharge, and 
ET/EOT. Urine pregnancy test may be performed but must be confirmed with a serum pregnancy test (screening only). The Follow-up/EOS visit test will be a urine 
pregnancy test only (pregnancy test kit will be provided to the patient when discharged). Additionally, local/country regulations will be followed as applicable (eg., monthly 
pregnancy test after the last dose of study treatment in female subjects of childbearing potential). 
h 
Efficacy parameter assessments: [1] Confirmation of whether the patient is discharged to home, is in the hospital, or has worsened to require an ICU. The number of days a 
patient has been hospitalized prior to study entry will be recorded in the eCRF. [2] PCR testing for SARS-CoV-2 will be performed by a local or central laboratory at 
screening. Results of confirmatory COVID-19 test already done as standard of care can be used to determine eligibility. All subsequent tests will be performed by a central 
laboratory at baseline/Day 1, Day 5 (+/-1 day) and Day 14 (+2 days). Also at Follow-up/EOS if patient is hospitalized. Either nasopharyngeal or mid-turbinate samples are 
allowed for central testing. Only one method should be used throughout the study for the participant. [3] Clinical improvement score will be measured using the WHO 
COVID-19 Clinical Improvement Ordinal Scale (refer to Appendix 7). [4] Patient mortality will be recorded up to Day 28. Every effort will be made to ascertain vital status 
in all randomized patients (eg, with a vital records search) up to Day 28. [5] Respiratory failure is considered as patient need for invasive mechanical ventilation, non-invasive 
ventilation, high-flow oxygen, or ECMO. The date of the start of the respiratory intervention must be recorded in the eCRF; no daily assessment is needed. [6] COVID-19 
symptoms (presence or absence of dry cough, dyspnea (shortness of breath/ difficulty in breathing), or chills/rigors, myalgia (muscle pain), headache, sore throat, and loss of 
taste or smell; other symptoms that could be related to COVID-19) will also be assessed during hospitalization, on discharge, ET/EOT and Follow-up/EOS visit (at the site, 
home visit, or via telephone or telemedicine if patient has been discharged). 
i 
Safety parameter assessments: [1] AEs will be assessed from signing the ICF (during hospitalization and post discharge at home) daily to Day 5 (+/-1 day), then Days 7 
(+1 day), 14 (+2 days), 28 (±2 days) until Follow-up/EOS; [2] Standard safety laboratory tests will include all parameters of hematology, clinical chemistry, and urinalysis 
(refer to Appendix 2) and will be performed as applicable at screening, at predose on Day 1, and at Day 5 (+/- 1 day), and Day 14 (+2 days) (a home visit, or a site visit if 
discharged). Screening laboratory tests will be assessed by a local laboratory, and baseline and postbaseline laboratory tests will be assessed by a central laboratory. If delays 
on transportation of the samples is encountered, then local safety laboratory samples can be obtained instead for samples that can’t be frozen for shipment (e.g. hematology 
and urine). Baseline laboratory tests can be done once patients eligibility is confirmed. [3] 12-lead ECGs to be performed at screening while the patient is in supine position 
and at rest for at least 5 minutes. Additionally, 12-lead ECGs will be performed at Day 14/EOT or early treatment termination while the patient is hospitalized or at the time of 
discharge if the patient is discharged prior to Day 14. [4] Prior and concomitant medications to be recorded from screening assessments daily to Day 5 (+/- 1 day), then Days 7 
(+1 day), 14 (+2 days), 28 (± 2 days). 
j 
Blood samples will be collected for patients in the sentinel cohort (first 20 patients) only on Day 3 at predose and 1, 2, 3, 4, 6, 8, and 12-hours postdose for hospitalized 
patients only. Samples are collected after the first study drug dose of the day. For discharged patients (ie, on Day 2)/outpatient visit, the 12-hour sample can be omitted. On 
Day 14, if patients are still hospitalized, predose and 2 hours postdose samples (after the first study drug dose of the day) will be collected. Pharmacokinetic parameters 
include Ctrough, Cmax. tmax, AUC0-1ast, and AUCtau. Patients who are discharged from the hospital on Day 2 prior to PK sampling will not need to return to the clinic for sample 
collection. 
k 
The PK of antroquinonol will be assessed in the sentinel cohort. The PK samples will not be collected for the expansion cohort. 
 
 
 


 
 
 
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Appendix 6. Reference List of Known Inducers, Inhibitors, and Substrates of Selected 
Cytochrome P450 Enzymes 
Table 4: Classification of In Vivo Inhibitors of CYP Enzymes 
CYP 
Enzymes 
Strong Inhibitors1 
≥5-fold increase in AUC or 
>80% decrease in CL 
Moderate Inhibitors2 
≥2-fold but <5-fold increase 
in AUC or 50% to <80% 
decrease in CL 
Weak Inhibitors3 
≥1.25-fold but <2-fold 
increase in AUC or  
20% to <50% decrease in 
CL 
CYP1A2 
ciprofloxacin 
enoxacin 
fluvoxamine 
methoxsalen 
mexiletine 
oral contraceptives 
phenylpropanolamine 
thiabendazole 
vemurafenib 
zileuton 
acyclovir 
allopurinol 
caffeine 
cimetidine 
daidzein4 
disulfiram 
echinacea4 
famotidine 
norfloxacin 
propafenone 
propranolol 
terbinafine 
ticlopidine 
verapamil 
 
CYP2B6 
– 
– 
clopidogrel 
ticlopidine 
prasugrel 
 
CYP2C8 
gemfibrozil5 
 
– 
fluvoxamine 
ketoconazole 
trimethoprim 
 
CYP2C9 
– 
amiodarone 
fluconazole 
miconazole 
oxandrolone 
 
capecitabine 
cotrimoxazole 
etravirine 
fluvastatin 
fluvoxamine 
metronidazole 
sulfinpyrazone 
tigecycline 
voriconazole 
zafirlukast 
 
CYP2C19 
fluconazole6 
fluvoxamine7 
ticlopidine8 
 
esomeprazole 
fluoxetine 
moclobemide 
omeprazole 
voriconazole 
 
allicin (garlic derivative) 
armodafinil 
carbamazepine 
cimetidine 
etravirine 
recombinant human growth 
hormone (rhGH) 
felbamate 
ketoconazole 
oral contraceptives9  


 
 
 
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CYP 
Enzymes 
Strong Inhibitors1 
≥5-fold increase in AUC or 
>80% decrease in CL 
Moderate Inhibitors2 
≥2-fold but <5-fold increase 
in AUC or 50% to <80% 
decrease in CL 
Weak Inhibitors3 
≥1.25-fold but <2-fold 
increase in AUC or  
20% to <50% decrease in 
CL 
CYP3A 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice10 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
mibefradil11 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
 
amprenavir 
aprepitant 
atazanavir 
ciprofloxacin 
crizotinib 
darunavir/ritonavir 
diltiazem 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit juice10 
imatinib 
verapamil 
 
 
alprazolam 
amiodarone 
amlodipine 
atorvastatin 
bicalutamide 
cilostazol 
cimetidine 
cyclosporine 
fluoxetine 
fluvoxamine 
ginkgo4 
goldenseal4 
isoniazid 
lapatinib 
nilotinib 
oral contraceptives 
pazopanib 
ranitidine 
ranolazine 
tipranavir/ritonavir 
ticagrelor 
zileuton 
 
CYP2D6 
bupropion 
fluoxetine 
paroxetine 
quinidine 
 
cinacalcet 
duloxetine 
terbinafine 
 
amiodarone 
celecoxib 
clobazam 
cimetidine 
desvenlafaxine 
diltiazem 
diphenhydramine 
echinacea4 
escitalopram 
febuxostat 
gefitinib 
hydralazine 
hydroxychloroquine 
imatinib 
methadone 
oral contraceptives 
pazopanib 
propafenone 
ranitidine 
ritonavir 
sertraline 
telithromycin 
verapamil 
vemurafenib 


 
 
 
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CYP 
Enzymes 
Strong Inhibitors1 
≥5-fold increase in AUC or 
>80% decrease in CL 
Moderate Inhibitors2 
≥2-fold but <5-fold increase 
in AUC or 50% to <80% 
decrease in CL 
Weak Inhibitors3 
≥1.25-fold but <2-fold 
increase in AUC or  
20% to <50% decrease in 
CL 
Abbreviations: AUC = area under the curve; CL = clearance; CYP = cytochrome P450 isoform; OATP1B1 = 
organic anion transporting polypeptide 1B1; rhGH = recombinant human growth hormone 
NOTE: This is not an exhaustive list. 
1. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate 
for that CYP by equal or more than 5-fold. 
2. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold. 
3. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 2-fold but equal to or more than 1.25-fold. 
4. Herbal product. 
5. Gemfibrozil also inhibits OATP1B1. 
6. Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is 
also metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor. 
7. Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A. 
8. Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP2B6 and CYP1A2. 
9. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. 
10. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” 
when a certain preparation was used (eg, high dose, double strength) or as a “moderate CYP3A 
inhibitor” when another preparation was used (eg, low dose, single strength). 
11. Withdrawn from the United States market. 
Source: Department of Health and Human Services, Food and Drug Administration. Guidance for Industry: 
Drug Interaction Studies - Study Design, Data Analysis, Implications for Dosing, and Labeling 
Recommendations. Draft, 2012. 
 


 
 
 
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Table 5: Classification of In Vivo Inducers of CYP Enzymes 
CYP Enzymes 
Strong Inducers 
 ≥80% decrease in AUC 
Moderate Inducers  
50% to <80% decrease in 
AUC 
Weak Inducers 
20% to <50% decrease 
in AUC 
CYP1A2 
– 
montelukast 
phenytoin 
smokers versus 
nonsmokers1 
 
moricizine 
omeprazole 
phenobarbital 
 
CYP2B6 
– 
efavirenz 
rifampin 
 
nevirapine 
 
CYP2C8 
– 
rifampin 
 
– 
CYP2C9 
– 
carbamazepine 
rifampin 
 
aprepitant 
bosentan 
phenobarbital 
St. John’s wort2,3 
 
CYP2C19 
– 
rifampin 
 
artemisinin 
 
CYP3A 
avasimibe4 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort2,3 
 
bosentan 
efavirenz 
etravirine 
modafinil 
nafcillin 
 
amprenavir 
aprepitant 
armodafinil 
clobazamechinacea3 
pioglitazone 
prednisone 
rufinamide 
vemurafenib 
 
CYP2D6 
None known 
None known 
None known 
Abbreviations: AUC = area under the curve; CYP = cytochrome P450 isoform. 
NOTE: This is not an exhaustive list. 
1. For a drug that is a substrate of CYP1A2, the evaluation of the effect of induction of CYP1A2 can 
be carried out by comparative pharmacokinetic studies in smokers vs. nonsmokers. 
2. The effect of St. John’s wort varies widely and is preparation-dependent. 
3. Herbal product. 
4. Not a marketed drug. 
Source: Department of Health and Human Services, Food and Drug Administration. Guidance for Industry: 
Drug Interaction Studies - Study Design, Data Analysis, Implications for Dosing, and Labeling 
Recommendations. Draft, 2012. 
 


 
 
 
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Table 6: Examples of Sensitive In Vivo CYP Substrates and CYP Substrates with Narrow 
Therapeutic Range 
CYP Enzymes 
Sensitive substrates1 
Substrates with narrow therapeutic 
range2 
CYP1A2 
alosetrone 
caffeine 
duloxetine 
melatonin 
ramelteon 
tacrine 
tizanidine 
 
theophylline 
tizanidine 
CYP2B63  
bupropion 
efavirenz 
– 
CYP2C8 
repaglinide4  
paclitaxel 
 
CYP2C9 
celecoxib 
warfarin 
phenytoin 
 
CYP2C19 
clobazam 
lansoprazole 
omeprazole 
S-mephenytoin 
CYP3A5 
alfentanil 
aprepitant 
budesonide 
buspirone 
conivaptan 
darifenacin 
darunavir 
dasatinib 
dronedarone 
eletriptan 
eplerenone 
everolimus 
felodipine 
indinavir 
fluticasone 
lopinavir 
lovastatin 
lurasidone 
maraviroc 
midazolam 
nisoldipine 
quetiapine 
saquinavir 
sildenafil 
simvastatin 
sirolimus 
tolvaptan 
tipranavir 
triazolam 
alfentanil 
astemizole6 
cisapride6 
cyclosporine 
dihydroergotamine 
ergotamine 
fentanyl 
pimozide 
quinidine 
sirolimus 
tacrolimus 
terfenadine6 


 
 
 
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CYP Enzymes 
Sensitive substrates1 
Substrates with narrow therapeutic 
range2 
ticagrelor 
vardenafil 
CYP2D6 
atomoxetine 
desipramine 
dextromethorphan 
metoprolol 
nebivolol 
perphenazine 
tolterodine 
venlafaxine 
 
thioridazine 
pimozide 
Abbreviations: AUC = area under the curve; CYP = cytochrome P450 isoform; OATP1B1 = organic anion 
transporting polypeptide 1B1; P-gp = P-glycoprotein 1. 
NOTE: This is not an exhaustive list. 
1. Sensitive CYP substrates refer to drugs with plasma AUC values that have been shown to increase 5-
fold or higher when coadministered with a known CYP inhibitor. 
2. CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small increases in their exposure levels by the concomitant use of CYP inhibitors may 
lead to serious safety concerns (eg, Torsades de Pointes). 
3. The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they 
represent the most sensitive substrates studied with available inhibitors evaluated to date. 
4. Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if the 
inhibition of OATP1B1 by the investigational drug has been ruled out. 
5. Because a number of CYP3A substrates (eg, darunavir, maraviroc) are also substrates of P-gp, the 
observed increase in exposure could be due to inhibition of both CYP3A and P-gp. 
6. Withdrawn from the US market. 
Source: Department of Health and Human Services, Food and Drug Administration. Guidance for Industry: 
Drug Interaction Studies - Study Design, Data Analysis, Implications for Dosing, and Labeling 
Recommendations. Draft, 2012. 
 


 
 
 
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Appendix 7. World Health Organization COVID-19 Clinical Improvement Ordinal Scale 
A special World Health Organization committee arrived at an ordinal scale (given in the table 
below) that measures COVID-19 illness severity over time. 
 
Abbreviations: ECMO = extracorporeal membrane oxygenation; RRT = renal replacement therapy. 
Source: World Health Organization. WHO R&D Blueprint. Novel Coronavirus COVID-19 Therapeutic Trial Synopsis. 
Draft February 18, 2020. 
 


Protocol Version 4.0 
 
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Page 1 of 13 
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Summary of Amended Protocol Changes 
A Phase 2 Randomized, Double-blind, Placebo-controlled, Proof of Concept Study to 
Evaluate the Safety and Efficacy of Antroquinonol in Hospitalized Patients with Mild to 
Moderate Pneumonia due to COVID-19 
Protocol Version 4.0 Date: 09 July 2021, Status: Final 
Protocol Version 3.1 Date: 29 March 2021 
Protocol Version 3.0 Date: 11 March 2021 
Protocol Version 2.0 Date: 02 September 2020 (submitted to FDA) 
Protocol Version 1.1 Date: 01 June 2020 (submitted to FDA) 
Original Protocol Version 1.0 Date: 14 May 2020 (submitted to FDA) 
Investigational Product: Antroquinonol (Hocena®) 
 
Protocol Reference Number: GHCovid-2-001 
Investigational New Drug: 149841 
 
 
Sponsor: 
Golden Biotechnology Corporation 
15F, No. 27-6, Sec. 2, Zhong-Zheng E. Rd., 
Tamsui Dist., New Taipei City 251, Taiwan 
 
 
 
Sponsor Signatory: 
Howard Cheng, PhD 
VP, Clinical Medicine Research Department 
Golden Biotechnology Corporation 
15F, No. 27-6, Sec. 2, Zhong-Zheng E. Rd., 
Tamsui Dist., New Taipei City 251, Taiwan 
Medical Monitor: 
Norberto Soto, MD 
Senior Medical Director 
LabCorp Drug Development 
E-mail: Norberto.Soto@labcorp.com 
Tel: + 1 609-212-7892 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
________________________________________ 
 
 


Protocol Version 4.0 
 
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Document History 
Protocol Version 
Date 
Reason for version change 
Protocol Version 4.0 
08 July 2021 
This version was updated to address feedback 
from Data Monitoring Committee (DMC) and 
Investigators.  
Protocol Version 3.1 
29 March 2021 
This version was updated to clarify and adapt to 
changes on management of COVID-19. 
Protocol Version 3.0 
11 March 2021 
This version was updated to clarify and adapt to 
changes on management of COVID-19. 
Protocol Version 2.0  
02 September 2020 This version was updated based on the ‘study 
may proceed’ letter from the Food and Drug 
Administration (FDA) on Version 1.1, and 
addressed feedback from DMC and 
Investigators. 
Protocol Version 1.1 
01 June 2020 
Submitted to the FDA in response to their 
questions. 
Original Protocol Version 1.0 
14 May 2020 
Submitted to the FDA in response to their 
questions. 
The primary changes in this amendment, along with the rationale for the/each change as 
appropriate, are: 
1. Section 4.1:  
• New inclusion criterion #3: Inclusion requirement of oxygen saturation <94% at 
room air at screening was added following the DMC recommendation to ensure 
the “sicker” of the mild/moderate patients can be enrolled.  
• Current inclusion criterion #4 (previous inclusion criterion #3): Based on DMC 
and Investigator’s feedback, this criterion was modified to exclude patients 
requiring oxygen therapy by mask with reservoir for treatment of severe Covid-19 
pneumonia. 
2. Section 7.2.3: 
• Edits made to allow samples to be obtained for local laboratories tests in case of 
delays in transportation of safety samples to the central laboratory. 
3. Section 7.2.4.2: 
• Based on site’s local practices, collection of non-oral body temperature (i.e., 
tympanic, rectal, axillary, and frontal) was also included. 
• Peripheral capillary oxygen saturation (SpO2) assessment was aligned with vital 
signs assessments. Data of fraction of inspired oxygen (FiO2) will be collected 
along with partial pressure of oxygen (PaO2) (if PaO2 is done as standard of care). 


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4. Section 8.2: 
• To be consistent with the statistical analysis plan (SAP), the Intention-to-Treat 
(ITT) set will be the primary analysis population for efficacy and the modified 
ITT (mITT) and Per Protocol Set (PPS) will be the supportive analysis 
populations for efficacy analysis. 
5. Appendix 5: 
• Schedule of assessments table and footnote ‘e’ were updated to include data to be 
captured for oxygenation and their assessments.  
• SpO2 assessment was aligned with vital signs assessments.  
• Schedule of assessments table and footnote ‘i’ was updated to include edits to 
allow samples to be obtained for local laboratories tests in case of delays in 
transportation of safety samples to the central laboratory. 
Minor changes not displayed in this summary are: 
1. The synopsis was updated according to the changes in the protocol body, as applicable. 
2. The version number and date were updated throughout the protocol. 
3. Editorial, typographical, and formatting errors that did not change the meaning of the text 
were corrected, as necessary. 
4. Abbreviations were added, as appropriate. 
5. Due to Brand Transition, name change from ‘Covance’ to ‘LabCorp Drug Development’ 
was updated on protocol Title page and in the protocol header. No edits in Sections 4.4.7 
and 7.2.1.2 where it will remain as ‘Covance’ Patient Safety Services. 


Protocol Version 4.0 
 
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A detailed summary of changes, documenting primary changes only, is presented below. 
Additions are marked by bold/underlined text and deletions are marked by strike-through 
text.  
Section 4.1. Inclusion Criteria 
Inclusion requirement of oxygen saturation <94% at room air at screening was added (new 
inclusion criterion #3) following the recommendations from the DMC to ensure the “sicker” of 
the mild/moderate patients can be enrolled. Based on DMC and Investigator’s feedback, the 
criterion (current inclusion criterion #4) was modified to exclude patients requiring of oxygen 
therapy by mask with reservoir for treatment of severe Covid-19 pneumonia.  
Previously read: 
1. Willing and able to provide informed consent. 
2. Male or female patients between 18 and 80 years of age. 
3. Hospitalized with mild COVID-19 disease (not requiring oxygen therapy [WHO 
COVID-19 Clinical Improvement Ordinal Scale, score of 3] or requiring oxygen therapy 
by mask or nasal prong [WHO COVID-19 Clinical Improvement Ordinal Scale, score of 
4]).  
Note: Hospitalized patients can also include patients admitted to centers conditioned as 
hospitals to treat COVID-19 patients. 
4. Chest x-ray or CT scan consistent with pneumonia. 
5. Onset of COVID-19 symptoms within 2 weeks prior to randomization. 
6. SARS-CoV-2 infection confirmed by a PCR test, antigen, or any authorized commercial 
or public health assay (nasopharyngeal, oropharyngeal, or respiratory samples, not 
serology testing). 
7. Male patients and female patients of childbearing potential must agree to use protocol-
specified methods of contraception (Appendix 4). 
8. Female patients of childbearing potential must have a negative pregnancy test at 
screening or pretreatment on Day 1. 
9. Male patients must agree not to donate sperm from the first dose through 90 days after 
the last dose of study treatment; female patients of childbearing potential should refrain 
from donation of ova from Day 1 until 90 days after the last dose of study treatment. 
10. Patient is, in the opinion of the investigator, willing and able to comply with the study 
treatment regimen and all other study requirements. 


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Now reads: 
1. Willing and able to provide informed consent. 
2. Male or female patients between 18 and 80 years of age. 
3. Oxygen saturation <94% in room air at screening. 
4. Hospitalized with mild COVID-19 disease (not requiring oxygen therapy [WHO 
COVID-19 Clinical Improvement Ordinal Scale, score of 3] or requiring oxygen therapy 
by mask or nasal prong [WHO COVID-19 Clinical Improvement Ordinal Scale, score of 
4]). Requirement of oxygen therapy by mask with reservoir to treat severe 
COVID-19 pneumonia is not allowed for enrollment.  
Note: Hospitalized patients can also include patients admitted to centers conditioned as 
hospitals to treat COVID-19 patients. 
5. Chest x-ray or CT scan consistent with pneumonia. 
6. Onset of COVID-19 symptoms within 2 weeks prior to randomization. 
7. SARS-CoV-2 infection confirmed by a PCR test, antigen, or any authorized commercial 
or public health assay (nasopharyngeal, oropharyngeal, or respiratory samples, not 
serology testing). 
8. Male patients and female patients of childbearing potential must agree to use protocol-
specified methods of contraception (Appendix 4). 
9. Female patients of childbearing potential must have a negative pregnancy test at 
screening or pretreatment on Day 1. 
10. Male patients must agree not to donate sperm from the first dose through 90 days after 
the last dose of study treatment; female patients of childbearing potential should refrain 
from donation of ova from Day 1 until 90 days after the last dose of study treatment. 
11. Patient is, in the opinion of the investigator, willing and able to comply with the study 
treatment regimen and all other study requirements. 
 
Section 7.2.3. Clinical laboratory evaluations 
Edits made to allow samples to be obtained for local laboratories tests in case of delays in 
transportation of safety samples to the central laboratory. 
Previously read: 
… 


Protocol Version 4.0 
 
CONFIDENTIAL 
LabCorp Drug Development Study: 8427146  Protocol Reference Number: GHCovid-2-001 
09 July 2021 
 
Page 6 of 13 
CONFIDENTIAL 
Screening laboratory test will be assessed by a local laboratory, and baseline and postbaseline 
laboratory tests will be assessed by a central laboratory. Baseline laboratory tests can be done 
once patients eligibility is confirmed. The investigator will perform a clinical assessment of all 
clinical laboratory data. 
… 
 
Now reads: 
….. 
Screening laboratory test will be assessed by a local laboratory, and baseline and postbaseline 
laboratory tests will be assessed by a central laboratory. If delays in transportation of the 
samples are encountered, then local safety laboratory samples can be obtained instead for 
samples that can’t be frozen for shipment (e.g. hematology and urine). Baseline laboratory 
tests can be done once patients eligibility is confirmed. The investigator will perform a clinical 
assessment of all clinical laboratory data. 
…. 
 
Section 7.2.4.2. Vital signs 
Based on site’s local practices, collection of non-oral body temperature (i.e., tympanic, rectal, 
axillary, and frontal) was also included. Peripheral capillary oxygen saturation (SpO2) 
assessment was aligned with vital signs assessments. Data of fraction of inspired oxygen (FiO2) 
will be collected along with partial pressure of oxygen (PaO2) (if PaO2 is done as standard of 
care). 
Previously read: 
… 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. Patients must be seated for at least 5 minutes before blood pressure and pulse 
rate measurements. Body temperature will be measured orally.  
Pulse oximetry to measure the peripheral capillary oxygen saturation (SpO2) (>94% on room air) 
will be collected in the eCRF during the study if done per standard of care.  
 
Now reads: 
….. 


Protocol Version 4.0 
 
CONFIDENTIAL 
LabCorp Drug Development Study: 8427146  Protocol Reference Number: GHCovid-2-001 
09 July 2021 
 
Page 7 of 13 
CONFIDENTIAL 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. Patients must be seated for at least 5 minutes before blood pressure and pulse 
rate measurements. Body temperature will be measured according to site’s local practices and 
may include orally, tympanic, rectal, axillary, or frontal.  
Pulse oximetry to measure the peripheral capillary oxygen saturation (SpO2) (>94% on room air) 
will be collected in the eCRF during the study if done per standard of care. SpO2 measurements 
should be collected at Screening, Day 1, Day 3, Day 5, Day 7, Day 14/EOT or Discharge/ET, 
and Day 28 visits if patient is in hospital (refer to Appendix 5). For discharged patients, 
SpO2 should be collected at the prior mentioned visits if conducted at a clinic/hospital. 
SpO2 may be collected if the visit is conducted at home by a home health service 
professional, but is not required.  
Fraction of inspired oxygen (FiO2) data will be collected and partial pressure of oxygen 
(PaO2) will also be collected if done as standard of care as per Appendix 5. 
 
Section 8.2. Analysis Populations 
To be consistent with the SAP, the ITT set will be the primary analysis population for efficacy 
and the mITT and PPS will be the supportive analysis populations for efficacy analysis. 
Previously read: 
… 
The mITT set will be the primary analysis population for efficacy and the ITT and PPS will be 
the supportive analysis populations for efficacy analysis.  ……. 
 
Now reads: 
…. 
The mITT set will be the primary analysis population for efficacy and the mITT and PPS will be 
the supportive analysis populations for efficacy analysis.  …… 
 
Appendix 5. 
Schedule of Assessments 
Schedule of assessments table and footnote ‘e’ were updated to include data to be captured for 
oxygenation and their assessments. SpO2 assessment was aligned with vital signs assessments. 
Schedule of assessments table and footnote ‘i’ was updated to include edits to allow samples to 
be obtained for local laboratories tests in case of delays in transportation of safety samples to the 
central laboratory.  


Protocol Version 4.0 
 
 
CONFIDENTIAL 
LabCorp Drug Development Study: 8427146  
 
Protocol Reference Number: GHCovid-2-001 
09 July 2021 
 
 
Page 8 of 13 
 
CONFIDENTIAL 
Previously read: 
Table 1: Schedule of Assessments 
Study Period 
Screening 
Treatment 
Discharge 
Follow-up 
Visit name 
Screening 
Baseline 
 
 
 
EOTa 
Discharge/ 
ET of Study 
Treatment/ 
EOTa 
EOSa/ Early 
Withdrawal/ 
ET of Study  
Study Day(s) 
-2 to 0 
1 
3  
5 (+/-1 
day) 
7 (+1 
day) 
14 (+2) 
2-28 
28 (±2) 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteriac 
X 
X 
 
 
 
 
 
 
Daily study treatment administrationd 
 
 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examinatione 
X 
X 
 
 
 
X 
X 
X 
Height, body weighte 
X 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-ray or CT scanf 
X 
 
 
 
 
X 
Pregnancy testg 
X 
X 
 
 
 
X 
X 
X 
Return unused study treatment 
 
 
 
 
 
X 
X 
 
Efficacyh 
[1] Confirm setting (outpatient, in hospital, in 
ICU) 
X 
 
X 
X 
X 
X 
X 
X 
[2] SARS-CoV-2 PCR test 
X 
X 
 
X 
 
X 
 
X 
[3] WHO COVID-19 Clinical Improvement 
Ordinal Scale 
X 
X 
X 
X 
X 
X 
X 
X 
[4] Vital status 
 
X 
X 
X 
X 
X 
X 
X 
[5] Respiratory failure status 
 
X 
X 
X 
X 
X 
X 
X 
[6] COVID-19 symptoms assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Safetyi  
[1] Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
[2] Laboratory assessments 
X 
X 
 
X 
 
X 
X 
 


Protocol Version 4.0 
 
 
CONFIDENTIAL 
LabCorp Drug Development Study: 8427146  
 
Protocol Reference Number: GHCovid-2-001 
09 July 2021 
 
 
Page 9 of 13 
 
CONFIDENTIAL 
Study Period 
Screening 
Treatment 
Discharge 
Follow-up 
Visit name 
Screening 
Baseline 
 
 
 
EOTa 
Discharge/ 
ET of Study 
Treatment/ 
EOTa 
EOSa/ Early 
Withdrawal/ 
ET of Study  
Study Day(s) 
-2 to 0 
1 
3  
5 (+/-1 
day) 
7 (+1 
day) 
14 (+2) 
2-28 
28 (±2) 
[3] Electrocardiogram 
X 
 
 
 
X 
X 
 
[4] Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokineticsj 
PK parametersk 
 
 
X 
 
 
X 
 
 
Abbreviations: AE = adverse event; AUC = area under the plasma concentration versus time siurve;AUC0-last = AUC from time zero the time of last quantifiable concentration; 
AUCtau = AUC within a dosing interval, tau = 12 hours; BID = twice daily; Cmax = maximum plasma concentration; Ctrough = trough (predose) plasma concentration; COVID-19 = 
COronaVIrus Disease 2019; CT = computerized tomography; CRF = case report form; DMC = Data Monitoring Committee; ECG = electrocardiogram; ECMO = extracorporeal 
membrane oxygenation; EOS = End of Study; EOT = End of Treatment; ET = early termination; HEENT = head, eyes, ear, nose and throat; ICF = informed consent form; 
ICU = intensive care unit; PCR = polymerase chain reaction; PK = pharmacokinetic; SpO2 = peripheral capillary oxygen saturation; SARS-CoV-2 = Severe Acute Respiratory 
Syndrome Coronavirus 2; tmax = time to Cmax; WHO = World Health Organization. 
Notes: 
General note: on days of laboratory assessments, discharged patients will have a home visit. On days of no laboratory assessments, discharged patients will complete all 
assessments via telephone or telemedicine visits. Patients will receive instructions for home administration of study treatment and a diary to capture all doses after a discharge.  
a 
Patients will undergo assessment during hospitalization or could be discharged after start of study treatment any time after Day 2 if judged to be ready for discharge. If 
discharged, patients will then be requested to take study treatment at home (as prescribed) up to Day 14. End of Treatment assessments at Day 14 (+2 days) (at home or site 
visit) will be performed. A Day 5 (+/- 1 day) visit (at home or site visit) will be performed if the patient is discharged prior to Day 5. If the patient is discharged after 
completion of treatment and before the follow up visit, he/she will be followed up on Day 28 (±2 days) for study assessments (a telephone or telemedicine visit). Post 
discharge, assessments will be done by telephone or via telemedicine or other means of remote communication, except for Day 5 (+/- 1 day), Day 14 (+2 days), and Early 
Termination (ET) of Study Treatment, which would be a home or site visit. If the discharge, ET or Early Withdrawal visit falls within the window of a schedule Day visit, the 
assessments for the visits can be combined as one visit.  
b 
Initial sentinel cohort of 20 patients to be enrolled to assess safety, tolerability, efficacy, and PK. Enrollment will pause after the 20th patient in the sentinel cohort has started 
treatment, until the results of the interim analysis are known. Once the 20th patient in the sentinel cohort has completed 14 days of treatment, an unblinded DMC will assess 
the safety, tolerability, efficacy, and PK of 100 mg BID antroquinonol in COVID-19 patients in the sentinel cohort (interim analysis 1). The DMC will issue a 
recommendation to enroll patients for the expansion cohort, or to stop the study depending on the safety and futility assessment. Once the 80th patient has been enrolled and 
completed 14 days of treatment, the DMC will review the safety, tolerability and efficacy data (interim analysis 2). Enrollment may be restricted at the 100th patient until the 
DMC has completed the assessment to prevent excessive enrollment. 
c 
Patients must satisfy all of the criteria at the screening visit unless otherwise stated (e.g. some criteria can be evaluated at Day 1 if needed). 
d 
Daily study treatment administration from Day 1 to Day 14. 
e 
A complete physical examination (general appearance, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, and dermatological 
systems) will be performed at screening. Vital signs (respiratory rate, temperature, blood pressure, and pulse rate) to be assessed during hospitalization, on discharge, ET/EOT 
and Follow-up/EOS visit (for site or in-person visits only). Pulse oximetry to measure SpO2 (>94% on room air) will be collected in the eCRF during the study if done per 
standard of care. Height and body weight will be measured only at screening.  
f 
Chest x-ray or CT scan should show findings consistent with pneumonia due to COVID-19 and will be performed at screening and either at hospital discharge, at ET of Study 
Treatment, or at ET of Study, whichever comes first (Note: only 1 scan must be done for hospital discharge, ET of Study Treatment, or ET of Study). Chest x-ray or CT scan 
does not need to be repeated at screening if performed as standard of care and done within 48 hours of screening. Chest x-ray or CT scan is not required post discharge. 


Protocol Version 4.0 
 
 
CONFIDENTIAL 
LabCorp Drug Development Study: 8427146  
 
Protocol Reference Number: GHCovid-2-001 
09 July 2021 
 
 
Page 10 of 13 
 
CONFIDENTIAL 
g 
Serum pregnancy test is to be performed in female patients of child-bearing potential at a local (site) laboratory, during screening or pretreatment Day 1, discharge, and 
ET/EOT. Urine pregnancy test may be performed but must be confirmed with a serum pregnancy test (screening only). The Follow-up/EOS visit test will be a urine 
pregnancy test only (pregnancy test kit will be provided to the patient when discharged). Additionally, local/country regulations will be followed as applicable (eg., monthly 
pregnancy test after the last dose of study treatment in female subjects of childbearing potential). 
h 
Efficacy parameter assessments: [1] Confirmation of whether the patient is discharged to home, is in the hospital, or has worsened to require an ICU. The number of days a 
patient has been hospitalized prior to study entry will be recorded in the eCRF. [2] PCR testing for SARS-CoV-2 will be performed by a local or central laboratory at 
screening. Results of confirmatory COVID-19 test already done as standard of care can be used to determine eligibility. All subsequent tests will be performed by a central 
laboratory at baseline/Day 1, Day 5 (+/-1 day) and Day 14 (+2 days). Also at Follow-up/EOS if patient is hospitalized. Either nasopharyngeal or mid-turbinate samples are 
allowed for central testing. Only one method should be used throughout the study for the participant. [3] Clinical improvement score will be measured using the WHO 
COVID-19 Clinical Improvement Ordinal Scale (refer to Appendix 7). [4] Patient mortality will be recorded up to Day 28. Every effort will be made to ascertain vital status 
in all randomized patients (eg, with a vital records search) up to Day 28. [5] Respiratory failure is considered as patient need for invasive mechanical ventilation, non-invasive 
ventilation, high-flow oxygen, or ECMO. The date of the start of the respiratory intervention must be recorded in the eCRF; no daily assessment is needed. [6] COVID-19 
symptoms (presence or absence of dry cough, dyspnea (shortness of breath/ difficulty in breathing), or chills/rigors, myalgia (muscle pain), headache, sore throat, and loss of 
taste or smell; other symptoms that could be related to COVID-19) will also be assessed during hospitalization, on discharge, ET/EOT and Follow-up/EOS visit (at the site, 
home visit, or via telephone or telemedicine if patient has been discharged). 
i 
Safety parameter assessments: [1] AEs will be assessed from signing the ICF (during hospitalization and post discharge at home) daily to Day 5 (+/-1 day), then Days 7 
(+1 day), 14 (+2 days), 28 (±2 days) until Follow-up/EOS; [2] Standard safety laboratory tests will include all parameters of hematology, clinical chemistry, and urinalysis 
(refer to Appendix 2) and will be performed as applicable at screening, at predose on Day 1, and at Day 5 (+/- 1 day), and Day 14 (+2 days) (a home visit, or a site visit if 
discharged). Screening laboratory tests will be assessed by a local laboratory, and baseline and postbaseline laboratory tests will be assessed by a central laboratory. Baseline 
laboratory tests can be done once patients eligibility is confirmed. [3] 12-lead ECGs to be performed at screening while the patient is in supine position and at rest for at least 
5 minutes. Additionally, 12-lead ECGs will be performed at Day 14/EOT or early treatment termination while the patient is hospitalized or at the time of discharge if the 
patient is discharged prior to Day 14. [4] Prior and concomitant medications to be recorded from screening assessments daily to Day 5 (+/- 1 day), then Days 7 (+1 day), 14 
(+2 days), 28 (± 2 days). 
j 
Blood samples will be collected for patients in the sentinel cohort (first 20 patients) only on Day 3 at predose and 1, 2, 3, 4, 6, 8, and 12-hours postdose for hospitalized 
patients only. Samples are collected after the first study drug dose of the day. For discharged patients (ie, on Day 2)/outpatient visit, the 12-hour sample can be omitted. On 
Day 14, if patients are still hospitalized, predose and 2 hours postdose samples (after the first study drug dose of the day) will be collected. Pharmacokinetic parameters 
include Ctrough, Cmax. tmax, AUC0-1ast, and AUCtau. Patients who are discharged from the hospital on Day 2 prior to PK sampling will not need to return to the clinic for sample 
collection. 
k 
The PK of antroquinonol will be assessed in the sentinel cohort. The PK samples will not be collected for the expansion cohort. 
 


Protocol Version 4.0 
 
 
CONFIDENTIAL 
LabCorp Drug Development Study: 8427146  
 
Protocol Reference Number: GHCovid-2-001 
09 July 2021 
 
 
Page 11 of 13 
 
CONFIDENTIAL 
Now reads: 
Table 2: Schedule of Assessments 
Study Period 
Screening 
Treatment 
Discharge 
Follow-up 
Visit name 
Screening 
Baseline 
 
 
 
EOTa 
Discharge/ 
ET of Study 
Treatment/ 
EOTa 
EOSa/ Early 
Withdrawal/ 
ET of Study  
Study Day(s) 
-2 to 0 
1 
3  
5 (+/-1 
day) 
7 (+1 
day) 
14 (+2) 
2-28 
28 (±2) 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteriac 
X 
X 
 
 
 
 
 
 
Daily study treatment administrationd 
 
 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examinatione 
X 
X 
 
 
 
X 
X 
X 
Height, body weighte 
X 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-ray or CT scanf 
X 
 
 
 
 
X 
Pregnancy testg 
X 
X 
 
 
 
X 
X 
X 
Oxygenatione 
X 
X 
X 
X 
X 
X 
X 
X 
Return unused study treatment 
 
 
 
 
 
X 
X 
 
Efficacyh 
[1] Confirm setting (outpatient, in hospital, in 
ICU) 
X 
 
X 
X 
X 
X 
X 
X 
[2] SARS-CoV-2 PCR test 
X 
X 
 
X 
 
X 
 
X 
[3] WHO COVID-19 Clinical Improvement 
Ordinal Scale 
X 
X 
X 
X 
X 
X 
X 
X 
[4] Vital status 
 
X 
X 
X 
X 
X 
X 
X 
[5] Respiratory failure status 
 
X 
X 
X 
X 
X 
X 
X 
[6] COVID-19 symptoms assessment 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol Version 4.0 
 
 
CONFIDENTIAL 
LabCorp Drug Development Study: 8427146  
 
Protocol Reference Number: GHCovid-2-001 
09 July 2021 
 
 
Page 12 of 13 
 
CONFIDENTIAL 
Study Period 
Screening 
Treatment 
Discharge 
Follow-up 
Visit name 
Screening 
Baseline 
 
 
 
EOTa 
Discharge/ 
ET of Study 
Treatment/ 
EOTa 
EOSa/ Early 
Withdrawal/ 
ET of Study  
Study Day(s) 
-2 to 0 
1 
3  
5 (+/-1 
day) 
7 (+1 
day) 
14 (+2) 
2-28 
28 (±2) 
Safetyi  
[1] Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
[2] Laboratory assessments 
X 
X 
 
X 
 
X 
X 
 
[3] Electrocardiogram 
X 
 
 
 
 
X 
X 
 
[4] Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokineticsj 
PK parametersk 
 
 
X 
 
 
X 
 
 
Abbreviations: AE = adverse event; AUC = area under the plasma concentration versus time siurve;AUC0-last = AUC from time zero the time of last quantifiable concentration; 
AUCtau = AUC within a dosing interval, tau = 12 hours; BID = twice daily; Cmax = maximum plasma concentration; Ctrough = trough (predose) plasma concentration; COVID-19 = 
COronaVIrus Disease 2019; CT = computerized tomography; CRF = case report form; DMC = Data Monitoring Committee; ECG = electrocardiogram; ECMO = extracorporeal 
membrane oxygenation; EOS = End of Study; EOT = End of Treatment; ET = early termination; FiO2 = fraction of inspired oxygen; HEENT = head, eyes, ear, nose and throat; 
ICF = informed consent form; ICU = intensive care unit; PaO2 = partial pressure of oxygen; PCR = polymerase chain reaction; PK = pharmacokinetic; SpO2 = peripheral 
capillary oxygen saturation; SARS-CoV-2 = Severe Acute Respiratory Syndrome Coronavirus 2; tmax = time to Cmax; WHO = World Health Organization. 
Notes: 
General note: on days of laboratory assessments, discharged patients will have a home visit. On days of no laboratory assessments, discharged patients will complete all 
assessments via telephone or telemedicine visits. Patients will receive instructions for home administration of study treatment and a diary to capture all doses after a discharge.  
a 
Patients will undergo assessment during hospitalization or could be discharged after start of study treatment any time after Day 2 if judged to be ready for discharge. If 
discharged, patients will then be requested to take study treatment at home (as prescribed) up to Day 14. End of Treatment assessments at Day 14 (+2 days) (at home or site 
visit) will be performed. A Day 5 (+/- 1 day) visit (at home or site visit) will be performed if the patient is discharged prior to Day 5. If the patient is discharged after 
completion of treatment and before the follow up visit, he/she will be followed up on Day 28 (±2 days) for study assessments (a telephone or telemedicine visit). Post 
discharge, assessments will be done by telephone or via telemedicine or other means of remote communication, except for Day 5 (+/- 1 day), Day 14 (+2 days), and Early 
Termination (ET) of Study Treatment, which would be a home or site visit. If the discharge, ET or Early Withdrawal visit falls within the window of a schedule Day visit, the 
assessments for the visits can be combined as one visit.  
b 
Initial sentinel cohort of 20 patients to be enrolled to assess safety, tolerability, efficacy, and PK. Enrollment will pause after the 20th patient in the sentinel cohort has started 
treatment, until the results of the interim analysis are known. Once the 20th patient in the sentinel cohort has completed 14 days of treatment, an unblinded DMC will assess 
the safety, tolerability, efficacy, and PK of 100 mg BID antroquinonol in COVID-19 patients in the sentinel cohort (interim analysis 1). The DMC will issue a 
recommendation to enroll patients for the expansion cohort, or to stop the study depending on the safety and futility assessment. Once the 80th patient has been enrolled and 
completed 14 days of treatment, the DMC will review the safety, tolerability and efficacy data (interim analysis 2). Enrollment may be restricted at the 100th patient until the 
DMC has completed the assessment to prevent excessive enrollment. 
c 
Patients must satisfy all of the criteria at the screening visit unless otherwise stated (e.g. some criteria can be evaluated at Day 1 if needed). 
d 
Daily study treatment administration from Day 1 to Day 14. 
e 
A complete physical examination (general appearance, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, and dermatological 
systems) will be performed at screening. Vital signs (respiratory rate, temperature, blood pressure, and pulse rate) to be assessed during hospitalization, on discharge, ET/EOT 
and Follow-up/EOS visit (for site or in-person visits only). Pulse oximetry to measure SpO2 (>94% on room air) will be collected in the eCRF during the study if done per 


Protocol Version 4.0 
 
 
CONFIDENTIAL 
LabCorp Drug Development Study: 8427146  
 
Protocol Reference Number: GHCovid-2-001 
09 July 2021 
 
 
Page 13 of 13 
 
CONFIDENTIAL 
standard of care at screening (room air) after screening with vital signs (Day 1; Day 3, Day 5, Day 7, Day 14/EOT and/or Discharge/ET visits, Day 28 if patient is in 
hospital). FiO2 data will be collected the same days as vital signs. PaO2 will be collected if done as part of the standard of care. Height and body weight will be 
measured only at screening. After patient is discharged from hospital, SpO2 should be collected at Day 5 and Day 14 if visits completed in clinic/hospital. Values 
collected by a home health provider may be utilized, but are not required (refer to Section 7.2.4.2). Body temperature will be measured according to site’s local 
practices and may include oral, tympanic, rectal, axillary, or frontal. 
f 
Chest x-ray or CT scan should show findings consistent with pneumonia due to COVID-19 and will be performed at screening and either at hospital discharge, at ET of Study 
Treatment, or at ET of Study, whichever comes first (Note: only 1 scan must be done for hospital discharge, ET of Study Treatment, or ET of Study). Chest x-ray or CT scan 
does not need to be repeated at screening if performed as standard of care and done within 48 hours of screening. Chest x-ray or CT scan is not required post discharge. 
g 
Serum pregnancy test is to be performed in female patients of child-bearing potential at a local (site) laboratory, during screening or pretreatment Day 1, discharge, and 
ET/EOT. Urine pregnancy test may be performed but must be confirmed with a serum pregnancy test (screening only). The Follow-up/EOS visit test will be a urine 
pregnancy test only (pregnancy test kit will be provided to the patient when discharged). Additionally, local/country regulations will be followed as applicable (eg., monthly 
pregnancy test after the last dose of study treatment in female subjects of childbearing potential). 
h 
Efficacy parameter assessments: [1] Confirmation of whether the patient is discharged to home, is in the hospital, or has worsened to require an ICU. The number of days a 
patient has been hospitalized prior to study entry will be recorded in the eCRF. [2] PCR testing for SARS-CoV-2 will be performed by a local or central laboratory at 
screening. Results of confirmatory COVID-19 test already done as standard of care can be used to determine eligibility. All subsequent tests will be performed by a central 
laboratory at baseline/Day 1, Day 5 (+/-1 day) and Day 14 (+2 days). Also at Follow-up/EOS if patient is hospitalized. Either nasopharyngeal or mid-turbinate samples are 
allowed for central testing. Only one method should be used throughout the study for the participant. [3] Clinical improvement score will be measured using the WHO 
COVID-19 Clinical Improvement Ordinal Scale (refer to Appendix 7). [4] Patient mortality will be recorded up to Day 28. Every effort will be made to ascertain vital status 
in all randomized patients (eg, with a vital records search) up to Day 28. [5] Respiratory failure is considered as patient need for invasive mechanical ventilation, non-invasive 
ventilation, high-flow oxygen, or ECMO. The date of the start of the respiratory intervention must be recorded in the eCRF; no daily assessment is needed. [6] COVID-19 
symptoms (presence or absence of dry cough, dyspnea (shortness of breath/ difficulty in breathing), or chills/rigors, myalgia (muscle pain), headache, sore throat, and loss of 
taste or smell; other symptoms that could be related to COVID-19) will also be assessed during hospitalization, on discharge, ET/EOT and Follow-up/EOS visit (at the site, 
home visit, or via telephone or telemedicine if patient has been discharged). 
i 
Safety parameter assessments: [1] AEs will be assessed from signing the ICF (during hospitalization and post discharge at home) daily to Day 5 (+/-1 day), then Days 7 
(+1 day), 14 (+2 days), 28 (±2 days) until Follow-up/EOS; [2] Standard safety laboratory tests will include all parameters of hematology, clinical chemistry, and urinalysis 
(refer to Appendix 2) and will be performed as applicable at screening, at predose on Day 1, and at Day 5 (+/- 1 day), and Day 14 (+2 days) (a home visit, or a site visit if 
discharged). Screening laboratory tests will be assessed by a local laboratory, and baseline and postbaseline laboratory tests will be assessed by a central laboratory. If delays 
on transportation of the samples is encountered, then local safety laboratory samples can be obtained instead for samples that can’t be frozen for shipment (e.g. 
hematology and urine). Baseline laboratory tests can be done once patients eligibility is confirmed. [3] 12-lead ECGs to be performed at screening while the patient is in 
supine position and at rest for at least 5 minutes. Additionally, 12-lead ECGs will be performed at Day 14/EOT or early treatment termination while the patient is hospitalized 
or at the time of discharge if the patient is discharged prior to Day 14. [4] Prior and concomitant medications to be recorded from screening assessments daily to Day 5 (+/- 1 
day), then Days 7 (+1 day), 14 (+2 days), 28 (± 2 days). 
j 
Blood samples will be collected for patients in the sentinel cohort (first 20 patients) only on Day 3 at predose and 1, 2, 3, 4, 6, 8, and 12-hours postdose for hospitalized 
patients only. Samples are collected after the first study drug dose of the day. For discharged patients (ie, on Day 2)/outpatient visit, the 12-hour sample can be omitted. On 
Day 14, if patients are still hospitalized, predose and 2 hours postdose samples (after the first study drug dose of the day) will be collected. Pharmacokinetic parameters 
include Ctrough, Cmax. tmax, AUC0-1ast, and AUCtau. Patients who are discharged from the hospital on Day 2 prior to PK sampling will not need to return to the clinic for sample 
collection. 
k 
The PK of antroquinonol will be assessed in the sentinel cohort. The PK samples will not be collected for the expansion cohort. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Sponsor Name: Golden Biotechnology Corporation 
Sponsor Protocol ID: GHCovid-2-001 
 
Covance Study ID: 000000203201 
 
CONFIDENTIAL 
 
 
Page 1 of 34 
Document Date: 29 Nov 2021 
 
ST-AD-008 version 05 
Statistical Analysis Plan 
A Phase 2 Randomized, Double-blind, Placebo-controlled, Proof of 
Concept Study to Evaluate the Safety and Efficacy of Antroquinonol 
in Hospitalized Patients with Mild to Moderate Pneumonia due to 
COVID-19 
 
 
Covance Study ID: 000000203201 
Document Version: Final 3.0 
Document Date: 29 Nov 2021 
 
 
 
 
 
 
 
Covance Inc. CDCS 
Clinical Development Commercialization Services 
1/34


Statistical Analysis Plan 
Sponsor Name: Golden Biotechnology Corporation 
Sponsor Protocol ID: GHCovid-2-001 
 
Covance Study ID: 000000203201 
 
CONFIDENTIAL 
 
 
Page 2 of 34 
Document Date: 29 Nov 2021 
 
ST-AD-008 version 05 
Table of Contents 
1. 
Source Documents ................................................................................. 7 
2. 
Protocol Details ..................................................................................... 8 
2.1 
Study Objectives................................................................................. 8 
2.2 
Overall Study Design ........................................................................... 8 
2.3 
Sample Size ....................................................................................... 9 
3. 
Efficacy and Safety Variables................................................................. 10 
3.1 
Primary Efficacy Endpoint .................................................................. 10 
3.2 
Secondary Efficacy Endpoints ............................................................. 10 
3.3 
Exploratory Efficacy Endpoint ............................................................. 11 
3.4 
Safety Variables................................................................................ 11 
4. 
Pharmacokinetic Variables .................................................................... 11 
5. 
Analysis populations ............................................................................. 11 
5.1 
All Enrolled Set ................................................................................. 11 
5.2 
Intention-to-treat (ITT) Set ................................................................ 11 
5.3 
Modified ITT (mITT) Set ..................................................................... 11 
5.4 
Per Protocol Set (PPS) ....................................................................... 12 
5.4.1 
Important Protocol Deviations Leading to Exclusion from the PPS Analysis ...................... 12 
5.5 
Safety Set (SS) ................................................................................ 14 
5.6 
Pharmacokinetic Set (PKS) ................................................................. 14 
6. 
DATA Handling .................................................................................... 14 
6.1 
Time points and Visit Windows ........................................................... 14 
6.2 
Handling of Dropouts, Missing Data, and Outliers .................................. 15 
7. 
Statistical Methods ............................................................................... 15 
7.1 
General Principles ............................................................................. 15 
7.2 
Patient Disposition and Data Sets Analyzed .......................................... 16 
7.3 
Protocol Deviations ........................................................................... 17 
7.4 
Baseline Disease Characteristics ......................................................... 17 
7.5 
Demographics and Other Baseline Characteristics ................................. 17 
7.5.1 
Medical History ................................................................................................................... 18 
7.5.2 
Prior and Concomitant Medications ................................................................................... 18 
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7.6 
Efficacy ............................................................................................ 19 
7.6.1 
Primary Efficacy Analysis ..................................................................................................... 19 
7.6.2 
Secondary Efficacy Analysis ................................................................................................ 19 
7.6.3 
Exploratory Efficacy Analysis ............................................................................................... 21 
7.7 
Safety ............................................................................................. 21 
7.7.1 
Extent of Exposure and Compliance ................................................................................... 21 
7.7.2 
Adverse Events .................................................................................................................... 22 
7.7.3 
Laboratory Evaluations ....................................................................................................... 24 
7.7.4 
Vital Signs ............................................................................................................................ 25 
7.7.5 
Electrocardiograms ............................................................................................................. 25 
7.7.6 
Physical Examination ........................................................................................................... 26 
7.7.7 
Chest Imaging ...................................................................................................................... 26 
7.7.8 
Oxygenation ........................................................................................................................ 26 
7.7.9 
Other Safety Variables ........................................................................................................ 26 
7.8 
Pharmacokinetics .............................................................................. 26 
7.8.1 
General ................................................................................................................................ 26 
7.8.2 
Criteria for Handling Concentrations Below the Limit of Quantification in Pharmacokinetic 
Analysis 27 
7.8.3 
Calculation of AUC .............................................................................................................. 27 
7.8.4 
Anomalous Values ............................................................................................................... 28 
7.8.5 
Pharmacokinetic Statistical Methodology .......................................................................... 28 
7.8.6 
Presentation of Pharmacokinetic Data ............................................................................... 28 
7.9 
Interim Analysis................................................................................ 29 
8. 
Changes in Planned Analysis ................................................................. 29 
9. 
Data Issues......................................................................................... 29 
10. 
References .......................................................................................... 30 
Appendices.................................................................................................. 31 
Appendix 1: 
Document History .................................................................. 31 
Appendix 2: 
Schedule of Assessments ........................................................ 32 
 
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Reviewers 
The following reviews of the SAP were conducted: 
 
 
 
Name and Title 
 Role 
Version Last 
Reviewed 
Company/ 
Organization 
Ray Lin, Senior Principle 
Biostatistician 
Peer Review 
Statistician 
Internal Draft 3.0 
Covance 
Reece, William, Director of 
Biometrics 
Peer Review 
Statistician 
Internal Draft 3.1 
Covance 
Shengzhe Wu, Senior Principle 
Statistical Programmer 
Lead Programmer 
Internal Draft 4.0 
Covance 
Norberto Soto, Senior Medical 
Director 
Project Physician 
Internal Draft 4.0 
Covance 
Parag Mandape, Senior 
Medical Writer 
Medical Writer 
Internal Draft 3.1 
Covance 
Celeste MacElrevey, Senior 
Pharmacokineticist 
Pharmacokineticist 
Internal Draft 3.1 
Covance 
Angela Dymond, Principle 
Pharmacokineticist 
Pharmacokineticist 
Internal Draft 3.1 
Covance 
Howard Cheng, VP Clinical 
Medicine Research 
Department 
Project Director 
Final 3.0 
Golden Biotech 
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Glossary of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
AUC 
area under the plasma concentration versus time curve 
AUC0-last 
area under the plasma concentration versus time curve from 
time zero to the time of last quantifiable concentration 
AUCtau 
area under the plasma concentration versus time curve within 
a dosing interval 
BMI 
Body Mass Index 
BID 
twice daily 
BLQ 
below the level of quantification 
BOR 
Best Overall Response 
CI 
Confidence Interval 
CT 
computerized tomography 
CV 
Coefficient of Variance 
Cmax 
maximum plasma concentration  
COVID-19 
Coronavirus Disease 2019 
Ctrough 
trough (predose) plasma concentration 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
EOS 
End of Study 
ET 
Early Termination 
eCRF 
Electronic Case report form 
ICF 
Informed Consent Form 
ICU 
intensive care unit 
ITT 
intention-to-treat 
LDL-C 
Low Density Lipoprotein-Cholesterol 
LLOQ 
the lower limit of quantification 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
not calculated 
mITT 
modified intention-to-treat 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetic Set 
PPS 
Per Protocol Set 
PT 
Preferred Term 
QTcB 
Bazett corrected QT interval 
QTcF 
Fridericia corrected QT interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SoC 
Standard of Care 
SS 
Safety Set 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
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tmax 
Time to Cmax 
WHO 
World Health Organization 
 
 
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1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following 
documentation: 
Document 
Date 
Version 
Protocol 
07 July 2021 
4.0 
eCRF 
06 September 2021 
3.06 
 
 
 
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2. Protocol Details 
2.1 Study Objectives 
The primary objectives of this study is: 
 
To evaluate the efficacy of antroquinonol treatment of mild to moderate 
pneumonia due to COVID-19, as measured by the proportion of patients alive 
and free of respiratory failure (i.e., no need for invasive mechanical ventilation, 
non-invasive ventilation, high-flow oxygen, or extracorporeal membrane 
oxygenation [ECMO]) on Day 14 
Secondary objectives of this study are: 
 
To further evaluate the efficacy of antroquinonol compared with placebo in this 
patient population as measured by: 
o World Health Organization (WHO) COVID-19 Clinical Improvement Ordinal 
Scale score on Days 7, 14, and 28 
o Duration of hospitalization up to Day 28 
o Virological clearance on Days 5, 14, and 28 
o Vital status (death) on Days 7, 14, and 28 
o Duration of intensive care unit (ICU) stay up to Day 28 
o Proportion of patients alive and free of respiratory failure on Days 7 and 
28 
o COVID-19 symptoms on Days 7, 14, and Day 28 
 
To evaluate the safety of antroquinonol treatment in patients with mild to 
moderate pneumonia due to COVID-19. 
 
To assess the pharmacokinetics (PK) of antroquinonol in a subset of 20 patients 
(first 10 patients randomized to antroquinonol and first 10 patients to placebo) 
Exploratory objective of this study is: 
 
To further evaluate efficacy via supportive analyses of: 
o Subgroup analyses of selected covariates 
o Impact on efficacy of any new authorized treatments recommended as 
standard of care (SoC) for COVID-19 during the course of the study. 
2.2 Overall Study Design 
This is a randomized, double blind, placebo-controlled, Phase 2, proof of concept 
study in hospitalized patients with mild to moderate pneumonia due to COVID-19. 
Written informed consent must be obtained from all patients during screening (Days 
-2 to 0). Following completion of all screening assessments and meeting of eligibility 
criteria, patients will either receive antroquinonol or placebo for 14 days in 
combination with SoC therapy per local SoC policies. 
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A total of 174 patients are planned to be randomized in a 1:1 ratio to antroquinonol 
or placebo. 
The study will consist of a sentinel cohort of 20 patients (10 patients randomized to 
antroquinonol and 10 patients to placebo), and an expansion cohort of 154 patients 
(77 patients in each treatment group).  Enrollment will pause after the 20th patient 
in the sentinel cohort has been enrolled and started treatment, until the results of 
the interim analysis 1 are known. Once the 20th patient in the sentinel cohort has 
completed 14 days of treatment, an unblinded Data Monitoring Committee (DMC) will 
assess the safety, tolerability, efficacy, and PK of 100 mg twice daily (BID) 
antroquinonol in COVID-19 patients in the sentinel cohort (interim analysis 1). The 
DMC will issue a recommendation to enroll patients for the expansion cohort, or to 
stop the study depending on the safety and futility assessment.  Once the 80th 
patient has been enrolled, and completed 14 days of treatment, the DMC will review 
the safety, tolerability, and efficacy data (interim analysis 2).  Enrollment may be 
restricted at the 100th patient until the DMC has completed the assessment to 
prevent excessive enrollment. The DMC will continue to review safety and assess the 
risk/benefit profile on an ongoing basis.  A DMC Charter, which includes detailed 
processes, will be prepared. 
Patients will undergo assessment during hospitalization or could be discharged after 
start of study treatment any time after Day 2 if judged to be ready for discharge. If 
discharged, patients will then be requested to take study treatment at home (as 
prescribed) up to Day 14. End of Treatment assessments at Day 14 (+2 days) (at 
home or site visit) will be performed. A Day 5 (+/- 1 day) visit (at home or site visit) 
will be performed if the patient is discharged prior to Day 5. If the patient is 
discharged after completion of treatment and before the follow-up visit, he/she will 
be followed up on Day 28 (±2 days) for study assessments (a telephone or 
telemedicine visit). Post discharge, assessments will be done by telephone or 
telemedicine, except for Day 5, Day 14, and Early Termination (ET) of Study 
Treatment. On days of laboratory assessments, discharged patients will have a home 
visit. On days of no laboratory assessments, discharged patients will complete their 
assessments via telephone, telemedicine, or other means of remote communication. 
Additionally, patients will receive a diary to capture all doses after a discharge. 
2.3 Sample Size  
A total of 174 patients are planned to be randomized into the study: 
 
20 patients in the sentinel cohort (10 patients in each treatment group) 
 
154 patients in the expansion cohort (77 patients in each treatment group). 
This enrollment level ensures 80% power to demonstrate proof of concept efficacy 
with one-sided alpha of 0.2. 
The sample size is based on the following assumptions: 
 
The randomized allocation ratio is 1:1 between the antroquinonol group and 
the placebo group 
 
The proportion of patients alive and free of respiratory failure is approximately 
78% on placebo vs 89% on antroquinonol 
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 
The following nonbinding rules will be considered by the DMC for futility, and 
the DMC will not make any recommendations to stop for early efficacy: 
o Interim analysis 1 (sentinel cohort): An odds ratio of 3.5 on the primary 
endpoint in favor of placebo. 
o  Interim analysis 2: An odds ratio of 1.2 on the primary endpoint in favor 
of placebo. This analysis will be conducted on all data collected up to 
the 80th randomized patient completing 14 days of treatment. 
Enrollment may be restricted at the 100th patient until the DMC has 
completed the assessment to prevent excessive enrolment. 
3. Efficacy and Safety Variables 
3.1 Primary Efficacy Endpoint 
The proportion of patients who are alive and free of respiratory failure (e.g., no need 
for invasive mechanical ventilation, non-invasive ventilation, high-flow oxygen, or 
ECMO) on Day 14. 
3.2 Secondary Efficacy Endpoints 
 
Clinical improvement score as measured by the WHO COVID-19 Clinical 
Improvement Ordinal Scale, as follows: 
o Time to 2-point improvement from baseline. 
o Supportive analysis, time to score 2 or lower. 
o Supportive analysis, time to score 0. 
 
Duration of hospitalization (days) up to Day 28 
 
Virological clearance evaluated using PCR testing from nasopharyngeal or mid-
turbinate samples on Day 5, 14, and 28: 
o Time to virological clearance, measured as study days from start of 
treatment to first negative SARS-CoV-2 PCR test 
o Rate of change in viral load will be evaluated depending on availability 
of quantitative assays. 
 
Vital status (death) on Days 7, 14, and 28 
 
Duration of ICU stay up to Day 28 
 
Proportion of patients alive and free of respiratory failure on Days 7 and 28 
 
COVID-19 symptoms on Days 7, 14, and 28. Assessment will evaluate: 
presence or absence of dry cough, dyspnea (shortness of breath/ difficulty in 
breathing), or chills/rigors, myalgia (muscle pain), headache, sore throat, and 
loss of taste or smell; other symptoms that could be related to COVID-19 will 
also be recorded. 
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3.3 Exploratory Efficacy Endpoint 
To further evaluate the impact of the following parameters on the primary endpoint, 
the interaction term of treatment and following parameters will be fitted into the 
primary model one at a time. 
 
Age, sex, and remdesivir or other authorized treatments for COVID-19 use at 
baseline. 
 
Use of any new authorized treatments recommended as SoC for COVID-19 
during the course of the study. 
3.4 Safety Variables 
 
Adverse events (AEs) 
 
Standard safety laboratory tests (hematology, clinical chemistry, and 
urinalysis) 
 
Vital signs: respiratory rate, body temperature, blood pressure, pulse rate 
 
Complete 
physical 
examination: 
general 
appearance; 
head, 
eyes, 
ear/nose/throat, and neck; and lymphatic, cardiovascular, respiratory, 
gastrointestinal, musculoskeletal, neurological, and dermatological systems 
 
12-lead ECG 
 
Chest imaging (x-ray or CT scan) findings 
4. Pharmacokinetic Variables 
 
Trough (predose) plasma concentration (Ctrough) 
 
Maximum plasma concentration (Cmax) 
 
Time to Cmax (tmax) 
 
Area under the plasma concentration versus time curve (AUC) from time zero 
to the time of last quantifiable concentration (AUC0-last) 
 
AUC within a dosing interval (AUCtau, where tau = 12 hours). 
5.  Analysis populations 
5.1 All Enrolled Set 
All patients who signed the informed consent form (ICF) will be included in the all 
enrolled set. 
5.2 Intention-to-treat (ITT) Set 
All randomized patients. Patients will be analyzed according to the treatment to which 
they were randomized. 
5.3 Modified ITT (mITT) Set 
All randomized patients who received at least one dose of study drug. 
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5.4 Per Protocol Set (PPS) 
All patients from the ITT set who have no important protocol deviations during the 
study. Patients with important protocol deviations considered to have a major effect 
on efficacy shall be excluded from the PPS prior to database lock. 
Protocol deviations are defined as any change, divergence, or departure from the 
study design or procedures defined in the study protocol.  Important protocol 
deviations are a subset of protocol deviations and may significantly impact the 
correctness, accuracy, and/or reliability of the study data or that may significantly 
affect a Patient’s rights, safety, or well-being.  Prospective approval of protocol 
deviations to recruitment and enrollment criteria, also known as protocol waivers or 
exemptions, is not permitted.  Section 5.4.1 details the deviations. 
5.4.1 Important Protocol Deviations Leading to Exclusion from the PPS 
Analysis 
Only those important protocol deviations considered to have a major effect on 
efficacy will lead to complete exclusion of the patient from the PPS.  For the purposes 
of this study, the following criteria have been identified as important protocol 
deviations leading to exclusion from the PPS as it is considered that the occurrences 
of any of these criteria might have an important influence on the primary efficacy 
endpoint.  Patients will be assessed purely by comparison of their eCRF data with the 
criteria below. 
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Type 
Important Protocol Deviation 
Leading to Exclusion from the 
PPS 
Method of Identification 
Inclusion 
Criteria 2 
patient aged under 18 or over 80. 
Non-Programmable check of age 
collected during screening visit. 
Inclusion 
Criteria 4 
patient does not meet the condition 
of mild COVID-19 disease. 
Non-Programmable check of the 
WHO COVID-19 Clinical Improvement 
Ordinal Scale collected during 
screening visit.  
Inclusion 
Criteria 5 
patient with Chest x-ray or CT scan 
inconsistent with pheumonia. 
Non-Programmable check of the 
chest imaging result during the 
screening visit. 
Inclusion 
Criteria 6 
patient does not meet: onset 
COVID-19 symptoms within 2 weeks 
prior to randomization. 
Non-Programmable check of 
COVID-19 symptoms assessment 
during the screening visit. 
Inclusion 
Criteria 7 
patient does not have SARS-CoV-2 
infection confirmed by a PCR test, 
antigen, or any authorized 
commercial or public health assay. 
Non-Programmable check of SARS-
CoV-2 test result during the 
screening visit. 
Exclusion 
Criteria 2 
patient with concomitant life 
threatening condition, including but 
not limited to: requiring mechanical 
ventilation, acute respiratory 
distress syndrome, shock, or cardiac 
failure. 
Non-Programmable check of the 
medical history.  
Exclusion 
Criteria 3 
patient with evidence of multi lobar 
consolidation pneumonia or cavities 
on chest x-ray or CT scan. 
Non-programmable check of the 
chest imaging form during the 
screening visit. 
Exclusion 
Criteria 4 
patient with score of 5, 6 or 7 in 
COVID-19 Clinical Improvement 
Ordinal Scale. 
Non-Programmable check of the 
WHO COVID-19 Clinical Improvement 
Ordinal Scale during the screening 
visit. 
Exclusion 
Criteria 5 
patient with medical history for the 
following pulmonary diseases: lung 
cancer, cystic fibrosis, empyema. 
Non-Programmable check of the 
medical history. 
Exclusion 
Criteria 6 
patient with respiratory rate >30 
respirations per minute. 
Non-Programmable check of the 
vital signs at the screening visit 
Exclusion 
Criteria 8 
patient treated with other drugs 
thought to possibly have activity 
against COVID-19 within 7 days 
prior to enrollment or concurrently. 
Note: remdesivir or other authorized 
treatments for COVID-19 is allowed 
if considered SoC, if started prior to 
randomization or during the study. 
Non-Programmable check of the 
prior medications. 
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Exclusion 
Criteria 12 
patient requires frequent or 
prolonged use of systemic 
corticosteroids (≥20 mg of 
prednisone/day or equivalent for >4 
weeks) or other immunosuppressive 
drugs (e.g., for organ 
transplantation or autoimmune 
conditions). 
Non-Programmable check of the 
prior medications. 
Treatment 
Compliance 
patient with study treatment 
compliance <50% 
Non-Programmable check the 
study treatment compliance based on 
drug accountability data. 
Prohibited 
Medication 
or Therapy 
patient has used prohibited 
medications or therapies 
documented in the protocol or 
identified by clinical or medical team 
Non-Programmable check of the 
concomitant medication data. 
As defined in the table, all important protocol deviations leading to exclusion from 
the PPS will be determined non-programmatically from the data.  Those criteria which 
require clinical or medical monitoring interpretation will be reviewed prior to database 
lock. 
All important protocol deviations leading to exclusion from the PPS occurring during 
the study will be reviewed and approved by Golden Biotechnology Corporation prior 
to database lock and unblinding.  Should additional important protocol deviations 
leading to exclusion from the PPS, not anticipated at the time of preparing this SAP, 
be identified during the study (and prior to unblinding) they will be documented in a 
SAP amendment/Per Protocol Set Identification Plan, other document and included in 
all relevant protocol deviation reviews and approvals. 
5.5 Safety Set (SS) 
All patients who have received at least 1 dose of the study treatment. Patients will 
be analyzed according to the study treatment they actually received. 
5.6 Pharmacokinetic Set (PKS) 
Patients in the sentinel cohort who have received at least 1 dose of the study 
treatment and have at least 1 evaluable plasma concentration without important 
protocol deviations or events thought to significantly affect the PK. 
6. DATA Handling 
6.1 Time points and Visit Windows 
Day 1 is defined as the day of first dose of study treatment. Relative days on or after 
Day 1 are calculated as (target date – Day 1 date) + 1.  Relative days prior to Day 1 
are calculated as (target date – Day 1 date).  The day prior to Day 1 is Day -1.  
The following visit windows will be used for by-visit analyses. 
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Visit 
Target Day of Visita 
Acceptable visit window 
Day 3 
Day 3 
Days 2 to 3 
Day 5 
Day 5 
Days 4 to 6 
Day 7 
Day 7 
Days 7 to 8 
Day 14 - EOT 
Day 14 
Days 14 to 16 
Day 28 - Follow up 
Day 28 
Days 26 to 30 
a relative to the date of first dose of study treatment. 
For all populations, multiple visits within the same window will be dealt with as 
follows: 
 
If both scheduled and unscheduled visits fall within the same visit window, the 
scheduled visit will be used for analysis. 
 
If multiple scheduled visits occur within a single visit window, then the visit 
closest to the target day of the visit window will be used in the analysis.  If there 
is a tie, the later visit will be used in the analysis. 
 
If multiple unscheduled visits occur within a single visit window (with no 
scheduled visit within the window) then the unscheduled visit closest to the 
target day of the visit window will be used in the analysis.  If there is a tie, the 
later unscheduled visit will be used in the analysis. 
Baseline value is defined as the last scheduled or unscheduled value collected prior 
to the first dose of study treatment.  Assessments carried out on day of first study 
treatment administration are considered to have taken place before the study 
treatment administration, if the corresponding times have not been recorded. 
6.2 Handling of Dropouts, Missing Data, and Outliers 
Unless specified otherwise, no imputation for missing/partial dates will be performed 
for missing safety, efficacy, PK variables. For time-to-event efficacy variables, the 
censoring rules for no event data will be included in efficacy analysis section. 
For patients with clinical improvement score above 2 or missing at discharge, missing 
scores on the next day after discharge will be imputed to 2. After above rule 
implemented, missing scores will be imputed using Last Observation Carried Forward 
for a maximum of 1 day at Day 7, 2 days at Day 14, and 4 days at Day 28. 
Dates in original form will be used in all listings. 
No rules for outlier detection are planned. 
7. Statistical Methods 
7.1 General Principles 
All data processing, summarization and analyses will be performed using Covance’s 
SAS Environment / Version 9.4 (or later) of the SAS statistical software package. 
The following principles will be applied to all TFLs unless otherwise stated: 
Principle 
Value 
Significant tests 
Results will be considered statistically significant at one 
sided alpha of 0.025, and considered to indicate promising 
trend at one sided alpha of 0.2. 
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Principle 
Value 
Treatment group labels and 
order 
Antroquinonol 100 mg BID           
Placebo  
Tables 
Data in summary tables presented by treatment group, 
assessment and visit (where applicable). 
Listings 
All data collected presented by treatment group, country, 
site, Patient, assessment and visit (where applicable), 
unless otherwise specified. 
Descriptive summary 
statistics for continuous 
variables 
Number of patients/observations (n), mean, standard 
deviation (SD), median, minimum (Min) and maximum 
(Max). 
Descriptive summary 
statistics for categorical 
variables 
Frequency counts and percentages [n (%)] 
Denominator and for 
percentages 
Number of patients in the analysis population, unless stated 
otherwise in table shell(s).  
Precision for percentages 
1 decimal place 
Include “Missing” as category 
Yes, when the number missing is greater than zero for at 
least one treatment group. 
Display to one more decimal 
place than collected value 
For efficacy and safety: 
  Mean 
  Mean Difference 
  Median 
Display to two more decimal 
places than collected value 
For efficacy and safety:  
  Standard Error 
  Standard Deviation 
  Confidence Interval  
Display to three significant 
figures 
For PK: 
  Mean 
  Standard Deviation 
  Geometric Mean 
  Median 
  Min 
  Max 
Limit of precision for displays 
4 decimal places 
Date Format 
DDMMMYYYY 
7.2 Patient Disposition and Data Sets Analyzed 
Patient disposition will be listed and summarized by treatment group and overall for 
the all enrolled population and will include the number and percentage of patients 
that fall into the categories below: 
 
screened (overall); 
 
screen failed, including a breakdown of the primary reasons for screen failure; 
 
eligible but not randomized; 
 
randomized; 
 
randomized but not treated; 
 
treated; 
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 
included in each study population (ITT set, mITT set, PPS, SS, PKS); 
 
completed/discontinued from the study treatment, including a breakdown of 
the primary reasons for discontinuation; 
 
completed/discontinued from the study, including a breakdown of the primary 
reasons for discontinuation. 
Summary of patient disposition by country and site will be provided for each 
treatment group and overall for the ITT set. 
7.3 Protocol Deviations 
All protocol deviations will be listed for the ITT set. 
All important protocol deviations leading to exclusion from the PPS (see Section 
5.4.1) will be listed and summarized by treatment group and overall for the ITT set. 
7.4 Baseline Disease Characteristics 
Baseline disease characteristics will be listed and summarized by treatment group 
and overall for the ITT set.  Standard descriptive statistics will be presented for the 
continuous variables of: 
 
oxygen saturation (SpO2) (%); 
 
WHO COVID clinical improvement ordinal scale. 
The total counts and percentages of patients will be presented for the categorical 
variables of: 
 
patient setting; 
 
chest imaging result (normal, abnormal NCS, abnormal CS); 
 
SARS-CoV-2 test result (negative, positive); 
 
WHO COVID clinical improvement ordinal scale (at or below each score); 
 
COVID-19 symptoms; 
 
COVID-19 symptoms – maximum severity; 
 
patients with diarrhea. 
7.5 Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be listed and summarized by 
treatment group and overall for the ITT set.  Standard descriptive statistics will be 
presented for the continuous variables of: 
 
age (years); 
 
weight (kg); 
 
height (cm); 
 
body mass index (BMI, kg/m2) [calculated as (weight/height2) where weight is 
in kg and height is in m]. 
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The total counts and percentages of patients will be presented for the categorical 
variables of: 
 
age (≤ 65 years, > 65 years); 
 
sex; 
 
race; 
 
ethnicity; 
 
remdesivir use or other authorized treatments for COVID-19. 
Other baseline measurements, such as vital signs and ECG, will be summarized with 
the post-baseline measurements. 
7.5.1 Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) [Version 23.0 dated 19 Apr 2020 or a later version if updated during the 
study (exclusively meant for COVID-19)].  All medical history will be listed, and the 
number and percentage of patients with any medical history will be summarized for 
the ITT set by system organ class (SOC) and preferred term (PT) for each treatment 
group and overall.   
7.5.2 Prior and Concomitant Medications 
Medications received prior to or concomitantly with study treatment will be coded 
using WHODrug Dictionary [Version Global B3 March 2020 (or a later version if 
updated during the study)].   
Prior medications and concomitant medications are defined as follows: 
Prior medications are those with a stop date prior to the first dose date of study 
treatment.  
Concomitant medications are those with a start date on or after the first dose date 
of study treatment, or those with a start date before the first dose date of study 
treatment and a stop date on or after the first dose date of study treatment or 
ongoing end of study. 
If a medication cannot be classified as “prior” or “concomitant” due to 
missing/incomplete dates, it will be classified as concomitant. 
Prior medications and concomitant medications will be listed together and 
summarized separately for the ITT set. 
The number and percentage of patients using each medication will be displayed 
together with the number and percentage of patients using at least one medication 
within each therapeutic class (ATC-Level 2) and generic term. 
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7.6 Efficacy 
Efficacy analyses will be conducted on ITT set, mITT set and PPS, separately, unless 
otherwise specified. The ITT set will be the primary analysis population for efficacy 
and the mITT set and PPS will be the supportive analysis populations for efficacy 
analysis.  If it turns out that ITT and mITT populations are identical, then only ITT 
results will be presented. 
7.6.1 Primary Efficacy Analysis 
The proportion of patients from each treatment group who are alive and free of 
respiratory failure on Day 14 will be summarized and compared using logistic 
regression, with treatment, remdesivir or other authorized treatments for COVID-19 
use at baseline (yes vs no) and age at baseline (> 65 years vs ≤ 65 years) as 
covariates.  The p-value for treatment effect will be provided based on the Wald test. 
P-value based on Fisher’s exact test will also be provided.  Odds ratio along with its 
95% confidence interval will be provided based on the exact method.  In addition, 
the risk difference for the treatment effect and 95% confidence interval will be 
calculated based on the proportion of patients alive and respiratory failure free in the 
control group and the estimates of odds ratio, along with its 95% confidence interval. 
7.6.2 Secondary Efficacy Analysis 
7.6.2.1 
Clinical Improvement Score as Measured by WHO COVID-19 
Clinical Improvement Ordinal Scale 
Clinical improvement measured as a score on the WHO COVID-19 Clinical 
Improvement Ordinal Scale will be analyzed using an ordinal logistic regression on 
Days 7, 14, and 28, with study treatment, clinical improvement score at baseline (as 
numerical variable), age at baseline (> 65 years vs ≤ 65 years), and remdesivir or 
other authorized treatments for COVID-19 use at baseline (yes vs no) as covariates.  
The p-value for treatment effect will be provided based on the Wald test. 
In addition, descriptive statistics will be provided for average score by treatment 
group, and the proportion of patients at or below each score, at each visit. 
Time to 2-point improvement from baseline in WHO COVID-19 Clinical Improvement 
score, time to score of 2 or lower, and time to score of 0, will also be analyzed.  The 
hazard ratio and its 95% confidence interval for these time-to-event endpoints will 
be estimated by Cox proportional hazard model, with treatment, remdesivir or other 
authorized treatments for COVID-19 use at baseline (yes vs no) and age at baseline 
(> 65 years vs ≤ 65 years) as covariates.  The analysis will be carried out using two 
different censoring rules: 1) Patients will be censored at the time they are provided 
any authorized treatment for COVID-19 not prescribed at baseline, or on Day 28 if 
they have not yet recovered or have died by Day 28;  2) Patients will only be censored 
on Day 28 if they have not yet recovered or have died by Day 28.  The p-value for 
comparison between treatment groups will be obtained based on the Cox proportional 
hazards model described above.  Median time to 2-point improvement, time to score 
of 2 or lower, and time to score of 0 will be estimated by Kaplan-Meier (KM) method, 
and the KM curve will be provided. 
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7.6.2.2 
Duration of Hospitalization and ICU Stay 
Duration in days of hospitalization and ICU stay up to Day 28 will be summarized 
descriptively and analyzed using normal regression, with treatment, remdesivir or 
other authorized treatments for COVID-19 use at baseline (yes vs no) and age at 
baseline (> 65 years vs ≤ 65 years) as covariates.  P-values for treatment effect will 
be provided using the Student’s t-test. 
Notes: 1) Only hospitalization or ICU stay days on or after the date of first dose of 
study treatment and up to Day 28 will be used in the calculation of duration of 
hospitalization or ICU stay, respectively;  2) Patients who have died or with unknown 
discharge date will be considered as continuing to require hospitalization or ICU stay 
up to Day 28.  
7.6.2.3 
SARS-CoV-2 PCR Test 
Time to virological clearance, measured as study days from start of treatment to first 
negative SARS-CoV-2 PCR test, will be evaluated using similar statistical methods as 
clinical improvement where in this case, the first negative SARS-CoV-2 PCR test is 
considered as an event.  Patients will be censored on Day 28 if they have not yet 
shown SARS-CoV-2 PCR negative or have died by Day 28. 
If quantitative SARS-CoV-2 PCR results are available, the following analyses will be 
conducted.  Note that if a patient has tested negative, they are assumed to be 
negative until they are tested again and for negative test result, viral load is assumed 
to be half of the lower limit of detection. 
 
Rate of change in viral load will be estimated using a Mixed Model for Repeated 
Measurements model.   
The model will include the treatment group, age at baseline (> 65 years vs ≤ 
65 years), remdesivir or other authorized treatments for COVID-19 use at 
baseline (yes vs no), log (viral load) at baseline, study day (numerical, 0 for 
baseline), and the interaction between study day and the treatment group as 
fixed factors, patient as random factor (random intercept and random slope).   
The model will use natural-log-transformed viral load as the response variable. 
An unstructured covariance structure will be used.  In case of a convergence 
problem with the unstructured covariance matrix, the following structures with 
robust sandwich estimator for the standard error of the fixed effect estimates 
will 
be 
assessed 
in 
a 
sequential 
fashion: 
heterogeneous 
Toeplitz, 
heterogeneous first-order autoregressive, Toeplitz and compound symmetry. 
The esitmate of the study day*treatment will be interpreted as the difference 
between treatment and placebo groups in terms of the rate of change in viral 
load.  The estimate, standard error and p-value of study day*treatment will be 
reported. 
 
Natural-log-transformed viral load with change from baseline will be 
summarized by treatment group and visit using descriptive statistics. 
 
Arithmetic mean (+SD) of natural-log-transformed viral load vs. time figure 
for each treatment group will be presented.  
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7.6.2.4 
Vital Status, Patients Alive and Free of Respiratory Failure, 
and COVID-19 Symptoms 
Proportion of patients with vital status of death in both groups on Days 7, 14, and 28 
will be summarized compared using the same logistic regression model as the 
primary model. 
Proportion of patients alive and free of respiratory failure on Days 7 and 28 will be 
summarized and compared using the same analysis as the primary endpoint. 
Proportion of patients with each COVID-19 symptoms at baseline and on Days 7, 14, 
and 28 will be summarized and compared using logistic regression following the same 
method as the primary endpoint.  Shift from baseline in severity table for each 
COVID-19 symptoms will be provided by treatment group. 
7.6.3 Exploratory Efficacy Analysis 
Subgroup analyses on primary endpoint will be provided for the parameters of age 
at baseline (> 65 years vs ≤ 65 years), sex, and remdesivir or other authorized 
treatments for COVID-19 use at baseline.  The interaction between each mentioned 
parameter and the treatment effect will be added one at a time into the primary 
logistic model and the corresponding p-value for that interaction term will be 
provided. 
The impact on efficacy of any new authorized treatments recommended as SoC for 
COVID-19 during the course of the study will also be evaluated using the same 
method as above.  
7.7 Safety 
7.7.1 Extent of Exposure and Compliance 
Duration of exposure will be defined in days as:  
(date of last dose – date of first dose) + 1 – off-drug days. 
If date of first dose is missing then date of first dose dispensed will be used.  If last 
dose date is missing then date of the last known dose consumed will be used. 
Duration of exposure will be listed and summarized using descriptive statistics for 
each treatment group for the SS.  The number and percentage of patients with 
treatment exposure by study day will be summarized for the SS. 
The total number of capsules taken over the study duration will be summarized 
descriptively for the SS, where the total number of capsules taken is calculated as 
total number of capsules dispensed (30) – total number of capsules returned. 
Percentage compliance is calculated as 100 * actual number of capsules 
taken/expected number of capsules taken, where actual number taken is defined as 
the number dispensed (30) – the number returned and expected number taken is 
defined as 2*(planned last treatment date – first treatment date + 1).  For patients 
who completed the study treatment, planned last treatment date is the day 14 date; 
for patients with treatment early termination due to reasons of adverse event, death, 
physician decision or sponsor decision, planned last treatment date is the end of 
treatment date; for patients with treatment early termination due to reasons other 
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than the ones mentioned above, planned last treatment date is either the day 14 
date or the end of study date, whichever occurs first. 
Percentage compliance will be summarized descriptively by treatment group for the 
SS.  The number and percentage of compliant patients will be presented for the SS, 
where compliant is defined as percentage compliance between 80.0% and 120.0% 
inclusive. The following percentage compliance categories will also be presented: 
 
<50.0% 
 
≥50.0% and <80.0% 
 
≥80.0% and ≤120.0% 
 
>120.0% 
7.7.2 Adverse Events 
All adverse events (AEs) recorded on the eCRF will be coded using the MedDRA 
dictionary [Version 23.0 dated 19 Apr 2020 or a later version if updated during the 
study (exclusively meant for COVID-19)] and classified as either pre-treatment AEs 
or treatment – emergent AEs (TEAEs) as follows: 
 
Pre-treatment AEs are events that start after the signing the informed 
consent form and prior to the date of first dose of study treatment. 
 
TEAEs are events with start date on or after the date of first dose of study 
treatment and up to 2 weeks after date of last dose of study treatment or 
events with start date prior to the date of first dose of study treatment whose 
severity worsens on or after the date of first dose of study treatment.  
If an AE can’t be classified as pre-treatment AE or TEAE due to missing/partial dates, 
it will be classified as TEAE. 
The number and percentage of patients reporting each pre-treatment AE will be 
summarized for each treatment group and overall, by System Organ Class (SOC) and 
Preferred Term (PT) for SS. 
All AE data will be listed by treatment group and overall.  Treatment-emergence 
status will be flagged in the listing.  In addition, corresponding listings of serious AEs 
(SAEs), treatment-related AEs, AEs leading to discontinuation of study treatment, 
AEs leading to discontinuation of study and AEs resulting in death will be produced 
for the SS. 
The severity of all AEs is recorded as mild, moderate, or severe.  If severity is missing 
for a TEAE, it will be considered severe only in the overall category in the summary 
tables.  
The relationship between an AE and treatment is assessed as related, possibly 
related, unlikely related, or not related.  A treatment-related AE is an AE considered 
by the investigator as related or possibly related to treatment or with missing 
relationship to treatment.   
An overview table will summarize the number and percentage of patients with at least 
one of the following TEAEs, along with the number of corresponding TEAEs, where 
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patients with more than one TEAE in a particular category are counted only once in 
that category: 
 
any AE;  
 
any AE by maximum severity (mild, moderate, severe); 
 
treatment-related AE;  
 
AE leading to study treatment discontinuation;  
 
AE leading to study discontinuation;  
 
AE leading to death;  
 
SAE;  
 
treatment-related SAE;  
 
treatment-related SAE leading to death; 
 
SAE leading to death; 
 
SAE leading to treatment discontinuation;  
 
SAE leading to study discontinuation. 
The number and percentage of patients reporting each AE will be summarized by 
System Organ Class (SOC) and Preferred Term (PT) for the SS. SOC and PT will be 
sorted by descending frequency in Antroquinonol group. The following summaries will 
be produced: 
 
AEs, by SOC and PT; 
 
AEs by PT; 
 
AEs related to study treatment, by SOC and PT; 
 
AEs related to study treatment, by PT; 
 
AEs by maximum severity, by SOC and PT; 
 
AEs related to study treatment by maximum severity, by SOC and PT; 
 
AEs by highest relationship to study treatment, by SOC and PT; 
 
AEs causing discontinuation from study treatment, by SOC and PT; 
 
AEs related to study treatment causing discontinuation from study treatment, by 
SOC and PT; 
 
AEs causing discontinuation from study, by SOC and PT; 
 
SAEs, by SOC and PT; 
 
SAEs related to study treatment, by SOC and PT; 
 
AEs leading to death, by SOC and PT. 
In the above summaries, patients with more than one AE within a particular SOC or 
PT are counted only once for that SOC or PT.  For summaries by maximum severity, 
patients with multiple AEs within a particular SOC or PT will be counted under the 
category of their most severe AE within that SOC or PT.  AEs with missing severity 
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will be included as severe in the overall count of patients with AEs, but will not be 
included in the counts of patients with AEs within a SOC or PT. For summaries by 
highest severity, patients with multiple AEs within a particular SOC or PT will be 
counted under the category of their highest relationship to study treatment within 
that SOC or PT.   
No statistical comparisons of AEs between treatment groups will be performed. 
7.7.3 Laboratory Evaluations 
Data for the following hematology, clinical chemistry, and urinalysis analytes will be 
listed and summarized by treatment group and overall by visit for the SS.  If data for 
any additional analytes are also received/recorded then these will be listed only.   
Hematology 
Clinical Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
MCH 
MCHC 
MCV 
Platelet count  
Red blood cell (RBC) 
count 
White blood cell (WBC) 
count 
WBC differential 
(% and absolute 
values): 
 
Basophils 
 
Eosinophils 
 
Lymphocytes 
 
Monocytes 
 
Neutrophils 
Albumin 
ALP 
ALT 
AST 
BUN 
Calcium 
Chloride 
Cholesterol 
Creatinine 
GGT 
Glucose 
eGFR 
LDH 
Phosphorus 
Potassium 
Sodium 
Total Bilirubin 
Total CO2 (measured as bicarbonate) 
Total Protein 
Triglycerides 
Uric acid 
Color and appearance  
pH and specific gravity 
Bilirubin 
Glucose 
Ketones  
Leukocytes  
Nitrite  
Occult blood  
Protein  
Microscopic (including 
RBCs and WBCs) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CO2 = carbon dioxide; 
eGFR = estimated glomerular filtration rate; GGT = gamma glutamyl transferase; LDH = lactate 
dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = mean corpuscular volume; RBC = red blood cell; WBC = white blood cell. 
All laboratory data will be reported in International System of Units (SI).  Out-of-
reference-range values will be flagged as high (H) or low (L) in the listings.  
For analysis purposes, values preceded by a “<” or a “>”sign (i.e. those below or 
above the limits of quantification) will be multiplied by 0.5 and 1.5 respectively. 
Results and changes from baseline (if applicable) of all laboratory parameters will be 
listed and summarized by treatment group and overall, for each scheduled visit using 
standard descriptive statistics for the SS.   
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For hematology, clinical chemistry and numerical urinalysis analytes, shift tables 
presenting movement in and out of reference range from baseline to each scheduled 
post-baseline visit will be provided for each treatment group and overall for the SS.   
7.7.4 Vital Signs 
The following vital sign parameters will be listed and summarized by treatment group 
and overall and visit. 
 
systolic and diastolic blood pressure (mmHg); 
 
pulse rate (bpm); 
 
respiration rate (breaths/min); 
 
body temperature (°C). 
Vital signs data and changes from baseline in vital signs will be listed and summarized 
by treatment group and overall, for each scheduled visit using standard descriptive 
statistics for the SS.   
7.7.5 Electrocardiograms 
The following quantitative ECG measurements will be taken during the study: 
 
heart rate (bpm); 
 
RR interval (msec); 
 
PR interval (msec); 
 
QRS interval (msec); 
 
QT interval (msec); 
 
Bazett corrected QT (QTcB) interval (msec); 
 
Fridericia corrected QT (QTcF) interval (msec). 
An overall Investigator assessment of ECG will be provided (categories “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”). 
The ECG measurements and changes from baseline in ECG will be listed and 
summarized by treatment group and overall for each scheduled visit using standard 
descriptive statistics for the SS.  
The Investigator assessment will be listed and the number and percentage of patients 
within each assessment category will be tabulated by treatment group and overall 
for each scheduled visit for the SS. Shifts from baseline in overall investigator 
assessment at each post-baseline visit will be presented. 
QTcB and QTcF intervals and change from baseline will be analyzed.  The analysis 
will include all scheduled and unscheduled values. 
The maximum baseline and post-baseline values will be summarized separately, by 
treatment group and overall according to the following categories: 
 
≤450 ms 
 
>450 and ≤480 ms 
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 
>480 and ≤500 ms 
 
>500 ms 
The maximum increases from baseline will be summarized by treatment group and 
overall according to the following categories: 
 
≤30 ms 
 
>30 and ≤60 ms  
 
>60 ms 
7.7.6 Physical Examination 
Physical examination results (categories “normal”, “abnormal, not clinically 
significant” and “abnormal, clinically significant”) and details of abnormalities will be 
listed for each patient. 
For each physical examination body system, shifts from baseline in examination 
results at each post-baseline visit will be presented by treatment group and overall 
for the SS. 
7.7.7 Chest Imaging 
Chest imaging (X-Ray or CT scan) results (categories “normal”, “abnormal, not 
clinically significant” and “abnormal, clinically significant”) and other details will be 
listed for each patient. Shift from baseline in results at each post-baseline visit will 
be presented by treatment group and overall for the SS. 
7.7.8 Oxygenation 
Oxygenation parameters (i.e., FiO2, SpO2, PaO2, SpO2/FiO2 and PaO2/FiO2, if 
available) and other details will be listed for each patient. Change from baseline of 
SpO2, SpO2/FiO2 and PaO2/FiO2, at each post-baseline visit will be presented by 
treatment group and overall for the SS, if available. 
7.7.9 Other Safety Variables 
Other safety variables and corresponding data, if collected, will be listed only. 
7.8 Pharmacokinetics 
7.8.1 General 
The PK parameters of antroquinonol will be calculated based on the actual sampling 
time using non-compartmental analysis (NCA) methods within Phoenix WinNonlin 
Version 8.1 or higher (Certara USA, Inc.).  If the actual sampling time is missing, the 
scheduled timepoint will be used in the PK parameter calculation with sponsor 
approval. 
The units of concentration and resulting PK parameters, will be presented as they are 
received from the analytical laboratory. 
The following PK parameters for antroquinonol will be determined where possible 
from the plasma concentration data collected on Day 3: 
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Parameter 
Definition 
AUC0-last 
area under the plasma concentration versus time curve (AUC) from 
time zero to the time of last quantifiable concentration 
AUCtau 
AUC within a dosing interval, where tau = 12 hours. 
Cmax 
maximum plasma concentration 
tmax 
time to Cmax 
Ctrough 
trough (predose) plasma concentration 
Additional PK parameters may be determined where appropriate. 
AUC parameters will be calculated using the linear trapezoidal rule for increasing 
concentrations and the logarithmic rule for decreasing concentrations. 
Cmax, Ctrough and tmax will be obtained directly from the plasma concentration-
time profiles. 
The predose and 2 hours post dose samples collected on Day 14 from patients who 
remained hospitalized will be listed and summarized. 
7.8.2 Criteria for Handling Concentrations Below the Limit of 
Quantification in Pharmacokinetic Analysis  
Concentration values that are below the level of quantification (BLQ) will be set to 
zero, with defined exceptions as follows; 
 
Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ 
values following the last quantifiable concentration in a profile will be set to 
missing for the purposes of PK analysis. 
 
If there are late positive concentration values following 2 BLQ concentration 
values in the apparent terminal phase, these values will be evaluated. If these 
values are considered to be anomalous, they will be set to missing. 
 
If an entire concentration-time profile is BLQ, the profile will be excluded from 
the PK parameter calculations. 
 
If the predose sample is missing on Day 3, the predose concentration may be 
set as equivalent to the concentration at the end of the dosing interval (12 
hours post dose) if available. 
 
If the 12 hours post dose sample is missing or not collected on Day 3, the 12 
hours concentration may be set as equivalent to the concentration at predose 
if available.  
7.8.3 Calculation of AUC  
 
The minimum requirement for the calculation of AUC will be the inclusion of at 
least three consecutive plasma concentrations above the lower limit of 
quantification (LLOQ), with at least one of these concentrations following Cmax.  
 
For any partial AUC determination (i.e. AUC within a dosing interval), nominal 
time will generally be used for the end of the interval. Actual times for partial 
AUC intervals may be used at the discretion of the Pharmacokineticist.  
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7.8.4 Anomalous Values  
If a value is considered to be anomalous due to being inconsistent with the 
expected pharmacokinetic profile, it may be appropriate to exclude this point from 
the PK analysis. However, the exclusion of data must have strong justification and 
will be documented in the raw data and study report.  
Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug.  
7.8.5 Pharmacokinetic Statistical Methodology 
All the PK data will be presented based on the PKS. 
Antroquinonol plasma concentration data will be listed and summarized by study day 
at every scheduled timepoints.  The following figures will be plotted: 
 
The arithmetic mean (+ standard deviation [SD]) plasma concentration-time 
plot (linear and semi-log) by study day according to the scheduled sampling 
timepoints;  
 
Individual plasma concentration-time plot (linear and semi-log) according to 
the actual sampling time on Day 3 and 14 for every patient. 
The PK parameters of Day 3 will be listed and summarized.   
7.8.6 Presentation of Pharmacokinetic Data 
7.8.6.1 
Presentation of Pharmacokinetic Plasma Drug Concentration 
Data 
 
Descriptive statistics of number of patients (n), number of BLQ values [n 
(BLQ)], arithmetic mean, SD, geometric mean, geometric coefficient of 
variance (CV), median, minimum and maximum will be calculated in 
summaries.   
 
For the calculation of summary statistics, the BLQ values will be set to zero. 
 
Where there is no result (NR), these will be set to missing. 
 
If there are less than three values in the data series, only the min, max and n 
will be presented. The other summary statistics will be denoted as not 
calculated (NC).  
 
If all the values are BLQ, then the arithmetic mean, arithmetic SD, median, 
min and max will be presented as zero, and the geometric mean and geometric 
CV% will be denoted as NC. 
 
If the value of the arithmetic mean or median is below the lower limit of 
quantification, these values will be presented as zero and the geometric mean 
and geometric CV% will be denoted as NC. 
 
Where the actual PK sample collection time deviates outside ± 10% from the 
planned time point,  the concentration may be excluded from the calculation 
of descriptive statistics. Note: Deviation from Nominal Time = Actual date time 
[h] of sample collection (relative to last administered dose) - Planned date 
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Sponsor Protocol ID: GHCovid-2-001 
 
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time [h] of sample collection (relative to last administered dose); Percent 
Deviation from Nominal Time (%) = 100 * (Deviation from nominal time [h] / 
Nominal time point [h]). 
7.8.6.2 
Presentation of Pharmacokinetic Parameters  
 
Descriptive statistics of number of patients (n), arithmetic mean, SD, 
geometric mean, geometric CV, median, minimum and maximum will be 
calculated in summaries. 
 
For the calculation of summary statistics of PK parameters, all NR and NC 
values in a data series will be set to missing. 
 
The AUC values will be set to NC if they have been calculated using fewer than 
three concentrations, and/or three concentrations if the last is Cmax. 
 
If there are less than three values in the data series, only the min, max and n 
will be presented. The other summary statistics will be denoted as not 
calculated (NC). 
7.9 Interim Analysis 
The following interim analyses will be conducted: 
 
Interim analysis 1, for safety and futility, will be conducted when the sentinel 
cohort has completed at least 14 days of treatment.  Enrollment will be paused 
once the 20th patient in the sentinel cohort has been enrolled and started 
treatment until the results of the interim analysis are known. 
 
Interim analysis 2, for safety and futility, will be conducted on all data collected 
up to the 80th randomized patient completing 14 days of treatment. Enrollment 
may be restricted at the 100th patient until the DMC has completed the 
assessment to prevent excessive enrollment.  
All interim analyses will be reviewed by the unblinded DMC.  The DMC will not make 
recommendations to stop the study early for efficacy.  Futility rules provided to the 
DMC will be nonbinding, and therefore no adjustment of the final analysis will be 
made. Should either ≥ 2 patients experience treatment related SAEs or severe AEs 
that are of a similar nature at any time, enrollment will be paused while the DMC 
reviews safety data.   
A DMC Charter, which includes detailed processes, will be prepared. 
8. Changes in Planned Analysis 
No changes on statistical analysis methods from the protocol. 
9. Data Issues 
There is no observed data issue while formulating the statistical analysis plan. Should 
any data issue identified after the SAP is finalized will be documented in regard to 
the handling of the data issue.” 
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10. References 
1 
ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
http://www.emea.eu.int/pdfs/human/ich/036396en.pdf 
2 
CPMP. Points to Consider on Missing Data. EMEA: London, 2001. Available at 
http://www.emea.eu.int/pdfs/human/ewp/177699EN.pdf 
3 
Phillips A and Haudiquet V. ICH E9 guideline “Statistical principles for clinical 
trials”: a case study. Statistics in Medicine 2003; 22:1-11 
4 
Brown D J. ICH E9 guideline “Statistical principles for clinical trials”: a case 
study. Response to A. Phillips and V. Haudiquet. Statistics in Medicine 2003; 
22:13-17 
5 
Phillips A, Ebbutt A, France L, Morgan D, Ireson M, Struthers L and Heimann 
G. Issues in applying recent CPMP “Points to Consider” and FDA guidance 
documents with biostatistical implications. Pharmaceutical Statistics 2003; 
2:241-251 
6 
Senn S. Statistical Issues in Drug Development. John Wiley & sons 
(Chichester), 1997. 
7 
Chow S-C and Liu J-P. Design and Analysis of Clinical Trials: Concepts and 
Methodologies. John Wiley & sons (New York), 1998. 
8 
Brown H and Prescott R. Applied Mixed Models in Medicine. John Wiley & sons 
(Chichester), 1999. 
9 
Fairclough D L. Design and Analysis of Quality of Life Studies in Clinical Trials. 
Chapman & Hall/CRC, 2002. 
10 
Green S, Benedetti J and Crowley J. Clinical Trials in Oncology (2nd edition). 
Chapman & Hall/CRC, 2002. 
11 
McEntegart D. Forced randomization when using interactive voice response 
systems. Applied Clinical Trials October 2003; 50-58. 
12 
CPMP. Points to Consider on Adjustment for Baseline Covaraites. EMEA: 
London, 2003 
13 
ICH. ICH E3 Guideline: Structure and Content of Clinical Study Reports 
Questions & Answers, 2012. Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Eff
icacy/E3/E3_QAs_R1_Step4.pdf 
 
 
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Appendices 
Appendix 1: Document History 
Document Version, Status, Date 
Summary/Reason for Changes 
Version 1, Final, 04 October 2020 
Not applicable; the first version 
Version 2, Final, 23 March 2021 
To address FDA’s comments, new 
changes in Protocol 3.0 and 
additional internal comments. 
Version 3, Final, 29 Nov 2021 
Protocol updated to version 4.0 
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Appendix 2: Schedule of Assessments 
Study Period 
Screening 
Treatment 
Discharge 
Follow-up 
Visit name 
Screening 
Baselin
e 
 
 
 
EOT a 
Discharge/ 
ET of Study 
Treatment/ 
EOTa 
EOSa/ Early 
Withdrawal/ 
ET of Study 
Study Day(s) 
-2 to 0 
1 
3 
5 (±1) 
7 (+1) 
14 (+2) 
2-28 
28 (±2) 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteriac 
X 
X 
 
 
 
 
 
 
Daily study treatment administrationd 
 
 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examinatione 
X 
X 
 
 
 
X 
X 
X 
Height, body weighte 
X 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-ray or CT scanf 
X 
 
 
 
 
X 
Pregnancy testg 
X 
X 
 
 
 
X 
X 
X 
Return unused study treatment 
 
 
 
 
 
X 
X 
 
Efficacyh 
[1] Confirm setting (outpatient, in hospital, in 
ICU) 
X 
 
X 
X 
X 
X 
X 
X 
[2] SARS-CoV-2 PCR test 
X 
X 
 
X 
 
X 
 
X 
[3] WHO COVID-19 Clinical Improvement 
Ordinal Scale 
X 
X 
X 
X 
X 
X 
X 
X 
[4] Vital status 
 
X 
X 
X 
X 
X 
X 
X 
[5] Respiratory failure status 
 
X 
X 
X 
X 
X 
X 
X 
[6] COVID-19 symptoms assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Safetyi  
[1] Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
[2] Laboratory assessments 
X 
X 
 
X 
 
X 
X 
 
[3] Electrocardiogram 
X 
 
 
 
 
X 
X 
 
[4] Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
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Statistical Analysis Plan 
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Study Period 
Screening 
Treatment 
Discharge 
Follow-up 
Visit name 
Screening 
Baselin
e 
 
 
 
EOT a 
Discharge/ 
ET of Study 
Treatment/ 
EOTa 
EOSa/ Early 
Withdrawal/ 
ET of Study 
Study Day(s) 
-2 to 0 
1 
3 
5 (±1) 
7 (+1) 
14 (+2) 
2-28 
28 (±2) 
Pharmacokineticsj 
PK blood collection  
 
 
X 
 
 
X 
 
 
Abbreviations: AE = adverse event; AUC = area under the plasma concentration versus time siurve;AUC0-last = AUC  from time zero the time of last quantifiable concentration; 
AUCtau = AUC within a dosing interval, tau = 12 hours; BID = twice daily; Cmax = maximum plasma concentration; Ctrough = trough (predose) plasma concentration; COVID-19 = 
COronaVIrus Disease 2019; CT = computerized tomography; CRF = case report form; DMC = Data Monitoring Committee; ECG = electrocardiogram; ECMO = extracorporeal 
membrane oxygenation; EOS = End of Study; EOT = End of Treatment; ET = early termination; HEENT = head, eyes, ear, nose and throat; ICF = informed consent form; 
ICU = intensive care unit; PCR = polymerase chain reaction; PK = pharmacokinetic; SpO2 = peripheral capillary oxygen saturation; SARS-CoV-2 = Severe Acute Respiratory 
Syndrome Coronavirus 2; tmax = time to Cmax; WHO = World Health Organization. 
Notes: 
General note: on days of laboratory assessments, discharged patients will have a home visit. On days of no laboratory assessments, discharged patients will complete all 
assessments via telephone or telemedicine visits. 
a 
Patients will undergo assessment during hospitalization or could be discharged after start of study treatment any time after Day 2 if judged to be ready for discharge. If 
discharged, patients will then be requested to take study treatment at home (as prescribed) up to Day 14. End of Treatment assessments at Day 14 (+2 days) (at home or site 
visit) will be performed. A Day 5 visit (at home or site visit) will be performed if the patient is discharged prior to Day 5. If the patient is discharged after completion of 
treatment and before the follow up visit, he/she will be followed up on Day 28 (±2 days) for study assessments (a telephone or telemedicine visit). Post discharge, assessments 
will be done by telephone or via telemedicine or other means of remote communication, except for Day 5, Day 14 (+2 days), and Early Termination of Study Treatment, 
which would be a home visit. 
b 
Initial sentinel cohort of 20 patients to be enrolled to assess safety, tolerability, efficacy, and PK. Enrollment will pause after the 20th patient in the sentinel cohort has started 
treatment, until the results of the interim analysis are known. Once the 20th patient in the sentinel cohort has completed 14 days of treatment, an unblinded DMC will assess 
the safety, tolerability, efficacy, and PK of 100 mg BID antroquinonol in COVID-19 patients in the sentinel cohort (interim analysis 1). The DMC will issue a 
recommendation to enroll patients for the expansion cohort, or to stop the study depending on the safety and futility assessment. Once the 80th patient has been enrolled and 
completed 14 days of treatment, the DMC will review the safety, tolerability and efficacy data (interim analysis 2). Enrollment may be restricted at the 100th patient until the 
DMC has completed the assessment to prevent excessive enrollment. 
c 
Patients must satisfy all of the criteria at the screening visit unless otherwise stated (e.g. some criteria can be evaluated at Day 1 if needed). 
d 
Daily study treatment administration from Day 1 to Day 14. 
e 
A complete physical examination (general appearance, HEENT, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, and dermatological 
systems) will be performed at screening. Vital signs (respiratory rate, temperature, blood pressure, and pulse rate) to be assessed during hospitalization, on discharge, ET/EOT 
and Follow-up/EOS visit (for site or in-person visits only). Pulse oximetry to measure SpO2 (>94% on room air) will be collected in the eCRF during the study if done per 
standard of care. Height and body weight will be measured only at screening.  
f 
Chest x-ray or CT scan should show findings consistent with pneumonia due to COVID-19 and will be performed at Screening and either at hospital discharge, at ET of Study 
Treatment, or at ET of Study, whichever comes first (Note: only 1 scan must be done for hospital discharge, ET of Study Treatment, or ET of Study).  Chest x-ray or CT scan 
does not need to be repeated at screening if performed as standard of care and done within 48 hours of diagnosis. Chest x-ray or CT scan is not required post discharge. 
g 
Serum pregnancy test is to be performed in female patients of child-bearing potential at a local (site) laboratory, during screening or pretreatment Day 1, discharge, and 
ET/EOT. Urine pregnancy test may be performed but must be confirmed with a serum pregnancy test (screening only). The Follow-up/EOS visit test will be a urine 
pregnancy test only (pregnancy test kit will be provided to the patient when discharged). Additionally, local/country regulations will be followed as applicable (eg., monthly 
pregnancy test after the last dose of study treatment in female subjects of childbearing potential). 
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h 
Efficacy parameter assessments: [1] Confirmation of whether the patient is discharged to home, is in the hospital, or has worsened to require an ICU. The number of days a 
patient has been hospitalized prior to study entry will be recorded in the eCRF. [2] PCR testing for SARS-CoV-2 will be performed by a local or central laboratory at 
screening. Results of confirmatory COVID-19 test already done as standard of care can be used to determine eligibility. All subsequent tests will be performed by a central 
laboratory at baseline/Day 1, Day 5 and Day 14. Also at Follow-up/EOS if patient is hospitalized. Either nasopharyngeal or mid-turbinate samples are allowed for central 
testing. Only one method should be used throughout the study for the participant. [3] Clinical improvement score will be measured using the WHO COVID-19 Clinical 
Improvement Ordinal Scale (refer to Appendix 7 of the protocol). [4] Patient mortality will be recorded up to Day 28. Every effort will be made to ascertain vital status in all 
randomized patients (e.g., with a vital records search) up to Day 28. [5] Respiratory failure is considered as patient need for invasive mechanical ventilation, non-invasive 
ventilation, high-flow oxygen, or ECMO. The date of the start of the respiratory intervention must be recorded in the eCRF; no daily assessment is needed. [6] COVID-19 
symptoms (presence or absence of dry cough, dyspnea (shortness of breath/ difficulty in breathing), or chills/rigors, myalgia (muscle pain), headache, sore throat, and loss of 
taste or smell; other symptoms that could be related to COVID-19) will also be assessed during hospitalization, on discharge, ET/EOT and Follow-up/EOS visit (at the site, 
home visit, or via telephone or telemedicine if patient has been discharged). 
i 
Safety parameter assessments: [1] AEs will be assessed from signing the ICF (during hospitalization and post discharge at home) daily to Day 5, then Days 7, 14 (+2 days), 
28 (±2 days) until Follow-up/EOS; [2] Standard safety laboratory tests will include all parameters of hematology, clinical chemistry, and urinalysis (refer to Appendix 2 of the 
protocol) and will be performed as applicable at Screening, at predose on Day 1, Day 5, and Day 14 (+2 days) (a home visit, or a site visit if discharged). Screening laboratory 
tests will be assessed by a local laboratory, and baseline and postbaseline laboratory tests will be assessed by a central laboratory. Baseline laboratory tests can be done once 
patients eligibility is confirmed. [3] 12-lead ECGs to be performed at screening while the patient is in supine position and at rest for at least 5 minutes. Additionally, 12-lead 
ECGs will be performed at Day 14/EOT or early treatment termination while the patient is hospitalized or at the time of discharge if the patient is discharged prior to Day 14. 
[4] Prior and concomitant medications to be recorded from screening assessments daily to Day 5, then Days 7, 14 (+2 days), 28 (± 2 days). 
j 
Blood samples for determination of antroquinonol plasma concentrations will be collected for patients in the sentinel cohort (first 20 patients) only on Day 3 at predose and 1, 
2, 3, 4, 6, 8, and 12-hours postdose for hospitalized patients only. Samples are collected after the first study drug dose of the day.  For discharged patients (ie, on 
Day 2)/outpatient visit, the 12-hour sample can be omitted. On Day 14, if patients are still hospitalized, predose and 2 hours postdose samples (after the first study drug dose 
of the day) will be collected. Patients who are discharged from the hospital on Day 2 prior to PK sampling will not need to return to the clinic for sample collection. 
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