A Randomized, Double-Blind, Placebo-Control Pilot Trial of Xuanfei Baidu Granules (XFBD), a Traditional Chinese Medicine (TCM), in Persons With COVID-19
Phase: PHASE2
Conditions: Covid19
Sponsor: Darcy Spicer

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A Randomized, Double-Blind, Placebo-Control Pilot Trial of Xuanfei Baidu Granules (XFBD), a 
Traditional Chinese Medicine (TCM), in Persons with COVID-19 
 
Short name: XFBD001 
 
Protocol Version 1.2 
 
Protocol Date: 06/22/2021 
 
 
University of Southern California 
 
 
 
Protocol Chairs: 
 
Peter Kuhn, PhD (Medicine, Biological Sciences and Engineering) 
 
Anne Hamilton, PhD (Preventive Medicine) 
 
Darcy Spicer, MD (Medicine) Medical Monitor 
 
Anna Wu, PhD (Preventive Medicine) 
 
 
Pharmacist: 
 
 
Elizabeth Qi, PharmD  
 
Biostatistician: 
 
 
Cheryl Vigen, PhD. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
AE 
adverse event 
ARDS 
acute respiratory distress syndrome  
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments  
COPD 
Chronic obstructive pulmonary disease  
COVID-19 
Coronavirus Disease 2019 
CVD 
cardiovascular disease 
DRESS 
drug reaction with eosinophilia and systemic symptoms  
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
EKG 
electrocardiogram 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HTN 
hypertension 
ICU 
Intensive care unit 
ICF 
informed consent form 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
intravenous 
MERS 
Middle East Respiratory Syndrome 
NIAID 
National Institute of Allergy and Infectious Diseases  
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections  
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2  
Severe Acute Respiratory Syndrome coronavirus 2  
TCM 
Traditional Chinese Medicine 
XFBD 
Xuanfei Baidu Granules 
WHO 
World Health Organization 
  
 
 

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SCHEMA 
 
 
XFBD001 
 
A Randomized Double-Blind Placebo-Control Pilot Trial of Xuanfei Baidu Granules (XFBD), a Traditional 
Chinese Medicine (TCM), in Persons with COVID-19 
 
 
DESIGN 
 
 
Pilot 
This is a randomized double-blind placebo-control pilot trial to document safety and 
efficacy endpoint assessments and to determine the feasibility of community recruitment 
and enrollment of symptomatic adult outpatients with COVID-19.   
 
 
 
DURATION 
12 weeks. Treatment will be for 14 days with 10 weeks of follow-up. 
 
 
SAMPLE SIZE 
 
 
Pilot 
60 patients who start study treatment; approximately 30 participants in each of the two 
treatment arms (A and B). Participants who are randomized and who do not start study 
treatment will be replaced 
 
POPULATION 
Symptomatic, outpatient, adults (≥18 years) with SARS-CoV-2 infection 
 
STRATIFICATION 
Stratification will be by “high” versus “low” risk of progression to severe COVID-19 
disease, where “high risk” is defined as a person age ≥60 years or having one of several 
specified comorbidities. 
 
REGIMEN  
Participants will be randomized 1:1 individuals. Participants will receive either XFBD (10 
g orally twice a day) for 14 days (Arm A) or a placebo twice a day for 14 days (Arm B).    
 
 

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1. HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1. Hypothesis 
 
1.1.1. 
Xuanfei Baidiu granules (XFBD) will prevent hospitalization and death in persons with 
symptomatic SARS-CoV-2 infection. 
 
1.2. Primary Objective 
:  
1.2.1. 
To document the feasibility of recruitment through community setting by assessment of the 
number of positive cases identified per week. 
 
1.2.2. 
To document the proportion of patients who agree to participate as measured by enrollment and 
randomization. 
 
1.2.3. 
To document the treatment emergent side effects and safety profile of the XFBD and placebo.  
 
1.2.4. 
To document the rate of hospitalization or death within 42 days of enrollment in the XFBD and 
placebo treated groups. 
 
 
1.3. Secondary Objectives 
 
1.3.1. 
To document the effect of XFBD on Symptom Severity Score within 28 days of enrollment in the 
XFBD and placebo treatment. 
 
1.3.2. 
To document the proportion of patients who are compliant taking greater than 90% of the test 
substance as measured by self-report  
 
1.3.3. 
To document the proportion of patients who comply with symptom monitoring. 
 
1.3.4. 
To document the proportion of patients who comply with repeated clinical testing. 
 
1.3.5. 
To document the hospital-free days from enrollment to 42 days (number of days patient not in 
hospital). 
 
1.3.6. 
To document cumulative incidence of serious adverse events, and adverse events leading to 
early discontinuation of XFBD or placebo. 
 
1.3.7. 
To document cumulative incidence of grade 3 and 4 adverse events. 
 
1.3.8. 
To obtain levels (detectable versus not detectable, and continuous on log10 scale) of SARS-CoV-
2 RNA from nasal swabs at approximately days 1, 7 and 14 among a subset. 
 
 
1.4. Exploratory Objectives 
 
1.4.1. 
To document the rate of subjects tested as negative for SARS-CoV-2 at day 14. 
 
1.4.2. 
To document the rate of housemate infection. 
 
1.4.3. 
To document if XFBD changed the severity and duration of self-reported symptom experience of 
COVID-19.  
 
 
 
 
 

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Figure 2.1: Timeline of 
COVID Disease Progression 
after Hospitalization. 
Onset refers to onset of 
symptoms. 
 
2. INTRODUCTION 
 
2.1. Background Threat 
A novel pneumonia caused by a previously unknown betacoronavirus emerged in Wuhan, China, in 
December 2019. The virus is closely related to the severe acute respiratory syndrome coronavirus (SARS 
CoV), which led to an outbreak in 2003 causing the disease SARS, and has been named SARS-CoV-2. 
The human disease caused by SARS-CoV-2 is called COVID-19. 
During the current SARS-CoV-2 outbreak, the incidence of known cases has rapidly increased such that, 
on January 5, 2020, there were 59 confirmed cases, 278 cases on January 20, 2118 cases on January 
26, and more than 80,000 cases and 2700 deaths by February 25, 2020, according to various international 
health reporting agencies. As a result, on January 30, 2020, the International Health Regulations 
Emergency Committee of the World Health Organization (WHO) declared the COVID-19 outbreak a 
Public Health Emergency of International Concern. On January 31, 2020, the US Department of Health 
and Human Services declared a public health emergency in the United States. As of July 14, 2020, there 
are more than 13 million cases of COVID-19 globally, including over 3.3 million cases in the United States 
(US), resulting in a total of over 574,000 deaths globally, with over 136,000 deaths in the US. Despite 
quarantine measures, SARS-CoV-2 continues to spread (1). Outbreak forecasting and modeling suggest 
that these numbers will continue to rise (2). 
 
Global efforts to evaluate novel antivirals and therapeutic interventions to treat COVID-19 have intensified. 
There is currently no approved  therapeutic agent to treat COVID-19 effectively. Therefore, there is an 
urgent public health need for the rapid development of novel interventions. 
Virology 
Coronaviruses (CoVs) are positive-sense, single stranded, enveloped RNA viruses, many of which are 
commonly found in humans and cause mild symptoms. Over the past two decades, emerging pathogenic 
CoVs capable of causing life-threatening disease in humans and animals have been identified, namely, 
SARS-CoV-1 in 2002-2003 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. 
Disease Course 
Once infection occurs, the clinical course is variable. Best current data suggests that fewer than 2.5% of 
infected persons will show symptoms within 2.2 days (CI, 1.8 to 2.9 days) of exposure, and symptom 
onset will occur within 11.5 days (CI, 8.2 to 15.6 days) for 97.5% of infected persons” (3) In most (~80%) 
cases, COVID-19 presents as a mild-to-moderately severe, self-limited acute respiratory illness with fever, 
cough, and shortness of breath. It remains unclear exactly what the rate of progression of COVID-19 is 
and what the predictors are for complications, including pneumonia, acute respiratory distress syndrome 
(ARDS), kidney failure, and death. It is also clear that older age, male sex, and comorbidities, including 
diabetes and hypertension, increase the risk for worse outcomes (Figure 2.1-1) (4-6). In a recent meta-
analysis, the main clinical symptoms were fever (88.5%), cough (68.6%), myalgia or fatigue (35.8%), 
expectoration (28.2%), and dyspnea (21.9%). Minor symptoms included headache or dizziness (12.1%), 
diarrhea (4.8%), and nausea and vomiting (3.9%). Laboratory examinations showed that lymphocytopenia 
(64.5%), increase of C-reactive protein (CRP) (44.3%), increase of lactate dehydrogenase (LDH) (28.3%), 
and leukocytopenia (29.4%) were more common in those with COVID-19 (7). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shedding 

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Viral infections jump from host to host through a variety of pathways. CoVs do this through respiratory 
droplets. Understanding this shedding is important to understanding epidemic spread and how shedding 
relates to disease progression. The best evidence available now suggests that viral shedding, especially 
in upper respiratory secretions, is detectable around 2 days before symptoms develop in people and 
continues throughout the symptomatic phase. This shedding can be quite high during active disease and 
can continue for up to 37 days, with a quarter of persons still shedding at 3 weeks, as detected by 
nasopharyngeal swabs (4). 
 
Biomedical Interventions 
There are no approved treatments for COVID-19. Some agents have shown activity against other 
betacoronaviruses, such as lopinavir/ritonavir, chlorpromazine, nitazoxanide, gemcitabine, and dasatinib 
(9), and two agents have shown in vitro activity against the virus, including chloroquine and the adenosine 
analog remdesivir (10). There is no clinically proven antiviral treatment for SARS-CoV-2 infection, 
although a clinical trial of remdesivir (11) is underway in China and the US for severe pulmonary disease 
(12), and anecdotal evidence has been published about Hydroxychloroquine and Azithro (13). 
 
TCM Interventions 
From February 16th to 24th, the Huazhong University of Science and Technology team completed 9 
autopsies of patients treated with non-invasive ventilation and died from COVID-19. The preprints are 
available. (14) 
 
The autopsy reports showed that a gray-white viscous liquid appeared in the lung tissue samples, a white 
foamy mucus was found in the trachea, and a sticky jelly-like mucus was found in the bronchi of the right 
lung as well as significant and severe fibrinoid exudate in alveolar spaces. The authors suggest that 
COVID-19 pneumonia mainly results from inflammatory reactions characterized by deep airway and 
alveolar damage.  
 
With this thick mucus occupying the alveoli, bronchi and pulmonary interstitium, respiratory function is 
significantly reduced. As a result, the patient’s blood oxygen saturation can be reduced to 80% or lower. 
In comparison to the 95% and above oxygen saturation of healthy individuals, the patient is considered 
hypoxic.  
 
Patients with hypoxia can be put on oxygen therapy to improve their oxygen saturation. However, if the 
patient’s lungs are unable to complete the oxygen exchange, no amount of concentrated oxygen will 
improve their blood oxygen saturation. Unlike SARS patients with hyaline membranes in the alveoli, 
COVID-19 patients had mucous plugs in all the respiratory tracts, terminal bronchioles, and pulmonary 
alveoli. These mucus plugs in the distal respiratory tracts seemed to have played a part in the failure of 
sputum suction by bronchoscopy. (15) 
 
After the autopsies, nearly 10,000 patients in fangcang (mobile cabin) hospitals specifically built for the 
COVID-19 outbreaks utilized traditional Chinese medicine with a coverage of 95% of all fangcang patients.  
 
According to Chinese national statistics, 91.5% of confirmed diagnosed patients (74,187) were prescribed 
TCM. There were those who refused or were found unsuitable to use TCM. Hubei province alone 
accounted for 61,449 (90.6%) of patients who utilized TCM. Clinical observation showed that 90% of mild 
and moderate cases were successfully relieved of their symptoms and/or prevented progression into 
severe and critical condition. (16) 
 
Currently, in Wuhan, the hospitalized patients with COVID-19 went from 60,000 two months ago to 
approximately 5000, and patients with severe illness decreased from 12,000 to approximately 1800. They 
had a period of 5 days without any increased new cases, critical cases, or deaths. (17) 
 
TCM Background 
Traditional Chinese medicine (TCM) takes a holistic approach in treating disease and categorizes health 
disorders from both its origin and the resulting symptoms. The origin of an illness can be from either cold 
or heat; the resulting symptoms can be cold-based (i.e. shivering, watery diarrhea, edema, cough with 
profuse, thin, and clear phlegm, etc.) or heat-based (i.e. fever, dry cough, sore throat, cough with thick, 
yellow phlegm, dysentery, etc.) The basis of treatment is to eliminate the original cause while treating the 
resulting symptoms concurrently. 

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Given the autopsy results and clinical presentation, in TCM theory, SARS-CoV-2 is seen as thriving in 
cold and damp weather while the disease COVID-19 consists of mostly warm-heat symptoms (i.e. fever, 
dry cough, heat induced cough with yellow phlegm). The TCM medicinals used in the treatment of COVID-
19 mainly consist of heat-clearing and toxin-removing medicinals to reduce fever and clear away bacteria 
and viruses; cough-suppressing and phlegm-transforming medicinals to thin the phlegm so it is easier to 
expectorate; and lung-diffusing and pant-calming to soothe the tracheal smooth muscle and relieve 
symptoms of dyspnea.  
 
The prescriptions for the prevention and treatment of COVID-19 were selected Shang Han Lun, or 
Treatise on Cold Damage Disorders, dated to the end of the Han Dynasty (220 AD). (18) In this treatise, 
all the diseases originate from cold, but the symptoms could either be cold-based or heat-based. This 
ancient treatise is a well-known reference for traditional Chinese medicine practitioners. Some of the 
botanical medicinals in the chosen prescriptions have also been isolated and developed into conventional 
medicine. (19) 
 
For example, ephedrine can be isolated and extracted from ephedrae herba (麻黄 mahuang). Ephedrine 
is a stimulant that excites the sympathetic nervous system, constricting blood vessels to act as a pressor 
and bronchodilator. In traditional Chinese medicine, the function of ephedrae herba is recognized similarly 
and is mostly used to treat bronchial asthma and prevent asthma attacks. (20-22) 
 
Another example is Glycyrrhizae radix et rhizoma (甘草 gancao), also known as Chinese liquorice, which 
is a medicinal and can also be used as a sweetener in food products. The medicinal function includes 
clearing heat (including the reduction of fever), removing toxins (anti-infection, anti-infective), loosening 
and transforming phlegm to eliminate, suppressing cough, easing tension, and relieving pain. This 
medicinal is used in the treatment of sore throat, oral mucosa ulcers, cough, palpitations, and pain.  
 
Generally, the design of a TCM prescription takes into account the source of the illness, the resulting 
symptoms, the external environment, and the personal constitution of the patient. In the following 
delineation, this document focuses on the aspects of a broad application TCM in which the prescription is 
balanced to be less dependent on environmental and individual factors for general application. 
 
Potential Risks of XFBD  
XFBD contains ephedra herba, which has levels of ephedrine and pseudoephedrine. Both are known 
sympathomimetic agents, which can cause an increase in blood pressure and heart rate. The level of 
ephedrine and pseudoephedrine in each packet is at most 15mg or 30mg per day. In some over-the-
counter (OTC) medication, the daily dose of pseudoephedrine can exceed 300 mg, which is 10 times the 
daily dosage of ephedrine and pseudoephedrine in XFBD. 
 
XFBD also contains armeniacae semen amarum with levels of amygdalin, or laetrile. In TCM prescription 
theory and analysis, the levels of amygdalin are lower in the XFBD combination than in the plant 
armeniacae semen amarum alone. The level of armeniacae semen amarum in each packet is at most 
80mg per day. Various studies have shown that 80mg is well below the level of toxicities manifesting. 
 
Assessment of Potential Risks and Benefits 
There is human clinical data on the XFBD prescription in Wuhan, China, with over 280 patients in clinical 
trials and approximately 6,000 patients in clinical care. In Wuhan, China, they saw a 50% reduction in 
progression of disease for patients with mild or moderate COVID-19 disease. (personal correspondence 
with Dr. Zhang Bo Li, dated Mar 31, 2020) The small risk with the use of the granules, including 30 mg of 
ephedrine per day, is amply outweighed by the potential for reducing serious consequences COVID-19 
progression.  
 
2.2. Rationale 
 
At present, there is no specific antiviral therapy for COVID-19. Few treatment studies have been 
conducted because most human CoV strains cause self-limited disease, and care is supportive. After 
SARS-CoV-1 was identified in 2002-2003 and caused a large global outbreak, there was an increased 
interest in the development of specific therapeutic agents. SARS-CoV-1 patients were treated with 
corticosteroids, type 1 IFN agents, convalescent plasma, ribavirin, and lopinavir or ritonavir; except for 

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ribavirin, many of these agents have in vitro pre-clinical data that support their efficacy (42-57). 
 
Given the lack of specific antiviral therapy for SARS-CoV-2 infection, and the known XFBD formulation, 
based on pre-clinical and small clinical studies, this randomized, placebo-controlled trial will evaluate the 
efficacy and safety of XFBD formulation in persons who have active SARS-CoV-2 infection and mild to 
moderate COVID-19 symptoms. 
 
Why XFBD for COVID-19? 
Xuanfei Baidu granules (XFBD) were developed by Dr. Zhang Boli, a member of the Chinese Academy 
of Engineering, and his team. They used this on the frontline in Hubei, Wuhan, under the direction of Dr. 
Zhang Boli and Dr. Liu Qingquan, Director of the Capital Medical University Beijing Hospital of Traditional 
Chinese Medicine.  
 
Expert Recommendation on Usage: Suitable for mild, moderate, and severe cases. For critical cases, at 
doctor’s discretion, based on the patient’s condition.  
 
Typically, in China, TCM prescriptions need to be boiled into a decoction and taken orally. For 
convenience, this TCM medicinal for COVID-19 control has been manufactured as a drink mix at the  
Tianjin Tasly Pharmaceutical Co., LTD ( https://www.tasly.com), a well-established and leading TCM 
research and manufacture center to integrate technology and innovation to update the practice of TCM for 
human health.  
 
The granules are already packaged into 10g packet per dose, 2 packets per day. These TCM packets 
have passed quality control tests for potency and standardization. To be taken in the morning and evening 
mixed into hot water to be taken 1 hour after a meal and 1 hour before or after conventional medicines: 
 
Chinese 
Latin 
Amount (g) of 
crude medicinal 
for 1000g of final 
XFBD product 
Source 
麻黄 (A,B) 
Ephedrae Herba 
150 
Ephedra sinica Stapf 
苦杏仁 (A,B) 
Armeniacae Semen Amarum 
375 
Prunus sibirica L.  
生石膏 (A,B) 
Gypsum Fibrosum 
750 
CaSO4·2H2O 
薏苡仁 (B,C) 
Coicis Semen 
750 
Coix Lacryma-jobi L.yar.mayuen 
苍术 (G) 
Atractylodis Rhizoma 
250 
Atractylodes chinensis (DC.) 
Koidz. 
广藿香 (G) 
Pogostemonis Herba 
375 
Pogostemon cabLin (Blanco) 
Benth. 
青蒿 (H) 
Artemisiae Annuae Herba 
300 
Artemisia annua L.  
马鞭草 (E) 
Verbenae Herba 
500 
Verbena Officinalis L.  
虎杖 (F) 
Polygoni Cuspidati Rhizoma 
et Radix 
750 
Polygonum cuspidatum Sieb.et 
Zucc. 
芦根 (C) 
Phragmitis Rhizoma 
750 
Phragmites communis Trin. 
葶苈子 (D) 
Descurainiae Semen  
375 
Descurainia sophia (L.) Webb. ex 
Prantl. 
化橘红 (H) 
Citri Grandis Exocarpium 
375 
Citrus grandis (L.) Osbeck 
甘草 (A,B) 
Glycyrrhizae Radix et 
Rhizoma 
250 
Glycyrrhiza uralensis Fisch. 
 
This prescription was derived from four previous prescriptions that have been in routine use in TCM over 
centuries and have been shown to be safe.  
  
 
A. 麻杏石甘汤 Maxing Shigan Tang (麻黄 Ephedrae Herba, 苦杏仁 Armeniacae Semen Amarum, 石
膏 Gypsum Fibrosum, 甘草 Glycyrrhizae Radix et Rhizoma) is a traditional preparation recorded 
from Shang Han Lun used to diffuse the lungs, calm panting, and clear heat. (23) The traditional 

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idea is cough and shortness of breath come from the lungs being congested or “unable to allow 
normal qi movement of the lungs.” (24) The ephedrae herba and gypsum fribrosum are a known 
pair to reduce fever and diffuse the lungs. (25) Ephedrae herba has been banned by the FDA in 
dietary supplements; however, the usage in TCM has not been restricted. (26) The concern 
stemmed from the various overdoses of epinephrine found in the plant Ephedra sinica Stapf in 
which the dried aerial parts are used in TCM. It has been found that the amounts of epinephrine 
and norepinephrine detected in the decoction of maxing shigan tang was much lower than in 
ephedrae herba alone. (27) Another common concern is the amount of amygdalin present in 
armeniacae semen amarum as it can be toxic in large amounts. There are a couple of studies 
showing that the concurrent usage of gypsum fibrosum and glycyrrhizae radix et rhizoma can 
decrease the amount of amygdalin content found in the prescription. (28-29) The studies showed 
that by combining the use of gypsum fibrosum and glycyrrhizae radix et rhizoma, the total levels 
of amygdalin are, in fact, lower than the levels if armeniacae semen amarum were used alone. 
These reports support the theory of TCM prescribing which uses specific combinations of 
medicinals to decrease toxicity and enhance efficacy. Rather than having direct bearing on 
acceptable amygdalin levels, these reports are intended to reinforce the efforts to mitigate toxicities 
and to show that the toxicity of using armeniacae semen amarum on its own is higher than that 
used in combination. 
 
B. 麻杏薏甘汤 Maxing Yigan Tang (麻黄 Ephedrae Herba, 苦杏仁 Armeniacae Semen Amarum, 薏
仁 Coicis Semen, 甘草 Glycyrrhizae Radix et Rhizoma) is a variation of the prescription above with 
coicis semen instead of gypsum fibrosum. Coicis semen, also colloquially known as Job’s tears, is 
used to disinhibit water and drain dampness (such as reducing edema), strengthen the spleen and 
stop loose stools, and resolve toxins and dissipate congestion. This medicinal is also a common 
food item in cereals, teas, and even distilled liquors.   
 
C. 千金苇金汤 Qianjin Weijing Tang (芦根 Phragmitis Rhizoma, 薏仁 Coicis Semen, etc.) is a 
prescription used to transforms phlegm and clears the lungs. This prescription has been used in 
randomized controlled trials on its own or in combination with other prescriptions for the treatment 
of bronchiectasis, asthma, and community-acquired pneumonia. (30-31) 
  
D. 葶苈大枣泻肺汤 Tinglidaozao Xiefei Tang (葶苈子 Descurainiae Semen / Lepidii Semen, etc.) is a 
prescription used to drain the lungs, reduce inflammation, disinhibit water, and calm panting. 
Descurainiae Semen / Lepidii Semen is commonly used in combination with glycyrrhizae radix et 
rhizoma and armeniacae semen amarum to treat symptoms of cough and shortness of breath. 
(32) This prescription, combined with maxing shigan tang as described above, also showed 
positive results in a small randomized controlled trial for elderly patients with community-acquired 
pneumonia. (33)  
 
Other consideration to developing the prescription, additional medicinals: 
E. Antibacterial and Antiviral Activity: 马鞭草 Verbenae Herba contains compounds that have shown 
to be inhibitory towards bacteria (such as gram-negative E.coli and gram-positive Staphylococcus 
aureus) and viruses such as hepatitis B virus (HBV). (34) This medicinal has a low toxicity profile 
but should not be used in pregnant patients. (35-36) 
F. Microvascular Thrombosis: From the autopsy, patients had significant micro-clotting, or 
microvascular thrombosis. 虎杖 Polygoni cuspidti rhizoma et radix can help clear heat (such as 
reduce fever), suppress cough, transform phlegm, and dissipate stasis (such as dissolving blood 
clots). [personal correspondence with Dr. Zhang Bo Li dated March 31, 2020] Verbenae herba 
also has blood quickening and stasis dissipating actions that could help break up the micro-clots 
without having a full anticoagulating effect. (34) 
G. Gastrointestinal: Both 藿香 Pogostemonis Herba and 苍术 Atractylodis Rhizoma help with 
gastrointestinal discomfort. Pogostemonis herba harmonizes the stomach (such as helping 
nausea, bloating, gastroprotective effects, etc.) and disperses damp. (37-38)  

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H. Transforming Phlegm: 化橘红 Citri grandis exocarpium can help the phlegm to resolve mucus 
plugs in the lungs. (39) This is dried pomelo peel, which can be found in foods such as teas and 
candies.  
I. Clearing heat: 青蒿 Artemisiae Annuae Herba is better known as the source of artemisinin used 
for malaria. In TCM, artemisiae annuae herba is described mainly as an antimalarial agent but also 
a heat-clearing agent. The component artemisinin has varying degrees of anti-inflammatory and 
antiviral effects for DNA and RNA viruses. (40) It may also help regulate the immune system, such 
as reducing the release of proinflammatory cytokines. (41) 
 
Wuhan Experience: Wuhan Jiangxia Fangcang Hospital used TCM prescriptions and other traditional 
methods (such as acupuncture, guasha, medicinal patches, etc.) in the treatment of COVID-19 while 
continuing the patient’s previous conventional medicines for underlying health conditions. From February 
14th to March 10th, the hospital treated a total of 564 patients with mild (71%) and moderate (29%) 
COVID-19. Upon hospitalization, approximately 30% of the patients had symptoms of fatigue and 
shortness of breath, while another approximately 40% had cough. Within the 14-day treatment and 
subsequent observation period, 482 patients recovered and were discharged. Among the patients 
admitted, none of their conditions progressed to severe or critical. It is of note that at Wuhan Jiangxia 
Fangcang Hospital, two main prescriptions with the addition of other TCM treatment modalities were used. 
The medical staff was also free of infection [personal correspondence with Dr. Zhang Bo Li dated March 
31, 2020] 
 
For the Xuanfei Baidu prescription, which was given to 273 patients, none of them progressed to severe 
or critical condition. 250 patients achieved two consecutive negative viral RNA tests in which the average 
time frame was about 11.02±3.59 days, with a 95% confidence interval (CI). 230 patients saw a significant 
improvement in their CT scans in about 13.13±4.20 days with a CI 95%. [personal correspondence with 
Dr. Zhang Junhua, dated April 28, 2020] 
 
At another fangcang hospital which had 330 patients, TCM was not used or if used, in an unstandardized 
manner, and 32 patients (9.7%) of those patients progressed to severe or critical condition. Other 
fangcang hospitals that utilized TCM prescriptions also saw a decrease in patients' progression of disease 
to approximately 2-5%. [personal correspondence with Dr. Zhang Bo Li dated March 31, 2020] 
 
Summary: Today, in China, mild and moderate cases are mainly treated with comprehensive TCM. The 
rate of mild or moderate cases progressing to severe was significantly reduced. Before the widespread 
usage of TCM, nationwide China saw a progression of disease of about 10% of their mild/moderate cases 
while after TCM utilization, the percentage dropped to 2-5% depending on the hospital. Overall, they saw 
an improvement in clinical symptoms. [see personal correspondence with Dr. Zhang Bo Li dated March 
31, 2020]. Due to the challenges of the rapidly evolving outbreak, these are clinical observations and not 
evidence from a controlled study.  
 
Preclinical Studies of XFBD 
Tianjin University of Traditional Chinese Medicine conducted an acute toxicity study for XFBD in mice at 
the concentrations of 91.39 g/kg, 114.24 g/kg, and 142.8 g/kg by single gavage followed by a 14-day 
observation. The data showed that mice given 142.8 g/kg appeared to be in prone positions with 
movement reduction, which resolved within 4 hours. The female mice in 142.8 g/kg group had soft or 
loose stools, but the mice recovered on the 4th day. No significant differences were found in the body 
weight between mice in the administration group and control group when measured on the 1st, 3rd, 7th, 
and 14th day after administration. No deaths were observed in the 14 days. After gross anatomical 
observation, there were no apparent abnormalities found in mice from either group. Therefore, we 
conclude that the maximum tolerated dose of XFBD given by single gavage in mice should be more than 
142.8 g /kg (equivalent to 84 times of the clinical dosage). [personal correspondence with Dr. Zhang 
Junhua, dated Apr 28, 2020] 
 
Long term toxicity studies are ongoing and will be updated as data becomes available.  
 
While all medicinals in the XFBD are widely used and within the appropriate dosing range, formal toxicity 
studies have not been conducted. Symptom comparisons and toxicities will be one part of both the pilot 
and the complete trial.  

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XFBD Availability  
This prescription is traditionally decocted in a pot from crude medicinals. However, it is now being 
manufactured with quality control mechanisms in place to make RCTs feasible. This TCM medicinal for 
COVID-19 control has been manufactured as a drink mix at the Tianjin Tasly Pharmaceutical Co., LTD 
(https://www.tasly.com). Tianjin Tasly Pharmaceutical Co., LTD, is a well-established and leading TCM 
research and manufacture center to integrate technology and innovation to update the practice of TCM 
for human health. XFBD is currently being manufactured for clinical use. XFBD had been used in clinical 
trials of over 280 patients and is being used in clinical care for approximately 6,000 patients. [personal 
correspondence with Dr. Zhang Junhua, dated Apr 28, 2020] 
 
Mitigation of Risk from XFBD  
XFBD contains ephedrae herba with levels of ephedrine and pseudoephedrine. In TCM prescription 
theory and analysis, ephedrine and pseudoephedrine levels are lower in the XFBD combination than in 
the ephedrae herba plant alone. The ephedrine and pseudoephedrine levels in each packet is at most 
15mg or 30mg per day. In some over-the-counter (OTC) medication, the daily dose of pseudoephedrine 
can exceed 300 mg, which is 10 times the daily dosage of ephedrine and pseudoephedrine in XFBD. 
However, to mitigate the potential risk, patients with uncontrolled blood pressure and heart disease will 
be excluded. 
 
The ephedrine and pseudoephedrine levels in each packet is at most 30mg per day. (58) In some over-
the-counter (OTC) medication, the daily dose of pseudoephedrine can exceed 300 mg, which is 10 times 
the daily dosage of ephedrine and pseudoephedrine in XFBD. In one study, they found the mean lethal 
dose (LD50) of ephedra alkaloids, which would include ephedrine and pseudoephedrine, in mice to be 
610 mg/kg taken orally. There were no abnormal clinical symptoms observed in mice administered 289 
mg/kg ephedra alkaloids. (59)  
 
Amygdalin (AMG), or laetrile, contained in XFBD averages to be 36.7-39.3 mg, or less than 40 mg, per 
packet. (60) Taken twice a day, the total daily dose is around 80 mg. In the 2015 Chinese Pharmacopeia, 
the accepted amount of armeniacae semen amarum is 5-10 g per day in which amygdalin levels cannot 
be above 24 mg/g. Amygdalin levels for armeniacae semen amarum are tested for before the medicinal 
can be sold on the market. (Appendix 3) Therefore, the acceptable limit of amygdalin is 120-240 mg per 
day. XFBD contains less than 80 mg of amygdalin per day. (Appendix 4)  
 
An in vivo study was conducted with rabbits being directly fed ground up apricot seeds as well as having 
an extract that was injected intramuscularly. The rabbits were taking 60 and 300 mg/kg of ground up 
apricot seeds, which is equivalent to 3.12 mg AMG/kg and 15.6 mg AMG/kg respectively, for 14 days. 
After 14 days, the researchers found no significant changes between the experimental groups, 60 and 
300 mg/kg of ground up apricot seeds, and control groups with no apricot seeds. All the biological marker 
changes were non-significant. (61) This would be equivalent to a 60kg adult taking 3.6 g or 18 g of AMG 
containing apricot seeds per day, which would be 187.2 mg and 936 mg of AMG respectively. Both doses 
are significantly higher than the daily amount in XFBD. 
 
In the Journal of Chinese Traditional Patent Medicine in 2003, Xiu et al. (62) found oral administration to 
have greater toxicity risks since intestinal microorganisms are the major converter of amygdalin to 
hydrocyanic acid. If humans ingest 4 g of amygdalin per day for half a month or receive injection 
intravenously for one month, common toxicities such as those to the digestive system as well as 
cardiovascular abnormalities will be observed. Reducing the daily dose to 0.6 to 1 g can prevent these 
toxicities. The 80 mg of amygdalin per day in XFBD fits within these parameters.  
 
Over the years, various cases of cyanide toxicity due to oral ingestion of AMG have been reported. Many 
of these cases were of people ingesting large amounts of apricot kernels or other amygdalin containing 
seeds all at one time. The people in these cases had typically ingested AMG containing seeds above the 
acceptable amount (i.e. 15 g of apricot kernels which is more than the 5-10g recommended dose from 
the Chinese Pharmacopeia). (63) 
 
In Wuhan, the TCM experts utilizing this prescription cited no adverse effects with patients with underlying 
conditions (such as diabetes, hypertension) or any adverse interactions with the patients’ long term 
conventional medicines. [personal correspondence with Dr. Zhang Bo Li dated March 31, 2020] However, 

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due to the nature of introducing any new medication, some experts cite potential concerns for those with 
congestive heart disease, cancer, end-stage liver failure as well as patients on dialysis. Patients with 
uncontrolled underlying conditions will be excluded.  
 
Justification for Dose 
Xuanfei Baidu prescription was developed from four old prescriptions: Maxing Shigan Tang, Maxing 
Yigan Tang, Qianjin Weijing Tang, and Tinglidaozao Xiefei Tang. Each of these has a long history of 
being used for clinical symptoms relevant to COVID-19. For example, since the Jin Dynasty, Maxing 
Shigan Tang has been documented to be used for persisting fever, cough, panting (shortness of breath), 
and chest pain. (63) In modern times, the same prescription is prescribed for bronchial asthma, acute 
and chronic bronchitis, and pneumonia. (68)  
 
As SARS-CoV-2 is a relatively new virus, there is limited peer reviewed literature on an appropriate dosing 
regimen beyond the clinical data obtained in Wuhan, China.  Of the 273 patients who received Xuanfei 
Baidu at Wuhan Jiangxia Fangcang Hospital for 2 to 3 weeks, 250 patients achieved two consecutive 
negative viral RNA tests in which the average time frame was about 11.02±3.59 days; and 230 patients 
showed a significant improvement in their CT scans in about 13.13±4.20 days. Based on these 
observations, Dr. Zhang Boli, a member of the Chinese Academy of Engineering who worked on the 
frontlines of Wuhan’s outbreak, determined the dosing regimen to be two weeks. [personal 
correspondence with Dr. Zhang Junhua, dated April 28, 2020] Currently, Dr. Zhang Boli and colleagues 
have difficulty repeating this trial because of the low number of COVID-19 cases in China.  
 
As this proposed trial is a no-contact community based clinical trial for an infectious disease, there will be 
substantial difficulties in monitoring systemic concentrations. The amount of ephedrine and 
pseudoephedrine is 30 mg per packet which is 60 mg per day. This dose is within the same boundaries 
as most over-the-counter pseudoephedrine medications. The 80 mg daily dose of amygdalin is also 
substantially lower than the dosage that manifest in toxicities. (63)  
 
The individual ingredient doses present in XFBD are within acceptable dosing range and report no toxicity 
under normal usage. (Chinese Pharmacopeia Vol 1, 2015). 
 
Justification for the Control Arm 
Considering the heterogeneity of disease progression in those with COVID-19, it is extremely important 
that this study include a control group. To this end, this trial will have a double-blind placebo control arm 
to best determine the efficacy and safety of XFBD in the outpatient setting for persons with COVID-19. 
 
Justification for Placebo Controlled Design 
There is public interest in several putative therapeutic agents for COVID-19. A well-powered placebo-
controlled trial will provide the best opportunity to recruit outpatients with COVID-19 and rigorously 
evaluate the safety and efficacy of this agent. 
 
Justification for Disease Severity Included 
In the recent experiences in China cited above, TCM was utilized among patients with mild to moderate 
Covid-19 and progression to severe disease diminished.  Demonstration that XFBD reduces the rate of 
such progression and the need for hospitalization in a randomized control trial ting as proposed here 
would be meaningful. This pilot trial is to demonstrate the feasibility of recruiting and enrolling patients 
with mild to moderate COVID-19.  The severity categorization is summarized in table 3. 
 
Table 3.  Baseline Severity Categorization 
 
Asymptomatic SARS-CoV-2 infection 
 
• 
Positive testing by standard RT-PCR assay 
 
• 
No symptoms 
Mild COVID-19 
 
• 
Positive testing by standard RT-PCR assay 
 
• 
Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, 
malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of 

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breath or dyspnea 
 
• 
No clinical signs indicative of Moderate, Severe, or Critical Severity 
Moderate COVID-19 
 
• 
Positive testing by standard RT-PCR assay 
 
• 
Symptoms of moderate illness with COVID-19, which could include any symptom of 
mild illness or shortness of breath with exertion 
 
• 
Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate 
≥ 20 breaths per minute, saturation of oxygen (SpO2) > 93% on room air at sea level, 
heart rate ≥ 90 beats per minute 
 
• 
No clinical signs indicative of Severe or Critical Illness Severity 
Severe COVID-19 
 
• 
Positive testing by standard RT-PCR assay 
 
• 
Symptoms suggestive of severe systemic illness with COVID-19, which could include 
any symptom of moderate illness or shortness of breath at rest, or respiratory distress 
 
• 
Clinical signs indicative of severe systemic illness with COVID-19, such as rate ≥ 30 
breaths per minute, heart rate ≥ 125 beats per minute, SpO2 ≤ 93% on room air at 
sea level or respiratory PaO2/FiO2 ratio < 300 
 
• 
No clinical signs indicative of for Critical Severity 
Critical COVID-19 
 
• 
Positive testing by standard RT-PCR assay 
 
• 
Evidence of critical illness, defined by at least one of the following: 
 
o 
Respiratory failure defined based on resource utilization requiring at least one 
of the following:  Endotracheal intubation and mechanical ventilation, oxygen 
delivered by high flow nasal cannula (heated, humidified, oxygen delivered via 
reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered 
oxygen ≥ 0.5), noninvasive positive pressure ventilation, Extracorporeal 
membrane oxygenation (ECMO, or clinical diagnosis of respiratory failure (i.e., 
clinical need for one of the preceding therapies, but preceding therapies not 
able to be administered in setting of resource limitation) 
 
o 
Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood 
pressure < 60 mm Hg or requiring vasopressors) 
 
o 
Multi-organ dysfunction/failure 
 
For this trial patients with SARS-CoV-2 infection (i.e., positive testing by standard RT-PCR assay) without 
symptoms will not be randomized unless they develop symptoms with 14 days of viral testing.  Patients 
with severe or worse Covid-19 will be excluded.   
 
Justification for Age Restriction 
Children and adolescents will not be included in this trial. Initial information about the epidemiology of 
COVID-19 indicates that the overwhelming burden of severe disease occurs among older adults, 
especially those with comorbidities. Given significant gaps in knowledge regarding SARS-CoV-2 infection 
in this population and a low incidence of severe morbidity/mortality in children, the risk/benefits do not 
warrant the inclusion of this population into this trial at this time.  
 
The elderly above the age of 75 are excluded in consideration of the higher possibility of multiple 
underlying conditions that may or may not be controlled at the time of infection. While the trials done in 
Wuhan saw no interaction with maintenance medications, the presence of multiple medications may have 
increased risk and complications that are not yet studied. Future trials will address this cohort of patients. 
 
Justification for Comorbidity Restrictions 
Individuals with multiple comorbidities have greater risks present, and there is no available data for 
patients with multiple comorbidities. Individuals with uncontrolled underlying conditions also present with 
more risk and complications. Without safety data available for these populations, these patients are to be 
excluded.  
 

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Justification for Vaccinated Individuals  
The phase 3 clinical trial data for both available messenger RNA (mRNA) vaccines showed efficacy in 
preventing severe symptomatic COVID-19 disease. The mRNA-1273 (Moderna) vaccine showed 94.1% 
efficacy at 14 days after the second dose (64) while the BNT162b2 (Pfizer) vaccine showed 95% efficacy 
at 7 days after the second dose. (65) Out of 36,659 California healthcare workers, 379 persons tested 
positive for SARS-COV-2 at least 1 day after vaccination, and 270 (71%) of those persons tested positive 
within the first 2 weeks of receiving the first dose. (66). There was no regular testing after the vaccination, 
therefore, it is safe to assume those who were reinfected experienced certain symptoms. In Los Angeles, 
about 62% have gotten their first dose and 53% have received both. (67)  With any level of probability for 
symptomatic reinfection, the vaccinated population are still eligible for XFBD.  
 
3. STUDY DESIGN 
 
The pilot phase is a double-blind, placebo-controlled randomized component designed to document safety 
and efficacy endpoint assessments and to determine the feasibility of recruitment and enrollment of 
symptomatic, community dwelling, adult, outpatients with COVID-19 as well as patient compliance with 
the protocol.   
 
The pilot phase will enroll a total of 60 participants (30 in each arm). Participants will be followed for 14 
days on treatment with an additional 10 weeks off treatment. Participants who do not start study treatment 
will be replaced. Participants will be randomized 1:1 as individuals. Participants will receive either XFBD 
(10 g orally twice a day) for 14 days or a placebo twice a day for 14 days.   
 
3.3 Stratification 
Randomization will be stratified by “high” versus “low” risk of severe disease, where “high” risk is defined 
by any of the following: 
• 
Patients aged 60 years and older 
• 
Patients having at least one of the following conditions under control: 
o 
Chronic lung disease including pulmonary fibrosis, COPD, pulmonary hypertension, moderate to 
severe asthma 
o 
Immunocompromised status due to disease (for example, those living with HIV with a CD4+ T-
cell count of <200/mm3) 
o 
Immunocompromised status due to medication (for example, persons taking 5 mg or more of 
prednisone equivalents a day, cancer therapies) 
o 
Solid organ transplant, hematologic stem cell transplant, rheumatological disease or inflammatory 
bowel disease on immunosuppressants 
o 
Severe obesity (body mass index [BMI] >40; may be based on self-report of height and weight) 
o 
Hypertension requiring treatment by more than one agent. 
o 
Cardiovascular disease including coronary artery disease, congestive heart failure, valvular heart 
disease 
o 
Diabetes 
o 
Chronic kidney disease including stage 3-4 CKD. 
o 
Chronic liver disease including cirrhosis, autoimmune hepatitis, uncontrolled hepatitis. 
 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 Recruitment  
 
4.1.1 
Recruitment 
 
This trial will recruit study participants through community health care sites and programs 
(Appendix 2 that lists the initial site) that are performing SARS-CoV-2 testing of symptomatic 
patients.  The initial site is based in Los Angeles County. 
 
4.1.2 
Race and Ethnicity 
 
Every effort will be made to maximize recruitment of a diverse participant population.  The 

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race/ethnicity of Los Angeles County is:  47.9% Hispanic; 26.7% White; 8.27% Black; 14.2% Asian.  
For this pilot study, this should reasonably ensure a diverse population. 
 
4.2 Inclusion Criteria 
 
4.2.1 
Participant provides informed consent prior to initiation of any study procedures. 
 
4.2.2 
Individual 18 to 75 years of age. 
 
4.2.3 
Documentation of confirmed active SARS-CoV-2 infection, as determined by an FDA authorized 
molecular test conducted at any US clinic or laboratory that has a Clinical Laboratory 
Improvement Amendments (CLIA) certification or its equivalent from any respiratory specimen 
collected <96 hours prior to study entry. 
 
4.2.4 
Mild or Moderate COVID-19 experiencing at least one SARS-CoV-2 infection symptom including: 
 
Mild Covid-19 
 
• 
Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, 
malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of 
breath or dyspnea 
Moderate Covid-19 
 
• 
Symptoms of moderate illness with COVID-19, which could include any symptom of 
mild illness or shortness of breath with exertion 
 
• 
Presence of clinical signs consistent with moderate illness with COVID-19, such as 
respiratory rate ≥ 20 breaths per minute, saturation of oxygen (SpO2) > 93% on room 
air at sea level, heart rate ≥ 90 beats per minute from a health care encounter within 
48 hours. 
 
4.2.5 
Agrees to not participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2 
during the study period up until reaching hospitalization or 28 days, whichever is earliest. 
 
4.2.6 
Agrees to not utilize TCM outside of this study. 
 
4.2.7 
Willing to be randomized to XFBD and placebo control arm for 14 days, and followed up to 12 
weeks. 
 
4.2.8 
Willing to comply with the study related questionnaires, procedures and measurements. 
 
4.2.9 
Will to not become pregnant during the 14 days of test substance ingestion using appropriate 
accepted 
methods 
of 
contraception. 
Acceptable 
methods 
of 
contraception 
include: 
postmenopausal 1 year of amenorrhea and over 50 years of age; prior tubal ligation or 
hysterectomy; or barrier contraception using condom or diaphragm plus spermicide. 
 
4.2.10 Able to provide the identity of their health care provider or health system clinical care entry 
information.  
 
4.2.11 Able to utilize telephone and telehealth platform to comply with the study related questionnaires, 
procedures and measurements.  Established during the recruitment process. 
 
4.2.12 Able to speak and communicate in English, Spanish, Mandarin Chinese or Cantonese. 
 
4.3 Exclusion Criteria 
 
4.3.1 
Need for hospitalization. 
 
4.3.2 
Severe or Critical COVID-19: 
 
Severe COVID-19 

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• 
Symptoms suggestive of severe systemic illness with COVID-19, which could include 
any symptom of moderate illness or shortness of breath at rest, or respiratory distress 
• 
Clinical signs indicative of severe systemic illness with COVID-19, respiratory rate ≥ 
30 breaths per minute, heart rate ≥ 125 beats per minute, SpO2 ≤ 93% on room air at 
sea level or respiratory PaO2/FiO2 < 300 
Critical COVID-19 
• 
Evidence of critical illness, defined by at least one of the following: 
• 
Respiratory failure defined based on resource utilization requiring at least one of the 
following:  Endotracheal intubation and mechanical ventilation, oxygen delivered by 
high flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal 
cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5), noninvasive 
positive pressure ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., 
clinical need for one of the preceding therapies, but preceding therapies not able to 
be administered in setting of resource limitation) 
• 
Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure   
< 60 mm Hg or requiring vasopressors) 
• 
Multi-organ dysfunction/failure 
 
4.3.3 
Positive SARS-CoV-2 molecular test in the absence of Covid-19 symptoms.  However if patients 
develop symptoms within 14 days of the positive test and fulfil all other enrollment criteria, they are 
eligible for participation. 
 
4.3.4 
Receiving the following classes of agents found in 5.4.1. Prohibited Medications 
 
4.3.5 
Use of drugs for anti-SARS-CoV-2 treatment including remdesivir, baricitinib, lopinavir/ritonavir 
fixed dose combination, ribavirin, chloroquine, hydroxychloroquine, and azithromycin, 
dexamethasone, bamlanivimab, casirivimab plus imdevimab convalescent plasma, or participation 
in a clinical trial involving any of these drugs whether for treatment or prophylaxis. 
 
4.3.6 
Participating in a study where co-enrollment is not allowed. 
  
4.3.7 
Known allergy/sensitivity or any hypersensitivity to components of XFBD  
 
4.3.8 
Active drug or alcohol use or dependence that, in the opinion of the site investigator, would 
interfere with adherence to study requirements. 
 
4.3.9 
Has known prior kidney disease. 
 
4.3.10 Has known cirrhosis, acute liver disease or uncontrolled chronic liver disease. 
 
4.3.11 Has known severe coronary artery disease. 
 
4.3.12 Has known narrow angle glaucoma. 
 
4.3.13 Has greater than two or a single uncontrolled underlying comorbid condition including 
cardiovascular disease (coronary artery disease, heart failure, valvular heart disease), 
hypertension, diabetes, chronic lung disease, chronic kidney disease, chronic liver disease, 
immunocompromised (HIV or daily users of more than 5 mg/day of prednisone), prior organ 
transplant. 
 
4.3.14 Fulfills the FDA EUA criteria of at high risk for progressing to severe COVID-19. This includes 
high-risk individuals specified in the EUA who meet at least one of the following criteria: Body 
mass index (BMI) ≥35; Chronic kidney disease; Diabetes mellitus; Immunocompromising 
condition/immunosuppressive disease; Currently receiving immunosuppressive treatment; Aged 
≥65 years; or Aged ≥55 years and have: Cardiovascular disease, or Hypertension, or Chronic 
obstructive pulmonary disease/other chronic respiratory disease. If the patient is not able to 
receive the EUA agent because of unavailability this exclusion may be waived. 

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4.3.15 Women who are currently pregnant or breastfeeding. 
  
4.4  Co-enrollment Guidelines 
 
For specific questions and approval for co-enrollment in other studies, the coordinator should contact 
the protocol team via e-mail or phone prior to enrollment. 
 
5. STUDY TREATMENT 
 
5.1 Regimens, Administration, and Duration 
 
Participants will be randomized to receive one of the following two regimens:  
 
ARM A: 
Days 1 - 14: XFBD (administered as 1 packet of granules dissolved in warm water) orally twice daily for 
14 day, 1 hour after food in the morning and at night with at least 8 hours in between doses 
 
ARM B: 
Days 1 - 14: Placebo (administered as 1 packet of granules dissolved in warm water) orally twice daily 
for 14 day, 1 hour after food in the morning and at night with at least 8 hours in between 
doses 
 
5.2 Study Product Formulation and Preparation 
 
5.2.1 
XFBD: Supplied as 10 g granules in plastic packaging. Store at controlled room temperature 20-
25°C. 
 
5.2.2 
Placebo: Supplied as 10 g granules in plastic packaging visually matching the XFBD. Store at 
controlled room temperature 20-25°C. 
 
5.3 Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 
Study Product Acquisition/Distribution 
 
XFDB are manufactured by Tianjin Tasly Pharmaceutical Co., LTD (https://www.tasly.com), a 
well-established TCM research and manufacture center to integrate technology and innovation 
to update the practice of TCM for human health. 
 
5.3.2 
Study Product Accountability 
A dedicated study team member will operate an accountability and dispensing log. The drug will 
be secured and stored in a safe location.  
 
5.4 Concomitant Medications 
 
Whenever a concomitant medication is initiated or a dose changed, investigators must review the 
concomitant medication’s and study agent’s most recent package insert, Investigator’s Brochure to 
obtain the most current information on drug interactions, contraindications, and precautions. 
 
5.4.1 
Prohibited Medications 
 
5.4.1.1 Non-study TCM prescriptions  
5.4.1.2 Ephedrine and pseudoephedrine products  
5.4.1.3 MAO inhibitors, ergot derivatives, digoxin, Artemether, Lumefantrine 
5.4.1.4 Strong inducers or inhibitors of CYP3A and other CYP enzymes, 
including 
apalutamide, 
carbamazepine, 
enzalutamide, 
mitotane, 
phenytoin, rifampin, St. John’s wort, boceprevir, cobicistat, danoprevir 

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and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and 
ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir 
and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, 
saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, telithromycin, 
troleandomycin, 
voriconazole, bupropion, 
fluoxetine, 
paroxetine, 
quinidine, terbinafine, fluconazole, fluvoxamine, ticlopidine, ciprofloxacin, 
enoxacin, gemfibrozil, clarithromycin, idelalisib, nefazodone, nelfinavir, 
tizanidine, 
repaglinide, 
tolbutamide, 
s-warfarin, 
lansoprazole, 
omeprazole, desipramine, dextromethorphan, nebivolol, midazolam, 
triazolam, clopidogrel, phenobarbital, theophylline  
 
 
 
 
 

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5.4.2 
Potential Drug-Drug Interactions  
 
Medicinal 
Latin 
Drug-Drug Interactions (DDI) 
Special Consideration 
麻黄 
Ephedrae Herba 
Do Not Use Together: 
• 
MAO Inhibitors -  ephedrae herba’s main component is 
ephedrine and MAO inhibitors may enhance the 
hypertensive effect of ephedrine. 
• 
Ergot Derivatives -  ephedrae herba’s main component is 
ephedrine and ergot derivatives may enhance the 
hypertensive effect of ephedrine 
• 
Inhalation Anesthetics -  ephedrae herba’s main component 
is ephedrine and inhalation anesthetics may sensitize the 
heart to arrhythmic actions of ephedrine.   
• 
Digoxina – ephedrae herba’s main component is ephedrine 
and digoxin may sensitize the heart to arrhythmic actions of 
ephedrine 
 
Potential DDIs:  
• 
Calcium channel blocker 
• 
Angiotensin II Antagonists 
• 
Alpha-/Beta-blockers 
• 
Alpha-/Beta-agonists 
• 
Guanethidine (NE blocker) 
• 
Methyldopa  
• 
Clonidine 
• 
Theophylline 
• 
Phenobarbital 
Renal failure – ephedrine is mostly 
excreted renally 
苦杏仁 
Armeniacae Semen 
Amarum 
Potential DDIs:  
• 
CNS depressants (benzodiazepines, barbiturates) 
 
生石膏 
Gypsum Fibrosum 
Potential DDIs:  
• 
Tetracyclines  
• 
Levodopa 
• 
Digoxin 
 
苍术 
Atractylodis 
Rhizoma 
 
Increases CYP3A4 activity (69) 
广藿香 
Pogostemonis 
Herba 
 
 
青蒿 
Artemisiae Annuae 
Herba 
Do Not Use Together: 
• 
Artemether – enhances toxic effect of Artemisinin  
• 
Lumefantrine – enhances toxic effect of Lumefantrine 
 
Potential DDIs:  
• 
Dapsone  
Increases CYP3A4 and 2B6 activity  

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a This has been theorized due to the mechanism of action for ephedrae herba and digoxin. However, no clinical study has been conducted to confirm 
the interaction.  
 
Drugs that are listed above as “Do Not Use Together” are prohibited and patients receiving such agents are ineligible for study participation. Given the 
short duration of administration of the XFBD patients receiving drugs listed as “Potential DDIs” are eligible, but, in the event of adverse events, such a 
DDI will be considered by the medical monitor in consultation with the patients’ health care provider. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
马鞭草 
Verbenae Herba 
 
 
虎杖 
Polygoni Cuspidati 
Rhizoma et Radix 
Zidovudine – decreases clearance, increases toxicity (68) 
 
Long term, large dosage can reduce 
synthesis of coagulation factors in the 
liver  
芦根 
Phragmitis Rhizoma 
 
 
葶苈子 
Descurainiae 
Semen 
 
 
化橘红 
Citri Grandis 
Exocarpium 
 
Inhibits CYP3A4, 1A2 (70) 
甘草 
Glycyrrhizae Radix 
et Rhizoma 
Potential DDIs: (68) 
• 
Diuretics (other than potassium-sparing ones) 
• 
Digoxin 
• 
Aspirin 
• 
Reserpine 
• 
Glucocorticoid 
• 
Sulfonamides 
• 
Theophylline 
 
Medications metabolized by the liver – 
induces liver enzymes and can 
accelerate the metabolism of liver 
metabolized drugs   
 
Induces CYP3A4, 2B1, 1A2  

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6. CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 Schedule of Evaluations (SOE) 
Table 6.1 
Evaluations 
Screeninga 
Entry 
Post Entry Evaluation 
Premature Study 
Discontinuation 
 
 
Day 0 
Day 1 
Day 3 
Day 7 
Day 14 
Day 21 
Day 28 
Day 42 
Week 12 
 
Visit Location 
Remote 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Documentation of Positive 
SARS-CoV-2 Molecular Test 
X 
 
 
 
 
 
 
 
 
 
 
COVID-19 Symptom Screen 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
Form 
X 
 
 
 
 
 
 
 
 
 
 
Identify health care providers 
X 
 
 
 
 
 
 
 
 
 
 
Identify Secondary Contactsb 
X 
 
 
 
 
 
 
 
 
 
 
Study Kit Dispensedc 
 
X 
 
 
 
 
 
 
 
 
 
Self-administration of Study 
Agent PO BID 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Confirmation of First Dose 
 
 
X 
 
 
 
 
 
 
 
 
Distribution of Symptom Self 
Reporting Application  
 
X 
 
 
 
 
 
 
 
 
 
Daily study questions via 
study App or phone 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Events Tracking 
 
 
 
 
X 
X 
X 
X 
 
 
 
Review of Adherence 
 
 
 
X 
X 
X 
 
 
 
 
X 
At home specimen collection 
for SARS-CoV-2 viral RNA 
testing 
 
 
X 
 
X 
X 
 
 
 
 
 
Study Endpoint 
Determination 
 
 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
  
a Participants must begin study treatment within 96 hours of onset of their first symptom. b To enable updating data in the event the participant is hospitalized or 
dies.  c Study kit contains: Copy of informed consent, Information about the study, Instructions on study procedures, QR Code and Internet link for Symptom 
Self Reporting Application, Study agent, Instructions on what to do if they have worsening symptoms/become hospitalized d Direct contact and medical record 
review. 

 
6.2 Study Enrollment Procedures 
 
6.2.1 
Recruitment and Informed Consent 
 
This trial will recruit study participants through community health care sites and programs (Appendix 2 
that lists the sites) that are performing SARS-CoV-2 testing of symptomatic patients.  
 
It is expected that potential participants will be referred to this trial immediately upon SARS-CoV-2 
diagnosis by FDA approved nucleic acid testing.   
 
At the time of disclosure of the SARS-CoV-2 positive test results by the health care provider, the patient 
will be informed about the study opportunity and provided with the study contact information.  If agreed to 
by the patient, the health care provider will directly provide the trial coordinating office with the patients 
contact information.  In this case, the health care provider will document in the patients EHR their consent 
to provide the trial staff with their contact information. 
 
The trial office will operate from 8:00 AM to 6 PM seven days per week to accept calls from these SARS-
CoV-2 positive patients inquiring about the study.  For patients, whose contact information is provided by 
their health care providers, contact will be made the same day. 
 
The study is designed to minimize in-person contact between participants and study staff. The informed 
consent process, screening, and randomization are performed remotely. 
 
If the patient signs up for COVID-19 testing through the Los Angeles county website, the patient can 
consent to being contacted by clinical trial study coordinators (Appendix VII). If a consenting patient tests 
positive, the initial recruitment telephone or video conference call will be made.   
 
At the initial recruitment telephone or video conference encounter the script information will be read to the 
study participant in their primary language (English, Spanish, Cantonese, Mandarin).  Potential 
participants expressing interest will be provided with the electronic informed consent in their primary 
language, California Experimental Subjects Bill of Rights and an authorization for medical information 
(HIPAA) as a digital document.  Potential participants will be informed that entry to the study must be 
within 96 hours of symptom onset. 
 
At this initial recruitment telephone or video conference encounter with the potential participants verbal 
consent the screening eligibility assessment may be completed.  If potential participants wish to review 
and sign the informed consent first, the screening and eligibility assessment can be completed at the next 
telephone or video conference encounter. 
 
6.2.2 
Informed Consent Process - Remote 
 
Potential participants will be provided with the electronic informed consent (eIC), California Experimental 
Subjects Bill of Rights and HIPAA agreement as digital documents.   
 
The informed consent process is done using videoconferencing or telephone between the study 
coordinator (delegated by the principal investigator) and includes discussion of the California 
Experimental Subjects Bill of Rights, discussion of the informed consent using the text of the approved 
informed consent as the text for the discussion of the informed consent and an explanation of the HIPAA 
authorization.  The consent process and documentation is consistent with 21 CFR part 11 in addition to 
parts 50, and 56, and 45 CFR 46. 
 
The research participant will be given the opportunity to discuss with their family and others including their 
health care providers.  All questions raised by the potential participant will be answered by the study 

 
coordinator.  Participants who have reviewed the eIC, and had all questions addressed, volunteer to 
participate will use the electronic signature of the eIC to document.  An official form of identification, such 
as a digital image of the patient’s birth certificate, government-issued passport or a driver’s license will be 
obtained to verify the identity of the patient.  They will receive a digital signed copy of the eIC via email 
and a physical unsigned blank.   
 
6.2.3 
Screening Visit - Remote 
 
For potential participants who elect to complete the screening and eligibility assessment after the informed 
consent process has been completed, this screening telephone/telemedicine visit will be conducted. 
 
6.2.4 
Documentation from a health care/provider encounter - Remote 
 
If the screening evaluation indicates either an encounter with a health care provider or symptoms 
greater than mild COVID-19 with shortness of breath (see table 3 above), documentation from the 
health care provider encounter will be obtained.  This must include vital signs, SpO2 to permit 
classification of COVID-19 as mild or moderate which are eligible or greater than moderate which are 
not eligible for participation. The participants consent and HIPAA authorization will be required to obtain 
this health information from the provider. 
 
6.2.5 
Screen Failures 
 
In addition to data being collected on participants who enroll into the study, demographic, clinical, and 
laboratory data on screening failures will be captured including the reason for screen failure. 
 
6.2.6 
Registration and Randomization 
 
When the potential research participant signs, the documents using the digital documents and the 
screening and eligibility assessment confirms eligibility, the research participant will be registered and 
randomized. 
 
6.2.7 
Study Entry Visit (Day 0) - Remote 
 
Upon receipt of the signed eIC, HIPAA authorization, and health information if required for greater than 
mild COVID-19, and completion of the screening and eligibility assessment for those eligible the study 
entry remote visit will be conducted. 
 
Screening and entry remote visits may be combined for mild COVID-19, but moderate COVID-19 will 
require separate visits so the medical information from the health provider can be reviewed to ensure they 
qualify as moderate COVID-19. The study entry visit is a remote contact telephone contact or video 
conference encounter. Participants must begin study treatment within 96 hours of the onset of symptoms. 
 
Participants will be informed that they are eligible.   
 
6.2.8 
Study Kit Dispensed  
 
The kit will include: 
6.1.1.1 
Study agent 
6.1.1.2 
Blank copy of informed consent and HIPPA authorization 
6.1.1.3 
Information about the study 
6.1.1.4 
Instructions on study procedures 
6.1.1.5 
3 sets of COVID-19 Test Home Collections Kits a 
6.1.1.6 
QR Code and Internet link for Symptom Self Reporting Application 
(Appendix VI) 
6.1.1.7 
Instructions on what to do if they have worsening symptoms/become 
hospitalized 

 
 
a An FDA Emergency Use Authorization approved home kit solution such as the Fulgent COVID-
19 by RT-PCR test will be used. (73) It is a nasal swab collection followed by a FDA EUA approved 
PCR test conducted in the CLIA/CAP laboratory of Fulgent Genomics, determining the presence 
or absence of RNA from SARS-CoV-2 virus. The kit will include instructions, a swab and tube, 
alcohol prep pad, kit ID stickers, biohazard bag, absorbent sheet, return label, return box, and 
return envelope. The participant will be provided sample collection instructions and how to return 
the sample both in an illustrated print out and video. (74) The print outs are available in the 
supplemental materials. 
 
6.2.9 
Study Day 1 (day of first study substance administration) – Remote 
 
Study staff will confirm the first dose taken by the participant by telephone. Participants who refuse the 
first dose after 2 days will be discontinued from the study.  
 
Study staff will also confirm by telephone the completion of first nasal swab home kit to be mailed out 
within 24 hours. The nasal swab home kit can be completed within days 1 to 3 to accommodate shipping 
limitations. 
 
The participant will utilize an application (app) available to self-report symptoms once daily as Patient-
reported outcomes (PRO). The application clarifies to the study participant the information they are 
providing is not a substitute for standard COVID-19 care with their health care provider.  The participant’s 
completion of the self-report or PRO will be reviewed. If the participant does not complete their self-report, 
study staff will initiate contact to facilitate the completion of the daily self-report PRO. If the self-report or 
PRO discloses onset or worsening of the symptom of shortness of breath or worsening of other symptoms 
the participant will be instructed to call 911, telephone their health care provider or go to the health care 
provider urgent or emergency care facility. 
 
Study staff will obtain and review the participant’s EHR for pertinent information for the primary, 
secondary and exploratory endpoints. 
 
6.2.10 Study Day 3 – Remote 
 
The participant will continue to self-administrate the study agent twice a day daily. They will have an 
application available to self-report taking the daily doses. The participant will also self-report symptoms to 
the same application once daily. The application clarifies to the study participant the information they are 
providing is not a substitute for standard COVID-19 care with their health care provider.  The participant’s 
completion of the self-report or PRO will be reviewed. If the participant does not complete their self-report, 
study staff will initiate contact to facilitate the completion of the daily self-report PRO. If the self-report or 
PRO discloses onset or worsening of the symptom of shortness of breath or worsening of other symptoms 
the participant will be instructed to call 911, telephone their health care provider or go to the health care 
provider urgent or emergency care facility. 
 
Study staff will obtain and review the participant’s EHR for pertinent information for the primary, secondary 
and exploratory endpoints. 
 
If the participant has had a resolution of listed symptoms for 3 days, study staff will confirm by telephone 
and change contact schedule to once weekly.  
 
6.2.11 Study Day 7 – Remote 
 
Study staff will also confirm by telephone the completion of the second nasal swab home kit to be mailed 
out within 24 hours. The nasal swab home kit can be completed within days 7 to 9 to accommodate 
shipping limitations. 
 
The participant will continue to self-administrate the study agent twice a day daily. They will have an 
application available to self-report taking the daily doses. The participant will also self-report symptoms to 
the same application once daily. The application clarifies to the study participant the information they are 

 
providing is not a substitute for standard COVID-19 care with their health care provider.  The participant’s 
completion of the self-report or PRO will be reviewed. If the participant does not complete their self-report, 
study staff will initiate contact to facilitate the completion of the daily self-report PRO. If the self-report or 
PRO discloses onset or worsening of the symptom of shortness of breath or worsening of other symptoms 
the participant will be instructed to call 911, telephone their health care provider or go to the health care 
provider urgent or emergency care facility. 
 
Study staff will obtain and review the participant’s EHR for pertinent information for the primary, secondary 
and exploratory endpoints. 
 
If the participant has had a resolution of listed symptoms for 3 days, study staff will confirm by telephone 
and change contact schedule to once weekly.  
 
6.2.12 Study Day 14 – Remote 
 
Study staff will confirm by telephone the completion of the final nasal swab home kit to be mailed out within 
24 hours. The nasal swab home kit can be completed within days 14 to 16 to accommodate shipping 
limitations. 
 
The participant will self-administrate the last two doses of the study agent and self-report taking daily dose 
for last time. Study staff will contact by telephone to verbally confirm the number of doses taken to reconcile 
any differences with the self-report. 
 
The participant will continue to self-report symptoms to the application once daily. The application clarifies 
to the study participant the information they are providing is not a substitute for standard COVID-19 care 
with their health care provider.  The participant’s completion of the self-report or PRO will be reviewed. If 
the participant does not complete their self-report, study staff will initiate contact to facilitate the completion 
of the daily self-report PRO. If the self-report or PRO discloses onset or worsening of the symptom of 
shortness of breath or worsening of other symptoms the participant will be instructed to call 911, telephone 
their health care provider or go to the health care provider urgent or emergency care facility. 
 
Study staff will obtain and review the participant’s EHR for pertinent information for the primary, secondary 
and exploratory endpoints. 
 
If the participant has had a resolution of listed symptoms for 3 days, study staff will confirm by telephone 
and change contact schedule to once weekly.  
 
6.2.13 Study Day 21 – Remote 
 
Study staff will contact by telephone to verbally reconcile any differences with the self-report.  
 
The participant will continue to self-report symptoms to the application once daily. The application clarifies 
to the study participant the information they are providing is not a substitute for standard COVID-19 care 
with their health care provider.  The participant’s completion of the self-report or PRO will be reviewed. If 
the participant does not complete their self-report, study staff will initiate contact to facilitate the completion 
of the daily self-report PRO. If the self-report or PRO discloses onset or worsening of the symptom of 
shortness of breath or worsening of other symptoms the participant will be instructed to call 911, telephone 
their health care provider or go to the health care provider urgent or emergency care facility. 
 
Study staff will obtain and review the participant’s EHR for pertinent information for the primary, secondary 
and exploratory endpoints. 
 
6.2.14 Study Day 28 – Remote 
 
The participant will self-report symptoms to the application for the last time. The application clarifies to the 
study participant the information they are providing is not a substitute for standard COVID-19 care with 
their health care provider.  The participant’s completion of the self-report or PRO will be reviewed. If the 
participant does not complete their self-report, study staff will initiate contact to facilitate the completion of 

 
the daily self-report PRO. If the self-report or PRO discloses onset or worsening of the symptom of 
shortness of breath or worsening of other symptoms the participant will be instructed to call 911, telephone 
their health care provider or go to the health care provider urgent or emergency care facility. 
 
Study staff will obtain and review the participant’s EHR for pertinent information for the primary, secondary 
and exploratory endpoints. 
 
6.2.15 Study Day 42 – Remote 
 
Study staff will contact by telephone to gather pertinent information for the primary, secondary and 
exploratory endpoints. If the self-report or PRO discloses onset or worsening of the symptom of shortness 
of breath or worsening of other symptoms the participant will be instructed to call 911, telephone their 
health care provider or go to the health care provider urgent or emergency care facility. 
 
Study staff will obtain and review the participant’s EHR for pertinent information for the primary, secondary 
and exploratory endpoints. 
 
6.2.16 Study Week 12 – Remote 
 
Study staff will contact by telephone to gather pertinent information for the primary, secondary and 
exploratory endpoints. If the self-report or PRO discloses onset or worsening of the symptom of shortness 
of breath or worsening of other symptoms the participant will be instructed to call 911, telephone their 
health care provider or go to the health care provider urgent or emergency care facility. 
 
Study staff will obtain and review the participant’s EHR for pertinent information for the primary, 
secondary and exploratory endpoints. 
 
6.2.17 Discontinuation Evaluations 
 
Evaluations for Participants Who Do Not Start Study Treatment 
Participants who are randomized but do not take the first (directly observed/confirmed) dose of study 
treatment do not need to be followed. An off study eCRF should be completed recording this and any 
evaluations completed for these participants should also be recorded on the Day 0 eCRFs. 
 
Premature Treatment Discontinuation Evaluations 
Participants who discontinue study treatment early should remain on study and all evaluations should be 
performed as outlined in the SOE. 
 
Premature Study Discontinuation Evaluations 
Participants who discontinue study participation should undergo premature study discontinuation 
evaluations as outlined in the SOE within 14 days of study discontinuation. If study discontinuation occurs 
on or prior to Day 13, all procedures should be performed as described in the SOE for premature study 
discontinuation evaluations. If study discontinuation occurs after Day 13, all evaluations EXCEPT 
treatment adherence should be performed. 
 
For participants who prematurely discontinue from the study for reasons other than withdrawal of consent, 
sites will attempt to obtain information regarding vital status and endpoints per the SOE (see section 6.1). 
 
6.2.18 COVID-19 Symptom Screen 
 
Participants will be asked about their first symptoms related to COVID-19 and their current symptoms, to 
document eligibility. This will include when and what symptoms the participant noticed having. This data 
will be collected via the Study App.  
 
6.2.19 Medical History 
 
The medical history must include all signs and symptoms regardless of grade and all diagnoses within the 
past 14 days. This data will be collected via the Study App.  

 
 
6.2.20 Medication History 
 
A medication history must be present, including drug name, dosage, and indication, for the past 3 months. 
The participants will be able to type it out into a word box in the Study App. 
 
6.2.21 Clinical Assessments 
 
Some events require clinical evaluations by the patient/participants health care providers.  Copies of 
these encounters by the health care providers will be obtained by the study team for review, 
documentation and coding. 
Refer to section 7.2 for AE collection requirements. 
 
6.2.22 Concomitant Medications 
 
At entry and post-entry, we will record new and discontinued concomitant medications. 
 
6.2.23 Study Treatment (Intervention) Modifications 
 
Record any modification to treatment, treatment interruption, and permanent discontinuation of treatment, 
and the reason for the modification, interruption, or discontinuation. 
 
6.2.24 Secondary Contact 
 
Sites will capture secondary contact information for two individuals that the site can contact if the 
participant cannot be reached (e.g., spouse, friend, neighbor, etc.).  
 
7 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An AE is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant 
during the conduct of the study REGARDLESS of the attribution (i.e., relationship of event to medical 
treatment/study product/device or procedure/intervention). This includes any occurrence that is new in 
onset or aggravated in severity or frequency from the baseline condition. 
 
Information sources include study assessments including daily and weekly PRO of telephone calls; 
health information obtained from the patients’ health care providers and health system encounters 
including outpatient visits, urgent care, emergency room or inpatient visits. 
 
Review by the study coordinator and medical monitor will be performed and those deemed a clinically 
significant worsening from baseline will be documented as an AE. 
 
A clinically-significant finding could include: worsening from baseline (eg, by at least 1 grade);  
concomitant signs or symptoms related to the abnormal study assessment; further diagnostic testing or 
medical/surgical intervention required; if study drug is withheld, or discontinuation from study drug 
Determination of clinical significance must be made by the medical monitor. 
 
Events that do not meet the definition of an AE or SAE include: planned hospital admissions or surgical 
procedures for a condition that existed before the subject signed the informed consent are not to be 
considered AEs unless the condition deteriorates in an unexpected manner during the study (eg, 
surgery had to be performed earlier than planned); anticipated day-to-day fluctuations of pre-existing 
disease(s), condition(s), and signs or symptoms present or detected prior to the start of the study that 
are not more severe than expected for the subject’s condition; and worsening of the COVID-19 including 
hospitalization, or death due to COVID-19. 
 
7.2 
Adverse Event Collection Requirements for This Protocol 

 
 
Post-entry, all AEs must be recorded on the eCRFs within 72 hours if any of the following criteria have 
been met: 
 
• 
All Grade ≥2 AEs 
• 
All AEs that led to a change in study treatment/intervention regardless of grade 
• 
All AEs meeting SAE definition 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening illness 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above). 
 
7.3. Relationship to Study Drug 
 
Investigators should use their knowledge of the subject, the information from the patients health care 
providers and the circumstances surrounding the event, and an evaluation of any potential alternative 
causes to determine whether or not an AE is considered to be related to study drug, indicating on the 
eCRF that an AE is either related or unrelated. The following guidance should be taken into 
consideration when determining the relationship of an AE to study drug: 
• 
Temporal relationship of event onset to initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
• 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the subject or environment, or use of concomitant medications known 
to be associated with the event 
• 
Presence of treatment-unrelated factors that are known to be associated with the occurrence of the 
event 
• 
Whether there is a reasonable alternative explanation for the event 
 
All AEs (including SAEs) will be assessed for the relationship of the AE to the study drug using the 
following definitions: not related; unlikely; possibly; probably; or definitely. For reporting and data 
analysis purposes, AEs reported with a causality assessment of “Definitely”, “Probably”, and “Possibly” 
are to be considered as “having a reasonable causal relationship” to study drug. 
 
7.4 
Study Monitoring 
 
7.4.1 
Adverse Events 
 
The study coordinator and medical monitor will review and assess EA reports for potential 
impact on the study participant safety and protocol conduct. The XFBD001 protocol chairs will 
review all serious adverse events, and this review will be conducted on a weekly basis in a 
blinded fashion. 
 
 
 
 
 
 

 
 
8 
TOXICITY MANAGEMENT 
 
8.1 
Toxicity Grading 
 
Criteria for participant management, dose interruptions, dose adjustments and discontinuation, or 
changes in treatment will be described only for toxicities attributable to the XFBD. The grading system 
for toxicities is CTCAE version 5. 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referenc
e_8.5x11.pdf 
 
 
 
8.2 Potential Toxicities 
The side effects which are described with the components of the XFBD are listed in Table 8.2. 
 
Table 8.2 Side Effects of the Components of XFBD 
Medicinal 
Latin 
Potential Side Effects 
Allergic Reactions 
麻黄 
Ephedrae Herba 
tachycardia, palpitations, increased 
blood pressure, nausea, vomiting, 
dizziness, strokes, seizures, sudden 
death, psychosis, insomnia, 
heatstroke, nervousness, anxiety, 
sweating 
avoid taking with MAO inhibitors  
To any ephedra plant 
(i.e. Mormon Tea) 
苦杏仁 
Armeniacae 
Semen Amarum 
dizziness, sudden fainting, 
palpitations, headache, nausea, 
vomiting, seizures, coma, cyanosis 
To almonds or any 
component of almonds 
生石膏 
Gypsum Fibrosum 
upset stomach, loss of appetite  
To calcium sulfate, 
calcium or sulfates 
薏苡仁 
Coicis Semen 
upset stomach, frequent urination, 
excessive sweating 
Use with Caution: Pregnancy  
To coix seed, also known 
as Job’s tears 
苍术 
Atractylodis 
Rhizoma 
nausea, dry mouth, bad taste in 
mouth, upset stomach, increased 
gastrointestinal motility 
To any plant in the genus 
Atractylodes, such as 
ragweed 
广藿香 
Pogostemonis 
Herba 
nausea, upset stomach, increased 
gastrointestinal motility 
To any plant in the 
Pogostemon genus (i.e. 
Patchouli) 
青蒿 
Artemisiae Annuae 
Herba 
nausea, vomiting, upset stomach, 
decreased blood pressure, decreased 
heart rate, decreased blood sugar, 
increased CYP3A4 and 2B6 activity 
To any Artemisiae or 
mugwort plant 
马鞭草 
Verbenae Herba 
nausea, vomiting, dizziness, 
headache, abdominal pain 
Contraindicate for pregnant 
patients 
To any Verbena plants, 
also known as verbena 
or vervain 
虎杖 
Polygoni Cuspidati 
Rhizoma et Radix 
nausea, vomiting, stomach upset, 
abdominal pain, diarrhea, dehydration; 
large doses can cause liver damage 
and could result in leukopenia and 
hematuria 
Contraindicate for pregnant 
patients 
To Polygonum 
cuspidatum, also known 
as Japanese Knotweed, 
Japanese Fleeceflower 
芦根 
Phragmitis 
Rhizoma 
fatigue, loss of appetite, diarrhea 
To any Phragmites, also 
known as common reed 

 
 
 
 
 
8.3 
Management of Side Effects 
 
It is possible that some participants will experience transient or prolonged AEs during the study. 
However, it is important to note that, in this trial, the visits will be conducted remotely and hence, AEs 
will be assessed remotely.  
 
Management of AEs and side effects will be by the participant’s health care providers. The single 
exception is to stop the study medication or placebo in the event of greater than grade 1 AE.  Clear 
instructions to participants to call 911, go to their local urgent care or emergency care center, or contact 
their health care provider are provided during the enrollment, consent process and by the app 
participants use to report symptoms. 
 
Patients report symptoms (PRO) that include potential adverse events daily and weekly on the app.  In 
the event, they have symptoms necessitating an encounter with the health provider, contact between 
the health provider by the study coordinator will be made. Participants will be given a card indicating 
they are on the trial and the telephone number for the study team.  Participants are instructed to notify 
the study coordinator when they seek a health encounter. A copy of the medical records related to that 
encounter are to be obtained to collect additional data to appropriately grade any potential toxicity. 
 
8.3.1 
Gastrointestinal Effects 
 
Sore or dry mouth or throat, bad taste in mouth, loss of appetite, upset stomach, nausea, vomiting 
increased gastrointestinal motility, abdominal pain, diarrhea, are listed as potential side effects of the 
components of XFBD. 
 
Symptom of loss of appetite (anorexia) is coded as a grade of nausea for the purposes of this trial. 
 
Table 8.3.1 – Selected Gastrointestinal Adverse Event Grading (CTCAE) 
 
Grade 
1 
2 
3 
4 
5 
Abdominal 
pain 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; 
limiting self 
care ADL 
 
 
Nausea  
 
Loss of 
appetite 
without 
alteration in 
eating habits 
 
Oral intake 
decreased 
without 
significant weight 
loss, 
dehydration or 
malnutrition 
Inadequate oral 
caloric or 
fluid intake; 
tube feeding, 
TPN, or 
hospitalization 
indicated 
 
 
Diarrhea 
Increase of <4 
stools per day 
over baseline; 
Increase of 4 - 6 
stools per day 
over baseline; 
Increase of ≥7 
stools per day 
over baseline; 
Life-
threatening 
consequences; 
Death 
葶苈子 
Descurainiae 
Semen  
nausea, vomiting, stomach upset 
To Descuriania sophia 
also known as flixweed or 
tansy mustard 
To similar plants such as 
garden cress, maca or 
dittany 
化橘红 
Citri Grandis 
Exocarpium 
large doses can lead to sore or dry 
throat 
To the pomelo fruit or 
peel; citrus fruits 
甘草 
Glycyrrhizae Radix 
et Rhizoma 
large doses can lead to fatigue, 
muscle weakness, increased blood 
pressure, headache, stomach upset, 
reduced testosterone levels; long term 
use can lead to abnormal weight gain 
To any Glycyrrhiza plant 
also known as licorice 
root 

 
mild increase 
in ostomy 
output 
compared to 
baseline 
moderate 
increase in 
ostomy output 
compared to 
baseline; 
limiting 
instrumental ADL 
hospitalization 
indicated; 
severe 
increase in 
ostomy output 
compared to 
baseline; 
limiting self-
care ADL 
urgent 
intervention 
indicated 
Vomiting  
Intervention 
not indicated  
Outpatient IV 
hydration; 
medical 
intervention 
indicated 
Tube feeding, 
TPN, or 
hospitalization 
indicated 
Life-
threatening 
consequences 
Death 
Grade 1 abdominal pain, nausea, diarrhea and vomiting do not require treatment discontinuation. In the 
event of GI symptoms, the study staff should review with the participant if XFBD is being taken with food.  
For grade 1 side effects, participants may be referred to their primary health care providers.  For grade 
2 nausea the study agent may be continued. For all other grade 2 or greater events or grade 3 nausea 
participants are instructed to discontinue study medication or placebo and must be referred to their 
health care provider for management. 
 
8.3.2 
Cardiovascular Effects 
 
Rapid heart rate, decreased heart rate, palpitations, increased blood pressure, decreased blood 
pressure, dizziness, fainting, cyanosis are listed as potential side effects of the components of XFBD. 
 
Table 8.3.2 – Selected Cardiovascular Adverse Event Grading (CTCAE) 
 
Grade 
1 
2 
3 
4 
5 
Chest pain – 
cardiac 
Mild pain 
Moderate pain; 
pain on exertion; 
limiting 
instrumental ADL; 
hemodynamically 
stable 
Pain at rest; 
limiting self care 
ADL; cardiac 
catheterization; 
new onset 
cardiac chest 
pain; 
unstable angina 
 
 
Cyanosis 
 
Present 
 
 
 
Dizziness 
Mild 
unsteadiness 
or sensation of 
movement 
Moderate 
unsteadiness or 
sensation of 
movement; 
limiting 
instrumental ADL 
Severe 
unsteadiness or 
sensation of 
movement; 
limiting self care 
ADL 
 
 
Hypertension 
Systolic BP 
120 - 139 
mm Hg or 
diastolic BP 
80 – 89 mm 
Hg; 
Systolic BP 140 – 
159 mm Hg or 
diastolic BP 90-99 
mm Hg if 
previously WNL; 
change in 
baseline medical 
intervention 
indicated; 
recurrent or 
persistent (≥24 
hrs); symptomatic 
increase by 
Systolic BP ≥ 
160 mm Hg or 
diastolic BP ≥ 
100 mm Hg; 
medical 
intervention 
indicated; more 
than one 
drug or more 
intensive 
therapy than 
previously used 
indicated; 
Life threatening 
consequences 
(e.g., malignant 
hypertension, 
transient or 
permanent 
neurologic 
deficit, 
hypertensive 
crisis); urgent 
intervention 
indicated 
Death 

 
>20 mm Hg 
(diastolic) or to 
>140/90 mm Hg; 
monotherapy 
indicated initiated 
Hypotension 
Asymptomatic, 
intervention 
not indicated 
Non-urgent 
medical 
intervention 
indicated 
Medical 
intervention 
indicated; 
hospitalization 
indicated 
Life-threatening 
consequences 
and urgent 
intervention 
indicated 
Death 
Palpitations 
Mild 
symptoms; 
intervention 
not indicated 
Intervention 
indicated 
 
 
 
Syncope 
 
 
 
Fainting, 
orthostatic 
collapse 
 
 
In the event of grade 1 or greater cardiovascular symptoms, the study staff must refer the participant to 
their primary health care providers.  For grade 2 or greater events participants must be referred to their 
health care provider for evaluation and study agent is discontinued.  
 
8.3.3 
Nervous and Psychiatric Events 
 
Headache, psychosis, insomnia, heatstroke, nervousness, anxiety, strokes, seizures, coma; are listed 
as potential side effects of the components of XFBD. 
 
Table 8.3.3 – Selected Nervous System and Psychiatric Adverse Event Grading (CTCAE) 
 
Grade 
1 
2 
3 
4 
5 
Anxiety 
Mild 
symptoms; 
intervention 
not indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self-
care ADL; 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
 
Depressed 
levels of 
consciousness 
Decreased 
level of 
alertness 
Sedation; slow 
response to 
stimuli; limiting 
instrumental 
ADL 
Difficult to 
arouse 
Life-threatening 
consequences; 
coma; urgent 
intervention 
indicated 
 
Headache 
Mild pain 
Moderate 
pain; limiting 
instrumental 
ADL 
Severe pain; 
limiting self-
care ADL 
 
 
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep 
or waking up 
early 
Moderate 
difficulty falling 
asleep, 
staying asleep 
or waking up 
early 
Severe 
difficulty falling 
asleep, staying 
asleep or 
waking up early 
 
 
Psychosis 
Mild psychotic 
symptoms 
Moderate 
psychotic 
symptoms 
(disorganized 
speech; 
Severe 
psychotic 
symptoms 
(paranoid, 
extreme 
Life-threatening 
consequences; 
threats of harm 
to self or 
others; 
Death 

 
impaired 
reality testing) 
disorganization
) hospitalization 
not indicated; 
new onset 
hospitalization 
indicated 
Stroke 
Incidental 
radiographic 
findings only 
Mild to 
moderate 
neurologic 
deficit; limiting 
instrumental 
ADL 
 
 
 
 
Severe 
neurologic 
deficit; limiting 
care ADL; 
hospitalization 
Life-threatening 
consequences; 
coma; urgent 
intervention 
indicated 
Death 
Seizure 
Brief partial 
seizure and no 
loss of 
consciousness 
Brief 
generalized 
seizure 
New onset 
seizures 
(partial or 
generalized); 
multiple 
seizures 
despite medical 
intervention 
Life-threatening 
consequences; 
prolonged 
repetitive 
seizures 
Death 
 
Grade 1 Anxiety and insomnia do not require treatment discontinuation. For grade 2 anxiety or insomnia 
the study agent is discontinued. For all other grade 1 or greater events in table 8.3.3 participants are 
instructed to discontinue study medication or placebo and must be referred to their health care provider 
for management. 
 
8.3.4 
Other side effects 
 
Fatigue, excessive sweating, muscle weakness, weight gain, dehydration, liver damage, reduced 
testosterone levels, sudden death, blood in the urine, frequent urination, or low white blood cell count. 
 
Table 8.3.4 – Selected Other Adverse Event Grading (CTCAE) 
 
Grade 
1 
2 
3 
4 
5 
Fatigue 
Fatigue 
relieved by 
rest 
Fatigue not 
relieved by 
rest; limiting 
instrumental 
ADL 
Fatigue not 
relieved by rest, 
limiting self-care 
ADL 
 
 
Urinary 
frequency 
Present 
Limiting 
instrumental 
ADL, medical 
management 
indicated 
 
 
 
Dehydration 
Increased oral 
fluids 
indicated; dry 
mucous 
membranes; 
diminished 
skin turgor 
IV fluids 
indicated 
Hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Hypoglycemia 
<LLN - 55 
mg/dL;  
<LLN - 3.0 
mmol/L 
<55 – 40 
mg/dL; 
 <3.0 - 2.2 
mmol/L 
<40 - 30 mg/dL; 
<2.2 - 1.7 
mmol/L 
<30 mg/dL; <1.7 
mmol/L; life 
threatening 
consequences; 
Death 

 
seizures 
White blood 
cell decreased 
<LLN - 
3000/mm3; 
<LLN - 3.0 x 
10e9 /L 
<3000 - 
2000/mm3; 
<3.0 - 2.0 
x 10e9 /L 
<2000 - 
1000/mm3;  
<2.0 - 1.0 
x 10e9 /L 
<1000/mm3; 
<1.0 x 10e9 /L 
 
Testosterone 
deficiency 
Asymptomatic; 
mild 
symptoms 
with no 
intervention 
indicated 
 
 
 
Replacement 
therapy 
initiated 
 
 
 
Hepatic failure    
 
Asterixis; mild 
encephalopathy; 
drug-induced 
liver injury 
(DILI); 
limiting self-care 
ADL 
Life-threatening 
consequences; 
moderate to 
severe 
encephalopathy; 
coma 
Death 
Hematuria 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention 
not indicated 
Symptomatic; 
urinary 
catheter or 
bladder 
irrigation 
indicated; 
limiting 
instrumental 
ADL 
Gross 
hematuria; 
transfusion, 
IV medications, 
or 
hospitalization 
indicated; 
elective invasive 
intervention 
indicated; 
limiting self-care 
ADL 
Life-threatening 
consequences; 
urgent 
invasive 
intervention 
indicated 
Death 
 
In the event of grade 1 or 2 fatigue the study agent may be continued, the study participant may contact 
their primary health care provider.  The study agent should be discontinued, and the patient referred to 
their primary health care providers for grade 3 fatigue. 
 
In the event of all other grade 1 or greater other side effects in table 8.3.4 the study staff must refer the 
participant to their primary health care providers and discontinue study agent.   
 
Dehydration, hypoglycemia, white blood cell decreased, testosterone deficiency, hepatic failure 
(measure of hepatic damage) and hematuria are captured on review of medical records for participants 
who have a health care encounter. 
 
9 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Drug-related toxicity or allergic reaction (see section 8.0). 
• 
Requirement for prohibited concomitant medications (see section 5.4.1). 
• 
Request by participant to terminate treatment. 
NOTE: The reason for treatment discontinuation should be documented (e.g. concern for AE, 
lack of efficacy, or other reason). 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in the section 
8.0 of the protocol. 

 
9.2 
Premature Study Discontinuation 
 
9.2.1 
Failure to take the first dose (directly observed/confirmed over telephone) of study treatment 
within 2 days of study entry. 
9.2.2 
Request by the participant to withdraw consent. 
9.2.3 
Request of the health care provider if she or he thinks the study is no longer in the best 
interest of the participant. 
9.2.4 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, investigator, or industry 
supporter. 
 
In the event that a participant prematurely discontinues from the study, unless they have withdrawn 
consent, sites will attempt to obtain information regarding vital status (including date last seen alive, 
hospitalization, date of death, and primary cause of death) from other sources (such as family members, 
other designated contacts, or clinic records) per section 6.2.15. 
 
10 STATISTICAL CONSIDERATIONS 
 
10.1 
General Design Issues 
 
This is a double-blind placebo-controlled pilot trial to document safety and efficacy endpoint 
assessments and to determine the feasibility of community recruitment and enrollment of symptomatic 
adult outpatients with COVID-19. 
  
The observational data from Wuhan comparing hospitals with and without the use of this TCM 
demonstrated a reduction of 10% progression without this TCM to 2-5% with this TCM. A key difference 
in patient care in the US is that patients with mild and moderate symptoms are staying home having 
been asked to self-quarantine. Initial data on hospitalization rates in the US in early 2020 points to rates 
of above 20%.   
  
A reasonable target of reduction through the use of the Xuanfei Baidu Granules would likely reduce the 
progression rate among those with mild/moderate symptoms, from 20% to 10%, which has the potential 
of an almost 30% reduction of fatalities, depending on the distribution of severity of disease at diagnosis 
in the population. 
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be utilized in the future studies’ primary 
Statistical Analysis Plan, which will define the content of the Primary Analysis Report.  
 
10.2.1 Primary Outcome Measure 
 
10.2.1.1 
To document the feasibility of recruitment in the community setting by assessment 
of the number of positive cases identified per week.  
 
10.2.1.2 
To document the proportion of patients who agree to participate as measured by 
enrollment and randomization.  
 
10.2.1.3 
To document the treatment emergent side effects and safety profile of the XFBD 
and placebo.   
 
10.2.1.4 
To document the rate of hospitalization or death within 42 days of enrollment in the 
XFBD and placebo treated groups.  
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 
To document the effect of XFBD on Symptom Severity Score within 28 days of 

 
study entry.  
 
10.2.2.2 
To document the proportion of patients who are compliant taking greater than 90% 
of the test substance as measured by self-report    
 
10.2.2.3 
To document the proportion of patients who comply with symptom monitoring.  
 
10.2.2.4 
To document the proportion of patients who comply with repeated clinical testing.  
 
10.2.2.5 
To document cumulative incidence of serious adverse events, and adverse events 
leading to early discontinuation of XFBD or placebo.  
 
10.2.2.6 
To document cumulative incidence of grade 3 and 4 adverse events.  
 
10.2.2.7 
To obtain levels (detectable versus not detectable, and continuous on 
log10 scale) of SARS-CoV-2 RNA from nasal swabs at approximately days 1, 7 
and 14 among a subset.  
 
10.3 
Randomization and Stratification 
 
Eligible participants will be randomized using a 1:1 ratio to each of the study arms. Housemates of 
participants previously enrolled will be independently randomized so that housemates will not be 
clustered within treatment group.  
  
Randomization will be stratified by “high” vs “low” risk of severe disease, where “high” risk is defined 
by any of the following: age ≥60 years, or having any of a number of conditions, as described in section 
3.3. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
10.4 
Sample Size and Accrual 
 
Pilot studies have many important purposes, as 
described in the objectives for this study (sections 1.1, 
1.2, and 1.3). However, the use of pilot studies to 
determine effect sizes for future larger studies is not 
recommended since such estimates tend to be both 
biased and very unstable due to the small pilot study 
size.(75) We illustrate this graphically for this study in 
Figure 1. Our current estimate is that the event rates 
in the control and XFBD groups will be 0.20 and 0.10, 
respectively. Thus, the relative risk estimate is 0.50. If 
these estimates are in fact attained in the pilot study, it 
will support our assumption, yet only mildly, since the 
80% confidence interval for that relative risk (given the 
20% event rate in the control group) will be 0.26-0.97. 
Furthermore, the environment in which COVID-19 
statistics are emerging is rapidly evolving due to 
changes in such factors as testing rates and exposure 
rates within subpopulations. At the time when we are 
putting forward a new trial proposal, we will look at the 
most recent data in order to make the best possible 
estimate for the treatment effect.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In addition to the relative risk, the event rate in the control group will be estimated in order to establish 
an appropriate sample size for a future study. Again, we will look at the most recent data available at the 
time of the study proposal to inform our hypothesis. The control group event rate, however, is expected 
to vary by the type of population sampled, so data specific to our sampling methods will be useful. As 
shown in Figure 2, the confidence intervals aren’t narrow, yet they provide guidelines for sensitivity 
analyses in estimating future necessary sample sizes.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 Figure 1 
Figure 2 

 
10.5 
Data and Safety Monitoring 
 
A DSMC will not be established for the pilot study.  The data and safety monitoring will be the 
responsibility of the investigators and medical monitor, reviewing the data contemporaneously. 
 
10.6 
Analyses 
 
All descriptive statistics will be documented in total and stratified by age, race/ethnicity, gender, risk 
group and assigned treatment, when applicable. This pilot study is not powered to find statistically 
significant differences by treatment group.  
 
All analyses involving randomized comparisons will include all randomized participants who received 
the first (confirmed) dose of study treatment, according to a modified intention-to-treat approach. 
However, as the study is blinded, the use of a modified intention-to-treat approach should not introduce 
bias into the comparison of randomized arms in this pilot study or in future larger-scale studies.  
 
10.6.1 Primary Outcome Measure 
 
The first two primary outcomes involve participant enrollment, and these results will help us to plan 
recruitment for a subsequent larger clinical trial. For example, these results may indicate that 
special efforts may be needed in the future to recruit certain underrepresented populations. The 
second two primary outcomes involve health events that will be analyzed with logistic or negative 
binomial regression models stratified and/or adjusted for covariates, for future planning purposes 
only. 
 
10.6.2  Secondary Outcomes 
 
Symptom severity scores will be determined from the COVID-19 symptom PROs reported daily by 
participants. Each symptom is rated by the participant on a scale from 0-4. Although the 
seriousness of the symptoms are not equal, summing the individual symptom ratings will give a 
rough measure of the participant’s disease severity. These daily symptom severity scores will be 
summed over the 28-day period using area under the curve (AUC). Comparisons of this AUC, as 
well as weekly symptom severity scores, by age, race/ethnicity, gender, risk group and assigned 
treatment will be performed using Wilcoxon rank sum tests. For this, and all comparisons by 
demographic or treatment variables, the results will be considered for planning purposes only. 
Secondary outcomes 2, 3, and 4 involve compliance proportions and will be documented in total 
and compared by demographic and treatment variables using Fisher exact tests. Secondary 
outcomes 5, 6, and 7 involve event rates which will be calculated in total and compared by 
demographic and treatment variables using negative binomial regression. Detectable versus not 
detectable SARS-CoV-2 RNA from nasal swabs at days 7 and 14 will be compared by demographic 
and treatment variables using Fisher exact tests, and continuous measures of SARS-CoV-2 RNA 
(on log10 scale) will be assessed for normality and tested using t-tests or Wilcoxon rank sum tests, 
as appropriate. 
 
10.7 
Unblinding 
 
In the event that single patient unblinding is required for emergency disclosure, the sponsor investigators 
and medical monitor should be contacted by telephone and will make the determination should an event 
arise. The sponsor investigator or pharmacist will make that information available to the treating 
physician. 
 
Planned Unblinding 
Unblinding of all study participants will take place after the last participant has completed the study, all 
data have been entered into the database and cleaned for primary and secondary endpoints. 
 
 
 

 
11 
DATA COLLECTION AND MONITORING 
 
11.1 
Records to Be Kept 
 
Electronic case report form screens will be made available to sites for data entry. Participants will be 
identified by the patient identification number provided upon randomization. 
 
11.2 
Data Management 
 
Instructions concerning entering study data on eCRFs will be provided.  Study coordinators are 
responsible for keying the data in a timely fashion. 
 
Given the epidemic spread of SARS-CoV-2 and the risk for visiting personnel, the study can be 
monitored remotely by clinical trial monitors. 
 
12 PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix 1) and any subsequent modifications will 
be reviewed and approved by the IRB or EC responsible for oversight of the study. Informed consent 
will be obtained from the participant through appropriate remote consenting procedures. The eIC will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy of the consent form will be provided to the participant and this fact will be 
documented in the participant’s record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be identified 
by coded number only to maintain participant confidentiality. All records will be kept locked. All computer 
entry and networking programs will be done with coded numbers only. Clinical information will not be 
released without written permission of the participant, except as necessary for monitoring by IRB/EC, 
the FDA, OHRP, other local, US, and international regulatory entities as part of their duties. 
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the FDA, IRB/EC, or OHRP as part of their duties to 
ensure that research participants are protected, or the industry supporters. 
 
13 PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be published and submitted to clinicaltrials.gov.  
 
14 BIOHAZARD CONTAINMENT 
 
As the transmission of SARS-CoV-2 and other droplet-borne pathogens can occur through contact with 
persons with active SARS-CoV-2 secretion precautions will be employed by all personnel in the clinical 
research setting and shipping and handling of all specimens for this study, as currently recommended 
by the Centers for Disease Control and Prevention and the National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious substances, must be 
transported using packaging mandated by CFR 42 Part 72. Please refer to instructions detailed in the 
International Air Transport Association (IATA) Dangerous Goods Regulations. 
  
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from Exocarpium Citri grands. Journal of Ethnopharmacology, 2014;156:97-101. doi: 
10.1016/j.jep.2014.08.030.  
40. Efferth T., Romero M.R., Wolf D.G., Stamminger T., Marin J.J.G., Marschall M. The Antiviral Activities of 
Arteminisin and Artesunate. Clinical Infectious Diseases. 2008;47:804-11. dos: 10/1086/591195 
41. 青蒿素及其衍生物用于治疗新型冠状病毒肺炎的探讨. 刘桂梅, 蔡楠, 谢静, 辛辰, 周怀瑜, 李荀, 王成. Drug 
Evaluation Research. (2020) ISSN: 1674-6376 
42. Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al. Treatment of severe acute respiratory syndrome 
with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406. 
43. Loutfy MR, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, et al. Interferon alfacon-1 plus corticosteroids in 
severe acute respiratory syndrome: a preliminary study. JAMA. 2003;290(24):3222-8. 
44. Wong VW, Dai D, Wu AK, Sung JJ. Treatment of severe acute respiratory syndrome with convalescent plasma. 
Hong Kong Med J. 2003;9(3):199-201. 
45. Barnard DL, Hubbard VD, Burton J, Smee DF, Morrey JD, Otto MJ, et al. Inhibition of severe acute respiratory 
syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-hydroxycytidine. Antivir 
Chem Chemother. 2004;15(1):15-22. 
46. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment 
of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6. 

 
47. Cinatl J, Jr., Michaelis M, Scholz M, Doerr HW. Role of interferons in the treatment of severe acute respiratory 
syndrome. Expert Opin Biol Ther. 2004;4(6):827-36. 
48. Haagmans BL, Kuiken T, Martina BE, Fouchier RA, Rimmelzwaan GF, van Amerongen G, et al. Pegylated 
interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med. 
2004;10(3):290-3. 
49. Hensley LE, Fritz LE, Jahrling PB, Karp CL, Huggins JW, Geisbert TW. Interferon-beta 1a and SARS 
coronavirus replication. Emerg Infect Dis. 2004;10(2):317-9. 
50. Stroher U, DiCaro A, Li Y, Strong JE, Aoki F, Plummer F, et al. Severe acute respiratory syndrome-related 
coronavirus is inhibited by interferon- alpha. J Infect Dis. 2004;189(7):1164-7. 
51. Tan EL, Ooi EE, Lin CY, Tan HC, Ling AE, Lim B, et al. Inhibition of SARS coronavirus infection in vitro with 
clinically approved antiviral drugs. Emerg Infect Dis. 2004;10(4):581-6. 
52. Yamamoto N, Yang R, Yoshinaka Y, Amari S, Nakano T, Cinatl J, et al. HIV protease inhibitor nelfinavir inhibits 
replication of SARS-associated coronavirus. Biochem Biophys Res Commun. 2004;318(3):719-25. 
53.  Zheng B, He ML, Wong KL, Lum CT, Poon LL, Peng Y, et al. Potent inhibition of SARS- associated coronavirus 
(SCOV) infection and replication by type I interferons (IFN- alpha/beta) but not by type II interferon (IFN-
gamma). J Interferon Cytokine Res. 2004;24(7):388-90. 
54. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of 
liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361(9374):2045-6. 
55. Groneberg DA, Poutanen SM, Low DE, Lode H, Welte T, Zabel P. Treatment and vaccines for severe acute 
respiratory syndrome. Lancet Infect Dis. 2005;5(3):147-55. 
56. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, et al. The effectiveness of 
convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections 
of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015;211(1):80-90. 
57. Public Health England. Treatment of MERS-CoV: information for clinicians. Clinical decision-making support for 
treatment of MERS-CoV patients. England: UK Government; 2015. 
58. 宣肺败毒颗粒苦杏仁苷含量初步测定. 天津中医药大学. 2020. 
59. Fan Y, Li J, Yin Q, et al. Effect of extractions from Ephedra sinica Stapf on hyperlipidemia in mice. Exp Ther 
Med. 2015;9(2):619-625. doi:10.3892/etm.2014.2117 
60. 盐酸麻黄碱、盐酸伪麻黄碱含量测定. 天津中医药大学. 2020. 
61. Kovacikova E, Kovacik A, Halenar M, et al. Potential toxicity of cyanogenic glycoside amygdalin and bitter 
apricot seed in rabbits-Health status evaluation. J Anim Physiol Anim Nutr (Berl). 2019;103(2):695-703. 
doi:10.1111/jpn.13055 
62. 邢国秀, 李楠, 杨美燕, 崔丽钧, 王童. 天然苦杏仁苷的研究进展. 中成药. 2003;25(12):1007-1009.  
63. Jaswal V, Palanivelu J, Ramalingam C, Dr. Effects of the Gut microbiota on Amygdalin and its use as an anti-
cancer therapy: Substantial review on the key components involved in altering dose efficacy and 
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64. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J 
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Med 2020;383:2603-2615. 
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68. 贾波, 赖玉琴, 胡鹏, 邓中甲. “对麻杏石甘汤功效、主治的再认识”. Forum on Traditional Chinese Medicine. 2000. 
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70. 胡晓燕, 张仕瑾, 杨思芸, 郭廷东, 黄 梅, 苏 强, 唐志立. “治疗新型冠状病毒肺炎的中药联用常用西药 不良相互作用
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of traditional Chinese medicines”. China Journal of Chinese Materia Medica. 2008. 
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Apr;31(2):180-91. 
 
 

 
 APPENDIX I: SAMPLE INFORMED CONSENT 
 
SAMPLE INFORMED CONSENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Version Date: 12/5/2020 
 
Page 1 of 9 
Study Title: A Randomized, Double-Blind, Placebo-Control Pilot Trial of Xuanfei Baidu 
Granules (XFBD), a Traditional Chinese Medicine (TCM), in Persons with COVID-19 
 
Principal Investigator:  Darcy Spicer MD 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
You have been asked to participate as a subject in a medical experiment. Before you 
decide whether you want to participate in the experimental procedure, you have a right to 
the following information: 
 
CALIFORNIA LAW REQUIRES THAT YOU MUST BE INFORMED ABOUT: 
 
1. 
The nature and purpose of the study. 
2. 
The procedures in the study and any drug or device to be used. 
3. 
Discomforts and risks reasonably to be expected from the study. 
4. 
Benefits reasonably to be expected from the study. 
5. 
Alternative procedures, drugs, or devices that might be helpful and their risks and 
benefits. 
6. 
Availability of medical treatment should complications occur. 
7. 
The opportunity to ask questions about the study or the procedure. 
8. 
The ability to withdraw from the study at any time and discontinue participation 
without affecting your future care at this institution. 
9. 
Be given a copy of the signed and dated written consent form for the study. 
10. The opportunity to consent freely to the study without the use of coercion. 
 
I have carefully read the information contained above and I understand fully my rights as 
a potential subject in this study. 
 
 
Date: ___________________ 
Time: ________________ 
 
 
Signature: _______________________________________ 
(Research Participant) 
 
 
 
 

 
Version Date: 12/5/2020 
 
Page 2 of 9 
INFORMED CONSENT FOR RESEARCH 
Study Title: A Randomized, Double-Blind, Placebo-Control Pilot Trial of Xuanfei 
Baidu Granules (XFBD), a Traditional Chinese Medicine (TCM), in Persons with 
COVID-19 
 
Principal Investigator: Darcy Spicer MD 
 
Department: Medicine 
 
24-Hour Telephone Number: 323-865-3000  
 
 
INTRODUCTION 
 
We invite you to take part in a research study. Please take as much time as you need to 
read the consent form. You may want to discuss it with your family, friends, or your 
personal doctor. If you find any of the language difficult to understand, please ask 
questions. If you decide to participate, you will be asked to sign this form. A copy of the 
signed form will be provided to you for your records. 
 
KEY INFORMATION 
 
The following is a short summary of this study to help you decide whether you should 
participate. More detailed information is listed later in this form. 
 
1. 
Being in this research study is voluntary–it is your choice. 
 
2. 
You are being asked to take part in this study because you had recent 
symptom(s) and test that showed you have been infected with the virus that 
causes COVID-19. The purpose of this study is to document the safety of taking 
a traditional Chinese medicine (TCM) in patients with COVID-19 and to gain 
information to determine whether a study with TCM can be conducted.  Your 
participation in this study will last for about 6 weeks with a follow-up contact at 
week 12. Procedures will include taking the study agent which may be the 
traditional Chinese medicine called Xuanfei Baidu Granules or a placebo for 14 
days.  You will provide nasal swabs on approximately days 1, 7, and 14 after 
discussion with the study coordinator. You will complete questions using an app 
on a tablet or phone daily for 21 days and again at 28 days and week 12. You 
must have access to a computer, laptop, tablet or smart phone to take part in 
this study 
 
3. 
There are risks from participating in this study. The most important risks are due 
to ephedrine or pseudoephedrine which is present in one of the plants used to 
make the traditional Chinese medicine granules.  It is very important that you do 
not take additional traditional Chinese medicines or other medications that 
include ephedrine or pseudoephedrine. The traditional Chinese medicine 
granules also include amygdalin or laetrile which can cause cyanosis (bluish or 
purplish discoloration of the skin or mucous membranes such as the lips).  More 

 
Version Date: 12/5/2020 
 
Page 3 of 9 
detailed information about the risks of this study can be found under the “Risk 
and Discomfort” section. 
 
4.  
The possible benefits to you for taking part in this study may include possible 
improvement in your COVID-19 symptoms.  
 
5.  
If you decide not to participate in this research, your other choices may include 
continuing the care and treatments with your health care providers. 
 
DETAILED INFORMATION 
 
PURPOSE 
 
The purpose of this study is to document the safety of taking a traditional Chinese 
medicine (TCM) in patients with COVID-19 and to gain information to determine whether 
a study with TCM can be conducted. The study will test a traditional Chinese medicine 
which has been made into a granule formulation called Xuanfei Baidu Granules. You are 
invited as a possible participant because you have symptoms and a test that shows you 
have the virus that causes COVID-19. About 60 or more participants will take part in the 
study. Half of the participants will receive the Xuanfei Baidu Granules and the other half 
will receive a placebo granule which does not contain the TCM. 
 
Participating in this research study doesn’t replace your medical care or treatment for 
COVID-19 or other health problems. If during the study, you have new or worsening 
symptoms you must contact your health care provider to manage your care.  This is true 
even if it is thought to be a side effect of the granules. 
 
PROCEDURES 
 
All visits for this study will be done using phone or videoconferencing technologies.   
 
If you decide to take part, this is what will happen: 
 
Screening Encounter:  The information in this informed consent will be reviewed with you.  
If you decide to participate you will be asked to sign this informed consent and a document 
called a HIPAA authorization using electronic methods. The HIPAA authorization permits 
the study team access to your clinic or hospital information for the 12 weeks covering 
your study participation including the COVID-19 test you recently received. You will 
complete a medical history and symptom screening survey, and list the medicines you 
have taken in the past 3 months.  We will determine if you are eligible for taking part in 
the study based on your medical history. If you are eligible, you will be asked to identify 
someone the study team can contact in the event you have been hospitalized and are not 
available. In addition, we will need to know who your health care providers are so that we 
may contact them to obtain copies of your health records before and during the study.  
 
If you agree to fulfill the criteria required for this study you will be randomized (1:1) to 
receiving the Xuanfei Baidu Granules or the placebo granules. You have a 50:50 chance 
of receiving the Xuanfei Baidu Granules or the placebo granules. The members of the 
study team will not know which arm of the study you are in. After you have been 
randomized, a study kit will be sent to you by courier.  We will have you download the 

University of Southern California 
 
Version Date: 12/5/2020 
 
Page 4 of 9 
study app to your device and provide assistance to assure that it is working properly.  The 
day you receive the kit and start taking the granules is called Day 1. During the study you 
must notify the study team if any of your regular medications are changed or new 
medications are started.  
 
Day 1:  You will complete the survey questionnaire on the app and begin taking the study 
granules twice per day. The study team will contact you to confirm you have taken your 
first dose.  You will do a home specimen collection (nasal swab) for the COVID-19 virus.  
The results of the nasal swab for the COVID-19 viral testing will be reported to the public 
health department in the same way as your original test. 
 
Days 2-14:  You will complete the survey questionnaire on the app and continue taking 
the study granules twice per day, once in the morning and once in the evening 1 hour 
after food. The study team will contact you on the 3rd, 7th, and 14th day to ask additional 
questions. On days 7 and 14 you will do a home specimen collection (nasal swab) for the 
COVID-19 virus. 
 
Days 15-21: You will complete the survey questionnaire on the app. You will have 
completed taking the study granules by day 14. 
 
Days 28, 42 and 84:  You will complete the survey questionnaire on the app. The study 
team may contact you by phone with additional questions. 
 
If necessary, the investigators can find out what arm a participant is in if needed in an 
emergency. 
 
This trial is not meant to replace your medical care or treatment for COVID-19 or other 
health problems. If during the study, you have new or worsening symptoms you must 
contact your health care provider to manage your care. 
 
If you are experiencing any of these signs, seek emergency medical care 
immediately: 
• Trouble breathing 
• Persistent pain or pressure in the chest 
• New confusion 
• Inability to wake or stay awake, 
• Bluish lips or face 
• High fever above 38.9 °C (102°F) 
 
This list is not all possible symptoms. Please call your medical provider for any other 
symptoms that are severe or concerning to you. 
 
If there is an emergency, please do not contact the study coordinator and directly call 
emergency services. 
 
Call 911 or call ahead to your local emergency facility: Notify the operator that you 
tested positive for the COVID-19 causing virus.  
 
 

University of Southern California 
 
Version Date: 12/5/2020 
 
Page 5 of 9 
RISKS AND DISCOMFORTS 
 
Side effects which have been reported from traditional Chinese medicines that contain 
the components of the study granules include:   
• 
General: fatigue, excessive sweating, muscle weakness, weight gain, reduced 
testosterone levels, sudden death: 
• 
Cardiovascular: rapid heart rate, decreased heart rate, palpitations, increased 
blood pressure, decreased blood pressure, dizziness, fainting, cyanosis (bluish or 
purplish discoloration of the skin or mucous membranes such as the lips), sudden 
death; 
• 
Gastrointestinal: sore or dry mouth or throat, bad taste in mouth, loss of appetite, 
upset stomach, nausea, vomiting increased gastrointestinal motility, abdominal 
pain, diarrhea, dehydration, liver damage:   
• 
Nervous system: headache, psychosis, insomnia, heatstroke, nervousness, 
anxiety, strokes, seizures, coma;  
• Kidney: blood in the urine, frequent urination; 
• Other: low white blood cell count.  
 
Nasal swabs: For self-collection of nasal swabs you may feel discomfort from the 
insertion of the swab into your nostril. 
 
Surveys/Questionnaires/Interviews: Some of the questions may make you feel uneasy 
or embarrassed. You can choose to skip or stop answering any questions you don’t want 
to. 
 
Breach of Confidentiality: There is a small risk that people who are not connected with 
this study will learn your identity or your personal information. 
 
Reproductive Risks: We do not know whether this study medication might hurt an 
unborn baby. You must use birth control while on this study. These are some birth control 
measures that you can use: condom or diaphragm with spermicidal. 
 
If you are pregnant, you cannot take part in this study.  
 
If you are breastfeeding and do not want to stop, you may not take part in this study. 
 
Unforeseen Risks: There may be other risks that are not known at this time.  
 
BENEFITS 
 
There may be no direct benefit to you. The potential benefits to you may include 
improvement in your COVID-19 symptoms.  
 

University of Southern California 
 
Version Date: 12/5/2020 
 
Page 6 of 9 
Your participation in this study may help us learn about the side effects of traditional 
Chinese medicines. 
 
PRIVACY/CONFIDENTIALITY 
 
We will keep your records for this study confidential as far as permitted by law.  However, 
if we are required to do so by law, we will disclose confidential information about you. 
Efforts will be made to limit the use and disclosure of your personal information, including 
research study and medical records, to people who are required to review this 
information. We may publish the information from this study in journals or present it at 
meetings. If we do, we will not use your name and individual data will not be presented. 
 
The University of Southern California’s Institutional Review Board (IRB) may review your 
records. Organizations that may also inspect and copy your information include the Food 
and Drug Administration.   
 
Federal law provides additional protections of your medical records and related health 
information. These are described in the HIPAA Authorization document. You will be asked 
to sign a separate HIPAA Authorization for Research form authorizing the access, use, 
creation, and disclosure of your health information. 
 
Your data or specimens will be analyzed and stored at the University of Southern 
California.  Your information or samples that is/are collected as part of this research will 
be used or distributed for future research studies without your additional informed 
consent. Any information that identifies you (such as your name) will be removed from 
your private information or samples before being shared with others.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at 
any time.  
 
ALTERNATIVES 
There may be alternative(s) to participating in this study. These include standard medical 
care provided by your health practitioner, participation in research studies, or use of 
traditional Chinese medicine without participating in this study.  
 
Remdesivir (Veklury®), an antiviral agent, is currently the only drug that is approved by 
the Food and Drug Administration for the treatment of COVID-19. It is recommended for 
use in hospitalized patients who require supplemental oxygen.  
 
The FDA has issued an emergency use authorization (EUA) for baricitinib in combination 
with remdesivir for the treatment of COVID-19 in hospitalized adults (and certain children) 
requiring supplemental oxygen, invasive mechanical ventilation or extracorporeal 
membrane oxygenation. An EUA has been issued for convalescent plasma for 
hospitalized patients. An EUA allows use of the medication while there is limited 
information available. The issuance of an EUA does not constitute FDA approval of a 
product. 

University of Southern California 
 
Version Date: 12/5/2020 
 
Page 7 of 9 
 
Dexamethasone, a corticosteroid, has been found to improve survival in hospitalized 
patients who require supplemental oxygen, with the greatest effect observed in patients 
who require mechanical ventilation. Therefore, the use of dexamethasone is strongly 
recommended in this setting. 
 
For patients with mild to moderate COVID-19 who are not hospitalized by who are at high 
risk for disease progression FDA has authorized the use of bamlanivimab or casirivimab 
plus imdevimab for adults (and certain children over 12). 
 
High-risk individuals specified in the EUA are those who meet at least one of the following 
criteria: 
• 
Body mass index (BMI) ≥35 
• 
Chronic kidney disease 
• 
Diabetes mellitus 
• 
Immunocompromising condition/immunosuppressive disease 
• 
Currently receiving immunosuppressive treatment 
• 
Aged ≥65 years 
• 
Aged ≥55 years and have: 
o Cardiovascular disease, or 
o Hypertension, or 
o Chronic obstructive pulmonary disease/other chronic respiratory disease 
PAYMENTS 
 
You will not be compensated for your participation in this research.  
 
COST  
 
You and/or your health plan/insurance will be billed for the tests and procedures you need 
for routine health care and COVID-19 treatment while you are in this study. You will be 
billed in the same way as if you were not in a study. You will be responsible for any co-
payments and deductibles required by your insurance. Some health plans/insurance 
companies will not pay these costs for people taking part in studies. Check with your 
health plan/insurance company to find out what they will pay for. If you have any questions 
about which tests or procedures will be billed to you and/or your health plan/insurance, 
ask the study doctor. 
 
The study traditional Chinese medicine will be provided to you at no cost.  The home test 
kit will be done at no cost. 
 
You and your third-party payer will continue to be responsible for payment for your 
health care and COVID-19 treatment. 
 
 
 
 
 

University of Southern California 
 
Version Date: 12/5/2020 
 
Page 8 of 9 
INJURY 
 
If you think you have been hurt by taking part in this study, contact your health care 
provider and tell the study coordinator.  If this is an emergency call 911.  If it is urgent, go 
to your local urgent care center or emergency room or hospital. 
 
If you require treatment because you were injured from participating in this study, 
treatment will be provided by your health plan. You or your health plan/insurance will be 
billed for the cost of this treatment. 
 
There are no plans to offer any type of payment for injury. However, by signing this form 
you have not given up any of your legal rights. 
 
NEW INFORMATION  
 
We will tell you about any new information that may affect your health, welfare, or 
willingness to stay in the research. 
 
VOLUNTARY PARTICIPATION 
 
It is your choice whether to participate. If you choose to participate, you may change your 
mind and leave the study at any time. Refusal to participate or stopping your participation 
will involve no penalty or loss of benefits to which you are otherwise entitled.  
 
If you stop being in the research, already collected data may not be removed from the 
study database. You will be asked whether the investigator can continue to collect data 
from your records. If you agree, this data will be handled the same as the research data. 
No new information or samples will be collected about you or from you by the study team 
without your permission.  
 
The study site may be required, after your withdrawal, to report any safety event that you 
may have experienced due to your participation to all entities involved in the study. Your 
personal information, including any identifiable information, that has already been 
collected up to the time of your withdrawal will be kept and used to guarantee the integrity 
of the study, to determine the safety effects, and to satisfy any legal or regulatory 
requirements. 
 
PARTICIPANT TERMINATION 
 
You may be removed from this study without your consent for any of the following 
reasons: you do not follow the study investigator’s instructions, at the discretion of the 
study investigator, your condition gets worse, or the investigator closes the study. If this 
happens, the study investigator will discuss other options with you.  
 
OTHER RELATED RESEARCH 
 
You may consent to being contacted for other related research studies. If you choose to 
participate in other studies, we will not be sharing your study information with other 
research institutes without your consent. 

University of Southern California 
 
Version Date: 12/5/2020 
 
Page 9 of 9 
 
CONTACT INFORMATION  
 
If you have questions, concerns, complaints, or think the research has hurt you, talk to 
the study investigator at Darcy Spicer 323-865-3000. 
 
This research has been reviewed by the USC Institutional Review Board (IRB). The 
IRB is a research review board that reviews and monitors research studies to protect 
the rights and welfare of research participants. Contact the IRB if you have questions 
about your rights as a research participant or you have complaints about the research. 
You may contact the IRB at (323) 442-0114 or by email at irb@usc.edu. 
 
STATEMENT OF CONSENT 
 
I have read (or someone has read to me) the information provided above. I have been 
given a chance to ask questions. All my questions have been answered. By signing this 
form, I am agreeing to take part in this study. 
 
 
 
 
 
Name of Research Participant 
Signature 
Date Signed  
 
 
(and Time*) 
 
I am willing to be contacted for other related research studies.  
 
                 (initials) YES, I agree 
                  (initials) NO, I do not agree 
 
Person Obtaining Consent 
I have personally explained the research to the participant using non-technical language. 
I have answered all the participant’s questions. I believe that the participant understands 
the information described in this informed consent and freely consents to participate.  
 
 
 
 
 
Name of Person Obtaining  
Signature  
Date Signed 
Informed Consent 
 
(and Time*) 

 
APPENDIX II: RECRUITMENT SITES 
  
1. Allied Pacific IPA 
1680 S Garfield Ave, 2nd Floor 
Alhambra, CA 91801 
Telephone: 626-282-0288 
 
2. County of Los Angeles Department of Public Health 
5050 Commerce Drive 
Baldwin Park, California 91706 
 
3. Greater El Monte Community Hospital 
1701 Santa Anita Ave,  
South El Monte, CA 91733 
 
4. Garfield Medical Center 
525 North Garfield Avenue,  
Monterey Park, CA 91754 
 
5. USC Keck Medical Center 
 
6. USC Verdugo Hills Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
APPENDIX III: THE SOURCE AND AUTHENTICATION OF MEDICINALS IN XUANFEI BAIDU GRANULES (XFBD) 
 
Example English Translation for Ephedrae Herba 
Full Chinese Document in Supplement Materials 
 
8.1.1. Ephedrae Herba (麻黄 ) 
8.1.1.1 Resource Overview  
1. Chinese Pharmacopeia Botanical Sources 
 
The 2015 Chinese Pharmacopeia refers to three botanical sources for ephedrae herba: Ephedra sinica 
Stapf, Ephedra intermedia Schrenk et C. A. Mey. or Ephedra equisetina Bge. The grassy green stems are 
harvested and dried in the autumn. 
 
2. Analysis of Botanical Sources 
 
a. 
Production 
 
Species 
Growing 
Environment 
Main Production 
Region 
Authentic 
Production 
Region 
Ephedra sinica Stapf. 
Mostly Wild 
Chifeng, Inner 
Mongolia 
Inner Mongolia, 
Gansu 
Ephedra intermedia 
Schrenk et C. A. Mey. 
Wild 
Gansu, China 
 
Ephedra equisetina Bge. 
Wild 
Xinjiang, China 
 
 
b. 
Confusion of Differentiating Botanical Sources 
 
Historically, all three kinds of ephedra plants were used for medicinals. [1]. China used to 
be the world's largest producer of ephedrine extract so the demand for wild ephedra was 
overwhelming, leading to the destruction and misuse of wild resources. In the early 2000s, 
the chemical synthesis of ephedrine on an industrial scale was successful. Therefore, the 
demand for wild ephedra fell substantially. Confusion on differentiating ephedra plants has 
essentially disappeared, and Ephedra sinica Stapf. is what is available on the main 
medicinal market. 
 
c. 
Current Resource Status and Future Trends 
 
The resource types of ephedra are divided into two categories: wild and cultivated 
ephedrae herba. For wild ephedrae herba, Chifeng, Inner Mongolia produces Ephedra 
sinica Stapf with an annual output of 1,000-2,000 tons, accounting for more than 60% of 
the usage in China. This is followed by Ephedra intermedia Schrenk et C. A. Mey. produced 
in Gansu and Ephedra equisetina Bge produced in Xinjiang. The other type is cultivated 
Ephedra sinica Stapf., which is mainly produced in Lanzhou, Gansu, Ordos, and elsewhere 
in 
Inner 
Mongolia, 
and 
the 
output 
is 
not 
as 
large 
(see 
Tiandi.com 
https://www.zyctd.com/zixun/202/20533.html for information on Chinese herbal medicine 
and market research information). Currently, the wild resources of ephedrae herba are 
abundant. At one point, they were greatly reduced due to the demand to extract ephedrine. 
However, this burden has been alleviated with the ability to completely synthesize the 
compound chemically. The ephedrae herba use in traditional Chinese medicine is relatively 
small in comparison, thus no longer posing a threat to the wild resource. The harvest is 
government-regulated so the price has been reasonable since the fall of 2011. The market 
for ephedrae herba is very stable. A small amount of cultivated ephedrae herba has been 
available since the beginning of the 2000s, and these cultivators have received government 
permission to continue their small-scale research. At this time, the wild resources have 
recovered and have strong self-regeneration capabilities. The main source of ephedrae 

 
herba will continue to be from the wild. 
 
d. 
Resource Availability 
 
Wild Ephedra sinica Stapf. is readily available for medicinal use. Cultivation technology is 
now mature so there is no risk of insufficient resource in the foreseeable future. 
 
8.1.1.2 Quality Assurance 
1. 2015 Chinese Pharmacopeia Book 1 Quality Standards and Regulations  
 
Refer to 8.2.1.1 The raw herb shall not have less than 0.80% of ephedrine hydrochloride and 
pseudoephedrine hydrochloride; the decoction pieces have the same requirements.  
 
2. Production Sites and Other Factors that Affect Quality (Mainly the Chemical Content) 
 
a. 
Different Varieties 
 
Different varieties of ephedrae herba have differing amounts of active ingredient. Jin Ling 
et. al [2] found that the varieties of ephedrae herba in Gansu and Inner Mongolia have 
different amounts of ephedrine and pseudoephedrine, which were 0.78-1.97% and 0.47-
0.97% respectively 
 
b. 
Different Production Region 
 
Different production areas did not amount to any significant differences in the amounts of 
active ingredient. For example, Chen Kang et al. [3] showed that the ephedrine and 
pseudoephedrine content for the regions Inner Mongolia, Shanxi, and Ningxia were 1.30-
1.56%, 1.08-1.83% and 1.30-2.16% respectively. 
 
8.1.1.3 Selection of Variety and Production Region  
1. Selection 
 
Ephedra sinica Stapf. from Chifeng, Inner Mongolia, as the main production region, was selected for the 
production of Xuanfei Baidu granules (XFBD). The resource is readily available. Since its native to the 
region and the locals also use the same variety, the confusion of differentiating plant varieties can be 
avoided. 
 
2. Quality Inspection Results 
 
The quality inspection results of the decoction pieces of ephedrae herba can be found at 8.2.1.3 and 
8.2.1.4. The quality of the decoction pieces selected for XFBD research and production meets quality 
assurance standards.  
 
Figure 8-1: Ephedrae Herba Decoction Pieces Quality Inspection Results 
Serial Number 
Batch Number 
Production 
Region 
Appearance 
Microscopic 
Identification 
2 
1910000801 
Inner Mongolia 
Pass 
Pass 
Physical and 
Chemical 
Identification 
Thin-Layer 
Chromatography 
(TLC) 
Moisture % 
cannot be 
greater than 
9.0% 
Total Ash % 
cannot be 
greater than 
9.0% 
Total % of 
Ephedrine and 
Pseudoephedrin
e cannot be less 
than 0.80% 
Pass 
Pass 
7.2% 
7.3% 
3.25% 
 
[1] 
肖培根主编. 新编中药志（第三卷）[M].北京：化学工业出版社, 2002,297-309.  
[2] 
晋玲, 张弦飞, 崔治家, 等. HPLC法测定不同产地和种属麻黄中麻黄碱与伪麻黄碱的含量[J]. 中兽医医药杂志, 2013, 32(01):43-46.  
[3] 
陈康, 林文津, 林励. HPCE法测定不同产地麻黄中麻黄碱和伪麻黄碱的含量[J]. 中药材, 2005, 28(8):664-665.  
 

 
APPENDIX IV: EXPERIMENTAL DATA AND LITERATURE REVIEW OF THE CHEMICAL COMPOSITION 
 
Example English Translation for Ephedrae Herba 
Full Chinese Document in Supplement Materials 
 
13.1.1 Research and Analysis of the Chemical Composition of Ephedrae Herba 
 
The 2015 Chinese Pharmacopeia refers to three botanical sources for ephedrae herba: Ephedra sinica Stapf, 
Ephedra intermedia Schrenk et C. A. Mey. or Ephedra equisetina Bge. [1] Xuanfei Baidu uses Ephedra sinica Stapf 
as its raw material. Ephedra herba has been used in the clinical practice of traditional Chinese medicine for more than 
2,000 years. It was first documented in the Shennong Materia Medica. Its effect was recorded as: "Mainly for stroke, 
cold damage headaches, malaria, promoting sweating, removing evil heat, suppressing cough, calming rapid gasping, 
eliminating cold heat, and breaking accumulations.” [2] The chemical components in ephedra herba are mainly 
alkaloids, flavonoids, volatile oils, phenolic acids, saccharides, and tannins. 
 
Alkaloids: Alkaloids are the main components as well as the active ingredients in most ephedra plants. The highest 
content is three pairs of stereoisomeric amphetamines. The stem of the ephedra plant contains L-ephedrine 
hydrochloride, L-methylephedrine, L-Norephedrine, R-pseudoephedrine, R-Norephedrine, and trace amounts of R-
methylephedrine. [3] Among them, L-ephedrine accounts for at least 60% of the total alkaloid content in Ephedra 
sinica Stapf, 30-40% of Ephedra intermedia Schrenk et C. A. Mey., and 85-90% in Ephedra equisetina Bge. The 
ephedra stem contains a small amount of benzylamine and an ephedrine of unknown structure [4]. 
 
Flavonoids: Flavonoids are another important component of ephedra plants. Li Zijiao et al. [5] measured the total 
flavonoid content of ephedra to be about 0.29%. Flavonoids mainly include apigenin, apigenin–5–O–rhamnoside, 
kaempferol, kaempferol–7–O–rhamnoside, quercetin, leucocyanidin, leucopelargonidin, leucodelphinidin, herbacetin, 
and others. In addition, ephedra contains Mahuannin A and Mahuannin B as well as catechins [6–7].  
 
Volatile oil: The known volatile oil isolated from Ephedra sinica Stapf are 1-alpha-terpinenol, beta-terpinenol, 2, 3, 4, 
6-tetramethylpyrazine, (+)-alpha-terpineol, and menthyl-2-ene-7-ol. Ephedra intermedia Schrenk et C. A. Mey. mainly 
contains palmitic acid. Ephedra equisetina Bge. has relatively high content of 6,10,14-trimethylpentadecane-2-ketone, 
3,7,11,15-tetramethyl-2-hexadecen-1-ol, methyl stearate, tetramethylpyrazine, and others. [8] 
 
Organic acids:  Several organic acids have been isolated from ephedra, including cinnamic acid, benzoic acid, ferulic 
acid, isoferulic acid, vanillic acid, palmitic acid, 4-hydroxybenzoic acid, 4-hydroxyphenylacetic acid, Linoleic acid, 
rhododendrol glucoside, and others. 
 
Saccharides and tannins: Ephedrae plants have many polysaccharides that can have an effect on coagulation and 
oxidation. Kuang et al. [9] isolated hyper-branched acidic polysaccharide (ESP-B4) from ephedra which seemed to 
show some immunosuppressive activity. Konno et al. [10] isolated ephedrae herba polysaccharide A, B, C, D, and E 
from Ephedra distachya which appeared to have a blood glucose lowering effect. The tannins found in ephedra are 
usually condensed tannins. 16 compounds have been isolated, such as catechol tannins. Riclo et al. [11] conducted 
a study on Ephedra Americana and concluded that the younger stems had higher content in total phenols and 
proanthocyanidins, while woody stems had mostly low molecular weight compounds. 
 
[1] 国家药典委员会. 中华人民共和国药典(一部) [S]．北京: 中国医药科技出版社，2015．  
[2] 丁丽丽,施松善,崔健,等.麻黄化学成分与药理作用研究进展[J]. 中国中药杂志, 2006, 31(20): 1661–1664．  
[3] 李佳莲, 方磊, 张永清, 等. 麻黄的化学成分和药理活性的研究进展[J]. 中国现代中药, 2012, 14(7): 21–27.  
[4] 周玲,吴德康,唐于平,等.麻黄中化学成分研究进展[J].南京中医药大学学报, 2008, 24(1): 71–72, 74.  
[5] 李姿娇,杨屹,丁明玉,等.麻黄非麻黄碱部分中黄酮、生物碱和有机酸的分析[J]. 分析试验室, 2005, 24(4): 67–69.  
[6] Okawa M, Kinjo J, Nohara T, et al. DPPH (1,1– diphenyl– 2– picrylhydrazyl) radical scavenging activity of flavonoids obtained from 
some medicinal plants[J]．Biological ＆Pharmaceutical Bulletin, 2001, 24 (10): 1202. 
[7] Mantani N, Andoh T, Kawamata H, et al. Inhabitory effect of Ephedrae herba, an oriental traditional medicine, on the growth of 
influenza A/PR/8 virus in MDCK cells [J]. Antiviral Research, 1999, 44(3): 193.  
[8] 张梦婷,张嘉丽,任阳阳,等.麻黄的研究进展[J].世界中医药, 2016, 11(9): 1917–1 921, 1928.  
[9] Kuang H X, Xia Y G, Liang J, et al. Structural characteristics of a hyperbranched acidic polysaccharide from the stems of Ephedra 
sinica and its effect on T–cell subsets and their cytokines in DTH mice[J]. Carbohydrate Polymers, 2011, 86(4): 1705–1711.  
[10] Konno C, Mizuno T, Hikino H. Isolation and hypoglycemic activity of Ephedrans A, B, C, D and E，Glycsns of Ephedra Distachya 
Herbs[J]. Planta Med, 1985, 2: 162.  

 
[11] Riclo R A, Sena G A, Vai V M. Determination of the presence of condensed tannins in Ephedra Americana Humb. et Bonpl. Ex Wild 
[J]. Activa Farm Bonaerense, 2004, 23(1): 11–14．  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
APPENDIX VI: SCORE PHONE APPLICATION 
 
 
 
iPhone QR code 
 
 
Android QR code 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
APPENDIX VII: LA COUNTY TESTING SITE CONSENT AND AUTHORIZATION 
TO BE CONTACTED FOR FUTURE COVID-19 RESEARCH STUDIES