A Multi-center, Randomized, Open-label, Controlled Trial to Evaluate the Efficacy and Tolerability of Hydroxychloroquine (HCQ) in Adult Patients With Mild to Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment
Phase: NA
Conditions: Coronavirus Infection
Sponsor: Taoyuan General Hospital

Title: A Multi-center, Randomized, Open-label, Controlled Trial to Evaluate the Efficacy and 
Tolerability of Hydroxychloroquine (HCQ) in Adult Patients with Mild to Moderate Coronavirus 
Disease (COVID-19) Compared to Standard of Care Treatment 
 
1. INTRODUCTION 
1.1 
BACKGROUND AND RATIONALE: 
 
On December 31, 2019, an outbreak of respiratory illness later proved to be caused by a novel 
coronavirus, officially named Coronavirus Disease 2019 (COVID-19), was notified first in Wuhan, a city 
of Hubei province, People’s Republic of China (PRC). COVID-19 rapidly spreads in China and to other 
parts of the world. Currently more than 370,000 laboratory-confirmed cases have been reported 
worldwide, and the case count has been rising daily, and caused a global health emergency. As of 
March 29, 2020, there were 298 confirmed cases in Taiwan.  
The effective medical treatment against COVID-19 infection is still unknown. Chloroquine phosphate is 
a well-known antimalarial drug which has been on the market for many years. Recently, in vitro study 
shown that Chloroquine is effective at both entry and at post-entry stages of the COVID-19 infection of 
Vero E6 cells with promising results. Chloroquine is also an immune-modifier and could distribute to 
the whole body including lung. Also, chloroquine is cheap and safe, and could be a promising agent 
against COVID-19 infection. However, only hydroxychloroquine (HCQ) with the extra hydroxyl group is 
available in Taiwan. Therefore, hydroxychloroquine instead become the best choice for the treatment 
candidate, since it shows higher in vitro potency (EC50) against COVID-19 with lower toxicity while 
retaining the original effect which compared with chloroquine. 
 
1.2 
STUDY OBJECTIVES 
 
1.2.1 Primary Objective:  
 
To evaluate the efficacy of HCQ, with respect to the time to negatively RT-PCR assessments in 
COVID-19 patients. 
1.2.2 Secondary Objective:  
 
To evaluate the efficacy of HCQ in the aspect of virologic assessments in COVID-19 patients 
(e.g. viral load and clearance) 
 
To explore the efficacy of HCQ regarding the change of clinical symptoms in COVID-19 patients 
(e.g. TTCR; proportion of discharge, CNS and respiratory symptoms; mortality) 
 
To evaluate the safety and tolerability of HCQ in COVID-19 patients  
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
 
2.1.1 Inclusion Criteria 
 
1. 
Male and female age between 20-79 years  
2. 
Patients who had fever (central temperature ≥38°C) or acute upper respiratory symptoms 
and laboratory confirmation (rRT-PCR) for COVID-19, with available same type of upper 
respiratory tract specimens from screening evaluation to the initial testing within 4 days of 
initial testing 
3. 
Patients have mild (no pneumonia) to moderate disease (pneumonia without respiratory 
distress) according to the following World Health Organization (WHO) definition of COVID-19 
clinical syndromes: 

 
Mild (Mild illness): 
Patients with uncomplicated upper respiratory tract viral infection, may have non-specific symptoms 
such as fever, fatigue, cough (with or without sputum production), anorexia, malaise, muscle pain, 
sore throat, dyspnea, nasal congestion, or headache. Rarely, patients may also present with diarrhoea, 
nausea and vomiting. 
 
Moderate (Pneumonia): 
Adult with pneumonia but no signs of severe pneumonia and no need for supplemental oxygen.  
4. 
Willing and able to comply with the study procedure and sign a written informed consent 
 
2.1.2 Exclusion Criteria 
 
1. 
Patients with the medical history of hypersensitivity to chloroquine, chloroquinine, or 
hydroxychloroquine  
2. 
Patients with retinal disease, hearing loss, severe neurological and mental illness 
3. 
Patients with pancreatitis 
4. 
Patients with severe lung, liver (alanine aminotransferase (ALT)/aspartate aminotransferase 
(AST) elevation more than 3 times the normal upper limit), kidney (estimated glomerular 
filtration rate [eGFR] <30 mL/min/1.73m2, using the MDRD or CKD-EPI methods), brain, 
haematological diseases or other important systemic diseases 
5. 
Medical history of uncontrolled but clinically significant abnormal cardiac conduction 
abnormalities at electrocardiogram (ECG) at screening, any history or evidence of long QT 
syndrome or QTcF interval >450 msec for males and >470 msec for females (according to 
Fridericia’s correction) at screening 
6. 
Known HIV infection; active hepatitis B or C without concurrent treatment (positive tests for 
hepatitis B [both HBsAg and HBeAg], or high titer of hepatitis C ribonucleic acid [RNA] 
>800,000 IU/ml) 
7. 
Uncontrolled and unstable concurrent medical condition including G6PD, psychiatric 
disorders and alcohol/substance dependence/abuse that will jeopardize the safety of the 
patient, interfere with the objectives of the study, or affect the patient compliance with 
study requirements, as determined by the Investigator 
8. 
Patients with concomitant use of medications that alter the absorption or excretion of 
hydroxychloroquine 
9. 
Patients were considered to be unable to complete the study, or not suitable for the study 
judged by Investigators 
10. Pregnant or breast-feeding women 
 
2.2 
SCREENING EVALUATION 
    
Patient who had fever (central temperature ≥ 38°C) or acute upper respiratory symptoms and are 
tested positive for COVID-19 from respiratory specimen by rRT-PCR methods. According to “the 
Interim Guideline for the Clinical Management of New Coronavirus (SARS-CoV-2) Infection”, the throat 
swabs, sputum (lower respiratory tract fluid) and serum should be collected while the initial test for 
confirmation of infection suspected candidate. The same type of respiratory specimens should be 
collected and assessed for eligibility confirmation in screening evaluation of the study. In addition, 
Hemogram, biochemistry, urinalysis, chest X ray and ECG will be checked.  Above baseline evaluation 
could be done before signing the written informed consent form as clinically needed.   
 

2.3 
RANDOMIZATION (OR STRATIFICATION) PROCEDURES (APPLICABLE FOR RANDOMIZED 
CONTROLLED TRIALS) 
 
After signing the written informed consent form, 3-digits screening number contains the first letter of 
S (starting from S01) will be assigned to subject sequentially. Subject screened but not eligible will 
have the screening number only.   
Subjects who meet all study criteria after the screening evaluation will be randomly assigned to in a 
2:1 ratio, stratified with mild illness (no pneumonia) and moderate disease (with pneumonia), to 
receive hydroxychloroquine or have standard of care (SOC) treatment. A randomization number 
(starting from 001) will be sequentially assigned to an eligible subject.  Replacement subjects will be 
assigned the corresponding number, starting from 101 (i.e., the replacement subject for 005 will be 
assigned a number of 105, etc.). 
2.4 
BASELINE EVALUATION 
     
       The day 0 (baseline) assessment of participants will be evaluated as follows: Chest X ray, 
throat swabs and sputum collection for COVID-19. Hemogram, biochemistry, urinalysis, and ECG, and 
been considered as baseline. Every effort will be made to collect all types of specimen (throat swabs, 
sputum, lower respiratory tract fluid, or serum) for rRT-PCR assessment from screening patients in Day 
0. For evaluation of primary efficacy endpoint, the type of respiratory tract specimens in each 
assessment day should be the same with baseline in Day 0. 
 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
       This is a multi-center, randomized, open-label, controlled trial to evaluate the efficacy and 
tolerability of Hydroxychloroquine Sulfate (HCQ) in adult Patients with mild to moderate coronavirus 
disease (COVID-19) compared to standard of care treatment (SOC). The primary endpoint for the 
study is to evaluate the efficacy of HCQ, with respect to the time to negatively rRT-PCR assessments 
from the randomization date up to 14 days. The secondary endpoint is to evaluate the efficacy of HCQ 
in the aspect of virological assessments and the change of clinical symptoms. In addition, the safety 
and tolerability of HCQ will be evaluated during treatment period in COVID-19 patients.  
       The study will employ an open-label parallel design, to evaluate the efficacy and safety 
between hydroxychloroquine sulfate (plaquenil) and controlled standard of care treatment. The 
administration plan of HCQ is 400 mg bid on Day 1 and 200 mg bid for 6 days on Day 2-7. All of the 
enrolled subjects will receive standard of care. The comparison group will receive standard of care, 
i.e., supportive treatment for subjects with mild COVID-19 clinical illness, and antimicrobial therapy 
for subjects who developed moderate COVID-19 clinical illness (ceftriaxone 2gm daily for 7 days ± 
azithromycin 500mg on Day1 and 250mg on Day2-5; or levofloxacin 750 mg daily for 5 days, or 
levofloxacin 500mg daily or moxifloxacin 400mg daily for 7-14 days for the subjects who had allergic 
history to ceftriaxone or azithromycin, or per physician’s discernation). Oseltamivir 75 mg bid for 5 
days will be given for subjects who have concomitant influenza A or B infection. The subjects will be 
randomly assigned to a 2:1 ratio to receive HCQ + SOC, or SOC alone. The estimated case number will 
be 30:15. No dose reduction, modification, or change in the frequency of HCQ will be recommended 
during the study period.   
       The investigators may determine to switch to HCQ treatment arm on Day 8 if the subjects 
developed progression of pneumonia clinically, or roentegenographically, or had persistent high viral 
load without 10 log of decline, compared to baseline data. 
An independent data monitoring committee (IDMC) will be instituted to ensure external objective 

medical and/or statistical review of efficacy to protect the ethical interests and well-being of 
participants and to protect the scientific validity of the study.   

3.2 
DRUG ADMINISTRATION 
 
The investigational product will be administered by direct observation. 
3.3 
DOSE MODIFICATIONS 
    
No dose reduction, modification, or change in the frequency of hydroxychloroquine will be 
recommended during the study period. 
 
3.4 
STUDY CALENDAR 
Schedule of Visits 
 
Procedure 
Screening 
/Baseline 
(Day 0) 
                     Schedule day 
Day 
1 
Day 
2 
Day 
4 
Day 
6 
Day 
7 
Day 
8 
Day 
10 
Day 
12 
Day 
14 
ICF 
X 
History and Eligibility  
X 
X 
Randomization 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/Biochemistry(C
BC+DC,PT, aPTT, CRP, ESR, 
GOT/GPT/TBIL,Cr, eGFR, Na, 
K, Cl, Ferritin, d-Dimer, CPK, 
LDH, hs-Troponin I ) 
X 
X 
X 
X 
Serology test (stored for 
antibody tests) 
X 
X 
X 
X 
Urinalysis 
X 
rRT-PCR assessment of 
respiratory tract specimen 
(thorat swabs, sputum. 
Stool if diarrhea) 
X 
X 
X 
X 
X 
X 
X 
X 
CNS symptoms assessment X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of SpO2,, or  
PaO2/FiO2 if any 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Radiological Assessments 
(X-ray) 
X 
X 
X 
X 
EKG 
X 
X 
X 
Pregnancy test 
X 
HBsAg, HBeAg and HCV Ab 
tests 
X 
Survival check 
X 
HCQ/SOC treatment 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Abbreviated title: hydroxychloroquine for COVID-19 
Protocol_Version 1.0_ 20200329 
 
3.5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
3.5.1 Off-Study Criteria 
 
Participants who developed adverse events including grade 3/4 liver toxicity, grade 3 
allergic reaction, or other severe adverse events (including progression to the stage 
of severe pneumonia) 
 
4 
CONCOMITANT MEDICATIONS/MEASURES 
 
       Concomitant medications will be recorded well.  
 
5 
BIOSPECIMEN COLLECTION 
5.1 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
 
All of the biospecimens are considered biohazard, and should be managed according 
to Taiwan CDC’s guidelines. Store serum will be shipped to contract laboratory, and 
will be destroyed if no more extended studies permitted.   
6 
DATA COLLECTION AND EVALUATION 
6.1 
DATA COLLECTION 
 
The study will use eCRF/EDC for data collection. Safety laboratory data will be 
entered into eCRF by authorized personnel at Investigational sites. Real-time RT-PCR 
data will be managed and stored within the laboratory information management 
system and only the date and time of specimens are recorded in the eCRF. Safety 
laboratory data will be integrated with the consolidated clinical data before database 
lock. 
 
All records should be kept in conformance to applicable national laws and 
regulations. 
 
 
Adverse events will be recorded according to the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events(Appendix 3), and  will be 
coded using the current MedDRA thesaurus (Version 19.0); concomitant medication 
will be coded using World Health Organization Collaborating Centre for Drug 
Statistics Methodology Anatomical Therapeutic Chemical/defined daily dose 
(WHOCC ATC/DDD). 
6.2 
CRITERIA OF PRIMARY ENDPOINTS 
6.2.1 Primary efficacy endpoints 

Abbreviated title: hydroxychloroquine for COVID-19 
Protocol_Version 1.0_ 20200329 
 
 
Transition time of SARS-CoV-2 nucleic acid rRT-PCR from positive 
results to negative results in respiratory tract specimen on day 0, 2, 4, 
6, 8, 10, 12, 14. For evaluation of primary efficacy endpoint, the type 
of respiratory tract specimens in each assessment day should be the 
same with Day 0. 
6.3 
SECONDARY ENDPOINTS 
6.3.1 Evaluation of Efficacy 
 
Virological clearance rate at day 8 
 
AUC of viral load on day 0, 2, 4, 6, 8, 10, 12, 14 
For the above 2 secondary efficacy evaluations, the type of respiratory tract 
specimens in each assessment day should be the same with Day 0. 
 
Time to Clinical recovery (TTCR): 
TTCR is defined as the time (in hours) from randomization (active or placebo) until 
normalization of fever, respiratory rate, and oxygen saturation, and alleviation of 
cough, sustained for at least 72 hours. 
Normalization and alleviation criteria: 
- 
Fever - ≤36.9°C or -axilla, ≤37.2 °C oral, 
- 
Respiratory rate - ≤20/minute on room air, 
- 
Oxygen saturation - ≥ 94% on room air, 
- 
Cough - mild or absent on a patient reported scale of severe, 
moderate, mild, absent 
 
Frequency of CNS symptoms (e.g. headache, dizziness, impaired 
consciousness, ataxia, acute cerebrovascular disease, and epilepsy)  
 
Frequency of respiratory progression:  
Defined as SpO2 < 94% on room air or PaO2/FiO2 < 300 mmHg and requirement for 
supplemental oxygen or more advanced ventilator support 
 
Proportion of Participants Discharged by Day 14 
 
The mortality rate of subjects at week 2 and week 3  
6.3.2 Evaluation of Safety 
 
Frequency of serious adverse events 
6.4 
TOXICITY CRITERIA 
 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that 
occurs during the course of the clinical trial associated with the use of a drug in 
humans, whether or not the event is considered related to the treatment or clinically 

Abbreviated title: hydroxychloroquine for COVID-19 
Protocol_Version 1.0_ 20200329 
 
significant.  
7.1.2 Suspected adverse Event 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity that 
has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. "Unexpected”, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug 
under investigation. 
7.1.4 Serious 
An adverse event or suspected adverse reaction is considered serious if in the view of 
the investigator or the sponsor, it results in any of the following: 
 
Death, 
 
A life-threatening adverse drug experience 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
7.1.5 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 
7.1.6 Life-threatening adverse drug experience 

Abbreviated title: hydroxychloroquine for COVID-19 
Protocol_Version 1.0_ 20200329 
 
Any adverse event or suspected adverse reaction that places the patient or subject, 
in the view of the investigator or sponsor, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that had it occurred in a 
more severe form, might have caused death. 
 
7.1.7 Unanticipated Problem 
Any incident, experience, or outcome that: 
 
Is unexpected in terms of nature, severity, or frequency in relation to 
(a) 
the research risks that are described in the IRB-approved research protocol 
and informed consent document; Investigator’s Brochure or other study 
documents, and 
(b) 
the characteristics of the subject population being studied; AND 
 
Is related or possibly related to participation in the research; AND 
 
Places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized. 
 
7.2 
REC OR IRB REPORTING 
 
Unexpected AE, SAE will be reported. And interim analysis will be reported to IRB 
when 22 participants are enrolled.       
7.3 
DATA AND SAFETY MONITORING PLAN 
DSMB will monitor the safety of the study, and the committee will be held every 2-4 
weeks aftr 1st participant enrolled. 
 
7.3.1 Principal Investigator/Research Team 
All protocols should include a DSM plan which describes how the investigator plans to 
oversee research subject safety and ensure data integrity. The PI and his/her research 
staff are part of the monitoring plan but may not be the only ones conducting 
monitoring activities for any given protocol. 
The clinical research team will meet on a regular basis {insert frequency} when 
patients are being actively treated on the trial to discuss each patient. Decisions 
about dose level enrollment and dose escalation if applicable will be made based on 
the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal 
investigator or a lead associate investigator. Adverse events will be reported as 
required above. Any safety concerns, new information that might affect either the 
ethical and or scientific conduct of the trial, or protocol deviations and violations will 

Abbreviated title: hydroxychloroquine for COVID-19 
Protocol_Version 1.0_ 20200329 
 
be immediately reported to the IRB using iRIS and if applicable to the Sponsor. 
The principal investigator will review adverse event and response data on each 
patient to ensure safety and data accuracy. The principal investigator will personally 
conduct or supervise the investigation and provide appropriate delegation of 
responsibilities to other members of the research staff. 
 
 
7.3.2 Data Safety Monitoring Board (DSMB)  
A DSMB is an impartial group established to oversee a clinical trial and review the 
results to determine if they are acceptable. Members of a DSMB must be 
multidisciplinary and include members with relevant clinical and statistical expertise. 
The DSMB should meet at least annually or more often depending on the activity and 
nature of the clinical trial being monitored. 
This protocol requires monitoring by the Data Safety Monitoring Board (DSMB) as 
described above in Section 7.3. Interim outcome results will not be revealed to the 
investigators of the trial; results will be presented to the investigators prior to final 
accrual to the trial only if the DSMB recommends early termination of the trial. 
(NOTE: the study statistician is responsible for providing the description of how the 
monitoring will take place, including endpoints to be monitored and the frequency or 
timing of monitoring.) 
 
8 
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