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A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19)

Objective In this study, we evaluated the efficacy of hydroxychloroquine (HCQ) against coronavirus disease 2019 (COVID-19) via a randomized controlled trial (RCT) and a retrospective study. Methods Subjects admitted to 11 designated public hospitals in Taiwan between April 1 and May 31, 2020, with COVID-19 diagnosis confirmed by pharyngeal real-time RT-PCR for SARS-CoV-2, were randomized at a 2:1 ratio and stratified by mild or moderate illness. HCQ (400 mg twice for 1 d or HCQ 200 mg twice daily for 6 days) was administered. Both the study and control group received standard of care (SOC). Pharyngeal swabs and sputum were collected every other day. The proportion and time to negative viral PCR were assessed on day 14. In the retrospective study, medical records were reviewed for patients admitted before March 31, 2020. Results There were 33 and 37 cases in the RCT and retrospective study, respectively. In the RCT, the median times to negative rRT-PCR from randomization to hospital day 14 were 5 days (95% CI; 1, 9 days) and 10 days (95% CI; 2, 12 days) for the HCQ and SOC groups, respectively (p = 0.40). On day 14, 81.0% (17/21) and 75.0% (9/12) of the subjects in the HCQ and SOC groups, respectively, had undetected virus (p = 0.36). In the retrospective study, 12 (42.9%) in the HCQ group and 5 (55.6%) in the control group had negative rRT-PCR results on hospital day 14 (p = 0.70). Conclusions Neither study demonstrated that HCQ shortened viral shedding in mild to moderate COVID-19 subjects.


Synopsis
Hemogram, biochemistry, urinalysis, chest X ray and ECG will be checked. Above screening and baseline evaluation could be done before signing the written informed consent form as clinically needed.

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.).

BASELINE EVALUATION
Baseline assessment of participants will be evaluated as follows (data collected at screening could be considered baseline): 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 before day 1. For evaluation of primary efficacy endpoint, the type of respiratory tract specimens in each assessment day should be the same with baseline. developed progression of pneumonia clinically, or roentegenographically, or had persistent high viral load without 10 log of decline, compared to baseline data.

STUDY DESIGN
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.

DRUG ADMINISTRATION
The investigational product will be administered by direct observation.

DOSE MODIFICATIONS
No dose reduction, modification, or change in the frequency of hydroxychloroquine will be recommended during the study period.

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)

CONCOMITANT MEDICATIONS/MEASURES
Concomitant medications will be recorded well.

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 designated laboratory, and will be destroyed if no more extended studies permitted at the end of 2020 (appendix 4).

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).

Primary efficacy endpoints
• 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. For the above 2 secondary efficacy evaluations, the type of respiratory tract specimens in each assessment day should be the same with Day 0.

SECONDARY ENDPOINTS
• 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.

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 significant.

Suspected adverse Event
Suspected adverse reaction means any adverse event for which there is a reasonable possibility Abbreviated title: hydroxychloroquine for COVID-19 Protocol_Version 2.1_ 20200420 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.

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.

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.

Disability
A substantial disruption of a person's ability to conduct normal life functions.

Life-threatening adverse drug experience
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.

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.

REC OR IRB REPORTING
Unexpected AE, SAE will be reported. And interim analysis will be reported to IRB when 22 participants are enrolled.

DATA AND SAFETY MONITORING PLAN
DSMB will monitor the safety of the study, and the committee will be held every 2-4 weeks aftr 1 st participant enrolled.

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 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.

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.)

STATISTICAL SECTION
Data will be listed and summarized using SAS ® V 9.2 or higher (SAS Institute, Inc., Cary, North Carolina) according to Sponsor-agreed reporting standards, where applicable. Complete details will be documented in the statistical analysis plan (SAP). All efficacy and safety data will be summarized using descriptive statistics by treatment. The following descriptive statistics will be used to summarize the trial data on the basis of their nature unless otherwise specified: • Continuous variables: number of non-missing observations, mean, standard deviation, median, minimum, and maximum.
• Time-to-event variables: number of non-missing observations (N), median, minimum, and maximum. Kaplan-Meier event rates may also be provided if applicable for specific time to event variables.