Study design and participants
This case series was approved by the Institutional Ethics Board of Zhongnan Hospital of Wuhan University (No. 2020011). The study consisted of a prospective series of patients with confirmed COVID-19 who received DRV/c and conventional treatment were admitted to Zhongnan Hospital of Wuhan University from February 3, 2020, to March 11, 2020. The patients who voluntarily took DRV/c and were enrolled in DRV/c group. Screening for enrollment was performed after all patients signed written informed consent. A case series of COVID-19 patients as non-DRV/c control group was retrospectively reviewed, including patients who were hospitalized during the same period, met the same study criteria but did not receive investigational antivirals such as DRV/c, LPV/r, or remdesivir, etc.
Zhongnan Hospital is located in Wuhan (Hubei Province), which was once a endemic area of COVID-19. It is a major teaching hospital and was responsible for the treatment of COVID-19, as assigned by the People’s Republic of China. All patients with COVID-19 enrolled in this study were diagnosed according to World Health Organization interim guidance .
Inclusion or ExclusionCriteria
Inclusion Criteria: Age between 18-65; Confirmed diagnosis of COVID-19; Relevant clinical symptoms onset until diagnosis within 10 days (such as fever, cough, etc).
Exclusion Criteria: Patients with known hypersensitivity to DRV/c; Patients planned for or with ongoing use of drugs that interact with DRV/c (including: drugs that are highly CYP3A dependent and have elevated plasma concentrations associated with serious and/or life-threatening events [narrow therapeutic index], CYP3A inducers [refer to package insert]), and cannot be discontinued or switched to other drugs; Alanine aminotransferase (ALT )/aspartate aminotransferase (AST) elevation greater than 5 times the upper limit of normal, or child-Pugh grade C; Critically ill patients with expected survival of < 48 hours; Women of childbearing potential with a positive pregnancy test; Participants of other clinical trials within 3 months; HIV-infected patients; Inappropriate in the opinion of the investigator.
Investigational drug and Group
DRV/c (800mg/150mg, one tablet daily with meal, Janssen Ortho, LLC, Product Batch Number: IKZ1000);
DRV/c group: DRV/c（800/150 mg once daily for 2 weeks）+ conventional treatment;
Conventional treatment: included symptomatic supportive treatment (such as oxygen inhalation, prevention and treatment of infection), arbidol antiviral, Thymalfasin or gamma globulin immunotherapy, corticosteroid therapy, detailed as follows.
Some patients received other antiviral treatment with arbidol (200 mg twice daily), interferon-alpha inhalation (50 μg twice daily) and immunomodulator Thymalfasin (1.6mg,ih,qod) for two weeks. Patients received treatment with corticosteroids (40-80 mg/day) and gamma globulin (10- 20 g/day) for 3-5 days, when their resting respiratory rate was >30 per min, oxygen saturation was <93% without oxygen, or multiple pulmonary lobes showed more than 50% progression of disease within 48 h of imaging. Patients also received treatment with probiotics in most cases. Quinolones and second-generation beta-lactams (oral and intravenous) were administered if fever lasted longer than seven days or C-reactive protein levels were >20 mg/L (normal range 0-10 mg/L). The discharge criteria were: (i) afebrile for at least 3 days, (ii) obvious alleviation of respiratory symptoms, (iii) improvement in radiological abnormalities on chest computed tomography (CT) or X-ray and (iv) two consecutive negative detections of SARS- CoV-2 at least 24 h apart.
Efficacy endpoints (primary and secondary endpoints)
Primary endpoints: The time to SARS-CoV-2nucleic acid conversion detected in respiratory specimens (such as throat swabs);
Secondary endpoints: all-cause mortality, time to normal body temperature, number of inpatient days, admission to intensive care unit (ICU) or not, invasive mechanical ventilation or not, lung computed tomographic (CT) improvement, and normalization rate of inflammatory indicators.
Safety endpoints: adverse events, laboratory tests (hematology, liver and kidney function, blood glucose, electrolytes, lipids, blood amylase, lipase, myocardial enzymes, urine routine), electrocardiogram.
COVID-19 was confirmed by detectingSARS-CoV-2RNA in throat swab samples using aSARS-CoV-2nucleic acid detection kit according to the manufacturer’s protocol (Shanghai BioGerm Medical Biotechnology Co.,Ltd). Virus detection by throat swab was repeated every 24-72 h. Throat swab specimens were collected from all patients upon admission and tested by real-time polymerase chain reaction (RT-PCR) forSARS-CoV-2RNA within 3 hours. Laboratory tests were conducted upon admission, Laboratory testing items were similar to our previous reports.
The medical records of patients were analyzed by the research team of the Department of Infectious Disease at Zhongnan Hospital of Wuhan University. Data collection was similar to our previous reports. Epidemiological, clinical, laboratory, and radiological characteristics, along with treatment and outcome data, were obtained from electronic medical records. The data were reviewed by a trained team of physicians. The date of disease onset was defined as the day when the symptoms were noticed by the patient, symptoms were defined as fever, cough, chest tightness, dyspnea, muscle pain et al.
The time to nucleic acid conversion was defined as two consecutive negative detections in throat swabs taken one day apart, and the conversion time was set at the time of the previous day. Adverse reactions after administration were collected during daily rounds.
Acute respiratory distress syndrome (ARDS) was defined according to the Berlin definition . The duration from disease onset to hospital admission, dyspnea, ARDS, intensive care unit (ICU) admission, and discharge were also recorded.
Categorical variables were described as frequency rates and percentages, and continuous variables were described using mean, standard deviation, median, and interquartile range (IQR) values. Means for continuous variables were compared using independent group t-test when the data were normally distributed. Proportions for categorical variables were compared using the χ2 test, although the Fisher exact test was used when the data were limited. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 22.0 software (SPSS Inc., Chicago, IL USA).