Participants:
Inclusion criteria
The study inclusion criteria are as follows:(All the following criteria are met before being selected)
(1) Age ≥18 years;
(2) Meet all the following criteria (refer to confirmed cases in the Diagnosis and Treatment of pneumonitis caused by novel coronavirus (trial version 5)):
① Epidemiological history;
② Clinical manifestations (in accordance with any 2 of the following): fever; normal or decreased white blood cell counts in the early stages of disease, or decreased lymphocyte counts; multiple small patchy shadows and interstitial changes in the early stage of chest imaging, which are evident with the extrapulmonary zones. Furthermore, it develops multiple ground glass infiltrations and infiltrates throughout both lungs. In severe cases, pulmonary consolidation may occur, and pleural effusion is rare.
③ Confirmed: The suspected case has one of the following pathogenic evidence: respiratory specimens, blood specimens, or stool specimens are detected by real-time fluorescent RT-PCR(Reverse Transcription PCR) to detect positive of novel coronavirus nucleic acid; the above-mentioned specimens are genetically sequenced and highly homologous to known novel coronavirus.
④ mild or general patients;
⑤ Those who have not used antiviral drugs.
Exclusion criteria
The exclusion criteria are as follows:
(If the subject meets any of the following conditions, they cannot enter the study)
- Patients with a history of allergy to chloroquine phosphate, lopinavir, and ritonavir;
- Patients with hematological diseases;
- Patients with chronic liver and kidney disease and reaching the end stage;
- Patients with arrhythmia and chronic heart disease;
- Patients known to have retinal disease, hearing loss;
- Patients known to have mental illness;
- Patients who must use digitalis because of the original underlying disease;
- Pancreatitis;
- Hemophilia;
- Broad bean disease;
- Female patients during pregnancy.
Sample size
In this study, Logrank method was used to compare the difference in clinical recovery time between the two groups of patients. According to the existing research, the median clinical recovery time of the control group is 8 days, and the experimental group is 4 days. According to the type I error α = 0.05, the test power is 0.85, and the ratio between the test group and the control group is 1: 1. Considering the 5% shedding rate, the number of statistical cases is no less than 56 respectively in the two groups (the experimental group and the control group), and a total of 112 subjects are included in the study.
Recruitment
Participants will be recruited from SARS-CoV-2 infected inpatients. The volunteers will be screened to determine if they meet the basic criteria. Once volunteered participants have been included or excluded from the criteria assessment, researchers will explain the research procedures in detail and require them to sign a written informed consent form (written informed consent form signed by the subject or his legal representative) . All participants can withdraw their consent at any time during the trial.
Randomization allocation and blinding
Grouping was performed using a block randomization method. Before the experiment, a statistical expert randomly assigns 1 to 112 numbers according to the statistical software to generate a random allocation table. The selected block length and random seed number are stored together with the statistical expert. According to the random allocation table in advance, the statistical expert gives random numbers (1-112) in ascending order. Each random number corresponds to an envelope. The envelope contains the corresponding random number. The envelope is sealed and given to the researchers responsible for screening. The qualified subjects are selected, and the envelopes are received in the order of enrollment. After the envelopes are opened, the random number is taken out and given to the researcher responsible for treatment and observation. The researcher will contact the statistician. The statistician informs the group corresponding to the random number according to the random allocation table, so that the subjects will be randomly assigned to the experimental group or the control group, and the corresponding treatment and observation were performed. Each subject's random number is unique and remains the same throughout the trial.
Interventions
The study subjects were divided into experimental group and control group for corresponding treatment regimens.
1.Experimental group (chloroquine phosphate): Chloroquine phosphate tablets were administered twice a day, 0.5 g each time (equivalent to 0.3 g of chloroquine). Novel coronavirus nucleic acids in respiratory tract samples continue to be negative for 3 days before discontinuation of the drug, the total course of treatment does not exceed 10 days.
Combination prohibited: Digitaloid drugs, Amiodarone, Domperidone, Droperidol, Haloperidol, Clarithromycin, Methadone, Procainamide, Hydrochlorothiazide, Cisapride, Indapamide, Quinolones.
Avoid co-administration: Phenylbutazone, Chlorpromazine, Streptomycin, Heparin, Penicillamine, Ammonium Chloride, Monoamine Oxidase Inhibitors, Triamcinolone.
2. Control group (lopinavir/ritonavir): lopinavir/ritonavir is administered twice a day, two tablets each time (equivalent to 400mg of lopinavir / 100mg of ritonavir). Novel coronavirus nucleic acids in respiratory tract samples continue to be negative for 3 days before discontinuation of the drug, the total course of treatment does not exceed 10 days.
This drug is a CYP3A inhibitor and is also metabolized by CYP3A. It cannot be combined with drugs that mainly rely on CYP3A for clearance and high blood concentrations that can cause serious or fatal adverse events.
Combination prohibited: Lovastatin, Simvastatin, Cisapride, Quetiapine, Dronedarone, Colchicine, Rifampicin, Rifapentine, Bromocriptine, Ranolazine, Midazolam (oral), Triazolam, Elbasvir, Grazoprevir, Pibrentasvir.
Avoid co-administration: Atorvastatin, Rosuvastatin, Domperidone, Amiodarone, Disopyramide, Quinidine, Voriconazole, Clarithromycin, Alprazolam, Diazepam, Clonazepam, Niratinib, Abemaciclib.
Researchers fill out the inpatient medical records at the same time when the subjects are being treated, ensuring that the data records are timely, complete, accurate and true. At the same time, the researcher fills out the case report form after the diagnosis and treatment of the subjects in time to ensure that the content of the case report form is consistent with the content on the outpatient or inpatient medical records. After each subject observes the treatment course, the researcher should fill out the relevant data on the case report form in time, and submit it to the main researcher at the center for review and signature confirmation.
Outcomes:
Primary outcome
The clinical recovery time (not more than 28 days), that is, the time (in hours) from the start of study drug intervention to normalization of body temperature, respiratory symptoms, respiratory frequency, and blood oxygen saturation. Specifically meet the following criteria at the same time:
①No fever, Axillary body temperature ≤37.2 ℃;
②Relief of respiratory symptoms (72 consecutive hours);
③Respiration rate ≤24 / minute (resting state);
④Fingertip blood oxygen> 94%;
Secondary outcome(not more than 28 days)
①Respiratory tract sample SARS-CoV-2 RT-PCR negative for two consecutive times (calculated based on the first time);
②Respiratory tract, blood, feces or all other samples to SARS-CoV-2 RT-PCR were negative twice in a row (both calculated at the first time);
③Death from all causes;
④Time for body temperature to return to normal (calculated from the onset of illness);
⑤The time of mild cough or no cough (cough is severe or moderate when enrollment);
⑥Time of progress to severity, according to the Diagnosis and Treatment of pneumonitis caused by novel coronavirus (trial version 5), the definition of severity is to meet any of the following: respiratory frequency greater than 30 times/minute, or fingertip blood oxygen ≤94% or PaO2(Partial Pressure of Oxygen)/FiO2(Fraction of inspiration O2) <300mmHg;
⑦The time for the improvement of chest imaging (chest CT), the improvement of imaging is determined by the professional doctor of radiology based on the reduction of the scope of the lesion and the decrease in density;
⑧Frequency of serious adverse events.
Safety assessment and adverse events
Test safety is monitored throughout the test. Typical laboratory safety tests include routine tests for blood, urine, liver function, eg: ALT(Alanine aminotransferase) and AST(Aspartate aminotransferase), and renal function, eg: blood urea nitrogen(BUN) and creatinine(Cr) will be performed during the treatment period. Along with treatment, safety will also be assessed by monitoring adverse events(AEs) and vital signs. An adverse event(AE) is defined as an adverse medical event that occurs during a patient or subject's treatment in a study, but is not necessarily causally related to treatment. Severe Adverse Event(SAE): Occurrence of hospitalization, prolonged hospital stay, disability, impact on work ability, life-threatening or death during clinical research.
The investigator should carefully observe any adverse events that occur in the subject during the clinical study. When an adverse event is found, the investigator can take necessary measures according to the condition. Regardless of whether the adverse event is related to chloroquine phosphate or lopinavir/ritonavir, the investigator should record it in detail in the case report form. The record of the adverse event should include: description of the adverse event and all related events, time of occurrence, Severity, duration, measures taken, and final results and outcomes to analyze the association of adverse events with chloroquine phosphate or lopinavir/ritonavir. Sign and date when recording.
Quality control
This study will be conducted in four hospitals and the following five measures will be taken to ensure its rigor and quality.
(1) Quality control measures
Researchers should adopt standard operating procedures to ensure the quality control of clinical research and the implementation of quality assurance systems. All observations and findings in clinical research should be verified to ensure the reliability of the data and to ensure that the conclusions in the clinical research are derived from the original data. Quality control must be used at each stage of data processing to ensure that all data is reliable and processed correctly.
(2) Researchers’ training
Before the formal start of clinical research, the responsibilities and attitudes of the researchers participating in the clinical research must be emphasized first. The head of the research center should train the researchers on the research plan, to help them to unify the knowledge, be familiar with the collection methods and procedures, and understand the special requirements of the research project, to improve the internal observational consistency and inter-observer consistency of clinical research data collectors, to ensure the reliability of clinical research conclusions. At the same time, researchers are required to strictly implement standard operation procedures(SOPs) throughout the clinical research process to ensure the implementation of quality control measures for clinical research and improve the quality of clinical research and case report forms.
(3) Measures to improve subject compliance
Investigators should conscientiously implement an informed consent so that subjects fully understand the research requirements and cooperate with the research.
(4) Monitoring of clinical research
A qualified auditor is appointed, and regular on-site inspections of the research center are conducted to ensure that all the contents and requirements of the research plan are strictly observed, and the original data is checked to ensure consistency in the content on the CRF(Clinical Research Flowchart).
(5) Audit of clinical research
The clinical research management department and the project responsible unit may entrust the inspectors to conduct a systematic inspection of the clinical research to determine whether the research execution is consistent with the research plan, and whether the reported data is consistent with the records of the clinical participating units, that is, whether the data recorded in the case report form is the same as that of the medical record or other original records. The audit should be performed by personnel who are not directly involved in the clinical study.
Statistical analyses
(1) Balance analysis of baseline values
For demographic data and other baseline values such as vital signs, disease history, and basic treatment, in order to measure the balance of each group, continuous comparison test was used to compare the count data between groups. When the theoretical frequency in the fourfold table is less than 5, Fisher's exact probability method is used; Measurement data normally distributed are compared using group t-tests, otherwise, comparisons between groups are tested using Wilcoxon Rank Sum. Baseline evaluations were performed on FAS(full analysis set).
(2) Effectiveness analysis
The comparison of the main efficacy indicators’ clinical recovery time was a log-rank test. If the influence of confounding factors needs to be considered, Cox proportional hazard model can be used. For the comparison of other efficacy indicators, t-test or Wilcoxon rank sum test was used for comparison of measurement data, and test or Fisher's exact probability method was used to compare the rate differences between groups.
(3) The negative rate and adverse reaction rate were the dependent variables on the 7th, 14th, and 21st days in the two groups. Its steady-state valley concentration is taken as the independent variable, Logistic regression analysis and receiver operating characteristic (ROC) curve analysis after assignment. Investigate the correlation between blood concentration and clinical efficacy and adverse reactions.
(4) The safety analysis
Use the test or Fisher's exact probability method to compare the incidence of adverse events in each group, and list the adverse events occurred in this study; the normal/abnormal changes in laboratory test results before and after the test, and the relationship with the test drug when abnormal changes occur, apply a statistical test when necessary.
Clinical trial registration
The trial was registered under the registration number ChiCTR2000029741(http://www.chictr.org.cn/showproj.aspx?proj=49263) on 11 Feb-ruary 2020. On February 10, 2020, this research was approved by the Medical Ethics Committee of the Fifth Affiliated Hospital of Sun Yat-sen University, ZDWY[2020] Lunzi No. (K15-1).
