The results of the world's first randomized controlled clinical trial of COVID-19 were announced. On March 19, Beijing time, the research teams of the National Respiratory Diseases Clinical Research Center, China-Japan Friendship Hospital, Wuhan Jinyintan Hospital, Beijing Ditan Hospital, Peking Union Medical College and other teams jointly joined the top medical journal "New England Medical Journal" (NEJM ) The online research paper "Trial of lopinavir-ritonavir (brand name" Celizhi ") in the treatment of patients with severe COVID-19 adult hospitalization" was published online.
Corresponding authors of the study are Cao Bin, deputy director of China-Japan Friendship Hospital, director of the Department of Respiratory and Critical Care Medicine, Zhang Dingyu, director of Wuhan Jinyintan Hospital, deputy director of the Chinese Academy of Engineering, dean of the Peking Union Medical College Hospital of the Chinese Academy of Medical Sciences, and national respiratory Wang Chen, director of the Center for Disease Clinical Medicine Research.
It is worth noting that since the outbreak of the COVID-19 epidemic, the world's top medical journal has published the results of clinical trials for the first time to treat COVID-19, and it is also the result of a handful of clinical trials of drugs published during the outbreak of new infectious diseases in the past 20 years. .
The overall conclusion of this study was that among the inpatients with severe COVID-19 adults, the research team did not observe the benefit of lopinavir-ritonavir treatment compared to standard treatment.
The research team mentioned during the discussion that this randomized trial found that the use of lopinavir-ritonavir plus standard supportive care for severely ill patients with COVID-19 has improved clinical outcomes compared with standard supportive care only. Or the reduction in mortality is not significant. However, in the analysis of modified intention-to-treat, after the study excluded three patients who died early, the median time to clinical improvement between the two groups showed a difference. Although the magnitude was not significant, it was statistically significant. Say the median is 15 days vs. 16 days.
It is worth noting that the overall mortality rate of the trial was 22.1%, which is still significantly higher than the mortality rate of 11% to 14.5% in the preliminary descriptive study report of COVID-19 hospitalized patients, which indicates that the patients included in the trial were seriously ill.
Lopinavir and ritonavir are a combination of two protease inhibitors, lopinavir and ritonavir, and are marketed under the tradename Cleeve. Approved by the US FDA for anti-AIDS treatment in 2000 Applied in clinical. It is worth mentioning that lopinavir ritonavir is also one of the oldest antiviral drugs used after the outbreak.
The clinical trial passed the ethical review on January 9, 2020, and was conducted at Wuhan Jinyintan Hospital from January 18 to February 3, 2020 (the date of enrollment of the last patient). A total of 199 laboratory-confirmed patients with COVID-19 virus infection who met the eligibility criteria were randomized. Among them, 100 cases were assigned to the standard treatment group; 99 cases were assigned to the lopinavir-ritonavir group, that is, in addition to the standard treatment, lopinavir-ritonavir treatment (400 mg each) was added. , 100mg twice daily for 14 days).
It is worth noting that 5 patients assigned to the lopinavir-ritonavir group did not receive lopinavir-ritonavir treatment (3 of whom died within 24 hours), but for the largest Limitation of randomized information was also included in the intention-to-treat (ITT) analysis. The research team also performed a modified intention-to-treat (mITT) analysis that excluded three patients who died early.
However, the study ultimately selected the ITT analysis set as the primary endpoint. A review written by the main investigator of this study in the public account "NEJM Frontiers of Medicine" mentioned that each scientific research team hopes that the interventions and drugs proposed by this team will show special effects. As researchers of this project, With strong desire, I hope the drug will be effective. However, in accordance with the principle that the results of the research must stand up to questioning and testing, both the editors of NEJM Magazine and us have adopted a cautious approach to select the ITT analysis set as the main endpoint result, which is the main conclusion of this article. End result.
In the ITT analysis, the median improvement time of the lopinavir-ritonavir group was 16 days, the improvement rate was 45.5% at 14 days, and the cumulative improvement rate at the end of 28 days was 78.8%. For the standard treatment group, the median improvement time was 16 days, 14 The daily improvement rate is 30%, and the cumulative improvement rate in the last 28 days is 70%. The improved hazard ratio (HR) of the two groups was 1.31 (95% CI, 0.95-1.80), P = 0.09.
In the mITT analysis set, the median improvement time of the lopinavir / ritonavir group was 15 days, the improvement rate of 4 days was 46.9%, and the cumulative improvement rate of the final 28 days was 81.3%; the standard treatment group, the median improvement time was 16 days, 14 The daily improvement rate is 30%, and the cumulative improvement rate in the last 28 days is 70%. The improved hazard ratio (HR) of the two groups was 1.39 (95% CI, 1.00-1.91), P = 0.0377.
In addition, in the subgroup analysis, the research team found that patients using lopinavir / ritonavir within 12 days of onset showed a more significant benefit trend.
199 patients included in clinical trials
Starting in December 2019, a new coronavirus (SARS-CoV-2) has caused an outbreak of a respiratory disease called COVID-19 worldwide. The complete disease spectrum of COVID-19 ranges from mild self-limiting respiratory diseases to severe progressive pneumonia, multiple organ failure, and death. To date, there are no specific treatments for coronavirus infections.
Previous studies have shown that after the emergence of severe acute respiratory syndrome (SARS) in 2003, screening of approved drugs found that lopinavir (human immunodeficiency virus [HIV] type 1 aspartic protease Inhibitor) has inhibitory activity against SARS-CoV virus in vitro.
The paper mentions that the combination of ritonavir and lopinavir is mainly to extend the plasma half-life of lopinavir by inhibiting cytochrome P450. An open-label study published in 2004 suggested that ribavirin plus lopinavir-ritonavir (400 mg and 100 mg, respectively) was compared to the historical control group receiving only ribavirin treatment. Reduced risk of adverse clinical outcomes (ARDS or death in acute respiratory distress syndrome) and viral load in SARS patients.
However, since the above studies were not randomized, no cohort was set up, and a combination of glucocorticoids and ribavirin was used, making it difficult to evaluate the effects of lopinavir-ritonavir.
Similarly, lopinavir is active against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in vitro and in animal models. And case reports indicate that the combination of lopinavir-ritonavir with ribavirin and interferon (IFN) alpha can clear the virus and make patients alive.
However, there are no firm data on the efficacy of this therapy in humans. A clinical trial (combined with recombinant interferon beta-1b) for the treatment of MERS is currently in progress (registered with ClinicalTrials.gov as NCT02845843).
To evaluate the efficacy and safety of oral lopinavir-ritonavir in the treatment of COVID-19 virus infection, the research team conducted a randomized, controlled, open-label trial of LOTUS China (Lopinavir Trial for Suppression of SARS-Cov-2 in China).
The inclusion criteria of this test are as follows: age ≥18 years, RT-PCR results of diagnostic specimens are positive, pneumonia is confirmed by chest imaging examination, oxygen saturation (SaO2) ≤94% or partial oxygen pressure (PaO2) and Male and non-pregnant female patients with a ratio of inhaled oxygen concentration (FiO2) (PaO2: FiO) ≤300 mm Hg.
The clinical study was conducted from January 18, 2020 to February 3, 2020 (the date of enrollment of the last patient) at Wuhan Jinyintan Hospital.
The research team randomly divided patients who met the participation criteria into two groups at a 1: 1 ratio, and received standard 14-day treatment combined with lopinavir-ritonavir twice daily (400 mg and 100 mg, orally ) Treatment, receiving standard treatment alone.
Depending on the patient's needs, standard treatments include oxygen inhalation, non-invasive and invasive ventilation, antibiotics, vasopressors, renal replacement therapy, and extracorporeal membrane oxygenation (ECMO).
As an indicator of the severity of respiratory failure, in order to balance the distribution of oxygen support between the two groups, the research team stratified randomized groups according to the respiratory support method when patients were enrolled: no oxygen support or oxygen using a nasal catheter or mask Support, either high-flow oxygen non-invasive ventilation or invasive ventilation including ECMO.
During the period from 0 to 28, the patient was discharged from the hospital or the patient died, the nurses evaluated the patient's condition twice a day based on a diary card, which recorded 7-point scale data and safety data.
The primary endpoint set by the research team was the time to improvement in clinical condition, which was defined as the improvement from randomization to a 7-point scale with a 2-point improvement (compared to the condition at the time of randomization) or the time to discharge, whichever occurred first. Item prevails.
The rating scale has previously been used as the endpoint of clinical trials for hospitalized patients with severe influenza. The 7-point scale includes the following levels: 1. No hospitalization and can continue to engage in daily activities; 2. No hospitalization but can not continue to engage in daily activities; 3. Hospitalization without oxygen inhalation; 4. Hospitalization with inhalation Oxygen; 5. hospitalization requires nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6. hospitalization, requires ECMO, invasive mechanical ventilation, or both; 7. death.
Other clinical outcomes included clinical status assessed on a 7-point scale on days 7 and 14, 28-day mortality, duration of mechanical ventilation, length of hospital stay for survivors, and time (days from initiation of treatment to death) ). Virological indicators include the proportion of patients with viral RNA detected over time, and the area under the viral RNA titer curve (AUC) measurements.
Safety outcomes include adverse events, severe adverse events, and early discontinuation of treatment during treatment.
The research team collected oropharyngeal swab samples from patients on day 1 (before taking lopinavir-ritonavir) and on days 5, 10, 14, 21, and 28 (until the patient was discharged or died) and performed Real-time RT-PCR detection. Sample collection was not stopped after a negative swab test at a time point.
Multiple data show no significant difference between the two groups, and a higher incidence of gastrointestinal adverse events
Of the 199 patients randomized, 99 patients were treated with lopinavir-ritonavir and 100 patients were treated with standard criteria alone. Of the 99 patients in the lopinavir-ritonavir group, 94 (94.9%) received assigned treatment.
Five patients in the lopinavir-ritonavir group did not receive lopinavir-ritonavir treatment. Three of these were due to early death within 24 hours of randomization. The other two were due to randomization. After the group, the attending physician refused to prescribe lopinavir-ritonavir.
The median age of the patients was 58 years (interquartile range, 49-68 years), and 60.3% were male patients. The median interval between symptoms and randomization was 13 days (interquartile range, 11-16 days).
There were no significant differences between the two groups in demographic characteristics, baseline laboratory test results, distribution of rating scale scores, or NEWS2 scores at enrollment. During the trial, the proportion of patients receiving systemic glucocorticoid therapy in the lopinavir-ritonavir group and the standard treatment group were 33.0% and 35.7%, respectively.
The research team concluded that in the intent-to-treat population, there was no difference in the time to clinical improvement between the lopinavir-ritonavir group and the standard treatment group (median, 16 days vs. 16 days; Hazard ratio, 1.31; 95% confidence interval, 0.95-1.85; P = 0.09).
However, in the modified intent-to-treat population, the median time to improvement in clinical status for patients in the lopinavir-ritonavir and standard treatment groups was 15 days and 16 days, respectively (risk ratio, 1.39; 95% confidence interval). , 1.00-1.91).
In the intent-to-treat population, receiving lopinavir-ritonavir treatment within 12 days of the onset of symptoms was associated with earlier improvement in clinical status (risk ratio, 1.25; 95% confidence interval, 1.77-2.05) and later acceptance Lopinavir-ritonavir treatment was not associated with earlier improvement in clinical status (risk ratio, 1.30; 95% confidence interval, 0.84-1.99).
During the discussion, the research team mentioned that the early use of lopinavir-ritonavir in patients with COVID-19 may have clinical benefits. This issue is important and requires further research. The study findings are consistent with the progression of COVID-19 viral pneumonia within the second week of the disease and with the time-to-treatment effect observed in antiviral studies previously performed in SARS and severe influenza.
In the intent-to-treat population, if the time to clinical improvement was evaluated based on the NEWS2 score at the time of enrollment, no significant difference was observed. In addition, there was no difference in time to clinical deterioration (defined as a 1-point increase in the 7-point scale) between the two groups (risk ratio for clinical improvement, 1.01; 95% confidence interval, 0.76-1.34).
In terms of secondary outcomes, in the intention-to-treat population (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% confidence interval, -17.3-5.7) or the modified intention-to-treat population (16.7% vs. 25.0%; difference , -8.3 percentage points; 95% CI, -19.6-3), the 28-day mortality rate of the lopinavir-ritonavir group was numerically lower than that of the standard treatment group.
Patients in the lopinavir-ritonavir group were shorter in intensive care unit (ICU) than patients in the standard treatment group (median, 6 days vs. 11 days; difference, -5 days; 95% CI, -9 -0), and the time from randomization to discharge was shorter than the standard treatment group (median, 12 days vs. 14 days; difference, 1 day; 95% CI, 0-3). In addition, at day 14, the percentage of patients with improved clinical status in the lopinavir-ritonavir group was higher than in the conventional treatment group (45.5% vs. 30.0%; difference, 15.5 percentage points; 95% CI, 2.2-28.8 ).
There were no significant differences in other outcomes, such as duration of oxygen inhalation, length of hospital stay, and time from randomization to death.
In terms of virology, the baseline viral RNA load average (± SD) of throat swab samples (samples obtained after obtaining informed consent) of patients in the lopinavir-ritonavir group was slightly higher than that in the conventional treatment group when randomized. (4.4 ± 2.0 log10 copies / ml vs. 3.7 ± 2.1 log10 copies / ml).
Over time, there was no difference in viral RNA load between patients in the lopinavir-ritonavir group and those in the standard treatment group, including analysis based on time of illness).
At any sampling time, the percentage of patients who could detect COVID-19 virus RNA in the lopinavir-ritonavir and standard treatment groups was similar (day 5, 34.5% vs. 32.9%; day 10, 50.0 % vs. 48.6%; Day 14, 55.2% vs. 57.1%; Day 21, 58.6% vs. 58.6%; Day 28, 60.3% vs. 58.6%).
The research team believes that compared with standard supportive care alone, no addition of lopinavir-ritonavir treatment has been found to reduce viral RNA load, nor has the patient detected a reduction in viral RNA detection time. At the end of the trial (day 28), COVID-19 virus RNA was still detected in 40.7% of patients in the lopinavir-ritonavir-treated group. A recent report showed that in patients with severe illness, the median time to detoxification of COVID-19 is 20 days, and some may be as long as 37 days.
Neither this study nor current studies found evidence of important antiviral effects of lopinavir-ritonavir. The reason for the lack of antiviral effect of lopinavir-ritonavir in the treatment of patients with COVID-19 virus pneumonia is uncertain, "but the sampling method used in the current trial is probably not the best choice."
Safety studies showed that 46 patients (48.4%) and 49 patients (49.5%) of the lopinavir-ritonavir group and the standard treatment group reported adverse events during the randomization to the 28th day. The incidence of gastrointestinal adverse events (including nausea, vomiting, and diarrhea) was higher in the lopinavir-ritonavir group than in the conventional treatment group. The percentage of patients with abnormal laboratory results was similar in the two groups.
A total of 51 patients had serious adverse events: 19 in the lopinavir-ritonavir group and 32 in the standard treatment group (Table 4). There were 4 serious gastrointestinal adverse events in the lopinavir-ritonavir group, but no serious gastrointestinal adverse events occurred in the standard treatment group. The research team determined that all four incidents were related to the test drug. The incidence of respiratory failure, acute kidney injury and secondary infection was higher in the standard treatment group than in the lopinavir-ritonavir group.
The research team mentioned that the side effects observed in this trial raised concerns about using higher or longer lopinavir-ritonavir dosage regimens to improve outcomes.
The research team also determined that all deaths during the observation period were unrelated to the intervention.
Overall, the research team found that in patients with severe COVID-19, lopinavir-ritonavir treatment did not significantly accelerate clinical improvement, reduce mortality, or reduce the detectability of throat virus RNA. These early data can provide reference for future research to evaluate the possibility of this drug and other drugs to treat COVID-19 virus infection.
The dilemma of new infectious disease drugs: the time window for effective treatment is extremely narrow
It is worth noting that the main study of this study also disclosed some information behind the clinical trial in the aforementioned review article.
First of all, why did you choose lopinavir-ritonavir for clinical trials, and why did you choose to run it at Jinyintan Hospital?
Zhang Dingyu previously disclosed, "We have an inherent advantage, because lopinavir / ritonavir is an anti-AIDS drug, our hospital is responsible for AIDS, and all of the province's AIDS drugs are with us. A patient is calculated on the basis of 14 days. It takes about 56 pills and a bottle of 120 pills, which can be taken by two patients. According to this algorithm, we have about 1,000 servings of pills. So we started the clinic soon. Some department directors, if there is a serious patient, quickly give this medicine, it may be useful. "
The main researchers wrote in the above review: In the early stages of the epidemic, facing the problems of rapid deterioration and irreversibility of some severely ill patients, we have been thinking about what drugs can treat more severely ill patients?
"In fact, we are very embarrassed to put forward lopinavir / ritonavir, fearing that the doctors would not understand it, and even the idea of waiting for the second cohort observation. However, Dean Zhang Dingyu and his team gave The China-Japan Hospital team firmly supported. Finally, the two teams of China-Japan Hospital and Jinyintan Hospital cooperated to complete the world's first randomized controlled clinical trial of COVID-19. "
They also mentioned that Radixivir was listed as the most important drug because it has the strongest antiviral activity in vitro, validated by animal experiments, and has I / II / III clinical trial data. "But because Radixivir is not available globally and it has insufficient clinical accessibility, we list Radixivir as the second drug to be evaluated."
However, the clinical trial was completed on January 9th, but until January 18th, the first patient was formally randomized, with a lot of twists and turns.
One of them includes registration of clinical trials. The research team hopes to register and disclose research information on the corresponding clinical trial platform as soon as possible, so that peer supervision can ensure that clinical trials are open and transparent. However, the registration website of ClinicalTrials.gov refused us to register with "COVID-19 is an endemic disease". Later, it was successfully registered on the Chinese clinical trial registration platform, but this delayed valuable time. When they completed the clinical trial registration, they were already in the first patient enrollment.
The review reads, "This is really a great irony. At the beginning of January, the registered website of ClinicalTrials.gov did not expect that COVID-19 had swept the world in just two months."
And, one week after the China-Japan Friendship Hospital team returned to Beijing on January 9 to participate in other epidemic prevention and control, the random number in the random system was always zero. After several communications, it was found that the project was difficult to progress. "The team of Dean Zhang Dingyu first convinced the clinician to try it in a small number of patients and found that the operation of inhaling interferon will increase the difficulty of clinical implementation and increase the risk of aerosol exposure.
Finally, the research team modified the protocol to use lopinavir-ritonavir alone as an intervention.
The China-Japan Friendship Hospital team returned to Jinyintan Hospital again on January 23. "We can't help but be filled with emotion, the severity of the epidemic situation in Wuhan at the time exceeded my imagination."
Researchers have mentioned that in the face of emerging respiratory infections, it is difficult to quickly identify effective treatments. In the history of trying to treat SARS and MERS, the opportunity to prove the efficacy and safety of lopinavir-ritonavir has been missed twice for many reasons.
"Two consecutive missed opportunities to explore and treat coronavirus drugs have indirectly led to the dilemma of the current global epidemic of COVID-19 without an antiviral drug." The research team believes that in the face of new emerging respiratory infectious diseases, effective treatment measures are being explored. The time window is extremely narrow, and the most precious resources need to be focused to prioritize several drugs with full potential.
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