Oral Liushen Pill for Patients with Covid-19 : A prospective, randomized, controlled trial

doi:10.21203/rs.3.rs-1957687/v1

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Oral Liushen Pill for Patients with Covid-19 : A prospective, randomized, controlled trial

https://doi.org/10.21203/rs.3.rs-1957687/v1

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Objective To analyze the efficacy and safety of Liushen Pill combined with basic treatment on patients with COVID-19.

Methods One-hundred-eighty-one patients hospitalized with COVID-19, classified as asymptomatic, mild type, were randomly separated into the experimental (n=91) and control (n=90) groups. The control group was given placebo (Maizao decoction), while the experimental group was given Maizao decoction and Liushen pill, in addition to standard care. The negative conversion rate of nucleic acid (Day 7), hospital discharge rate (Day 8, 10, 14), symptom disappearance rate (Day 3, 5, 7), inflammatory cytokines and adverse events between the two groups were compared.

Results The negative viral conversion rate in the experimental group was significantly higher than that in the control group (48.35% vs 31.11%, P＜0.05). Subgroup analysis showed a similar significant trend when the Ct value was ≤ 30 at baseline. After 10 days, the hospital discharge rate was significantly higher in the experimental than the control group (69.23% vs 53.33%, P＜0.05). After 3 days of medication, the headache symptoms significantly disappeared in the experimental group (88.57%) compared to the control group (63.33%) (P＜0.05). After 5 days, symptom disappearance rate of headache in the experimental group (97.14%) was still significantly higher than that in the control group (80.00%) (P＜0.05), as was the symptom disappearance rate of cough (82.65% vs 58.93%, P＜0.01). After treatment, the PCT level was significantly lower in the experimental than the control group (0.09±0.00 ng/L vs 0.14±0.05 ng/L) (P＜0.05). There were no significant between-groups differences in clinical safety test indexes.

Conclusion Early intervention with Liushen Pill could improve the symptoms of cough and headache, and increase negative viral conversion and discharge rate.

Trial registration Chinese Clinical Trial Registry, No. ChiCTR2200058859. Registered on April 18, 2022. https://www.chictr.org.cn/edit.aspx?pid=166975&htm=4

Liushen Pill

COVID-19 infection

virus negative conversion

clinical trials

COVID-19 (COVID-19) is an acute respiratory human infectious disease caused by infection with novel coronavirus-2 (SARS-CoV-2), which is seriously harmful to human health ^[1]. Since the outbreak of the epidemic, SARS-CoV-2 has constantly mutated, resulting in a variety of variants. The BA.2 subvariant of the Omicron SARS-CoV-2 strain has a higher infectivity, stronger vaccine breakthrough, and stronger antibody escape ability than prior variants. As such, it has spread to many countries and regions around the world, to become the predominant epidemic strain in May, 2022^{[2, 3]}. According to recent epidemiological statistics of the World Health Group (WHO), as of June 5, 2022, there were more than 500 million confirmed COVID-19 cases worldwide, resulting in more than 6 million deaths ^[4]. The strong transmission and weak pathogenicity of the new variants have led to great changes in the concepts and strategies of global clinical diagnosis, treatment and prevention management ^[5].

According to the transmission characteristics and clinical manifestations of COVID-19, it is classified as a "Wenyi disease" in traditional Chinese medicine (TCM)^{[6, 7]}. Since the outbreak of the epidemic in 2019, traditional Chinese medicine has made an important contribution to the prevention and control of the epidemic, and is one of the important treatment methods of COVID-19 infection^[6]. Liushen Pill is composed of musk, bezoar, toad, realgar and six other medicinal herbs; however, the exact formulation is a national top-secret formula. Liushen allows the clearing away of heat and detoxification, while simultaneously exerting anti-inflammation effects and relieving pain. Liushen is a classic prescription for heat-clearing and detoxification of febrile diseases, and has been used for more than a hundred years. In recent years, the related research on Liushen Pill has gradually deepened, and Liushen Pill has been found to exert a variety of pharmacological activities, such as analgesia, anti-inflammation, cardiotonic, enhancing immunity, anti-tumor and anti-virus, and can further inhibit the expression of many kinds of novel coronavirus strains ^{[8, 9]}. In clinical studies Liushen Pill has played a role in treating COVID-19 infection. A prospective randomized controlled study found that administration Liushen pill can shorten the antipyretic time of patients with novel coronavirus infection and improve TCM syndromes and clinical symptoms^[10]. The main functions of Liushen pill are heat-clearing and detoxification, anti-inflammation, and analgesia. It is recommended as a treatment for COVID-19 in many domestic regions of China for patients with fever, dry cough, sore throat, and headache. Considering the main respiratory infection of Omicron and the indication of Liushen pill, in order to further confirm the therapeutic effect of early intervention of Liushen pill on COVID-19, our hospital carried out a randomized controlled clinical trial of Liushen pill in the treatment of novel coronavirus infection (asymptomatic, mild type).

Patient enrollment:

This study adopted a prospective design and planned to include 200 patients with COVID-19 infection (asymptomatic, mild, common type). Patients were randomly assigned to the experimental group or the control group in a 1:1 ratio using the random table method.

From April 10 to May 2, 2022, a total of 181 patients with asymptomatic infection and mild OmicronBA.2 were randomly assigned to the trial group (n = 91) or the control group (n = 90). All patients completed treatment. This study was registered in the China Clinical Trials Registration Center (ChiCTR2200058859).

The Inclusion criteria were as follows: (1) age ≥ 14 years old; (2) patients met the diagnostic criteria of novel coronavirus infection based on the "novel coronavirus pneumonia diagnosis and treatment Program (trial Ninth Edition)" issued by the National Health Commission. (3) the subjects voluntarily joined this study and signed the informed consent form.

The exclusion criteria were (1) Presence of other respiratory tract infections caused by primary immunodeficiency disease, acquired immunodeficiency syndrome, congenital respiratory malformation, congenital heart disease, gastroesophageal reflux disease, pulmonary dysplasia and other basic diseases, or clear evidence of bacterial infection. (2) subjects with the following conditions: asthma requiring daily treatment, any other chronic respiratory diseases, respiratory bacterial infections such as suppurative tonsillitis, acute tracheobronchitis, sinusitis, otitis media, and other respiratory diseases which may affect the evaluation of clinical trials. Patients with severe pulmonary interstitial lesions, bronchiectasis and other basic lung diseases confirmed by chest CT; (3) patients with severe pneumonia requiring mechanical ventilation; (4) A history of past or present illnesses which may affect patients' participation in trials or affect the outcome of the study, including malignant diseases, autoimmune diseases, liver and kidney diseases, hematological diseases, nervous system diseases, and endocrine diseases; or diseases that seriously affect the immune system, such as human immunodeficiency virus (HIV) infection, or blood system, or splenectomy, organ transplantation, etc.; (5) pregnant or lactating women; (6) patients who have participated in other clinical trials within 1 month; (7) allergies to two or more drugs or food, or allergies to any of the ingredients of this drug. (8) Any participants for whom the researchers believed that there are any factors which made them unsuitable for enrollment or which affect the evaluation of the efficacy of the subjects.

Treatment plan

Patients in both groups were routinely managed in accordance with the requirements of "novel coronavirus pneumonia diagnosis and treatment Program (trial version 9)" ^[11]. The experimental group was treated with Liushen pill (Lei Yun Shang Pharmaceutical Group Co., Ltd., batch number: UA01002, specification: 10 tablets / branch * 6 tablets / box), 3 tablets each time and oral 7 tablets ^[12], 3 times a day and Maizao decoction (15g fried malt, 10g jujube, 200ml decoction, 1 dose a day, Take it in 2 doses). The control group was treated with placebo (Maizao decoction). Each treatment course lasted 7 days; if the patient tested negative before this, the treatment was ended early.

Laboratory examination:

Fasting venous blood was collected on the first hospitalization day, or the morning of the next day to examine glutamic pyruvic transaminase (ALT), aspartate oxaloacetic transaminase (AST), procalcitonin (PCT), interleukin-6 (IL-6), lymphocyte count(L), neutrophil count (N), lactate dehydrogenase (LDH), D-dimer, serum creatinine (Cr), serum troponin c (c-TnT) and creatine kinase isoenzyme (CK-MB). The reference range of each index is as follows: ALT: 9 ~ 52 U/L, AST: 1.10–3.20×10⁹ /L, PCT < 0.5 ng/L, IL-6: 3 ~ 5000pg/L,L:1.1 ~ 3.2×109 /L, N༚1.8 ~ 6.3×10⁹ /L, LDH༚120–246 U/L, D-dimer༚0 ~ 550 µg/L, Cr: 46 ~ 92 µmol/L, c-TnT < 14pg/L, CK-MB: < 3.61 ng/L.

Efficacy indicators:

The main study objectives were: (1) the virus negative conversion rate of the two groups on the 7th day after admission, (2) the discharge rate of the two groups on the 8th, 10th and 14th day after admission. The secondary objectives were: (1) the effectiveness of clinical symptom improvement on the 3rd, 5th and 7th day after entering the group, (2) the index of inflammatory factors: the changes of PCT, IL-6 and neutrophil count in the two groups before and 7th day after treatment.

Safety:

The occurrence of any adverse events (AEs) that occurred during the trial was recorded.

Discharge or release criteria:

The discharge criteria were formulated according to the requirements of "novel coronavirus pneumonia diagnosis and treatment Program (trial version 9)"; viral negative conversion means that the Ct values of the ORF and N genes detected by novel coronavirus were ≥ 35 on two consecutive times taken at least 24 hours apart.

Statistical analysis:

SPSS19.0 software was used to process the data, and the measurement data were described by ±s or M (Q1 Q3). Bilateral t-test and independent sample median test were used to verify the differences between normal distribution and non-normal distribution variable groups. Chi-square test or exact probability test were used for classified data, P < 0.05 indicates a statistically significant difference

Baseline data:

A total of 181cases of COVID-19 were randomly assigned to the control group (n = 90) or the experimental group (n = 91). The control group (83 cases with asymptomatic infection and 7 cases with mild infection) and the experimental group (89 cases with asymptomatic infection and 3 cases with mild infection) were comparable in age, sex, BMI, history of basic diseases, and vaccination times (Table 1).

Negative conversion rate of the two groups on the 7th day after group allocation:

As shown in Table 2, on the 7th day after group allocation, the virus negative conversion rate of the test group was 48.35%, which was significantly higher than that of the control group (31.11%), and the difference was statistically significant (P = 0.027 < 0.05). According to the baseline Ct value, the patients were divided into two subgroups: baseline Ct value ≤ 30 and baseline Ct value > 30. The virus negative conversion rate was analyzed on the 7th day. The results showed that when the baseline Ct value was ≤ 30, the virus negative conversion rates of the test group and the control group on the 7th day were 44.26% and 25.40%, there was a statistical difference between the two groups (P = 0.038༜0.05). When the baseline Ct value was greater than 30, the virus negative conversion rate on the 7th day was 56.67% in the test group, and 44.44% in the control group, and the difference was not statistically significant (P = 0.437 > 0.05) (Fig. 1).

Discharge rates of the two groups on the 8th, 10th, and 14th day after admission:

As shown in Table 3, on the 8th day after admission, the discharge rates of the test group and the control group were 23.08% and 16.67% respectively, with no statistical difference (P = 0.371 > 0.05). On the 10th day after group allocation, the discharge rate of the test group was 69.23%, while that of the control group was 53.33%. The discharge rate of the test group was significantly higher than that of the control group, and there was a statistically significant difference between the two groups (P = 0.041 < 0.05). On the 14th day after group allocation, the discharge rates of the test group and the control group were 90.11% and 88.89% respectively, and there was no significant difference between the two groups (P = 0.813 > 0.05).

Disappearance rates of clinical symptoms on the 3rd, 5th and 7th day after group allocation:

On the 3rd day, the disappearance rate of headache symptoms in the test group (88.57%) was significantly higher than that in the control group (63.33%), with a significant difference between the two groups (P = 0.020 < 0.05). On the fifth day, the disappearance rate of headache in the test group (97.14%) was still significantly higher than that in the control group (P = 0.042 < 0.05). In addition, the disappearance rate of cough symptoms in the test group and the control group was 82.76% and 58.93%, respectively. The disappearance rate in the test group was significantly higher than that in the control group, and the difference was statistically significant (P = 0.007 < 0.01). On the 3rd, 5th and 7th days, the disappearance rate of cough, pharyngeal discomfort, nausea and vomiting, fatigue, nasal congestion and runny nose, loose stools, body ache and fever in the experimental group was higher than that in the control group, but there was no statistical significance between the two groups (P > 0.05, Tables 4, 5, & 6).

Changes in inflammatory indexes before and after treatment

As shown in Table 7, there was no significant difference in the levels of PCT, IL-6, lymphocyte and neutrophil count between the two groups before treatment. After treatment, the level of PCT in the test group was significantly lower than that in the control group, and there was significant difference between the two groups.

Clinical safety monitoring index

During the study period, 6 subjects in the experimental group experienced gastrointestinal adverse events such as nausea and vomiting, and the incidence of adverse events was 6.59%, the researchers concluded that it might be related to research drugs, after symptomatic treatment, all patients returned to normal. No other drug-related adverse events were observed during the study, and no adverse events were observed in the control group. Other safety indicators during the study are shown in Table 8, and there was no significant difference in safety indicators between the two groups before and after treatment (P > 0.05).

The Omicron variant of SARS-CoV-2 was first discovered in 2021, and has since spread rapidly around the world, becoming the predominant strain. Most patients infected with Omicron have no or mild clinical symptoms ^[13], but because of its high transmission, the global population base of infection is large, meaning that the number of related deaths remains high ^[5]. In addition, the Omicron mutant has a higher infectivity and transmission concealment, allowing it to easily cause a large-scale epidemic outbreak in a short time, endanger people's health, and increase medical pressure. Therefore, the prevention and control of the Omicron mutant and the treatment of infected patients remain the focus of epidemic prevention.

According to the theory of traditional Chinese medicine, COVID-19 can be classified as a "febrile (epidemic) disease", and its etiology is mainly "dampness". With the progress of the disease, there are many signs of "dampness and toxin" and "dampness-toxin heat" ^{[6, 14]}. The development and prognosis of patients depend on the results of vital qi (immune function) and toxic pathogen (exogenous epidemic qi) testing. Liushen Pill is a classic heat-clearing and detoxifying prescription of the febrile disease school. Modern pharmacological studies have shown that Liushen Pill exerts anti-inflammatory, detoxifying, analgesic, and immune-enhancing effects, and can regulate NF- κ B/MAPK signal pathway, thus inhibiting the expression of novel coronavirus ^{[9, 15]}. It has also been reported that Liushen Pill can significantly inhibit the replication of two SARS-CoV-2 variants and the expression of proinflammatory cytokines induced by viruses in vitro and improve the survival rate of virus-infected mice ^[15]. Liushen Pill can promote the relief of clinical symptoms and inhibit the expression of inflammatory factors in COVID-19 patients^[15].

In order to further confirm the efficacy and safety of Liushen Pill in the treatment of novel coronavirus infection, in this clinical study, 181 patients with COVID-19 infection (asymptomatic, mild, common type) were randomly divided into the experimental treatment (n = 91) and control (n = 90) groups. The results showed that on the 7th day, the virus negative conversion rates of the test group and the control group (both the ORF and N genes) were 48.35% and 31.11%, respectively. The negative conversion rate of the test group was significantly higher than that of the control group, and the difference was statistically significant (P༜0.05). At the same time, the results of subgroup analysis showed that when the baseline viral nucleic acid Ct value was less than 30, the virus negative conversion rate of the test group on the 7th day was significantly higher than that of the control group (44.26% vs 25.40%, P < 0.05). It is suggested that early treatment with Liushen Pill can promote early negative transformation in patients with higher viral load. In vitro studies have confirmed that Liushen Pill has a good inhibitory effect on novel coronavirus, especially on the Omicron mutant^[15]. However, this study confirmed for the first time that early intervention with Liushen Pill can promote the negative conversion of Omicron infection with fever, cough, sore throat and headache as the main symptoms. Considering the main characteristics of Omicron upper respiratory tract infection, and that Liushen pill may cause gastrointestinal discomfort symptoms, in this study, Liushen pill were used for only 7 days, and fried malt, jujube medicine and food homologous traditional Chinese medicine were used to protect digestive function. The results showed that 10 days after group allocation, the discharge rate of the test group (69.23%) was significantly higher than that of the control group (53.33%) (P < 0.05). In addition, the results showed that on the third day, the clinical symptoms of the patients in the test group showed a significant improvement trend, the improvement rates of headache in the experimental and control groups were 88.57% and 63.33% respectively (P < 0.05). On the 5th day, the improvement rate of headache in the test group (97.14%) was still significantly higher than that in the control group (80.00%) (P < 0.05). We hypothesize that this is related to the heat-clearing and detoxifying, anti-inflammatory, and analgesic effects of Liushen pill, so the headache symptoms of the patients could be improved on the 3rd and 5th day of treatment, Cough is the main clinical symptom of COVID-19 in the acute phase and persists after infection ^[16]. Cough also promotes the transmission of respiratory droplets in the community, especially during the COVID-19 pandemic, and thus the control of COVID-19-related cough may reduce community transmission. This study found that on the 5th day, the improvement rate of cough in the test group was significantly higher than that in the control group (82.65% vs 58.93%, P < 0.01). To sum up, taking Liushen pill can improve patients' clinical symptoms, and increase patients' virus negative conversion rate and discharge rate, so as to save medical resources and reduce medical pressure.

The patients included in this study were all patients infected with Omicron strain. Considering that Omicron has a low inhibition of interferon response in host cells, mainly invading the upper respiratory tract ^[17], and the proportion of viral pneumonia was also low, so the level of inflammatory factors did not significantly increase before treatment. There was no significant difference in the levels of PCT and IL-6 between the experimental and control groups before treatment, but the levels of PCT and IL-6 in the experimental group were lower than those in the control group after treatment. Among them, the level of PCT in the test group was significantly lower than that in the control group (0.09 ± 0.00 ng/L vs 0.14 ± 0.05 ng/L, P < 0.05). These results show that taking Liushen pill can down-regulate the level of serum inflammatory factors and inhibit airway inflammation. The curative effect of Liushen Pill embodies the theoretical idea of "clearing heat and resolving dampness" in traditional Chinese medicine to treat COVID-19. At present, many clinical and experimental studies have been performed to reveal the relevant molecular mechanism of "clearing heat and resolving dampness" in regulating airway inflammation and effectively relieving cough, fever and other related clinical symptoms of COVID-19 patients ^{[14, 18]}.

To sum up, Liushen Pill combined with basic treatment can improve the condition of COVID-19 infection (asymptomatic, mild, common type), and significantly increase the virus negative conversion rate and discharge rate of patients. This study further confirmed the efficacy and safety of Liushen pill in the treatment of COVID-19, and indicate it as a new medicine for the treatment of this disease. However, this study is only a single center clinical observation, although randomized control and allocation concealment were adopted, there was no blind method, and there was a certain risk of bias in the\/study, In the future, double-blind and multi-center large-sample studies should be carried out when conditions are ripe to further verify the research results.

Funding：Jiangsu Provincial Administration of Traditional Chinese Medicine emergency Research Project on COVID-19 Prevention and Treatment（JSZYJ202201）

Acknowledgments

We thank all participants for their contributions to the study.

Author contributions

SCL, HJA, and ZJP conceived and contributed to the study design.SCL and ZJP obtained ethical approval. LYA、LW and CXsupervised the study.。YZ and SJH contributed to the study collaboration. TT、CX、LJ participated in clinical treatment and data collection. SCL and SJH were responsible for data management and analysis. SCL drafted the manuscript. HJA and ZJP reviewed the manuscript. All authors read and approved the fnal manuscript.

Funding

This study was supported and funded by Jiangsu Provincial Administration of Traditional Chinese Medicine emergency Research Project on COVID-19 Prevention and Treatment（JSZYJ202201） . Funding played no role in the study design, collection, management, or analysis, nor in the interpretation of the data, writing of the report, or decision to submit the report for publication.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

This study was reviewed and approved by theThis study was approved by the Ethics Review Committee of our hospital (approval No. (2022-006) in April 2022. Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Tables 1 to 8 are available in the Supplementary Files section

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Version 1

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You are reading this latest preprint version

Oral Liushen Pill for Patients with Covid-19 : A prospective, randomized, controlled trial

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Patient enrollment:

Treatment plan

Laboratory examination:

Efficacy indicators:

Safety:

Discharge or release criteria:

Statistical analysis:

Results

Baseline data:

Negative conversion rate of the two groups on the 7th day after group allocation:

Discharge rates of the two groups on the 8th, 10th, and 14th day after admission:

Disappearance rates of clinical symptoms on the 3rd, 5th and 7th day after group allocation:

Changes in inflammatory indexes before and after treatment

Clinical safety monitoring index

Discussion

Declarations

References

Tables

Supplementary Files

Status:

Version 1