Chinese medicine compound for the convalescent COVID-19 patients: A multicenter, randomized, double-blind, placebo-controlled clinical trial protocol

Chinese medicine compound for the convalescent COVID-19 patients: A multicenter, randomized, double-blind, placebo-controlled clinical trial protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Chinese medicine compound for the convalescent COVID-19 patients: A multicenter, randomized, double-blind, placebo-controlled clinical trial protocol Rui Fang, Wanyao Yang, Yue Zhou, Le Xie, Jiaxuan Tian, Lei Zhao, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5332179/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Convalescent coronavirus disease 2019 (COVID-19) refers to a series of clinical syndromes in patients with COVID-19 infection that follow the relevant discharge indications but do not fulfill the criteria for a clinical cure, and these patients are discharged from the hospital with residual multifunctional deficits, including coughing, fatigue, and insomnia. The World Health Organization's preliminary statistics revealed that over 65 million individuals worldwide experience a 'long COVID', and the incidence rate in each country varied from 34–77%. Due to the prolonged convalescent COVID-19 infection, patients continue to experience symptoms or develop new symptoms after three months of infection, and some symptoms persist for over two months without any apparent triggers, which has a significant impact on the health status and quality of life of the population. Patients with convalescent COVID-19 lack a definitive pharmacological treatment. Traditional Chinese medicine (TCM) exhibits a distinct, synergistic effect on the treatment of convalescent COVID-19. However, there exists a limited number of clinical trials on TCM with lower evidence levels in convalescent COVID-19; therefore, randomized trials are urgently required. Methods A multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial was performed to evaluate the efficacy and safety of Shenlingkangfu (SLKF) granules in treating patients with convalescent COVID-19 and lung-spleen qi deficiency syndrome. The trial was conducted through ten hospitals in China's Hunan province, with subjects recruited from outpatient medical record platforms, inpatient case systems, and subject recruitment advertisements. Eligible participants were aged 18–75 years, had a confirmed or physician-suspected severe acute respiratory syndrome coronavirus 2 infection at least six months prior, and satisfied clinical criteria. Individuals with a history of severe pulmonary dysfunction or major liver and kidney illness or those on medications were excluded. After a 2-day adjustment period, all participants were randomly divided into an intervention group (n = 77) and a control group (n = 77). The intervention group was given the SLKF granules orally once a bag, 16.9 g, twice daily, whereas the control group received the SLKF granule simulation at the same dosage. The trial was conducted over 14 days, with assessments performed at baseline and 14 days. The primary outcomes were the therapeutic efficacy rate and total clinical symptom score. The secondary outcomes included the fatigue self-assessment scale, pain visual analog scale, Pittsburgh sleep quality index, mini-mental state examination, hospital anxiety and depression scale, TCM syndrome score, C-reactive protein, erythrocyte sedimentation rate, and interleukin-6. Three routine examinations, liver and kidney function tests, and electrocardiography were used as safety indicators. Discussion This study aimed to verify whether SLKF granules can significantly improve clinical symptoms, including fatigue, loss of appetite, cough, phlegm, and insomnia, in patients with convalescent COVID-19. For a comprehensive investigation, additional clinical trials with larger sample sizes and longer intervention periods are required. Trial registration Registered 26 January 2024, https://www.chictr.org.cn , identifier ChiCTR2400080348. Chinese medicine alternative and complementary medicine convalescent COVID-19 randomized controlled trial protocol Figures Figure 1 Background Coronavirus disease 2019 (COVID-19) is an acute infectious disease caused by the coronavirus, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of July 21, 2024, World Health Organization (WHO) statistics revealed that over 775 million people worldwide have been infected with COVID-19, and more than seven million people have died since the pandemic began over four years ago [ 1 ]. Convalescent COVID-19 denotes patients infected with the novel coronavirus who conform to relevant discharge indications. However, below the clinical cure standards, these patients experience a series of 'long COVID' syndromes, including cough, fatigue, insomnia, and other multifunctional disorders after discharge [ 2 – 3 ]. Common clinical manifestations include musculoskeletal symptoms (general fatigue, muscle soreness, headache, and joint pain), neurological symptoms (transient cognitive function or impairment of consciousness and thinking, referred to as brain fog), and autonomic neuropathy (loss of smell and taste, sleep disorders, and recurrent sweating). Cardiopulmonary dysfunction includes chronic cough, shortness of breath, and palpitations, and gastrointestinal symptoms include diarrhea and vomiting [ 4 – 5 ]. Moreover, patients may experience mental health problems, including anxiety and depression [ 6 ]. Preliminary statistics suggest that over 65 million individuals worldwide have suffered from 'long COVID' [ 7 ]. Its incidence ranges from 34–77% across various countries [ 8 ]. According to the Medical Expenditure Panel Survey , as of the beginning of 2023, about 17.8 million (6.9%) of adults in the United States have experienced 'long COVID' symptoms [ 9 ]. A Bayesian meta-analysis that consolidated data from 22 countries globally between 2020 and 2021 on 1.2 million patients with symptomatic COVID-19 revealed that at least 6.2% of patients experienced 'long COVID' syndromes, including persistent fatigue, physical pain or mood swings, persistent breathing problems, and cognitive impairment, and the proportion of the above symptoms were approximately 51.0%, 60.4% and 35.4% of patients with COVID-19, respectively [ 10 ]. Another cohort study involving 4,708 patients with COVID-19 documented that 22.5% of patients did not recover within 90 days after infection, with a median recovery time of 20 days [ 11 ]. Therefore, patients with convalescent COVID-19 may sustain uncomfortable symptoms or new concurrent symptoms after three months of infection, which significantly affects their health status and quality of life. Currently, the National Institutes of Health has recommended oral small-molecule drugs (Nematavir-Ritonavir and Monolavir) as the primary antiviral treatments for COVID-19. It exhibits a certain preventive effect against convalescent COVID-19 [ 12 ]; however, its safety requires additional verification [ 13 ]. Domestic specialist consensus considers that symptomatic treatments, including cough and pain relief, anti-anxiety and depression, and cognitive therapy, should be the primary treatment for patients experiencing 'long COVID' syndrome in the convalescence period[ 6 ]. Patients with pulmonary fibrosis and low cortisol levels can be treated with low-dose glucocorticoids [ 6 ]. Moreover, health authorities in China and other provinces and cities have successively issued guidelines on traditional Chinese medicine (TCM) for preventing and treating COVID-19 infection or health management. In January 2023, the National Health Commission and State Administration of Traditional Chinese Medicine revised and promulgated the ' Diagnosis and Treatment of COVID-19 (trial tenth edition) , which recommended light, medium, heavy, critical, and convalescent Chinese patent medicine and massage therapy, based on syndrome discrimination [ 14 ]. In December 2022, Beijing formulated ' the Expert Guidelines on Health Management for the Convalescent COVID-19 Patients (first edition) ' which provided self-rehabilitation guidance for the main symptoms of people in convalescent COVID-19, including medicinal diet and dietary therapy [ 15 ]. However, among the above programs and consensus, there is less high-quality evidence-based medical evidence on the efficacy and safety evaluation of TCM interventions for COVID-19. COVID-19 belongs to the categories of 'plague,' 'pestilence,' and 'warm disease' in TCM, which is caused by the 'pestilential pathogen.' However, the characteristics of 'pestilential pathogens' differ in different periods and regions. In view of the etiology, pathogenesis, and treatment of COVID-19, academician Boli Zhang believed that the treatment should be based on 'noxious dampness pestilence'[ 16 ], while academician Xiaolin Tong emphasized that the cold-dampness epidemic toxin was the main evil, and the method of dispelling cold and dampness should be adopted [ 17 ]. Generally, COVID-19 is caused by wind, cold, and dampness toxicity, which invades the human body and causes a struggle between vital qi and evil. After eliminating evil, the primordial qi of the patients is damaged. When the patient is in the recovery period for a long time, the evil qi gradually fades, the primordial qi deficiency and decline, the lung qi of the body is damaged, and the dispersive and descending qi movement are dysregulated. Spleen qi deficiency leads to qingyang not rising; spleen deficiency cannot nourish the lung, which eventually results in qi deficiency of the lung and spleen in the recovery period [ 18 – 19 ]. TCM granules possess the distinctive advantages of being simple, economical, and effective in the prevention and treatment of COVID-19 and play a synergistic role owing to their treatment based on syndrome differentiation and individualized prescription[ 20 ]. The results of large-scale clinical trials led by Academician Luqi Huang and Xiaolin Tong demonstrated that TCM has significant therapeutic advantages in treating clinical symptoms, including fever, cough, fatigue, chest tightness, and lung inflammation; however, the intervention effect on 'long COVID symptoms among various demographics in the recovery stage requires additional investigation [ 21 – 22 ]. Consequently, to clarify the TCM advantages in preventing and treating convalescent COVID-19, alleviate the 'long COVID' symptoms, and establish an evidence-based optimization program, it may exert a significant social impact in highlighting TCM's regulatory role in convalescent COVID-19. Through long-term clinical diagnosis and treatment practice, we observed that in the epidemic's late stage, patients frequently exhibit clinical manifestations, including long-term chronic cough and sputum, asthma, fatigue, anorexia, spontaneous sweating, sleep disorders, loose stools, pale tongue, and greasy white fur because of lung-qi deficiency and spleen-yang insufficiency [ 23 ]. This study examined the clinical efficacy and safety of Shenlingkangfu (SLKF) granules in patients with convalescent COVID-19 and lung-spleen qi deficiency syndrome. We conducted a multicenter, randomized, double-blind, simulant, and parallel controlled clinical trial, aiming to provide higher-quality evidence-based medical data for the optimization of treatment of patients with convalescent COVID-19 and lung-spleen qi deficiency syndrome. Materials and methods Study design This study was designed as a multicenter, randomized, double-blind, placebo-controlled clinical trial that lasted for 14 days, including 2 days of screening period, 14 days of treatment period, and the 14th day follow-up period. Screening was undertaken within two days before enrollment to assess eligibility and collect baseline data regarding basic medical history, combined medications, laboratory and auxiliary examinations [novel coronavirus immunoglobulin G (IgG) antibody and inflammatory factors], signs and symptoms, and assessment scales. Eligible participants were randomized into the SLKF granules group and the control group at a ratio of 1:1. Participants' medication, signs and symptoms, rating scales, and laboratory biochemical examinations on the scheduled day for the follow-up period were recorded. A workflow diagram and schedule are presented in Fig. 1 and Table 1 , respectively. The trial protocol was designed following the Recommendations for Interventional Trials Traditional Chinese Medicine (SPIRIT-TCM) Extension 2018 Statement checklist. (Online Supplemental Appendix 1). Participants Participants, diagnosed as outpatients or inpatients, were recruited and screened in the following ten clinical research sub-centers: Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (the Affiliated Hospital of Hunan Academy of Chinese Medicine), the Second Xiangya Hospital of Central South University, the First Hospital of Hunan University of Chinese Medicine, the Second Hospital of Hunan University of Chinese Medicine, Hunan Province Directly Affiliated TCM Hospital, the First Affiliated Hospital of Shaoyang University, the First Traditional Chinese Medicine of Changde, Hengyang Hospital of Traditional Chinese Medicine, and Zhangjiajie Hospital of Traditional Chinese Medicine. This trial started with recruitment from January 2024 to December 2024. Most participants were recruited through advertisements and posters in ten selected clinical research subcenters. Other participants diagnosed with convalescent COVID-19 were invited by telephone through the research team or clinical observers. All participants were required to be negative for novel coronavirus antibody or nucleic acid detection; IgG antibody levels were elevated [ 24 ] and re-screened by a specialist. Each participant signed an informed consent form (ICF) indicating that they fully understood the clinical study information concerning the trial. Diagnostic Criteria Diagnostic Criteria for the Convalescent COVID-19 According to the ' Diagnosis and Treatment of COVID-19 (trial tenth edition) ' and the Expert Guidelines on Health Management for Convalescent COVID-19 Patients (first edition) '[ 14 – 15 ], Convalescent COVID-19 refers to those who have been infected, met any of the following criteria, and had significantly improved other symptoms. (1) Two consecutive nucleic acid detections were negative, and the cycle threshold (Ct) values were ≥ 35. (2) Negative antigen test results on three consecutive days. (3) The level of novel coronavirus-specific IgG antibodies in convalescence was four times or higher than that in the acute stage. (4) In the absence of antipyretics, fever symptoms subsided for more than 24 h. (5) Pulmonary imaging demonstrated that acute exudative lesions were significantly improved and could be converted to oral drug therapy without complications necessitating further treatment. Diagnostic criteria for TCM syndrome The TCM symptom scoring table for lung-spleen qi deficiency syndrome was formulated following ' the Guiding Principles of Clinical Research on the Treatment of Diarrhea with New Chinese Medicine (2002 edition) '[ 25 ], ' the Diagnostic criteria for TCM syndromes of coronavirus disease 2019 ( trial edition )' [ 26 ], and ' the Diagnostic criteria of TCM Syndromes of Chronic Obstructive Pulmonary Disease (2011 edition) ' [ 27 ]. The cardinal and minor symptoms included in the scale were as follows: Cardinal symptoms of cough without or less phlegm, fatigue, panting, shortness of breath, torpid intake, and sloppy stool, and minor symptoms of spontaneous sweating and aversion to wind, low-grade fever, abdominal distension, cognitive impairment, insomnia, pale white complexion, dizziness, and tinnitus. Five or more points were allocated for the cardinal and minor symptoms, combined with fat tongue, teeth-marked tongue, pale tongue, white or white greasy tongue coating, sunken, fine, moderate, and weak pulse. If the above conditions were met, it was identified as lung-spleen qi deficiency syndrome. Inclusion criteria (1) Male and female patients aged 18–75 years. (2) Participants had a confirmed or physician-suspected SARS-CoV-2 infection at least six months earlier. (3) Diagnosed with convalescent COVID-19. (4) Diagnosed with lung-spleen qi deficiency syndrome. (5) The participants had no short-term migration intentions and agreed to cooperate with the follow-up. (6) Provision of written informed consent. Exclusion criteria (1) Severe liver dysfunction: ALT > 2-time normal value upper limit or AST > 2-time the normal upper limit or severe kidney dysfunction Scr > 1.5-time normal value the upper limit). (2) Severe pulmonary dysfunction [(forced expiratory volume in one second (FEV1%) of predicted value, including obstruction or restriction: severe: 35–49%, extremely severe: A value of less than 35% for FEV1% or a value of less than 40% for carbon monoxide diffusing capacity. For all measurements using z-values, severe impairment was < − 4.1] [ 28 ]. (3) Underlying blood disorders, acute rheumatic connective tissue diseases, or acute pulmonary conditions. (4) Pregnancy, planning to become pregnant, or breastfeeding. (5) History of drug rashes or anaphylactic reactions to medications. (6) Having participated in another clinical study within three months. (7) Combined with severe mental illness. (8) Recently used traditional Chinese medicine or proprietary Chinese medicine with an identical effect. Withdrawal criteria (1) The patient's condition worsened or relapsed during the administration period, and other treatment measures are required. (2) Subjects did not meet the inclusion criteria and were mistakenly included in the trial or met the trial's exclusion criteria. (3) Subjects with poor compliance were not recommended to withdraw from the trial but were no longer receiving drug treatment and were lost to follow-up. (4) Voluntary withdrawal. (5) Subjects experienced other complications, and it was inappropriate to continue the trial during the clinical trial [ 29 – 30 ]. Randomization and allocation This trial adopted a stratified block randomization method. First, an appropriate block length was selected (block size = 4), and random assignment was conducted using SAS (version 9.4) statistical software developed by statisticians from the Drug Clinical Evaluation Research Center of Central South University. A total of 154 random sequences were generated for each group; specifically, a randomized coding table (No. 001-154) was developed. The subjects in each group were randomly divided into an intervention group and a control or placebo group at an allocation ratio of 1:1. Randomized codes were used as drug numbers, which were kept in an opaque sealed envelope and taken to Hinye Pharmaceutical Co., Ltd. (Changsha Hunan, China) for unified drug label production. The identification code for each subject was similar to that of the number of drugs. Blinding Doctors, patients, outcome investigators, and statisticians were blinded to the patient's treatment assignments. The statisticians completed the randomized codes, and the staff of Hinye Pharmaceutical Co., Ltd. affixed the drug number label to the eye-catching position of the external drug packaging according to the drug number label corresponding to the formed random code. The record of the blinding process, the blind record, was kept as a clinical trial document. The contents of the blinding record included the preparation of the sponsor's drugs, drug packaging, usage, storage and assignment, generation of randomized codes, the subject's drug box production, emergency letter, test report of SLKF granules and placebo, storage of blinding codes, rules for breaking the blind law, and dispensing numbers of each research center. Blinded coding, the initial randomization number, and block length were sealed in two copies. For proper storage, the two copies were handed to the clinical trial group leader, the Department of Drug Clinical Trial Administration at Hunan University of Chinese Medicine, and the sponsor. The blinding codes were kept strictly confidential and remained sealed until statistical analysis at the end of the trial, only if serious adverse events (SAEs) or emergencies occurred. Intervention Treatments Multicenter subjects satisfying all criteria were assigned (1:1) randomly into an intervention group and a control group. All participants received health management guidance (maintaining good personal and environmental hygiene, balanced nutrition, moderate exercise, adequate rest, and avoiding fatigue). Subjects with chronic underlying diseases were administered corresponding treatments. The intervention group was treated with SLKF granules orally (once per bag, 16.9 g, twice daily). Subjects in the control group were treated with a placebo at the same dosage, which had an identical appearance and nearly similar taste to SLKF granules. If necessary, routine treatment, including cough relief and other symptomatic support, was administered. The treatment for the two groups lasted 14 days. Each center was assigned a clinical coordinator (CRC) responsible for allocating drugs based on the recruitment sequence before filling out the dispensing record form. Preparation of drugs SLKF granules were composed of traditional TCM formula granules that met the quality standards according to the proportion of prescriptions. Each package was equivalent to decoction: Dangshen (C odonopsis Radix ) 3.75 g (9.8%), Huangqi ( Astragali Radix ) 3.75 g (9.8%), Fuling ( Poria ) 3.75 g (9.8%), Baizhu ( Atractylodis Macrocephalae Rhizoma ) 2.25 g (5.88%), Maidong ( Ophiopogonis Radix ) 3.75 g (9.8%), Guizhi ( Cinnamomi Ramulus ) 2.25 g (5.88%), Tianma ( Gastrodiae Rhizoma ) 3 g (7.84%), Jiegeng ( Platycodonis Radix ) 2.25 g (5.88%), Zhiqiao ( Aurantii Fructus ) 2.25 g (5.88%), Gegen ( Puerariae Lobatae Radix ) 2.25 g (5.88%), Baihe ( Lilii Bulbus ) 3 g (7.84%), Baishao ( Paeoniae Radix Alba ) 2.25 g (5.88%), Chuanxiong ( Chuanxiong Rhizoma ) 2.25 g (5.88%) and Zhigancao ( Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle ) 1.5 g (3.92%). An SBH-200 three-dimensional mixer, BW-1500 mixer, or EYH-2000 two-dimensional motion mixer was used for the operation. Following the prescription, the formula particles of each Chinese medicine were placed in the total mixer, mixed for 10 min, and discharged. A DS-100 automatic vertical high-speed trilateral sealing particle packaging machine was used for the subpackaging. The qualified composite film bag was packaged and sealed according to the packaging specifications (16.9 g/package). Finally, the label and box were used to obtain the finished drug. The placebo was developed based on caramel color liquid, maltodextrin, and purified water at a weight ratio of 1:20:25. The caramel color liquid and maltodextrin were dissolved in purified water in turn, mixed into thick paste, and dried to dry paste at 90℃. Subsequently, the dry paste was sieved to remove fine particles through an 60 mesh sieve, and discharged a pale yellow powder. SBH-200 three-dimensional mixer, BW-1500 mixer, or EYH-2000 two-dimensional motion mixer were used for total mixing. After mixing, 1/3 of the powder was first mixed with Chinese medicine powder flavor, bitter agent and sucralose for 10 min, then 1/3 of the powder was added for 10 min, and finally the remaining 1/3 of the powder was added for 5 min. The GFS-200/ LGP200 dry granulator was used to granulate, the powder was pressed into a strip, and the particles were made after passing through a 12–14 stainless steel mesh sieve, whose package, color, and flavor were consistent with those of the SLKF granules. Thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) were used to characterize the primary active ingredients of SLKF granules. Compounds, such as gastrodin (C 13 H 18 O 7 ), p-hydroxybenzyl alcohol (C 7 H 8 O 2 ), parishin E (C 19 H 24 O 13 ), parishin B (C 32 H 40 O 19 ), parishin C (C 32 H 40 O 19 ) and parishin A (C 45 H 56 O 25 ), were the primary bioactive components of Tianma in SLKF granules with a concentration of 43.0 ~ 80.0 mg/g. 2-acetate regaloside A (C 20 H 26 O 11 ), was identified as the primary active ingredient of Baihe with a concentration of 3.0–8.5 mg/g. Ferulic acid (C 10 H 10 O 4 ), the primary active ingredient of Chuanxiong was 1.5–4.5 mg/g. Platycodin D (C 57 H 92 O 28 ), the primary active ingredient of Jiegeng was 1.2–4.0 mg/g. Paeoniflorin (C 23 H 28 O 11 ), the primary active ingredient of Baishao was 65.0–137.0mg/g. Puerarin (C 21 H 20 O 9 ), the primary active ingredient of Gegen was 55.0–110.0 mg/g. Neochlorogenic acid (C 16 H 18 O 6 ), chlorogenic acid (C 16 H 18 O 6 ) and cryptochlorogenic acid (C 16 H 18 O 9 ), the primary active components of Baizhu were 0.12–0.95mg/g. It also contains fructose (C 6 H 12 O 6 ) and sucrose (C 12 H 22 O 11 ), and the total amount is 30.0–155.0mg/g. Each gram of Zhiqiao granules contained neohesperidin (C 28 H 34 O 15 ) 49.0–101.0mg and naringin (C 27 H 32 O 14 ) 66.0–148.0mg. Cinnamic acid (C 9 H 8 O 2 ), the primary active ingredient of Guizhi was 4.5–18.5mg/g. Calycosin-7-glucoside (C 22 H 22 O 10 ), the primary active ingredient of Huangqi was 1.20–3.50mg/g. Lobetyolin (C 20 H 28 O 8 ), the primary active ingredient of Dangshen was 0.08–0.03mg/g. Ophiopogon methylflavanone A (C 19 H 18 O 6 ) and Ophiopogon methylflavanone B (C 19 H 20 O 5 ), the primary active ingredients of Maidong were 0.010–0.100 mg/g. Each gram of licorice granules contained Liquiritin (C 21 H 22 O 9 ) 6.5–23.0mg and glycyrrhizic acid (C 42 H 62 O 16 ) 12.9– 60.0mg. Prohibited drugs Nonsteroidal anti-inflammatory drugs, steroids, and antibiotics were prohibited. The Chinese medical treatments used to treat those residual symptoms were prohibited during the study period. Outcome measures Determination of core outcome indicators for the effectiveness trial based on Core Outcome Measures in Effectiveness Trials (COMET) ( https://www.comet-initiative.org/ )[ 31 – 33 ]. Primary outcome Improvement of lung-spleen qi deficiency syndrome using the therapeutic effective rate on day 14 and total clinical symptom score on days 0 and 14. Secondary outcomes (1) Improvement in the fatigue self-assessment scale (FAS) on days 0 and 14. (2) Changes in the pain visual analog scale (VAS) scores on days 0 and 14. (3) Improvement of the Pittsburgh sleep quality index (PSQI) on days 0 and 14. (4) Improvement of mini-mental state examination (MMSE) on days 0 and 14. (5) Improvement of hospital anxiety and depression scale (HADS) on days 0 and 14. (6) Changes in TCM syndrome scores on days 0 and 14. (7) Changes in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6) on days 0 and 14. Safety outcomes (1) Adverse events (AEs) related to study treatment. (2) Blood routine tests [red blood cell (RBC), white blood cell (WBC), hemoglobin (HGB), and platelet count (PLT)], urine routine tests (WBC, RBC, and urine glucose), and stool routine tests (qualitative + occult blood). (3) Liver function [alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), total bilirubin (TBiL), and alkaline phosphatase (ALP), blood urea nitrogen (BUN), serum creatinine (Scr), urine acid (UA), estimated glomerular filtration rate (eGFR), and electrocardiogram (ECG). These assessments were conducted before enrollment and on the 14th day after enrollment. SLKF granules, Shenlingkangfu granules; FAS, fatigue self-assessment scale; VAS, pain visual analog scale; PSQI, Pittsburgh sleep quality index; MMSE, mini-mental state examination; HADS, hospital anxiety and depression scale; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, interleukin-6; AEs, adverse events; ECG, electrocardiogram. Table 1 Study Schedule Items Screening Period Treatment Period Follow-Up Period -2nd Day ± 2 Days 1st-14th Day 14th Day ENROLMENT: Informed consent X Eligibility screen X X Demographic information X Basic medical history X Combined medication X X X Random assignment X Novel coronavirus IgG antibody detection X INTERVENTIONS : SLKF granules X Placebo X ASSESSMENTS : Therapeutic effective rate X Total clinical symptom score X X FAS X X VAS X X PSQI X X MMSE X X HADS X X TCM syndrome score X X CRP, ESR, IL-6 X X Three routine tests X X Liver and kidney function X X ECG X X AEs X X SLKF granules, Shenlingkangfu granules; FAS, fatigue self-assessment scale; VAS, pain visual analogue scale; PSQI, Pittsburgh sleep quality index; MMSE, mini-mental state examination; HADS, hospital anxiety and depression scale; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, interleukin-6; three routine tests, routine blood tests, urine routine tests, and stool routine tests; ECG, electrocardiogram; AEs, adverse events. Assessments (1) The effectiveness of clinical treatment Following the ' Guidelines for Clinical Research of New Chinese Medicinal Drugs (2002 edition) ' [ 25 ], the efficacy of TCM syndromes was determined using the following nimodipine method calculation formula: [(pre-treatment score ˗ post-treatment score) / pre-treatment score] × 100%. a) Clinical cure: The disappearance or near-complete disappearance of TCM clinical symptoms and signs, with a reduction in syndrome score of ≥ 95%. b) Significant effect: Significant improvement in TCM clinical signs and symptoms, with a reduction in syndrome score of ≥ 70%. c) Effective: Improvement in TCM clinical symptoms and signs, with a reduction in syndrome score of ≥ 30%. d) Ineffective: No significant improvement in TCM clinical symptoms and signs, or even worsening, with a reduction in syndrome score of < 30%. The total score for clinical symptoms included the following 16 items: fatigue/tiredness, pain/discomfort (muscle, joint, headache, and chest pain), cough or sputum production, sleep disturbances, excessive sweating, decreased physical stamina, taste disorders, smell disorders, and others. Based on the patient's actual condition and experience, they indicated the presence or absence of these symptoms. 'Absent' was recorded as 0 points and 'present' as 1 point, with the total amount representing the overall clinical symptom score. A higher score indicated a more severe manifestation of 'long COVID' symptoms during the recovery phase. (2) FAS The FAS, VAS, PSQI, MMSE, HADS, and TCM syndrome scores were evaluated at baseline and 14 days after enrollment. The FAS employed a Likert-type scale scoring method consisting of 10 items to assess chronic fatigue symptoms. Each item was rated on a 5-point scale ranging from 1 ('never') to 5 ('always') [ 34 ]. The total score ranged from 10 to 50, with a score of 10 representing the lowest level of fatigue and 50 indicating the highest level. Items 4 and 10 were reverse-scored in comparison with the other eight items. (3) VAS The VAS utilized a 10 cm line segment marked with 10 increments, with one end labeled '0 points' and the other '10 points.' Patients were instructed to mark a point along the line that corresponded to the intensity of their pain at that moment (using a dot or an '✕') [ 35 ]. A measurement of 0 cm (0 points) indicated no pain; 1–3 cm (1–3 points) represented mild pain, did not affect work or daily life; 4–6 cm (4–6 points) signified moderate pain, impacting work but not daily activities; 7–10 cm (7–10 points) indicated severe pain, substantially affecting both work and life. (4) PSQI The PSQI is used to evaluate a patient's sleep quality over the past month. It comprises seven components: sleep quality score, time to fall asleep score, sleep duration score, sleep efficiency score, sleep disturbances score, use of sleeping medication score, and daytime dysfunction score. Each component was scored from 0 to 3, with the total PSQI score ranging from 0 to 21. The scoring thresholds were as follows: 0–5 points (very good sleep quality), 6–10 points (fair sleep quality), 11–15 points (average sleep quality), and 16–21 points (very poor sleep quality) [ 36 ]. The PSQI score is inversely related to sleep quality, with a higher score indicating poorer sleep quality. (5) MMSE The MMSE consists of 12 items that assess a participant's intellectual status and degree of cognitive impairment across dimensions, including orientation, memory, attention and calculation, recall, and naming ability [ 37 ]. The highest possible score is 30, with scores between 27 and 30 indicating normal cognitive functioning and scores below 27 suggesting cognitive impairment. (6) HADS The HADS consists of 14 items, with seven items assessing depression and seven items evaluating anxiety. There are six reverse-scored items, five of which are included in the depression subscale and one in the anxiety subscale. Each item is rated on a 4-level scale from 0 to 3, with scores of 0 to 3 assigned based on the absence, mild, moderate, and severe impact on the subject, respectively[ 38 ]. A total score ranging from 0 to 7 indicated no symptoms, a score from 8 to 10 suggested the possible presence of anxiety or depression symptoms, and a score from 11 to 21 confirmed the presence of anxiety or depression symptoms. (7) TCM syndrome score The collection of TCM symptom scores included the following main symptoms: cough with little or no phlegm, fatigue and weakness, wheezing and shortness of breath, decreased appetite, and loose stools. These symptoms were rated based on severity, with scores of 0, 2, 4, and 6 for none, mild, moderate, and severe, respectively. Additionally, secondary symptoms, including spontaneous sweating and aversion to wind, low-grade fever, abdominal distension, cognitive impairment, insomnia, pallor, and dizziness with tinnitus, were evaluated and assigned scores of 0, 1, 2, and 3 according to their severity [ 25 ]. (8) Blood test Venous blood samples were collected from all participants to determine C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and interleukin-6 (IL-6) levels. Patient visit and data collection Baseline data Baseline data included general demographic data, past medical history, course of disease, treatment history, drinking history, participation in clinical trials, total clinical symptom score, fatigue, sleep, pain, cognition, depression scales, TCM syndrome score, and safety evaluations. The main components included the vital signs of the subjects (body temperature, blood pressure, respiration, and heart rate), main signs and symptoms, personal history and medication, total score of clinical symptoms, FAS, VAS, PSQI, MMSE, HADS, TCM syndrome score, CRP, ESR, IL6, routine blood, urine and stool tests, liver and kidney function, and ECG. Assessment data On the 14th day of treatment, the symptoms and signs, medication, FAS, VAS, PSQI, MMSE, HADS, a total score of clinical symptoms, TCM syndrome score, CRP, ESR, and IL6 were assessed. Laboratory examination results were collected, including routine blood, urine, and stool tests, liver and kidney function, and ECG. The onset time, severity, duration, effective measures, outcomes of AEs, completion of trials, and time of discontinuation of trials were recorded in the case report form (CRF), including an analysis of whether AEs were associated with clinical drug trials. Indicators detection During the screening and treatment periods, all subjects were required to take 3–5 mL of peripheral venous blood in the morning on an empty stomach and then left to stand for 1–2 h. Whole blood, serum, and plasma supernatants were collected (extracted after centrifugation at 3,000 rpm for 10–15 min) for routine blood tests, liver and kidney function, CRP, ESR, and IL6. Three tubes of urine from each subject's midstream specimen were collected for urine sediment microscopy and routine urine analysis. An appropriate amount of stool samples were kept for routine stool and occult blood tests. Laboratory biochemical examinations were performed using a cobas8000 (702/502), cobasU601/701 Roche automatic biochemical analyzer, and SYSMEX-Xi 9000 blood cell analyzer. Adverse events The protocols for handling specific AEs and SAEs are described in Supplemental Appendix 2. Participants were asked if they had experienced any AEs at each study visit. AEs were assessed by a study physician and reported to the Data Safety and Monitoring Board. SAEs, including death, life-threatening conditions, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital anomaly, or birth defect [ 39 ], were reported to the Ethics Review Committee of Hunan Academy of Chinese Medicine Affiliated Hospital within 24 h after acknowledgment. For mild AEs, the patient was reassured to continue taking medication following the protocol [ 40 – 41 ]. Sample Size The determination of sample size in a superior clinical trial design with qualitative variables is calculated using the following formula: $$\:\text{n}=\frac{{{\pi\:}}_{\text{t}}\times\:\left(1-{{\pi\:}}_{\text{t}}\right)+{{\pi\:}}_{\text{c}}\times\:\left(1-{{\pi\:}}_{\text{c}}\right)}{{\left({{\pi\:}}_{\text{t}}-{{\pi\:}}_{\text{c}}-\varDelta\:\right)}^{2}}\times\:{\left({{\mu\:}}_{{\alpha\:}/2}+{{\mu\:}}_{{\beta\:}}\right)}^{2}$$ A clinical trial investigating the effects of TCM in treating patients with convalescent COVID-19 and lung and spleen qi deficiency syndrome demonstrated that the medicine improves patients' symptoms, including fatigue, shortness of breath, cough, and poor appetite. After two weeks of treatment, the improvement rate for individual symptoms in the TCM group ranged from 85.4–89.7%, whereas that in the placebo group ranged from 42.2–64.7% [ 40 ]. Assuming a clinical effective rate of 90% for the experimental group (treated with SLKF Granules) and 65% for the control group (receiving a placebo simulation of SLKF Granules), with a significance level of 5%, an anticipated dropout rate of 15%, setting α = 0.025 (one-sided) and β = 0.20 (one-sided), and Δ = 5%, the sample size calculation indicated that at least 63 participants were required for each group. Considering the 15% dropout rate, 154 participants were needed for both groups. Statistical Methods All statistical analyses were performed using SAS software (version 9.4). For continuous variables, the sample size, mean, standard deviation, median, and minimum and maximum values were calculated. Intergroup comparisons for the treatment groups were performed using one-way analysis of variance or rank-sum tests. For counting data, the frequency and composition ratio were calculated, with intergroup comparisons for the treatment groups using the chi-squared or Fisher's exact test. Regarding medication adherence and analysis of concomitant medication, the percentage of participants with adherence rates between 80% and 120% was calculated, and group differences were compared using the chi-square test or Fisher's exact probability method. The percentage of participants taking concomitant medications was also calculated, and differences between groups were compared using the chi-square test or Fisher's exact probability method. Additionally, an analysis based on the WHO anatomical therapeutic chemical (ATC) classification for concomitant medications was conducted, employing either the chi-square test or Fisher's exact probability method to compare group differences. The comparison and analysis of the effectiveness indicators employed non-parametric tests or an analysis of covariance. If baseline differences existed between the two groups, baseline measurements were adjusted as covariates before conducting intergroup comparisons. The safety analysis primarily involved assessing the AE incidence between the groups, abnormal laboratory data, electrocardiograms, and physical examination results before and after treatment. The full analysis set was conducted for the therapeutic indices of all subjects included in the study. Statistical analysis in accordance with the per protocol set (PPS) was conducted for the therapeutic indices of subjects completing the drug intervention on the 14th day. The full analysis set (FAS) used the last-observed-carried forward method to adjust for missing data and complete the intention-to-treat analysis. Safety analysis was performed using the safety analysis set. All statistical tests were two-sided. P ≤ 0.1 was considered a statistical difference, while P ≤ 0.05 was considered a statistically significant difference. Quality Control and Data Monitoring Quality assurance First, all participating researchers and laboratories were required to adhere to the laboratory's quality control measures and drug batch quality control following standard operating procedures and quality control protocols. Each participating unit provided the 'normal value range for laboratory tests' specific to their facility, and any changes during the trial were promptly documented. Second, to control for participant compliance, a combination of drug counting and questioning methods was used to monitor adherence to the study medication. Adequate explanations were provided to participants, and follow-ups were strengthened to ensure good compliance among the subjects. The participants received training before the trial to ensure that they fully understood the informed consent. When distributing diary cards, researchers carefully explained the filling requirements, methods, and return procedures, as well as educated participants on potential adverse reactions to the trial medication and actions to take if such reactions occur. Finally, in terms of investigator control, training was held before the clinical trial was launched to ensure that the investigators fully understood the clinical trial protocol and the specific connotations of each indicator. Moreover, the consistency of the quantitative standard of symptoms and signs was tested, the consistency of the TCM syndrome was trained and evaluated, and the investigators' subjective symptom description was aimed to avoid inducing or hinting. The objective indicators were checked according to specified time points and methods. Attention was paid to observing adverse reactions or unexpected toxic side effects, followed by follow-up assessments. Research assistants filled out the CRF following the researcher's manual in each center, requiring them to record the contents of the form accurately and thoroughly to ensure the authenticity and reliability of the CRF content. All observations and findings in the clinical trial were verified to ensure the reliability of the data, and all conclusions in the clinical trial were based on the original data. Data management In terms of data monitoring and management, this trial employed CRFs for data collection and utilized Epidata for data management. An independent third party, separate from the CRC, was entrusted with data verification for the CRFs. The database was provided by the Clinical Evaluation Research Center of Central South University, and the data were entered into the database by two personnel to ensure accuracy. Subsequently, statistical personnel from the center crosschecked the raw data. Any identified issues were promptly questioned and returned for modification and enhancement. Once the verification was completed and accurate, data management and statistical analysis were performed. Confidentiality All study-related information was stored on secure network drives or servers. Participants were allocated study identification (ID) numbers, and a master file linking the study ID and personal information was saved separately to protect their privacy. Access to data The study principal investigator, co-investigators, CRC, research assistants, and statistician have access to the collected data. Ethics approval and study registration This study was approved by the Ethics Review Committee of Hunan Academy of Chinese Medicine Affiliated Hospital (reference number: 2023 − 144), any protocol modifications will be reported to the Ethics Review Committee. The research staff obtained consent from interested participants through ten hospitals in Hunan province in China, an outpatient medical record platform, an inpatient case system, and recruitment advertisements. Participants received information regarding the ICF and had the opportunity to discuss the trial specifics and meet with the CRC or research assistant before deciding to participate. The ICF is provided in the Online Supplemental Appendix 3. The trial was subjected to inspections or audits by the Ethics Review Committee of Hunan Academy of Chinese Medicine Affiliated Hospital and Hunan Provincial Health Commission to determine whether research activities were conducted following the protocol, Good Clinical Practice, and guidelines of the International Conference on Harmonization. Under the identifier ChiCTR2400080348, the research protocol has been filed in the Clinical trials registry. Discussion Since 2019, the novel coronavirus has been spreading rapidly around the world, and as strains of the virus continue to mutate, resulting in wave-like outbreaks, infected individuals may experience 'reinfection' time and again. For most people, the coronavirus causes only mild or moderate symptoms, but multiple organ failure can occur in patients with underlying diseases and weakened immune systems. The infected patients' symptoms gradually reduce, and the nucleic acid becomes negative, there are still varying degrees of damage to the cardiopulmonary, musculoskeletal, neurological, and digestive systems, including persistent fatigue, joint/muscle pain, coughing, shortness of breath, sweating, insomnia, hyposmia, and hypogeusia, it means that the patients with COVID-19 step into the 'recovery period' ('Long COVID') [ 10 ]. Currently, most physicians and researchers focus on the treatment of severe patients and vaccine development and pay insufficient attention to health management and interventions for convalescent COVID-19. Studies have demonstrated that anti-COVID-19 small molecule drugs (Nematrevir/Ritonavir and Monoravir) and RNA virus inhibitors (Raltegravir and Azulfidine) can reduce the risk of more than 10 types of 'Long COVID' symptoms [ 42 ], shorten the time to symptomatic improvement in patients with medium-sized COVID-19 infections [ 43 ], and reduce the risk of severe hospitalization or death [ 44 ]. However, relevant meta-analyses have revealed that the benefits of these drugs in patients with COVID-19 with severe symptoms are unclear, and their safety is questionable [ 45 ]. TCM has been recognized for its remarkable effects in the fight against infectious diseases. Acting as a preventive treatment for diseases, it has the advantage of preventing disease recurrence after recovery. Evidence indicates that TCM-related treatment measures have good efficacy in treating mild-to-moderate COVID-19 infections and can play a synergistic role in multiple targets [ 21 – 22 ]. Acupuncture, Chinese exercises (Qigong and Tai Chi), Chinese patent medicine, and TCM decoction can improve difficulty in falling asleep, shallow sleep, dreamy sleep, and other sleep problems. To regulate the body's immunity and improve the impairment of multi-system function, this is a scientific issue that deserves an in-depth discussion: how can we utilize the advantageous role of Chinese patent medicine for the convalescence of COVID-19 patients? In previous studies, SLKF granules have been used to treat upper respiratory infections, including pneumonia and the spleen and lung deficiency syndrome caused by COVID-19. SLKF granules are mainly composed of Huangqi ( Astragali Radix ), Fuling ( Poria ), and Dangshen (C odonopsis Radix ) to supplement the body's qi, combined with Gegen ( Puerariae Lobatae Radix ), Baizhu ( Atractylodis Macrocephalae Rhizoma ), Baishao ( Paeoniae Radix Alba ), and Guizhi ( Cinnamomi Ramulus ), to enhance the functions of spleen and lung and promote the regulation of Qi and Yang. Modern pharmacological studies have discussed the preventive and therapeutic effects of the mentioned TCM and its active ingredients on COVID-19 from various perspectives. Based on web-based bioinformatics workflows integrating multiple databases, it is suggested that Huangqi ( Astragali Radix ) can upregulate microRNA-148b (miR-148b) and microRNA-148b (miR-146a), and reduce the pathogenesis of COVID-19 infection, inhibit pro-inflammatory cytokines including IL-6 and tumor necrosis factor-α (TNF-α), prevent acute respiratory distress syndrome caused by COVID-19, and inhibit the activity of the COVID-19 Mpro protease; therefore, reducing virus entry and replication [ 46 ]. Network pharmacological studies have confirmed that the targets of Fuling ( Poria ) intervention are mainly related to the damage response, peptide serine phosphorylation, response of cells to biological stimuli, establishment of protein localization regulation, lipopolysaccharide response, and other biological processes. Further research has demonstrated that the active ingredient pachymic acid in Fuling ( Poria ) inhibits the COVID-19 main protease Mpro[ 47 ]. Other studies have identified codonopsis pilosula and white peony as representative major components of papain-like protease inhibitors against COVID-19 after screening [ 48 ]. In conclusion, we designed a multicenter, randomized, double-blind, placebo-controlled clinical trial to confirm the efficacy of SLKF granules on convalescent COVID-19 symptoms (fatigue, cough, and insomnia) and to clarify its safety profile. During the data analyses, we performed a sensitivity analysis to test the robustness of the results by comparing the FAS and PPS. This study's results provide a clear intervention for clinical or outpatient treatment of convalescent COVID-19. Over the past four years, the novel coronavirus has evolved rapidly and continues to mutate, with the ability to evade vaccine protection. It is foreseeable that humans will coexist with viruses for a long time. Currently, the long-term effects and damage of the coronavirus on humans still require further observation, and the exploration of interventions for convalescent COVID-19 is also an urgent scientific issue. However, this trial remains an exploratory study, with deficiencies in the diagnosis of study subjects, sample size, treatment duration, and selection of outcome measures. Moreover, the intervention period in this study was relatively short, and the long-term course and safety still need to be determined in follow-up studies. Consequently, increasing the sample size and conducting multicenter clinical trials with longer observation periods are crucial to clarify the efficacy and safety of TCM in convalescent COVID-19. Conclusion The purpose of this multicenter, randomized, double-blind, simulant, and parallel controlled clinical trial is to evaluate the clinical effectiveness and safety of SLKF granules in patients with convalescent COVID-19 and lung-spleen qi deficiency syndrome.It is expected that its subsequent findings will provide higher-quality evidence-based medical data for the optimization of treatment of these patients. Abbreviations SLKF Shenlingkangfu COVID-19 Coronavirus disease 2019 TCM traditional Chinese medicine IgG immunoglobulin G SPIRIT-TCM the Recommendations for Interventional Trials Traditional Chinese Medicine ICF informed consent form Ct the cycle threshold SAEs serious adverse events AEs Adverse events CRC clinical coordinator COMET Core Outcome Measures in Effectiveness Trials FAS the fatigue self-assessment scale VAS the pain visual analog scale PSQI the Pittsburgh sleep quality index MMSE mini-mental state examination HADS hospital anxiety and depression scale CRP C-reactive protein ESR erythrocyte sedimentation rate IL-6 interleukin-6 RBC red blood cell WBC white blood cell HGB hemoglobin PLT platelet count ALT alanine aminotransferase AST aspartate transaminase GGT gamma-glutamyl transferase TBiL total bilirubin ALP alkaline phosphatase BUN blood urea nitrogen Scr serum creatinine UA urine acid eGFR estimated glomerular filtration rate ECG electrocardiogram PPS the per protocol set FAS the full analysis set Declarations Acknowledgements The authors thank all the funding supports in this study. The authors also acknowledge all the participants in this study and other practitioners who will contribute to the study but are not on the list of authors. Author contributions JG and DW is responsible for this study. JG, DW, RF and LX designed the study protocol. RF and WY wrote the manuscript. YZ, JT and LZ revised the manuscript. RF and YZ devised a plan for statistical analysis. JT, DL, GW, QC, LL and YL took part in the recruiting process. LX and DW supervised the clinical trial. YP and SZ finished the batch testing of study products. RF, WY and YZ were involved in developing the main documents regarding ethics approval and data assurance that constitute the basis of this manuscript. All authors contributed to the article and approved the final version of the manuscript. Funding This project was funded by the Key Research and Development Program of Hunan Province (No. 2023SK2003). 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Study on screening potential traditional Chinese medicines against 2019-nCoV based on Mpro and PLP. Zhongguo Zhong Yao Za Zhi. 2020;45:1219–24. Additional Declarations No competing interests reported. Supplementary Files Appendix1SPIRITTCM.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5332179","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":374292928,"identity":"a389154d-d1f0-4b75-acef-0f20e6958a8a","order_by":0,"name":"Rui Fang","email":"","orcid":"","institution":"Institute of Clinical Pharmacology of Chinese Materia Medica, Hunan Academy of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Fang","suffix":""},{"id":374292929,"identity":"1d41e299-faee-4f1d-8b14-de376a2a18a8","order_by":1,"name":"Wanyao Yang","email":"","orcid":"","institution":"School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Wanyao","middleName":"","lastName":"Yang","suffix":""},{"id":374292930,"identity":"f1b3d6de-8247-4792-aa9b-612b08fe2b93","order_by":2,"name":"Yue Zhou","email":"","orcid":"","institution":"Institute of Clinical Pharmacology of Chinese Materia Medica, Hunan Academy of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Zhou","suffix":""},{"id":374292931,"identity":"ad51b54b-fa8c-47ba-8de4-f13dce0c3a17","order_by":3,"name":"Le Xie","email":"","orcid":"","institution":"Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Le","middleName":"","lastName":"Xie","suffix":""},{"id":374292932,"identity":"f53f5eb2-1316-41a4-a5b8-82351b772332","order_by":4,"name":"Jiaxuan Tian","email":"","orcid":"","institution":"Institute of Clinical Pharmacology of Chinese Materia Medica, Hunan Academy of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jiaxuan","middleName":"","lastName":"Tian","suffix":""},{"id":374292933,"identity":"f60866dd-c033-485d-b6b6-b7e2473b0020","order_by":5,"name":"Lei Zhao","email":"","orcid":"","institution":"School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Zhao","suffix":""},{"id":374292934,"identity":"682fc382-bc35-48c8-b066-76de6b778846","order_by":6,"name":"Danhong Liu","email":"","orcid":"","institution":"Institute of Clinical Pharmacology of Chinese Materia Medica, Hunan Academy of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Danhong","middleName":"","lastName":"Liu","suffix":""},{"id":374292935,"identity":"924ea8fa-bf15-4f16-930c-f3cece8828dc","order_by":7,"name":"Shasha Zhou","email":"","orcid":"","institution":"School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shasha","middleName":"","lastName":"Zhou","suffix":""},{"id":374292936,"identity":"ef9ffb30-aead-4bce-9974-43ae5863bcae","order_by":8,"name":"Guozuo Wang","email":"","orcid":"","institution":"The Second Hospital of Hunan University of Chinese Medicine (Hunan Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Guozuo","middleName":"","lastName":"Wang","suffix":""},{"id":374292937,"identity":"21f257dc-4ce0-4cc1-96c8-9e935f8e78a0","order_by":9,"name":"Qing Chen","email":"","orcid":"","institution":"The First Hospital of Hunan University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Chen","suffix":""},{"id":374292938,"identity":"ade8a58d-cae3-46bb-a8cc-bc57f55155d2","order_by":10,"name":"Yanmei Peng","email":"","orcid":"","institution":"Institute of Innovative Traditional Chinese Medications, Hunan Academy of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yanmei","middleName":"","lastName":"Peng","suffix":""},{"id":374292939,"identity":"6a488693-ffb8-4d1a-88b3-8c46daf9c699","order_by":11,"name":"Litao Liu","email":"","orcid":"","institution":"The First Affiliated Hospital of Shaoyang University","correspondingAuthor":false,"prefix":"","firstName":"Litao","middleName":"","lastName":"Liu","suffix":""},{"id":374292940,"identity":"0764a7bb-0b6b-484e-ba85-db6e5eaf09a6","order_by":12,"name":"Yunhua Luo","email":"","orcid":"","institution":"Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Yunhua","middleName":"","lastName":"Luo","suffix":""},{"id":374292941,"identity":"c17c5538-3cc5-44af-85a8-c1cac138d6b5","order_by":13,"name":"DaHua Wu","email":"","orcid":"","institution":"Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"DaHua","middleName":"","lastName":"Wu","suffix":""},{"id":374292942,"identity":"7058299c-443e-42b1-b871-455dba93e6bd","order_by":14,"name":"Jinwen Ge","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYBACxmbmww8S//yT4ydaC3N7W5rBw4YDxpINxGph7zljIAnUkmhwgFgtvDPSEgwSd9xJMD6evIHhR8U2wlokZyQfeJB45lme2ZlnBYw9Z24T1mIIsiWBjbnY7EaOATNjGxFa7IEqJYBaEjfPIFYL0C0GEolthxM3SBCtBRTICWfSjCWAfjlIlF9AUfnwR4WNHH978sYHPyqI0IIEEoiPGoQWUnWMglEwCkbBCAEAQhNFhWqjknsAAAAASUVORK5CYII=","orcid":"","institution":"Institute of Clinical Pharmacology of Chinese Materia Medica, Hunan Academy of Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jinwen","middleName":"","lastName":"Ge","suffix":""}],"badges":[],"createdAt":"2024-10-25 11:53:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5332179/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5332179/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70386565,"identity":"1714c54a-7771-4155-a61d-c113f76ac4e4","added_by":"auto","created_at":"2024-12-02 17:21:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":263168,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flowchart and outcomes.\u003c/p\u003e\n\u003cp\u003eSLKF granules, Shenlingkangfu granules; FAS, fatigue self-assessment scale; VAS, pain visual analog scale; PSQI, Pittsburgh sleep quality index; MMSE, mini-mental state examination; HADS, hospital anxiety and depression scale; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, interleukin-6; AEs, adverse events; ECG, electrocardiogram.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5332179/v1/3fb79212e5e57cf2e08f40fb.jpg"},{"id":70788716,"identity":"998a1f4d-6991-4246-b11c-07da568679f6","added_by":"auto","created_at":"2024-12-06 17:46:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1180816,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5332179/v1/969da4f8-ff02-4a2b-a403-f0b9d0c10456.pdf"},{"id":70386560,"identity":"bbf2327a-742b-4016-845d-78c3357682a0","added_by":"auto","created_at":"2024-12-02 17:21:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":122334,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix1SPIRITTCM.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5332179/v1/fe82d40b46f91781ab9704b3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Chinese medicine compound for the convalescent COVID-19 patients: A multicenter, randomized, double-blind, placebo-controlled clinical trial protocol","fulltext":[{"header":"Background","content":"\u003cp\u003eCoronavirus disease 2019 (COVID-19) is an acute infectious disease caused by the coronavirus, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of July 21, 2024, World Health Organization (WHO) statistics revealed that over 775\u0026nbsp;million people worldwide have been infected with COVID-19, and more than seven million people have died since the pandemic began over four years ago [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Convalescent COVID-19 denotes patients infected with the novel coronavirus who conform to relevant discharge indications. However, below the clinical cure standards, these patients experience a series of 'long COVID' syndromes, including cough, fatigue, insomnia, and other multifunctional disorders after discharge [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Common clinical manifestations include musculoskeletal symptoms (general fatigue, muscle soreness, headache, and joint pain), neurological symptoms (transient cognitive function or impairment of consciousness and thinking, referred to as brain fog), and autonomic neuropathy (loss of smell and taste, sleep disorders, and recurrent sweating). Cardiopulmonary dysfunction includes chronic cough, shortness of breath, and palpitations, and gastrointestinal symptoms include diarrhea and vomiting [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Moreover, patients may experience mental health problems, including anxiety and depression [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePreliminary statistics suggest that over 65\u0026nbsp;million individuals worldwide have suffered from 'long COVID' [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Its incidence ranges from 34\u0026ndash;77% across various countries [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. According to the \u003cem\u003eMedical Expenditure Panel Survey\u003c/em\u003e, as of the beginning of 2023, about 17.8\u0026nbsp;million (6.9%) of adults in the United States have experienced 'long COVID' symptoms [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A Bayesian meta-analysis that consolidated data from 22 countries globally between 2020 and 2021 on 1.2\u0026nbsp;million patients with symptomatic COVID-19 revealed that at least 6.2% of patients experienced 'long COVID' syndromes, including persistent fatigue, physical pain or mood swings, persistent breathing problems, and cognitive impairment, and the proportion of the above symptoms were approximately 51.0%, 60.4% and 35.4% of patients with COVID-19, respectively [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Another cohort study involving 4,708 patients with COVID-19 documented that 22.5% of patients did not recover within 90 days after infection, with a median recovery time of 20 days [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, patients with convalescent COVID-19 may sustain uncomfortable symptoms or new concurrent symptoms after three months of infection, which significantly affects their health status and quality of life.\u003c/p\u003e \u003cp\u003eCurrently, the National Institutes of Health has recommended oral small-molecule drugs (Nematavir-Ritonavir and Monolavir) as the primary antiviral treatments for COVID-19. It exhibits a certain preventive effect against convalescent COVID-19 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]; however, its safety requires additional verification [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Domestic specialist consensus considers that symptomatic treatments, including cough and pain relief, anti-anxiety and depression, and cognitive therapy, should be the primary treatment for patients experiencing 'long COVID' syndrome in the convalescence period[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Patients with pulmonary fibrosis and low cortisol levels can be treated with low-dose glucocorticoids [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Moreover, health authorities in China and other provinces and cities have successively issued guidelines on traditional Chinese medicine (TCM) for preventing and treating COVID-19 infection or health management. In January 2023, the National Health Commission and State Administration of Traditional Chinese Medicine revised and promulgated the '\u003cem\u003eDiagnosis and Treatment of COVID-19 (trial tenth edition)\u003c/em\u003e, which recommended light, medium, heavy, critical, and convalescent Chinese patent medicine and massage therapy, based on syndrome discrimination [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In December 2022, Beijing formulated '\u003cem\u003ethe Expert Guidelines on Health Management for the Convalescent COVID-19 Patients (first edition)\u003c/em\u003e' which provided self-rehabilitation guidance for the main symptoms of people in convalescent COVID-19, including medicinal diet and dietary therapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, among the above programs and consensus, there is less high-quality evidence-based medical evidence on the efficacy and safety evaluation of TCM interventions for COVID-19.\u003c/p\u003e \u003cp\u003eCOVID-19 belongs to the categories of 'plague,' 'pestilence,' and 'warm disease' in TCM, which is caused by the 'pestilential pathogen.' However, the characteristics of 'pestilential pathogens' differ in different periods and regions. In view of the etiology, pathogenesis, and treatment of COVID-19, academician Boli Zhang believed that the treatment should be based on 'noxious dampness pestilence'[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], while academician Xiaolin Tong emphasized that the cold-dampness epidemic toxin was the main evil, and the method of dispelling cold and dampness should be adopted [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Generally, COVID-19 is caused by wind, cold, and dampness toxicity, which invades the human body and causes a struggle between vital qi and evil. After eliminating evil, the primordial qi of the patients is damaged. When the patient is in the recovery period for a long time, the evil qi gradually fades, the primordial qi deficiency and decline, the lung qi of the body is damaged, and the dispersive and descending qi movement are dysregulated. Spleen qi deficiency leads to qingyang not rising; spleen deficiency cannot nourish the lung, which eventually results in qi deficiency of the lung and spleen in the recovery period [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. TCM granules possess the distinctive advantages of being simple, economical, and effective in the prevention and treatment of COVID-19 and play a synergistic role owing to their treatment based on syndrome differentiation and individualized prescription[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The results of large-scale clinical trials led by Academician Luqi Huang and Xiaolin Tong demonstrated that TCM has significant therapeutic advantages in treating clinical symptoms, including fever, cough, fatigue, chest tightness, and lung inflammation; however, the intervention effect on 'long COVID symptoms among various demographics in the recovery stage requires additional investigation [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Consequently, to clarify the TCM advantages in preventing and treating convalescent COVID-19, alleviate the 'long COVID' symptoms, and establish an evidence-based optimization program, it may exert a significant social impact in highlighting TCM's regulatory role in convalescent COVID-19.\u003c/p\u003e \u003cp\u003eThrough long-term clinical diagnosis and treatment practice, we observed that in the epidemic's late stage, patients frequently exhibit clinical manifestations, including long-term chronic cough and sputum, asthma, fatigue, anorexia, spontaneous sweating, sleep disorders, loose stools, pale tongue, and greasy white fur because of lung-qi deficiency and spleen-yang insufficiency [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This study examined the clinical efficacy and safety of Shenlingkangfu (SLKF) granules in patients with convalescent COVID-19 and lung-spleen qi deficiency syndrome. We conducted a multicenter, randomized, double-blind, simulant, and parallel controlled clinical trial, aiming to provide higher-quality evidence-based medical data for the optimization of treatment of patients with convalescent COVID-19 and lung-spleen qi deficiency syndrome.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis study was designed as a multicenter, randomized, double-blind, placebo-controlled clinical trial that lasted for 14 days, including 2 days of screening period, 14 days of treatment period, and the 14th day follow-up period. Screening was undertaken within two days before enrollment to assess eligibility and collect baseline data regarding basic medical history, combined medications, laboratory and auxiliary examinations [novel coronavirus immunoglobulin G (IgG) antibody and inflammatory factors], signs and symptoms, and assessment scales. Eligible participants were randomized into the SLKF granules group and the control group at a ratio of 1:1. Participants' medication, signs and symptoms, rating scales, and laboratory biochemical examinations on the scheduled day for the follow-up period were recorded. A workflow diagram and schedule are presented in \u003cb\u003eFig.\u0026nbsp;1 and Table\u0026nbsp;1\u003c/b\u003e, respectively. The trial protocol was designed following the Recommendations for Interventional Trials Traditional Chinese Medicine (SPIRIT-TCM) Extension 2018 Statement checklist. (Online Supplemental Appendix 1).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003e Participants, diagnosed as outpatients or inpatients, were recruited and screened in the following ten clinical research sub-centers: Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (the Affiliated Hospital of Hunan Academy of Chinese Medicine), the Second Xiangya Hospital of Central South University, the First Hospital of Hunan University of Chinese Medicine, the Second Hospital of Hunan University of Chinese Medicine, Hunan Province Directly Affiliated TCM Hospital, the First Affiliated Hospital of Shaoyang University, the First Traditional Chinese Medicine of Changde, Hengyang Hospital of Traditional Chinese Medicine, and Zhangjiajie Hospital of Traditional Chinese Medicine. This trial started with recruitment from January 2024 to December 2024.\u003c/p\u003e \u003cp\u003eMost participants were recruited through advertisements and posters in ten selected clinical research subcenters. Other participants diagnosed with convalescent COVID-19 were invited by telephone through the research team or clinical observers. All participants were required to be negative for novel coronavirus antibody or nucleic acid detection; IgG antibody levels were elevated [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and re-screened by a specialist. Each participant signed an informed consent form (ICF) indicating that they fully understood the clinical study information concerning the trial.\u003c/p\u003e\n\u003ch3\u003eDiagnostic Criteria\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic Criteria for the Convalescent COVID-19\u003c/h2\u003e \u003cp\u003eAccording to the '\u003cem\u003eDiagnosis and Treatment of COVID-19 (trial tenth edition)\u003c/em\u003e' and \u003cem\u003ethe Expert Guidelines on Health Management for Convalescent COVID-19 Patients (first edition)\u003c/em\u003e'[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], Convalescent COVID-19 refers to those who have been infected, met any of the following criteria, and had significantly improved other symptoms.\u003c/p\u003e \u003cp\u003e(1) Two consecutive nucleic acid detections were negative, and the cycle threshold (Ct) values were \u0026ge;\u0026thinsp;35.\u003c/p\u003e \u003cp\u003e(2) Negative antigen test results on three consecutive days.\u003c/p\u003e \u003cp\u003e(3) The level of novel coronavirus-specific IgG antibodies in convalescence was four times or higher than that in the acute stage.\u003c/p\u003e \u003cp\u003e(4) In the absence of antipyretics, fever symptoms subsided for more than 24 h.\u003c/p\u003e \u003cp\u003e(5) Pulmonary imaging demonstrated that acute exudative lesions were significantly improved and could be converted to oral drug therapy without complications necessitating further treatment.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnostic criteria for TCM syndrome\u003c/h3\u003e\n\u003cp\u003eThe TCM symptom scoring table for lung-spleen qi deficiency syndrome was formulated following '\u003cem\u003ethe Guiding Principles of Clinical Research on the Treatment of Diarrhea with New Chinese Medicine (2002 edition)\u003c/em\u003e'[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], '\u003cem\u003ethe Diagnostic criteria for TCM syndromes of coronavirus disease 2019\u003c/em\u003e (\u003cem\u003etrial edition\u003c/em\u003e)' [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], and '\u003cem\u003ethe Diagnostic criteria of TCM Syndromes of Chronic Obstructive Pulmonary Disease (2011 edition)\u003c/em\u003e' [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The cardinal and minor symptoms included in the scale were as follows:\u003c/p\u003e \u003cp\u003eCardinal symptoms of cough without or less phlegm, fatigue, panting, shortness of breath, torpid intake, and sloppy stool, and minor symptoms of spontaneous sweating and aversion to wind, low-grade fever, abdominal distension, cognitive impairment, insomnia, pale white complexion, dizziness, and tinnitus. Five or more points were allocated for the cardinal and minor symptoms, combined with fat tongue, teeth-marked tongue, pale tongue, white or white greasy tongue coating, sunken, fine, moderate, and weak pulse. If the above conditions were met, it was identified as lung-spleen qi deficiency syndrome.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eInclusion criteria\u003c/h2\u003e \u003cp\u003e(1) Male and female patients aged 18\u0026ndash;75 years.\u003c/p\u003e \u003cp\u003e(2) Participants had a confirmed or physician-suspected SARS-CoV-2 infection at least six months earlier.\u003c/p\u003e \u003cp\u003e(3) Diagnosed with convalescent COVID-19.\u003c/p\u003e \u003cp\u003e(4) Diagnosed with lung-spleen qi deficiency syndrome.\u003c/p\u003e \u003cp\u003e(5) The participants had no short-term migration intentions and agreed to cooperate with the follow-up.\u003c/p\u003e \u003cp\u003e(6) Provision of written informed consent.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eExclusion criteria\u003c/h3\u003e\n\u003cp\u003e(1) Severe liver dysfunction: ALT\u0026thinsp;\u0026gt;\u0026thinsp;2-time normal value upper limit or AST\u0026thinsp;\u0026gt;\u0026thinsp;2-time the normal upper limit or severe kidney dysfunction Scr\u0026thinsp;\u0026gt;\u0026thinsp;1.5-time normal value the upper limit).\u003c/p\u003e \u003cp\u003e(2) Severe pulmonary dysfunction [(forced expiratory volume in one second (FEV1%) of predicted value, including obstruction or restriction: severe: 35\u0026ndash;49%, extremely severe: A value of less than 35% for FEV1% or a value of less than 40% for carbon monoxide diffusing capacity. For all measurements using z-values, severe impairment was \u0026lt; \u0026minus;\u0026thinsp;4.1] [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e(3) Underlying blood disorders, acute rheumatic connective tissue diseases, or acute pulmonary conditions.\u003c/p\u003e \u003cp\u003e(4) Pregnancy, planning to become pregnant, or breastfeeding.\u003c/p\u003e \u003cp\u003e(5) History of drug rashes or anaphylactic reactions to medications.\u003c/p\u003e \u003cp\u003e(6) Having participated in another clinical study within three months.\u003c/p\u003e \u003cp\u003e(7) Combined with severe mental illness.\u003c/p\u003e \u003cp\u003e(8) Recently used traditional Chinese medicine or proprietary Chinese medicine with an identical effect.\u003c/p\u003e\n\u003ch3\u003eWithdrawal criteria\u003c/h3\u003e\n\u003cp\u003e(1) The patient's condition worsened or relapsed during the administration period, and other treatment measures are required.\u003c/p\u003e \u003cp\u003e(2) Subjects did not meet the inclusion criteria and were mistakenly included in the trial or met the trial's exclusion criteria.\u003c/p\u003e \u003cp\u003e(3) Subjects with poor compliance were not recommended to withdraw from the trial but were no longer receiving drug treatment and were lost to follow-up.\u003c/p\u003e \u003cp\u003e(4) Voluntary withdrawal.\u003c/p\u003e \u003cp\u003e(5) Subjects experienced other complications, and it was inappropriate to continue the trial during the clinical trial [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRandomization and allocation\u003c/h2\u003e \u003cp\u003eThis trial adopted a stratified block randomization method. First, an appropriate block length was selected (block size\u0026thinsp;=\u0026thinsp;4), and random assignment was conducted using SAS (version 9.4) statistical software developed by statisticians from the Drug Clinical Evaluation Research Center of Central South University. A total of 154 random sequences were generated for each group; specifically, a randomized coding table (No. 001-154) was developed. The subjects in each group were randomly divided into an intervention group and a control or placebo group at an allocation ratio of 1:1. Randomized codes were used as drug numbers, which were kept in an opaque sealed envelope and taken to Hinye Pharmaceutical Co., Ltd. (Changsha Hunan, China) for unified drug label production. The identification code for each subject was similar to that of the number of drugs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eBlinding\u003c/h2\u003e \u003cp\u003eDoctors, patients, outcome investigators, and statisticians were blinded to the patient's treatment assignments. The statisticians completed the randomized codes, and the staff of Hinye Pharmaceutical Co., Ltd. affixed the drug number label to the eye-catching position of the external drug packaging according to the drug number label corresponding to the formed random code. The record of the blinding process, the blind record, was kept as a clinical trial document. The contents of the blinding record included the preparation of the sponsor's drugs, drug packaging, usage, storage and assignment, generation of randomized codes, the subject's drug box production, emergency letter, test report of SLKF granules and placebo, storage of blinding codes, rules for breaking the blind law, and dispensing numbers of each research center. Blinded coding, the initial randomization number, and block length were sealed in two copies. For proper storage, the two copies were handed to the clinical trial group leader, the Department of Drug Clinical Trial Administration at Hunan University of Chinese Medicine, and the sponsor. The blinding codes were kept strictly confidential and remained sealed until statistical analysis at the end of the trial, only if serious adverse events (SAEs) or emergencies occurred.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eIntervention\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003eTreatments\u003c/h2\u003e \u003cp\u003eMulticenter subjects satisfying all criteria were assigned (1:1) randomly into an intervention group and a control group. All participants received health management guidance (maintaining good personal and environmental hygiene, balanced nutrition, moderate exercise, adequate rest, and avoiding fatigue). Subjects with chronic underlying diseases were administered corresponding treatments. The intervention group was treated with SLKF granules orally (once per bag, 16.9 g, twice daily). Subjects in the control group were treated with a placebo at the same dosage, which had an identical appearance and nearly similar taste to SLKF granules. If necessary, routine treatment, including cough relief and other symptomatic support, was administered. The treatment for the two groups lasted 14 days. Each center was assigned a clinical coordinator (CRC) responsible for allocating drugs based on the recruitment sequence before filling out the dispensing record form.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePreparation of drugs\u003c/h2\u003e \u003cp\u003eSLKF granules were composed of traditional TCM formula granules that met the quality standards according to the proportion of prescriptions. Each package was equivalent to decoction: Dangshen (C\u003cem\u003eodonopsis Radix\u003c/em\u003e) 3.75 g (9.8%), Huangqi (\u003cem\u003eAstragali Radix\u003c/em\u003e) 3.75 g (9.8%), Fuling (\u003cem\u003ePoria\u003c/em\u003e) 3.75 g (9.8%), Baizhu (\u003cem\u003eAtractylodis Macrocephalae Rhizoma\u003c/em\u003e) 2.25 g (5.88%), Maidong (\u003cem\u003eOphiopogonis Radix\u003c/em\u003e) 3.75 g (9.8%), Guizhi (\u003cem\u003eCinnamomi Ramulus\u003c/em\u003e) 2.25 g (5.88%), Tianma (\u003cem\u003eGastrodiae Rhizoma\u003c/em\u003e) 3 g (7.84%), Jiegeng (\u003cem\u003ePlatycodonis Radix\u003c/em\u003e) 2.25 g (5.88%), Zhiqiao (\u003cem\u003eAurantii Fructus\u003c/em\u003e) 2.25 g (5.88%), Gegen (\u003cem\u003ePuerariae Lobatae Radix\u003c/em\u003e) 2.25 g (5.88%), Baihe (\u003cem\u003eLilii Bulbus\u003c/em\u003e) 3 g (7.84%), Baishao (\u003cem\u003ePaeoniae Radix Alba\u003c/em\u003e) 2.25 g (5.88%), Chuanxiong (\u003cem\u003eChuanxiong Rhizoma\u003c/em\u003e) 2.25 g (5.88%) and Zhigancao (\u003cem\u003eGlycyrrhizae Radix Et Rhizoma Praeparata Cum Melle\u003c/em\u003e) 1.5 g (3.92%). An SBH-200 three-dimensional mixer, BW-1500 mixer, or EYH-2000 two-dimensional motion mixer was used for the operation. Following the prescription, the formula particles of each Chinese medicine were placed in the total mixer, mixed for 10 min, and discharged. A DS-100 automatic vertical high-speed trilateral sealing particle packaging machine was used for the subpackaging. The qualified composite film bag was packaged and sealed according to the packaging specifications (16.9 g/package). Finally, the label and box were used to obtain the finished drug.\u003c/p\u003e \u003cp\u003eThe placebo was developed based on caramel color liquid, maltodextrin, and purified water at a weight ratio of 1:20:25. The caramel color liquid and maltodextrin were dissolved in purified water in turn, mixed into thick paste, and dried to dry paste at 90℃. Subsequently, the dry paste was sieved to remove fine particles through an 60 mesh sieve, and discharged a pale yellow powder. SBH-200 three-dimensional mixer, BW-1500 mixer, or EYH-2000 two-dimensional motion mixer were used for total mixing. After mixing, 1/3 of the powder was first mixed with Chinese medicine powder flavor, bitter agent and sucralose for 10 min, then 1/3 of the powder was added for 10 min, and finally the remaining 1/3 of the powder was added for 5 min. The GFS-200/ LGP200 dry granulator was used to granulate, the powder was pressed into a strip, and the particles were made after passing through a 12\u0026ndash;14 stainless steel mesh sieve, whose package, color, and flavor were consistent with those of the SLKF granules.\u003c/p\u003e \u003cp\u003eThin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) were used to characterize the primary active ingredients of SLKF granules. Compounds, such as gastrodin (C\u003csub\u003e13\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e), p-hydroxybenzyl alcohol (C\u003csub\u003e7\u003c/sub\u003eH\u003csub\u003e8\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e), parishin E (C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eO\u003csub\u003e13\u003c/sub\u003e), parishin B (C\u003csub\u003e32\u003c/sub\u003eH\u003csub\u003e40\u003c/sub\u003eO\u003csub\u003e19\u003c/sub\u003e), parishin C (C\u003csub\u003e32\u003c/sub\u003eH\u003csub\u003e40\u003c/sub\u003eO\u003csub\u003e19\u003c/sub\u003e) and parishin A (C\u003csub\u003e45\u003c/sub\u003eH\u003csub\u003e56\u003c/sub\u003eO\u003csub\u003e25\u003c/sub\u003e), were the primary bioactive components of Tianma in SLKF granules with a concentration of 43.0\u0026thinsp;~\u0026thinsp;80.0 mg/g. 2-acetate regaloside A (C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eO\u003csub\u003e11\u003c/sub\u003e), was identified as the primary active ingredient of Baihe with a concentration of 3.0\u0026ndash;8.5 mg/g. Ferulic acid (C\u003csub\u003e10\u003c/sub\u003eH\u003csub\u003e10\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e), the primary active ingredient of Chuanxiong was 1.5\u0026ndash;4.5 mg/g. Platycodin D (C\u003csub\u003e57\u003c/sub\u003eH\u003csub\u003e92\u003c/sub\u003eO\u003csub\u003e28\u003c/sub\u003e), the primary active ingredient of Jiegeng was 1.2\u0026ndash;4.0 mg/g. Paeoniflorin (C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e28\u003c/sub\u003eO\u003csub\u003e11\u003c/sub\u003e), the primary active ingredient of Baishao was 65.0\u0026ndash;137.0mg/g. Puerarin (C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eO\u003csub\u003e9\u003c/sub\u003e), the primary active ingredient of Gegen was 55.0\u0026ndash;110.0 mg/g. Neochlorogenic acid (C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003e), chlorogenic acid (C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003e) and cryptochlorogenic acid (C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eO\u003csub\u003e9\u003c/sub\u003e ), the primary active components of Baizhu were 0.12\u0026ndash;0.95mg/g. It also contains fructose (C\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003e) and sucrose (C\u003csub\u003e12\u003c/sub\u003eH\u003csub\u003e22\u003c/sub\u003eO\u003csub\u003e11\u003c/sub\u003e), and the total amount is 30.0\u0026ndash;155.0mg/g. Each gram of Zhiqiao granules contained neohesperidin (C\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e34\u003c/sub\u003eO\u003csub\u003e15\u003c/sub\u003e) 49.0\u0026ndash;101.0mg and naringin (C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e32\u003c/sub\u003eO\u003csub\u003e14\u003c/sub\u003e) 66.0\u0026ndash;148.0mg. Cinnamic acid (C\u003csub\u003e9\u003c/sub\u003eH\u003csub\u003e8\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e), the primary active ingredient of Guizhi was 4.5\u0026ndash;18.5mg/g. Calycosin-7-glucoside (C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e22\u003c/sub\u003eO\u003csub\u003e10\u003c/sub\u003e), the primary active ingredient of Huangqi was 1.20\u0026ndash;3.50mg/g. Lobetyolin (C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e28\u003c/sub\u003eO\u003csub\u003e8\u003c/sub\u003e), the primary active ingredient of Dangshen was 0.08\u0026ndash;0.03mg/g. Ophiopogon methylflavanone A (C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003e) and Ophiopogon methylflavanone B (C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e), the primary active ingredients of Maidong were 0.010\u0026ndash;0.100 mg/g. Each gram of licorice granules contained Liquiritin (C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e22\u003c/sub\u003eO\u003csub\u003e9\u003c/sub\u003e) 6.5\u0026ndash;23.0mg and glycyrrhizic acid (C\u003csub\u003e42\u003c/sub\u003eH\u003csub\u003e62\u003c/sub\u003eO\u003csub\u003e16\u003c/sub\u003e) 12.9\u0026ndash; 60.0mg.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eProhibited drugs\u003c/h2\u003e \u003cp\u003eNonsteroidal anti-inflammatory drugs, steroids, and antibiotics were prohibited. The Chinese medical treatments used to treat those residual symptoms were prohibited during the study period.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measures\u003c/h2\u003e \u003cp\u003eDetermination of core outcome indicators for the effectiveness trial based on Core Outcome Measures in Effectiveness Trials (COMET) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.comet-initiative.org/\u003c/span\u003e\u003cspan address=\"https://www.comet-initiative.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)[\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcome\u003c/h2\u003e \u003cp\u003eImprovement of lung-spleen qi deficiency syndrome using the therapeutic effective rate on day 14 and total clinical symptom score on days 0 and 14.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003e(1) Improvement in the fatigue self-assessment scale (FAS) on days 0 and 14.\u003c/p\u003e \u003cp\u003e(2) Changes in the pain visual analog scale (VAS) scores on days 0 and 14.\u003c/p\u003e \u003cp\u003e(3) Improvement of the Pittsburgh sleep quality index (PSQI) on days 0 and 14.\u003c/p\u003e \u003cp\u003e(4) Improvement of mini-mental state examination (MMSE) on days 0 and 14.\u003c/p\u003e \u003cp\u003e(5) Improvement of hospital anxiety and depression scale (HADS) on days 0 and 14.\u003c/p\u003e \u003cp\u003e(6) Changes in TCM syndrome scores on days 0 and 14.\u003c/p\u003e \u003cp\u003e(7) Changes in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6) on days 0 and 14.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSafety outcomes\u003c/h2\u003e \u003cp\u003e(1) Adverse events (AEs) related to study treatment.\u003c/p\u003e \u003cp\u003e(2) Blood routine tests [red blood cell (RBC), white blood cell (WBC), hemoglobin (HGB), and platelet count (PLT)], urine routine tests (WBC, RBC, and urine glucose), and stool routine tests (qualitative\u0026thinsp;+\u0026thinsp;occult blood).\u003c/p\u003e \u003cp\u003e(3) Liver function [alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), total bilirubin (TBiL), and alkaline phosphatase (ALP), blood urea nitrogen (BUN), serum creatinine (Scr), urine acid (UA), estimated glomerular filtration rate (eGFR), and electrocardiogram (ECG).\u003c/p\u003e \u003cp\u003eThese assessments were conducted before enrollment and on the 14th day after enrollment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSLKF granules, Shenlingkangfu granules; FAS, fatigue self-assessment scale; VAS, pain visual analog scale; PSQI, Pittsburgh sleep quality index; MMSE, mini-mental state examination; HADS, hospital anxiety and depression scale; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, interleukin-6; AEs, adverse events; ECG, electrocardiogram.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy Schedule\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eItems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eScreening Period\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTreatment Period\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFollow-Up Period\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e-2nd Day\u0026thinsp;\u0026plusmn;\u0026thinsp;2 Days\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1st-14th Day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14th Day\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eENROLMENT:\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformed consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEligibility screen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic information\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasic medical history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombined medication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRandom assignment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNovel coronavirus IgG antibody detection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eINTERVENTIONS\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSLKF granules\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eASSESSMENTS\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapeutic effective rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal clinical symptom score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSQI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHADS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTCM syndrome score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP, ESR, IL-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree\u0026nbsp;routine tests\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver and kidney function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSLKF granules, Shenlingkangfu granules; FAS, fatigue self-assessment scale; VAS, pain visual analogue scale; PSQI, Pittsburgh sleep quality index; MMSE, mini-mental state examination; HADS, hospital anxiety and depression scale; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, interleukin-6; three routine tests, routine blood tests, urine routine tests, and stool routine tests; ECG, electrocardiogram; AEs, adverse events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eAssessments\u003c/h2\u003e \u003cdiv id=\"Sec22\" class=\"Section3\"\u003e \u003ch2\u003e(1) The effectiveness of clinical treatment\u003c/h2\u003e \u003cp\u003eFollowing the '\u003cem\u003eGuidelines for Clinical Research of New Chinese Medicinal Drugs (2002 edition)\u003c/em\u003e' [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], the efficacy of TCM syndromes was determined using the following nimodipine method calculation formula: [(pre-treatment score ˗ post-treatment score) / pre-treatment score] \u0026times; 100%.\u003c/p\u003e \u003cp\u003ea) Clinical cure: The disappearance or near-complete disappearance of TCM clinical symptoms and signs, with a reduction in syndrome score of \u0026ge;\u0026thinsp;95%.\u003c/p\u003e\u003cp\u003eb) Significant effect: Significant improvement in TCM clinical signs and symptoms, with a reduction in syndrome score of \u0026ge;\u0026thinsp;70%.\u003c/p\u003e \u003cp\u003ec) Effective: Improvement in TCM clinical symptoms and signs, with a reduction in syndrome score of \u0026ge;\u0026thinsp;30%.\u003c/p\u003e \u003cp\u003ed) Ineffective: No significant improvement in TCM clinical symptoms and signs, or even worsening, with a reduction in syndrome score of \u0026lt;\u0026thinsp;30%.\u003c/p\u003e \u003cp\u003eThe total score for clinical symptoms included the following 16 items: fatigue/tiredness, pain/discomfort (muscle, joint, headache, and chest pain), cough or sputum production, sleep disturbances, excessive sweating, decreased physical stamina, taste disorders, smell disorders, and others. Based on the patient's actual condition and experience, they indicated the presence or absence of these symptoms. 'Absent' was recorded as 0 points and 'present' as 1 point, with the total amount representing the overall clinical symptom score. A higher score indicated a more severe manifestation of 'long COVID' symptoms during the recovery phase.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e(2) FAS\u003c/h2\u003e \u003cp\u003eThe FAS, VAS, PSQI, MMSE, HADS, and TCM syndrome scores were evaluated at baseline and 14 days after enrollment.\u003c/p\u003e \u003cp\u003eThe FAS employed a Likert-type scale scoring method consisting of 10 items to assess chronic fatigue symptoms. Each item was rated on a 5-point scale ranging from 1 ('never') to 5 ('always') [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The total score ranged from 10 to 50, with a score of 10 representing the lowest level of fatigue and 50 indicating the highest level. Items 4 and 10 were reverse-scored in comparison with the other eight items.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e(3) VAS\u003c/h2\u003e \u003cp\u003eThe VAS utilized a 10 cm line segment marked with 10 increments, with one end labeled '0 points' and the other '10 points.' Patients were instructed to mark a point along the line that corresponded to the intensity of their pain at that moment (using a dot or an '✕') [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. A measurement of 0 cm (0 points) indicated no pain; 1\u0026ndash;3 cm (1\u0026ndash;3 points) represented mild pain, did not affect work or daily life; 4\u0026ndash;6 cm (4\u0026ndash;6 points) signified moderate pain, impacting work but not daily activities; 7\u0026ndash;10 cm (7\u0026ndash;10 points) indicated severe pain, substantially affecting both work and life.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003e(4) PSQI\u003c/h2\u003e \u003cp\u003eThe PSQI is used to evaluate a patient's sleep quality over the past month. It comprises seven components: sleep quality score, time to fall asleep score, sleep duration score, sleep efficiency score, sleep disturbances score, use of sleeping medication score, and daytime dysfunction score. Each component was scored from 0 to 3, with the total PSQI score ranging from 0 to 21. The scoring thresholds were as follows: 0\u0026ndash;5 points (very good sleep quality), 6\u0026ndash;10 points (fair sleep quality), 11\u0026ndash;15 points (average sleep quality), and 16\u0026ndash;21 points (very poor sleep quality) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The PSQI score is inversely related to sleep quality, with a higher score indicating poorer sleep quality.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003e(5) MMSE\u003c/h2\u003e \u003cp\u003eThe MMSE consists of 12 items that assess a participant's intellectual status and degree of cognitive impairment across dimensions, including orientation, memory, attention and calculation, recall, and naming ability [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The highest possible score is 30, with scores between 27 and 30 indicating normal cognitive functioning and scores below 27 suggesting cognitive impairment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003e(6) HADS\u003c/h2\u003e \u003cp\u003eThe HADS consists of 14 items, with seven items assessing depression and seven items evaluating anxiety. There are six reverse-scored items, five of which are included in the depression subscale and one in the anxiety subscale. Each item is rated on a 4-level scale from 0 to 3, with scores of 0 to 3 assigned based on the absence, mild, moderate, and severe impact on the subject, respectively[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. A total score ranging from 0 to 7 indicated no symptoms, a score from 8 to 10 suggested the possible presence of anxiety or depression symptoms, and a score from 11 to 21 confirmed the presence of anxiety or depression symptoms.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003e(7) TCM syndrome score\u003c/h2\u003e \u003cp\u003eThe collection of TCM symptom scores included the following main symptoms: cough with little or no phlegm, fatigue and weakness, wheezing and shortness of breath, decreased appetite, and loose stools. These symptoms were rated based on severity, with scores of 0, 2, 4, and 6 for none, mild, moderate, and severe, respectively. Additionally, secondary symptoms, including spontaneous sweating and aversion to wind, low-grade fever, abdominal distension, cognitive impairment, insomnia, pallor, and dizziness with tinnitus, were evaluated and assigned scores of 0, 1, 2, and 3 according to their severity [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003e(8) Blood test\u003c/h2\u003e \u003cp\u003eVenous blood samples were collected from all participants to determine C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and interleukin-6 (IL-6) levels.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient visit and data collection\u003c/h3\u003e\n\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eBaseline data\u003c/h2\u003e \u003cp\u003eBaseline data included general demographic data, past medical history, course of disease, treatment history, drinking history, participation in clinical trials, total clinical symptom score, fatigue, sleep, pain, cognition, depression scales, TCM syndrome score, and safety evaluations. The main components included the vital signs of the subjects (body temperature, blood pressure, respiration, and heart rate), main signs and symptoms, personal history and medication, total score of clinical symptoms, FAS, VAS, PSQI, MMSE, HADS, TCM syndrome score, CRP, ESR, IL6, routine blood, urine and stool tests, liver and kidney function, and ECG.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eAssessment data\u003c/h2\u003e \u003cp\u003eOn the 14th day of treatment, the symptoms and signs, medication, FAS, VAS, PSQI, MMSE, HADS, a total score of clinical symptoms, TCM syndrome score, CRP, ESR, and IL6 were assessed. Laboratory examination results were collected, including routine blood, urine, and stool tests, liver and kidney function, and ECG. The onset time, severity, duration, effective measures, outcomes of AEs, completion of trials, and time of discontinuation of trials were recorded in the case report form (CRF), including an analysis of whether AEs were associated with clinical drug trials.\u003c/p\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003eIndicators detection\u003c/h2\u003e \u003cp\u003eDuring the screening and treatment periods, all subjects were required to take 3\u0026ndash;5 mL of peripheral venous blood in the morning on an empty stomach and then left to stand for 1\u0026ndash;2 h. Whole blood, serum, and plasma supernatants were collected (extracted after centrifugation at 3,000 rpm for 10\u0026ndash;15 min) for routine blood tests, liver and kidney function, CRP, ESR, and IL6. Three tubes of urine from each subject's midstream specimen were collected for urine sediment microscopy and routine urine analysis. An appropriate amount of stool samples were kept for routine stool and occult blood tests. Laboratory biochemical examinations were performed using a cobas8000 (702/502), cobasU601/701 Roche automatic biochemical analyzer, and SYSMEX-Xi 9000 blood cell analyzer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eThe protocols for handling specific AEs and SAEs are described in Supplemental Appendix 2. Participants were asked if they had experienced any AEs at each study visit. AEs were assessed by a study physician and reported to the Data Safety and Monitoring Board. SAEs, including death, life-threatening conditions, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital anomaly, or birth defect [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], were reported to the Ethics Review Committee of Hunan Academy of Chinese Medicine Affiliated Hospital within 24 h after acknowledgment. For mild AEs, the patient was reassured to continue taking medication following the protocol [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eSample Size\u003c/h3\u003e\n\u003cp\u003eThe determination of sample size in a superior clinical trial design with qualitative variables is calculated using the following formula:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:\\text{n}=\\frac{{{\\pi\\:}}_{\\text{t}}\\times\\:\\left(1-{{\\pi\\:}}_{\\text{t}}\\right)+{{\\pi\\:}}_{\\text{c}}\\times\\:\\left(1-{{\\pi\\:}}_{\\text{c}}\\right)}{{\\left({{\\pi\\:}}_{\\text{t}}-{{\\pi\\:}}_{\\text{c}}-\\varDelta\\:\\right)}^{2}}\\times\\:{\\left({{\\mu\\:}}_{{\\alpha\\:}/2}+{{\\mu\\:}}_{{\\beta\\:}}\\right)}^{2}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eA clinical trial investigating the effects of TCM in treating patients with convalescent COVID-19 and lung and spleen qi deficiency syndrome demonstrated that the medicine improves patients' symptoms, including fatigue, shortness of breath, cough, and poor appetite. After two weeks of treatment, the improvement rate for individual symptoms in the TCM group ranged from 85.4\u0026ndash;89.7%, whereas that in the placebo group ranged from 42.2\u0026ndash;64.7% [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Assuming a clinical effective rate of 90% for the experimental group (treated with SLKF Granules) and 65% for the control group (receiving a placebo simulation of SLKF Granules), with a significance level of 5%, an anticipated dropout rate of 15%, setting α\u0026thinsp;=\u0026thinsp;0.025 (one-sided) and β\u0026thinsp;=\u0026thinsp;0.20 (one-sided), and Δ\u0026thinsp;=\u0026thinsp;5%, the sample size calculation indicated that at least 63 participants were required for each group. Considering the 15% dropout rate, 154 participants were needed for both groups.\u003c/p\u003e\n\u003ch3\u003eStatistical Methods\u003c/h3\u003e\n\u003cp\u003eAll statistical analyses were performed using SAS software (version 9.4). For continuous variables, the sample size, mean, standard deviation, median, and minimum and maximum values were calculated. Intergroup comparisons for the treatment groups were performed using one-way analysis of variance or rank-sum tests. For counting data, the frequency and composition ratio were calculated, with intergroup comparisons for the treatment groups using the chi-squared or Fisher's exact test. Regarding medication adherence and analysis of concomitant medication, the percentage of participants with adherence rates between 80% and 120% was calculated, and group differences were compared using the chi-square test or Fisher's exact probability method. The percentage of participants taking concomitant medications was also calculated, and differences between groups were compared using the chi-square test or Fisher's exact probability method. Additionally, an analysis based on the WHO anatomical therapeutic chemical (ATC) classification for concomitant medications was conducted, employing either the chi-square test or Fisher's exact probability method to compare group differences. The comparison and analysis of the effectiveness indicators employed non-parametric tests or an analysis of covariance. If baseline differences existed between the two groups, baseline measurements were adjusted as covariates before conducting intergroup comparisons. The safety analysis primarily involved assessing the AE incidence between the groups, abnormal laboratory data, electrocardiograms, and physical examination results before and after treatment.\u003c/p\u003e \u003cp\u003eThe full analysis set was conducted for the therapeutic indices of all subjects included in the study. Statistical analysis in accordance with the per protocol set (PPS) was conducted for the therapeutic indices of subjects completing the drug intervention on the 14th day. The full analysis set (FAS) used the last-observed-carried forward method to adjust for missing data and complete the intention-to-treat analysis. Safety analysis was performed using the safety analysis set. All statistical tests were two-sided. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.1 was considered a statistical difference, while \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.05 was considered a statistically significant difference.\u003c/p\u003e \u003cdiv id=\"Sec37\" class=\"Section2\"\u003e \u003ch2\u003eQuality Control and Data Monitoring\u003c/h2\u003e \u003cdiv id=\"Sec38\" class=\"Section3\"\u003e \u003ch2\u003eQuality assurance\u003c/h2\u003e \u003cp\u003eFirst, all participating researchers and laboratories were required to adhere to the laboratory's quality control measures and drug batch quality control following standard operating procedures and quality control protocols. Each participating unit provided the 'normal value range for laboratory tests' specific to their facility, and any changes during the trial were promptly documented.\u003c/p\u003e \u003cp\u003eSecond, to control for participant compliance, a combination of drug counting and questioning methods was used to monitor adherence to the study medication. Adequate explanations were provided to participants, and follow-ups were strengthened to ensure good compliance among the subjects. The participants received training before the trial to ensure that they fully understood the informed consent. When distributing diary cards, researchers carefully explained the filling requirements, methods, and return procedures, as well as educated participants on potential adverse reactions to the trial medication and actions to take if such reactions occur.\u003c/p\u003e \u003cp\u003eFinally, in terms of investigator control, training was held before the clinical trial was launched to ensure that the investigators fully understood the clinical trial protocol and the specific connotations of each indicator. Moreover, the consistency of the quantitative standard of symptoms and signs was tested, the consistency of the TCM syndrome was trained and evaluated, and the investigators' subjective symptom description was aimed to avoid inducing or hinting. The objective indicators were checked according to specified time points and methods. Attention was paid to observing adverse reactions or unexpected toxic side effects, followed by follow-up assessments. Research assistants filled out the CRF following the researcher's manual in each center, requiring them to record the contents of the form accurately and thoroughly to ensure the authenticity and reliability of the CRF content. All observations and findings in the clinical trial were verified to ensure the reliability of the data, and all conclusions in the clinical trial were based on the original data.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec39\" class=\"Section2\"\u003e \u003ch2\u003eData management\u003c/h2\u003e \u003cp\u003eIn terms of data monitoring and management, this trial employed CRFs for data collection and utilized Epidata for data management. An independent third party, separate from the CRC, was entrusted with data verification for the CRFs. The database was provided by the Clinical Evaluation Research Center of Central South University, and the data were entered into the database by two personnel to ensure accuracy. Subsequently, statistical personnel from the center crosschecked the raw data. Any identified issues were promptly questioned and returned for modification and enhancement. Once the verification was completed and accurate, data management and statistical analysis were performed.\u003c/p\u003e \u003cdiv id=\"Sec40\" class=\"Section3\"\u003e \u003ch2\u003eConfidentiality\u003c/h2\u003e \u003cp\u003eAll study-related information was stored on secure network drives or servers. Participants were allocated study identification (ID) numbers, and a master file linking the study ID and personal information was saved separately to protect their privacy.\u003c/p\u003e \u003cp\u003e \u003cem\u003eAccess to data\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe study principal investigator, co-investigators, CRC, research assistants, and statistician have access to the collected data.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval and study registration\u003c/strong\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e This study was approved by the Ethics Review Committee of Hunan Academy of Chinese Medicine Affiliated Hospital (reference number: 2023\u0026thinsp;\u0026minus;\u0026thinsp;144), any protocol modifications will be reported to the Ethics Review Committee.\u003c/p\u003e \u003cp\u003e The research staff obtained consent from interested participants through ten hospitals in Hunan province in China, an outpatient medical record platform, an inpatient case system, and recruitment advertisements. Participants received information regarding the ICF and had the opportunity to discuss the trial specifics and meet with the CRC or research assistant before deciding to participate. The ICF is provided in the Online Supplemental Appendix 3.\u003c/p\u003e \u003cp\u003e The trial was subjected to inspections or audits by the Ethics Review Committee of Hunan Academy of Chinese Medicine Affiliated Hospital and Hunan Provincial Health Commission to determine whether research activities were conducted following the protocol, Good Clinical Practice, and guidelines of the International Conference on Harmonization. Under the identifier ChiCTR2400080348, the research protocol has been filed in the Clinical trials registry.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSince 2019, the novel coronavirus has been spreading rapidly around the world, and as strains of the virus continue to mutate, resulting in wave-like outbreaks, infected individuals may experience 'reinfection' time and again. For most people, the coronavirus causes only mild or moderate symptoms, but multiple organ failure can occur in patients with underlying diseases and weakened immune systems. The infected patients' symptoms gradually reduce, and the nucleic acid becomes negative, there are still varying degrees of damage to the cardiopulmonary, musculoskeletal, neurological, and digestive systems, including persistent fatigue, joint/muscle pain, coughing, shortness of breath, sweating, insomnia, hyposmia, and hypogeusia, it means that the patients with COVID-19 step into the 'recovery period' ('Long COVID') [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Currently, most physicians and researchers focus on the treatment of severe patients and vaccine development and pay insufficient attention to health management and interventions for convalescent COVID-19.\u003c/p\u003e \u003cp\u003eStudies have demonstrated that anti-COVID-19 small molecule drugs (Nematrevir/Ritonavir and Monoravir) and RNA virus inhibitors (Raltegravir and Azulfidine) can reduce the risk of more than 10 types of 'Long COVID' symptoms [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], shorten the time to symptomatic improvement in patients with medium-sized COVID-19 infections [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], and reduce the risk of severe hospitalization or death [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. However, relevant meta-analyses have revealed that the benefits of these drugs in patients with COVID-19 with severe symptoms are unclear, and their safety is questionable [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. TCM has been recognized for its remarkable effects in the fight against infectious diseases. Acting as a preventive treatment for diseases, it has the advantage of preventing disease recurrence after recovery.\u003c/p\u003e \u003cp\u003eEvidence indicates that TCM-related treatment measures have good efficacy in treating mild-to-moderate COVID-19 infections and can play a synergistic role in multiple targets [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Acupuncture, Chinese exercises (Qigong and Tai Chi), Chinese patent medicine, and TCM decoction can improve difficulty in falling asleep, shallow sleep, dreamy sleep, and other sleep problems. To regulate the body's immunity and improve the impairment of multi-system function, this is a scientific issue that deserves an in-depth discussion: how can we utilize the advantageous role of Chinese patent medicine for the convalescence of COVID-19 patients?\u003c/p\u003e \u003cp\u003eIn previous studies, SLKF granules have been used to treat upper respiratory infections, including pneumonia and the spleen and lung deficiency syndrome caused by COVID-19. SLKF granules are mainly composed of Huangqi (\u003cem\u003eAstragali Radix\u003c/em\u003e), Fuling (\u003cem\u003ePoria\u003c/em\u003e), and Dangshen (C\u003cem\u003eodonopsis Radix\u003c/em\u003e) to supplement the body's qi, combined with Gegen (\u003cem\u003ePuerariae Lobatae Radix\u003c/em\u003e), Baizhu (\u003cem\u003eAtractylodis Macrocephalae Rhizoma\u003c/em\u003e), Baishao (\u003cem\u003ePaeoniae Radix Alba\u003c/em\u003e), and Guizhi (\u003cem\u003eCinnamomi Ramulus\u003c/em\u003e), to enhance the functions of spleen and lung and promote the regulation of Qi and Yang. Modern pharmacological studies have discussed the preventive and therapeutic effects of the mentioned TCM and its active ingredients on COVID-19 from various perspectives. Based on web-based bioinformatics workflows integrating multiple databases, it is suggested that Huangqi (\u003cem\u003eAstragali Radix\u003c/em\u003e) can upregulate microRNA-148b (miR-148b) and microRNA-148b (miR-146a), and reduce the pathogenesis of COVID-19 infection, inhibit pro-inflammatory cytokines including IL-6 and tumor necrosis factor-α (TNF-α), prevent acute respiratory distress syndrome caused by COVID-19, and inhibit the activity of the COVID-19 Mpro protease; therefore, reducing virus entry and replication [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Network pharmacological studies have confirmed that the targets of Fuling (\u003cem\u003ePoria\u003c/em\u003e) intervention are mainly related to the damage response, peptide serine phosphorylation, response of cells to biological stimuli, establishment of protein localization regulation, lipopolysaccharide response, and other biological processes. Further research has demonstrated that the active ingredient pachymic acid in Fuling (\u003cem\u003ePoria\u003c/em\u003e) inhibits the COVID-19 main protease Mpro[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Other studies have identified \u003cem\u003ecodonopsis pilosula\u003c/em\u003e and white peony as representative major components of papain-like protease inhibitors against COVID-19 after screening [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, we designed a multicenter, randomized, double-blind, placebo-controlled clinical trial to confirm the efficacy of SLKF granules on convalescent COVID-19 symptoms (fatigue, cough, and insomnia) and to clarify its safety profile. During the data analyses, we performed a sensitivity analysis to test the robustness of the results by comparing the FAS and PPS. This study's results provide a clear intervention for clinical or outpatient treatment of convalescent COVID-19.\u003c/p\u003e \u003cp\u003eOver the past four years, the novel coronavirus has evolved rapidly and continues to mutate, with the ability to evade vaccine protection. It is foreseeable that humans will coexist with viruses for a long time. Currently, the long-term effects and damage of the coronavirus on humans still require further observation, and the exploration of interventions for convalescent COVID-19 is also an urgent scientific issue. However, this trial remains an exploratory study, with deficiencies in the diagnosis of study subjects, sample size, treatment duration, and selection of outcome measures. Moreover, the intervention period in this study was relatively short, and the long-term course and safety still need to be determined in follow-up studies. Consequently, increasing the sample size and conducting multicenter clinical trials with longer observation periods are crucial to clarify the efficacy and safety of TCM in convalescent COVID-19.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe purpose of this multicenter, randomized, double-blind, simulant, and parallel controlled clinical trial is to evaluate the clinical effectiveness and safety of SLKF granules in patients with convalescent COVID-19 and lung-spleen qi deficiency syndrome.It is expected that its subsequent findings will provide higher-quality evidence-based medical data for the optimization of treatment of these patients.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSLKF\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eShenlingkangfu\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOVID-19\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCoronavirus disease 2019\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTCM\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etraditional Chinese medicine\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eimmunoglobulin G\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSPIRIT-TCM\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ethe Recommendations for Interventional Trials Traditional Chinese Medicine\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003einformed consent form\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCt\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ethe cycle threshold\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAEs\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eserious adverse events\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAEs\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRC\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eclinical coordinator\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCore Outcome Measures in Effectiveness Trials\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFAS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ethe fatigue self-assessment scale\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVAS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ethe pain visual analog scale\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSQI\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ethe Pittsburgh sleep quality index\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMSE\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emini-mental state examination\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHADS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehospital anxiety and depression scale\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eerythrocyte sedimentation rate\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003einterleukin-6\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRBC\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ered blood cell\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ewhite blood cell\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHGB\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehemoglobin\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eplatelet count\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ealanine aminotransferase\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003easpartate transaminase\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGGT\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egamma-glutamyl transferase\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTBiL\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etotal bilirubin\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ealkaline phosphatase\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eblood urea nitrogen\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScr\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eserum creatinine\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eurine acid\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eestimated glomerular filtration rate\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECG\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eelectrocardiogram\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ethe per protocol set\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFAS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ethe full analysis set\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all the funding supports in this study. The authors also acknowledge all the participants in this study and other practitioners who will contribute to the study but are not on the list of authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJG and DW is responsible for this study. JG, DW, RF and LX designed the study protocol. RF and WY wrote the manuscript. YZ, JT and LZ revised the manuscript. RF and YZ devised a plan for statistical analysis. JT, DL, GW, QC, LL and YL took part in the recruiting process. LX and DW supervised the clinical trial. YP and SZ finished the batch testing of study products. RF, WY and YZ were involved in developing the main documents regarding ethics approval and data assurance that constitute the basis of this manuscript. All authors contributed to the article and approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was funded by the Key Research and Development Program of Hunan Province (No. 2023SK2003).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eThe study will be conducted in compliance with the Declaration of Helsinki and ICH-GCP guidelines.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePublisher\u0026rsquo; s note\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Coronavirus disease (COVID-19) Epidemiological Updates and Monthly Operational Updates. (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang J, Cheng X, Ling Y, Gong R, Zhang X, Li H et al. Expert consensus on health management during recovery period of COVID-19 infection. \u003cem\u003eHealth Research\u003c/em\u003e. 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Zhongguo Zhong Yao Za Zhi. 2020;45:1219\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chinese medicine, alternative and complementary medicine, convalescent COVID-19, randomized controlled trial, protocol","lastPublishedDoi":"10.21203/rs.3.rs-5332179/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5332179/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eConvalescent coronavirus disease 2019 (COVID-19) refers to a series of clinical syndromes in patients with COVID-19 infection that follow the relevant discharge indications but do not fulfill the criteria for a clinical cure, and these patients are discharged from the hospital with residual multifunctional deficits, including coughing, fatigue, and insomnia. The World Health Organization's preliminary statistics revealed that over 65\u0026nbsp;million individuals worldwide experience a 'long COVID', and the incidence rate in each country varied from 34\u0026ndash;77%. Due to the prolonged convalescent COVID-19 infection, patients continue to experience symptoms or develop new symptoms after three months of infection, and some symptoms persist for over two months without any apparent triggers, which has a significant impact on the health status and quality of life of the population. Patients with convalescent COVID-19 lack a definitive pharmacological treatment. Traditional Chinese medicine (TCM) exhibits a distinct, synergistic effect on the treatment of convalescent COVID-19. However, there exists a limited number of clinical trials on TCM with lower evidence levels in convalescent COVID-19; therefore, randomized trials are urgently required.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial was performed to evaluate the efficacy and safety of Shenlingkangfu (SLKF) granules in treating patients with convalescent COVID-19 and lung-spleen qi deficiency syndrome. The trial was conducted through ten hospitals in China's Hunan province, with subjects recruited from outpatient medical record platforms, inpatient case systems, and subject recruitment advertisements. Eligible participants were aged 18\u0026ndash;75 years, had a confirmed or physician-suspected severe acute respiratory syndrome coronavirus 2 infection at least six months prior, and satisfied clinical criteria. Individuals with a history of severe pulmonary dysfunction or major liver and kidney illness or those on medications were excluded. After a 2-day adjustment period, all participants were randomly divided into an intervention group (n\u0026thinsp;=\u0026thinsp;77) and a control group (n\u0026thinsp;=\u0026thinsp;77). The intervention group was given the SLKF granules orally once a bag, 16.9 g, twice daily, whereas the control group received the SLKF granule simulation at the same dosage. The trial was conducted over 14 days, with assessments performed at baseline and 14 days. The primary outcomes were the therapeutic efficacy rate and total clinical symptom score. The secondary outcomes included the fatigue self-assessment scale, pain visual analog scale, Pittsburgh sleep quality index, mini-mental state examination, hospital anxiety and depression scale, TCM syndrome score, C-reactive protein, erythrocyte sedimentation rate, and interleukin-6. Three routine examinations, liver and kidney function tests, and electrocardiography were used as safety indicators.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis study aimed to verify whether SLKF granules can significantly improve clinical symptoms, including fatigue, loss of appetite, cough, phlegm, and insomnia, in patients with convalescent COVID-19. For a comprehensive investigation, additional clinical trials with larger sample sizes and longer intervention periods are required.\u003c/p\u003e\u003ch2\u003eTrial registration Registered 26 January 2024,\u003c/h2\u003e \u003cp\u003e \u003cspan class=\"ExternalRef\"\u003e \u003cspan class=\"RefSource\"\u003ehttps://www.chictr.org.cn\u003c/span\u003e \u003cspan address=\"https://www.chictr.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e \u003c/span\u003e, identifier ChiCTR2400080348.\u003c/p\u003e","manuscriptTitle":"Chinese medicine compound for the convalescent COVID-19 patients: A multicenter, randomized, double-blind, placebo-controlled clinical trial protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-02 16:27:47","doi":"10.21203/rs.3.rs-5332179/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"53f8a2bc-e3ab-4871-b697-93ff1ec0c03a","owner":[],"postedDate":"December 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-06T17:38:33+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-02 16:27:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5332179","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5332179","identity":"rs-5332179","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}