Clinical efficacy of Luohua Anshen oral liquid in the treatment of short-term insomnia disorders (syndrome of depressed liver qi transforming into fire): protocol for a single-center, double-blinded, randomized, placebo-controlled trial

Clinical efficacy of Luohua Anshen oral liquid in the treatment of short-term insomnia disorders (syndrome of depressed liver qi transforming into fire): protocol for a single-center, double-blinded, randomized, placebo-controlled trial | 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 Clinical efficacy of Luohua Anshen oral liquid in the treatment of short-term insomnia disorders (syndrome of depressed liver qi transforming into fire): protocol for a single-center, double-blinded, randomized, placebo-controlled trial Ting Jiang, Yuan-Xin Lee, Chun-Yan Li, Yin Wang, Yu-Ling Huang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4119690/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 : At present, insufficient attention and unsatisfactory treatment for short-term insomnia disorder are widespread problems. This group of people should receive safe and effective treatment as soon as possible and avoid developing into chronic insomnia disorder. We hope to intervene and treat these patients through Luohua Anshen oral Liquid, which is made of peanut branches and leaves and has been used to effectively treat insomnia disorder, this method can be conducive to preventing short-term insomnia disorder chronicity and reducing the burden of health economics. Methods : This double-blinded, randomized, placebo-controlled trial will be conducted at Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine. After the one-week baseline, 96 short-term insomnia patients will be allocated 1:1:1 to intervention group A (treatment with Luohua Anshen oral liquid placebo 30 min after breakfast, and Luohua Anshen oral liquid 30 min before retiring for sleep),intervention group B (treatment with Luohua Anshen oral Liquid 30 min after breakfast, and Luohua Anshen oral liquid placebo 30 min before retiring for sleep) or the control group (treatment with oral placebo twice a day), with 4 weeks of treatment and 12 weeks of follow-up. The primary outcome will be evaluated with the Pittsburgh Sleep Quality Index (PSQI). The secondary outcomes included the incidence of chronic insomnia, the Insomnia Severity Index (ISI), Traditional Chinese Medicine Syndrome Scale (TCMSS) and Morning and Evening Questionnaire-5 (MEQ-5) scores; the sleep parameters recorded in the GENEActiv and Sleep Diary;and the Hamilton Rating Scale for Depression (HAMD-17) and Hamilton Anxiety Scale (HAMA) scores. The mechanistic evidence will be full-spectrum detection via serum and fecal sample metabolomics. Discussion : This study provides more subjective and objective evidence of the efficacy and safety of Luohua Anshen oral liquid for improving sleep quality and exploreing the metabolic pathway of Serum and feces in patients with short-term insomnia. Trial registration : This trial was registered in the Chinese Clinical Trial Registry (ChiCTR) (Identifier: ChiCTR2300071930) on 30 May 2023. Short-term insomnia Luohua Anshen oral liquid Randomized controlled trial Figures Figure 1 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Clinical efficacy of Luohua Anshen oral liquid in the treatment of short-term insomnia disorders (Syndrome of depressed liver qi transforming into fire): protocol for a single-center, double-blinded, randomized, placebo-controlled trial Trial registration {2a and 2b}. Registered in the Chinese Clinical Trial Registry (ChiCTR) (Identifier: ChiCTR2300071930) on 30 May 2023 Protocol version {3} 28 June 2023, VERSION 3.0 Funding {4} This study is supported by National Key Research and Development Program of China [number: 22021YFC2501500] and Shanghai Technical Superiority Project of “Preventive Treatment of Disease”, Shanghai Municipal Health Commission [ZY (2021-2023)-0104-02-GF-04] to W-JZ. Author details {5a} Ting Jiang 1 , 2 , Yuan-Xin Lee 2 , Chun-Yan Li 1 , 2 , Yin Wang 2 , Yu-Ling Huang 1 , Guo-Hua Wang 1 , Hui-Ru Wang 1 , Wen-Jing Zhang 1 , Fei-Yi Zhao 3 . Department of Psychiatry, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Shanghai University of Traditional Chinese Medicine, Shanghai, China. Department of Nursing, School of International Medical Technology, Shanghai Sanda University, Shanghai, China. Name and contact information for the trial sponsor {5b} Prof. Wen-Jing Zhang, Department of Psychiatry, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, NO.274 ZhiJiang Middle Road, Shanghai ,200071, China. Tel: +86 56639310 E-mail: [email protected] Role of sponsor {5c} This trial is solely funded by non-commercial sources. Funding sources have had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results Introduction Background and rationale {6a} Insomnia disorder is characterized by a range of symptoms, including difficulty initiating and/or maintaining sleep, waking too early, and difficulty returning to sleep, and a decrease in the quantity or quality of sleep leads to the impairment of patients' daytime function, such as fatigue or malaise; impairment of attention, concentration or memory; and decreased work and study performance [1].It is also the precursor and maintenance factor of many physical diseases and mental disorders[2]、[3]. The Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) divides Insomnia disorder into chronic Insomnia Disorder (CID) and short-term insomnia disorder (STID) according to whether the course of disease is ≥3 months [4]. Most people experience short-term insomnia when facing social stress factors or rapid changes in circadian rhythm. Because it can often be relieved spontaneously, it does not cause serious physical or mental damage, and it has not attracted widespread attention as well as chronic insomnia disorder. However, two prospective studies by Ellis et al. reported that the annual prevalence of short-term insomnia was as high as 36%, and about 40% of patients eventually developed chronic insomnia[5-6]. These two studies show a high prevalence of acute insomnia and chronic insomnia, and suggest that short-term insomnia is a critical period of chronic insomnia, which is highly significant and requires active clinical intervention and treatment. At the same time, the American Academy of Sleep Medicine emphasizes that short-term insomnia disorder may be easier to treat than chronic insomnia disorder[7]. At present, there are no clear treatment guidelines for short-term insomnia disorder. In the past, sedative and hypnotic drugs (including benzodiazepines, nonbenzodiazepines, orexin receptor antagonists and melatonin receptor agonists) were usually used to treat short-term insomnia disorder. However, the adverse reactions such as side effects and addiction caused by drugs cannot be ignored, and their long-term efficacy is not clear. Research shows that for short-term insomnia disorder, only when insomnia leads to serious and incurable personal stress can we consider using nonbenzodiazepines[8] . Cognitive behavioral therapy for insomnia (CBT-I) is a first-line recommended nondrug treatment for chronic insomnia[9]. In recent years, domestic and foreign sleep experts preliminarily explored its effectiveness in treating short-term insomnia, but further research is needed to verify[10]. Traditional Chinese herbs have been used for centuries to induce sleep. Therefore, we hope to intervene and treat patients with short-term insomnia through traditional Chinese medicine, which is conducive to preventing its chronicity and reducing the burden of health economics[11]. Luohua Anshen oral liquid is a standardized product made from the branches and leaves of groundnut. One-third of the aboveground branches and leaves of groundnuts are sweet, light and slightly bitter, and it enters the liver, heart and lung meridians. It has the effects of calming the liver and suppressing yang, calming the nerves and strengthening the brain, and its preliminary research effect is remarkable[12]. A serum metabonomics study revealed that the sedative and hypnotic effects of Luohua Anshen Oral liquid were related to four metabolic pathways. The serum metabolites of insomnia rats were detected[13]. The results showed that 37 different metabolites were differentially expressed between the model group and the peanut branch group, and there were 5 common differentiall abundant metabolites among them. These include serine, hippuric acid, indole 3 propionic acid, butanediol and cytosine. Serine can promote awakening[14], and the concentration of serine can be reduced after intervention with Luohua Anshen Oral Liquid. Luohua Anshen Oral liquid has been clinically to treat insomnia more than 100,000 times, and more than 1,200 cases have been identified in scientific research[12]. Statistical analysis, revealed that yin deficiency can obviously improve the symptoms of insomnia patients with liver depression and fire hyperactivity[15]. Subsequently, Feng Beilei divided 30 patients with insomnia due to liver depression and fire into a treatment group and a control group, both of whom were given Estazolam, while the treatment group was given Luohua Anshen oral liquid. The results showed that the efficacy of Luohua Anshen oral liquid combined with Estazolam in treating insomnia due to liver depression and fire was better than that of Estazolam alone, and there were few adverse reactions[16]. In 2017, Zhang Wenjing[17] conducted a randomized controlled double-blind trial. The results showed that the effective rate of Luohua Anshen Oral liquid in treating insomnia was 77.4%, and the effective rate of placebo was 33.3%, which proved its remarkable clinical efficacy, safety and lack of toxicity. Therefore, we intend to conduct a high-quality, well-designed, randomized, placebo-controlled trial to further provide subjective and objective evidence of the efficacy and safety of Luohua Anshen oral liquid in short-term insomnia patients. Objectives {7} Main objective: To verify the clinical efficacy of Luohua Anshen Oral liquid in the treatment of patients with short-term insomnia disorder (syndrome of depressed liver qi transforming into fire). Secondary objectives: To explore the improvement of Luohua Anshen Oral liquid on subjective and objective sleep evaluation indexes in patients with short-term insomnia disorders. To explore the effectiveness of Luohua Anshen Oral liquid in preventing short-term insomnia into chronic insomnia. To explore the effect of Luohua Anshen Oral liquid in improving the Traditional Chinese Medicine Syndrome in patients with depressed liver qi transforming into fire type sleeplessness. To investigate the difference between serum metabolites in patients with short-term insomnia disorder and healthy people, and whether Luohua Anshen oral liquid solution can decrease the concentration of serine in human serum metabolites. To verify whether different time of taking the oral liquid will affect the treatment efficacy. Trial design {8} This is a single-center, double-blinded, randomized, placebo-controlled trial aimed at evaluating the clinical efficacy of Luohua Anshen oral liquid in the treatment of short-term insomnia disorders (syndrome of depressed liver qi transforming into fire). The trial will be performed in the insomnia department of Shanghai Municipal Hospital of Traditional Chinese Medicine. We plan to recruit 96 patients who meet the inclusion criteria and randomly assign them to one of three groups, receiving Luohua Anshen oral liquid and/or its placebo (1/10 of the effective dose) at different times. After one-week baseline, participants will enter a 4-week treatment period. All treatments will be given 2 times a day, each time 2 oral bottles of designated will be used. Participants will be assessed at the following time points: the baseline (1 week before treatment), the middle of the treatment (2 weeks after treatment starts), the end of the treatment (4 weeks after treatment starts) and follow-up (1 week, 3 months after the treatment finishes). All participants will complete the assessments by the PSQI, ISI, GENEActiv, Sleep Diary, HAMD-17, HAMA and adverse event assessment forms (detailed trial process shown in Fig. 1). Methods: Participants, interventions and outcomes Study setting {9} The study will be conducted at the Department of Insomnia, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People’s Republic of China, which is a third-class Grade A comprehensive hospital with good performance in clinical medicine and scientific research. The person in charge of this study obtained good clinical practice (GCP) certification. All the researchers received homogeneity training, such as the introduction of clinical consultation, operation, and instructions on how to complete the Case Report Form (CRF). The data analysts will receive training in data input, coding, security, and storage. Statisticians will be trained in data evaluation and analysis. To control of the quality of the subjects, they will be screened strictly according to the criteria for admission. Those with inaccurate TCM syndrome differentiation will be diagnosed by TCM clinicians with the title of an attending physician or above before deciding whether to be included. Eligibility criteria {10} Ninety-six patients will be recruited for this study. To ensure the precision of the results, we developed the following eligibility criteria. Inclusion criteria Participants meeting the following criteria will be included: The diagnostic criteria for met the diagnostic criteria[18] for syndrome of depressed liver qi transforming into fire type sleeplessness in the "Clinical Practice Guidelines for Insomnia in Traditional Chinese Medicine (WHO/WPO)" and the diagnostic criteria for short-term insomnia disorder in DSM-5. Age 18~40 years old (including 18 years old and 40 years old), regardless of sex. PSQI score ≥6 points. The course of this onset is more than 2 weeks. Clear consciousness, stable vital signs, certain expression and execution ability, and being able to cooperate with the completion of testing and treatment. Voluntarily participated in the research of this project and signed the informed consent form. Exclusion criteria Participants who reported any of the following conditions were excluded: The total score of the HAMD-17 is >= 18 points and/or the HAMA score is > 14. Those who suffer from other mental disorders and are unstable and/or suicidal and at risk; Psychotropic drugs that affect central nervous system function (such as antidepressants, nonbenzodiazepines) being added or changed within 2 weeks before enrollment. Laboratory tests and electrocardiograms show have obvious clinically significant abnormalities, which can affect drug evaluation or patient safety. Women who were pregnant or lactating at the time of study and follow-up. Caffeine, alcohol or drug addicts. Those who were allergic to the experimental medication or ingredients included in this protocol. Who will take informed consent? {26a} Researchers will ensure that the study schedule and participation requirements are fully explained before consent is obtained and signed, and that participants are aware of the potential risks and benefits of the treatment. Of course, there is no need to pay any research-related expenses. We will do our best to protect the information provided by patients from being leaked and strictly abide by the laws and regulations on privacy and personal information protection. Additional consent provisions for collection and use of participant data and biological specimens {26b} If patients are willing to participate in this study, we will ask them whether they are willing to participate in the additional part of this study, and biological samples and health-related information will be used for future medical scientific research. The patient were informed that the participation in the supplementary part was entirely voluntary, that the patient had the right to decide whether to participate,and that participation did not affect the main part of the patient's participation in this study or the corresponding rights and interests. Interventions Explanation for the choice of comparators {6b} The Luohua Anshen oral liquid (Shanghai Hospital of Traditional Chinese Medicine lot number: Z05190756) at a used in the present study was prepared by BaoLong Pharmaceutical Factory for processing and production,and conform to the relevant regulations for the oral l of traditional Chinese medicine (General Rules of Pharmacopoeia 2015), and the content is determined by high performance liquid chromatography(HPLC) (General Rules of Four Parts of Pharmacopoeia 2015). The Conventional dose, volume of 10mL/ piece and contained15 g of groundnut branches and leaves. The placebo, volume of 10mL/ piece and composed of 1.5g of groundnut branches and leaves, matches the active material in terms of appearance,smell and taste. Intervention description {11a} Test group A Half an hour after breakfast, two oral bottles of Luo Hua Anshen oral liquid placebo, and half an hour before going to bed, two oral bottles of Luo Hua Anshen oral liquid Test group B Half an hour after breakfast, two oral bottles of Luo Hua Anshen oral liquid, and half an hour before going to bed, two oral bottles of Luo Hua Anshen oral liquid placebo Test group C two oral bottles of Luo Hua Anshen oral liquid placebo, twice a day. Participants in both groups will receive 12 boxes of Luohua Anshen oral liquid for free, 6 boxes each time. All three groups shall follow the outer packaging label to take two doses 30 min after breakfast and two doses 30 min before retiring for sleep, respectively, for 4 weeks in total. All participants were provided with sleep hygiene education before their first treatment session, which is the standard intervention given to all patients. Criteria for discontinuing or modifying allocated interventions {11b} Exit criteria Subjects who withdraw from the study for any reason need to record the reasons, including but not limited to the following aspects: The subject withdrew the informed consent; Serious adverse events thar caused the subjects to continue to participate in the trial; The researcher thinks that the medical condition of the subject may endanger the safety of the subject or that continuing the research will harm the health of the subject; poor compliance (that is, Morisk drug compliance scale < 6 points at the second week of follow-up) Serious protocol violation/protocol deviation (for example, during the 4-week intervention period, the subject changed the existing treatment protocol and added drugs that affect sleep); Death; Others. termination criteria serious safety problems occurred during the test; Major mistakes were found in the clinical trial scheme during the trial; The Ethics Committee requested that the experiment be terminated. Handling of shedding cases When the subject falls off, the researcher should contact the subject as much as possible, ask about the reason for the subject's withdrawal through the registered telephone, record the last medication time in detail and complete the evaluation items that can be completed. If the subjects quit the trial for various reasons such as allergic reactions, adverse reaction or ineffective treatment during the treatment, the researchers should take corresponding treatment measures according to the actual situation of the subjects. Once a random number is obtained, it will become the observation object of this experiment, regardless of whether the treatment has been completed, the patients who have fallen off do not need to be supplemented, and the files should be kept to properly keep the data of the fallen cases. Strategies to improve adherence to interventions {11c} Once formally enrolled in the group, a special researcher will call the patients on the fixed follow-up day to remind them to take medicine on time and other precautions. Participants in both groups will be required to return the empty boxes to the researchers after the fourth week of treatment, and recorded the quantity. We will conduct free safety check (The patient's general vital signs, such as birth, height, weight, handedness, heart rate, respiration, blood pressure, body temperature, etc.) and laboratory tests, including blood routine, urine routine, pregnancy urine test for female, stool routine, Hepatic function (alanine aminotransferase (ALT), aspartate aminotransferase (AST), renal function (serum creatinine (SCr), and blood urea nitrogen (BUN) will be performed once before and after treatment. All participants were provided with sleep hygiene education before their first treatment session, which is the standard intervention given to all patients. Relevant concomitant care permitted or prohibited during the trial {11d} Some patients used regular administration of antidepressants, sedatives, hypnotics or anxiolytics regularly before the trial. Researchers must record the dose, especially when patients reduce the amount, and dose change will not be allowed unless patients have consulted a psychiatrist. Provisions for post-trial care {30} We will educate all the patients on sleep hygiene, and the subjects still have insomnia at the third month of follow-up, the researchers will give them professional advice and recommend that the patients continue their treatment, including routine clinical chemotherapy, traditional Chinese medicine treatment, sleep cognitive behavioral treatment, acupuncture and auricular point treatment. Outcomes {12} Primary outcome The PSQI is composed of 19 sleep-related items, that are integrated into 7 components: subjective sleep quality, sleep latency, sleep time, sleep efficiency, sleep disorder, hypnotic drugs and daytime dysfunction. It mainly evaluates the frequency of these sleep problems and the overall sleep quality of the subjects in the past month. Each component is rated from 0 to 3 as mild to severe, for a total score of 21 points. The total PSQI score is ＞ 5, and the diagnostic sensitivity and specificity of distinguishing good and bad sleepers are 89.6% and 86.5%[19]. It is going to evaluate at baseline, week 4 and week 16 respectively. Secondary outcomes The incidence of chronic insomnia: At the 12th week after the end of the treatment and the 16th week of the experiment, all participants in the three groups were interviewed clinically based on DSM-5 diagnostic criteria for insomnia, to determine whether the patients met the DSM-5 diagnosis of chronic insomnia. Traditional Chinese Medicine Syndrome Scale (TCMSS): According to the diagnostic criteria of insomnia syndrome caused by liver depression and fire in the Guide to Clinical Practice of Insomnia in TCM (WHO/WPO), according to previous research[20] and the reliability and validity evaluation of the scale, the TCMSS collected by quantitative classification reflects the degree of symptom changes before and after treatment. The subjects evaluated the severity of the main symptom and the secondary symptom in turn (the researcher is responsible for explaining the meaning of each item in plain language), and the tongue pulse was recorded (and photographed) by the researcher. The patients will be evaluated at baseline, week 4 and week 16. Insomnia Severity Index Scale (ISI):The ISI consists of 7 items to evaluate the degree of difficulty in falling asleep or maintaining asleep, that is, sleep satisfaction, daytime function, impaired attention due to sleep, the degree of pain of insomnia, and the degree of attention to insomnia, each of which is measured by five scales, with a total score ranged from 0 to 28 points, 0–7 points without insomnia, 8–14 points for mild insomnia, 15–21 points for moderate insomnia, and 22–28 points for severe insomnia[21]. It will be evaluated at baseline, week 2, week 4, week 5 and week 16 respectively. GENEActiv: The GENEActiv is a cost-effective and practical option for monitoring the sleep quality in clinical trials. It can provide objective parameters of sleep, such as total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset[22]. We suggest that seven days of monitoring, including on Saturday and Sunday, for all participants using the wrist-worn GENEActiv accelerometer. The patients will be evaluated at baseline, week 4, and week 16 respectively. Sleep Diary: Sleep diary is the "gold standard" for subjective sleep evaluation[23]. The participants fill out a sleep diary after they reached the morning, including bedtime at night, the amount time to fall asleep, the number of times they woke up after fell asleep, the amount of time they woke up, the feeling after woke up, the total sleep time, and the factors that interfere with sleep, and before going to bed, including daytime fatigue, the nap times, the nap total time, the diet, the drinking, etc. Subjects can record their own sleep behavior patterns and daytime conditions affected by sleep through a sleep diary. Through the analysis by clinicians, they can intuitively grasp the sleep information of patients, which is of great significance for the diagnosis and evaluation of insomnia. The application of sleep diary in the study can provide subjective recorded sleep-wake data, supplement the shortcomings or defects of body motion recorder, help ensure the resting state in the data recorded by body motion recorder and improve the accuracy of sleep start time. The data will be recorded at baseline, week 4 and week 16, respectively. HAMD-17:It was developed by Hamilton in 1960, and it is the most widely used scale in the clinical evaluation of depression, and is used to evaluate the severity of depression in patients in the last two weeks. The scale consists of 17 items, with a total score ranging from 0 to 53 points: 0–7 points without depression, 8–17 points with mild depression, 17–24 points with moderate depression, and > 24 points with severe depression. It will be evaluated at baseline, week 4 and week 16. Hamilton Anxiety Scale (HAMA): The HAMA was developed by Hamilton in 1959 to assess the severity of anxiety symptoms. In China, the HAMA has become the most widely used scale for assessing anxiety symptoms in psychiatric clinical and scientific research fields. With respect to the 14 items, all items were scored on a five point scale ranging from of 0 ~ 4 points, and the standards at all levels were none, mild, moderate, severe and extremely severe. The higher the score is, the more severe the anxiety symptoms are. The total score is ≥29, which may indicate serious anxiety; ≥21 points, there must be obvious anxiety; ≥14 points, there must be anxiety; more than 7 points, there may be anxiety; < 7, no anxiety symptoms. It will be evaluated at baseline, week 4 and week 16 respectively. MEQ-5：The purpose of the evaluation is to understand the sleep-wake phase of patients. The higher the score, the more obvious the characteristics of early sleep and early wake, the more clear the early morning diagnosis, the more obvious the characteristics of late sleep and the more clear the night diagnosis. At baseline, at week 2, at week 4, at week 5 and at week 16, the assessment is conducted once each. Other Outcomes: The Morisk Drug Adherence Scale: MMAS is widely used to evaluate drug compliance in the treatment of various diseases and has good validity and reliability[24]. The alternative answers of the items in questionnaires 1-4 and 6-7 are Yes =0, No =1, the fifth item is the reverse score, and the eighth item is Never =1, Occasionally =0.75, Sometimes =0.50, Frequently =0.25, All the time. They were evaluated once in the second week and once in the fourth week. It will be evaluated at baseline, week 4 respectively. Participant treatment satisfaction questionnaire: It is used to evaluate patients' satisfaction with the treatment of this research scheme, with a total of 8 questions. The alternative answers to each question are "Very Disagree" =0, "Not Agree" =1, "Fair" =2, "Agree" =3, and "Very Agree" =4, out of 32. A score of < 16 indicates poor satisfaction, 16-24 indicates moderate satisfaction, and 25-32 indicates good satisfaction. Evaluate once in the fourth week. Blinded assessment questionnaires: To test the success of blinding, all participants will be asked to make a guess of their group allocations intuitively at the end of treatment. participants who choose wrongly or can't make a judgement are regarded as blinded to the group assignments. Statisticians will use Bang's index[25] to evaluate the success of blind method. Participant timeline {13} The trial period for each participant is approximately 119 days. All participants will complete the same outcome assessments at baseline (day-7—0) and at follow-up (day 14, day 29, day 35 and day119), as presented in Fig. 1 and Table1 Table 1 Study Period Sample size {14} Since the clinical research of Luohua Anshen oral liquid for short-term insomnia patients, which is measured by the PSQI as an outcome measure, has not been studied previously, no such information was available to guide sample size considerations. By consulting authoritative statistical experts, it is suggested that we use the data obtained in the research design similar to this study to estimate the sample size. According to the previous clinical study [17] of Luohua Anshen Oral liquid , the score of Spiegel scale in the experimental group decreased to 10.90 ± 4.0 after treatment, and the score of Spiegel scale in the placebo group decreased to 17.80±6.80 after treatment, The sample size is calculated in the following formula, with the two-sided significance level (α) set at 0.01 and a statistical power of 0.90. After calculation, n=29 cases in each group. Considering a 10% loss to follow-up, we aim to recruit 32 patients in each group, in a total of 96 patients, and 32 healthy people as a healthy group. Recruitment {15} We will post recruitment advertisements through the hospital's official WeChat account. When patients see the recruitment information, they can add the researchers' enterprise WeChat or take the phone for initial screening, and then those qualified patients will be asked for a face-to-face interview in the hospital where they need to fill in some forms and then will be asked to wear a wrist GENEActiv and record sleep diary to monitor their sleep quality for 7 days with guidance from researchers with professional training. Once the participants meet the inclusion criteria, they will be informed about the objective, approaches, potential adverse effects, and advantages of the trial. After obtaining written informed consent from the participants and their legal guardians, participants who meet the eligibility criteria received a unique subject code. The participants will undergo a 4-week treatment period and a 14-week follow-up. In addition, we will also recruit outpatients who meet the inclusion criteria. Assignment of interventions: allocation Sequence generation {16a} Randomization will be conducted after the baseline assessment via computer-generated random numbers. Concealment mechanism {16b} Opaque, sealed envelopes according to the random table are prepared. Subjects who met the inclusion criteria opened the corresponding sealed envelopes in the order of enrollment and were assigned to the study group according to the assignment on the envelopes. GuoHua- Wang, the pharmacist in charge of our department, will assign, package and code all drugs according to the random distribution list, then put the cards with serial number, random number and grouping into 96 sealed, opaque and sequentially numbered envelopes. All research drugs will be labeled, including the words "for clinical research only", drug number, indications, usage and dosage, specifications, production date, expiration date, storage conditions, manufacturers and other information. According to the visit time and the drug distribution plan, the drug is a medium package every two weeks and a large package every four weeks. After the blind coding is completed, the drugs are arranged from small to large and packed for easy access. Because the appearance, packaging, color and other aspects of the experimental drugs and the control drugs are the same, it is difficult for subjects, researchers or other experimental participants to distinguish the groups of drugs after blind editing. Implementation {16c} An independent research assistant, Y-XL, who is out of the intervention, evaluation, data collection and analysis of this clinical trial, used SPSS 25.0 statistical software to generate a random allocation list according to the ratio of treatment group A: treatment group B: placebo group C =1:1:1. The random seeds were recorded and sealed separately. W-JZ, H-RW, TJ and C-YL will enrol and follow up participants. On-site researchers will be responsible for the intervention assignment. Assignment of interventions: Blinding Who will be blinded {17a} Both the trial participants and the care providers will be blinded at recruitment and during the study. The outcome assessor and data analyst will also be blinded. When the patients enrolled in, they will get a unique subject code. The drug distributor, will register the patient information and drug serial number, and distribute the corresponding drug to the patient. At the final study visits participants will be asked to indicate whether they thought they had received placebo. Procedure for unblinding if needed {17b} In the event of a serious adverse event (SAE) or reaction, the allocation list will be retrieved to reveal the participant’s allocated treatment during the trial, and the PI and on-site researchers will be responsible for signature and documentation. The process needs to be reported to the Ethics Committee. Data collection and management Plans for assessment and collection of outcomes {18a} All researchers will receive professional training about correct assessments, procedures regarding the use of the study medicine, Case Report Form CRF completion, and use of the GENEActiv PC software before and during this trial. Double data entry will be used for all data. Plans to promote participant retention and complete follow-up {18b} Dates for assessments will be planned by on-site researchers together with each participant, and all participants will be able to connect with the responsible researcher via their telephone or WeChat. Participants are aware of being able to receive rescheduled follow-ups within 3 days before or after to prevent temporary accidents. Data management {19} All researchers will receive professional training about correct assessments, procedures regarding the use of the study medicine, CRF completion, and use of the GENEActiv computer software before and during this trial. Double data entry will be used for all data. Confidentiality {27} All participants’ data will be collected in a specific reception room instead of in public areas to avoid revealing their personal information to others. Initial patient names and unique subject codes will be used on the CRF. And all documents will be stored confidentially before, during and after the trial. The principal investigators will have access to the final trial database, which will be available upon reasonable request. Personal information about the potential and enrolled participants will only be consulted by the researchers of this study and will not be shared. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} At baseline, weeks 4 of the experiment, totalling approximately 10 mL blood samples were collected from patients and centrifuged at 3500 rpm for 15 minutes in a low-temperature centrifuge. The upper layer of serum was extracted and directly frozen at - 80 ℃. Fecal samples were collected from patient baseline, weeks 4 of the experiment of the experiment, dissolved in preservation solution (glycerol: water = 1:9) (with 8 g of feces dissolved in 40 ml of preservation solution), filtered, aliquoted, and stored at - 80 °C. The above serum and fecal samples were processed according to the method of the previous research [25] , and metabolomics analysis is performed using a Shimadzu LCMS-8045 machine to explore potential metabolic pathways related to insomnia. Statistical methods Statistical methods for primary and secondary outcomes {20a} We will use SPSS 27.0 statistical software for the data analysis. The statistical analysis of all data will be conducted by an independent researcher who will not participate in the experiment. Descriptive statistics will be used to describe the demographic data of sample groups. A chi-squared test will be used to assess the sample characteristics and gender. The Shapiro-Wilk test is used to test the normality of the distribution of each parameter. Continuous variables that conform to a normal distribution will be expressed as the mean ± standard deviation. Continuous variables that are not normally distributed will be represented by medians (interquartile ranges) [M (IQRs)], and classified variables will be represented by numerical values or percentages. The primary analysis will be a comparison of the changes in patients' PSQI scores among three groups at 4 weeks after inclusion (comparison of the primary endpoint). The secondary analysis will be performed to assess the changes in sleep efficiency, total sleep time and sleep awakenings recorded in the GENEActiv, which will be analyzed with the R- package GGIR version 1.2-0, as well as the ISI, HAMD-17, HAMA scores from baseline to 4 weeks after inclusion. For comparisons of the three groups, normality and homogeneity of variance are analyzed by variance analysis. If the variance is not uniform or normality is not conformed, the Mann-Whitney U test will be used. Counting data is chi-square test. All the statistical tests will be conducted bilaterally, and P < 0.05 indicates statistical significance. Interim analyses {21b} Interim analyses are not applicable. There were no adverse events in our pilot trial or earlier studies, so this trial involved a low-risk intervention. Methods for additional analyses (e.g. subgroup analyses) {20b} Subgroup analyses by age will be performed in the future. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Data analysis will follow the intention-to-treat (ITT) principles including participants who have at least one treatment. We will also perform a complete-case analysis without imputation of missing data, to determine whether the results are consistent. Plans to give access to the full protocol, participant level-data and statistical code {31c} The full protocol, participant-level data, and statistical code are available from the corresponding author upon reasonable request. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} The trial Steering Committee will hold weekly internal meetings to review study progress and communications received from the site investigators and site coordinators to promptly address any issues that may arise. Composition of the data monitoring committee, its role and reporting structure {21a} The study is no greater than minimal risk, and therefore, an independent research medical monitor is not needed. Data and safety monitoring will be the shared responsibility of all members of the research team. Adverse event reporting and harms {22} The researcher should collect and record the adverse events (AEs) and serious adverse events (SAEs) of each subject from the signing of the informed consent form to the end of the trial. All the details will be recorded in the CRF. When an adverse event is found, such as dizziness, headache, nausea and vomiting, anorexia, diarrhea, constipation, rash, or palpitation, the researcher can decide whether to terminate the trial according to the condition, and the subjects with adverse events should be followed up clinically until the adverse event is recovered (back to a normal state or a baseline state), until the condition is stable, or until the researcher thinks it is reasonable. If adverse events have not resolved to the above results by the end of the trial, the researcher will continue to provide necessary treatment, reports and records. Special cases can be handled according to the opinions of relevant management departments. Upon the discovery of serious adverse events, the researcher shall immediately take appropriate protective facilities for the subjects, and report to the Ethics Approval Committee of the Shanghai Municipal Hospital of Traditional Chinese Medicine within 24 hours. The researcher shall sign the report and indicated the date. Except for the indexes related to disease progression, all clinical events and clinically significant laboratory adverse reactions can be treated with reference to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Frequency and plans for auditing trial conduct {23} This trial will be supervised and audited once a year by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} This trail was conducted in accordance with the Helsinki Declaration and was approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China (2023SHL-KY-49-01, 2023SHL-KY-49-02). Any revision of this agreement will be reported and approved by the ethics committee. Only after approval is obtained can further research can be carried out. And the modified protocol will be uploaded to the trial registry. Dissemination plans {31a} We plan to publish and disseminate the results in an influential medical journal. We are also delighted to share the results with medical professionals, the public, and relevant organizations in the form of a conference report after it is published. Discussion Research on chronic insomnia has become increasingly mature, but the attention paid to acute insomnia is insufficient. There are no quantitative or qualitative criteria for the diagnosis of early acute insomnia, which directly affects whether acute insomnia can be identified and treated in time. The DSM-5, published in 2013, put forward diagnostic criteria for short-term insomnia, but the causes of short-term insomnia are not clear enough to be attributed to a single cause, including acute stress, environmental changes, behavioral changes, diseases and drugs, and many other factors that may lead to high arousal. Because many clinical signs show that this type of insomnia is self-healing, and a large number of individuals have alleviated it without any intervention, and have not developed into chronic insomnia, so the treatment scheme for acute insomnia is still controversial. However, regardless of the patient experience and health and economic benefits, clinicians need to pay more attention to the treatment of acute insomnia. In the past clinical experience, sedative and hypnotic drugs are often the first choice for treating acute insomnia, but drugs will bring untold adverse reactions, and we should further determine which treatments are safe and effective. Herbal medicines have been used for centuries to induce sleep and aid in relaxation. Some of the popular herbsused include Ziziphus spinosa seeds, Polygala tenuifolia Willd, Schisandrae Chinensis Fructus, valerian root, lavender, branches and leaves of groundnut[ 26 ]-[ 29 ]. Data from the US National Health Interview indicated that 82% of people with sleep trouble who had tried herbal therapies found them to be helpful [30] . However, the therapeutic effect on acute insomnia is unknown. At the time of this writing, there were no RCTs about Luohua Anshen liquid as a complementary therapy for short-term insomnia. Our trial intends to present a strictly designed trial to study the effects of Luohua Anshen liquid for short-term insomnia patients and to overcome some existing limitations, including illogical design, imperfect blinding method and practical difficulties in previous herbs clinical researches. With a medium follow-up period, we will explore the sustained effect of Luohua Anshen liquid on insomnia and determine whether it can destroy the occurrence of chronic insomnia. At present, more clinical studies[ 31 ] have used body motion recorders to objectively measure sleep activity. Actigraphy is a technique for measuring limb movement activity with actigraphic devices that are wearable on wrists or ankles. The data for movement activity is then gathered over a period, ultimately giving us patterns for wakefulness and sleep. With the patterns, general sleep parameters, including sleep latency, sleep efficiency, total sleep time, and wake after sleep onset, can be obtained. These parameters could greatly aid in evaluating insomnia. The use of sleep diary has an essential role in helping to diagnose short-term insomnia. Patients are generally asked to report their sleep patterns such as time in bed, nighttime awakenings, sleep satisfaction, sleep onset latency, and total sleep time. These are measured from two to four weeks and are brought in for the clinician to review. Of course, sleep health education must be an active part of the treatment of acute insomnia, and we also regard this part as the basic treatment for every participant in the study. In conclusion, this trial will provide high-quality evidence on the effectiveness and safety of the Luohua Anshen liquid, which can be used to guide clinical practice for short-term insomnia. Trial status This protocol is VERSION 3.0, 28 June 2023. Recruitment began in July 2023 and is expected to be completed in May 2024. Abbreviations PSQI Pittsburgh Sleep Quality Index ISI Insomnia Severity Index TCMSS Traditional Chinese Medicine Syndrome Scale MEQ-5 Morning and Evening Questionnaire-5 HAMD-17 Hamilton Rating Scale for Depression-17 HAMA Hamilton Rating Scale for Anxiety ChiCTR Chinese Clinical Trial Registry DSM-5 Diagnostic and Statistical Manual of Mental Disorders 5 CID Chronic Insomnia Disorder STID short-term insomnia disorder CBT-I Cognitive behavioral therapy for insomnia HPLC High-performance liquid chromatography ALT alanine aminotransferase AST aspartate aminotransferase SCr serum creatinine BUN blood urea nitrogen MMAS-8 Morisk Medical Compliance Scale-8 items AEs adverse events SAEs serious adverse events CFR Case Report Form ITT intention-to-treat DMC data monitoring committee CTCAE Common Terminology Criteria for Adverse Events Declarations Acknowledgements The authors want to thank all the participants for cooperating and supporting the trial. Authors’ contributions {31b} TJ and W-JZ studied the concept and designed the manuscript. TJ drafted the manuscript. G-HW and H-RW critically revised the manuscript for important intellectual content. W-JZ obtained the funding. Y-XL and F-YZ drew up the statistical analysis plan. W-JZ, H-RW, TJ and C-YL recruited and followed up the subjects. G-HW, YW and Y-LW were in charge of the laboratory. All the authors read and approved the final manuscript. Funding {4} This study was supported by the National Key Research and Development Program of China [number: 22021YFC2501500] and the Shanghai Technical Superiority Project of “Preventive Treatment of Disease”, Shanghai Municipal Health Commission [ZY(2021-2023)-0104-02-GF-04] to W-JZ. Availability of data and materials {29} According to regulations of the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, all clinical data and information that can identify participants obtained for the purpose of this study will be treated as confidential and stored safely. Participant data will be identified by a unique code number for respecting privacy rights of participants and protect their identities, that will be allocated after the participant sign informed consent form. The identity/personal details (e.g. name, date of birth) of the link participants will be stored in a password-encrypted file and cannot be accessed from the Internet. All data will be stored in written and computer format in Shanghai Municipal Hospital of Traditional Chinese Medicine. Participant information will be stored on a secure server that is backed up regularly. Only researchers related to the study can access participants' data. he Ethics Committee will continuously monitor and evaluate the research progress and safety internally. Upon reasonable request, the correspondent author can provide complete scheme, participant level data and statistical code. If anyone wants to get the data of this study, they should contact Wen-Jing Zhang 1 . Ethics approval and consent to participate {24} The trial was approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China (number: 2023SHL-KY-49-01, 2023SHL-KY-49-02). Written, informed consent to participate will be obtained from all participants prior to trial participation. Consent for publication {32} The unsigned model informed consent form is available from the corresponding author on request. Competing interests {28} The authors have no competing interests, or other interests that might be perceived to influence the results and/or discussion reported in this paper Authors ’ information (optional) Refer to above {5a}. References Riemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res . 2017;26(6):675-700. doi:10.1111/jsr.12594. Riemann D, Krone LB, Wulff K, et al. Sleep, insomnia, and depression. Neuropsychopharmacology 2020;45(1):74-89. Jarrin DC, Alvaro PK, Bouchard MA, et al. Insomnia and hypertension: A systematic review. Sleep Med Rev 2018;41:3-38 Ohayon MM, Reynolds CF, 3rd. Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the International Classification of Sleep Disorders (ICSD). Sleep Med 2009;10(9):952-60. Ellis JG, Gehrman P, Espie CA, Riemann D, Perlis ML. Acute insomnia: current conceptualizations and future directions. Sleep Med Rev . 2012;16(1):5-14. Doi:10.1016/j.smrv.2011.02.002 Ellis JG, Cushing T, Germain A. Treating Acute Insomnia: A Randomized Controlled Trial of a "Single-Shot" of Cognitive Behavioral Therapy for Insomnia. Sleep . 2015;38(6):971-978. American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien: American Academy of Sleep Medicine,2014:19-47. Morin CM. Definition of acute insomnia: diagnostic and treatment implications. Sleep Med Rev . 2012;16(1):3-4. doi:10.1016/j.smrv.2011.08.005 Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med . 2021;17(2):255-262. doi:10.5664/jcsm.8986 Ellis JG, Cushing T, Germain A. Treating Acute Insomnia: A Randomized Controlled Trial of a "Single-Shot" of Cognitive Behavioral Therapy for Insomnia. Sleep . 2015;38(6):971-978. Published 2015 Jun 1. doi:10.5665/sleep.4752 Leach MJ, Page AT. Herbal medicine for insomnia: A systematic review and meta-analysis. Sleep Med Rev . 2015;24:1-12. doi:10.1016/j.smrv.2014.12.003 Qiao-Chu Wang. Peanut branches and leaves to treat insomnia-20 years of research results. Shanghai: Shanghai Science and Technology Literature Publishing House, 2009:2-3,11-14,16-30,37-49,53.（in Chinese） Sonn JY, Lee J, Sung MK, et al. Serine metabolism in the brain regulates starvation-induced sleep suppression in Drosophila melanogaster . Proc Natl Acad Sci U S A . 2018;115(27):7129-7134. doi:10.1073/pnas.1719033115 Guo R, Shi AM, Deng L, et al. Flavonoid-Like Components of Peanut Stem and Leaf Extract Promote Sleep by Decreasing Neuronal Excitability. Mol Nutr Food Res . 2022;66(1):e2100210. doi:10.1002/mnfr.202100210 Yi-Fang Wang, Hua-Fang Li, Yi-Feng Xu, et al. Clinical blind observation of groundnut branch and leaf preparation in the treatment of insomnia. Shanghai Journal of Traditional Chinese Medicine, 2001,35(5):11-14. （in Chinese） Bei-Lei Feng, Jing-Xia, Zheng-Yuan Li, et al. 30 cases of insomnia due to liver depression and fire were treated with integrated traditional Chinese and western medicine [J]. Bulletin of Traditional Chinese Medicine, 2005,(02):56-58. （in Chinese） Wen-Jing Zhang, Guo-Hua Wang, Qiao-Chu Wang. Efficacy of Luohua Anshen Oral L on insomnia: A randomized, double-blind, placebe-controlled clinical trial [J]. Chinese Journal of Traditional Chinese Medicine, 2017,32(06):2801-2804. （in Chinese） Chen XJ. Internal Medicine of Traditional Chinese Medicine. Shanghai: Shanghai Scientific & Technical Publishers, 2004. （in Chinese） Fabbri M, Beracci A, Martoni M, Meneo D, Tonetti L, Natale V. Measuring Subjective Sleep Quality: A Review. Int J Environ Res Public Health . 2021;18(3):1082. Published 2021 Jan 26. doi:10.3390/ijerph18031082 Yan XL, Xu J, Wang HR, Xu H, Xu L, Wang GH, Wang QC, Li Y. Design and use of Dr. Yan’s insomnia prospective assessment scale for syndrome differentiation, diagnosis and treatment. Zhongyi Wenxian Zazhi, 2015, 33(4): 31-33. Gagnon C, Bélanger L, Ivers H, Morin CM. Validation of the Insomnia Severity Index in primary care. J Am Board Fam Med. 2013 Nov-Dec;26(6):701-10. Smith MT, McCrae CS, Cheung J, et al. Use of Actigraphy for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med . 2018;14(7):1231-1237. Published 2018 Jul 15. doi:10.5664/jcsm.7230 Natale V, Léger D, Bayon V, et al. The consensus sleep diary: quantitative criteria for primary insomnia diagnosis. Psychosom Med . 2015;77(4):413-418. doi:10.1097/PSY.0000000000000177 Moon SJ, Lee WY, Hwang JS, Hong YP, Morisky DE. Accuracy of a screening tool for medication adherence: A systematic review and meta-analysis of the Morisky Medication Adherence Scale-8. PLoS One. 2017 Nov 2;12(11): e0187139. BangH,NiL,DavisCE.Assessmentofblindinginclinicaltrials.ControllClinTrials.(2004) 25:143–56. doi: 10.1016/j.cct.2003.10.016 Luo Y, Zhang X, Zhang W, et al. Compatibility with Semen Sojae Praeparatum attenuates hepatotoxicity of Gardeniae Fructus by regulating the microbiota, promoting butyrate production and activating antioxidant response. Phytomedicine . 2021;90:153656. doi:10.1016/j.phymed.2021.153656 Yang M, Wang H, Zhang YL, et al. The Herbal Medicine Suanzaoren (Ziziphi Spinosae Semen) for Sleep Quality Improvements: A Systematic Review and Meta-analysis. Integr Cancer Ther. 2023;22:15347354231162080. doi:10.1177/15347354231162080. Zare Elmi HK, Gholami M, Saki M, Ebrahimzadeh F. Efficacy of Valerian Extract on Sleep Quality after Coronary Artery bypass Graft Surgery: A Triple-Blind Randomized Controlled Trial. Chin J Integr Med. 2021;27(1):7-15. doi:10.1007/s11655-020-2727-1 . Shi MM, Piao JH, Xu XL, et al. Chinese medicines with sedative-hypnotic effects and their active components. Sleep Med Rev. 2016;29:108-118. doi:10.1016/j.smrv.2015.10.001 Adjaye-Gbewonyo D, Ng AE, Black LI. Sleep Difficulties in Adults: United States, 2020. NCHS Data Brief . 2022;(436):1-8. FEKEDULEGN D,ANDREW M E,SHI M,et al.Actigraphy-based assessment of sleep parameters［J］. Ann Work Expo Health, 2020,64（4）：350-367. Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1StudyPeriod.docx 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. 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randomized, placebo-controlled trial","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eTitle\u0026nbsp;{1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eClinical efficacy of Luohua Anshen oral liquid in the treatment of short-term insomnia disorders (Syndrome of depressed liver qi transforming into fire):\u0026nbsp;protocol for a single-center, double-blinded, randomized, placebo-controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eRegistered in the Chinese Clinical Trial Registry (ChiCTR) (Identifier: ChiCTR2300071930) on 30 May 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003e28\u0026nbsp;June\u0026nbsp;2023,\u0026nbsp;VERSION 3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eThis study is supported by National Key Research and Development Program of China [number: 22021YFC2501500] and Shanghai Technical Superiority Project of \u0026ldquo;Preventive Treatment of Disease\u0026rdquo;, Shanghai Municipal Health Commission [ZY (2021-2023)-0104-02-GF-04] to W-JZ.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eTing Jiang\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e,\u0026nbsp;Yuan-Xin Lee\u003csup\u003e2\u003c/sup\u003e,\u0026nbsp;Chun-Yan Li\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e,\u0026nbsp;Yin Wang\u003csup\u003e2\u003c/sup\u003e,\u0026nbsp;Yu-Ling Huang\u003csup\u003e1\u003c/sup\u003e,\u0026nbsp;Guo-Hua Wang\u003csup\u003e1\u003c/sup\u003e,\u0026nbsp;Hui-Ru Wang\u003csup\u003e1\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eWen-Jing Zhang\u003csup\u003e1\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eFei-Yi Zhao\u003csup\u003e3\u003c/sup\u003e.\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003eDepartment of Psychiatry, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine,\u0026nbsp;Shanghai, China.\u003c/li\u003e\n \u003cli\u003eShanghai University of Traditional Chinese Medicine,\u0026nbsp;Shanghai, China.\u003c/li\u003e\n \u003cli\u003eDepartment of Nursing, School of International Medical Technology, Shanghai Sanda University, Shanghai, China.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eProf.\u0026nbsp;Wen-Jing Zhang,\u0026nbsp;Department of Psychiatry, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, NO.274 ZhiJiang Middle Road,\u0026nbsp;Shanghai ,200071, China.\u003c/p\u003e\n \u003cp\u003eTel: +86 56639310 \u0026nbsp; \u0026nbsp; \u0026nbsp;E-mail: [email protected]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eThis trial is solely funded by non-commercial sources. Funding sources have had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale {6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInsomnia disorder is characterized by a range of symptoms, including difficulty initiating and/or maintaining sleep, waking too early, and difficulty returning to sleep, and a decrease in the quantity or quality of sleep leads to the impairment of patients\u0026apos; daytime function, such as fatigue or malaise; impairment of attention, concentration or memory; and decreased work and study performance\u0026nbsp;[1].It\u0026nbsp;is\u0026nbsp;also the precursor and maintenance factor of many physical diseases and mental disorders[2]、[3].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5)\u0026nbsp;divides Insomnia disorder into chronic Insomnia Disorder (CID) and short-term insomnia disorder (STID) according to whether the course of disease is\u0026nbsp;\u0026ge;3 months\u0026nbsp;[4]. Most people experience short-term insomnia when facing social stress factors or rapid changes in circadian rhythm. Because it can often be relieved spontaneously, it does not cause serious physical or mental damage, and it has not attracted widespread attention as well as chronic insomnia disorder. However, two prospective studies by Ellis et al. reported that the annual prevalence of short-term insomnia was as high as 36%, and about 40% of patients eventually developed chronic insomnia[5-6]. These two studies show a high prevalence of acute insomnia and chronic insomnia, and suggest that short-term insomnia is a critical period of chronic insomnia, which is highly significant and requires active clinical intervention and treatment. At the same time, the American Academy of Sleep Medicine emphasizes that short-term insomnia disorder may be easier to treat than chronic insomnia disorder[7].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt present, there are no clear treatment guidelines for short-term insomnia disorder. In the past, sedative and hypnotic drugs (including benzodiazepines, nonbenzodiazepines, orexin receptor antagonists and melatonin receptor agonists) were usually used to treat short-term insomnia disorder. However, the adverse reactions such as side effects and addiction caused by drugs cannot be ignored, and their long-term efficacy is not clear. Research shows that for short-term insomnia disorder, only when insomnia leads to serious and incurable personal stress can we consider using nonbenzodiazepines[8]\u003csup\u003e.\u003c/sup\u003e Cognitive behavioral therapy for insomnia\u0026nbsp;(CBT-I)\u0026nbsp;is a first-line recommended nondrug treatment for chronic insomnia[9]. In recent years, domestic and foreign sleep experts preliminarily explored its effectiveness in treating short-term insomnia, but further research is needed to verify[10].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTraditional Chinese herbs have been used for centuries to induce sleep. Therefore, we hope to intervene and treat patients with short-term insomnia through traditional Chinese medicine, which is conducive to preventing its chronicity and reducing the burden of health economics[11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLuohua Anshen oral liquid is a standardized product made from the branches and leaves of groundnut. One-third of the aboveground branches and leaves of groundnuts are sweet, light and slightly bitter, and it enters the liver, heart and lung meridians. It has the effects of calming the liver and suppressing yang, calming the nerves and strengthening the brain, and its preliminary research effect is remarkable[12]. A serum metabonomics study revealed that the sedative and hypnotic effects of Luohua Anshen Oral liquid were related to four metabolic pathways. The serum metabolites of insomnia rats were detected[13]. The results showed that 37 different metabolites were differentially expressed between the model group and the peanut branch group, and there were 5 common differentiall abundant metabolites among them. These include serine, hippuric acid, indole 3 propionic acid, butanediol and cytosine. Serine can promote awakening[14], and the concentration of serine can be reduced after intervention with Luohua Anshen Oral Liquid. Luohua Anshen Oral liquid has been clinically to treat insomnia more than 100,000 times, and more than 1,200 cases have been identified in scientific research[12]. Statistical analysis, revealed that yin deficiency can obviously improve the symptoms of insomnia patients with liver depression and fire hyperactivity[15]. Subsequently, Feng Beilei divided\u0026nbsp;30\u0026nbsp;patients with insomnia due to liver depression and fire into a treatment group and a control group, both of whom were given Estazolam, while the treatment group was given Luohua Anshen oral liquid. The results showed that the efficacy of Luohua Anshen oral liquid combined with Estazolam in treating insomnia due to liver depression and fire was better than that of Estazolam alone, and there were few adverse reactions[16]. In 2017, Zhang Wenjing[17]\u0026nbsp;conducted a randomized controlled double-blind trial. The results showed that the effective rate of Luohua Anshen Oral liquid in treating insomnia was 77.4%, and the effective rate of placebo was 33.3%, which proved its remarkable clinical efficacy, safety and lack of toxicity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTherefore, we intend to conduct a high-quality, well-designed, randomized, placebo-controlled trial to further provide subjective and objective evidence of the efficacy and safety of Luohua Anshen oral liquid in short-term insomnia patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMain objective:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo verify the clinical efficacy of Luohua Anshen Oral liquid in the treatment of patients with short-term insomnia disorder (syndrome of depressed liver qi transforming into fire).\u003c/p\u003e\n\u003cp\u003eSecondary objectives:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo explore the improvement of Luohua Anshen Oral liquid on subjective and objective sleep evaluation indexes in patients with short-term insomnia disorders.\u003c/p\u003e\n\u003cp\u003eTo explore the effectiveness of Luohua Anshen Oral liquid in preventing short-term insomnia into chronic insomnia.\u003c/p\u003e\n\u003cp\u003eTo explore the effect of Luohua Anshen Oral liquid in improving the Traditional Chinese Medicine Syndrome in patients with depressed liver qi transforming into fire type sleeplessness.\u003c/p\u003e\n\u003cp\u003eTo investigate the difference between serum metabolites in patients with short-term insomnia disorder and healthy people, and whether Luohua Anshen oral liquid solution can decrease the concentration of serine in human serum metabolites.\u003c/p\u003e\n\u003cp\u003eTo verify whether different time of taking the oral liquid will affect the treatment efficacy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a single-center, double-blinded, randomized, placebo-controlled trial aimed at evaluating the clinical efficacy of Luohua Anshen oral liquid in the treatment of short-term insomnia disorders (syndrome of depressed liver qi transforming into fire).\u003c/p\u003e\n\u003cp\u003eThe trial will be performed in the insomnia department of Shanghai Municipal Hospital of Traditional Chinese Medicine. We plan to recruit 96 patients who meet the inclusion criteria and randomly assign them to one of three groups, receiving Luohua Anshen oral liquid and/or its placebo (1/10 of the effective dose) at different times.\u003c/p\u003e\n\u003cp\u003eAfter one-week baseline, participants will enter a 4-week treatment period. All treatments will be given 2 times a day, each time 2 oral bottles of designated will be used. Participants will be assessed at the following time points: the baseline (1 week before treatment), the middle of the treatment (2 weeks after treatment starts), the end of the treatment (4 weeks after treatment starts) and follow-up (1 week, 3 months after the treatment finishes). All participants will complete the assessments by the PSQI, ISI, GENEActiv, Sleep Diary, HAMD-17, HAMA and adverse event assessment forms (detailed trial process shown in Fig. 1).\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study will be conducted\u0026nbsp;at the\u0026nbsp;Department of Insomnia, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People\u0026rsquo;s Republic of China,\u0026nbsp;which is a third-class\u0026nbsp;Grade A comprehensive hospital with good performance in clinical medicine and scientific research. The person in charge of this study obtained\u0026nbsp;good\u0026nbsp;clinical\u0026nbsp;practice (GCP) certification. All\u0026nbsp;the\u0026nbsp;researchers received homogeneity training,\u0026nbsp;such as\u0026nbsp;the\u0026nbsp;introduction of clinical consultation, operation, and instructions on how to\u0026nbsp;complete the Case\u0026nbsp;Report\u0026nbsp;Form\u0026nbsp;(CRF). The data analysts will receive training in data input, coding, security, and storage. Statisticians will be trained in data evaluation and analysis. To control of the quality\u0026nbsp;of the subjects,\u0026nbsp;they will be screened strictly according to the criteria for admission. Those with inaccurate TCM syndrome differentiation will be diagnosed by TCM clinicians with the title of\u0026nbsp;an\u0026nbsp;attending physician or above before deciding\u0026nbsp;whether to be included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNinety-six patients will be recruited for this study. To ensure the precision of the results, we developed the following eligibility criteria.\u003c/p\u003e\n\u003cp\u003eInclusion criteria\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eParticipants meeting the following criteria will be included:\u003c/li\u003e\n \u003cli\u003eThe diagnostic criteria for met the diagnostic criteria[18]\u003csup\u003e\u0026nbsp;\u003c/sup\u003efor syndrome of depressed liver qi transforming into fire type sleeplessness in the \u0026quot;Clinical Practice Guidelines for Insomnia in Traditional Chinese Medicine (WHO/WPO)\u0026quot; and the diagnostic criteria for short-term insomnia disorder in DSM-5.\u003c/li\u003e\n \u003cli\u003eAge 18~40 years old (including 18 years old and 40 years old), regardless of sex.\u003c/li\u003e\n \u003cli\u003ePSQI\u0026nbsp;score\u0026nbsp;\u0026ge;6 points.\u003c/li\u003e\n \u003cli\u003eThe course of this onset is more than 2 weeks.\u003c/li\u003e\n \u003cli\u003eClear consciousness, stable vital signs, certain expression and execution ability, and being able to cooperate with the completion of testing and treatment.\u003c/li\u003e\n \u003cli\u003eVoluntarily participated in the research of this project and signed the informed consent form.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eExclusion criteria\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants who reported any of the following conditions were excluded:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eThe total score of\u0026nbsp;the\u0026nbsp;HAMD-17\u0026nbsp;is \u0026gt;= 18 points and/or\u0026nbsp;the\u0026nbsp;HAMA\u0026nbsp;score is\u0026nbsp;\u0026gt; 14.\u003c/li\u003e\n \u003cli\u003eThose who suffer from other mental disorders and are unstable and/or suicidal and at risk;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePsychotropic drugs that affect central nervous system function (such as antidepressants, nonbenzodiazepines) being added or changed within 2 weeks before enrollment.\u003c/li\u003e\n \u003cli\u003eLaboratory tests and electrocardiograms show have obvious clinically significant abnormalities, which can affect drug evaluation or patient safety.\u003c/li\u003e\n \u003cli\u003eWomen who were pregnant or lactating at the time of study and follow-up.\u003c/li\u003e\n \u003cli\u003eCaffeine, alcohol or drug addicts.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThose who were allergic to the experimental medication or ingredients included in this protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearchers will ensure that the study schedule and participation requirements are fully explained before consent is obtained and signed, and that participants are aware of the potential risks and benefits of the treatment. Of course, there is no need to pay any research-related expenses. We will do our best to protect the information provided by patients from being leaked and strictly abide by the laws and regulations on privacy and personal information protection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIf patients are willing to participate in this study, we will ask them whether they are willing to participate in the additional part of this study, and biological samples and health-related information will be used for future medical scientific research. The patient were informed that the participation in the supplementary part was entirely voluntary, that the patient had the right to decide whether to participate,and that participation did \u0026nbsp;not affect the main part of the patient\u0026apos;s participation in this study or the corresponding rights and interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Luohua Anshen oral\u0026nbsp;liquid (Shanghai Hospital of Traditional Chinese Medicine lot number: Z05190756)\u0026nbsp;at a\u0026nbsp;used in\u0026nbsp;the present\u0026nbsp;study\u0026nbsp;was prepared\u0026nbsp;by BaoLong Pharmaceutical Factory for processing and production,and conform to the relevant regulations\u0026nbsp;for the\u0026nbsp;oral l of traditional\u0026nbsp;Chinese medicine (General Rules of Pharmacopoeia 2015), and the content is determined by high performance liquid chromatography(HPLC) (General Rules of Four Parts of Pharmacopoeia 2015).\u0026nbsp;The Conventional dose, volume of\u0026nbsp;10mL/ piece\u0026nbsp;and contained15\u0026nbsp;g of groundnut branches and leaves. The placebo, volume of\u0026nbsp;10mL/ piece\u0026nbsp;and\u0026nbsp;composed of 1.5g of groundnut branches and leaves,\u0026nbsp;matches the\u0026nbsp;active\u0026nbsp;material\u0026nbsp;in terms of appearance,smell and taste.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Test group A\u003c/p\u003e\n\u003cp\u003eHalf an hour after breakfast, two oral bottles of Luo Hua Anshen oral liquid placebo, and half an hour before going to bed, two oral bottles of Luo Hua Anshen oral liquid\u003c/p\u003e\n\u003cp\u003eTest group B\u003c/p\u003e\n\u003cp\u003eHalf an hour after breakfast, two oral bottles of Luo Hua Anshen oral liquid, and half an hour before going to bed, two oral bottles of Luo Hua Anshen oral liquid placebo\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTest group C\u003c/p\u003e\n\u003cp\u003etwo oral bottles of Luo Hua Anshen oral liquid placebo, twice a day.\u003c/p\u003e\n\u003cp\u003eParticipants in both groups will receive 12 boxes of Luohua Anshen oral liquid for free, 6 boxes each time. All three groups shall follow the outer packaging label to take two doses 30 min after breakfast and two doses 30 min before retiring for sleep, respectively, for 4 weeks in total. All participants were provided with sleep hygiene education before their first treatment session, which is the standard intervention given to all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExit criteria\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eSubjects who withdraw from the study for any reason need to record the reasons, including but not limited to the following aspects:\u003c/li\u003e\n \u003cli\u003eThe subject withdrew the informed consent;\u003c/li\u003e\n \u003cli\u003eSerious adverse events\u0026nbsp;thar caused\u0026nbsp;the subjects to continue to participate in the trial;\u003c/li\u003e\n \u003cli\u003eThe researcher thinks that the medical condition of the subject may endanger the safety of the subject or\u0026nbsp;that\u0026nbsp;continuing\u0026nbsp;the research will harm the health of the subject;\u003c/li\u003e\n \u003cli\u003epoor compliance (that is, Morisk drug compliance scale \u0026lt; 6 points at the second week of follow-up)\u003c/li\u003e\n \u003cli\u003eSerious protocol violation/protocol deviation (for example, during the 4-week intervention period, the subject changed the existing treatment protocol and added drugs that affect sleep);\u003c/li\u003e\n \u003cli\u003eDeath;\u003c/li\u003e\n \u003cli\u003eOthers.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003etermination criteria\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eserious safety problems occurred during the test;\u003c/li\u003e\n \u003cli\u003eMajor mistakes were found in the clinical trial scheme during the trial;\u003c/li\u003e\n \u003cli\u003eThe Ethics Committee requested that the experiment be terminated.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eHandling of shedding cases\u003c/p\u003e\n\u003cp\u003eWhen the subject falls off, the researcher should contact the subject as much as possible, ask about the reason for the subject\u0026apos;s withdrawal through the registered telephone, record the last medication time in detail and complete the evaluation items that can be completed.\u003c/p\u003e\n\u003cp\u003eIf the subjects quit the trial for various reasons such as allergic reactions, adverse reaction or ineffective treatment during the treatment, the researchers should take corresponding treatment measures according to the actual situation of the subjects.\u003c/p\u003e\n\u003cp\u003eOnce a random number is obtained, it will become the observation object of this experiment, regardless of whether the treatment has been completed, the patients who have fallen off do not need to be supplemented, and the files should be kept to properly keep the data of the fallen cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnce formally enrolled in the group, a special researcher will call the patients on the fixed follow-up day to remind them to take medicine on time and other precautions.\u003c/p\u003e\n\u003cp\u003eParticipants in both groups will be required to return the empty boxes to the researchers after the fourth week of treatment, and recorded the quantity.\u003c/p\u003e\n\u003cp\u003eWe will conduct free safety check\u0026nbsp;(The patient\u0026apos;s general vital signs,\u0026nbsp;such\u0026nbsp;as\u0026nbsp;birth,\u0026nbsp;height,\u0026nbsp;weight,\u0026nbsp;handedness,\u0026nbsp;heart rate, respiration, blood pressure, body temperature, etc.) and laboratory tests,\u0026nbsp;including blood routine, urine routine, pregnancy urine test for female, stool routine, Hepatic function (alanine aminotransferase (ALT), aspartate aminotransferase (AST), renal function (serum creatinine (SCr), and blood urea nitrogen (BUN) will be performed once before and after treatment.\u003c/p\u003e\n\u003cp\u003eAll participants were provided with sleep hygiene education before their first treatment session, which is the standard intervention given to all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSome patients used regular administration of antidepressants, sedatives, hypnotics or anxiolytics regularly before the trial. Researchers must record the dose, especially when patients reduce the amount, and dose change will not be allowed unless patients have\u0026nbsp;consulted a psychiatrist.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will educate all the patients on sleep hygiene, and the subjects still have insomnia at the third month of follow-up, the researchers will give them professional advice and recommend that the patients continue their treatment, including routine clinical chemotherapy, traditional Chinese medicine treatment, sleep cognitive behavioral treatment, acupuncture and auricular point treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary outcome\u003c/p\u003e\n\u003cp\u003eThe PSQI is composed of 19 sleep-related items, that are integrated into 7 components: subjective sleep quality, sleep latency, sleep time, sleep efficiency, sleep disorder, hypnotic drugs and daytime dysfunction. It mainly evaluates the frequency of these sleep\u0026nbsp;problems and the overall sleep quality of the subjects in the past month. Each component is rated from 0 to 3 as mild to severe,\u0026nbsp;for\u0026nbsp;a total score of 21 points. The total PSQI\u0026nbsp;score is\u0026nbsp;＞\u0026nbsp;5, and the diagnostic sensitivity and specificity of distinguishing good and bad sleepers are 89.6% and 86.5%[19]. It is going to evaluate at baseline, week 4 and week 16 respectively.\u003c/p\u003e\n\u003cp\u003eSecondary outcomes\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eThe incidence of chronic insomnia:\u0026nbsp;At the 12th week after the end of the treatment\u0026nbsp;and\u0026nbsp;the 16th week of the experiment,\u0026nbsp;all participants in the three groups were interviewed clinically based on DSM-5 diagnostic criteria for insomnia,\u0026nbsp;to determine\u0026nbsp;whether the patients met the DSM-5 diagnosis of chronic insomnia.\u003c/li\u003e\n \u003cli\u003eTraditional Chinese Medicine Syndrome Scale\u0026nbsp;(TCMSS):\u0026nbsp;According to the diagnostic criteria of insomnia syndrome caused by liver depression and fire in the Guide to Clinical Practice of Insomnia in TCM (WHO/WPO), according\u0026nbsp;to previous research[20]\u0026nbsp;and\u0026nbsp;the reliability and validity evaluation of the scale, the TCMSS collected by quantitative classification reflects the degree of symptom changes before and after treatment. The subjects evaluated the severity of the main symptom and the secondary symptom in turn (the researcher is responsible for explaining the meaning of each item in plain language), and the tongue pulse was recorded (and photographed) by the researcher. The patients will be evaluated at baseline, week 4 and week 16.\u003c/li\u003e\n \u003cli\u003eInsomnia Severity Index Scale\u0026nbsp;(ISI):The\u0026nbsp;ISI consists of 7 items to evaluate the degree of difficulty in falling asleep or maintaining asleep, that is, sleep satisfaction, daytime function, impaired attention due to sleep, the degree of pain of insomnia, and\u0026nbsp;the degree of attention to insomnia, each of which is measured by five scales, with a total score ranged from 0 to 28 points, 0\u0026ndash;7 points without insomnia, 8\u0026ndash;14 points for mild insomnia, 15\u0026ndash;21 points for moderate insomnia, and 22\u0026ndash;28 points for severe insomnia[21]. It will be evaluated at baseline, week 2, week 4, week 5 and week 16 respectively.\u003c/li\u003e\n \u003cli\u003eGENEActiv:\u0026nbsp;The GENEActiv is a cost-effective and practical option for monitoring\u0026nbsp;the sleep quality in clinical trials. It can provide objective parameters of sleep, such as total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset[22].\u0026nbsp;We suggest that seven days of monitoring, including on Saturday and Sunday, for all participants using the wrist-worn GENEActiv accelerometer. The patients will be evaluated at baseline, week 4, and week 16 respectively.\u003c/li\u003e\n \u003cli\u003eSleep\u0026nbsp;Diary:\u0026nbsp;Sleep diary is the \u0026quot;gold standard\u0026quot;\u0026nbsp;for\u0026nbsp;subjective sleep evaluation[23].\u0026nbsp;The participants\u0026nbsp;fill out\u0026nbsp;a\u0026nbsp;sleep diary\u0026nbsp;after they reached\u0026nbsp;the morning, including bedtime at night, the\u0026nbsp;amount\u0026nbsp;time to fall asleep, the number of times\u0026nbsp;they woke up after fell\u0026nbsp;asleep, the amount of time they woke up, the feeling after woke up, the total sleep time, and the factors that interfere with sleep, and before going to bed, including daytime fatigue, the nap times, the nap total time, the diet, the drinking, etc. Subjects can record their own sleep behavior patterns and daytime conditions affected by sleep through a sleep diary. Through the analysis by clinicians, they can intuitively grasp the sleep information of patients, which is of great significance for the diagnosis and evaluation of insomnia. The application of sleep diary in the study can provide subjective recorded sleep-wake data, supplement the shortcomings or defects of body motion recorder, help ensure the resting state in the data recorded by body motion recorder and improve the accuracy of sleep start time. The data will be recorded at baseline, week 4 and week 16, respectively.\u003c/li\u003e\n \u003cli\u003eHAMD-17:It was developed by Hamilton in 1960, and it is the most widely used scale in the clinical evaluation of depression, and is used to evaluate the severity of depression in patients in the last two weeks. The scale consists of 17 items, with a total score ranging from 0 to 53 points: \u0026nbsp;0\u0026ndash;7 points without depression, 8\u0026ndash;17 points with mild depression, 17\u0026ndash;24 points with moderate depression, and \u0026gt; 24 points with severe depression. It will be evaluated at baseline, week 4 and week 16.\u003c/li\u003e\n \u003cli\u003eHamilton Anxiety Scale (HAMA): The HAMA was developed by Hamilton in 1959 to assess the severity of anxiety symptoms. In China, the HAMA has become the most widely used scale for assessing anxiety symptoms in psychiatric clinical and scientific research fields. With respect to the \u0026nbsp;14 items, all items were scored on a five point scale ranging from of 0 ~ 4 points, and the standards at all levels were none, mild, moderate, severe and extremely severe. The higher the score is, the more severe the anxiety symptoms are. The total score is \u0026ge;29, which may indicate serious anxiety; \u0026ge;21 points, there must be obvious anxiety; \u0026ge;14 points, there must be anxiety; more than 7 points, there may be anxiety; \u0026lt; 7, no anxiety symptoms. It will be evaluated at baseline, week 4 and week 16 respectively.\u003c/li\u003e\n \u003cli\u003eMEQ-5：The purpose of the evaluation is to understand the sleep-wake phase of patients. The higher the score, the more obvious the characteristics of early sleep and early wake, the more clear\u0026nbsp;the early morning diagnosis, the more obvious the characteristics of late sleep and the more clear the night diagnosis. At baseline, at week 2, at week 4, at week 5 and at week 16, the assessment is conducted once each.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eOther Outcomes:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eThe\u0026nbsp;Morisk Drug Adherence Scale:\u0026nbsp;MMAS\u0026nbsp;is widely used to evaluate drug compliance in the treatment of various diseases and has good validity and reliability[24]. The alternative answers of the items in questionnaires 1-4 and 6-7 are Yes =0, No =1, the fifth item is the reverse score, and the eighth item is Never =1, Occasionally =0.75, Sometimes =0.50, Frequently =0.25, All the time. They were evaluated once in the second week and once in the fourth week. It will be evaluated at baseline, week 4 respectively.\u003c/li\u003e\n \u003cli\u003eParticipant treatment satisfaction questionnaire:\u0026nbsp;It is used to evaluate patients\u0026apos; satisfaction with the treatment of this research scheme, with a total of 8 questions. The alternative answers to each question are \u0026quot;Very Disagree\u0026quot; =0, \u0026quot;Not Agree\u0026quot; =1, \u0026quot;Fair\u0026quot; =2, \u0026quot;Agree\u0026quot; =3, and \u0026quot;Very Agree\u0026quot; =4, out of 32. A score of \u0026lt; 16 indicates poor satisfaction, 16-24 indicates moderate satisfaction, and 25-32 indicates good satisfaction. Evaluate once in the fourth week.\u003c/li\u003e\n \u003cli\u003eBlinded assessment questionnaires:\u0026nbsp;To test the success of blinding, all participants will be asked to make a guess of their group allocations intuitively at the end of treatment. participants who choose wrongly or can\u0026apos;t make a judgement are regarded as\u0026nbsp;blinded to the group assignments. Statisticians will use Bang\u0026apos;s index[25]\u0026nbsp;to evaluate the success of blind method.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial period for each participant is approximately 119 days. All participants will complete the same outcome assessments at baseline (day-7\u0026mdash;0)\u0026nbsp;and at follow-up (day 14,\u0026nbsp;day 29,\u0026nbsp;day 35\u0026nbsp;and\u0026nbsp;day119), as presented in Fig. 1 and Table1\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Table 1 Study Period\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince the clinical research of Luohua Anshen oral liquid for short-term insomnia patients, which is measured by the PSQI as an outcome measure, has not been studied previously, no such information was available to guide sample size considerations. By consulting authoritative statistical experts, it is suggested that we use the data obtained in the research design similar to this study to estimate the sample size. According to the previous clinical study [17] of Luohua Anshen Oral liquid , the score of Spiegel scale in the experimental group decreased to 10.90 \u0026plusmn; 4.0 after treatment, and the score of Spiegel scale in the placebo group decreased to 17.80\u0026plusmn;6.80 after treatment, The sample size is calculated in the following formula, with the two-sided significance level (\u0026alpha;) set at 0.01 and a statistical power of 0.90.\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" width=\"188\" height=\"62\"\u003e\u003c/p\u003e\n\u003cp\u003eAfter calculation, n=29 cases in each group. Considering a 10% loss to follow-up, we aim to recruit 32 patients in each group, in a total of 96 patients,\u0026nbsp;and 32 healthy people as a healthy group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will post recruitment advertisements through the hospital\u0026apos;s official WeChat account. When patients see the recruitment information, they can add the researchers\u0026apos; enterprise WeChat or take the phone for initial screening, and then those\u0026nbsp;qualified patients will be asked for a face-to-face interview in the hospital where they need to fill in some forms and then will be asked to wear a wrist GENEActiv and record sleep diary to monitor their sleep quality for 7 days with guidance from\u0026nbsp;researchers\u0026nbsp;with professional training.\u0026nbsp;Once the participants meet the inclusion criteria, they will be informed about the objective, approaches, potential adverse effects, and advantages of the trial. After obtaining written informed consent from the participants and their legal guardians, participants who meet the eligibility criteria received a unique subject\u0026nbsp;code. The\u0026nbsp;participants will undergo a 4-week treatment period and a 14-week follow-up. In addition, we will also recruit outpatients who meet the inclusion criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRandomization will be conducted after the baseline assessment via computer-generated random numbers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOpaque,\u0026nbsp;sealed envelopes according to the random table are prepared. Subjects who met the inclusion criteria opened the corresponding sealed envelopes in the order of enrollment and were assigned to the study group according to the assignment on the envelopes. GuoHua-\u0026nbsp;Wang, the pharmacist in charge of our department, will assign, package and code all drugs according to the random distribution list, then put the cards with serial number, random number and grouping into 96 sealed, opaque and sequentially numbered envelopes. All research drugs will be labeled, including the words \u0026quot;for clinical research only\u0026quot;, drug number, indications, usage and dosage, specifications, production date, expiration date, storage conditions, manufacturers and other information. According to the visit time and the drug distribution plan, the drug is a medium package every two weeks and a large package every four weeks. After the blind coding is completed, the drugs are arranged from small to large and packed for easy access. Because the appearance, packaging,\u0026nbsp;color\u0026nbsp;and other aspects of the experimental drugs and the control drugs are the same, it is difficult for subjects, researchers or other experimental participants to distinguish the groups of drugs after blind editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn independent research assistant,\u0026nbsp;Y-XL,\u0026nbsp;who is out of the intervention, evaluation, data collection and analysis of this clinical trial, used SPSS 25.0 statistical software to generate a random allocation list according to the ratio of treatment group A: treatment group B: placebo group C =1:1:1. The random seeds were recorded and sealed separately. W-JZ, H-RW, TJ and C-YL will enrol\u0026nbsp;and\u0026nbsp;follow\u0026nbsp;up\u0026nbsp;participants. On-site researchers will be responsible for the intervention assignment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoth the trial participants and the care providers will be blinded at recruitment and during the study. \u0026nbsp; The outcome assessor and data analyst will also be blinded.\u003c/p\u003e\n\u003cp\u003eWhen the patients enrolled in, they will get a unique subject code. The drug distributor, will register the patient information and drug serial number, and distribute the corresponding drug to the patient.\u003c/p\u003e\n\u003cp\u003eAt the final study visits participants will be asked to indicate whether they thought they had received placebo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the event of a serious adverse event (SAE) or reaction, the allocation list will be retrieved to reveal the participant\u0026rsquo;s allocated treatment during the trial, and the PI and on-site researchers will be responsible for signature and documentation. The process needs to be reported to the Ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll researchers will receive professional training about correct assessments, procedures regarding the use of the study medicine,\u0026nbsp;Case Report Form\u0026nbsp;CRF completion, and use of the GENEActiv PC software before and during this trial. Double data entry will be used for all data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDates for assessments will be planned by on-site researchers together with each participant, and all participants will be able to connect with the responsible researcher via their telephone or WeChat. Participants are aware of being able to receive rescheduled follow-ups within 3 days before or after to prevent temporary accidents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll researchers will receive professional training about correct assessments, procedures regarding the use of the study medicine, CRF completion, and use of the GENEActiv\u0026nbsp;computer\u0026nbsp;software before and during this trial. Double data entry will be used for all data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants\u0026rsquo; data will be collected in a specific reception room instead of in public areas to avoid revealing their personal information to others. Initial patient names and unique subject codes will be used on the CRF. And all documents will be stored confidentially before, during and after the trial. The principal investigators will have access to the final trial database, which will be available upon reasonable request. Personal information about the potential and enrolled participants will only be consulted by the researchers of this study and will not be shared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt baseline, weeks\u0026nbsp;4\u0026nbsp;of the experiment, totalling approximately 10 mL blood samples were collected from patients and centrifuged at 3500 rpm for 15 minutes in a low-temperature centrifuge. The upper layer of serum was extracted and\u0026nbsp;directly frozen at - 80\u0026nbsp;℃. Fecal samples were collected from patient baseline, weeks\u0026nbsp;4\u0026nbsp;of the experiment of the experiment, dissolved in preservation solution (glycerol: water = 1:9) (with 8 g of feces dissolved in 40 ml of preservation solution), filtered, aliquoted, and stored at - 80 \u0026deg;C. The above serum and fecal samples were processed according to the method of the previous research\u003csup\u003e[25]\u003c/sup\u003e, and metabolomics analysis is performed using a Shimadzu LCMS-8045 machine to explore potential metabolic pathways related to insomnia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will use SPSS 27.0 statistical software for the data analysis. The statistical analysis of all data will be conducted by an independent researcher who will not participate in the experiment. Descriptive statistics will be used to describe the demographic data of sample groups. A chi-squared test will be used to assess the sample characteristics and gender. The Shapiro-Wilk test is used to test the normality of the distribution of each parameter. Continuous variables that conform to a normal distribution will be expressed as the mean \u0026plusmn; standard deviation. Continuous variables that are not normally distributed will be represented by medians (interquartile ranges) [M (IQRs)], and classified variables will be represented by numerical values or percentages. The primary analysis will be a comparison of the changes in patients\u0026apos; PSQI scores among three groups at 4 weeks after inclusion (comparison of the primary endpoint). The secondary analysis will be performed to assess the changes in sleep efficiency,\u0026nbsp;total sleep time\u0026nbsp;and sleep awakenings recorded in the GENEActiv, which will be analyzed with the R- package GGIR version 1.2-0, as well as the ISI,\u0026nbsp;HAMD-17,\u0026nbsp;HAMA scores from baseline to 4 weeks after inclusion. For comparisons of the three groups, normality and homogeneity of variance are analyzed by variance analysis. If the variance is not uniform or normality is not conformed, the Mann-Whitney U test will be used. Counting data is chi-square test. All the statistical tests will be conducted bilaterally, and P \u0026lt; 0.05 indicates statistical significance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInterim analyses\u0026nbsp;are\u0026nbsp;not applicable. There were no adverse events in our pilot trial or earlier studies, so this trial involved a low-risk intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubgroup analyses by\u0026nbsp;age\u0026nbsp;will be performed in the future.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData analysis will follow the intention-to-treat (ITT) principles including participants who have at least one treatment. We will also perform a complete-case analysis without imputation of missing data, to determine whether the results are consistent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe full protocol, participant-level data, and statistical code are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial Steering Committee\u0026nbsp;will hold weekly internal meetings to review study progress and communications received from the site investigators and site coordinators to promptly address any issues that may arise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is no greater than minimal risk, and therefore, an independent research medical monitor is not needed.\u0026nbsp;Data and safety monitoring will be the shared responsibility of all members of the research team.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe researcher should collect and record the adverse events\u0026nbsp;(AEs)\u0026nbsp;and serious adverse events\u0026nbsp;(SAEs)\u0026nbsp;of each subject from the signing of the informed consent form to the end of the trial. All\u0026nbsp;the\u0026nbsp;details will be recorded in the CRF. When an adverse event is found, such as dizziness, headache, nausea and vomiting, anorexia, diarrhea, constipation, rash,\u0026nbsp;or\u0026nbsp;palpitation, the researcher can decide whether to terminate the trial according to the condition, and the subjects with adverse events should be followed up clinically until the adverse event is recovered (back to a normal state or a baseline state), until the condition is stable, or until the researcher thinks it is reasonable. If adverse events have not resolved to the above results by the end of the trial, the researcher will continue to provide necessary treatment, reports and records. Special cases can be handled according to the opinions of relevant management departments.\u003c/p\u003e\n\u003cp\u003eUpon the discovery of serious adverse events, the researcher shall immediately take appropriate protective facilities for the subjects, and report to the Ethics Approval Committee of the Shanghai Municipal Hospital of Traditional Chinese Medicine within 24 hours. The researcher shall sign the report and indicated the date.\u003c/p\u003e\n\u003cp\u003eExcept for the indexes related to disease progression, all clinical events and clinically significant laboratory adverse reactions can be treated with reference to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trial will be supervised and audited once a year by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trail was conducted in accordance with the Helsinki Declaration and was approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China (2023SHL-KY-49-01, 2023SHL-KY-49-02).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAny revision of this agreement will be reported and approved by the ethics committee. Only after approval is obtained can further research can be carried out. And the modified protocol will be uploaded to the trial registry.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe plan to publish and disseminate the results in an influential medical journal. We are also delighted to share the results with medical professionals, the public, and relevant organizations in the form of a conference report after it is published.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eResearch on chronic insomnia has become increasingly mature, but the attention paid to acute insomnia is insufficient. There are no quantitative or qualitative criteria for the diagnosis of early acute insomnia, which directly affects whether acute insomnia can be identified and treated in time. The DSM-5, published in 2013, put forward diagnostic criteria for short-term insomnia, but the causes of short-term insomnia are not clear enough to be attributed to a single cause, including acute stress, environmental changes, behavioral changes, diseases and drugs, and many other factors that may lead to high arousal. Because many clinical signs show that this type of insomnia is self-healing, and a large number of individuals have alleviated it without any intervention, and have not developed into chronic insomnia, so the treatment scheme for acute insomnia is still controversial. However, regardless of the patient experience and health and economic benefits, clinicians need to pay more attention to the treatment of acute insomnia. In the past clinical experience, sedative and hypnotic drugs are often the first choice for treating acute insomnia, but drugs will bring untold adverse reactions, and we should further determine which treatments are safe and effective.\u003c/p\u003e \u003cp\u003eHerbal medicines have been used for centuries to induce sleep and aid in relaxation. Some of the popular herbsused include Ziziphus spinosa seeds, Polygala tenuifolia Willd, Schisandrae Chinensis Fructus, valerian root, lavender, branches and leaves of groundnut[\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]-[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Data from the US National Health Interview indicated that 82% of people with sleep trouble who had tried herbal therapies found them to be helpful\u003csup\u003e[30]\u003c/sup\u003e. However, the therapeutic effect on acute insomnia is unknown.\u003c/p\u003e \u003cp\u003eAt the time of this writing, there were no RCTs about Luohua Anshen liquid as a complementary therapy for short-term insomnia. Our trial intends to present a strictly designed trial to study the effects of Luohua Anshen liquid for short-term insomnia patients and to overcome some existing limitations, including illogical design, imperfect blinding method and practical difficulties in previous herbs clinical researches. With a medium follow-up period, we will explore the sustained effect of Luohua Anshen liquid on insomnia and determine whether it can destroy the occurrence of chronic insomnia.\u003c/p\u003e \u003cp\u003eAt present, more clinical studies[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] have used body motion recorders to objectively measure sleep activity. Actigraphy is a technique for measuring limb movement activity with actigraphic devices that are wearable on wrists or ankles. The data for movement activity is then gathered over a period, ultimately giving us patterns for wakefulness and sleep. With the patterns, general sleep parameters, including sleep latency, sleep efficiency, total sleep time, and wake after sleep onset, can be obtained. These parameters could greatly aid in evaluating insomnia.\u003c/p\u003e \u003cp\u003eThe use of sleep diary has an essential role in helping to diagnose short-term insomnia. Patients are generally asked to report their sleep patterns such as time in bed, nighttime awakenings, sleep satisfaction, sleep onset latency, and total sleep time. These are measured from two to four weeks and are brought in for the clinician to review.\u003c/p\u003e \u003cp\u003eOf course, sleep health education must be an active part of the treatment of acute insomnia, and we also regard this part as the basic treatment for every participant in the study.\u003c/p\u003e \u003cp\u003eIn conclusion, this trial will provide high-quality evidence on the effectiveness and safety of the Luohua Anshen liquid, which can be used to guide clinical practice for short-term insomnia.\u003c/p\u003e"},{"header":"Trial status","content":"\u003cp\u003eThis protocol\u0026nbsp;is\u0026nbsp;VERSION 3.0,\u0026nbsp;28 June 2023.\u003c/p\u003e\n\u003cp\u003eRecruitment began in July 2023 and is expected to be completed in May 2024.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"482\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003ePSQI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003ePittsburgh Sleep Quality Index\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eISI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eInsomnia Severity Index \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eTCMSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eTraditional Chinese Medicine Syndrome Scale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eMEQ-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eMorning and Evening Questionnaire-5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eHAMD-17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eHamilton Rating Scale for Depression-17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eHAMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eHamilton Rating Scale for Anxiety\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eChiCTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eChinese Clinical Trial Registry\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eDSM-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eDiagnostic and Statistical Manual of Mental Disorders 5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eCID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eChronic Insomnia Disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eSTID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eshort-term insomnia disorder\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eCBT-I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eCognitive\u0026nbsp;behavioral therapy\u0026nbsp;for insomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eHPLC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eHigh-performance liquid chromatography\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eALT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003ealanine aminotransferase\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eAST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003easpartate aminotransferase\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eSCr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eserum creatinine\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eBUN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eblood urea nitrogen\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eMMAS-8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eMorisk Medical Compliance Scale-8 items\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eadverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eSAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eserious adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eCFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eCase Report Form\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eITT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eintention-to-treat\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eDMC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003edata monitoring committee\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003eCTCAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"74.48132780082987%\" valign=\"top\"\u003e\n \u003cp\u003eCommon Terminology Criteria for Adverse Events\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors want to thank all the participants for cooperating and supporting the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTJ and W-JZ studied the concept and designed the manuscript. TJ drafted the manuscript. G-HW and H-RW critically revised the manuscript for important intellectual content. W-JZ obtained the funding. Y-XL and F-YZ drew up the statistical analysis plan. W-JZ, H-RW, TJ and C-YL recruited and followed up the subjects. G-HW, YW and\u0026nbsp;Y-LW were in charge of the laboratory. All the authors read and approved the final manuscript.\u003cbr\u003e\u0026nbsp;\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Key Research and Development Program of China \u0026nbsp;[number: 22021YFC2501500] and the Shanghai Technical Superiority Project of \u0026ldquo;Preventive Treatment of Disease\u0026rdquo;, Shanghai Municipal Health Commission [ZY(2021-2023)-0104-02-GF-04] to W-JZ.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to regulations of the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, all clinical data and information that can identify participants obtained for the purpose of this study will be treated as confidential and stored safely. Participant data will be identified by a unique code number for respecting privacy rights of participants and protect their identities,\u0026nbsp;that will be allocated after the participant sign informed consent form. The identity/personal details (e.g. name, date of birth) of the link participants will be stored in a password-encrypted file and cannot be accessed from the Internet. All data will be stored in written and computer format in Shanghai Municipal Hospital of Traditional Chinese Medicine. Participant information will be stored on a secure server that is backed up regularly. Only researchers related to the study can access participants\u0026apos; data. he Ethics Committee will continuously monitor and evaluate the research progress and safety internally. Upon reasonable request, the correspondent author can provide complete scheme, participant level data and statistical code.\u0026nbsp;If anyone wants to get the data of this study, they should contact Wen-Jing Zhang\u003csup\u003e1\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial was approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China (number:\u0026nbsp;2023SHL-KY-49-01,\u0026nbsp;2023SHL-KY-49-02). Written, informed consent to participate will be obtained from all participants prior to trial participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe unsigned\u0026nbsp;model informed consent form is available from the corresponding author on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests, or other interests that might be perceived to influence the results and/or discussion reported in this paper\u003cbr\u003e\u0026nbsp;\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003einformation (optional)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRefer to above {5a}.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eRiemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of insomnia. \u003cem\u003eJ Sleep Res\u003c/em\u003e. 2017;26(6):675-700. doi:10.1111/jsr.12594.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRiemann D, Krone LB, Wulff K, et al. Sleep, insomnia, and depression. Neuropsychopharmacology 2020;45(1):74-89.\u003c/li\u003e\n \u003cli\u003eJarrin DC, Alvaro PK, Bouchard MA, et al. Insomnia and hypertension: A systematic review. Sleep Med Rev 2018;41:3-38\u003c/li\u003e\n \u003cli\u003eOhayon MM, Reynolds CF, 3rd. Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the International Classification of Sleep Disorders (ICSD). Sleep Med 2009;10(9):952-60.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eEllis JG, Gehrman P, Espie CA, Riemann D, Perlis ML. Acute insomnia: current conceptualizations and future directions. \u003cem\u003eSleep Med Rev\u003c/em\u003e. 2012;16(1):5-14. Doi:10.1016/j.smrv.2011.02.002\u003c/li\u003e\n \u003cli\u003eEllis JG, Cushing T, Germain A. Treating Acute Insomnia: A Randomized Controlled Trial of a \u0026quot;Single-Shot\u0026quot; of Cognitive Behavioral Therapy for Insomnia. \u003cem\u003eSleep\u003c/em\u003e. 2015;38(6):971-978.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAmerican Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien: American Academy of Sleep Medicine,2014:19-47.\u003c/li\u003e\n \u003cli\u003eMorin CM. Definition of acute insomnia: diagnostic and treatment implications. \u003cem\u003eSleep Med Rev\u003c/em\u003e. 2012;16(1):3-4. doi:10.1016/j.smrv.2011.08.005\u003c/li\u003e\n \u003cli\u003eEdinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. \u003cem\u003eJ Clin Sleep Med\u003c/em\u003e. 2021;17(2):255-262. doi:10.5664/jcsm.8986\u003c/li\u003e\n \u003cli\u003eEllis JG, Cushing T, Germain A. Treating Acute Insomnia: A Randomized Controlled Trial of a \u0026quot;Single-Shot\u0026quot; of Cognitive Behavioral Therapy for Insomnia. \u003cem\u003eSleep\u003c/em\u003e. 2015;38(6):971-978. Published 2015 Jun 1. doi:10.5665/sleep.4752\u003c/li\u003e\n \u003cli\u003eLeach MJ, Page AT. Herbal medicine for insomnia: A systematic review and meta-analysis. \u003cem\u003eSleep Med Rev\u003c/em\u003e. 2015;24:1-12. doi:10.1016/j.smrv.2014.12.003\u003c/li\u003e\n \u003cli\u003eQiao-Chu Wang. Peanut branches and leaves to treat insomnia-20 years of research results. Shanghai: Shanghai Science and Technology Literature Publishing House, 2009:2-3,11-14,16-30,37-49,53.（in Chinese）\u003c/li\u003e\n \u003cli\u003eSonn JY, Lee J, Sung MK, et al. Serine metabolism in the brain regulates starvation-induced sleep suppression in \u003cem\u003eDrosophila melanogaster\u003c/em\u003e. \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e. 2018;115(27):7129-7134. doi:10.1073/pnas.1719033115\u003c/li\u003e\n \u003cli\u003eGuo R, Shi AM, Deng L, et al. Flavonoid-Like Components of Peanut Stem and Leaf Extract Promote Sleep by Decreasing Neuronal Excitability. \u003cem\u003eMol Nutr Food Res\u003c/em\u003e. 2022;66(1):e2100210. doi:10.1002/mnfr.202100210\u003c/li\u003e\n \u003cli\u003eYi-Fang Wang, Hua-Fang Li, Yi-Feng Xu, et al. Clinical blind observation of groundnut branch and leaf preparation in the treatment of insomnia. Shanghai Journal of Traditional Chinese Medicine, 2001,35(5):11-14.\u0026nbsp;（in Chinese）\u003c/li\u003e\n \u003cli\u003eBei-Lei Feng, Jing-Xia, Zheng-Yuan Li, et al. 30 cases of insomnia due to liver depression and fire were treated with integrated traditional Chinese and western medicine [J]. Bulletin of Traditional Chinese Medicine, 2005,(02):56-58.\u0026nbsp;（in Chinese）\u003c/li\u003e\n \u003cli\u003eWen-Jing Zhang, Guo-Hua Wang, Qiao-Chu Wang. Efficacy of Luohua Anshen Oral L on insomnia: A randomized, double-blind, placebe-controlled clinical trial [J]. Chinese Journal of Traditional Chinese Medicine, 2017,32(06):2801-2804.\u0026nbsp;（in Chinese）\u003c/li\u003e\n \u003cli\u003eChen XJ. Internal Medicine of Traditional Chinese Medicine. Shanghai: Shanghai Scientific \u0026amp; Technical Publishers, 2004.\u0026nbsp;（in Chinese）\u003c/li\u003e\n \u003cli\u003eFabbri M, Beracci A, Martoni M, Meneo D, Tonetti L, Natale V. Measuring Subjective Sleep Quality: A Review. \u003cem\u003eInt J Environ Res Public Health\u003c/em\u003e. 2021;18(3):1082. Published 2021 Jan 26. doi:10.3390/ijerph18031082\u003c/li\u003e\n \u003cli\u003eYan XL, Xu J, Wang HR, Xu H, Xu L, Wang GH, Wang QC, Li Y. Design and use of Dr. Yan\u0026rsquo;s insomnia prospective assessment scale for syndrome differentiation, diagnosis and treatment. Zhongyi Wenxian Zazhi, 2015, 33(4): 31-33.\u003c/li\u003e\n \u003cli\u003eGagnon C, B\u0026eacute;langer L, Ivers H, Morin CM. Validation of the Insomnia Severity Index in primary care.\u0026nbsp;J Am Board Fam Med. 2013 Nov-Dec;26(6):701-10.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSmith MT, McCrae CS, Cheung J, et al. Use of Actigraphy for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An American Academy of Sleep Medicine Clinical Practice Guideline. \u003cem\u003eJ Clin Sleep Med\u003c/em\u003e. 2018;14(7):1231-1237. Published 2018 Jul 15. doi:10.5664/jcsm.7230\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNatale V, L\u0026eacute;ger D, Bayon V, et al. The consensus sleep diary: quantitative criteria for primary insomnia diagnosis. \u003cem\u003ePsychosom Med\u003c/em\u003e. 2015;77(4):413-418. doi:10.1097/PSY.0000000000000177\u003c/li\u003e\n \u003cli\u003eMoon SJ, Lee WY, Hwang JS, Hong YP, Morisky DE. Accuracy of a screening tool for medication adherence: A systematic review and meta-analysis of the Morisky Medication Adherence Scale-8. PLoS One. 2017 Nov 2;12(11): e0187139.\u003c/li\u003e\n \u003cli\u003eBangH,NiL,DavisCE.Assessmentofblindinginclinicaltrials.ControllClinTrials.(2004) 25:143\u0026ndash;56. doi: 10.1016/j.cct.2003.10.016\u003c/li\u003e\n \u003cli\u003eLuo Y, Zhang X, Zhang W, et al. Compatibility with Semen Sojae Praeparatum attenuates hepatotoxicity of Gardeniae Fructus by regulating the microbiota, promoting butyrate production and activating antioxidant response. \u003cem\u003ePhytomedicine\u003c/em\u003e. 2021;90:153656. doi:10.1016/j.phymed.2021.153656\u003c/li\u003e\n \u003cli\u003eYang M, Wang H, Zhang YL, et al. The Herbal Medicine Suanzaoren (Ziziphi Spinosae Semen) for Sleep Quality Improvements: A Systematic Review and Meta-analysis. Integr Cancer Ther. 2023;22:15347354231162080. doi:10.1177/15347354231162080.\u003c/li\u003e\n \u003cli\u003eZare Elmi HK, Gholami M, Saki M, Ebrahimzadeh F. Efficacy of Valerian Extract on Sleep Quality after Coronary Artery bypass Graft Surgery: A Triple-Blind Randomized Controlled Trial. Chin J Integr Med. 2021;27(1):7-15. doi:10.1007/s11655-020-2727-1\u003c/li\u003e\n \u003cli\u003e. Shi MM, Piao JH, Xu XL, et al. Chinese medicines with sedative-hypnotic effects and their active components. Sleep Med Rev. 2016;29:108-118. doi:10.1016/j.smrv.2015.10.001\u003c/li\u003e\n \u003cli\u003eAdjaye-Gbewonyo D, Ng AE, Black LI. Sleep Difficulties in Adults: United States, 2020. \u003cem\u003eNCHS Data Brief\u003c/em\u003e. 2022;(436):1-8.\u003c/li\u003e\n \u003cli\u003eFEKEDULEGN D,ANDREW M E,SHI M,et al.Actigraphy-based assessment of sleep parameters［J］. Ann Work Expo Health, 2020,64（4）：350-367.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\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":"Short-term insomnia, Luohua Anshen oral liquid, Randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-4119690/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4119690/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e:\u0026nbsp;At present,\u0026nbsp;insufficient attention and unsatisfactory treatment\u0026nbsp;for\u0026nbsp;short-term insomnia disorder\u0026nbsp;are\u0026nbsp;widespread\u0026nbsp;problems.\u0026nbsp;This\u0026nbsp;group\u0026nbsp;of\u0026nbsp;people\u0026nbsp;should\u0026nbsp;receive\u0026nbsp;safe and effective treatment as soon as possible and avoid developing into chronic insomnia disorder. We hope to intervene and treat\u0026nbsp;these\u0026nbsp;patients\u0026nbsp;through Luohua Anshen oral Liquid,\u0026nbsp;which is made of\u0026nbsp;peanut branches and leaves and has been used to effectively treat insomnia disorder,\u0026nbsp;this\u0026nbsp;method\u0026nbsp;can be conducive to\u0026nbsp;preventing\u0026nbsp;short-term insomnia disorder\u0026nbsp;chronicity and reducing the burden of health economics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e:\u0026nbsp;This double-blinded,\u0026nbsp;randomized,\u0026nbsp;placebo-controlled trial will be conducted at Shanghai Municipal Hospital of Traditional Chinese Medicine,\u0026nbsp;Shanghai University of Traditional Chinese Medicine.\u0026nbsp;After\u0026nbsp;the\u0026nbsp;one-week baseline,\u0026nbsp;96 short-term insomnia patients will be allocated 1:1:1 to intervention group A (treatment with Luohua Anshen oral\u0026nbsp;liquid\u0026nbsp;placebo 30 min after breakfast, and\u0026nbsp; Luohua Anshen oral\u0026nbsp;liquid\u0026nbsp;30 min before retiring for sleep),intervention group B (treatment with Luohua Anshen oral Liquid 30 min after breakfast,\u0026nbsp;and\u0026nbsp;Luohua Anshen oral\u0026nbsp;liquid\u0026nbsp;placebo 30 min before retiring for sleep) or\u0026nbsp;the\u0026nbsp;control group (treatment with oral placebo twice a day),\u0026nbsp;with 4 weeks of treatment and 12 weeks of follow-up. The primary outcome will be evaluated with the Pittsburgh Sleep Quality Index (PSQI). The\u0026nbsp;secondary outcomes included the incidence of chronic insomnia, the Insomnia Severity Index (ISI),\u0026nbsp;Traditional Chinese Medicine Syndrome Scale\u0026nbsp;(TCMSS)\u0026nbsp;and Morning and Evening Questionnaire-5 (MEQ-5) scores; the\u0026nbsp;sleep parameters recorded in the GENEActiv and Sleep Diary;and the Hamilton Rating Scale for Depression\u0026nbsp;(HAMD-17)\u0026nbsp;and Hamilton Anxiety Scale (HAMA) scores. The mechanistic evidence will be full-spectrum detection via serum and fecal sample metabolomics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e:\u0026nbsp;This study provides more subjective and objective evidence of the efficacy and safety of Luohua Anshen oral liquid for improving sleep quality and exploreing the metabolic pathway of Serum and feces in patients with short-term insomnia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e: This trial was registered in the Chinese Clinical Trial Registry (ChiCTR) (Identifier: ChiCTR2300071930) on 30 May 2023.\u003c/p\u003e","manuscriptTitle":"Clinical efficacy of Luohua Anshen oral liquid in the treatment of short-term insomnia disorders (syndrome of depressed liver qi transforming into fire): protocol for a single-center, double-blinded, randomized, placebo-controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-04 19:46:31","doi":"10.21203/rs.3.rs-4119690/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":"8e272563-5b40-41e6-ae57-7abd4f47234c","owner":[],"postedDate":"April 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-25T17:18:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-04 19:46:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4119690","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4119690","identity":"rs-4119690","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}