This study is a randomized, double-blind, placebo-controlled pilot clinical trial. Eligible participants will be randomly assigned to either the JTW or placebo group in an equal proportion. The drug intervention will last for 1 week. Fig. 1 briefly shows the study flow chart, and Fig. 2 enumerates the treatment schedule and outcome measures. The study adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT 2013) checklist  (additional file 1).
Patients suffering from insomnia symptoms caused by the disharmony of the heart and kidney will be recruited from the Traditional Chinese
Medicine Department and Sleep Centre of the First Affiliated Hospital of Wenzhou Medical University in Wenzhou, Zhejiang Province, China.
Participants are 18-60 years of age, either male or female, and with a level of education above junior high school.
Insomnia is almost the only symptom, including difficulty sleeping, deep sleep, dreaminess, early-morning awakening, trouble going back to sleep, feeling tired after waking up, or daytime sleepiness (excluding secondary insomnia).
A Pittsburgh sleep quality index score of 7 or higher according to the Chinese Classification and Diagnostic Criteria of Mental Disorders-3 Version, CCMD-3.
A Disharmony of Heart and Kidney Scoring System score of 9 or higher.
Signed the informed consent before treatment.
Insomnia caused by physical diseases or lifestyle changes or environmental disturbances.
Affective disorders, anxiety disorder, depression, schizophrenia and any other serious mental disorders.
Suffering from somatic diseases that affect the central nervous system
Serious heart, liver, kidney and hematopoietic system diseases, abnormal liver and kidney function.
Regular use of antipsychotic drugs in the last month.
Use of medicine to treatment sleeping disorders in the past week.
Allergic to a certain ingredient of the drug involved in this trial or suffering from allergies.
Alcohol abuse or (and) psychotropic drug addiction.
Pregnancy or lactation.
Randomization and allocation concealment
A medical statistics professional will generate random sequences using the software R. The sequences will be concealed to all investigators and eligible participants. One hundred twenty-eight participants will be assigned to one of two groups by blocked randomization. Furthermore, allocation concealment will be maintained throughout the entire study.
This study will use a double-blind method. The placebos will be packaged identically as the study drugs in appearance, smell and colour. Then, the study coordinator will assign JTW or placebo according to the randomization codes and place them in special containers. The participants, outcome assessors, study coordinators, data managers, and statisticians will be blinded to the group allocation and numbered drug containers throughout the entire study. At the end of the study, the blinding codes will be revealed.
These eligible participants will ingest 2 g granules of JTW or placebo, twice a day at 4 PM and 9 PM for 1 week and present themselves at the termination of medication, followed by a scheduled examination.
Both JTW and placebo are manufactured by the Kangren Pharmaceutical Factory according to good manufacturing practice standards. JTW will be produced in the form of granules with a yellowish-brown color. The medication will be 2 g, containing 1.1 g JTW soft extract with 0.37 g of lactose hydrate and 0.88 g of corn starch as the excipient. The JTW soft extract will be made of a water extract of a mixture of two herbal medicines, as follows: Rhizome Coptidis (10 g) and Cortex Cinnamomi (1 g). The placebo will consist of corn starch,lactose hydrate, citric acid, and caramel color. The placebo and JTW will have the same appearance, smell and color.
Medication compliance monitoring
To ensure compliance with the medication, participants will be asked to count the actual intake, and return the empty wrapping papers for the medication and any remaining medicine.
Prohibition and permission for concomitant treatment
The use of any sedative hypnotics to help sleep will be prohibited during the study.
The use of any traditional medicine designed to treat insomnia, except for the intervention of this trial, will be prohibited during the study.
The use of functional foods or other medications intended to improve the symptoms of insomnia will be prohibited during the study.
Any psychotherapy for accelerating sleep quality will be prohibited during the study.
Medications used to treat other chronic diseases at the beginning of this trial will be allowed.
Routine physical training prior to the start of this clinical trial will be allowed.
Any change in medications or physical exercise during the study will be recorded in a clinical report form.
Pittsburgh sleep quality index (PSQI)
The Pittsburgh Sleep Quality Index will be used at the baseline and the end of the drug intervention. The PSQI version used in this study is a 19-item self-reported retrospective questionnaire to access the quality of sleep in the past 7 days, and it is designed to measure 7 domains called component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medications, and daytime dysfunction[16,17]. Component scores range from 0 (no difficulty) to 3 points (severe difficulty), and when summed, produce a global score ranging from 0 to 21. A higher score denotes worse sleep. These syndromes arecategorized as mild (0-1), moderate (2-7), or severe (8 or more). Then, the scores the participants obtained at baseline will be recorded as score 0, and the scores obtained at the end of drug intervention will be recorded as score 1. The recorder will calculate the reduction rate (RR) according to the following formula: RR＝( score 1-score 0)/score 0*100%. Finally, we will assess the clinical curative effect based on the results of the RR. RR values greater than 75% will be regarded as a clinical cure, RR values between 50%-75% will be considered clinically effective, RR values between 25%-50% will be recognized as a clinical success and RR values less than 25% will be considered ineffective. Therefore,the mean change of the PSQI score from the baseline to the end of intervention and the RR will be the primary outcome measures of this study.
In addition, Xiancheng Liuet al.  presented their opinion that the Pittsburgh Sleep Quality Index is suitable for Chinese patients after they conducted reliability and validity tests.
Polysomnography (PSG) will be taken twice both at the baseline and the end of drug intervention. On the first night, participants will adapt themselves to the laboratory environment. On the second night, participants will be placed on polysomnography monitoring to record the multiple physiological sleep parameters. The parameters [19,20] will include total sleep time, sleep efficiency, sleep latency, REM stage latency, wake after sleep onset and the time duration of the particular sleep stages (such as N1, N2, N3). The mean changes of all the parameters from the baseline to the end of drug intervention will be used to measure the changes in sleep quality.
PSG is considered the gold standard for scoring sleep disorders.The scoring of sleep and arousals relies on visual inspection of continuous surface electroencephalography (EEG), electromyography (EMG), and electrooculography (EOG) during PSG and then divides human sleep into 5 stages: wakefulness(W), rapid eye movement(REM), nonrapid eye movement (NREM), including N1, N2 and N3. The American Academy of Sleep Medicine (AASM) defined the quantitative reference standard in PSG for adult insomnia as follows: sleep latency ≥ 30min; total sleep time < 390 min; number of wake after sleep onset (WASO) ≥ 2 or time of WASO ≥ 40 min; time in N1/total sleep time > 60%; time in N2 / total sleep time > 60% or time in N3/total sleep time < 10%, or time in REM / total sleep time < 20%. A higher or lower score corresponds to more severe symptoms.
1H-magnetic resonance spectroscopy(1H-MRS)
1H-magnetic resonance spectroscopy (1H-MRS) will also be taken at the baseline and the end of drug intervention. 1H-MRS, with its unique noninvasive advantages, is able to detect and quantify the important metabolites of living brain tissue, including N-acetylaspartate(NAA),
choline(Cho), creatine(Cr), gamma-aminobutyric acid (GABA) and myo-inositol (mI). In this study, single voxel hippocampus and thalamus metabolite ratios of GABA with Cr will be measured. The altered ratios of GABA with Cr between baseline and the end of drug intervention will be the second outcome measure.
Studies have revealed that the GABA/Cr ratio in the frontal lobe is significantly lower, and the average brain GABA levels are nearly 30% lower in patients with primary insomnia.
Disharmony of Heart and Kidney Scoring System
The Disharmony of Heart and Kidney Scoring System will be used
at the baseline and the end of drug intervention. It is a checklist covering 1 indispensable and 7 accompanying items. These items are the symptoms and signs of the disharmony of heart and kidney pattern according to the theory of the pattern identification system in traditional East Asia medicine. The score of the indispensable item uses a four-point scale (0, 3, 6 and 9) depending on the severity of the insomnia (0=none, 9=very severe); the 7 accompanying items including palpitations, dizziness, spermatorrhea or menstrual
irregularity, and night sweat and use 0-4-point scale based on their frequency. A total score of more than 9 out of 30 points is thought to demonstrate disharmony of the heart and kidney[26,27].
Although there is no accurate evidence to explain the validity and reliability of this questionnaire, no other methods are currently available to identify the disharmony of heart and kidney pattern.
The levels of adenosine (AD) and melatonin (N-acetyl-5-
methoxytryptamine) in blood samples will be recorded at the baseline and the end of the drug intervention, will then be analyzed by the clinical lab.
Sleep homeostasis in adults is affected by the sleep-regulatory substances AD and melatonin[28,29]. AD is a product of brain metabolism, and is closely related to sleep parameters. A previous study showed that AD levels were elevated as a consequence of sustained wakefulness. Melatonin is an endogenous hormone produced by the pineal gland and is released exclusively at night. Melatonin has been shown to synchronize the circadian rhythms, and improve the onset, duration and quality of sleep. Takaesu Y and his colleagues thought that reduced melatonin secretion may be involved in the mechanism of insomnia.
In this study, high-performance liquid chromatography (HPLC) will be developed to determine the levels of adenosine, and an enzyme-linked immunosorbent assay will be used to detect the concentration of melatonin.
At the end of this trial, participants will participate in a routine
physical examination, including breath rate, heart rate, temperature, blood pressure, weight, routine urine test, routine blood test, liver, kidney function tests, and an electrocardiogram.
Adverse event reporting and treating
During the treatment period, the researchers will record any adverse events (AEs) that will be defined as unpredictable, undesirable symptoms, signs or diseases related to the treatment during daily telephone calls. Then, the researchers will comprehensively evaluate the correlation between these adverse events and the experimental drugs according to the recorded details about AEs, including the manifestation, occurrence time, duration, cause and treatment measures. Simultaneously, if any AE occurs, the investigator will take proper measures such as dose adjustment, drug withdrawal and symptomatic treatment to ensure the safety of participants, and all details will be written down carefully. Furthermore, continuous follow-up will be insisted upon until the condition of the participants returns to normal.
The ratio of cases between the JTW group and the placebo group is set to 1:1, and this study is designed to achieve a statistical power of 85% (one-sided type-1 error of =5%， =10%). Based on previous clinical practice[32,33], we assume a treatment success rate of 40% in the placebo group and 70% in the JTW group over 7 days using the following formula:
where is the cumulative distribution function of the standard normal distribution. Considering a 20% drop-out rate, a sample size of N≈53×1.2≈64 is needed for each group. Thus a total of 128 patients are needed in this study.
The experimental data will be carefully saved in Microsoft Access, which is a database management system (DBMS) from Microsoft. To guarantee the data quality, data will be input and checked twice by two researchers along with regular monitoring.
R is used for statistical analysis in this study by an independent statistician. The mean and standard deviation shall be applied to the continuous variables, and percentages to the categorical variables. For comparison of two independent samples, the t test and analysis of variance will be applied for continuous variables and the chi-square test will be applied for categorical variables. In addition,the rank sum test has the best efficiency among
nonparametric tests, and is frequently used. Then p < 0.05 is considered statistically significant.