Trail design
This is a multi-center, randomized controlled, blind evaluated and non-inferiority study, with estazolam as a control, aiming to explore whether “Chou’s Tiaoshen” acupoints is non-inferior to estazolam and the possible mechanism of acupuncture for short-term insomnia. A total of 88 participants will be randomly assigned to two different groups. Participants will receive acupuncturing “Chou’s Tiaoshen” acupoints in the acupuncture group five times a week and last for 2 weeks. While participants in the estazolam group will take estazolam before bedtime in the day and the treatment will also be given for 2 weeks. Polysomnography, heart rate variability, cortisol and related scales will be measured before and after treatment to detect the changes in symptoms and signs. The time schedule can be seen in figure 1. This protocol is reported based on the SPIRIT guidelines[i] (the SPIRIT checklist of this protocol is available in the supplementary material).
Participants and recruitment
Participants with short-term insomnia will be recruited from the outpatient clinic at two different wards of Beijing TCM Hospital ( Dongcheng ward and Shunyi ward) from 2024.3 to 2025.3.
Sample size estimation
According to the existing literature[ii], estazolam treatment for insomnia can make PSQI score decrease 5.51 ± 3.37 than before. According to our previous work[iii], acupuncturing “Chou’s Tiaoshen” acupoints for insomnia can make PSQI score decreased 5.17 ± 3.55 than before. Therefore, the non-inferiority test was used in this study, and the non-inferiority threshold “Δ” was set as “-2”. The test level is set as α =0.025 (one side), the test efficiency is 1- β =0.80, and the sample size calculation formula is based on the comparing of means of the two samples. It was calculated that a minimum of 35 patients will be required in each group. Considering lost follow-up, excluded and detached cases (controlled below 20%), it requires the sample size of at least 44 cases in each group and the total sample size of at least 88 cases.
Inclusion criteria
1. Meet the diagnostic criteria for short-term insomnia according to the Diagnostic and Statistical Manual of Mental Disorders Text Revision, 5th edition (DSM-V) and Chinese Adult Insomnia Diagnosis and Treatment Guide 2017[iv]: A predominant complaint of dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms: 1)Difficulty initiating sleep. 2). Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings. 3) Early-morning awakening with inability to return to sleep. 4) The sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning. The duration of the sleep difficulty is 1 week to 3 months.
2. Aged between 18 and 70 years old. Male or female.
3. Patients who agreed to participant in this trial and assigned the informed consent (Available in the related files).
Exclusion criteria
1. People with other DSM-V Axis I, Axis II mental disorders or substance abuse/dependence.
2. Patients with serious primary diseases such as cardiovascular and cerebrovascular diseases, hypertension, digestive system, hematopoietic system, liver, kidney, or severe anxiety and depression.
3. Caused by alcohol or drugs.
4. Pregnant or lactating women.
5. Easy to combine infection and bleeding.
6. Patients who have used psychotropic drugs, such as antidepressants, mania drugs or other drugs used to treat psychosis, in the last month, and patients who have taken sleeping pills in the last 1 month.
7. Those who cannot cooperate with treatment.
Elimination criteria
Take other anti-insomnia drugs or other treatments during the observation period.
Shedding criteria
1. Quit due to poor efficacy or sever adverse effects;
2. Patients who were lost to follow-up.
Randomization and allocation concealment
The included participants were divided into acupuncture group or estazolam group according to the randomization principle. The group randomization method generated random number table using SPSS 20.0 software, corresponding group code into envelopes and sealed (unrecoverable after unpacking). The allocation ratio of the two groups is 1:1. Random envelopes are made by special personnel to achieve covert grouping. Qualified patients were enrolled according to the randomized protocol. The number of the randomized envelope is the serial number of the patients enrolled. Select in the order of small to large, open the randomized envelope, and operate according to the prompts in the randomized envelope. We will keep the concealment of the randomized method during the trials.
Blinding
It is difficult to blind the researchers and participants in this study, we only perform blinded evaluation.
Provisions for concomitant medication or treatment
Allowed concomitant medication / treatment: In the course of the trial, the medication of the Pre-existing disease, such as coronary heart disease, diabetes mellitus and hyperlipidemia, can be remain unchanged, and the combined medication of the subjects should be recorded in detail. Concomitant medication / treatment prohibited: other anti-insomnia drugs or other insomnia treatment.
Acupuncture group
“Chou’s Tiaoshen” acupoints include Baihui (GV-20), Shenting (GV-24), Benshen(BG-13), Sishencong (EX-HN1), Neiguan(PC-6), Shenmen (HT-7), and Sanyinjiao (SP-6). Using stainless steel needles (0.18×40 mm, HuaTuo, China). Then some other points like, Taichong (LR3), Daling(PC-7), Danzhong(CV-17), Taixi (KI-3), Qihai (CV-6), and Qiuxu(GB-40) are chosen based on participant’s unique pattern. Operation: Patients in supine position. Baihui (GV-20), Shenting (GV-24), Benshen(BG-13), and Sishencong (EX-HN1) are punctured at a depth of 5-10mm obliquely. Neiguan(PC-6), Sanyinjiao (SP-6), and Shenmen (HT-7) are inserted 10-15mm perpendicularly. Until feeling tactile sensation then manually manipulated by rotation methods to produce a characteristic sensation known is known as "De Qi". Technique: Mild reinforcing and attenuating, retaining the needle for 30minutes. The treatment will be given once a day and 5 times a week in weekdays, the course will last 2 weeks.
Estazolam group
Participants will take estazolam tablets (1 mg/day) 30min prior to bedtime. The course will last 2 weeks.
Primary outcome measure
Sleep quality will be measured using the scale of Pittsburgh Sleep Quality Index (PSQI) at baseline, day 14 and day 28. PSQI is a self-rated questionnaire which assesses sleep quality and disturbances. Eighteen individual items generate seven “component” scores: subjective sleep quality (SQ), sleep-onset latency (SOL), total sleep time (TST), habitual sleep efficiency (SE), sleep disturbances ( Dyssomnia), use of sleeping medication, and daytime dysfunction (DD).The cumulative component score is the PSQI total score ranging from 0 to 21, higher scores indicates worse sleep quality.
Secondary outcome measures
- Objectivity sleep quality and related sleep events are measured by polysomniography (PSG) at baseline and day 14. PSG is a classic instrument for detecting sleep conditions. The following data can be obtained by PSG monitoring: total sleep time, sleep latency, The percentage of time spent in each sleep stage. Previous studies have shown differences between subjective and objective sleep. PSG is of great value for the degree and differential diagnosis of insomnia.
- Heart rate variability (HRV) is used to assess autonomic tone at baseline and day 14. The degree and regularity of heart rate changes can be reflected by measuring the variability of continuous normal R-R interphase changes by dynamic electrocardiogram, so as to judge its impact on cardiovascular activities, which can reflect the activity of autonomic nervous system and quantitatively evaluate the balance of sympathetic and vagal nerve tension.
- Serum cortisol is used to assess autonomic tone at baseline and day 14. Cortisol changes in the body in a circadian rhythm and we will test serum cortisol at 8 am. Serum cortisol is elevated during stress, which can reflect excessive arousal. The serum samples are only marked with the subject number, and will be disposed in a standardized manner after testing.
- Daytime function or daytime fatigue will be measured by the scale of Fatigue Scale (FS) at baseline, day 14 and day 28. FS consists of 14 items, each of which is a fatigue-related question, reflecting both physical fatigue and mental fatigue.
- Hyper-sleep reactivity is measured by The Ford Insomnia Stress Response Test (FIRST) at baseline, day 14 and day 28. FIRST is a self-reporting tool including nine items designed to assess sleep response, The minimum total score is 9 and the maximum is 36. Higher scores on the FIRST indicate a more highly reactive sleep system.
- Traditional Chinese Medicine(TCM) symptom score scale is used to evaluate the changes of patients' TCM symptoms at baseline, day 14 and day 28.
Safety monitoring
Patients will sign informed consent upon enrollment. Any adverse event related to acupuncture treatment, including pain, subcutaneous hematoma and fainting, will be reported by patients and doctors during each treatment. Adverse events of esazolam will also be monitored, recorded and reported. Besides, all participants will be detected blood routine, urine routine, liver and kidney function and ECG to exclude severe heart/liver/kidney diseases and evaluate the possible side effects of the treatments. In the event of serious adverse effects (AEs), we will stop the intervention and take timely rescue measures. The research group of this study will bear the corresponding medical expenses and provide the corresponding economic compensation.
Data collection and management
All researchers will be trained before the start of the study so that they can correctly grasp the content of the study protocol. Two research recorders are trained to fill the case report form (CRF) which includes general demographic information, clinical history, medication use, data from testing and evaluation, AEs, quantity of drugs recovered, etc. The data will be double entered in SPSS27.0 to ensure the accuracy.
Personal data of participants will be kept confidential. Blood/urine/stool specimens will be identified by study number rather than name. Information that can identify the participants will not be disclosed to members outside the study group without their permission. CRFs will be kept in a locked filing cabinet and will be accessible only to researchers. In order to ensure that the study is conducted in accordance with the regulations, the members of the government administration or ethics committee may, as required, access the participants’ personal data at the research facility. When the results of this study are published, no identifying information of the participants will be disclosed.
Statistical analysis
All cases randomized and treated at least once will be analyzed. Statistical analyses of the clinical data will be performed using SPSS 27.0 statistical software (IBM Corporation, Armonk, NY, USA) and supervised by a skilled statistician blinded to group allocation. The Kolmogorov– Smirnov test will be used to test the normal distribution of continuous variables. Continuous normally distributed data will be reported as means and standard deviations; continuous non-normally distributed data will be expressed as medians with interquartile ranges. Categorical data will be presented as frequencies or percentages. For the demographic and clinical information at baseline, the chi-squared test or Fisher’s exact test will be used for comparison of dichotomous data. To compare baseline and post-treatment changes in the same group, we will use the paired t test. To compare the changes before and after treatment between the two groups, we will use the statistical analysis method of non-inferiority test.
Quality control measures
To ensure the quality of the clinical trial research project and control the risks, two quality supervisors from our team will supervise the intervention process, the authenticity of the data collection, and the occurrence of AEs every 3 months. They will write monitoring reports and give feedback to the research team to discuss whether to communicate important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses). Any important change should be reported to the participants, the funder, ethical committee, journals and trail registration website if necessary.
[i] Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin J,et al. SPIRIT 2013 Explanation and Elaboration: Guidance for protocols of clinical trials. BMJ. 2013;346:e7586
[ii] Yang L, Li YX, Yu XG, Li W, Zhang CC. Clinical effect of burying Wuzang Shu with press-needle and Ji-shu on insomnia. Journal of Practical Medicine.2021,37(13):1765-1768.
[iii] Li HQ, Zhou HY, Guo J, Wei J, Cao KG. Treatment of 30 cases of primary insomnia by Chou's Tiaoshen acupuncture. Global Traditional Chinese Medicine. 2017,10(07):882-885.
[iv] Sleep Disorders Group, Chinese Society of Neurology, Chinese Society of Neurology. China's diagnosis and treatment of adult insomnia guide (2017 edition). Chinese neurologist magazine, 2018 ploidy (5) : 324-335.