Trial strategy
A single-center randomized controlled trial has been designed to compare the effects of manual versus sham acupuncture in the management of insomnia comorbid with stable angina pectoris in perimenopausal women. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) [26] checklist is delineated in the Additional file 1. The study flow diagram is shown in Fig. 1, and the schedule for enrollment, interventions, assessments, and data collection is outlined in Table 1.
Table 1
Timetable for data collection and follow-up assessment
| Screening | Treatment period | | Follow-up period |
Timepoint | Baseline day-7-0 | 4-Week | 8-Week | 12-Week | | 16-Week | 24-Week |
Enrollment | | | | | | | |
Screening for Eligibility | √ | | | | | | |
Informed consent | √ | | | | | | |
Allocation | √ | | | | | | |
Demographics | √ | | | | | | |
Vital signs | √ | √ | √ | √ | | √ | √ |
Intervention | | | | | | | |
Manual acupuncture | | √ | √ | √ | | | |
Sham acupuncture | | √ | √ | √ | | | |
Assessment | | | | | | | |
PSQI | √ | √ | √ | √ | | √ | √ |
CRP | √ | | | √ | | | |
Lp-PLA2 | √ | | | √ | | | |
C-FABP | √ | | | √ | | | |
SAQ | √ | √ | √ | √ | | √ | √ |
SF-36 | √ | √ | √ | √ | | √ | √ |
Dosage of sleeping pills | √ | √ | √ | √ | | √ | √ |
HAMD | √ | √ | √ | √ | | √ | √ |
GAD-7 | √ | √ | √ | √ | | √ | √ |
Electrocardiography | √ | √ | √ | √ | | | √ |
Assessments of safety | | | | | | | |
Laboratory examinationa | √ | | | √ | | | |
Adverse events | | √ | √ | √ | | √ | √ |
Legends: PSQI,Pittsburgh Sleep Quality Index; HAMD, Hamilton Depression Scale; GAD-7, Generalized Anxiety Disorder Scale; CRP,C-reactive protein; Lp-PLA2,lipoprotein-associated phospholipase A2; C-FABP, cardiac fatty acid-binding protein levels; SAQ, Seattle Angina Questionnaire; SF-36, Health-Related Quality of Life Questionnaire. |
Laboratory examinationa:Blood, urine and stool routine;ALT alanine aminotransferase,AST aspartate aminotransferase,BUN blood urea nitrogen, Cr creatinine |
Patients
This trial is slated to commence in September 2023, concluding in June 2024, with a target enrollment of 110 patients exhibiting insomnia comorbid with perimenopausal stable angina. Recruitment advertisements shall be situated in clinical environments, public venues, and online platforms to ensure adequate sample accretion. Eligible subjects shall be apprised of the prospective benefits and potential risks of participation, with written Participant Information and Consent Form (Additional file 2) obtained to guarantee voluntary enrollment. Participants shall be considered successfully recruited upon provision of signed informed consent. All patients will receive conventional medications (e.g. aspirin, rosuvastatin, trimetazidine), plus lifestyle measures including dietary modification, appropriate exercise, and risk factor management.
Diagnostic Criteria
1. The diagnosis of stable angina pectoris followed the 2019 ESC Guidelines for the diagnosis and treatment of chronic coronary syndromes [27]. Coronary artery disease was established via coronary angiography, CT angiography or positive treadmill exercise testing. Patients exhibited Canadian Cardiovascular Society grade II-III angina, with a history of ≥ 30 days of stable angina, 2–5 anginal attacks per week.
2. Insomnia was defined as Pittsburgh Sleep Quality Index > 5 per the International Classification of Sleep Disorders [28]. Questionnaires assessing insomnia duration and frequency were administered at admission by two blinded independent assessors, with consensus analysis to ensure consistent results. All enrolled patients exhibited self-reported insomnia of at least 30 days duration occurring ≥ 3 times per week.
Inclusion Criteria
1. Meet diagnostic criteria for both stable angina pectoris and insomnia as delineated above;
2. Female gender, 45–55 years of age, in the perimenopausal period;
3. No acupuncture treatment for minimum 6 months prior to enrollment;
4. Provide informed consent and agree to randomized group allocation.
Exclusion Criteria
1. Not in perimenopausal phase;
2. Severe renal, hepatic, hematologic or other systemic diseases;
3. Psychiatric disorders or impaired consciousness;
4. Uncontrolled severe hypertension, diabetes mellitus or malignant arrhythmia;
5. valvular disease, Recent acute myocardial infarction, unstable angina, myocarditis, hypertrophic cardiomyopathy, or post-pacemaker severe heart failure (NYHA grade ≥ III);
6. Major surgery, trauma, bleeding event or severe infection within past 3 months;
7. Insomnia attributable to medications, alcohol or environmental factors;
8. Local skin infections near acupoint sites;
9. Malignancy or hyperthyroidism;
10. History of syncope or severe needle phobia;
11. Any other condition potentially interfering with study participation or completion as deemed by the investigator.
Criteria for Withdrawal and Termination
Per ethical imperatives safeguarding patient autonomy, subjects retain the prerogative to withdraw from the study at any juncture for any reason. For subjects electing withdrawal, the rationale must be meticulously documented and incorporated as an evaluative metric for trial cessation. Clinical investigators should fastidiously document the basis for trial termination and its pertinence to the study, with analysis of the potential impact of the endpoint event on study conclusions.
All primary data on study withdrawals and terminations will remain sealed for examination upon trial completion. Moreover, grounds for termination include: any adverse events arising during the study; comorbidities, complications, or physiological alterations precluding ongoing participation; poor treatment compliance; contraindicated interventions; missed visits; and unblinding events.
Randomization Procedure and Allocation Concealment
In this trial, the research coordinator will generate randomization numbers independently utilizing SPSS 24.0 software without contacting study participants. To ensure allocation concealment, sequentially numbered opaque sealed envelopes will be employed, with an assigned designee independently administering the randomization sequence. Subsequent to informed consent, subjects will be randomly allocated in a 1:1 ratio to the treatment arm (acupuncture group) or the control arm (sham acupuncture group).
Blinding
The allocation of groups will remain concealed from patients, evaluators, and data analysts. The acupuncture points and techniques will be comparable between the two groups. The control group will undergo sham acupuncture with a non-penetrating device mimicking the look of real needles to preserve blinding. To evaluate the success of blinding, we will survey participants on their belief about receiving either genuine or sham acupuncture after the intervention. Due to the distinct nature of performing acupuncture, blinding the practitioners is not feasible.
Interventions
Participants will undergo 36 acupuncture sessions over 12 weeks, at a frequency of 3 treatments per week. Acupuncture shall be administered solely by licensed acupuncturists. They are required to receive training in standardized techniques including needle manipulation and point location.
Treatment group
Sterile acupuncture needles of 0.30 mm diameter and 40 mm length were utilized (Hualun Medical Appliance Co, Ltd, Suzhou). The acupuncture points were identified and localized conforming to the World Health Organization's standards. The prescribed acupoints were HT7 (Shenmen), EX-HN3 (Yintang), KI6 (Zhaohai), RN17 (Danzhong), HT3 (Shaohai), and SP6 (Sanyinjiao). HT7, EX-HN3, and RN17 were inserted to a depth of 5mm, while KI6, HT3, and SP6 were inserted perpendicularly until reaching 20mm depth. The acupuncture procedure consisted of: disinfecting the skin and instruments; needle insertion at the acupoints, rotating bidirectionally between 90°-180° at 60–90 rotations/min until Deqi sensations of numbness, fullness, soreness, and aching were elicited, quantified using the Chinese Modified Massachusetts General Hospital Acupuncture Sensory Scale (C-MASS). Each 30-minute acupuncture session incorporated manual stimulation for 1 minute every 10 minutes.
Control group
The sham acupuncture group received non-insertive needling using blunt-tipped needles of 0.30 mm diameter and 40 mm length (Hualun Medical Appliance Co, Ltd, Suzhou). The treatment protocol replicated that of the manual acupuncture group in terms of timing and acupoint selection, however the blunt needles were only tapped lightly on the skin surface without tissue penetration or manipulation to elicit Deqi. Sham needle stimulation was simulated for 1 minute every 10 minutes over the 30-minute session.
Primary outcomes
The Pittsburgh Sleep Quality Index (PSQI), comprising 19 self-rated and 5 hetero-rated items, will be employed to evaluate the primary outcome of global sleep quality over the past month across 7 components: sleep duration, sleep latency, sleep efficiency, sleep medication use, sleep disturbances, subjective sleep quality, and daytime dysfunction. PSQI will be assessed at baseline, after each 4-week treatment phase (weeks 4, 8, 12), and during follow-up at weeks 16 and 24.
Secondary Outcomes
1. Assessment of stable angina pectoris (SAP): SAP was evaluated at baseline, week 4, week 8, and week 12 using the Seattle Angina Questionnaire (SAQ) [29] to quantify angina symptoms before and after treatment. Blood biomarkers of SAP: Fasting venous blood samples were collected from the cubital fossa on the start and final of the treatment period in both groups. Levels of C-reactive protein, lipoprotein-associated phospholipase A2, and cardiac fatty acid-binding protein were assayed by an independent laboratory blinded to group allocation.
2. Quality of life assessment using the 36-Item Short Form Health Survey (SF-36).
3. Dosage of hypnotic medications.
4. Hamilton Depression Rating Scale (HAMD).
5. Generalized Anxiety Disorder 7-item (GAD-7) scale.
Data gathering and administration
At screening, study personnel initiated collection of data on individuals meeting eligibility criteria, encompassing demographics (age, gender, occupation, ethnicity, marital status), anthropometrics (weight, height), education level, risk factors, medical history, medication history, and vital signs. During the intervention, study data were collected and documented per protocol via electronic transcription of paper case report forms, with data entry within 1 week of each study visit using EpiData software (version 3.0). Logical validation and double data entry with verification were implemented to ensure accuracy. An independent data manager external to the study oversaw data entry, verification, security, and resolution of abnormal values beyond clinically expected ranges. Finally, the database was locked for analysis after sign-off by the study sponsor, principal investigator, biostatistician, and data administrator, with no further modifications permitted.
Patients’ safety and adverse events
Safety assessments were conducted at each study visit including: vital signs (temperature, blood pressure, respiration rate, heart rate); routine blood and urine tests; liver and renal function tests; electrocardiography. All adverse events were monitored, managed, and reported according to standard operating procedures detailing time of onset, duration, severity, interventions, and outcome. Trial suspension or withdrawal would be determined by the investigator contingent on adverse event (AE) severity. Any serious AE must be reported to the principal investigator and ethics committee within 24 hours.
Sample size
The Pittsburgh Sleep Quality Index (PSQI) score following the full acupuncture intervention regimen was utilized to determine the requisite sample size. Statistical significance was defined as α = 0.05 with a power of 90%. Based on a prior study, perimenopausal women with insomnia had mean ± SD PSQI scores of 11.43 ± 2.11 with sham acupuncture and 9.20 ± 3.24 with manual acupuncture [30]. Using the sample size formula:
$$\text{n}=2\times {\left[ \frac{\left({\text{Z}}_{{\alpha }}+{\text{Z}}_{{\beta }}\right)\times {\sigma }}{{\delta }} \right]}^{2}$$
Using the larger standard deviation of 3.24, with δ = 11.43–9.20 = 2.23, β = 0.1, 1-β = 0.9, and α = 0.05. The resultant sample size required per group was 44. Allowing for a 20% loss to follow-up, the total sample size needed for the study was 110 participants.
Statistical analysis
Group allocation will be concealed from the statistician. All randomized participants will be included in the intention-to-treat (ITT) analysis, regardless of study completion status. To ensure accuracy, double data entry will be performed. Statistical analyses will be conducted using SPSS 24.0. Continuous variables will be summarized as mean ± standard deviation or median (interquartile range). Between-group comparisons will utilize two-sample t-tests or non-parametric tests for skewed data. Within-group baseline to endpoint changes will be analyzed by paired t-tests. Categorical variables will be compared using Fisher’s exact or Chi-square tests. Statistical significance will be defined as p < 0.05.