This prospective, randomized and parallel design clinical trial of high normal BP participants will be conducted in a large public-sector clinic in Beijing, China. The trial protocol was approved and reviewed by the Ethics Committee of Beijing University of Chinese Medicine, and will be reported based on SPIRIT guidelines. The corresponding author will be responsible for trial scientific oversight. The study was registered on Chinese Clinical Trial Registry (ChiCTR 1900024982) on August 6, 2019.
The study population will be comprised of individuals with high-normal BP (2018 Chinese Guidelines for Prevention and Treatment of Hypertension ) at a community service center (Nanyuan community health service centers in Beijing, China). Study investigators will be responsible for recruiting and gaining informed consent. All participants will provide written informed consent before enrollment and randomization at the outpatient department.
- Aged between 35 and 65 years (either gender)
- SBP of 120-140 mmHg and/or DBP of 80-90 mmHg on at least 2 separate visits
- No language disorder or mental retardation, so that participants will be able to answer and complete the questionnaire completely
- Willing to sign written informed consent
- Contraindications for the use of electrostimulation: such as use of a cardiac pacemaker or other implanted medical devices; suffering from acute diseases, infectious diseases, malignant tumors, cardiovascular disease, cerebrovascular disease, liver and kidney dysfunction or other malignant diseases; dermatological abnormalities on the skin of the acupuncture points
- Secondary hypertension
- Received antihypertensive drugs or other drugs that affect BP in the previous 2 months
- Uncontrolled diabetes
- Received acupuncture treatment in the previous 1 month
- Drug or alcohol abuse
- Pregnant, lactating or planning pregnancy during the trial
- Participated in another research trial
Randomization and allocation concealment
Eligible participants will be randomized into one of two groups: the intervention group, or the control group (1:1), using block random method and the block size is 6. The randomization sequence will be prepared by a professional statistician (Na Zhang) with the SAS9.3 software, who is not involved in assessment, treatment or analysis of the study, to ensure balance in baseline BP across the groups. When an eligible participant needed to receive a random group, the random number and the group assignment will be sent from the random number administrator to the recruiter via phone or short message.
The participants and study staff interacting with participants will not be blinded to group assignment in the trial. The outcome assessors and trial statisticians, who will not be involved in the intervention, will be blinded.
Transcutaneous electrical stimulation will be applied to the acupuncture points in the intervention group, and the control group will not have TEAS. Based on the nature of chronic disease and barrier of time necessary for frequent transportation to hospital, the majority of treatment during 12 weeks will be operated by participants themselves at home. And participants may distinguish whether the instrument is on or not. It is difficult to blind the participants. Hence, we do not set sham therapy as the control group. Both groups will be educated about lifestyle modification because the guidelines clearly recommend that lifestyle changes should be basic treatments at high-normal blood pressure.
A household transcutaneous nerve stimulator (SDP-330; Yuwell, Suzhou Medical Appliances Co, Ltd., Suzhou, China) with two 100-Hz output channels at a pulse width of 0-100 μs will be used for the application of TEAS. It has 10 different stimulus intensities, and the intensity of the stimulation will be individually adjusted by the participants with the recommendation to increase the intensity gradually to trigger the maximum sensory threshold without discomfort or pain. The self-adhesive electrodes measuring 5 × 5 cm will be placed on the acupuncture points region. The stimulator has 8 different modes, but the participants will be asked to select one of the “press” or “knock” or “knead” mode, which cannot be changed during treatment. The participants will be asked to keep a treatment diary and register the time of stimulation.
The following four bilaterally acupoints with relevance for BP lowering according to traditional Chinese medicine concepts determined by a literature review  will be used in the intervention group: Hegu (LI4), Quchi (LI11), Zusanli (ST36), and Taichong (LR3) (Table 1 and Figure 1). The main pathogenesis of hypertension is liver failing to discharge and store blood, viscera dysfunction, endogenous wind and heat, qi and blood adversity according to the traditional Chinese medicine. The above acupuncture points are considered to regulate qi, blood and viscera and internal organs and restore blood pressure to normal. Some of the acupoints were supported by previous studies which used the TEAS treating Hegu and Quchi on the forearm and showed significant reduction in blood pressure [23, 24]. Furthermore, these 4 points were on the limbs so it is very easy for participants to access and apply treatments.
The first treatment will be at LI4 and LI11 on the same arm for 15 minutes, followed by the same acupoints on the opposite arm for 15 minutes. The second treatment will be at ST36 and LR3 on the same leg for 15 minutes, and then the same acupoints on the opposite leg will be took for 15 minutes. Each treatment will last a total of 30 minutes, and different acupoints will be used. Participants will be asked to alternate treatment on alternate days to guarantee they will receive 4 times TEAS per week and 48 times in total, and cannot increase or decrease the number of times.
Each participant in the intervention group will receive a stimulator with written instructions as well as the participants’ manual on how to do the TEAS treatment properly. Treatment will be performed at the participants' home, and TEAS will be performed by the participants. At the beginning of the trial, the study investigators will instruct the participants to locate the acupoints. Participants will be asked to take photos to provide feedback to investigators during the initial treatment, to ensure that participants can accurately find all 4 acupoints. In addition, acupoint pictures and videos will be produced to assist participants. Study investigators will ensure the participants fully understand the operation of TEAS and the location of acupoints. Figure 2 shows the study design.
Participants in both groups will receive recommendation for lifestyle modification. All participants will receive relevant weekly information through the WeChat app (Tencent, Shenzhen, China) in mobile phone and monthly educational activities in the community. They contain information about weight control, increase physical activity, healthy eating, dietary sodium reduction, smoke abatement and set limit to alcohol.Outcomes
The primary outcome will be the change in mean SBP from baseline to 12 weeks.
BP will be measured as proposed by the 2018 Chinese Guidelines for Prevention and Treatment of Hypertension . Participants will be asked to avoid exercise, alcohol, cigarettes and coffee/tea for at least 30 minutes before the BP measurement. BP will be measured with the participant in a seated position after 5 minutes of quiet rest. Participants will be required to take blood pressure measurement in the morning. A digital BP monitor (HEM-7136, OMRON Corporation, Kyoto, Japan) with suitable cuff size will be used. Clinicians will record three sequential BP readings at 5-minute intervals, and the final BP will be calculated by removing the initial reading and calculating the mean from the two remaining readings.
Changes in mean blood pressure at other time points
Other secondary outcomes include measures of changes in mean SDP and DBP from baseline to 4, 8, 12, 24 and 36 weeks.
Proportion of progression to hypertension
The proportion of subjects with hypertension (BP>140/90 mmHg) will be calculated among the high-normal BP participants at 12, 24 and 36 weeks.
Quality of life (QoL)
The 12-item Short Form Health Survey (SF-12)  will be used for quality of life at baseline, 12, 24 and 36 weeks. The questionnaire consists of a mental domain and a physical domain (each domain ranges from 0 to 100), and a higher score will be considered to indicate a better quality of life.
Body mass index (BMI) and waist circumference
Net change in BMI and waist circumference will be measured at baseline, 12, 24 and 36 weeks. The BMI, defined as the weight (kg) divided by the participant’s height squared (m2) , will be calculated as an index for obesity. And the waist circumference will be measured (at the smallest circumference between the iliac crest and the lower costal margin) in centimeters (cm).
Adverse events (AEs)
Any AEs will be monitored and documented throughout the trial by the investigators and participants. Based on their potential association with the TEAS procedure, AEs will be categorized by specialists as treatment-related or non-treatment-related within 24 hours of occurrence. Potential AEs of TEAS used in the trial include continuous post-electrostimulation sensation, and skin numbness. The schedule of enrolment, intervention and assessments is shown in Figure. 3. If acute or uncontrolled hypertension or other serious adverse reactions occur, the participants will be asked to discontinue from this trial and seek medical attention immediately.
Quality Assurance and Quality Control
To guarantee the quality of the study, the trial protocol was reviewed and revised by experts in hypertension, acupuncture, methodology and statistics. A pre-specified standard operating procedure of BP measurement, including selection of appropriate cuffs, reading and calculation of mean BP, maintain and calibrate of electronic sphygmomanometer will be developed to reduce measurement error. Other standardized procedures for the operational aspects of the study include details in filling out questionnaires, recruitment, lifestyle intervention coaching, assessment of AEs and data management will also be used to train the study personnel. The Clinical Research Associate (CRA) will review the data regularly, for authenticity and timeliness of data collection, and data quality. All data will be collected onto paper questionnaires and then transferred to an Excel spreadsheet, and will be preserved for at least five years after publication of the trial results. Hence, all data collected during the course of the research will be kept strictly confidential and only accessed by the study staff. The private information of patients includes name, telephone number, will be critically protected and will never be allowed to disclose. If reviewers or readers have any questions regarding our published data, or any researchers will meta-analyses, they can contact the corresponding author for access to the anonymised data. Detailed instructions, acupoint pictures, videos and treatment procedures of the TEAS will be produced and distributed to each participant in the intervention group. Study investigators will ensure participants' compliance with the intervention protocol. Participants will be registered with a phone number and address for further contact in case of missing outlined visits.
This pilot study aims to assess the effectiveness and safety of TEAS combined with lifestyle modification for high-normal BP, and determine the feasibility of a further large clinical trial. The minimum sample size for exploratory trials is 20 to 30 per group according to Provisions for Drug Registration in China. It is generally accepted that at least 30 participants are required for a pilot study . We selected the maximum of 30 participants, and the sample size of 60 participants was determined. The results of this study will facilitate the calculation of an appropriate sample size for further randomized clinical trials.
Analysis will be carried out on an intention-to-treat (ITT) basis and will be performed using SPSS 23.0 statistical software (IBM SPSS Statistics, New York, USA) with a 2-sided P value of less than 0.05 considered significant. The measurement of data that conforms to the normal distribution will be expressed as mean ± SD, and the measurement data that does not conform to a normal distribution will be expressed by the median (interquartile range), and counting data will be represented by cases (percentages). The continuous variables will be evaluated by using a t test or the Mann-Whitney U test for comparison. The Chi-square test or Fisher’s exact test will be employed to compare binary variables. Missing data will be imputed using the last observation carried forward.