Trial design
This is a multi-center, prospective randomized controlled trial supported by Shanghai Science and Technology Commission.The trial will be carried out jointly by the Seventh People’s Hospital affiliated to Shanghai University of Traditional Chinese Medicine and two other hospitals in Shanghai.Patients meeting the pre-defined criteria will be randomly divided into three groups: acupuncture group undergoing fascial point acupuncture on the basis of routine rehabilitation treatment, sham acupuncture group undergoing sham acupuncture near the fascial point on the basis of routine rehabilitation treatment, and control group undergoing routine rehabilitation treatment. The patients will be followed up for half a year to observe the hand spasm and limb function after treatment. The study flow chart is shown in Figure. 1. When 120 eligible cases are registered, we will conduct a mid-term analysis and then assess whether trial should be continued or terminated based on the results of the mid-term analysis. An example template for the content of admission plans, interventions and evaluation recommendations is shown in Figure 2.
Ethics
The ethical committee of the Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine approved the ethical approval of this study on June 21, 2018 (reference number 2018-IRBQYYS–012). The research scheme, patient information table and informed consent form were approved by the ethics committee. All participants will receive informed consent. The real names of the participants will not appear in the relevant reports of the trial to protect their privacy.
Study setting
The research objects will be recruited from the Seventh People’s Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai Second Rehabilitation Hospital and Shanghai Hudong Hospital. Interventions for all patients will be conducted in hospitals where participants are recruited. The Seventh People’s Hospital affiliated to Shanghai University of Traditional Chinese Medicine will be responsible for trail coordination and data management.
Sample size
Our study will be designed as a randomized controlled trial, and the main outcome is whether hand spasm after stroke is relieved after treatment. Current experience shows that the previou effective rate of conventional acupuncture treatment is about 50%, and the expected effective rate is 85%. The significance test level was 0.05, and the test power was 0.9. Sample size was calculated by using N = (Uα+Uβ)²*2P(1-P)/(P1-P0)². Among them, N was the required sample size for each treatment group, and the sample size of each group was equal. When α was 0.05 and β was 0.1, the normal distribution quantile table shows that: Uα(0.05) = 1.65, Uβ(0.1) = 1.28; P0 and P1 represent the original curative effect and the expected curative effect, 50% and 85% respectively. By substituting the above parameters and values into the formulas, 63 cases were needed for each group.Accounting for a 10% expulsion rate, the final estimated sample size was about 70 cases per group (210 in total).
Inclusion criteria
(1) Cerebral hemorrhage or cerebral infarction confirmed by CT or MRI;
(2) First onset, unilateral hemiplegia;
(3) The onset time is more than 2 weeks, and the vital signs are stable;
(4) Age 30–80 years old;
(5) The clinical manifestations are spastic paralysis of upper limbs, Brunnstrom stage II-IV of upper limbs and hands with hemiplegia;
(6) The improved Ashworth score of hemiplegic side hand is 1+ - 3 grade;
(7) Stable condition, clear consciousness, no aphasia, no intellectual impairment, can understand the content of the scale and cooperate with the examination and treatment;
(8) No sedative or muscle relaxant is taken in 2 weeks;
(9) Patients have signed informed consent forms.
Exclusion criteria
(1) The condition in critical or acute stage is not stable;
(2)Those with deafness, aphasia or severe cognitive impairment who are difficult to communicate normally;
(3) Patients with psychiatric diseases, malignant tumors, severe bleeding tendency and infections of treatment sites;
(4) Systolic blood pressure is more than 180 mmHg or diastolic blood pressure is more than 110 mmHg;
(5) Participating in other clinical trials or studies within 3 months and receiving other related treatments in the middle of the study may affect the judgement of the efficacy of this study;
(6) Dysfunction of muscle tone caused by other causes and previous motor dysfunction;
(7) Pregnant and lactating women;
(8) Fear of needling, fainting needles, etc.
Elimination criteria
(1) Patients who have been mistakenly admitted or misdiagnosed;
(2) No intervention is given to the patients after admission.
Recruitment
Recruitment of patients began on 1 June 2019 and will be completed in June 2021, or after the required number is obtained, whichever is earlier. Patients who meet the criteria will be invited to participate in the trial, and researchers will explain to them the relevant issues in the course of the trial.
Randomization
After signing the informed consent, participants will be randomly divided into three groups: acupuncture group, sham acupuncture group and control group. Randomization is accomplished by qualified researchers using randomization software to generate random number sequences. In the process of randomization, allocation should be kept hidden. All patients will be randomly divided into groups according to the ratio of 1:1:1. The strips revealing treatment allocation are placed in sealed opaque envelopes with sequential numbers. After obtaining informed consent, the envelopes will be opened in turn. Patients and data analysts are not clear about the randomized grouping.
Intervention
The interventions in the three groups are as follows:
Acupuncture group
On the basis of routine rehabilitation treatment, fascial point acupuncture will be given 5 times a week for 4 weeks, with 30 minutes each time.
Location of fascial points: the patient is in a sitting or supine position and the doctor is placed on the affected side. Firstly, 75% alcohol cotton ball is used to routinely disinfect the area of the the first web and the finger of the operator. Then, one-way pressure is applied between the first and second metacarpal bones on the dorsal palm of the patient from the far side to the proximal side with the thumb pulp. At this time, a cord-shaped nodule can be touched. Or the patient feels the most obvious soreness point, which is the fascial point. As shown in Figure 3.
Acupuncture method: routine disinfection is carried out on the hand of the operator and the fascial spot area of the patient. According to individual differences of patients, different specifications and models of needles are selected. Doctors quickly penetrate the needle tip vertically through the epidermis into the subcutaneous about 0.5–1.0 inches by using single-handed or two-handed needle insertion method, and then through lifting, inserting and twisting to enhance the sense of needle. When the doctor feels a slight sense of needle stagnation, such as fish swallowing hook. At the same time, the patient’s fascial point area will be sore, numb and painful, accompanied by finger conduction pain and tremor and convulsion. Press the needle hole with dry cotton ball after needle discharge to prevent bleeding. In the process of needling operation, attention should be paid to the coordinated operation of both hands so as to achieve accurate, rapid, painless or less pain.
Sham acupuncture group
On the basis of routine rehabilitation treatment, treatment of false acupuncture beside Fascial Points will be given 5 times a week for 4 weeks, with 30 minutes each time.
Control group
Routine rehabilitation treatment will be given 5 times a week for 4 weeks. Conventional rehabilitation treatment mainly includes:
(1) Good limb position: the affected upper limb maintains the position of abduction, external rotation, elbow extension, forearm supination, wrist and finger extension;
(2) Bobath’s handshake exercises: the arm is raised over the head, and the mind is used to force the limbs on both sides 10 times a time for 6 times a day;
(3) Exercise therapy: Continuous pulling of spastic muscle and joint loosening if necessary. The induced segregation movement and other manipulations are performed after the relaxation of the spastic muscle, 45 minutes each time for once a day.
Uniformity in acupuncture performance
To ensure the uniformity of fascial point acupuncture is the key to our multicenter clinical trial.Therefore, the coordinating center will designate qualified doctors to train doctors from other participating units and monitor the operation process to ensure the qualified performance before the experiment.
Outcome measures
Therapeutic evaluation will be carried out by the same team member without knowing the patients’grouping and observation time point. The primary evaluation indicators in this study are hand spasm score and duration of spasm relief. The secondary evaluation indicators included EMG detection of affected limbs, limb function and activity of daily living evaluation. The modified Ashworth scale will be used to evaluate the degree of hand spasm on the affected side at baseline, four weeks after intervention and at 1, 2, 4 and 6 months of follow-up [21]. The modified Ashworth scale was divided into 0, 1, 1 +, 2, 3 and 4 grades, and was quantified as 0, 1, 2, 3, 4 and 5 points respectively (Table 1). Surface electromyography will be used to record the changes of surface electromyography of upper limbs on the affected side at baseline and four weeks after intervention [22]. Simplified Fugl-Meyer scale will be used to evaluate the upper limb motor function on the affected side and modified barthel index will be used to evaluate activities of daily living at baseline, four weeks after intervention and at 1, 2, 4 and 6 months of follow-up [23, 24]. All measurements will be recorded in the data center.
Harms
In our study an adverse event will be defined as any untoward medical occurrence in a subject without regard to the possibility of a causal relationship. Adverse events will be collected after the subject has provided consent and enrolled in the study. If a subject experiences an adverse event after the informed consent document is signed (entry) but the subject has not started to receive study intervention, the event will be reported as not related to acupuncture. All adverse events occurring after entry into the study and until hospital discharge will be recorded. An adverse event that meets the criteria for a serious adverse event (SAE) between study enrollment and hospital discharge will be reported to the local IRB [Institutional Review Board] as an SAE.
Data management
Data collection
All information should be truthfully, accurately and timely recorded in the case report form (CRF). Scale evaluators trained in rehabilitation will be responsible for assessing the simplified Fugl-Meyer scale, Modified Ashworth scale and Modified Barthel index, while other scales and case reports will be recorded by researchers. In the course of the experiment, special personnel will be arranged to manage the relevant data, and the personal information of participants will be kept strictly confidential. All data will be named using participant numbers, which do not directly display participant’s personal information. Data will not be shared without the explicit permission of researchers. At the end of the trial, the research participants should submit the case record form in time and submit the test summary according to the requirements. The research center will appoint a supervisor to check the integrity and accuracy of CRF. Statisticians are responsible for the analysis and summary of all the data submitted, and we finally come to a conclusion.
Case report form
In the trial, the content recorded in CRF should be consistent with the original material. CRF must meet the following criteria:
(1) Fill in data with pen or black signature pen;
(2) If the participant has received more than two weeks of intervention and evaluation, the data of the volunteer should still be recorded and counted;
(3) If an error occurs in the record and needs to be corrected, the recorder should draw a horizontal line under the original record, then sign the amendment and indicate the date of correction. Note that you should ensure that the original record is identifiable after modification.
Database management and quality control
The team will take effective measures to control the quality. Data in CRF will be entered into the database uniformly. Data entry personnel carry out manual checks at the first time of data entry, and carry out systematic checks after all data entry is completed. After final confirmation, the database is locked and saved. Any future changes to the database must be agreed in writing by the clinical research director, statistician and data administrator.
Data analysis
Interim analysis
When the number of enrolled cases reaches 120, a mid-term analysis will be conducted to determine any evidence that the trial intervention does have an advantage. The interim report includes the following:
(1) Number of participants and schedule completion time
(2) Number of cases of conformity or non-conformity
(3) Material quality is evaluated according to submission time, completeness and accuracy.
(4) Preliminary analysis of therapeutic effect, including remission of hand spasm, limb function and daily living ability.
(5) Types and incidence of adverse reactions
The trail center will regularly inform the the above information to sub-centers. If necessary, the trail will be adjusted or terminated based on the mid-term analysis results.
Statistical analysis
Statistical analysis of research data is performed by health statisticians and major researchers using SPSS or SAS. Pearson’s χ2 test or Fisher’s exact test will be used to analyze classified variables and continuous variables will be evaluated by Student’s t-test or an appropriate non-parametric method. All statistical tests will be double-sided. Statistical significance level will be set at 5%. The measured data will be described by mean±standard deviation. Before the analysis, the normality test and homogeneity test of variance are carried out. If the normal distribution is satisfied, t test is used. LSD or SNK method is used for multiple comparisons, and rank sum test is used for non-normality or non-uniformity of variance.