The purpose of this study is to evaluate the efficacy and safety of acupuncture combined herbs treating post-stroke cognitive impairment by comparing changes in cognitive assessment, activity of daily living，depressive state and the changes of brain regions after treatment. This study is expected to develop a standard, systematic and safe TCM integrative treatment plan for cognitive impairment after stroke, and improve the quality of life of patients.
126 patients treated in the Third Affiliated Hospital of Zhejiang Chinese Medical University, Jiaxing Hospital of Traditional Chinese Medicine, Hangzhou Hospital of Traditional Chinese Medicine will be recruited from April 2019 to December 2023. The study plan has got approved by the ethics committee of the three hospitals. The clinical trial will be conducted in accordance with the 2010 Consolidated Standards of Reporting Trials (CONSORT) guidelines[18, 19] and the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) . The 126 patients will be distributed to the control group and the TCM group in a 1:1 ratio. The control group will receive basic treatment and cognitive function regular training for 12 weeks, while the TCM group will receive basic treatment, cognitive function regular training, acupuncture and herbs for 12 weeks. The results will be measured by Montreal Cognitive Assessment (MOCA), mini-Mental State Examination, Activity of Daily Living (ADL) score, Hamilton Depression Scale (HAMD), Functional near-infrared spectroscopy (fNIRS) and RESTing-state functional MRI (RS-fmri). Fig 1 shows the trial design.
Patients admitted to the Acupuncture and Moxibustion Department, Neurology Department and Rehabilitation Department of the Third Affiliated Hospital of Zhejiang Chinese Medical University, Rehabilitation Department of Jiaxing Hospital of Traditional Chinese Medicine, and Rehabilitation Department of Hangzhou Hospital of Traditional Chinese Medicine. The public obtain the message of this study by each hospital’s WeChat Official Account, local newspapers, hospital’s roll up banners and brochure. Interested patients can contact the investigator through phone, message, email, or WeChat.
The patients should meet all the following criteria, which will be screened by a neurologist:
(1) Diagnosis of stroke in traditional Chinese medicine and PSCI ;
(2) Age above 18;
(3) The course of disease ranges from 30 to 180 days;
(4) The patient's legal guardian signs the informed consent;
(5) Montreal Cognitive Assessment (MoCA) score is 17-26, and if the duration of patient’s education is less than or equal to 12 years, one score will be deducted;
(6) Hamilton Depression Scale (HAMD) score <20;
(7) Patient meets the requirements for indications of acupuncture and moxibustion techniques, and volunteers to accept acupuncture treatment without serious complications.
The patients who meet the following criteria should be excluded and it will be screened by a neurologist:
(1) Cognitive impairment caused by subarachnoid hemorrhage, transient ischemic attack, or other intracranial lesions such as intracranial tumors, aneurysms, vascular malformations, cysticercosis, schistosomiasis, encephalitis, meningitis, hydrocephalus, sequelae of brain trauma;
(2) non-atherosclerotic thrombotic cerebral infarction (such as cardiac embolism, coagulation state, endovascular shedding, arteritis);
(3) Pregnant or lactating women;
(4) Patients with severe primary chronic diseases including heart, liver, kidney and other viscera, as well as the endocrine system and hematopoietic system), severe dementia, serious language understanding disorders, mental illness;
(5) Patient with a variety of bleeding tendency diseases;
(6) Patients who do not meet the inclusion criteria and are not suitable for clinical observation.
Both of the two groups will receive basic treatment and cognitive function regular training, which is conducted by experienced doctors and rehabilitation therapists following the Standard Operation Procedure document (SOP) and Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders. During the whole study process, training sessions for investigators will be held regularly so that the equal quality of all the interventions will be guaranteed.
The control group will receive basic treatment and cognitive function regular training, including cognitive function training, daily life activity training, psychological support therapy and so on. Treatment will be performed 30min each time, and 5 times a week for 12 weeks.
Integrative Medicine group
The integrative medicine group will receive basic treatment and cognitive function regular training, which are the same as the control group. Besides, acupuncture and herbs are administered 5 times a week for 4 weeks.
Acupoints: Shenting (GV24) (bilateral), Benshen (GB13), Baihui (GV20), Sishencong (EX-HN1), Fengchi (GB20) (bilateral), Fenglong (ST40) (bilateral), Zusanli (ST36) (bilateral), Xuanzhong (GB39) (bilateral), Top midline, Forehead midline, No.1 line near the top (bilateral).
Needles: 0.25mm×40mm stainless steel needle of Huatuo Brand (produced by Suzhou Medical Supplies Factory Co., LTD.).
Manipulation: The patient will lie in prone position, and the acupoints skin will be disinfected with 75% ethanol. Different manipulations are used for different acupoints (table 1). Acupuncture will be applied five times weekly for 12 weeks, and every treatment lasts 30min.
The herbal treatment will be based on the syndrome differentiation. All the syndromes and treatments will be divided into the following five types. The herbs will be given five times weekly for 12 weeks, and twice for one day.
(1) Liver and kidney yin deficiency syndrome
Treatment: To tonify liver and kidney, fill essence and restore energy.
The formulas: Liu-Wei-Di-Huang-Wan (Six-Ingredient Rehmannia Pill) or Chinese patent medicine with similar efficacy.
(2) Spleen and kidney deficiency syndrome
Treatment: To tonify kidney and spleen, replenish qi to invigorate essence.
The formulas: Gui-Pi-Tang (Spleen-Restoring Decoction) and Huan-Shao-Dan, or Chinese patent medicine with similar efficacy.
(3) Phlegm and turbidity obstruct brain
Treatment: To clear phlegm for resuscitation, invigorate the spleen and transform turbidity.
The formulas: Di-Tan-Tang (Phlegm-Flushing Decoction) or Chinese patent medicine with similar efficacy.
(4) Stagnation of blood stasis syndrome
Treatment: To promote blood circulation to remove blood stasis, awake and enlighten brain
The formulas: Tong-Qiao-Huo-Xue-Tang （Orifice-Opening and Blood-Invigorating Decoction）or Chinese patent medicine with similar efficacy.
(5) Hyperactivity of liver-yang syndrome
Treatment: To calm liver wind, active blood and clear heat, tonify the liver and kidney.
The formulas: Tian-Ma-Gou-Teng-Yin (Gastrodia and Uncaria Decoction) or Chinese patent medicine with similar efficacy.
Table 2 Outcome measurements at each timepoint
Primary outcome measures
Improvement of Cognitive function: we will use Montreal Cognitive Assessment (MOCA) score from baseline to 12 weeks. This assessment has high sensitivity and specificity of assessing cognitive impairment, and it is evaluated from visual spatial function, language function, image ability, orientation and so on.
Secondary outcome indicators
1. Montreal cognitive assessment scale score change trend
The MoCA scores of baseline, 0 week, 8 weeks, 12 weeks, 16 weeks and 24 weeks will be analyzed to evaluate the Montreal cognitive assessment scale score change trend.
2. Changes in memory, attention and computational ability, language function
We will divide MoCA scores of baseline and 12 weeks into memory, attention and computational ability, and language function. Different analyses will be used to evaluate different abilities.
3. The rate of change in the scores of mini-Mental State Examination (MMSE)
MMSE scores will be analyzed at baseline, 0 week, 8 weeks, 12 weeks, 16 weeks and 24 weeks.
4. Changes in Daily Living ability
The Activity of Daily Living (ADL) score will be analyzed at 0 week, 12 weeks, 16 weeks and 24 weeks.
5. Changes in depressive status
Hamilton Depression Scale (HAMD) scores will be analyzed 0 week, 12 weeks, 16 weeks and 24 weeks.
6. Changes in the patterns of related brain regions in cognitive impairment
The changes of amplitude of low-frequency fluctuations (ALFFs), regional homogeneity (ReHo) and functional connecting (FC) of RESTing-state functional MRI (RS-fmri) will be analyzed at baseline and 12 weeks.
7. Neural activity in the brain
The changes of the concentration of oxy-hemoglobin (HbO2), deoxy-hemoglobin (Hbb), cerebral blood flow (CBF) and cerebral blood volume of Functional near-infrared spectroscopy (fNIRS) will be analyzed at baseline and 12 weeks.
8. Effective rate of cognitive function treatment
MoCA score will be calculated from baseline to 12 weeks of treatment and effective rate of treatment will follow the specific criteria. Recovered: the score increased by ≥90% compared with the baseline. Significantly effective: the score increased between 70% and 89% compared with the baseline. Effective: the score increased between 30% and 69% compared with the baseline. Ineffective: the score increased < 30% compared with the baseline.
The calculation of sample size will be based on the change of MoCA scores. Research and clinical experience suggest that in an acupuncture group and a non-acupuncture group, a clinically significant therapeutic effect is defined as a MoCA score difference of 2.6 between [12, 24, 25]. A two-sided, two-sample t test at the 0.05 significance level will be used. With an estimated 20% dropout rate at final follow-up, 63 cases are required for each group, which means 126 patients in total will be enrolled.
Randomization and blinding
Eligible patients will be randomly assigned (1:1) to either the TCM group or the control group. Randomisation will be stratified by centers. The permuted block (4 or 6 patients per block) randomisation sequence, including stratification, will be prepared by a statistician not involved in the trial using R (version 4.0.0).
Because it is an open trial, no blind will be required. The acupuncture and herbal treatments will be performed by licensed acupuncturists with a master degree. The efficacy of acupuncture will be evaluated by a RA. Patients who are enrolled will be aware of their group assignment.
No matter the primary or secondary outcomes will be analyzed by using modified intention-to-treat exposed population. In this study, the primary and secondary outcomes will be analyzed by using the modified intention-to-treat analysis. The primary outcome measures will be analyzed using a hybrid effects model (MMRM) designed by repeated measurements. The secondary outcome measures (MMSE, ADL, HAMD) will be analyzed by means of covariance analysis. The study will carry out statistical description of the adverse events, and compare the differences between groups using Chi-square test or Fisher's exact as an appropriate method.
The results of rs-fMRI and fNIRS will be imputed using multiple imputation methods, and the specialized analysis will be supported by Jia XZ group from Hangzhou Normal University.
Collection and management of data
The designed case report form (CRF) will collect each participant’s data and transfer them into our database. We set up a data collection database to make sure the integrity of the trail, which is established on O-trial + Clinical Trial Execution management platform V4.0 (o-Trial). The core management system of platform is applied for the registered clinical projects. With mobile internet technology, the experimental trial is able to finish completely, and achieve the steady progress of the trail.
Presently, adverse events (AEs) of acupuncture are few and mild, such as pain, numbness, skin bruising. And herbs may cause allergy, liver and renal dysfunctions. We will record any serious AEs associated with the trial, and immediately report to the main researchers and take corresponding measures. If the AEs are too severe, the patients will be withdrawn from the study.
All the intervention and measures will be conducted by experienced physicians and therapists with the professional license. All the physicians and therapists will receive two-day professional training to familiarize with treatment options and training sessions will be held regularly.
To standardize clinical practices and provide clinical quality assurance, a Standard Operation Procedure document (SOP) will be developed to ensure consistency among different investigators. The SOP will include how to screen the participants, how to carry out randomization and blinding, and standardized manipulation procedures. Therefore, the management will be standardized and achievable.