Combining Acupuncture and Acupressure for Dementia Elderly: an Assessor-blinded, Randomized Controlled Trial
Phase: NA
Conditions: Dementia
Sponsor: The University of Hong Kong

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Study Protocol 
 
Combining acupuncture and acupressure for dementia elderly: an assessor-
blinded, randomized controlled trial 
 
 
Affiliated institution: 
School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong 
 
 
Principal Investigator for grant 
Zhang-Jin Zhang, MD, PhD 
School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong 
Tel no.: (+852)3917-6445 
E-mail: zhangzj@hku.hk 
 
 
Last edited and approved: 21 August 2020 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is the intellectual property of the Investigators. The information provided in this document 
is strictly confidential and is available for review to the sponsor, investigators, potential investigators, 
appropriate Ethics Committees, Investigational Review Boards, and other government regulatory bodies. 
No disclosure should take place without written authorization from the protocol developing investigators, 
except to the extent necessarily needed to obtain informed consent from potential subjects. 
 
 
 
 

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Introduction  
 
Dementia in the local community and impacts 
 
Dementia is a syndrome describing a decline in memory and many other cognitive domains, and is 
associated with many neurodegenerative diseases, such as Alzheimer's disease (AD), vascular disease 
(for vascular dementia), etc.1 Mild cognitive impairment (MCI) is an intermediate state between normal 
cognitive aging and dementia, with a slight decline in memory and cognitive abilities compared to their 
counterparts. MCI is regarded as an intermediate state between normal cognitive aging and dementia, 
and the rates of conversion from MCI to dementia ranged from 6.0% to 44.8%, as reported in previous 
studies.2 
According to the World Health Organization (WHO), dementia is one of the major causes of 
disability and dependency in elderly people.3 The WHO reported that 2.1 billion people could live to 
the age of over 60 by 2050, and the number of people with dementia could rise to 139 million in 2050, 
compared to 55 million in 2019.4 In Hong Kong, about 1.2 million people currently live to the age of 
over 65, and about one-tenth of them are suffering from dementia.5 It is expected that almost one in 
three of our population will be aged 65 or above by 2041.5 Many elderly people with dementia live in 
nursing homes and elderly daycare centers. It poses a significant burden on caregivers, families, and the 
public healthcare system. 
Until now, no interventions have been proven to totally cure dementia, and current drug therapies 
can only postpone its progression.6 For AD dementia, the Food and Drug Administration has approved 
several categories of medications, such as acetylcholinesterase inhibitors and N-methyl-D-aspartate 
(NMDA) receptor antagonists.1,6 For MCI and other dementia etiologies, pharmacological treatments 
are limited. The treatment of dementia should achieve different goals, not only slowing down cognitive 
deterioration but also improving patients’ quality of life.  
Patients with dementia not only have a wide range of cognitive impairments, including progressive 
memory loss, increasing difficulty in communication and language, concentration and attention, 
reasoning and judgment, but also develop a variety of frailty-related symptoms, mainly including 
physical and psychological frailty, such as musculoskeletal deterioration, neurological disorders, sleep, 
emotional, and even psychotic symptoms.7-8 Medical comorbidities in the elderly may limit their 
tolerance of medication. Management of dementia is sophisticated and has become a huge burden in 
future public healthcare systems. 
The overall purpose of the management of dementia in the elderly is to reduce dementia- and 
frailty-caused adverse outcomes that increase disability, dependency, hospitalization, and long-term 
care admission. However, there is a dearth of effective interventions improving the quality of life of 
elderly with dementia. The development of holistic management strategies that not only prevent and 
slow down cognitive deterioration, but also reduce various other symptoms is therefore highly desired. 
 
Acupuncture and acupressure for dementia and elderly frailty-related symptoms 
 
Acupuncture has been widely used in local clinical practice. Numerous studies have shown the 
benefits of acupuncture in reducing cognitive deterioration in patients with cognitive impairment and 
dementia and in animal models. Acupuncture is also effective in improving physical disability, rigidity, 
gait, and postural balance in aging adults with stroke and Parkinson’s disease.9-10 A large body of 
evidence further confirms the effectiveness of various acupuncture regimens in treating pain, fatigue, 
sleep disturbance, anxiety, and depression. On the other hand, it is well demonstrated that, as a 
convenient therapy, acupressure has particular benefits in alleviating sleep disturbance, anxiety, 
depression, and agitation in elderly people with dementia.11-15 Acupressure also has positive effects on 
the recovery of motor function and the daily activities of stroke patients.16 These studies suggest that 
the elderly with dementia could benefit from acupuncture and acupressure. 
 

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Our related studies 
 
We have developed a novel acupuncture mode called comprehensive acupuncture therapy (CAT). 
CAT was built up from “dense cranial electroacupuncture stimulation (DCEAS)”,17 which consists of 
dense frontal acupoints with additional electrical stimulation, together with manual stimulation of 
multiple body acupoints selected based on previous clinical trials, the experience of acupuncture 
experts, and traditional Chinese Medicine (TCM) theory on the elderly’s constitutions.18 The efficacy 
of CAT has been well proven in our previous studies.17,19-21 Most recently, we have completed three 
clinical trials that evaluated the efficacy of acupuncture treatment for vascular dementia;22 stroke-
caused cognitive deterioration;19 and chemotherapy-induced cognitive impairment.20 All these trials 
have consistently revealed that acupuncture is effective in alleviating cognitive impairment. 
Furthermore, our several studies have confirmed the efficacy of acupuncture in improving major 
depression;17,23 insomnia and anxiety;24-25 poststroke depression and movement disability.19,21 
Acupressure is a form of massage therapy involving the application of pressure to acupoints or 
specific body surfaces. We have developed a caregiver-performed acupressure protocol called ‘Comfy 
Acupressure for the Elderly (CAE)’ and a demonstration video is accessible at 
https://www.youtube.com/watch?v=pAqNIZPKmnM.26 CAE protocol was initially developed based on 
traditional Chinese Medicine theory and practice, with the aim of improving the quality of life and 
preventing aging and age-related conditions in the elderly. We have also shown the effectiveness of 
caregiver-performed acupressure on the general quality of life in frail older people,26 and self-
administered acupressure for insomnia disorder.27 
These studies have led us to hypothesize that (1) CAT and CAE monotherapy could reduce 
cognitive impairment and related comorbid symptoms in aged people with dementia; and (2) CAT and 
CAE as a holistic intervention could produce additive effects than routine care in improving cognitive 
impairment, frailty-related disability and dependency, as well as comorbid symptoms in elderly people 
with dementia. 
 
Hypothesis and aims to be tested  
 
Our hypothesis is that for the elderly with cognitive impairment or dementia, acupuncture and 
acupressure are feasible, safe, and could produce better management outcomes than routine care. The 
aims of this study are: (1) to determine whether the conditions of cognitive impairment in the treatment 
groups improve significantly when compared to control; (2) to determine whether other symptoms 
(e.g., functional independence, pain, depression, and sleep disorder) in the treatment groups improve 
more than in control; and (3) to investigate whether acupuncture or acupressure is safe for the elderly 
with cognitive impairment or dementia. 
 
 
Plan of Investigation   
 
Design 
 
This is an assessor-blinded, randomized controlled trial. A total of 248 eligible subjects will be 
recruited from local nursing and care homes. They will be randomly assigned to either an acupuncture 
group (named the “comprehensive acupuncture therapy [CAT]” group), an acupressure group (named 
the “Comfy Acupressure for the Elderly [CAE]” group), a combined acupuncture and acupressure 
group (named the CAT+CAE group), or a control group (named the routine care group), with 62 
subjects per group. Subjects assigned to the CAT, CAE, and CAT+CAE groups will respectively 
receive 2 sessions of CAT, 3 sessions of CAE, and a combination of both per week for 12 weeks. The 
primary outcome is the baseline-to-endpoint change in score of the Montreal Cognitive Assessment 

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(MoCA). Secondary outcomes include various domains of MoCA, functional independence, 
psychological well-being, sleep quality, and level of pain. A generalized linear mixed-effect model will 
be used to compare outcomes over time among the four groups. This trial has been approved by the 
Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West 
Cluster (Ref No.: UW 19-821). The study protocol has been registered at ClinicalTrials.gov 
(NCT04305951) before enrolment. The trial will be conducted in compliance with the protocol, the 
ethical principles of the Declaration of Helsinki and its subsequent amendment. The study flow chart is 
shown in Figure 1. 
   
Subjects 
 
Inclusion criteria 
Subjects will be eligible for this study if they: (a) are aged 65 years or above, (b) have a clinical 
diagnosis of any type of dementia or met the criteria of major and mild neurocognitive disorder based 
on the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5);1 and (c) 
have mild to moderate dementia at a stage of 3 to 5 (Stage 3: mild cognitive decline; Stage 4: moderate 
cognitive decline/mild dementia; Stage 5: moderately severe cognitive decline/moderate dementia) on 
the Global Deterioration Scale.28 
 
Exclusion criteria 
Subjects will be excluded if they: (a) have the severity of dementia with a stage below 3 or above 5 
on the Global Deterioration Scale; (b) have severe skin lesions on acupuncture and acupressure areas; 
(c) have a significant bleeding tendency; (d) have a heart pacemaker or implantable cardioverter 
defibrillator; (e) are currently receiving acupressure as a regular therapy; (f) had surgery on the head or 
neck; or (g) are currently receiving anti-coagulant treatment. 
 
Estimation of sample size 
Our recent study showed that CAT treatment for 8 weeks produced a 2.3±2.8 (SD) score greater 
improvement than control (minimum acupuncture stimulation, MAS) on MoCA in patients with 
poststroke cognitive impairment.19 One similar trial has reported that acupuncture treatment alone for 3 
months yielded a 1.9±4.1 greater improvement than nimodipine, a commonly used anti-hypertension 
drug, on MoCA in patients with poststroke cognitive impairment.29 Based on these two trials, we 
expect that CAT could yield an average 2.1 [(2.3+1.9)/2 = 2.1] score greater improvement on MoCA 
than routine care, with an average standard deviation (SD) equal to a 1.7-fold of mean difference 
[(2.8/2.3 + 4.1/1.9)/2 = 1.7)], i.e., SD = 1.7 x 2.1 = 3.6. The following formula is then used to further 
calculate the sample size:  
 
 
 
where n is the number of 
subjects required in each arm and M is 
the mean difference that is equal to 2.1. SD is the standard deviation that is 3.6. Cp,power is equal to 7.9 
when the two-tailed level of  and power (1-) are set at 0.05 and 80%, respectively. It requires 62 
subjects per arm, with an assumed dropout rate of 25%. We propose to recruit a total of 248 subjects (n 
= 62 per arm for 4 arms). 
 
Methods 
 
Screening 
Screening will be conducted by general physicians, registered occupational therapists, social 
workers, and research assistants in nursing and care homes. 
 
n =
2 
(M/SD)2 x Cp,power 

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Randomization, central allocation and blindness 
One independent research assistant will be in charge of randomization and central allocation as the 
central coordinator. After confirmation of patients’ eligibility and completion of the baseline 
assessment, participants will be randomly assigned to CAT, CAE, CAT+CAE, or routine care groups 
in a ratio of 1:1:1:1. Random codes were produced in advance using simple, complete, non-sequential 
numbers, with a block of 4, 8 and 12, through a random allocation software at 
http://mahmoodsaghaei.tripod.com/Softwares/randalloc.html. Randomization information will be 
sealed in sequentially numbered opaque envelopes.  
Central allocation will be conducted, i.e., site investigators who are responsible for subjects’ 
eligibility will obtain the opaque envelope from the central coordinator for an eligible subject who will 
be allocated to one of the four groups. Each envelope will be opened by acupuncturists after the 
participant completes the baseline assessment. Clinical assessors and data analysts will be blind to 
patients’ treatment. 
 
Treatment procedure 
(a) Routine care: All participants in the four groups will continue their current routine care and 
medications as usual. These routine cares will serve as covariates included in outcome analysis.  
(b) CAT regimen: Subjects assigned to the CAT group will receive CAT treatment in addition to 
routine care. CAT will be conducted for 2 sessions per week for 12 consecutive weeks, a total of 24 
treatment sessions. Registered Chinese medicine practitioners (CMPs) with a master's degree or above 
and with at least 5 years of acupuncture experience will be responsible for acupuncture treatment. A 
brief introduction to acupuncture procedures will be given by a CMP during the ﬁrst visit. Details of 
selected acupoints are illustrated and summarized in Figure 2 and Table 1. 
The acupuncture treatments will be conducted at the subjects’ corresponding care homes. Each 
subject will receive a maximum of 26 needles per treatment session, adjusted by their tolerance, in a 
supine position. The following 14 body acupoints with only manual stimulation will be used: Shenmen 
(HT7, 神門), Hegu (LI4, 合谷), Waiguan (TH5, 外關), Zusanli (ST36, 足三里), Fenglong (ST40, 
豐隆) and Sanyinjiao (SP6, 三陰交) on both sides, and Zhongwan (CV12, 中脘) and Guanyuan 
(CV4, 關元) in the midline. Meanwhile, electrical stimulation will be conducted on six pairs of frontal 
acupoints with positive (+) and negative (-) electrode cord connections as follows: Baihui (GV20, 百
會) and Yintang (EX-HN3, 印堂), left Sishencong (EX-HN1, 四神聰) and Toulinqi (GB15, 頭臨泣), 
right Sishencong (EX-HN1, 四神聰) and Toulinqi (GB15, 頭臨泣), bilateral Shuaigu (GB8, 率谷), 
bilateral Taiyang (EX-HN5, 太陽), and bilateral Touwei (ST8, 頭維). 
Disposable acupuncture needles with 0.25 mm in diameter and 25 or 40 mm in length (Agent: 
MOCM International Medical Instrument Limited; manufacturer: Wuxi Jiajian Medical Instrument Co., 
Ltd.) will be inserted at a depth of 10-30 mm perpendicularly or obliquely into acupoints. Manual 
manipulation will be carried out on all acupoints to evoke a needling sensation de qi. Electrical 
stimulation is additionally delivered on the 6 pairs of frontal acupoints. The output peak current and 
voltage of the machine (model: ITO ES-360) are 6 V and 48 mA, respectively, with a constant wave at 
a frequency of 2 Hz and a phase duration of 100 µs for 30 minutes. The stimulation intensity will be 
adjusted to a level at which patients feel most comfortable. The low frequency could produce broader 
neuromodulation compared to the higher frequency. The electrical stimulation will be adjusted 
according to the patients’ tolerance. Each session of treatment will last for 30 minutes. 
(c) CAE regimen: Subjects assigned to the CAE group will receive CAE in addition to routine care. 
The detailed procedure for CAE is summarized in Table 2. CAE interventions will be conducted 3 
times per week for 12 consecutive weeks, a total of 36 treatment sessions. Trained research assistants 
or registered CMPs will be responsible for CAE treatment. CAE consists of 12 steps that take about 15 
minutes to complete and mainly concentrate on the acupoints on the face, head, neck, and shoulder. All 
chosen acupoints are easily localized and conveniently operated by informal caregivers after proper 

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training. All techniques that demand professional training or involve potential risks (e.g., joint 
mobilization) are excluded.  
(d) CAT+CAE: Subjects assigned to the CAT+CAE group will receive CAT+CAE in addition to 
routine care. The procedure is a combination of CAT+CAE as described above. 
(e) Post-trial treatment of subjects in the routine care group: Those who are initially assigned to the 
routine care group will have a choice to receive CAT, CAE, or CAT+CAE treatment for 12 weeks after 
they complete the trial. The post-trial treatment will serve as compensation for their participation. 
(f) Termination criteria and post-termination management: To ensure participants’ safety, those 
who cannot tolerate acupuncture or acupressure or are hospitalized due to the aggravation of their 
condition will be discontinued from the study and given individual clinical treatment. 
 
Control group 
The group that receives routine care only will serve as the control group. For acupuncture, sham 
acupuncture techniques such as Streitberger needle may not be suitable for elderly subjects as they are 
associated with an increased risk of skin injury. Also, sham acupuncture has been proved not to be an 
inert method.30 For acupressure, the CAE regimen involved multiple steps like pressing and kneading 
different body parts. Typical sham acupressure procedures, like using a non-acupoint or placebo 
acupressure device, are not applicable for the CAE treatment.31 
      
Assessment 
(a) Primary outcome: The primary outcome will be evaluated by the mean change of the Montreal 
Cognitive Assessment (MoCA) score between baseline and endpoint. The MoCA test assesses seven 
domains of cognitive function, including visuospatial, naming, attention, language, abstraction, recall, 
and orientation domains, for a total possible score of 30 points.32-33 It has been well established for the 
detection of MCI, with sensitivity for detecting MCI of 90% compared to 18% for the Mini-Mental 
State Examination (MMSE),32 and the evaluation of the severity of cognitive impairment. A score of 25 
points or less is indicative of cognitive impairment, but the score needs to be adjusted for age and 
education.32 We have applied MoCA in the two previous studies.19-20  
(b) Secondary outcomes: The secondary outcomes will include the Digit span test for attentional 
function, short-term memory, and working memory, the Modified Barthel Index (MBI) for functional 
independence, the Visual Analogue Scale (VAS) for pain, the 15-item Geriatric Depression Scale 
(GDS-15) for depression, and the Insomnia Severity Index (ISI) for insomnia. 
Digit Span is a measure of working and short-term memory, and is evaluated in two formats, 
Forward Digit Span and Reverse Digit Span, with a total possible score of 14 points, respectively. The 
Digit span test is a simple test to further evaluate subjects’ attentional function, short-term memory, 
and working memory.34 
MBI is a validated outcome measure to evaluate the functional status of patients. MBI consists of 
10 items, i.e., feeding, bathing, grooming, dressing, bowel control, bladder control, toileting, chair 
transfer, ambulation, and stair climbing, to score with a five-step scoring system.35-36 MBI score ranges 
from 10 to 50, with a higher score indicating a higher level of independence. VAS is a simple 
instrument to measure subjective experience in pain. A horizontal line that represents the severity of 
symptoms from 0, no pain, to 10, very severe pain, is shown, and the patient should mark the point on 
the line that reflects the subject’s perception of the current state.37 Functional independence and pain 
are measured, as previous studies have confirmed the benefits of acupressure and acupuncture in 
improving disability and pain.9,11 
The GDS-15 consists of 15 questions in which subjects are asked to respond by answering yes or 
no in reference to how they felt over the past week.38-39 Of the 15 items, 5 items (question numbers 1, 
5, 7, 11, 13) indicate depression when answered negatively, while the rest (question numbers 2, 3, 4, 6, 
8, 9, 10, 12, 14, 15) indicate the presence of depression when answered positively. The GDS-15 score 
is interpreted as follows: normal (0-4), mild depression (5-8), moderate depression (9-11), and severe 
depression (12-15). GDS can be used in mild to moderately cognitively impaired older adults.40 ISI is a 

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validated 7-item scale to assess the severity of insomnia.41 The total score ranges from 0 to 28, with 
scores of 0-7 indicating no clinically significant insomnia, 8-14 indicating subthreshold insomnia, 15-
21 indicating moderate insomnia, and 22-28 indicating severe insomnia. Depressive and sleep 
symptoms are investigated because elderly people with cognitive impairment often have comorbid 
emotional and sleep disorders. The benefits of acupuncture and acupressure for depression and 
insomnia have been confirmed in our previous studies.17,21,24 
(c) Adverse events: The severity of adverse events (AEs) will be assessed according to the 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria.42 AEs will be 
systematically recorded, in which AEs that ﬁrst appear in the study or worsen relative to the pre-study 
status will be recorded at each visit, including the date and time of onset, duration, severity, 
relationship to intervention, and action taken accordingly. All possible events will be independently 
evaluated by staff who do not assess treatment outcomes. The causality between treatment procedures 
and AEs will be assessed. 
Fatal or life-threatening unexpected AEs will be reported to the regulatory bodies as soon as 
possible but no later than 7 calendar days after first knowledge by the principal investigator (PI) that a 
case qualifies, followed by as complete a report as possible within 8 additional calendar days. This 
report would include an assessment of the importance and implications of the findings, including 
relevant previous experience with the same or similar medicinal products. For other serious, 
unexpected AEs that are not fatal or life-threatening, they will be reported as soon as possible but no 
later than 15 calendar days after first knowledge by the PI or that the case meets the minimum criteria 
for expedited reporting. For non-serious AEs and serious AEs that are expected, they will be reported 
in a brief summary at the conclusion of the trial. 
(d) Assessment schedule: Clinical assessment will be conducted at baseline, week 6, and week 12 
(Table 3). For AEs, participants in active treatment groups will be asked whether they have 
experienced any AEs on each treatment and assessment session. Participants in the control group will 
be recorded for all AEs on a regular basis (baseline, 6, and 12 weeks).  
 
Data Management 
(a) Maintenance of consistency and fidelity: The study will last about 3 years and be carried out at 
multiple sites. There will also be many different professional investigators involved in the study. To 
ensure consistency and fidelity of intervention and assessment across sites and throughout a study 
period, training workshops will be conducted pre-trial and once per year thereafter. All investigators 
and caregivers will receive training. A training manual will be prepared for CAT and CAE procedures 
and clinical assessment instruments. 
For intervention training, the PI and a senior CMP will instruct and demonstrate CAT and CAE. 
Trainees will practice CAT and CAE with each other. Investigators and caregivers who will perform 
CAT and CAE must obtain satisfactory training outcomes, which will be rated by the PI and a senior 
CMP. 
For clinical assessment training, an investigator who has extensive experience in clinical 
assessment will instruct clinical instruments. An elderly person with dementia will be invited to be 
evaluated for MoCA by investigators who will be responsible for clinical assessment. An inter-rater 
reliability coefficient (k value) of >0.80 must be achieved after the completion of each training 
workshop. 
To further ensure consistency and fidelity, the following additional measures will be taken: (1) all 
assessors will be deployed to each site via central allocation; (2) all assessments from baseline 
throughout the endpoint for each individual will be performed, if possible, by the same assessor who is 
blind to participants’ interventions; and (3) all interventions of each patient will be conducted by the 
same investigator or caregiver, if possible. 
(b) Safety assurance and ethical consideration: A Case Record Form (CRF) will be used to record 
each participant’s treatment. Emergency contact numbers (the investigator’s mobile number and a 
designated center staff member’s mobile number) will be provided in the informed consent for 

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caregivers to report and seek advice in case of any AE. Paper copies of CRFs are stored in locked 
cabinets. Data will be entered using the double-entry strategy on password-protected computers.  
The study will be carried out in accordance with the ethical principles of the Declaration of 
Helsinki and its subsequent amendment, and ICH-GCP. This trial has been approved by the 
Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West 
Cluster (Ref No.: UW 19-821). The study protocol has been previously registered at ClinicalTrials.gov 
(NCT04305951) before enrolment. A full explanation of the study goal, procedures, and potential side 
effects and risks will be presented to each patient recruited. All participants are required to provide 
written consent. For those who cannot fully understand the study due to cognitive impairment, consent 
will be obtained from their guardians. Informed consent and other documents provided to patients will 
be written in both English and Chinese. This study is conducted on Chinese patients. Patients would 
not receive remuneration, but treatments and assessments directly associated with the clinical trial will 
be provided at no cost. The issue of confidentiality is a major ethical issue, and will be solved by 
recording the data in a manner that does not allow the participants to be identified (i.e., using a non-
recognizable code for each patient). A review of medical records that have already been recorded as 
part of clinical care. Therefore, this poses no physical risks. 
(c) Record retention: The PI, research team, and ethical review authority are responsible for 
overseeing this study to get access to, use, and retain subjects’ personal data for the purposes of clinical 
study, and the relevant regulatory bodies can get access to subjects’ personal data for the purposes of 
checking and verifying the integrity of study data and assessing compliance with the study protocol and 
relevant requirements. All collected data will be secured in compliance with the Hong Kong Personal 
Data (Privacy) Ordinance (CAP 486). The collected personal information and study data will be kept 
for 3 years after the completion of the study. 
     
Data processing and analysis  
One biostatistician who is blinded to interventions will be responsible for statistical analysis. The 
analysis will be carried out on the intention-to-treat (ITT) population, for which participants have been 
randomized.43 A linear mixed-effect model will be applied to compare the primary outcome (changes 
in total MoCA score from baseline) and secondary outcomes (changes in scores of the Digit span test, 
MBI, VAS, GDS and ISI), with time (baseline, week 6, and week 12) and group (CAT, CAE, 
CAT+CAE, and routine care) as categorical fixed factors and random intercepts within a scaled identity 
covariance matrix. Gender, age, baseline MoCA score, and baseline medication will serve as 
covariates. Subgroup analysis will be further conducted to compare outcomes by gender, age, and 
severity of dementia to detect whether these factors are associated with the outcomes. Pairwise 
comparisons will be further carried out to examine between-group differences. One-way analysis of 
variance (one-way ANOVA) will be used to detect differences in continuous baseline variables. 
Categorical baseline variables, including discontinuation and incidence of AEs, will be analyzed using 
the Chi-square test or Fisher’s exact test. Statistical significance was defined as a two-tailed P < 0.05. 
The analysis will be conducted using R Studio software. 
 
Termination criteria 
(a) Premature termination or suspension of study: The study will be completed as planned unless 
one or more of the following criteria are satisfied that require temporary suspension or early 
termination of the study: (1) new information or other evaluation regarding the safety or efficacy of the 
study drug that indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study; (2) a significant violation of 
Good Clinical Practice (GCP) that compromises the ability to achieve the primary study objectives or 
compromises subject safety. 
(b) Premature termination or suspension of investigational sites: A study site may be terminated 
prematurely or suspended if the site (including the investigator) is found to be in significant violation 
of GCP, protocol, or contractual agreement, is unable to ensure adequate performance of the study, or 

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is otherwise permitted by the contractual agreement. 
(c) Procedures for premature termination or suspension: In the event that the PI, an institutional 
review board (IRB) / research ethics committee (REC) or a regulatory authority elects to terminate or 
suspend the study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the PI; the procedure will be followed by applicable 
investigational sites during the course of termination or study suspension. 
(d) Criteria for discontinuation or withdrawal of a subject: (1) pretreatment event or AE: the subject 
has experienced a pretreatment event or AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject's health or the subject is unwilling to continue 
because of the pretreatment event or AE; (2) major protocol deviation: the discovery post-
randomization that the subject failed to meet protocol entry criteria or did not adhere to protocol 
requirements, and continued participation poses an unacceptable risk to the subject's health; (3) lost to 
follow-up: the subject does not return to the site, and attempts to contact the subject are unsuccessful; 
(4) withdrawal of consent: the subject wishes to withdraw from the study; (5) study termination: the PI, 
IRB, REC, or regulatory agency terminates the study. 
(e) Procedures for discontinuation or withdrawal of a subject: The investigator may terminate a 
subject's study participation at any time during the study when the subject meets the study termination 
criteria. In addition, a subject may discontinue his or her participation without giving a reason at any 
time during the study. Should a subject's participation be discontinued, the primary criterion for 
termination would be recorded. Subjects who discontinue the study during the treatment period will 
visit the site as soon as possible for clinical assessment, if applicable. To ensure participants’ safety, 
those discontinued because of severe side effects or hospitalizations due to any reason will be given 
individual clinical treatment. Discontinued or withdrawn subjects will not be replaced. 
 
 
Anticipated results and potential pitfalls 
 
Our several previous studies have confirmed the effectiveness of CAT and CAE monotherapy in 
elderly patients. This provides a direct and solid basis to ensure the success of the proposed study. We 
therefore expect that CAT and CAE could produce better outcomes than routine care in improving 
cognitive deterioration, functional dependence, psychological, sleep, and pain symptoms. Furthermore, 
related collaborative networks, protocols, and the research team have been well established. It is very 
unlikely that impassable obstacles will be encountered in the proposed studies. Despite this, the 
completion of the recruitment in a timely manner may be a potential issue. If the recruitment cannot 
reach the goal within the designed timeframe at the end of the first year, additional study sites will be 
sought. 
 
 
Publication policy 
 
The results of this study are going to be published in peer-reviewed journals, with the abstract 
available online at the clinical trial register. Subjects enjoy rights of the protection of the confidentiality 
of their personal data. 
 
 
Impact on People’s Health and Health Services as well as Plan to Disseminate 
Research Findings to End Users 
  
If the proposed study could achieve positive results, it would demonstrate that CAT and CAE 
therapy could be effective in improving the quality of life for the elderly with dementia. We will then 

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establish a collaborative network consisting of acupuncturists, nurses, physiotherapists, and other 
caregivers and hold serial training workshops to introduce such treatment strategies to community 
caregivers and family members. Through these training workshops, CAT and CAE could become 
standard interventions for the elderly with dementia. We hope the elderly with dementia can obtain 
benefits from this study and reduce caregivers’ family and public health care system burdens. 
 
 
 

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Key References 
 
1. American Psychiatric Pub. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). 
American Psychiatric Pub; 2013. 
2. Zhu Y, Shulin C, Yates J, Paddick SM, Robinson L, Stephan BCM; DePEC team. Risk of 
conversion from mild cognitive impairment to dementia in low- and middle-income countries: 
A systematic review and meta-analysis. Alzheimers Dement (N Y). 2022 Mar 13;8(1):e12267. 
doi: 10.1002/trc2.12267 
3. 2023 Alzheimer's disease facts and figures. Alzheimers Dement. 2023 Apr;19(4):1598-1695. 
doi: 10.1002/alz.13016 
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Page 14 
Figure 1. Study flow chart. t, timepoint; CAT, comprehensive acupuncture therapy; CAE, Comfy 
Acupressure for the Elderly 
 
 
 
 

Page 15 
Figure 2. Illustration of selected acupoints in the trial 
 
 
 
 

Page 16 
Table 1. Location, traditional Chinese medicine (TCM)-based therapeutic effects and manipulation of 
the selected acupoints in the trial 
 
Acupoint 
Location 
TCM-based therapeutic effects 
Manipulation 
Number of 
needles 
insertion 
GV20 
(Baihui,  
百會) 
At the vertex of the 
scalp, 7 cun directly 
above the midpoint of 
the posterior hairline. 
Tonifies Yang, opens the orifices 
and rejuvenates the mind, relieves 
headache and dizziness, is widely 
used for senile dementia, 
insomnia, and mental disorders. 
Transverse 
insertion, 0.5-0.8 
cun, forwards or 
backwards. 
1, 
unilateral 
EX-HN3 
(Yintang,  
印堂) 
At the midway of the 
medial ends of the 
eyebrows 
Calms the mind and reduces 
anxiety, is widely used for 
headache, dizziness, 
forgetfulness, agitation, and 
insomnia. 
Transverse 
insertion, 0.3-0.5 
cun, downwards. 
1, 
unilateral 
EX-HN1 
(Sishencong, 
四神聰) 
Four points in all, at 
the vertex of the scalp, 
1 cun respectively 
anterior, posterior, and 
lateral to GV20 
(Baihui). 
Calms the mind, restores 
consciousness and opens the 
orifices, and suppresses 
sympathetic activity, is widely 
used for insomnia, epilepsy and 
mental disorders. 
Transverse 
insertion, 0.5-0.8 
cun. 
2, left and 
right  
GB15 
(Toulinqi,  
頭臨泣) 
One the forehead, 0.5 
cun within the anterior 
headline, midway 
between GV24 
(Shenting) and ST8 
(Touwei). 
Reduces headache and dizziness, 
opens the orifices, rebalances 
mood, and suppresses convulsion 
and nervousness. 
Transverse 
insertion, 0.5-0.8 
cun, backwards. 
2, bilateral 
ST8 
(Touwei,  
頭維) 
At the corner of the 
head, 0.5 cun directly 
above the hairline, 4.5 
cun lateral to the 
midline of the head. 
Dispels wind, relieves pain and 
improves eyesight, is commonly 
used for headache, dizziness, and 
eye diseases. 
Transverse 
insertion, 0.5-1 
cun, backwards 
subcutaneously. 
2, bilateral 
GB8 
(Shuaigu,  
率谷) 
On the temple, 1.5 cun 
directly above the apex 
of the car. 
Dispels head cloudiness, opens 
the orifices, relieves pain and 
agitation, is commonly used for 
migraine and vertigo. 
Subcutaneous 
insertion, 0.5-0.8 
cun. 
2, bilateral 
EX-HN5 
(Taiyang,  
太陽) 
At the temple, in the 
depression about 1 cun 
posterior to the 
midpoint between the 
lateral of the eyebrow 
and the outer canthus. 
Alleviates headache, dizziness, 
insomnia, and eye diseases. 
Oblique insertion, 
0.3-0.5 cun 
inferiorly. 
2, bilateral 
CV12 
(Zhongwan, 
中脘) 
On the anterior midline 
of the abdomen, 4 cun 
above the umbilicus. 
Strengths the spleen, reduces 
indigestion and diuresis, improves 
stomach movement, particularly 
benefits stress-related digestive 
disorders, e.g., stomachache, 
heartburn, and diarrhea. 
Modulates the limbic-medial 
prefrontal network related to 
emotional and cognitive function. 
Perpendicular 
insertion, 0.5-1.2 
cun. 
1, 
unilateral 

Page 17 
CV4 
(Guanyuan, 
關元) 
On the anterior midline 
of the abdomen, 3 cun 
below the umbilicus. 
Tonifies Qi and Yang, strengthens 
the foundation of the body, 
benefits constipation, urine 
retention, frequent nocturia and 
indigestion. Modulates the limbic-
medial prefrontal network related 
to emotional and cognitive 
function. 
Perpendicular 
insertion, 0.5-1.2 
cun. 
1, 
unilateral 
HT7 
(Shenmen,  
神門) 
At the wrist joint, on 
the radial side of the 
tendon of flexor carpi 
ulnaris, along the most 
distal transverse crease 
of the wrist. 
Calms the mind and tranquilizes 
the spirit, is commonly used for a 
variety of psychogenic conditions, 
including insomnia and neurosis. 
 
Perpendicular 
insertion, 0.3-0.5 
cun. 
2, bilateral 
TH5 
(Waiguan,  
外關) 
2 cun above the 
transverse crease on 
the back of the wrist, 
in the depression 
between the ulnar and 
radius. 
Expels Wind and clears heat, 
tonifies Qi and Yang, and 
activates meridians, is widely 
used for febrile disease, headache, 
dizziness, and psychogenic pain. 
Perpendicular 
insertion, 0.5-1 
cun. 
2, bilateral 
LI4 (Hegu, 
合谷) 
Over the dorsum of the 
hand, between first and 
second metacarpal 
bones, at the level of 
the midpoint of the 
second metacarpal 
bone on the radial side. 
Expels Wind and releases the 
exterior, relieves pain and 
strengthens immunity, is used for 
febrile disease, stroke sequela, 
psychogenic tension and pain. 
Commonly used acupoint for 
anesthesia. 
Perpendicular 
insertion, 0.5-1 
cun. 
2, bilateral 
ST36 
(Zusanli,  
足三里)  
3 cun below the 
depression in the 
lateral patellar 
ligament, 1 
fingerbreadth lateral to 
the anterior crest of the 
tibia. 
Harmonizes and strengthens the 
spleen and the stomach, reinforces 
healthy and original Qi, calms the 
spirit and activates meridians, is 
commonly used for 
gastrointestinal discomfort, stress 
and fatigue. Evokes a robust 
response in the limbic-paralimbic-
neocortical network involved in 
autonomic, pain, mood, and 
cognitive function. 
Perpendicular 
insertion, 1-1.5 
cun. 
2, bilateral 
SP6 
(Sanyinjiao, 
三陰交) 
3 cun superior to the 
prominence of the 
medial malleolus, 
posterior to the medial 
crest of the tibia. 
Tonifies Yin and improves vitality 
and immunity, clams the mood by 
nourishing the three foot 
meridians, including the spleen, 
kidney and liver, is widely used 
for endocrine and immune system 
disorders, e.g., insomnia, fatigue 
and pain. 
Perpendicular 
insertion, 1-1.5 
cun. 
2, bilateral 
ST40 
(Fenglong, 
豐隆) 
8 cun below the 
depression in the 
lateral patellar 
ligament, 2 
fingerbreadth lateral to 
the anterior crest of the 
tibia. 
Harmonizes and strengthens the 
spleen and the stomach, relieves 
phlegm, calms the mind and 
opens the orifices, is widely used 
for dizziness, epilepsy and mental 
disorders. 
Perpendicular 
insertion, 0.5-1 
cun. 
2, bilateral 

Page 18 
Table 2. Detailed treatment procedures of “Comfy Acupressure for the Elderly (CAE)” 
 
Step 
Operating location 
Procedure 
Opening 
Tianmen (開
天門) 
From the center of the 
eyebrow to the forehead  
Apply massage oil to the center of the subject’s forehead, then 
use the pad of the index and middle fingers of both hands, or 
the middle finger alone, to synchronously push straight upward 
from the midpoint between the subject’s eyebrows (EX-HN3, 
Yintang) to the hairline (GV24, Shenting). Repeat 15 times. 
Pushing 
Kangong (分
推坎宮) 
From the inside to the 
outside of the eyebrows 
Apply massage oil to the subject’s eyebrow, then use the pad 
of the index and middle fingers of both hands, or the middle 
finger alone, to synchronously push from the medial end of 
both eyebrows (BL2, Cuanzhu) to the depression on the 
supraorbital margin, at the lateral end of the eyebrows (SJ23, 
Sizhukong). Repeat 15 times. 
Pressing and 
Kneading 
Taiyang (按揉
太陽) 
Acupoint EX-HN5 
(Taiyang) 
Using the pad of the middle finger of both hands, press and 
knead the acupoint EX-HN5 (Taiyang), in synchronized 
circular motion. Knead deeply to move the subcutaneous layer 
of the skin, instead of just rubbing the surface. Repeat 15 
times. 
Kneading Face  
(揉抹面部) 
7 facial acupoints: GB14, 
(Yangbai), EX-HN5 
(Taiyang), SI18 
(Quanliao), LI20 
(Yingxiang), ST6 
(Jiache), ST4 (Dicang) 
and CV24 (Chengjiang) 
Using the pads of the index, middle, and ring fingers of both 
hands, or the middle finger alone, to synchronously massage 
the subject’s face in circular motion, following the sequence 
below: forehead, temporal area, orbital area, zygomatic area, 
cheek area, nasal area, lower jaw. Focus on the following 
acupoints: GB14, (Yangbai), EX-HN5 (Taiyang), SI18 
(Quanliao), LI20 (Yingxiang), ST6 (Jiache), ST4 (Dicang), and 
CV24 (Chengjiang) by repeating the circular kneading action 
on each acupoint.  Repeat the action 3 times. 
Grasping Wu 
Jing (拿五經) 
The head area that Du 
meridian, Bladder 
meridian, and Gallbladder 
meridian circulate 
Place a thin towel on the subject's head, then place one hand on 
top of the towel, with the pad of the middle finger on the Du 
meridian, index and ring fingers on the Bladder meridian, and 
thumb and little finger on the Gallbladder meridian. Move and 
synchronize all 5 fingers to lift and press on the treatment area. 
Move the hand up and down the meridians and sideways to 
cover the subject's entire head. Repeat for 3 minutes, spending 
1 minute on the top, 1 minute on the sides, and 1 minute on the 
back of the skull. 
Pressing and 
Kneading 
Fengchi (按揉
風池) 
Acupoint GB20 (Fengchi) 
Place a thin towel on the subject's head, then use both thumbs 
or the thumb and index/middle finger of one hand to 
synchronously press and knead the acupoint GB20 (Fengchi) 
on both sides of the neck. Repeat 5 times. 
Pressing and 
kneading the 
neck (按揉頸
項部) 
Neck 
Place a thin towel on the subject’s neck area and use the thumb 
and index/middle finger of one hand to lift and massage both 
sides of the neck.  Ensure that the action is rhythmic and 
synchronized. Repeat for 3 minutes, spending 1 minute on the 
upper, 1 minute on middle, and 1 minute on the lower part of 
the neck. 
Pressing and 
Kneading 
Jianjing (按揉
肩井) 
Acupoint GB21 (Jianjing) 
Place a thin towel on the subject's shoulder, then use both 
hands to massage the shoulder muscle with mellow force. 
Ensure that the action is rhythmic and synchronized. Repeat 
for 3 minutes. 
Pressing and 
Kneading 
Acupoint SI11 (Tianzong) Use the thumbs or middle fingers of both hands to 
synchronously massage the acupoint SI11 (Tianzong) on both 
sides of the back. Repeated 5 times. 

Page 19 
Tianzong (按
揉天宗) 
Pushing 
Qiaogong (推
橋弓) 
Anterior cervical 
sternocleidomastoid 
muscle 
Apply massage oil to the subject’s sternocleidomastoid 
muscles in the front neck area, then use the pads of the index 
and middle fingers, or the middle finger alone, move swiftly 
downwards from the back of the ear, along the 
sternocleidomastoid muscle. The movement should be light 
and cause no discomfort to the subject. Repeat 50 times on 
each side. 
Grasping 
Jianjing (拿肩
井) 
Acupoint GB21 (Jianjing) 
Place a thin towel on the subject's shoulder, then use the 
thumbs and index/middle fingers of both hands to lift and 
grasp the shoulder muscle of both shoulders with appropriate 
force.  Repeat 5 times. 
Grasping Hegu 
(拿合谷) 
Acupoint LI4 (Hegu) 
Use the thumb and index/middle fingers of one hand to lift and 
grasp the acupoint LI4 (Hegu) of both hands of the subject 
with appropriate force.  Repeat 5 times. 
 
 
 

Page 20 
Table 3. Standard protocol items: recommendations for intervention trials (SPIRIT) schedule of 
enrollment, interventions, and assessment.  
 
 
 
Study Period 
 
Enrolment 
Allocation 
Post-allocation 
Timepoint 
-t1 
t0 
 
t1 
Start 
t2 
6-week 
t3 
12-week 
Enrolment 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Allocation 
 
X 
 
 
 
Interventions 
 
 
 
 
 
Intervention: CAT 
 
 
 
 
 
Intervention: CAE 
 
 
 
 
 
Control: routine care 
 
 
 
 
 
Assessments 
 
 
 
 
 
MoCA 
 
X 
 
X 
X 
Digit Span 
 
X 
 
X 
X 
MBI 
 
X 
 
X 
X 
VAS 
 
X 
 
X 
X 
GDS 
 
X 
 
X 
X 
ISI 
 
X 
 
X 
X 
 
Abbreviations: t, timepoint; CAT, comprehensive acupuncture therapy; CAE, Comfy Acupressure for 
the Elderly; MoCA, Montreal Cognitive Assessment; MBI, Modified Bathel Index; VAS, Visual 
Analogue Scale; GDS, Geriatric Depression Scale; ISI, Insomnia Severity Index.