― 96 ―Dementia Japan 37 : 96-132, 2023

Review

Study designs and statistical analyses in randomized
controlled trials of non-pharmacological preventive
and therapeutic interventions for dementia
continuum : A statistical review
Ryoichi Hanazawa1）, Hiroyuki Sato1）, Masanao Sasaki1）,
Keisuke Suzuki2）, Akihiro Hirakawa1）

ability ; however, the variations in study designs

Introduction

among the clinical trials and the low quality of the clinical trial methodology are barriers to deriving reliable

Non pharmacological interventions for dementia-

conclusions.

For instance, systematic reviews evalu-

prevention in people with risk factors for cognitive

ating the effectiveness of non-pharmacological inter-

decline, treatment and care in patients with mild cogni-

ventions in preventing cognitive decline among older

tive impairment（MCI）and dementia, and reducing

people（Yao et al., 2020）and at-risk individuals due tothe burden on caregivers of patients with dementia

age or cognitive frailty（Whitty et al., 2020）have been

play significant roles in preventive and therapeutic

performed recently ; however, these reviews com-

interventions.

Various systematic reviews and meta-

monly identified a difficulty in drawing a unified con-analyses have attempted to synthesize the effects ofclusion on the effectiveness of non-pharmacologicalpreventive and therapeutic interventions across clini-

preventive interventions due to the heterogeneity incal trials to assess their effectiveness and accept-

study designs and the low quality of studies.

認知症領域の非薬物介入のランダム化対照試験の試験デザインと統計解析法 : 統計的レビュー
花澤遼一 1），佐藤宏征1），佐々木誠治1），鈴木啓介2），平川晃弘1）1）
東京医科歯科大学大学院医歯学総合研究科臨床統計学分野［〒 113-8510 東京都文京区湯島 1-5-45］
Department of Clinical Biostatistics, Graduate School of Medical
and Dental Sciences, Tokyo Medical and Dental University（1-5-45
Yushima, Bunkyo-ku, Tokyo 113-8510, Japan）
2）
国立長寿医療研究センター 先端医療開発推進センター［〒 4748511 愛知県大府市森岡町 7-430］
Innovation Center for Translational Research, National Center for
Geriatrics and Gerontology（7-430 Morioka, Obu, Aichi 474-8511,
Japan）

Hu et al.

（2022）assessed the utility of four non-pharmacological interventions（physical activity, cognitive intervention, multicomponent of physical activity and cognitive
intervention, and nutrition）in people with MCI
through an overview of systematic reviews and network meta-analyses.

In this study, of the 42 random-ized controlled trials（RCTs）included, the quality of40（95%）RCTs was considered questionable.

In asystematic review of non-pharmacological interven-

― 97 ―

Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review

tions for improving activities of daily living in people

RCTs, we selected the Clinical Practice Guidelines forwith moderate to severe dementia, the certainty of

Dementia 2017 in Japan（Japanese Society of Neurol-

evidence was moderate or low, partially due to the het-ogy, 2017）and the Cochrane Database of Systematic

erogeneity between the included studies（Na et al.,

Reviews（https://www.cochranelibrary.com/cdsr/about-2019）. We consider that these issues are caused bycdsr）that reviewed and authorized the evidence ofthe complexity of the study design and implementation

non-pharmacological preventive and therapeutic inter-

due to the difficulty in homogeneous implementation

ventions by multiple medical experts.

of non pharmacological interventions among partici-

RCTs on non pharmacological interventions cited inpants and the involvement of many healthcare profes-

the Clinical Practice Guidelines for Dementia 2017 insionals in delivering the interventions.

Japan and 23 Cochrane Review reports selected from-

We extracted-

To address these issues, the use of adequate meth-

Cochrane Database of Systematic Reviews using theodologies of study design and statistical analysis thatwords “dementia”, “alzheimer’s disease”, or “mildcan improve the quality of study results and the gener-

cognitive impairment” in March 2020（Abraha et al.,alization of interventions in practice, is encouraged.

2017 ; Bahar-Fuchs et al., 2013 ; Bahar-Fuchs et al.,The components that characterize the design and anal-

2019 ; Cook et al., 2012 ; Deshmukh et al., 2018 ;ysis include the target population, control arm, ran-Forbes et al., 2015 ; Gates et al., 2019a ; Gates et al.,domization, number of arms, primary outcome, blind-

2019b ; Gates et al., 2020 ; Herke et al., 2018 ; Kar-ing, number of measurement time points after baseline

kou & Meekums, 2017 ; Lai et al., 2019 ; Lins et al.,assessment, sample size, primary analysis, and analy-

2014 ; Liu et al., 2018 ; Martin et al., 2011 ; Möhler

sis sets.

To the best of our knowledge, only a limited

et al., 2018 ; Neal & Wright, 2003 ; Orgeta et al.,number of reviews on non pharmacological interven-

2020 ; van der Steen et al., 2018 ; Vernooij-Dassen ettions have focused on these components.

In thisal., 2011 ; Woods et al., 2012 ; Woods et al., 2018 ;study, we aimed to investigate the study designs andYoung et al., 2015）. In the Clinical Practice Guide-

statistical analyses used in the RCTs of the following

lines for Dementia 2017, the editorial committee con-types of non-pharmacological interventions :（i）ducted searches in MEDLINE, PubMed, and Japandementia prevention in people with risk factors for

Medical Abstracts Society using relevant keywords on

cognitive decline,（ii）treatment and care in patientsnon-pharmacological intervention.

with MCI and dementia, and（iii）burden reduction oftematic review was carried out for 63 studies publishedcaregivers of patients with dementia.

between January 2000 and April 2015.

-

Based on the

A qualitative sysThe commit-

findings of this review, we offer common practical rec-tee rated each selected study’s grade of evidence forommendations for investigators to design RCTs on

the effectiveness of non-pharmacological inter-nonpharmacological preventive and therapeutic inter-

ventions.

ventions.

196 studies reviewed in the 23 Cochrane Review
reports.

Materials and Methods

In addition to these studies, we included
After excluding review articles, duplicatedarticles, and articles not written in English, weselected 200 studies and recorded the following

In this study, we focused on the review of study

variables : publication year, target population（individ-

designs and statistical analyses of the RCTs showing

uals with normal cognition, MCI, or dementia ;evidence of non-pharmacological preventive and thera-

caregivers only ; mixed population［two or more popu-

peutic interventions.

lations such as individuals with MCI and individuals

Therefore, as sources of such― 98 ―

Dementia Japan Vol. 37 No. 1 January 2023

with dementia］）, type of intervention（dietary inter-

Types of non-pharmacological interventions

vention, cognitive intervention, exercise therapy, ani-

Non-pharmacological interventions can be divided

mal therapy, art therapy, music therapy, reminiscence

into interventions for patients with dementia and thosetherapy, validation therapy, multidomain intervention,

for caregivers.

psychoeducational intervention, cognitive-behavioral

Dementia 2017 in Japan and the Cochrane Review

therapy, counseling, general support, multidomain

reports reviewed the literature on RCTs on the follow-

intervention for caregivers）, study design（parallel

ing non-pharmacological interventions.

-

The Clinical Practice Guidelines forgroup randomized controlled trial, cluster randomized

1） Dietary intervention（Herke et al., 2018）

trial, crossover trial）, control arm（observation, usual

Dietary intervention is designed to modify the meal-care, other type of intervention, no description）, ran-

time environment of people with dementia, improvedomization（simple randomization, block randomiza-

the mealtime behavior of people with dementia or theirtion, stratified randomization, minimization method,caregivers, or integrate aspects of both to improve foodcluster randomization, no description）, number ofand fluid intake and nutritional status.

arms, blinding（blinded to the outcome assessment,2） Cognitive intervention（cognitive stimulation,

unblinded, no description）, follow-up period, number

cognitive training, and cognitive rehabilitation）

of time points for outcome measurements after base-（Bahar-Fuchs et al., 2013 ; Woods et al., 2012）line assessment, description of primary outcome, num-

Cognitive stimulation aims to improve general cog-

ber of outcomes, outcome domain（s）（cognition/mem-

nitive function and sociality through various activities

ory, behavioral and psychological symptoms ofin personalized or group settings.

dementia［BPSD］, activities of daily living［ADL］,

focuses on specific areas of cognitive function, such as

physical outcome, quality of life［QOL］, biological out-memory, attention, and problem solving, and uses

come, onset of dementia, onset of MCI, adherence topaper- or computer-based tasks tailored to an individ-

intervention, depression among caregivers, caregiverual’s level of function.

burden, caregivers' knowledge, QOL of caregivers,

personalized intervention that sets goals for eachstress among caregivers, and other category）, samplepatient to improve their ADL.

size, analysis sets（intention-to-treat, full analysis set,real-life setting, and it rarely involves interventions

per protocol set, no description）, primary analysis

that target specific cognitive functions.

, analysis of（t-test, analysis of variance［ANOVA］
covariance［ANCOVA］, repeated-measures ANOVA,

Cognitive training

Cognitive rehabilitation is a
It is performed in a3） Exercise therapy（Forbes et al., 2015 ; Younget al., 2015）

regression model analysis including logistic regression

Exercise therapy includes aerobic exercises, muscle

and Cox proportional hazard model, mixed-effects

strengthening training, and balance training, and it ismodel, mixed-effects model for repeated measuresoften performed in combination with multiple exercise［MMRM］, and generalized estimating equations, oth-therapies.

ers［e.g., chi square test and nonparametric test］, no4） Animal therapy（Lai et al., 2019）

description）, and description of sample size rationale.

Animal therapy is thought to help people with

Two statisticians（RH and AH）independently investi-

dementia by providing companionship and support ofgated the variables for quality control.

animals in daily activities.

-

All 199 papers

This may improve physicalthat included the results of 200 studies we reviewed

and mental health outcomes, including better moodare presented in the appendix.

and fewer problematic behaviors.

― 99 ―

Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review

5） Art therapy（Deshmukh et al., 2018）

dyads of caregivers and care recipients.

Art therapy is a form of psychotherapy that uses art12） General support（Winter & Gitlin, 2006 ; Walter & Pinquart, 2020）

media as the primary mode of communication.
6） Music therapy（van der Steen et al., 2018）

General support refers to unstructured specialist-

Music therapy includes listening to music, singing,led and caregiver-group-led support that focuses on

playing musical instruments, and rhythmic exercises,

creating opportunities for discussing caregiving issues

all of which are often conducted in combination.

and emotions.

7） Reminiscence therapy（Woods et al., 2018）
In reminiscence therapy, the listener listens to theTypes of randomization（Friedman et al, 2015 ;life history of the older adult in a receptive, empa-

Donner & Klar, 2000）

thetic, and supportive manner.

The goal is to support

Simple randomization is a method that assigns par-older adults’ mental health through therapy, specifically

ticipants to each treatment group using a prespecified

to enhance their self-esteem and promote good inter-ratio.

personal relationships.

groups A and B, a simple randomization procedure

For example, if there are two treatment arms,

8） Validation therapy（Neal & Wright, 2003）

assigns participants to group A with probability p andValidation therapy is based on the general principle ofparticipants to group B with probability 1-p.

Blockvalidation, acceptance of reality, and the personal truth of

randomization is a method that assigns participants toanother individual’s experience. The specific interven-

each treatment group in a prespecified ratio for eachtions and techniques used within this approach involve

block of a certain number of participants.

behavioral and psychotherapeutic methods to meet themethod avoids serious imbalances in the number ofneeds of individuals at different stages of dementia.

participants assigned to each group.

9） Psychoeducational intervention（Hébert et al.,This

Stratified ran-domization is a method that performs randomization
within each stratum（or subgroup）and is usually cate-2003 ; Walter & Pinquart, 2020）
Psychoeducational intervention includes passive

gorized based on the status of a prognostic factor.

The

Incorporation of stratification into randomization

goal is to transmit knowledge and skills regarding

enhanced the similarity of prognostic factor（s）, called

dementia, caregiving, available services, and stresscomparability, between the groups we compared. The

coping mechanisms.

minimization method assigns participants to each

information provision and active skills training.

10） Cognitive-behavioral therapy（Akkerman &Ostwald, 2004 ; Walter & Pinquart, 2020）

treatment group in a manner that dynamically adjusts
the allocation ratio to balance the distribution of pre-Cognitive-behavioral therapy aims to modify behav-

specified prognostic factors among the treatment

ioral, cognitive, and affective responses to caregiving,groups.

as well as to directly change the mental health of thecluster randomization randomly assigns social units or

We categorized mindfulness based stressclusters of individuals, rather than individuals them-caregiver.

-reduction interventions into cognitive behavioral ther-

Apart from these randomization methods,

selves, to different intervention groups.

apy in this study.
11） Counseling（Salfi et al., 2005 ; Walter & Pin-

Results

quart, 2020）
Counseling includes assessment and planning.

It istailored to specific problems of individual caregivers orCharacteristics of participants and studies
Table 1 shows the descriptive characteristics of the― 100 ―Dementia Japan Vol. 37 No. 1 January 2023
Table 1.

Descriptive characteristics of the studies on each target population（n = 200）
Caregivers
only
n = 22

Mixed
population
n=2

Normalcognitionn = 31

Mild cognitive
impairmentn = 19Mean age, median（range）

72.3（58.9-86.9）

71.5（58.5-80.1）

80.4
63.3
74.7
（66.5-88.7） （46.9-74.0） （74.0-75.4）

Percent of female, median（range）

68.2
58.0
（39.0-100.0） （41.9-85.2）

68.7
81.0
57.1
（0.0-100.0） （0.0-100.0） （57.1-57.1）

Mean of education year, median（range）

14.2（4.0-16.3）

10.9（5.7-16.4）

8.8（2.3-14.6）

14.3（14.1-14.4）

8.4（7.0-9.8）5（16.1）0（0.0）
2（6.5）
2（6.5）
0（0.0）
0（0.0）
2（6.5）
3（9.7）
5（16.1）0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
1（5.3）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（5.3）
0（0.0）
0（0.0）

15（11.9）2（1.6）
3（2.4）
2（1.6）
5（4.0）
6（4.8）
7（5.6）
6（4.8）
4（3.2）
4（3.2）
6（4.8）

0（0.0）
1（4.5）
0（0.0）
0（0.0）
3（13.6）3（13.6）1（4.5）
1（4.5）
6（27.3）0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

3（9.7）
1（3.2）
1（3.2）
2（6.5）
2（6.5）
2（6.5）
1（3.2）
0（0.0）
0（0.0）

2（10.5）1（5.3）
2（10.5）2（10.5）5（26.3）1（5.3）
1（5.3）
1（5.3）
2（10.5）8（6.3）
9（7.1）
8（6.3）
9（7.1）
8（6.3）
9（7.1）
9（7.1）
3（2.4）
3（2.4）

0（0.0）
2（9.1）
0（0.0）
0（0.0）
2（9.1）
1（4.5）
1（4.5）
1（4.5）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
2（100.0）0（0.0）
0（0.0）

1（3.2）
17（54.8）6（19.4）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
17（89.5）2（10.5）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

3（2.4）
41（32.5）12（9.5）7（5.6）
2（1.6）
17（13.5）
18（14.3）
2（1.6）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
2（100.0）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

7（22.6）0（0.0）

0（0.0）
0（0.0）

9（7.1）
7（5.6）

0（0.0）
0（0.0）
7（31.8）0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
3（2.4）
0（0.0）
5（4.0）

10（45.5）0（0.0）
1（4.5）
4（18.2）0（0.0）
0（0.0）
0（0.0）
0（0.0）

Publication year, n（%）≤ 19992000（224）*
2001（169）*
2002（265）*
2003（287）*
2004（289）*
2005（330）*
2006（328）*
2007（245）*
2008（288）*2009（275）*
2010（312）*
2011（335）*
2012（350）*
2013（401）*
2014（396）*
2015（395）*
2016（394）*
2017（416）*
2018（457）*
Type of intervention, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
Cognitive-behavioral therapy
Counseling
General support
Multidomain intervention for caregiver

Dementia
n = 126*Figures in parentheses indicate the number of publications of clinical trials related to dementia, which were extractedusing the search keywords（“Dementia”［Mesh］OR dementia）AND（clinical trial［Filter］）in PubMed.

Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review
Table 2.

― 101 ―

Study designs and randomization methods by target population and type of intervention（n = 200）
Study design

Target population

Type of intervention

Parallel-grouprandomized
controlled trials

Cluster
randomized
trials

CrossovertrialsNormal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

28（90.3）
1（100.0）15（88.2）
5（83.3）7（100.0）2（6.5）
0（0.0）
1（5.9）
1（16.7）0（0.0）

1（3.2）
0（0.0）
1（5.9）
0（0.0）
0（0.0）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

19（100.0）17（100.0）2（100.0）0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver

99（78.6）2（66.7）35（85.4）
11（91.7）2（28.6）2（100.0）14（82.4）
14（77.8）2（100.0）7（77.8）3（42.9）2（66.7）5（100.0）18（14.3）
1（33.3）2（4.9）
1（8.3）
4（57.1）0（0.0）
1（5.9）
3（16.7）0（0.0）
1（11.1）4（57.1）1（33.3）0（0.0）

9（7.1）
0（0.0）
4（9.8）
0（0.0）
1（14.3）0（0.0）
2（11.8）1（5.6）
0（0.0）
1（11.1）0（0.0）
0（0.0）
0（0.0）

Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

22（100.0）7（100.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

10（100.0）1（100.0）4（100.0）0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

1（50.0）0（0.0）

1（50.0）1（50.0）0（0.0）

1（50.0）General support
Multidomain intervention for caregiver
Total, n（%）

Mixed population
n=2

Cognitive intervention

participants and the included studies.

Between 2000

and dementia patients gradually decreased from 14.2 toand 2018, the number of annually published studies on

8.8 years.

normal cognition, MCI, dementia, and caregiversof the mean age was 63.3 years, and the median per-ranged from 0 5, 0 5, 2 9, and 0 6, respectively.

The

centage of female participants was 81.0%.

The

medians of the mean age enrolled in the studies formedian of the mean education was 14.3 years.

The

normal cognition（72.3 years old）and MCI（71.5 years

most and second most interventions evaluated in theold）were similar, while that for dementia was 80.4

studies were cognitive interventions（n=17, 54.8%）

years old.

The median percentage of female partici-

and multidomain therapy（n=7, 22.6%）for normal

pants with normal cognition, MCI, and dementia wascognition, cognitive interventions（n=17, 89.5%）andapproximately 60-70%.

The median of the mean

exercise therapy（n=2, 10.5%）for MCI, cognitive

duration of education in the normal cognition, MCI,

interventions（n=41, 32.5%）and reminiscence ther-

-

-

-

-

In studies targeting caregivers, the median-― 102 ―Dementia Japan Vol. 37 No. 1 January 2023
Table 2. （continued）
Randomization

Target population

Type of intervention

SimplerandomizationBlockrandomization

Stratified
randomization

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

4（12.9）0（0.0）
3（17.6）0（0.0）
1（14.3）1（3.2）
0（0.0）
0（0.0）
1（16.7）0（0.0）

5（16.1）0（0.0）
3（17.6）1（16.7）1（14.3）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

4（21.1）
2（11.8）2（100.0）2（10.5）2（11.8）0（0.0）

2（10.5）2（11.8）0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver

13（10.3）
1（33.3）8（19.5）1（8.3）
1（14.3）0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（11.1）0（0.0）
1（33.3）0（0.0）

6（4.8）
0（0.0）
2（4.9）
0（0.0）
0（0.0）
0（0.0）
2（11.8）0（0.0）
0（0.0）
2（22.2）0（0.0）
0（0.0）
0（0.0）

23（18.3）0（0.0）
8（19.5）3（25.0）1（14.3）0（0.0）
5（29.4）4（22.2）0（0.0）
0（0.0）
1（14.3）0（0.0）
1（20.0）Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

3（13.6）0（0.0）

2（9.1）
1（14.3）2（9.1）
1（14.3）3（30.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）
1（25.0）0（0.0）
0（0.0）
1（25.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

2（100.0）2（100.0）

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention

apy（n=18, 14.3%）for dementia, and cognitive-behav-（Table 2）. Studies on normal cognition, MCI, demen-ioral therapy（n=10, 45.5%）and psychoeducationaltia, and caregivers approximately 10-20% applied sim-interventions（n=7, 31.8%）for caregivers.

In Tableple randomization（or stratified randomization）. In

S1, we also show the number of studies published eachthe studies on dementia, 18（14.3%）studies used

year according to the type of intervention.

cluster randomization.

Approximately 50% of thestudies in each target population did not describe theStudy designs

randomization methodology.

In studies on normal cognition, MCI, dementia, andThe number of arms

evaluated in each study and the presence or absence of

caregivers, the number（percentage）of parallel groupblinding are presented in Table 3.

RCTs was 28（90.3%）, 19（100%）, 99（78.6%）, and 22of studies on MCI, dementia, and caregivers compared（100%）, respectively ; those of cluster RCTs were 2

two arms（73.7% for MCI, 72.2% for dementia, and（6.5%）, 0（0%）, 18（14.3%）, and 0（0%）, respectively

86.4% for caregivers）, 64.5% of the studies on normal-

While the majority

Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review― 103 ―

Table 2. （continued）
Randomization
Target population

Type of intervention

Minimization
methodCluster
randomizationNo
description

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

1（3.2）
0（0.0）
0（0.0）
1（16.7）0（0.0）

2（6.5）
0（0.0）
1（5.9）
1（16.7）0（0.0）

18（58.1）1（100.0）10（58.8）2（33.3）5（71.4）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

11（57.9）11（64.7）0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver5（4.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（50.0）0（0.0）
3（16.7）0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（20.0）18（14.3）
1（33.3）2（4.9）
1（8.3）
4（57.1）0（0.0）
1（5.9）
3（16.7）0（0.0）
1（11.1）4（57.1）1（33.3）0（0.0）

61（48.4）
1（33.3）21（51.2）
7（58.3）1（14.3）1（50.0）9（52.9）8（44.4）2（100.0）5（55.6）2（28.6）1（33.3）3（60.0）Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy2（9.1）
1（14.3）0（0.0）
0（0.0）

13（59.1）
4（57.1）1（10.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

6（60.0）1（100.0）2（50.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention

cognition evaluated three arms or more.

The numberof ≤ 6 months, and approximately 50% of the studies（percentages）of blinded studies were 8（25.8%）, 16

had two or more measurement time points after base-（84.2%）, 78（61.9%）, and 5（22.7%）for normal cogni-line assessment（Table 4）.

tion, MCI, dementia, and caregivers, respectively, but
22（71.0%）studies on normal cognition did notPrimary outcome

describe the blinding status.

Studies with blinding

More than 50% of the studies did not describe theincreased slightly as the years progressed（Figure S1primary outcome in each target population（Table 5）,（a））. The type of control arm evaluated in the stud-and this was observed in each publication year（Figure

ies varied depending on the type of intervention irre-

S1（b））. In the studies on normal cognition, demen-

spective of the target population（Table 3）. In stud-tia, and caregivers, 40-50% used 2-5 outcomes.

ies on nor mal cognition, MCI, dementia, andmost and second-most frequently measured outcomescaregivers, >70% of the studies had a follow-up period

were cognition/memory（n=26, 83.9%）and ADLThe― 104 ―Table 3.

Dementia Japan Vol. 37 No. 1 January 2023
Number of arms, blinding, and control arm by target population and type of intervention（n = 200）

Target population

Type of intervention

Number of arms
2

3

4

5

6

Normalcognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

11（35.5）0（0.0）
6（35.3）4（66.7）1（14.3）10（32.3）
1（100.0）7（41.2）
1（16.7）1（14.3）9（29.0）0（0.0）
4（23.5）1（16.7）4（57.1）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

1（3.2）
0（0.0）
0（0.0）
0（0.0）
1（14.3）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

14（73.7）
12（70.6）2（100.0）3（15.8）3（17.6）0（0.0）

1（5.3）
1（5.9）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

1（5.3）
1（5.9）
0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy

91（72.2）
2（66.7）26（63.4）9（75.0）5（71.4）2（100.0）13（76.5）
13（72.2）
1（50.0）29（23.0）1（33.3）11（26.8）3（25.0）2（28.6）0（0.0）
4（23.5）4（22.2）
1（50.0）5（4.0）
0（0.0）
3（7.3）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（5.6）
0（0.0）

1（0.8）
0（0.0）
1（2.4）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

7（77.8）6（85.7）3（100.0）4（80.0）1（11.1）1（14.3）0（0.0）
1（20.0）1（11.1）0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）

19（86.4）7（100.0）3（13.6）0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

8（80.0）1（100.0）3（75.0）2（20.0）0（0.0）
1（25.0）0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

2（100.0）2（100.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver
Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy
General support
Multidomain intervention for caregiver

Mixed population
n=2

Total, n（%）
Cognitive intervention（n=8, 25.8%）for normal cognition ; those were cog-

included per trial for normal cognition, MCI, dementia,

nition/memory（n=18, 94.7% for MCI ; n=79, 62.7%

and caregivers were 106, 40, 58, and 92, respectively

for dementia）and BPSD（n=8, 42.1% for MCI ;（Table 6）. Eleven（57.9%）studies on MCI enrolled

n=87, 69.0% for dementia）for MCI and dementia.

≤ 50 patients, whereas 17（54.8%）studies on normal

The most and second most frequently measured care-cognition enrolled >100 participants.

giver related outcomes were depression among care-size varied throughout the study period（Figure S1

givers（n=14, 63.6%）and caregiver burden（n=9,（c））. Only 20-25% of studies in each target popula-

40.9%）, respectively.

tion calculated the sample size using power analysis--

Table S2 shows the outcome

measures used as primary outcomes.

The sample（Table 6）. More than 50% of the studies did notdescribe the power analysis throughout the study

Statistical considerations
Sample size : The median number of participants

period（Figure S1（d））.
Analysis set : The number（percentage）of studies

― 105 ―Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review
Table 3. （continued）
Blinding
Target population

Type of intervention

Blinded to theoutcome assessment

Unblinding

No description

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

8（25.8）1（100.0）2（11.8）3（50.0）2（28.6）1（3.2）
0（0.0）
0（0.0）
0（0.0）
1（14.3）22（71.0）0（0.0）
15（88.2）
3（50.0）4（57.1）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

16（84.2）
14（82.4）2（100.0）1（5.3）
1（5.9）
0（0.0）

2（10.5）2（11.8）0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver78（61.9）1（33.3）29（70.7）
9（75.0）3（42.9）0（0.0）
12（70.6）
11（61.1）
2（100.0）3（33.3）4（57.1）3（100.0）1（20.0）6（4.8）
1（33.3）0（0.0）
0（0.0）
2（28.6）0（0.0）
1（5.9）
0（0.0）
0（0.0）
0（0.0）
1（14.3）0（0.0）
1（20.0）42（33.3）
1（33.3）12（29.3）
3（25.0）2（28.6）2（100.0）4（23.5）7（38.9）0（0.0）
6（66.7）2（28.6）0（0.0）
3（60.0）Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

5（22.7）3（42.9）7（31.8）1（14.3）10（45.5）3（42.9）1（10.0）0（0.0）
1（25.0）6（60.0）0（0.0）
0（0.0）

3（30.0）1（100.0）3（75.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

2（100.0）2（100.0）

General support
Multidomain intervention for caregiver
Total, n（%）

Mixed population
n=2

Cognitive intervention

using the intention-to-treat or full analysis sets forand statistical analyses of RCTs that evaluated thenormal cognition, MCI, dementia, and caregivers was

effects of non-pharmacological preventive interven-

10（32.2%）, 4（21.1%）, 30（23.8%）, and 7（31.5%）,

tions in participants with normal cognition and thera-

respectively, although 60-70% of studies in each target

peutic interventions in patients with MCI and demen-

population did not describe the analysis sets（Table 6）.

tia along with interventions to reduce the burden on

Primary analysis : ANCOVA, repeated measures-caregivers.

In each target population, >70% of the

ANOVA, and mixed effects model were frequently

trials had a follow-up period ≤ 6 months.

used in each target population（Table 6）.

of the studies on normal cognition or caregivers had a-

About 50%

sample size of >100, while 50% of the studies on peo-

Discussion

ple with MCI or dementia had a sample size of ≤ 50.
Furthermore, among the number of publications of

We comprehensively reviewed the study designs

clinical trials related to dementia that were extracted

― 106 ―Dementia Japan Vol. 37 No. 1 January 2023
Table 3. （continued）
Type of control arm

Target population

Type of intervention

Observation

Usual care

Other types ofinterventionNo
description

Normalcognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

15（48.4）0（0.0）
10（58.8）3（50.0）2（28.6）1（3.2）
1（100.0）0（0.0）
0（0.0）
0（0.0）

14（45.2）0（0.0）
6（35.3）3（50.0）5（71.4）1（3.2）
0（0.0）
1（5.9）
0（0.0）
0（0.0）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

4（21.1）4（23.5）0（0.0）

1（5.3）
1（5.9）
0（0.0）

14（73.7）
12（70.6）2（100.0）0（0.0）
0（0.0）
0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver

16（12.7）2（66.7）8（19.5）3（25.0）0（0.0）
0（0.0）
0（0.0）
3（16.7）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

58（46.0）1（33.3）11（26.8）4（33.3）5（71.4）0（0.0）
10（58.8）
12（66.7）2（100.0）5（55.6）4（57.1）3（100.0）1（20.0）50（39.7）0（0.0）
21（51.2）
5（41.7）2（28.6）2（100.0）7（41.2）3（16.7）0（0.0）
4（44.4）2（28.6）0（0.0）
4（80.0）2（1.6）
0（0.0）
1（2.4）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（14.3）0（0.0）
0（0.0）

Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy2（9.1）
0（0.0）

5（22.7）3（42.9）15（68.2）
4（57.1）0（0.0）
0（0.0）

1（10.0）0（0.0）
1（25.0）1（10.0）1（100.0）0（0.0）

8（80.0）0（0.0）
3（75.0）0（0.0）
0（0.0）
0（0.0）

1（50.0）1（50.0）0（0.0）
0（0.0）

1（50.0）1（50.0）0（0.0）
0（0.0）

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention

using the search keywords（“Dementia”［Mesh］OR

controlled RCTs is desired for each type of nonpharma-dementia）AND（clinical trial［Filter］）in PubMed

cological intervention（or target population）.

（see Table 1）, the percentage of studies of non-phar-In the remainder of this section, based on the find-macological interventions investigated in this study

ings of our review, we suggest the following for consid-

was less than 10% throughout the study period.

eration when designing and analyzing non-pharmaco-

These results possibly indicate that it would be difficult

logical preventive and therapeutic intervention studies.

to conduct RCTs of non pharmacological interventions-（especially, with a long-term follow-up period given a

Common points to be considered in designinglarge sample size）, probably because of the complexity

and conducting randomized controlled trials ofof implementing the interventions.

nonpharmacological interventions

To address thisissue, the establishment of nationwide study groups

The complexity of interventions varies depending

for administering and implementing adequate and well-on the number of study staff delivering the interven-

Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review
Table 4.

― 107 ―

Follow-up period and number of measurement time points by target population and type of intervention（n = 200）
Follow-up period

Target population

Type of intervention≤ 6 months

7-12
months≥ 13months

No
description

Normalcognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

27（87.1）1（100.0）13（76.5）
6（100.0）7（100.0）1（3.2）
0（0.0）
1（5.9）
0（0.0）
0（0.0）

3（9.7）
0（0.0）
3（17.6）0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

13（68.4）
11（64.7）2（100.0）4（21.1）4（23.5）0（0.0）

2（10.5）2（11.8）0（0.0）

0（0.0）
0（0.0）
0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver

99（78.6）3（100.0）32（78.0）11（91.7）
6（85.7）1（50.0）15（88.2）
15（83.3）0（0.0）
7（77.8）3（42.9）2（66.7）4（80.0）19（15.1）0（0.0）
7（17.1）1（8.3）
0（0.0）
0（0.0）
2（11.8）3（16.7）2（100.0）0（0.0）
3（42.9）0（0.0）

7（5.6）
0（0.0）
2（4.9）
0（0.0）
1（14.3）1（50.0）0（0.0）
0（0.0）
0（0.0）
1（11.1）1（14.3）1（33.3）1（0.8）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（11.1）0（0.0）
0（0.0）

1（20.0）0（0.0）

0（0.0）

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

20（90.9）5（71.4）0（0.0）
0（0.0）

2（9.1）
2（28.6）0（0.0）
0（0.0）

10（100.0）1（100.0）4（100.0）0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

2（100.0）2（100.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

Caregivers onlyn = 22

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive interventiontion, the interactions involved, and the degree of flexi-

dure manual.

bility allowed in their delivery.

In such interventions,intervention allowed in the study（e.g., change in tim-

to improve the quality of study results, there are sev-

ing and number of interventions）should be clarified.

eral points that should be adequately addressed in

Fourth, data were collected on the quality of the deliv-

designing and conducting RCTs of non pharmacologi-

ered intervention and monitored during the study.

cal intervention : First, standardization of materials

The general guidelines for planning and conducting

and equipment used in the study as well as the inten-

non-pharmacological interventions is also provided bysity of interaction between deliverers（e.g., clinicians

the extended CONSORT statement for non-pharmaco--

and caregivers）and participants.

Second, pre-trial

training was implemented to improve the homogeneityof the intervention, using a standard operating proce-

Third, the degree of flexibility of thelogical treatment（Boutron et al., 2008）.

― 108 ―Dementia Japan Vol. 37 No. 1 January 2023
Table 4. （continued）

Target population

Number of time points for measurements
after baseline assessment

Type of intervention
12

3

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

17（54.8）0（0.0）
7（41.2）5（83.3）5（71.4）7（22.6）0（0.0）
5（29.4）1（16.7）1（14.3）3（9.7）
0（0.0）
3（17.6）0（0.0）
0（0.0）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

9（47.4）8（47.1）1（50.0）9（47.4）8（47.1）1（50.0）1（5.3）
1（5.9）
0（0.0）

Dementia
n = 126

Total
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver

57（45.2）
1（33.3）21（51.2）
7（58.3）2（28.6）1（50.0）4（23.5）9（50.0）1（50.0）5（55.6）4（57.1）1（33.3）1（20.0）46（36.5）
1（33.3）12（29.3）
5（41.7）4（57.1）0（0.0）
7（41.2）8（44.4）1（50.0）3（33.3）2（28.6）1（33.3）2（40.0）10（7.9）0（0.0）
5（12.2）0（0.0）
1（14.3）0（0.0）
2（11.8）0（0.0）
0（0.0）
0（0.0）
1（14.3）0（0.0）
1（20.0）Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

12（54.5）
5（71.4）7（31.8）0（0.0）

0（0.0）
0（0.0）

5（50.0）1（100.0）1（25.0）5（50.0）0（0.0）
2（50.0）0（0.0）
0（0.0）
0（0.0）

1（50.0）1（50.0）1（50.0）1（50.0）0（0.0）
0（0.0）

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention

Randomization and blinding

crossover designs.

Of 200 studies we investigated, twenty（10.0%）and

come with placebo effects, such as cognition/memory

eleven（5.5%）studies employed cluster randomization

and BPSD, is often used, an individual randomizationand crossover designs, respectively ; however, these

design might be better in many cases.

designs have several known limitations.

Considering that the primary out-

Specifically,

the clustering effect（i.e., intraclass correlation coeffi-

Outcomes

cients）should be accounted for when calculating the

A total of 187 studies（94.5%）used multiple pri-sample size and performing statistical analysis, andmary outcomes.

As dementia is a multifaceted condi-

blinding is not always feasible in cluster randomized

tion with long term disease progression, evaluating

trials（Boutron et al., 2011）. Carryover and period

the effectiveness of therapeutic interventions for MCI

effects should be adequately addressed in the study

and dementia based on multiple outcomes may bedesign or statistical modeling in studies employing

useful.

-Guidelines on drug development for Alzheim-

― 109 ―Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review
Table 4. （continued）
Target population

Number of time points for measurements after
baseline assessment

Type of intervention

4≥5

Other*

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention2（6.5）
0（0.0）
1（5.9）
0（0.0）
1（14.3）2（6.5）
1（100.0）1（5.9）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver4（3.2）
0（0.0）
2（4.9）
0（0.0）
0（0.0）
0（0.0）
2（11.8）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

8（6.3）
1（33.3）1（2.4）
0（0.0）
0（0.0）
1（50.0）2（11.8）1（5.6）
0（0.0）
1（11.1）0（0.0）
0（0.0）
1（20.0）1（0.8）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（33.3）0（0.0）

Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy0（0.0）
0（0.0）

3（13.6）2（28.6）0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
1（25.0）0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention*One study with time-to-event outcomes was categorized into “Other”.

er’s disease（Food and Drug Administration, 2018 ;Repeated measures data analysis

Committee for Medical Products for Human Use,Of the 103 studies with repeated measures data in2018）also recommend the use of multiple primary

this review, 38（36.9%）did not use appropriate analy-

outcomes.

sis for repeated measures data.

From a statistical point of view, however,

RCTs of non-pharma-

we recommend testing one primary outcome, which iscological interventions often collect repeated measures

recognized as the most compelling measure among

data, which are typically obtained from multiple mea-

stakeholders such as patients, caregivers, and clini-

surements of the outcome（s）of interest.

cians, because the use of multiple primary outcomesrepeated measures data, it is recommended to use

complicates the sample size calculation and causes

repeated measures data analysis that can account for

problems with the multiplicity of statistical testing.

correlations among measures within a patient by rep-

For suchresenting the individual effects of participants as a ran-― 110 ―Dementia Japan Vol. 37 No. 1 January 2023
Table 5.

Outcome information by target population and type of intervention（n = 200）

Target population

Type of intervention

Description of primary outcome

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

13（41.9）0（0.0）
7（41.2）4（66.7）2（28.6）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

6（31.6）5（29.4）1（50.0）Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver

44（34.9）0（0.0）
13（31.7）2（16.7）2（28.6）0（0.0）
7（41.2）9（50.0）0（0.0）
4（44.4）4（57.1）1（33.3）2（40.0）Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

10（45.5）
4（57.1）

General support
Multidomain intervention for caregiver
Mixed population
n=2

dom effect.

Total, n（%）
Cognitive intervention

Among them, the MMRM method, a type3（30.0）0（0.0）
3（75.0）1（50.0）1（50.0）level of understanding of statistical methodologies andof mixed-effects model that includes both fixed

programming techniques.

（group-specific）effects and random（individual-spe-

why only two studies used MMRM in this study.

This may be the reason

cific）effects, is a powerful approach in repeated measures data analysis.

When analyzing repeated mea-sures data with missing observations, it is well known

Sample size calculation
Only 20-25% of studies in each target populationthat the exclusion of participants with missing data

performed a power analysis.

When planning RCTs,

from the analysis causes a serious bias in the interven-the statistical hypothesis for the primary outcome（s）

tional effect estimation（Mallinckrod et al., 2018）.

and the sample size rationale based on this hypothesis

MMRM often provides better inferences for interven-should be adequately determined.

tional effects at the time point of interest under

the sample size required to evaluate the statistical

repeated measures data with missing observations, but

hypothesis is also important for an appropriate inter-the software implication of MMRM requires a certain

pretation of the study results.

The rationale for

When the sample size

― 111 ―Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review
Table 5.（continued）
Target population

Number of outcomesType of intervention

1

2-5

6-10

≥ 11

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

3（9.7）
0（0.0）
3（17.6）0（0.0）
0（0.0）

14（45.2）
1（100.0）8（47.1）
2（33.3）3（42.9）10（32.3）0（0.0）
5（29.4）2（33.3）3（42.9）4（12.9）0（0.0）
1（5.9）
2（33.3）1（14.3）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy0（0.0）
0（0.0）
0（0.0）

3（15.8）3（17.6）0（0.0）

8（42.1）7（41.2）
1（50.0）8（42.1）7（41.2）
1（50.0）Dementia
n = 126

Total, n（%）

9（7.1）

59（46.8）

49（38.9）9（7.1）

0（0.0）
0（0.0）
1（8.3）
2（28.6）0（0.0）
3（17.6）1（5.6）
0（0.0）
0（0.0）
1（14.3）1（33.3）0（0.0）

1（33.3）14（34.1）
8（66.7）4（57.1）0（0.0）
10（58.8）
11（61.1）
2（100.0）4（44.4）4（57.1）0（0.0）
1（20.0）2（66.7）21（51.2）
3（25.0）1（14.3）2（100.0）3（17.6）5（27.8）0（0.0）
4（44.4）2（28.6）2（66.7）4（80.0）0（0.0）
6（14.6）0（0.0）
0（0.0）
0（0.0）
1（5.9）
1（5.6）
0（0.0）
1（11.1）0（0.0）
0（0.0）
0（0.0）

Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

1（4.5）
0（0.0）

11（50.0）4（57.1）9（40.9）3（42.9）1（4.5）
0（0.0）

0（0.0）
0（0.0）
1（25.0）5（50.0）1（100.0）1（25.0）4（40.0）0（0.0）
2（50.0）1（10.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

1（50.0）1（50.0）0（0.0）
0（0.0）

1（50.0）1（50.0）

Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention

is not determined based on a statistical hypothesis, itplanning and conducting randomized controlled trials

is better to clearly state that the sample size is basedon non-pharmacological interventions in the future.

on the feasibility of participant enrollment during theIn particular, the appropriate choice of one primarystudy period.

outcome, use of statistical analysis for repeated measures data, and sample size calculation based on power

Conclusion

analysis are important for improving the quality of
study results.

Although, there may be a possible

This review elucidated the current status of study

selection bias in this study because we did not selectdesigns and statistical analyses in RCTs of non phar-the literature based on the method recommended formacological preventive and therapeutic interventions

selecting articles for a systematic review（Rethlefsen

for dementia continuum.

Based on the findings of thiset al., 2021）. To address selection bias, further stud-

review, we offer suggestions for consideration whenies based on a systematic review approach are war--

― 112 ―Dementia Japan Vol. 37 No. 1 January 2023
Table 5. （continued）
Outcome domain*

Target population

Type of intervention

Cognition /MemoryBPSD

ADL

PhysicaloutcomeNormal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

26（83.9）0（0.0）
16（94.1）
4（66.7）6（85.7）5（16.1）0（0.0）
2（11.8）2（33.3）1（14.3）8（25.8）0（0.0）
6（35.3）0（0.0）
2（28.6）6（19.4）1（100.0）0（0.0）
3（50.0）2（28.6）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

18（94.7）
16（94.1）
2（100.0）8（42.1）8（47.1）0（0.0）

5（26.3）4（23.5）1（50.0）1（5.3）
0（0.0）
1（50.0）Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver79（62.7）0（0.0）
39（95.1）
9（75.0）3（42.9）2（100.0）5（29.4）13（72.2）0（0.0）
3（33.3）3（42.9）0（0.0）
2（40.0）87（69.0）0（0.0）
24（58.5）
6（50.0）5（71.4）2（100.0）17（100.0）12（66.7）2（100.0）7（77.8）6（85.7）2（66.7）4（80.0）33（26.2）0（0.0）
16（39.0）4（33.3）3（42.9）1（50.0）3（17.6）3（16.7）0（0.0）
2（22.2）
1（14.3）0（0.0）
0（0.0）

12（9.5）1（33.3）1（2.4）
6（50.0）3（42.9）0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（11.1）0（0.0）
0（0.0）
0（0.0）

Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

3（13.6）0（0.0）

6（27.3）2（28.6）3（13.6）1（14.3）0（0.0）
0（0.0）

1（10.0）0（0.0）
2（50.0）3（30.0）0（0.0）
1（25.0）1（10.0）0（0.0）
1（25.0）0（0.0）
0（0.0）
0（0.0）

2（100.0）2（100.0）1（50.0）1（50.0）2（100.0）2（100.0）0（0.0）
0（0.0）

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention

ranted, although we focused on studies included in theClinical Practice Guidelines for Dementia 2017 in

Conflict of Interest : The authors declare no conflictof interest associated with this manuscript.

Japan and the Cochrane Database of Systematic
Reviews.

References

Acknowledgements : We would like to thank the

Abraha I, Rimland JM, Lozano-Montoya I, Dell’Aquila G, Vélez-editor and referees for their comments, which helped

Díaz-Pallarés M, Trotta FM, Cruz-Jentoft AJ, Cherubini A

us improve the manuscript.

This study was partially

supported by the Japan Agency for Medical Researcha n d D e v e l o p m e n t （ G r a n t/Aw a r d N u m b e r :22de0107004h9904）.

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― 113 ―Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review
Table 5. （continued）
Outcome domain*
Target population

Type of intervention

QOL

BiologicaloutcomeOnset ofdementia

Onset of MCI

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention2（6.5）
0（0.0）
0（0.0）
2（33.3）0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy

4（21.1）4（23.5）0（0.0）

1（5.3）
0（0.0）
1（50.0）1（5.3）
1（5.9）
0（0.0）

1（5.3）
1（5.9）
0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver30（23.8）0（0.0）
11（26.8）1（8.3）
0（0.0）
1（50.0）5（29.4）8（44.4）0（0.0）
1（11.1）
2（28.6）1（33.3）0（0.0）

3（2.4）
0（0.0）
1（2.4）
0（0.0）
0（0.0）
0（0.0）
2（11.8）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

1（0.8）
0（0.0）
1（2.4）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention

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Table 5. （continued）
Outcome domain*

Target population

Type of intervention

Adherencetointervention

Depression
amongcaregivers

CaregiverburdenQOLofcaregivers

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention

1（3.2）
0（0.0）
0（0.0）
0（0.0）
1（14.3）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

Mild cognitive
impairment
n= 19

Total, n（%）
Cognitive intervention
Exercise therapy

2（10.5）2（11.8）0（0.0）

1（5.3）
1（5.9）
0（0.0）

1（5.3）
1（5.9）
0（0.0）

1（5.3）
1（5.9）
0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention

2（1.6）
0（0.0）

11（8.7）0（0.0）

18（14.3）
1（33.3）8（6.3）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（11.1）0（0.0）
0（0.0）
1（20.0）5（12.2）0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（5.6）
0（0.0）
1（11.1）1（14.3）1（33.3）2（40.0）6（14.6）2（16.7）0（0.0）
1（50.0）1（5.9）
3（16.7）0（0.0）
0（0.0）
1（14.3）1（33.3）2（40.0）1（2.4）
0（0.0）
0（0.0）
0（0.0）
1（5.9）
2（11.1）0（0.0）
0（0.0）
2（28.6）0（0.0）

2（9.1）
1（14.3）14（63.6）3（42.9）9（40.9）4（57.1）6（27.3）2（28.6）1（10.0）0（0.0）
0（0.0）

7（70.0）1（100.0）3（75.0）3（30.0）1（100.0）1（25.0）4（40.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver
Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy
General support
Multidomain intervention for caregiver

Mixed populationn= 2

Total, n（%）
Cognitive intervention

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― 115 ―Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review
Table 5. （continued）
Outcome domain*
Target population

Type of intervention

Caregiver’s
knowledge

Stress among
caregivers

Othercategory

Normal cognitionn = 31

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Multidomain intervention0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

5（16.1）1（100.0）3（17.6）1（16.7）0（0.0）

Mild cognitive
impairmentn = 19Total, n（%）
Cognitive intervention
Exercise therapy0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）

3（15.8）3（17.6）0（0.0）

Dementia
n = 126

Total, n（%）
Dietary intervention
Cognitive intervention
Exercise therapy
Animal therapy
Art therapyMusic therapy
Reminiscence therapy
Validation therapy
Multidomain intervention
Psychoeducational intervention
CounselingMultidomain intervention for caregiver3（2.4）
1（33.3）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（5.6）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
1（20.0）6（4.8）
0（0.0）
2（4.9）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
2（11.1）0（0.0）
1（11.1）0（0.0）
1（33.3）0（0.0）

35（27.8）2（66.7）9（22.0）3（25.0）1（14.3）0（0.0）
1（5.9）
6（33.3）1（50.0）3（33.3）2（28.6）3（100.0）4（80.0）Caregivers onlyn = 22

Total, n（%）
Psychoeducational intervention
Cognitive-behavioral therapy

6（27.3）3（42.9）7（31.8）2（28.6）18（81.8）5（71.4）1（10.0）0（0.0）
2（50.0）5（50.0）0（0.0）
0（0.0）

8（80.0）1（100.0）4（100.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）

0（0.0）
0（0.0）

General support
Multidomain intervention for caregiver
Mixed population
n=2

Total, n（%）
Cognitive intervention*Some are overlapped. BPSD, behavioral and psychological symptoms of dementia ; ADL, activities of dailyliving ; QOL, quality of life ; MCI, mild cognitive impairment.

Gates NJ, Rutjes AW, Di Nisio M, Karim S, Chong LY, March E,

Burckhardt M（2018） Environmental and behavioural modi-

Martínez G, Vernooij RW（2020） Computerised cognitive

fications for improving food and fluid intake in people withtraining for 12 or more weeks for maintaining cognitive func-

dementia.

tion in cognitively healthy people in late life.

Cochrane

Cochrane Database Syst Rev 7 : CD011542

Hu M, Hu H, Shao Z, Gao Y, Zeng X, Shu X, Huang J, Shen S,
Wu IXY, Xiao LD, Feng H（2022） Effectiveness and accept-

Database Syst Rev 2 : CD012277
Hébert R, Lévesque L, Vézina J, Lavoie JP, Ducharme F, Gen-ability of non-pharmacological interventions in people withdron C, Préville M, Voyer L, Dubois MF（2003） Efficacy of

mild cognitive impairment : Overview of systematic reviews

a psychoeducative group program for caregivers of demented
persons living at home : a randomized controlled trial.

J

Gerontol B Psychol Sci Soc Sci 258 : S58-67
Herke M, Fink A, Langer G, Wustmann T, Watzke S, Hanff AM,

and network meta-analysis.

J Affect Disord 311 : 383-390

Japanese Society of Neurology（2017） Ninchisyo Shikkan
Shinryo Guideline 2017（Clinical Practice Guidelines for
Dementia 2017）. Tokyo, Japan : Igakushoin pp 67-293

― 116 ―Dementia Japan Vol. 37 No. 1 January 2023

Table 6.

Considerations for statistical analyses by target population and type of intervention（n = 200）
Normalcognitionn = 31

Sample size, median（range）≤ 50, n（%）
51-100Mild cognitive
impairmentn = 19Dementia
n = 126

Caregivers
only
n = 22

Mixed
population
n=2

106.0
40.0
58.0
92.0
334.5
（15.0-6742.0） （17.0-223.0） （11.0-653.0） （28.0-329.0） （321.0-348.0）7（22.6）
11（57.9）56（44.4）8（36.4）0（0.0）
7（22.6）17（54.8）5（26.3）3（15.8）39（31.0）31（24.6）4（18.2）10（45.5）0（0.0）
2（100.0）

Power analysis, n（%）

6（19.4）5（26.3）27（21.4）

5（22.7）0（0.0）

Analysis sets, n（%）
ITT
FAS
PPS
No description

9（29.0）1（3.2）
0（0.0）
21（67.7）4（21.1）0（0.0）
2（10.5）13（68.4）

28（22.2）2（1.6）
2（1.6）
94（74.6）

6（27.3）1（4.5）
2（9.1）
13（59.1）0（0.0）
0（0.0）
0（0.0）
2（100.0）3（9.7）
0（0.0）
8（25.8）13（41.9）0（0.0）

4（21.1）1（5.3）
3（15.8）4（21.1）0（0.0）

14（11.1）9（7.1）
18（14.3）
33（26.2）2（1.6）

0（0.0）
1（4.5）
11（50.0）4（18.2）0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

MMRM

4（12.9）1（3.2）

5（26.3）0（0.0）

27（21.4）
1（0.8）

Generalized estimating equations
OthersNo description0（0.0）
2（6.5）
0（0.0）

0（0.0）
2（10.5）0（0.0）

5（4.0）
16（12.7）1（0.8）>100

Primary analysis, n（%）
t-testANOVAANCOVA
Repeated measures ANOVARegression model analysis
Mixed-effects model

3（13.6）2（100.0）0（0.0）
2（9.1）
0（0.0）
1（4.5）

0（0.0）
0（0.0）
0（0.0）
0（0.0）

ITT, intention-to-treat ; FAS, full analysis set ; PPS, per-protocol set ; ANOVA, analysis of variance ; ANCOVA,
analysis of covariance ; MMRM, mixed-effects model for repeated measures.
Karkou V, Meekums B（2017） Dance movement therapy fordementia.

Cochrane Database Syst Rev 2 : CD011022

people and people with mild cognitive impair ment.
Cochrane Database Syst Rev 1 : CD006220

Lai NM, Chang SMW, Ng SS, Tan SL, Chaiyakunapruk N, Stan-

Möhler R, Renom A, Renom H, Meyer G（2018） Personallyaway F（2019） Animal-assisted therapy for dementia.

tailored activities for improving psychosocial outcomes for

Cochrane Database Syst Rev 11 : CD013243

people with dementia in long-term care. Cochrane Database

Lins S, Hayder-Beichel D, Rücker G, Motschall E, Antes G,

Syst Rev 2 : CD009812

Meyer G, Langer G（2014） Efficacy and experiences of

Na R, Yang JH, Yeom Y, Kim YJ, Byun S, Kim K, Kim KW

telephone counselling for informal carers of people with（2019） A Systematic Review and Meta-Analysis of Non-

dementia.

pharmacological Interventions for Moderate to Severe

Cochrane Database Syst Rev 9 : CD009126

Liu Z, Sun YY, Zhong BL（2018） Mindfulness based stress-

reduction for family carers of people with dementia.
Cochrane Database Syst Rev 8 : CD012791

Dementia.

Psychiatry Investig 16 : 325-335

Neal M, Wright PB（2003） Validation therapy for dementia.
Cochrane Database Syst Rev 3 : CD001394

Mallinckrod CH, Lane PW, Schnell D, Peng Y, Mancuso JP

Orgeta V, McDonald KR, Poliakoff E, Hindle JV, Clare L, Leroi I（2018） Recommendations for the primary analysis of con-（2020） Cognitive training interventions for dementia andtinuous endpoints in longitudinal clinical trials.

mild cognitive impairment in Parkinson’s disease.

Drug Inf J

42 : 303 319-

Cochrane

Database Syst Rev 2 : CD011961

Martin M, Clare L, Altgassen AM, Cameron MH, Zehnder F

Rethlefsen ML, Kirtley S, Waffenschmidt S, Ayala AP, Moher D,（2011） Cognition-based interventions for healthy older

Page MJ, Koffel JB ; PRISMA-S Group（2021） PRISMA-

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Ageing Res Rev 62 : 101113

Syst Rev 10 : 39

Salfi J, Ploeg J, Black ME（2005） Seeking to understand telephone support for dementia caregivers.

West J Nurs Res

27 : 701-721
MS, Scholten RJ, Vink AC（2018） Music-based therapeuticinterventions for people with dementia.

Cochrane Database

Syst Rev 7 : CD003477
Vernooij Dassen M, Draskovic I, McCleery J, Downs M（2011）
Cognitive reframing for carers of people with dementia.
Cochrane Database Syst Rev 11 : CD005318

Am J Alzheimers

Dis Other Demen 21 : 391 397-

Woods B, Aguirre E, Spector AE, Orrell M（2012） Cognitive
stimulation to improve cognitive functioning in people withdementia.

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Cochrane Database Syst Rev 2 : CD005562

Woods B, O’Philbin L, Farrell EM, Spector AE, Orrell M（2018）
Reminiscence therapy for dementia.

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Walter E, Pinquart M（2020） How effective are dementia
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support group intervention for female caregivers of community-dwelling individuals with dementia.

van der Steen JT, Smaling HJ, van der Wouden JC, Bruinsma

caregiver interventions?

Winter L, Gitlin LN（2006） Evaluation of a telephone-based

An updated comprehensive meta-

Gerontologist 60 : 609-619

Yao S, Liu Y, Zheng X, Zhang Y, Cui S, Tang C, Lu L, Xu N
（2020） Do non-pharmacological interventions prevent cognitive decline?

Whitty E, Mansour H, Aguirre E, Palomo M, Charlesworth G,a systematic review and meta-analysis.

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Ramjee S, Poppe M, Brodaty H, Kales HC, Morgan Trimmer

Young J, Angevaren M, Rusted J, Tabet N（2015） Aerobic

S, Nyman SR, Lang I, Walters K, Petersen I, Wenborn J, Mini-

exercise to improve cognitive function in older people withouthane AM, Ritchie K, Huntley J, Walker Z, Cooper C（2020）

known cognitive impairment.

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― 118 ―Dementia Japan Vol. 37 No. 1 January 2023

Appendix
Table S1.

Number of studies published in each year by types of intervention（n = 200）
Publication year

Type of intervention≤ 1999n = 20

2000
n=3

2001
n=5

2002
n=5

2003
n=8

Cognitive intervention, n（%）
Validation therapy, n（%）
Multidomain intervention for caregivers, n（%）
Psychoeducational intervention, n（%）
Multidomain intervention, n（%）
Reminiscence therapy, n（%）
Dietary intervention, n（%）
Music therapy, n（%）
Animal therapy, n（%）
Cognitive-behavioral therapy, n（%）

11（55.0）2（10.0）1（5.0）
1（5.0）
1（5.0）
1（5.0）
1（5.0）
1（5.0）
1（5.0）

1（33.3）0（0.0）
1（33.3）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

1（20.0）0（0.0）
0（0.0）
1（20.0）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

2（40.0）0（0.0）
0（0.0）
0（0.0）
2（40.0）1（20.0）0（0.0）
0（0.0）
0（0.0）

2（25.0）0（0.0）
2（25.0）3（37.5）1（12.5）0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

1（33.3）0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
2（40.0）1（20.0）0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

Exercise therapy, n（%）
Counseling, n（%）
Art therapy, n（%）
General support, n（%）

Table S1. （continued）
Publication year
Type of intervention

2004
n=9

2005
n = 102006
n = 102007
n = 162008
n=4

Cognitive intervention, n（%）
Validation therapy, n（%）
Multidomain intervention for caregivers, n（%）
Psychoeducational intervention, n（%）
Multidomain intervention, n（%）
Reminiscence therapy, n（%）
Dietary intervention, n（%）
Music therapy, n（%）
Animal therapy, n（%）
Cognitive-behavioral therapy, n（%）

2（22.2）0（0.0）
2（22.2）
1（11.1）1（11.1）1（11.1）0（0.0）
0（0.0）
0（0.0）

5（50.0）0（0.0）
0（0.0）
1（10.0）1（10.0）0（0.0）
1（10.0）0（0.0）
0（0.0）

3（30.0）0（0.0）
0（0.0）
2（20.0）0（0.0）
1（10.0）0（0.0）
1（10.0）0（0.0）

7（43.8）0（0.0）
0（0.0）
2（12.5）1（6.2）
1（6.2）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
1（25.0）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

1（11.1）1（11.1）0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
2（20.0）0（0.0）
0（0.0）

0（0.0）
2（20.0）0（0.0）
1（10.0）0（0.0）

3（18.8）1（6.2）
0（0.0）
0（0.0）
1（6.2）

0（0.0）
3（75.0）0（0.0）
0（0.0）
0（0.0）

Exercise therapy, n（%）
Counseling, n（%）
Art therapy, n（%）
General support, n（%）

― 119 ―Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review
Table S1. （continued）
Publication year
Type of intervention

2009
n=6

2010
n = 152011
n = 112012
n = 112013
n = 15

Cognitive intervention, n（%）
Validation therapy, n（%）
Multidomain intervention for caregivers, n（%）
Psychoeducational intervention, n（%）
Multidomain intervention, n（%）
Reminiscence therapy, n（%）
Dietary intervention, n（%）
Music therapy, n（%）
Animal therapy, n（%）
Cognitive-behavioral therapy, n（%）

1（16.7）0（0.0）
0（0.0）
1（16.7）0（0.0）
0（0.0）
0（0.0）
1（16.7）0（0.0）

3（20.0）0（0.0）
1（6.7）
0（0.0）
1（6.7）
2（13.3）1（6.7）
3（20.0）0（0.0）

4（36.4）0（0.0）
0（0.0）
0（0.0）
2（18.2）1（9.1）
1（9.1）
1（9.1）
0（0.0）

3（27.3）0（0.0）
0（0.0）
0（0.0）
0（0.0）
4（36.4）0（0.0）
2（18.2）0（0.0）

5（33.3）0（0.0）
0（0.0）
1（6.7）
3（20.0）0（0.0）
0（0.0）
3（20.0）0（0.0）

0（0.0）
3（50.0）0（0.0）
0（0.0）
0（0.0）

1（6.7）
3（20.0）0（0.0）
0（0.0）
0（0.0）

0（0.0）
1（9.1）
0（0.0）
1（9.1）
0（0.0）

0（0.0）
2（18.2）0（0.0）
0（0.0）
0（0.0）

2（13.3）1（6.7）
0（0.0）
0（0.0）
0（0.0）

Exercise therapy, n（%）
Counseling, n（%）
Art therapy, n（%）
General support, n（%）

Table S1. （continued）
Publication year
Type of intervention

2014
n = 162015
n = 132016
n = 14

2017
n=4

2018
n=5

Cognitive intervention, n（%）
Validation therapy, n（%）
Multidomain intervention for caregivers, n（%）
Psychoeducational intervention, n（%）
Multidomain intervention, n（%）
Reminiscence therapy, n（%）
Dietary intervention, n（%）
Music therapy, n（%）
Animal therapy, n（%）
Cognitive-behavioral therapy, n（%）

8（50.0）0（0.0）
0（0.0）
0（0.0）
1（6.2）
2（12.5）0（0.0）
2（12.5）1（6.2）

4（30.8）0（0.0）
2（15.4）0（0.0）
1（7.7）
2（15.4）0（0.0）
2（15.4）2（15.4）6（42.9）0（0.0）
0（0.0）
0（0.0）
1（7.1）
2（14.3）0（0.0）
1（7.1）
3（21.4）4（100.0）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

5（100.0）0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

1（6.2）
1（6.2）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

1（7.1）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

0（0.0）
0（0.0）
0（0.0）
0（0.0）
0（0.0）

Exercise therapy, n（%）
Counseling, n（%）
Art therapy, n（%）
General support, n（%）

Multidimensional Observation Scale for Elderly Subjects（1）, Nursing Home Behavior Problem Scale（1）Cohen-Mansfield Agitation Inventory（3）, Alzheimer’s Disease-Related Quality of Life（1）, Behavior Pathology in Alzheimer’s Disease Rating
Scale（1）, Dementia Care Mapping（1）, Dementia Quality of Life（1）, Geriatric Depression Scale（1）, Hamilton Scale（1）, NeuropsychiatricInventory（1）, Autobiographical Memory InterQuality of Life-Alzheimer’s Disease Scale（3）, Multidimensional Observation Scale for Elderly Subjects（2）view（1）, Clinical Dementia Rating（1）, Cornell Scale for Depression in Dementia（1）, General Health Questionnaire-28 item version（1）, Self
Reported Quality of Life Scale（1）, Short Form-12（1）, Social Engagement Scale（1）Agitation Behavior Mapping Instrument（1）, Cornell Scale for Depression in Dementia（1）, Eriksen Flanker Task（1）, Hamilton Depression
Rating Scale（1）, Hopkins Verbal Learning Test（1）, Neuropsychiatric Inventory（1）, Presence of the target behavior（1）, Rating Anxiety in
Dementia（1）, Self-Ordered Pointing Task（1）, Sickness Impact Profile（1）, Spatio-Temporal Walking Parameters（1）, Task Switching Test（1）,Trail Making Test（1）, Wechsler Memory Scale-III（1）, 1-Back Tests（1）, 2-Back Tests（1）, 36-item Short-Form Health Survey（1）Revised Memory and Problem Behavior Checklist（2）, Adapted-Gilleard Problem Checklist（1）, Center for Epidemiologic Studies-Depression
Scale（1）, Cohen-Mansfield Agitation Inventory（1）, Neuropsychiatric Inventory（1）, Quality of Life-Alzheimer’s Disease Scale（1）, The proportion of patients receiving neuroleptic treatment（1）, Zarit Burden Interview（1）Beck Anxiety Inventory（1）, Center for Epidemiologic Studies Depression Scale（1）, Hamilton Anxiety Scale（1）, Revised Memory and Behavior Problems Checklist（1）Time to institutionalization（1）Animal therapyMusic therapy

Reminiscence therapy

Multidomain intervention

Psychoeducational intervention

Cognitive-behavioral therapy

Counseling

Figures in parentheses indicate the counts used as the primary outcome.

Center for Epidemiologic Studies Depression Scale（2）, Caregiver upset（1）, Confidence in managing the target problem behavior（1）, Frequency of the problem behavior（1）, Hospital Anxiety and Depression Scale（1）, Informant Questionnaire for Cognitive Decline in the Elderly（1）, Medication Appropriateness Index（1）, Pittsburgh Agitation Scale（1）, Responses to the semi-structured interviews（1）, Revised Memory
and Behavior Problem Checklist（1）, Zarit Burden Interview（1）Letter and category fluency（2）, Trail Making Test（2）, AI score for the 3 tracking trials（1）, Category Verbal Fluency Test（1）, Chinese Version
Verbal Learning Test（1）, Digit Span（1）, Digit Symbol Substitution Test（1）, Eriksen Flanker Test（1）, Katz Activities of Daily Living score（1）, List learning test（1）, Neurobehavioral Cognitive Status Examination（1）, Quantitative electroencephalogram（1）, Rey Auditory Verbal
Learning Test（1）, Rivermead Behavioural Memory Test（1）, Stroop Test（1）, Useful Field of View（1）, Wechsler Memory Scale-Revised（1）Exercise therapy

Multidomain intervention for caregiver

Mini-Mental State Examination（8）, Alzheimer’s Disease Assessment Scale-Cognitive subscale（3）, Rey Auditory Verbal Learning Test（3）,Bayer Activities of Daily Living Scale（2）, Brief Story Recall（2）, Minimum Data Set-Home Care Instrumental Activities of Daily Living Scale（2）, Neuropsychiatric Inventory（2）, Phonemic and Semantic Fluency（2）, Rey-Osterrieth Complex Figure Test（2）, Short Story Test（2）,Verbal Naming Test（2）, Avoidance of specific driving situations（1）, Boston Naming Test（1）, Brief Assessment of Prospective Memory-Short
Form（1）, Brief test of attention（1）, Cambridge Cognitive Examination-Revised（1）, Canadian Occupational Performance Measure（1）, CANTAB Stockings of Cambridge problems solved in minimum moves score（1）, Clinician Interview-Based Impression of Change（1）, Complex figure test（1）, Complex Reaction Time（1）, DemTect（1）, Direct Measure of Training（1）, Driving difficulty（1）, Everyday Problems Test（1）,
FAS phonemic fluency test（1）, Hong Kong List Learning Test（1）, Letter verbal fluency（1）, Mattis Dementia Rating Scale（1）, Memo（1）,Mindstreams battery（1）, Mindstreams Stroop Interference test（1）, Nuremberg Aging Observation Scale（1）, Observed Tasks of Daily Living（1）, Phonological Verbal Fluency Test（1）, Quality of Life Questionnaire（1）, Raven’s Coloured Matrices（1）, Recall test（1）, Repeatable Battery for the Assessment of Neuropsychological Status（1）, Self-Care of Heart Failure Index（1）, Semantic verbal fluency（1）, The rate ofpatients alive and without moderately severe to severe dementia（1）, Texas Functional Living Scale（1）, Timed Instrumental Activities of Daily
Living（1）, Trail Making Test（1）, Visual Verbal Learning Test（1）, Word Fluency test（1）, Word recall（1）, 15-dimensional instrument（1）Outcome measures used as primary outcome

Outcome measures used as primary outcome by types of interventions

Cognitive intervention

Intervention

Table S2.

― 120 ―
Dementia Japan Vol. 37 No. 1 January 2023

Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive and therapeutic interventions for dementia continuum : A statistical review（a） Blinding（b） Primary outcome（c） Sample size（d） Power analysis
Figure S1.

Trends of study design quality with publication years― 121 ―

― 122 ―Dementia Japan Vol. 37 No. 1 January 2023

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Study designs and statistical analyses in randomized controlled trials of non-pharmacological preventive andtherapeutic interventions for dementia continuum : A statistical review
Ryoichi Hanazawa1）, Hiroyuki Sato1）, Masanao Sasaki1）,
Keisuke Suzuki2）, Akihiro Hirakawa1）
1）

Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University

2）

Innovation Center for Translational Research, National Center for Geriatrics and Gerontology

Background : Various systematic reviews of non-pharmacological interventions involving the target population of normal cognition, mild cognitive impairment（MCI）, dementia, or caregivers of patients with dementia have attempted to synthesize the effects of interventions ; however, the variations in study designs and the low quality of clinical trial methodology are barriers to deriving reliable conclusions.
Aim : We comprehensively investigated the study designs and statistical analyses used in randomized controlled trials（RCTs）of non-pharmacological preventive or therapeutic interventions for the four target populations, offering common
practical recommendations for designing RCTs on non-pharmacological interventions.
Results : We reviewed 200 RCTs（31 on normal cognition, 19 on MCI, 126 on dementia, 22 on caregivers, and 2 on
mixed populations）. In each target population, >70% of the trials had a follow-up period ≤ 6 months.

About 50% of thestudies on normal cognition or caregivers had a sample size of >100, while 50% of the studies on people with MCI ordementia had a sample size of ≤ 50.

Only 20-25% of studies in each target population performed a power analysis.

Conclusions : Based on the findings of this review, we offer suggestions for future consideration when planning andconducting RCTs on nonpharmacological interventions.
Keywords : Randomized controlled trial ; dementia ; non-pharmacological interventions ; systematic review

Address correspondence to Dr. Akihiro Hirakawa, Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo
Medical and Dental University（1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan）