The Role of Chair Exercise and Intergenerational Activities in Older Adults With Physico-Cognitive Decline Syndrome: An Investigation of Frailty and Serum Mature Brain-Dervied Neurotrophic Factor Level
Phase: NA
Conditions: Cognitive Frailty
Sponsor: Atma Jaya Catholic University of Indonesia

 
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The INTERGEN-INA Study 
 
Effect of Chair-Exercise Followed by Social Heterochronic Parabiosis-
Based Intervention in Community-Dwelling Elderly People with Physio-
Cognitive Decline Syndrome: a Randomized-Controlled Trial 
 
 
 
 
 RESEARCH PROTOCOL  
December 28th, 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Date 
December 28th, 2025 
Institution(s)      
- 
Faculty of Medicine, Universitas Indonesia, Indonesia 
- 
School of Medicine and Health Sciences, Atma Jaya Catholic 
University of Indonesia  
Subsidising party 
None  
Study Site(s) 
- 
School of Medicine and Health Sciences, Atma Jaya Catholic 
University of Indonesia  
Jalan Pluit Selatan Raya No.19, Penjaringan, North Jakarta, Jakarta 
14440 
Funding support 
None (funded personally by the investigator)                                       
Leading 
Investigators               
Rensa (Principal Investigator) 
Department of Internal Medicine, School of Medicine and Health 
Sciences, Atma Jaya Catholic University of Indonesia 
Jalan Pluit Raya No.2, Penjaringan, North Jakarta, Jakarta 14440 
Email: rensa@atmajaya.ac.id ; phone: +6221 6694366 
Project Leader 
Rensa 
Team of 
Investigators   
1. Rensa (Principal Investigator) 
Department of Internal Medicine, School of Medicine and Health 
Sciences, Atma Jaya Catholic University of Indonesia. 
Jalan Pluit Raya No.2, Penjaringan, North Jakarta, Jakarta 14440 
Email: rensa@atmajaya.ac.id; phone: +62 6694366 
2. Siti Setiati  
Division of Geriatric Medicine, Department of Internal Medicine,    
Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo 
Hospital  
Jl. Diponegoro no.71 Central Jakarta, Jakarta 10430, Indonesia 

 
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Email: s_setiati@yahoo.com; phone: +62 31900275 
3. Tirza Z. Tamin 
Departement of Physical Medicine and Rehabilitation, Faculty of 
Medicine, Universitas Indonesia / Cipto Mangunkusumo Hospital  
Jl. Diponegoro no.71 Central Jakarta, Jakarta 10430, Indonesia 
Email: tirzaediva.tamin@gmail.com ; phone: +62 31900275 
4. Purwita Wijaya Laksmi 
Division of Geriatric Medicine, Department of Internal Medicine,    
Faculty of   Medicine Universitas Indonesia / Cipto Mangunkusumo 
Hospital  
Jl. Diponegoro no.71, Central Jakarta, Jakarta 10430, Indonesia 
Email: pwlaksmi@yahoo.com; phone: +62 31900275 
Independent 
experts 
Utami Susilowati 
Research Coordination Center, Department of Internal Medicine 
Faculty of Medicine Universitas Indonesia / Cipto Mangunkusumo 
Hospital 
 Jl. Diponegoro no.71 Jakarta Pusat, Jakarta 10430, Indonesia 
Email: utami.susilowati.ridwan@gmail.com ; phone: +62 8156209540 
 Study sites         
- 
School of Medicine and Health Sciences, Atma Jaya Catholic 
University of Indonesia  
Jalan Pluit Selatan Raya No.19, Penjaringan, North Jakarta, Jakarta 
14440 
- 
Balita Tunas Bangsa Orphanage  
Jalan Bina Marga No.79, Cipayung, East Jakarta, Jakarta 13840 
- 
Pelayanan Kasih Bakti Mandiri (PKBM) Orphanage 
Jalan Abdulrahman No.16, Cibubur, Ciracas, East Jakarta, Jakarta 
13720 
- 
Komunitas Anak Maria Immaculatta (KAMI) Orphanage 
Jalan Pondok Mitra Lestari No.2 Blok C.15, Jatiasih, Bekasi, West Java 
17424 
- 
Putra Utama 1 Orphanage  

 
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Jalan KH Maisin no. 107,  Klender, East Jakarta, Jakarta 13470 
TABLE OF CONTENTS 
1. INTRODUCTION AND RATIONALE 
…………………………………………………………………………………… 
11 
2. OBJECTIVES 
…………………………………………………………………………………… 
11 
3. STUDY DESIGN 
…………………………………………………………………………………… 
12 
4. STUDY POPULATION 
…………………………………………………………………………………… 
13 
4.1 Population (base) 
…………………………………………………………………………………… 
13 
4.2 Inclusion criteria 
…………………………………………………………………………………… 
13 
4.3 Exclusion criteria 
…………………………………………………………………………………… 
14 
4.4 Screening 
…………………………………………………………………………………… 
15 
4.5 Sample size calculation 
…………………………………………………………………………………… 
15 
5. TREATMENT OF SUBJECTS 
…………………………………………………………………………………… 
16 
5.1 Investigational product/treatment 
…………………………………………………………………………………… 
16 
5.2 Use of co-intervention (if applicable) 
…………………………………………………………………………………… 
17 
5.3 Escape medication (if applicable) 
…………………………………………………………………………………… 
17 
6. INVESTIGATIONAL PRODUCT 
…………………………………………………………………………………… 
18 
6.1 Name and description of investigational product(s) 
…………………………………………………………………………………… 
18 
6.2 Summary of findings from non-clinical studies 
…………………………………………………………………………………… 
18 
6.3 Summary of findings from clinical studies 
…………………………………………………………………………………… 
18 
6.4 Summary of known and potential risks and benefits 
…………………………………………………………………………………… 
19 
6.5 Description and justification of route of 
administration and dosage 
 
…………………………………………………………………………………… 
 
19 
6.6 Preparation and labelling of Investigational 
(Medicinal) Product 
 
…………………………………………………………………………………… 
 
19 
6.7 Preparation of transporting and delivery of 
investigational product to Indonesia 
 
…………………………………………………………………………………… 
 
19 
6.8 Drug accountability 
…………………………………………………………………………………… 
20 
7. METHODS 
…………………………………………………………………………………… 
20 
7.1 Study parameters/endpoints 
…………………………………………………………………………………… 
20 
7.1.1 Main study parameter/endpoint 
…………………………………………………………………………………… 
20 
7.1.2 Secondary study parameters/endpoints (if 
applicable) 
 
…………………………………………………………………………………… 
 
20 
7.1.3 Other study parameters (if applicable) 
…………………………………………………………………………………… 
20 
7.2 Randomization, blinding and treatment allocation 
…………………………………………………………………………………… 
21 
7.3 Study procedures 
…………………………………………………………………………………… 
21 
7.3.1 Anthropometry and vital sign 
…………………………………………………………………………………… 
21 
7.3.2 Nutritional status 
…………………………………………………………………………………… 
21 
7.3.3 Blood sampling and laboratory analysis 
…………………………………………………………………………………… 
21 
7.3.4 Physical and functional performances 
…………………………………………………………………………………… 
22 
7.3.5 Cognitive and psychological assessments 
…………………………………………………………………………………… 
22 
7.3.6 Health-related quality of life and comorbidity 
…………………………………………………………………………………… 
22 
7.3.7 Intervention-specific procedures 
…………………………………………………………………………………… 
22 
7.3.8 Monitoring and adherence 
…………………………………………………………………………………… 
23 
7.3.9 Questionnaires 
…………………………………………………………………………………… 
23 
7.4 Study visits 
…………………………………………………………………………………… 
24 
7.5 Withdrawal of individual subjects 
…………………………………………………………………………………… 
25 

 
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7.5.1 Drop out criteria 
…………………………………………………………………………………… 
26 
7.6 Replacement of individual subjects after drop out 
…………………………………………………………………………………… 
26 
7.7 Follow-up of subjects withdrawn from treatment 
…………………………………………………………………………………… 
27 
7.8 Premature termination of the study 
…………………………………………………………………………………… 
27 
8. SAFETY REPORTING 
…………………………………………………………………………………… 
27 
8.1 AEs, SAEs and SUSARs 
…………………………………………………………………………………… 
27 
8.1.1 Adverse events (AEs) 
…………………………………………………………………………………… 
27 
8.1.2 Serious adverse events (SAEs) 
…………………………………………………………………………………… 
28 
8.1.3 Suspected unexpected serious adverse reactions 
(SUSARs) 
 
…………………………………………………………………………………… 
 
28 
8.3 Annual safety report 
…………………………………………………………………………………… 
28 
8.4 Follow-up of adverse events 
…………………………………………………………………………………… 
29 
8.5 Data Safety Monitoring Board (DSMB) / Safety 
Committee 
 
…………………………………………………………………………………… 
 
29 
9. STATISTICAL ANALYSIS 
…………………………………………………………………………………… 
29 
10. ETHICAL CONSIDERATIONS 
…………………………………………………………………………………… 
30 
10.1 Objection by minors or incapacitated subjects (if 
applicable) 
 
…………………………………………………………………………………… 
 
30 
10.2 Benefits and risks assessment, group relatedness 
…………………………………………………………………………………… 
30 
10.3 Compensation for injury 
…………………………………………………………………………………… 
30 
10.4 Incentives (if applicable) 
…………………………………………………………………………………… 
31 
11. ADMINISTRATIVE ASPECTS, MONITORING AND 
PUBLICATION 
 
…………………………………………………………………………………… 
 
31 
11.1 Handling and storage of data and documents 
…………………………………………………………………………………… 
31 
11.2 Monitoring and Quality Assurance (if applicable) 
…………………………………………………………………………………… 
31 
11.3 Amendments 
…………………………………………………………………………………… 
32 
11.4 Annual progress report 
…………………………………………………………………………………… 
32 
11.5 End of study report 
…………………………………………………………………………………… 
32 
11.6 Public disclosure and publication policy 
…………………………………………………………………………………… 
33 
12. STRUCTURED RISK ANALYSIS 
…………………………………………………………………………………… 
33 
12.1 Potential issues of concern 
…………………………………………………………………………………… 
33 
12.2 Synthesis 
…………………………………………………………………………………… 
34 
13. REFERENCES 
…………………………………………………………………………………… 
35 
 
 
 
 
 
 
 
 
 

 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
Abbreviation 
Definition 
ACSM 
American College of Sports Medicine 
AE 
Adverse Event  
AMIR  
Ayo Minum Air (educational program from Indonesian Hydration Working 
Group) 
ANCOVA 
Analysis of Covariance 
ASHT 
American Society of Hand Therapists 
BMI 
Body Mass Index 
CCI 
CHS 
Charlson Comorbidity Index 
Cardiovascular Health Study 
CRF  
Case Report Form 
GCP  
Good Clinical Practice 
GDS-15  
IADL 
Geriatric Depression Scale-15 
Instrumental Activities of Daily Living 
IHWG 
Indonesian Hydration Working Group 
 ITT 
Suspected Unexpected Serious Adverse Reaction  
mBDNF 
MNA 
MoCA-Ina 
PASE 
PCDS 
PEROSI 
PP 
SAE 
SD 
Mature Brain-Derived Neurotrophic Factor 
Mini Nutritional Assessment 
Montreal Cognitive Assessment – Indonesian Version 
Physical Activity Scale for the Elderly 
Physio-Cognitive Decline Syndrome 
Perhimpunan Osteoporosis Indonesia (Indonesian Osteoporosis Association) 
Per-Protocol 
Serious Adverse Event 
Standard Deviation 

 
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SF-12 
SHP 
SPSS 
ToT 
VAS 
WHO 
Short Form-12 (health-related quality of life questionnaire) 
Social Heterochronic Parabiosis 
Statistical Package for the Social Sciences 
Training of Trainers 
Visual Analog Scale 
World Health Organization 
 
 
 
 

 
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SUMMARY 
Rationale: Indonesia is an ageing population with increasing life expectancy, but many elderly 
people experience functional decline leading to physio-cognitive decline syndrome (PCDS), a 
reversible condition combining physical (slow gait and reduced grip strength) and cognitive 
decline (without dementia or disability). PCDS increases the risk of frailty syndrome, disability, 
and reduced quality of life. Structured physical exercise improves the muscle-brain axis and 
neuroplasticity markers like mature BDNF. Social isolation worsens PCDS; intergenerational 
interactions (social heterochronic parabiosis, SHP) may improve cognitive and social domains. 
However, integrated community-based interventions addressing both physical and psychosocial 
domains remain limited in Indonesia.Sch 
Objective: This study aims to evaluate the effectiveness of a structured chair-based exercise 
program combined with intergenerational activities compared with usual care in improving 
physical function, cognitive performance, and frailty status among community-dwelling older 
adults with physio-cognitive decline syndrome. 
Study design: This study is a randomized controlled trial with two parallel arms: (1) chair-based 
exercise followed by intergenerational activities and (2) usual care. The intervention will be 
conducted over a defined intervention period with baseline and post-intervention assessments. 
Setting: This study will be conducted among community-dwelling elderly individuals in programs 
managed by the School of Medicine and Health Sciences at Atma Jaya Catholic University of 
Indonesia and the Archdiocese of Jakarta. The study will include remote tele-exercise and 
nutritional education, as well as in-person intergenerational sessions at orphanages. 
Study population: Community-dwelling elderly aged 60-75 years with PCDS, plus healthy 
cooperative children aged 5-8 years from orphanages for the intervention arm. 
Intervention: Both groups receive nutritional education. Participants in the intervention group 
will receive a structured chair-based exercise program followed by guided intergenerational 
activities designed to enhance physical capacity, cognitive stimulation, and social engagement. 
The control group will receive usual care. Intervention group: 12 weeks structured chair-exercise 
(PEROSI protocol, progressive frequency 1-3x/week, 60 min/session) followed by 4 weeks SHP (8 
sessions, 2x/week, 45 min, paired elderly-child activities using AMIR materials). The control group 
will receive education only. 
Main study parameters/endpoints: The primary outcomes include changes in physical 
performance and cognitive function. Secondary outcomes include changes in frailty status, 
quality of life, and psychosocial well-being. 
 
 

 
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Nature and extent of the burden and risks associated with participation, benefit, and group 
relatedness: Participation in this study involves minimal to low risk. The primary potential risks 
are related to the structured chair-based exercise, including mild musculoskeletal discomfort, 
transient fatigue, muscle soreness, dizziness, or shortness of breath, particularly during the initial 
sessions. These risks are considered low and are commonly associated with light-to-moderate 
physical activity in older adults. To minimize these risks, all exercise sessions will be conducted 
under supervision by trained personnel, with prior health screening and continuous monitoring 
of participants’ physical condition. 
Intergenerational activities are non-invasive and pose no physical risk; however, minor 
psychological discomfort, such as temporary feelings of anxiety or social unease, may occur 
during initial interactions. These activities will be conducted in a supportive and controlled 
environment to ensure participants’ comfort and emotional safety. 
The overall burden to participants includes time commitment for attending intervention sessions 
and undergoing physical, cognitive, and laboratory assessments. Blood sampling for laboratory 
analysis may cause mild pain, bruising, or discomfort at the puncture site, with no expected long-
term adverse effects. 
Potential benefits for participants include improvement in physical function, cognitive 
performance, frailty status, social engagement, and overall quality of life. The anticipated 
benefits are considered to outweigh the minimal risks associated with study participation. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. INTRODUCTION AND RATIONALE 
Indonesia is a country with an ageing population, with older adults comprising approximately 
12% of the total population and a current life expectancy of 72.39 years. The World Health 
Organization (WHO) has introduced the concept of healthy aging, which emphasizes the 
importance of maintaining functional ability and intrinsic capacity in older adults to enable them 
to remain healthy and independent. Impairment of functional ability can lead to disability, which 
has a greater impact than multimorbidity, underscoring the need for early intervention. 
One important early condition in older adults that requires particular attention is physio-
cognitive decline syndrome (PCDS), which is defined as the coexistence of physical functional 
decline (i.e., reduced gait speed or handgrip strength, in the absence of disability) and cognitive 
decline (without dementia). PCDS increases the risk of frailty and deterioration in quality of life; 
however, it remains a potentially reversible condition. Multidomain interventions, such as 
physical and cognitive exercise, have been shown to improve this condition. 
One important biomarker of brain neuroplasticity is mature brain-derived neurotrophic factor 
(mBDNF), which reflects the muscle–brain axis. Social isolation, loneliness, and depression 
further exacerbate PCDS. Therefore, social interventions such as social heterochronic parabiosis 
(SHP)—defined as direct interactions between older adults and younger generations, particularly 
children or adolescents—may represent a promising strategy to improve cognitive function. 
Intergenerational activities have been shown to enhance mental health, cognitive function, and 
physical performance in healthy older adults. 
To date, no studies have specifically described the model and/or role of SHP-based interventions 
in improving physical and cognitive decline among older adults with PCDS. This study utilizes 
educational materials with the potential to facilitate SHP-based interventions in Indonesia, 
namely the “Ayo Minum Air” (AMIR) campaign developed by the Indonesian Hydration Working 
Group (IHWG). These educational materials serve as media to facilitate direct interactions 
between older adults and children (e.g., illustrated comics, exercise videos, and related 
materials), which are essential components of SHP-based interventions. 
This study aims to examine the effects of structured physical exercise followed by SHP-based 
interventions on frailty syndrome and changes in serum mBDNF levels among older adults with 
PCDS, as a novel approach integrating physical and social interventions with biomolecular 
assessment. 
 
2. OBJECTIVES  
Primary Objectives 
To evaluate the effects of 12 weeks of structured physical exercise (chair-based PEROSI protocol) 
followed by 4 weeks of social heterochronic parabiosis (SHP)-based intergenerational 

 
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intervention on frailty syndrome and serum mature brain-derived neurotrophic factor (mBDNF) 
levels in community-dwelling elderly with physio-cognitive decline syndrome (PCDS). 
Secondary objectives 
• To analyze the effects of the combined intervention over 16 weeks on hand grip strength 
in elderly with PCDS. 
• To analyze the effects of the combined intervention over 16 weeks on gait speed in elderly 
with PCDS. 
• To analyze the effects of the combined intervention over 16 weeks on cognitive function 
as measured by the MoCA-Ina score in the elderly with PCDS. 
• To evaluate the effects of the combined intervention over 16 weeks on health-related 
quality of life in the elderly with PCDS. 
• To assess correlations between changes in serum mBDNF levels and changes in MoCA-Ina 
score, hand grip strength, and gait speed in the elderly with PCDS. 
 
Hypothesis 
Elderly people with physio-cognitive decline syndrome (PCDS) who receive 12 weeks of 
structured physical exercise followed by 4 weeks of social heterochronic parabiosis (SHP)-based 
intergenerational intervention on top of nutritional education have significantly better frailty 
syndrome status and higher serum mature brain-derived neurotrophic factor (mBDNF) levels 
than those receiving nutritional education alone after 16 weeks of intervention, along with 
greater improvements in hand grip strength, gait speed, cognitive function (MoCA-Ina score), and 
health-related quality of life.  
 
3. STUDY DESIGN  
This is a single-center, randomized, open-label (unblinded), parallel-group controlled clinical trial 
evaluating the efficacy of a sequential multimodal intervention (structured physical exercise 
followed by SHP-based intergenerational activities) compared to nutritional education alone in 
community-dwelling elderly aged 60–75 years with physio-cognitive decline syndrome (PCDS). 
The study duration per participant is 16 weeks, consisting of: 
• 
Baseline assessment (week 0) 
• 
Intervention period: 12 weeks of chair-exercise + 4 weeks of intergenerational activities 
(intervention arm) or continued education (control arm) 
• 
Intermediate assessment (end of week 12) 
• 
Final assessment (end of week 16) 
 

 
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Participants are randomized in a 1:1 ratio into two arms: 
• 
Intervention arm (n=50): Nutritional education + 12 weeks structured chair-based 
exercise (PEROSI protocol, progressive frequency from 1 to 3 sessions/week, 60 
minutes/session, supervised online) followed sequentially by 4 weeks SHP-based 
intergenerational activities (8 sessions, 2x/week, 45 minutes/session, paired 1:1 elderly-
child using AMIR educational materials at selected orphanages). 
• 
Control arm (n=50): Nutritional education only (2 personalized dietitian tele-conferences 
at weeks 1 and 11; 5 educational e-flyers at weeks 3, 5, 7, 13, and 15). 
Randomization is computer-generated using permuted block randomization (block size 4), 
stratified if necessary, with allocation concealment managed by an independent third party. 
Blinding of participants and instructors is not feasible due to the nature of the behavioral 
interventions; however, outcome assessors for laboratory analyses (mBDNF) are blinded to group 
allocation where possible. 
The trial follows intention-to-treat principles with per-protocol sensitivity analysis. Recruitment 
targets consecutive eligible elderly from community programs under the School of Medicine and 
Health Sciences at Atma Jaya Catholic University of Indonesia and the Archdiocese of Jakarta. 
Child participants (aged 5–8 years, n=50) are recruited from cooperating orphanages exclusively 
for the intervention arm. 
 
4. STUDY POPULATION  
4.1 Population (base) 
The base population consists of community-dwelling elderly individuals aged 60–75 years 
residing in Jakarta, Indonesia, who participate in community programs managed by the School of 
Medicine and Health Sciences at Atma Jaya Catholic University of Indonesia and the Archdiocese 
of Jakarta. Additionally, healthy children aged 5–8 years from cooperating orphanages (Panti 
Asuhan) in the Jakarta area are recruited exclusively for the intergenerational activities in the 
intervention arm. 
4.2 Inclusion criteria 
For elderly participants: 
• 
Aged 60–75 years 
• 
Meet diagnostic criteria for physio-cognitive decline syndrome (PCDS): gait speed <1.0 
m/s and/or hand grip strength <28 kg (men) or <18 kg (women), and MoCA-Ina score 22–
26 
• 
Instrumental Activities of Daily Living (IADL) score >5 

 
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• 
Able to understand and follow instructions adequately 
• 
Willing to participate and provide written informed consent 
For child participants (intervention group only): 
• 
Aged 5–8 years 
• 
In good health and cooperative 
• 
Able to understand and follow instructions 
• 
Written permission obtained from orphanage management 
 
4.3 Exclusion criteria 
For elderly participants: 
• 
Presence of disability or dementia 
• 
Depression or other mental health disorders 
• 
Total immobility 
• 
Acute illness at screening (e.g., pneumonia, acute arthritis with VAS >6/10, acute stroke, 
acute myocardial infarction, uncontrolled hypertension ≥180/100 mmHg, acute COPD 
exacerbation) 
• 
Uncontrolled chronic lung or heart disease 
• 
Hemodynamic instability or hypotension (<90/60 mmHg) at screening 
• 
Recent hospitalization or major surgery within 2 weeks prior to screening 
• 
Illiteracy (unable to read/write) 
• 
Unwilling to participate 
For child participants: 
• 
History of chronic illness, behavioral disorders, intellectual disability, or psychiatric 
conditions 
• 
History of sensory integration therapy, speech therapy, or child psychological therapy 
• 
Unwilling to complete the study 
 

 
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4.4 Screening 
Potential elderly participants are identified consecutively through community programs. 
Screening involves: 
• 
Medical history and informed consent 
• 
MoCA-Ina cognitive assessment 
• 
Hand grip strength (dominant hand, best of 3 trials) 
• 
6-meter gait speed test (average of 2 trials) 
• 
IADL assessment 
• 
Basic physical examination and vital signs to rule out acute/uncontrolled conditions 
Eligible elderly are then randomized. Child participants are selected in collaboration with 
orphanage management based on age, health status, cooperation, and written permission. 
 
4.5 Sample size calculation 
The sample size was calculated to detect clinically meaningful differences between the 
intervention and control groups in key outcome measures, including handgrip strength, gait 
speed, cognitive function (MoCA-Ina score), health-related quality of life (SF-12), and serum 
mature brain-derived neurotrophic factor (mBDNF) levels. 
Sample size estimation was performed using the formula for comparison of two independent 
means, with a two-sided significance level (α) of 5% and a statistical power (1−β) of 80%. The 
standard deviation and expected mean differences for each outcome were derived from 
previously published studies involving older adults, as no prior studies have specifically evaluated 
SHP-based interventions or their combination with structured physical exercise. 
Based on these calculations, the required sample sizes for individual outcome parameters ranged 
from 9 to 42 participants per group. Considering the largest estimated sample size requirement 
and allowing for potential dropouts, the minimum required sample size for this randomized 
controlled trial was determined to be 100 older adult participants, with 50 participants allocated 
to each group (intervention and control). 
This sample size is considered sufficient to evaluate the primary and secondary outcomes of the 
study and to ensure adequate statistical power while accounting for potential attrition during the 
study period. 
  
 

 
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5. TREATMENT OF SUBJECTS 
Subjects will be randomly assigned to one of two groups: structured physical exercise followed 
by a social heterochronic parabiosis (SHP)–based intervention (intervention group) or usual care 
only (control group). Randomization will be computer-generated using a block-permuted 
randomization method with variable block sizes of four. The randomization list will be held by an 
independent third party (staff of the Department of Internal Medicine, School of Medicine and 
Health Sciences, Atma Jaya Catholic University of Indonesia) who is not involved in the research 
team. Both the investigators and the participants will be blinded to group allocation. 
5.1 Investigational product/treatment 
All participants (both arms) receive standardized nutritional education as a base intervention: 
• 
Two personalized nutritional consultations via Zoom tele-conference with a certified 
dietitian (week 1 and week 11), focusing on balanced nutrition tailored to elderly needs. 
• 
Five educational e-flyers on nutrition, physical activity recommendations for the elderly, 
and related topics (sent via mobile device at weeks 3, 5, 7, 13, and 15). 
Intervention group (n=50 elderly + 50 children): In addition to nutritional education, participants 
receive a sequential multimodal intervention: 
1. Structured physical exercise (weeks 1–12): 
• 
Chair-exercise using the Indonesian Osteoporosis Association (PEROSI) protocol, 
adapted for tele-exercise. 
• 
Sessions: 60 minutes duration, consisting of 10 min warm-up (light aerobic + 
flexibility), 30 min core (moderate aerobic, strength, balance), 5–10 min cool-down 
(light aerobic + stretching). 
• 
Frequency progression: 1 session/week (weeks 1–2), 2 sessions/week (weeks 3–6), 
3 sessions/week (weeks 7–12). 
• 
Delivery: Online (tele-exercise) supervised by 1 certified PEROSI instructor and 
assisted by 1 research team member. 
• 
Safety: Pre-session physical condition check; exercise termination based on Borg 
scale and American College of Sport Medicine (ACSM) guidelines for the elderly. 
2. Social Heterochronic Parabiosis (SHP)-based intergenerational intervention (weeks 13–
16): 
• 
Group-based direct interaction: Each elderly participant paired 1:1 with one child 
participant (aged 5–8 years). 

 
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• 
Sessions: 8 total (2 sessions/week, 45 minutes each) conducted in-person at 
selected orphanages. 
• 
Content: Educational and interactive activities using “Ayo Minum Air” (AMIR) 
materials from Indonesian Hydration Working Group (comic reading, simple 
gymnastics demonstration, educational games promoting hydration and healthy 
lifestyle). 
• 
Organization: Elderly divided into 5 groups (10 elderly each); scheduled visits with 
research team accompaniment; facilities prepared for conducive interaction 
(seating, materials, spacing). 
• 
Preparation: Training of Trainers (ToT) for elderly participants and research team 
during weeks 11–12 (3 sessions, 30 min each, outside exercise schedule). 
Control Group 
Participants in the control group will receive usual care according to existing community health 
services. They will not participate in the structured exercise or SHP-based intergenerational 
activities during the study period. However, they will continue to receive standard health 
education and routine activities available within their respective community settings. 
 
5.2 Use of co-intervention (if applicable)  
Co-interventions are minimized and monitored: 
• 
Routine medications and medical care are permitted and recorded. 
• 
Additional structured exercise or intergenerational programs outside the study are not 
allowed during the 16-week period and will be queried at follow-up visits. 
• 
Both arms receive identical monitoring (phone counseling 2–3 times/month) to 
encourage adherence and prevent dropout. 
 
 
5.3 Escape medication (if applicable)  
Not applicable. This is a non-pharmacological intervention study; no escape medication is 
provided. In case of clinical deterioration or acute illness, participants are withdrawn and referred 
for standard medical care. 
 
 
 

 
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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational product 
This is a non-pharmacological behavioral intervention study. There is no investigational medicinal 
product or device. The investigational interventions are: 
• 
Structured physical exercise: Chair-based osteoporosis prevention exercise protocol 
developed by the Indonesian Osteoporosis Association (PEROSI). 
• 
Social heterochronic parabiosis (SHP)-based intergenerational intervention: Direct 
interactive activities between elderly participants and children using educational 
materials from the “Ayo Minum Air” (AMIR) program of the Indonesian Hydration 
Working Group (IHWG), including illustrated comics, simple gymnastics videos, and 
hydration-focused educational games. 
Both interventions are combined sequentially with standard nutritional education (tele-
conferences and e-flyers). 
6.2 Summary of findings from non-clinical studies 
Not applicable. The interventions are non-pharmacological and based on established exercise 
physiology, geriatrics, and intergenerational program research. 
6.3 Summary of findings from clinical studies  
Structured chair-based exercise (similar to PEROSI protocol) has been shown in previous studies 
to improve muscle strength, balance, gait speed, and reduce fall risk in elderly populations, with 
short (12 weeks) benefits. Sequential multimodal interventions (physical exercise followed by 
cognitive/social tasks) have demonstrated superior increases in serum BDNF levels compared to 
the reverse order. Intergenerational programs have shown positive effects on mental health, 
cognitive function, and social well-being in healthy elderly and youth, with reciprocal benefits. 
However, no prior studies have specifically evaluated the combination of structured PEROSI 
exercise followed by SHP-based intervention using AMIR materials in the elderly with PCDS. 
 
 

 
18 | P a g e  
 
6.4 Summary of known and potential risks and benefits 
Known risks: Minimal. 
• 
Physical exercise: Mild fatigue, muscle soreness, low risk of fall or strain (mitigated by 
progressive intensity, supervision, pre-session checks, and termination criteria using Borg 
scale and ACSM guidelines). 
• 
Blood sampling: Minor bruising, pain, or dizziness at the venipuncture site. 
• 
Intergenerational activities: Initial psychological discomfort (awkwardness or anxiety) in 
interacting with unfamiliar children or the elderly. 
• 
Overall: Low risk profile comparable to routine community exercise programs for the 
elderly. 
Potential benefits: 
• 
Improved physical function (grip strength, gait speed), reduced frailty, enhanced cognitive 
performance (MoCA-Ina), increased serum mBDNF (marker of neuroplasticity and 
muscle-brain axis), and better health-related quality of life. 
• 
Additional benefits: Reduced social isolation, enhanced intergenerational empathy, free 
nutritional counseling, and health monitoring for participants. 
The benefit-risk ratio is considered highly favorable, as the interventions are non-invasive, 
reversible, and target a reversible condition (PCDS) with established components of low risk. 
6.5 Description and justification of route of administration and dosage 
Not applicable (non-medicinal product). Justification for “dosage” (intensity/duration): 
• 
Exercise: 12 weeks progressive frequency (1–3 sessions/week, 60 min) based on evidence 
for sufficient stimulus to improve strength, balance, and neuroplasticity in frail/pre-frail 
elderly without overload. 
• 
SHP: 4 weeks, 8 sessions (2/week, 45 min) selected to allow meaningful intergenerational 
bonding and cognitive-social stimulation while minimizing burden on participants and 
orphanages. 
6.6 Preparation and labelling of Investigational Product 
Not applicable. 
6.7. Preparation of transporting and delivery of investigational product to Indonesia 
Not applicable. 
 

 
19 | P a g e  
 
 
6.8 Drug accountability  
Not applicable. Exercise sessions and intergenerational activities are documented for adherence 
(attendance logs, session completion records). Educational materials (e-flyers, AMIR 
comics/videos) are tracked for delivery/receipt. 
 
7. METHODS  
7.1 Study parameters/endpoints 
7.1.1 Main study parameter/endpoint 
• Change in frailty syndrome status (assessed using Cardiovascular Health Study criteria: 
score 0 robust, 1–2 pre-frail, ≥3 frail) from baseline to week 16. 
• Change in serum mature brain-derived neurotrophic factor (mBDNF) levels (measured by 
ELISA) from baseline to week 16. 
7.1.2 Secondary study parameters/endpoints 
• Change in hand grip strength (in kilogram; dominant hand, best of 3 trials using hand 
dynamometer) from baseline to week 16. 
• Change in gait speed (m/s; average of 2 trials over 6-meter walk test) from baseline to 
week 16. 
• Change in cognitive function (MoCA-Ina total score, range 0–30) from baseline to week 
16. 
• Change in health-related quality of life (SF-12 questionnaire) from baseline to week 16. 
• Correlations between changes in serum mBDNF levels and changes in MoCA-Ina score, 
hand grip strength, and gait speed. 
7.1.3. Other parameters (exploratory) 
• Adherence to exercise sessions and intergenerational activities (attendance logs). 
• Nutritional status (Mini Nutritional Assessment, MNA). 
• Physical activity level (Physical Activity Scale for the Elderly, PASE). 
• Depressive symptoms (Geriatric Depression Scale-15, GDS-15). 
• Loneliness (De Jong Gierveld Loneliness Scale, Indonesian version). 
• Quality of life additional domains (EQ-5D-5L). 
• Charlson Comorbidity Index (CCI). 
• Adverse events and dropout reasons. 
7.2 Randomization, blinding, and treatment allocation  
Randomization is performed after screening and baseline assessments using computer-
generated permuted block randomization (block size 4). Allocation is managed by an 
independent third party (staff from the Department of Internal Medicine, School of Medicine and 

 
20 | P a g e  
 
Health Sciences at Atma Jaya Catholic University of Indonesia), not involved in the study. 
Sequence is concealed until assignment. Participants are allocated 1:1 to intervention or control 
arm. 
Due to the behavioral nature of the intervention, blinding of participants, instructors, and 
research team is not possible (open-label design). However, laboratory analysts for mBDNF 
measurement are blinded to group allocation. Outcome assessors for physical measurements 
(grip strength, gait speed) are trained for consistency (inter-rater reliability tested with Kappa 
statistic). 
 
 7.3 Study procedures  
All procedures are performed by trained research personnel (principal investigator, assistants, 
certified instructors). Inter-rater reliability for grip strength and gait speed measurements is 
established prior to study start (Kappa evaluation on 50 elderly people between the principal 
investigator and assistants). Assessments are conducted at three time points: baseline (week 0), 
intermediate (end of week 12, post-exercise phase), and final (end of week 16, post-full 
intervention). Additional monitoring occurs as described. 
7.3.1 Anthropometry and Vital Signs 
• Height: Measured using a stadiometer (or knee-height estimation if standing is difficult). 
• Body weight: Measured with calibrated digital scale (light clothing, no shoes). 
• Body Mass Index (BMI): Calculated as weight (kg)/height² (m²). 
• Vital signs: Blood pressure (seated, average of 2 measurements), heart rate, respiratory 
rate (to rule out acute instability). 
7.3.2 Nutritional Status 
Mini Nutritional Assessment (MNA): Full version administered via interview (screening + 
assessment sections; maximum 30 points). 
Dietary habits: Brief anamnesis on usual intake; no formal 24-hour recall unless needed for 
dietitian consultation.  
7.3.3 Blood sampling and Laboratory analysis 
• Venous blood draw (5–10 mL) from the antecubital vein by a trained phlebotomist. 
• Timing: Fasting preferred but not mandatory; performed at baseline, week 12, and week 
16. 
• Processing: Serum separated by centrifugation, aliquoted, and stored at -80°C until batch 
analysis. 
• Primary biomarker: Mature brain-derived neurotrophic factor (mBDNF) quantified using 
a commercial ELISA kit specific for the mature form (to avoid pro-BDNF cross-reactivity). 
Analysis performed in an accredited laboratory with blinding to group allocation. 
 

 
21 | P a g e  
 
7.3.4 Physical and functional performances  
• Hand-grip strength: Measured using a calibrated hand dynamometer from the American 
Society of Hand Therapists (ASHT) protocol: 
- 
Seated position, shoulder adducted/neutral rotation, elbow 90° flexion, forearm 
neutral, wrist 0–30° dorsiflexion, and 0–15° ulnar deviation. 
- 
Feet flat on floor, dry hands. 
- 
Three maximal efforts on the dominant hand with 30-second rest; the highest value 
recorded (kg). 
- 
Procedure terminated if pain or discomfort is reported.  
• 
Gait speed: 6-meter walk test: 
- 
10-meter straight pathway marked at 0, 2, 6, 8, and 10 meters (2m acceleration, 6m 
timed, 2m deceleration).  
- 
Usual walking pace, no running, assistive device allowed if habitual.  
- 
Two trials; time recorded from 2m to 8m mark; average speed (m/s) calculated.  
• 
Frailty status: Cardiovascular Health Study (CHS) criteria:  
- 
Unintentional weight loss (>4.5 kg or >5% in past year). 
- 
Weakness (grip strength lowest quintile by sex/BMI).  
- 
Exhaustion (self-reported). 
- 
Slowness (gait speed lowest quintile by sex/height). 
- 
Low physical activity (weighted score of kcal/week). 
- 
Scoring: 0 = robust, 1–2 = pre-frail, ≥3 = frail.  
• 
Instrumental Activities of Daily Living (IADL): Lawton scale (score >5 required at 
inclusion; monitored for changes). 
7.3.5 Cognitive and psychological assessments 
• 
Montreal Cognitive Assessment Indonesian version (MoCA-Ina): Administered face-to-
face by trained assessor; total score 0–30 (education adjustment: +1 if ≤12 years formal 
education). 
• 
Geriatric Depression Scale-15 (GDS-15): Self-reported or interviewer-assisted. 
• 
De Jong Gierveld Loneliness Scale (Indonesian version): 11-item questionnaire. 
• 
Physical Activity Scale for the Elderly (PASE): Interviewer-administered; converted 
frequency and duration scores. 
7.3.6 Health-related quality of life and comorbidity 
• 
Short Form-12 (SF-12): Physical and mental component summaries. 
• 
EQ-5D-5L: 
5 
domains 
(mobility, 
self-care, 
usual 
activities, 
pain/discomfort, 
anxiety/depression) plus visual analog scale. 
• 
Charlson Comorbidity Index (CCI): Calculated from medical history and records. 
7.3.7 Intervention-specific procedures 
• 
Nutritional education (both groups): 
- 
Tele-conference consultations (Zoom): Personalized meal planning by dietitian. 
- 
E-flyers: Digital delivery with confirmation of receipt. 
• 
Structured exercise (intervention group): 
- 
Pre-session screening: Symptom query, vital signs if needed. 

 
22 | P a g e  
 
- 
Session monitoring: Borg Rating of Perceived Exertion scale; termination if 
excessive dyspnea, pain, dizziness, or hemodynamic changes. 
• 
Intergenerational activities (intervention group): 
- 
Pre-session preparation: Facility check (seating, materials, spacing). 
- 
Session structure: Introduction, AMIR-based activities (comic reading, joint 
gymnastics, games), reflection. 
- 
Post-session: Brief feedback from the elderly and children. 
7.3.8 Monitoring and adherence 
Adherence and safety are monitored proactively to maximize retention and minimize risks. 
• 
Adherence monitoring: 
- 
Exercise sessions (intervention arm): Attendance logged by instructor and 
research assistant; session completion confirmed (≥85% of planned sessions 
required for per-protocol analysis). 
- 
Intergenerational activities: Attendance sheets signed by research team and 
orphanage staff; activity completion checklists.  
- 
Nutritional education (both arms): Confirmation of tele-conference attendance 
and e-flyer receipt/viewing (via read receipts or follow-up query).  
- 
Overall: Monthly telephone counseling (2–3 calls/month) by research team to 
encourage compliance, address barriers, and reinforce motivation. 
• 
Safety monitoring:  
- 
During exercise phase: Weekly (Monday) pre-session symptom and condition 
checks by team/instructor; Borg Rating of Perceived Exertion scale monitored 
throughout sessions; immediate termination for excessive symptoms (severe 
dyspnea, palpitations, dizziness, heavy weakness, pre-syncope).  
- 
Bi-weekly direct evaluations (weeks 4, 6, 8, 10): Remote or in-person query on 
complaints, with direct supervision during selected sessions.  
- 
Intergenerational phase: On-site supervision by research team and orphanage 
staff; post-session brief feedback on comfort/discomfort.  
- 
General: Participants provided with contact number for immediate reporting; all 
potential adverse events (fatigue, muscle pain, emotional discomfort, minor 
injuries) documented, managed, and reported to Ethics Committee if serious. 
 
7.3.9 Questionnaires  
All questionnaires are administered by trained research assistants through structured interviews 
to ensure consistency, especially for participants with limited literacy or visual impairment. 
Questionnaires are completed at baseline (week 0), intermediate (week 12), and final (week 16) 
assessments unless otherwise specified. Validated Indonesian versions are used where available. 
• 
Short Form-12 (SF-12): Measures health-related quality of life with 12 items covering 
physical and mental component summaries (PCS and MCS). Scores are calculated using 
standard algorithms (range 0–100; higher scores indicate better quality of life). Primary 
focus on changes in physical and mental health domains. 

 
23 | P a g e  
 
• 
EQ-5D-5L (EuroQol 5 Domains – 5 Levels): Assesses five dimensions (mobility, self-care, 
usual activities, pain/discomfort, anxiety/depression) with 5 response levels each, plus a 
visual analog scale (EQ-VAS) for overall health state (0–100). Utility scores are derived 
using Indonesian value sets if available. 
• 
Geriatric Depression Scale-15 (GDS-15): Screens for depressive symptoms with 15 yes/no 
items (score range 0–15; ≥5 suggests depression). Used for monitoring psychological well-
being and exclusion criteria confirmation. 
• 
De Jong Gierveld Loneliness Scale (Indonesian version): 11-item scale measuring 
emotional and social loneliness (range 0–11; higher scores indicate greater loneliness). 
Helps evaluate the impact of social isolation and potential benefits from intergenerational 
activities. 
• 
Physical Activity Scale for the Elderly (PASE): Assesses leisure, household, and 
occupational physical activity over the past week. Scores are calculated based on 
frequency, duration, and intensity weights (higher scores indicate greater activity level). 
Administered to monitor baseline activity and changes. 
• 
Mini Nutritional Assessment (MNA) – Full version: 18-item tool including 
anthropometric measures, global assessment, dietetic assessment, and subjective items 
(maximum 30 points: ≥24 normal, 17–23.5 at risk, <17 malnourished). Complements 
nutritional education intervention. 
• 
Charlson Comorbidity Index (CCI): Calculated from medical history (19 conditions 
weighted 1–6 points) to quantify comorbidity burden and adjust for confounding in 
analyses. 
 
7.4 Study visits  
Study visits are scheduled to minimize burden while ensuring complete data collection. Visits 
occur at community centers, participant homes (if needed), or orphanages. 
• 
Screening/Baseline visit (week 0, 1–2 days): 
- 
Explanation of study, informed consent (elderly and orphanage for children).  
- 
Medical history, comorbidity assessment (CCI), medication review.  
- 
Full physical examination, vital signs, anthropometry.  
- 
Cognitive (MoCA-Ina), physical (hand-grip strength, gait speed), functional (IADL), 
frailty (CHS), nutritional (MNA), and psychological assessments.  
- 
All questionnaires (SF-12, EQ-5D-5L, GDS-15, PASE, loneliness scale).  
- 
Blood sampling. 
- 
Randomization (post-eligibility confirmation). 
- 
Nutritional education initiation (first tele-conference scheduling). 

 
24 | P a g e  
 
• 
Intermediate visit (end of week 12, post-exercise phase):  
- 
Repeat anthropometry, vital signs.  
- 
Physical performance (hand-grip strength, gait speed), frailty status.  
- 
Cognitive (MoCA-Ina) and selected questionnaires (SF-12, EQ-5D-5L, GDS-15, 
loneliness). 
- 
Blood sampling.  
- 
Adherence review; ToT preparation for SHP (intervention arm). 
• 
Final visit (end of week 16):  
- 
Comprehensive repeat of baseline assessments (all physical, cognitive, functional, 
nutritional, psychological, and questionnaires). 
- 
Blood sampling.  
- 
Adherence summary, adverse event review. 
- 
Compensation distribution (transport reimbursement, snacks provision during 
study). 
• 
Ongoing visits/activities: 
- 
Exercise: Weekly tele-sessions (intervention group).  
- 
Intergenerational: 8 in-person sessions at orphanages (weeks 13–16). 
- 
Nutritional: 2 tele-conferences + 5 e-flyers (both groups). 
- 
Monitoring calls. 
Home visits arranged if mobility limits attendance. 
 
7.5 Withdrawal of individual subjects 
Participants (elderly or children via orphanage representative) may withdraw voluntarily at any 
time without providing reasons and without impact on routine care or relationship with 
researchers. Withdrawal is documented but no further study procedures performed unless 
consented for final assessment. 
Investigator-initiated withdrawal occurs for: 
• 
Development of exclusion criteria (e.g., new disability, dementia suspicion, uncontrolled 
chronic disease). 
• 
Acute illness requiring hospitalization or prohibiting continuation (e.g., pneumonia, acute 
stroke, uncontrolled hypertension). 
• 
Non-adherence (>3 consecutive missed exercise sessions or <85% overall intervention 
completion). 
• 
Intolerable adverse events suspected related to intervention. 
Withdrawn participants are encouraged to complete safety follow-up and/or final assessments 
for intention-to-treat analysis. All withdrawals are fully documented (reason, date, partial data 

 
25 | P a g e  
 
collected) and reported to Ethics Committee if related to safety. No replacement of withdrawn 
subjects. 
7.5.1 Drop out Criteria 
Subjects are classified as drop-outs if they do not complete the study protocol through the final 
assessment (week 16) for any reason. Specific drop-out criteria include: 
• 
Non-adherence to intervention: Failure to attend >3 consecutive structured exercise 
sessions (intervention arm) or <85% of total planned exercise sessions; failure to attend 
≥2 intergenerational activity sessions or <85% overall attendance for SHP phase. 
• 
Development of exclusion criteria during study: New onset of disability, 
suspected/confirmed dementia, depression (GDS-15 score indicating moderate-severe 
depression requiring intervention), total immobility, uncontrolled chronic disease, or 
hemodynamic instability. 
• 
Acute illness or clinical worsening: Occurrence of acute conditions (e.g., pneumonia, 
acute arthritis with VAS >6/10, acute stroke, acute myocardial infarction, uncontrolled 
hypertension ≥180/100 mmHg, acute COPD exacerbation) requiring hospitalization or 
prohibiting continuation. 
• 
Adverse events suspected related to intervention: Intolerable or serious symptoms (e.g., 
persistent severe fatigue, muscle pain, dizziness, fall during exercise, significant emotional 
distress during intergenerational activities) leading to investigator decision for 
withdrawal. 
• 
Voluntary withdrawal: Subject (or orphanage representative for children) requests 
discontinuation for any personal reason (e.g., lack of time, loss of motivation, 
transportation difficulties). 
• 
Loss to follow-up: Inability to contact subject despite ≥3 attempts via phone/WhatsApp 
over 2 weeks, or permanent relocation outside study area. 
• 
Death: Any mortality during study period (reported immediately as serious adverse 
event). 
All drop-outs are documented in detail (date, reason, last completed assessment/procedure) on 
the case report form and in the trial master file. 
7.6 Replacement of individual subjects after drop out 
Dropped-out subjects are not replaced. The initial sample size calculation (minimum 100 elderly 
participants, 50 per group) incorporates an anticipated drop-out rate of up to 15% (based on 
similar community-based geriatric intervention studies) to ensure sufficient statistical power for 
primary endpoints. Child participants are paired 1:1 with elderly in the intervention group; if an 
elderly participant drops out during the SHP phase, the paired child continues if feasible and 

 
26 | P a g e  
 
willing, or the session is adjusted accordingly without recruitment of new children. No over-
recruitment or replacement strategy is employed to maintain the integrity of consecutive 
recruitment and randomization. 
7.7 Follow-up of subjects withdrawn from treatment  
Withdrawn subjects are encouraged to complete final assessments for intention-to-treat analysis 
where possible. 
7.8 Premature termination of the study  
The study may be terminated early if significant safety concerns arise, futility is evident, or upon 
recommendation of the Ethics Committee. 
 
8. SAFETY REPORTING  
8.1 AEs, SAEs and SUSARs  
8.1.1 Adverse events (AEs)  
An adverse event (AE) is defined as any untoward medical occurrence, unintended symptom, or 
clinical worsening in a study participant during the study period (from informed consent to final 
assessment), whether or not considered related to the study interventions (structured exercise, 
intergenerational activities, nutritional education, assessments, or blood sampling). 
All AEs are recorded by the research team: 
• 
Spontaneously reported by participants (elderly or children via orphanage 
representative). 
• 
Observed during sessions, monitoring calls, or assessments (e.g., fatigue, muscle 
soreness, minor bruising from blood draw, emotional discomfort). 
• 
Elicited during routine queries (e.g., weekly pre-exercise checks, bi-weekly evaluations, 
post-session feedback). 
AEs are documented in the case report form (CRF) with details on description, onset date, 
severity 
(mild/moderate/severe), 
duration, 
relationship 
to 
intervention 
(unlikely/possible/probable), actions taken, and outcome. Mild AEs (e.g., transient muscle 
soreness, initial awkwardness in interactions) are managed supportively (rest, reassurance, 
session adjustment). 
8.1.2 Serious adverse events (SAEs)  
A serious adverse event (SAE) is any AE that: 
• 
Results in death. 

 
27 | P a g e  
 
• 
Is life-threatening (immediate risk of death). 
• 
Requires hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Constitutes any other medically important event (e.g., acute illness requiring urgent 
intervention that significantly impacts study participation or health). 
Given the low-risk nature of the interventions, SAEs are expected to be rare and mostly unrelated 
(e.g., acute unrelated illness in elderly). All SAEs are reported to the principal investigator 
immediately (within 24 hours of awareness) and to the approving Ethics Committee (Komite Etik 
Penelitian Kedokteran FKUI-RSCM or equivalent) within 15 days. SAEs resulting in death or life-
threatening are reported expedited (initial report within 7 days, complete follow-up within 
additional 8 days). 
8.2.3 Suspected unexpected serious adverse reactions (SUSARs)  
Not applicable. As this is a non-medicinal product study with established low-risk behavioral 
interventions (PEROSI chair-exercise and intergenerational programs), no unexpected serious 
reactions attributable to an investigational product are anticipated. 
 
8.3 Annual safety report  
An annual safety report summarizing all AEs and SAEs (including relatedness assessment and 
cumulative overview) will be submitted to the Ethics Committee if the study duration exceeds 
one year or upon request. The report includes participant enrollment status, deviations, and any 
emerging safety concerns. 
 
8.4 Follow-up of adverse events  
All AEs and SAEs are followed until resolution, stabilization, or return to baseline. Follow-up may 
include: 
• 
Additional phone contacts or visits. 
• 
Medical referral (e.g., to geriatrician or primary care physician). 
• 
Repeat assessments if clinically indicated. 
• 
Documentation of outcome (recovered, ongoing, sequelae). 
Participants withdrawn due to AEs/SAEs receive continued safety monitoring 
 

 
28 | P a g e  
 
8.5 Data Safety Monitoring Board (DSMB) / Safety Committee  
Not applicable. Given the minimal risk profile of the interventions (community-based exercise 
and social activities in screened healthy/cooperative participants), no independent Data Safety 
Monitoring Board is established. Safety oversight is provided directly by the principal investigator 
and supervisor. Any emerging patterns of AEs will prompt ad-hoc review and consultation with 
the Ethics Committee if needed. 
 
9. STATISTICAL ANALYSIS 
All collected data will be initially recorded on research case report forms (CRFs) and subsequently 
transferred to secure electronic storage for data cleaning, coding, and verification. Descriptive 
data and analytical results will be presented in narrative text, tables, or figures as appropriate. 
Normality of data distribution will be assessed using the Kolmogorov-Smirnov or Shapiro-Wilk 
test (p > 0.05 indicates normal distribution). Normally distributed continuous data will be 
presented as mean ± standard deviation (SD); non-normally distributed data as median with 
minimum-maximum range. Categorical data will be presented as frequencies and percentages. 
Statistical significance will be set at p < 0.05. All analyses will be performed using SPSS version 20 
software. 
Primary analyses will be conducted on the per-protocol (PP) population, excluding drop-out 
subjects. Between-group comparisons of changes in study outcomes (hand grip strength, gait 
speed, MoCA-Ina score, serum mBDNF levels, and health-related quality of life) will use unpaired 
t-tests (parametric) or Mann-Whitney U tests (non-parametric), selected based on normality test 
results. 
Correlations between serum mBDNF levels and MoCA-Ina score, hand grip strength, and gait 
speed will be evaluated using Pearson correlation (for normally distributed variables) or 
Spearman correlation (for non-normally distributed variables), according to normality 
assessment of each variable. 
 
10. ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the principles of the Declaration of Helsinki (2013 
revision), Good Clinical Practice (GCP) guidelines, and applicable Indonesian regulations for 
clinical research involving human subjects. The protocol, informed consent forms (for elderly 
participants and orphanage representatives for children), and all study-related materials have 
been submitted for review and approval by the Komite Etik Penelitian Kedokteran Fakultas 
Kedokteran Universitas Indonesia – Rumah Sakit Cipto Mangunkusumo (KEPK FKUI-RSCM) or the 
relevant institutional ethics committee. The study will not commence until written approval is 

 
29 | P a g e  
 
obtained. Any amendments to the protocol will be submitted for ethical review and approval 
prior to implementation. 
10.1 Recruitment and informed consent 
Eligible elderly participants will be informed about the study purpose, procedures, potential risks, 
benefits, voluntary nature, and right to withdraw at any time without consequence through 
verbal explanation and written information sheets. Informed consent will be obtained in writing 
by the principal investigator or trained research assistant, with opportunity for questions. If 
needed, family members or caregivers may accompany the participant during consent, but the 
decision remains with the participant. 
For child participants (intervention arm only), written permission will be obtained from the 
orphanage management (as legal guardian representative). Child-friendly verbal explanations 
will be provided to children, and assent will be sought based on their understanding and 
willingness. Children may refuse or withdraw at any time. 
10.2 Vulnerable subjects 
This study involves two vulnerable groups: 
• 
Elderly (geriatric) participants: Aged 60–75 years with physio-cognitive decline syndrome 
(PCDS), screened for adequate comprehension (MoCA-Ina 22–26, IADL >5). Protection 
measures include clear, repeated explanations (with family/caregiver if desired), 
assurance of voluntariness, close monitoring for discomfort, and immediate withdrawal 
option. 
• 
Children (aged 5–8 years from orphanages): Recruited only for low-risk intergenerational 
activities. Protection includes orphanage guardian consent, child-friendly preparation and 
explanations, constant on-site supervision by research team and orphanage staff, post-
session reflection for emotional well-being, and unrestricted right to refuse or stop 
participation. 
10.3 Benefits and risks assessment, group relatedness 
The study targets a reversible condition (PCDS) with established low-risk interventions. Potential 
benefits include improved physical/cognitive function, reduced frailty, enhanced neuroplasticity 
(mBDNF), 
better 
quality 
of 
life, 
reduced 
social 
isolation, 
and 
free 
nutritional 
counseling/monitoring for elderly; social-emotional development and healthy lifestyle education 
for children. Control group receives education and assessments, minimizing inequity. 
Risks are minimal: mild physical strain or fatigue from exercise, minor venipuncture discomfort, 
initial social awkwardness. These are mitigated by screening, supervised progressive 
interventions, safety monitoring, and termination criteria. The benefit-risk ratio is highly 
favorable for both groups. 

 
30 | P a g e  
 
10.4 Compensation and incentives 
Participation is voluntary. Elderly participants receive transport reimbursement (Rp 100,000 per 
orphanage visit if using their own transport) or free shuttle service, plus snacks/drinks (≈Rp 
50,000 value per intergenerational session). Compensation for assessment visits (three time 
points) covers time/travel. Children receive stationery/books as an appreciation after sessions. 
No cash incentives are provided to avoid coercion. 
10.5 Confidentiality 
Participant identity and data confidentiality are strictly protected. Data are coded with unique 
study IDs; personal identifiers are stored separately in password-protected files accessible only 
to authorized research team members. Paper records are kept in locked cabinets. Data will be 
used solely for research purposes; publications/presentations will use aggregated or anonymized 
data only. No individual data will be shared with third parties without additional consent or 
ethical approval. 
10.6 Insurance and compensation for injury 
Although risks are minimal and no serious intervention-related injury is anticipated, the principal 
investigator maintains professional liability coverage. In the unlikely event of study-related harm, 
participants will receive appropriate medical care at no cost, coordinated by the research team. 
 
11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION  
11.1 Handling and storage of data and documents 
All study data will be handled with strict confidentiality and in compliance with Indonesian 
regulations on personal data protection. 
• 
Participant identifiers (name, contact details, date of birth) will be linked to a unique study 
ID in a separate, password-protected master file accessible only to the principal 
investigator and authorized research team members. 
• 
Case report forms (CRFs) will be completed in paper format initially and stored in locked 
cabinets at the principal investigator’s secure office (School of Medicine and Health 
Sciences, Atma Jaya Catholic University of Indonesia or affiliated site). 
• 
Data will be double-entered into a password-protected electronic database (SPSS or 
equivalent) for analysis. Electronic files will be stored on encrypted institutional 
computers or secure cloud storage with access restricted to the research team. 
• 
Informed consent forms will be stored separately from CRFs in a locked cabinet. 
• 
Audio/video recordings (if any, e.g., tele-exercise sessions) will be deleted after quality 
checks. 

 
31 | P a g e  
 
• 
Biological samples (serum aliquots) will be coded with study ID only and stored at -80°C 
in an accredited laboratory until analysis; remaining samples will be destroyed after study 
completion. 
• 
All study documents and data will be retained for at least 15 years post-study completion, 
after which they will be securely destroyed.  
11.2 Monitoring and Quality Assurance  
Given the minimal-risk nature of this community-based behavioral intervention study, formal 
external monitoring is not required. Quality assurance and internal monitoring will be conducted 
by the principal investigator: 
• 
Regular site visits to community centers and orphanages to verify adherence to protocol, 
facility preparation, and session conduct. 
• 
Review of attendance logs, session checklists, and adverse event records monthly. 
• 
Inter-rater reliability checks for physical measurements maintained through periodic 
calibration and co-assessments. 
• 
Data entry accuracy verified by random spot-checks (10% of CRFs). 
• 
Any protocol deviations will be documented and reported to the Ethics Committee if 
substantial. 
11.3 Amendments  
Substantial amendments (changes potentially affecting participant safety, rights, or scientific 
integrity) will be submitted in writing to the approving Ethics Committee for review and approval 
before implementation. Non-substantial amendments (e.g., minor administrative updates, 
contact details) will be recorded internally and notified annually or at study close-out. 
11.4 Annual progress report  
If the study duration exceeds one year, an annual progress report (including enrollment status, 
adverse events summary, deviations, and preliminary safety data) will be submitted to the Ethics 
Committee within 60 days of the approval anniversary date. 
11.5 End of study report  
• 
Temporary halt for safety or logistical reasons will be notified to the Ethics Committee 
within 15 days, with reasons and resumption plan.  
• 
The end of the study (defined as the last participant’s final assessment) will be notified to 
the Ethics Committee within 8 weeks.  
• 
A final study report summarizing methods, results, adverse events, and conclusions will 
be submitted within one year of study completion. 
 

 
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11.6 Public disclosure and publication policy 
The study will be conducted with commitment to transparent dissemination of results. 
• 
Results will be published in peer-reviewed scientific journals. 
• 
Authorship will follow International Committee of Medical Journal Editors (ICMJE) 
guidelines, with principal contributors listed. 
• 
No sponsor or external party has veto rights over publication. 
• 
Aggregated results will be shared with participating community programs and 
orphanages for feedback and potential implementation. 
• 
Individual participant data will not be publicly disclosed. 
• 
The study protocol and summary results may be registered on a public clinical trial registry 
(e.g., ClinicalTrials.gov or Indonesian equivalent) if required by journal policies. 
 
12. STRUCTURED RISK ANALYSIS  
12.1 Potential issues of concern 
The study involves minimal-risk non-pharmacological interventions in vulnerable populations 
(elderly with physio-cognitive decline syndrome and young children from orphanages). Potential 
concerns include: 
• 
Physical risks to elderly participants: Mild fatigue, muscle soreness, minor strain, or low 
risk of fall during supervised chair-based exercise; minor bruising or discomfort from 
venipuncture (three blood draws). 
• 
Psychological/emotional risks: Initial anxiety, awkwardness, or discomfort during 
intergenerational interactions for both elderly (interacting with unfamiliar children) and 
children (interacting with elderly with physical/cognitive limitations); potential transient 
emotional distress if interactions are not harmonious. 
• 
Logistical/operational risks: Transportation issues to/from orphanages; adherence 
challenges due to elderly mobility or motivation; potential loss to follow-up in community 
setting; coordination difficulties with multiple orphanages. 
• 
Data and confidentiality risks: Unintentional breach of personal data during digital 
transfer (e-flyers, tele-conferences) or storage. 
• 
Equity and coercion risks: Perception of undue influence on orphanage children or elderly 
due to incentives (snacks, transport reimbursement, stationery). 

 
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• 
Unforeseen risks: Acute unrelated illness in elderly triggering withdrawal; seasonal factors 
(e.g., weather, holidays) affecting session attendance. 
12.2 Synthesis 
This structured risk analysis concludes that the overall risk level is minimal and acceptable given 
the study’s objectives and population. The interventions (PEROSI chair-exercise and AMIR-based 
intergenerational activities) are established, low-intensity, community-based practices with 
proven safety profiles in similar geriatric and intergenerational programs. 
All identified risks are effectively mitigated through: rigorous screening/exclusion criteria; 
progressive/supervised exercise with termination guidelines; professional blood sampling; 
preparatory training (ToT) and on-site supervision for intergenerational sessions; child-friendly 
approaches and orphanage oversight; proactive adherence support (phone counseling, transport 
provision); secure data handling; and voluntary participation with clear withdrawal rights. 
Potential benefits (improved physical/cognitive function, reduced frailty and isolation, enhanced 
neuroplasticity via mBDNF, intergenerational empathy, and healthy lifestyle education) 
substantially outweigh the minimal risks for both elderly and child participants. The control group 
receives meaningful nutritional education and monitoring, ensuring ethical equipoise. No serious 
intervention-related harm is anticipated; any adverse events will be promptly managed and 
reported. The benefit-risk balance strongly supports proceeding with the study under close 
internal oversight and Ethics Committee approval. 
 
 
 
 

 
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13. REFERENCES 
1. World Health Organization. Healthy ageing and functional ability. WHO. 2020. 
2. World Health Organization. International Classification of Functioning, Disability and 
Health. Edisi ke-1. Geneva: World Health Organization, 2001. 
3. World Health Organization. Handbook Guidance on Person-Centred Assessment and 
Pathways in Primary Care ICOPE. WHO. 2019. 
4. Beard JR, Officer A, De Carvalho IA, Sadana R, Pot AM, Michel JP, et al. The World report 
on ageing and health: a policy framework for healthy ageing. The Lancet. 2016 
May;387(10033):2145–54. 
5. Sum G, Lau LK, Jabbar KA, Lun P, George PP, Munro YL, et al. The world health organization 
(WHO) integrated care for older people (ICOPE) framework: a narrative review on its 
adoption worldwide and lessons learnt. Int J Environ Res Public Health. 2022 Dec 
22;20(1):154. 
6. Liu W, Qin R, Zhang X, Li G, Qiu Y, Zhang G, et al. Effectiveness of integrated care for older 
people (ICOPE) in improving intrinsic capacity in older adults: a systematic review and 
metaanalysis. J Clin Nurs. 2025 Mar;34(3):1013–31. 
7. Kementrian Kesehatan. Keputusan Menteri Kesehatan Republik Indonesia Nomor 
HK.01.07/MENKES/2015/2023 Tentang Petunjuk Teknis Integrasi Pelayanan Kesehatan 
Primer. Kemenkes. 2023. 
8. Chen LK, Woo J, Assantachai P, Auyeung TW, Chou MY, Iijima K, et al. Asian working group 
for sarcopenia 2019 consensus update on sarcopenia diagnosis and treatment. J Am Med 
Dir Assoc. 2020 Mar;21(3):300-307.e2. 
9. Wilkinson DJ, Piasecki M, Atherton PJ. The age-related loss of skeletal muscle mass and 
function: Measurement and physiology of muscle fibre atrophy and muscle fibre loss in 
humans. Ageing Res Rev. 2018 Nov;47:123–32. 
10. Larsson L, Degens H, Li M, Salviati L, Lee YI, Thompson W, et al. Sarcopenia: Aging-Related 
Loss of Muscle Mass and Function. Physiol Rev. 2019 Jan 1;99(1):427–511. 
11. Milanovic Z, Jorgi B, Trajkovi N, Sporis, Panteli S, James. Age-related decrease in physical 
activity and functional fitness among elderly men and women. Clin Interv Aging. 2013 
May;5:49. 
12. Booth FW, Zwetsloot KA. Basic concepts about genes, inactivity and aging. Scand J Med 
Sci Sports. 2010 Feb;20(1):1–4. 
13. Inns TB, Bass JJ, Hardy EJO, Wilkinson DJ, Stashuk DW, Atherton PJ, et al. Motor unit 
dysregulation following 15 days of unilateral lower limb immobilisation. J Physiol. 2022 
Nov;600(21):4753–69. 
14. Sarto F, Stashuk DW, Franchi MV, Monti E, Zampieri S, Valli G, et al. Effects of shortterm 
unloading and active recovery on human motor unit properties, neuromuscular junction 
transmission and transcriptomic profile. J Physiol. 2022 Nov;600(21):4731–51. 
15. Gustafsson T, Ulfhake B. Aging Skeletal Muscles: What Are the Mechanisms of Age-
Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and 
Progression? Int J Mol Sci. 2024 Oct 1;25(20):10932. 
16. American College of Sports Medicine, Liguori G, Feito Y, Fountaine CJ, Roy B, editors. 
ACSM’s guidelines for exercise testing and prescription. Eleventh edition. Philadelphia, 

 
35 | P a g e  
 
Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Wolters Kluwer; 
2022. 513 p. 
17. Lohne-Seiler H, Kolle E, Anderssen SA, Hansen BH. Musculoskeletal fitness and balance in 
older individuals (65-85 years) and its association with steps per day: a cross sectional 
study. BMC Geriatr. 2016 Jan 12;16:6. 
18. Jackson AS, Sui X, Hébert JR, Church TS, Blair SN. Role of Lifestyle and Aging on the 
Longitudinal Change in Cardiorespiratory Fitness. Arch Intern Med Internet. 2009 Oct 
26;169(19). 
19. Gaspar-Silva F, Trigo D, Magalhães J. Ageing in the brain: mechanisms and rejuvenating 
strategies. Cell Mol Life Sci. 2023 Jul;80(7):190. 
20. Elobeid A, Libard S, Leino M, Popova SN, Alafuzoff I. Altered Proteins in the Aging Brain. J 
Neuropathol Exp Neurol. 2016 Apr;75(4):316–25. 
21. Azam S, Haque MdE, Balakrishnan R, Kim IS, Choi DK. The Ageing Brain: Molecular and 
Cellular Basis of Neurodegeneration. Front Cell Dev Biol. 2021 Aug 13;9:683459.