Multi-Component Prehabilitation Program for High-Risk Older Adults Undergoing Major Elective Surgery: A Pilot and Feasibility Study
Phase: NA
Conditions: Frailty, Functional Recovery, Prehabilitation
Sponsor: Beth Israel Deaconess Medical Center

 
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Multi-Component Prehabilitation Program for High-Risk 
Older Adults Undergoing Major Elective Surgery:  
A Pilot and Feasibility Study Protocol 
 
Clinical Trial Registration: NCT05752474 
 
Update History: 
Version 1: 02/20/2023 
Version 2: 04/19/2023 
Version 3: 06/15/2023 
Version 4: 08/04/2023 
Version 5: 09/06/2023 

 
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Table of Contents 
1. UPDATE HISTORY ....................................................................................................................................... 4 
2. OVERVIEW .................................................................................................................................................... 5 
3. STUDY OBJECTIVES ................................................................................................................................... 6 
3.1 Objective/Aim 1. .............................................................................................................................................. 6 
3.2 Objective/Aim 2. .............................................................................................................................................. 7 
4. BACKGROUND ............................................................................................................................................. 7 
5. STUDY POPULATION .................................................................................................................................. 9 
5.1 Inclusion Criteria: ......................................................................................................................................... 9 
5.2 Exclusion Criteria: ........................................................................................................................................ 9 
6. ENROLLMENT .............................................................................................................................................. 9 
6.1 Baseline Assessment ................................................................................................................................ 10 
6.2 Medical Record Review: ............................................................................................................................ 11 
7. STUDY INTERVENTION ............................................................................................................................. 11 
7.1 Component 1: Exercise ............................................................................................................................. 12 
7.2 Component 2: Nutrition ............................................................................................................................. 13 
7.3 Component 3: Meditation ......................................................................................................................... 14 
7.4 Component 4: Cognitive Behavioral Interventions ............................................................................ 14 
8. STUDY ENDPOINTS/OUTCOMES ............................................................................................................ 15 
8.1 Primary Outcome ........................................................................................................................................ 15 
8.2 Secondary Outcomes ................................................................................................................................ 15 
8.3 Exploratory Outcomes ............................................................................................................................... 16 
9. QUALITATIVE INTERVIEWS ..................................................................................................................... 18 
10. DATA AND SAFETY MONITORING ........................................................................................................ 19 
10.1 Adverse Events ......................................................................................................................................... 19 
10.2 Adverse Event Monitoring ...................................................................................................................... 19 
10.3 Interim Analysis ........................................................................................................................................ 20 
10.4 Data Safety Monitoring Plan .................................................................................................................. 20 
11. ANALYSIS PLAN ...................................................................................................................................... 21 
11.1 Statistical Analysis for Feasibility ........................................................................................................ 22 

 
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11.2 Statistical Analysis for Qualitative Research .................................................................................... 22 
12. HUMAN SUBJECT PROTECTION AND PROTECTION OF CONFIDENTIALTY ................................ 22 
12.1 Risks to Human Subjects ....................................................................................................................... 22 
12.2 Protection Against Risks ........................................................................................................................ 22 
12.3 Potential Benefits to Human Subjects and Others .......................................................................... 23 
12.4 Importance of Knowledge to be gained .............................................................................................. 24 
13. REFERENCES ........................................................................................................................................... 25 
 
 
 
 

 
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1. UPDATE HISTORY 
 
Date 
Summary 
02/20/2023 
Initial protocol completed 
04/19/2023 
Offer in-person consenting, meditation, and nutrition group classes 
06/15/2023 
Add the Brief Capacity Assessment Questionnaire 
08/04/2023 
Add cardiovascular procedures to the inclusion criteria 
09/06/2023 
Update the screening procedure by removing the high-risk feature 
requirement and increasing the age to 70 for email screening. 
Surgeons can directly refer their patients to the study team 
(including patients aged 65-69 years) if they feel these patients are 
high-risk based on their clinical judgement. 
 

 
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2. OVERVIEW 
 
The purpose of this feasibility pilot study is to understand how a prehabilitation program 
for older adults with frailty can best be optimized to prepare at-risk patients for major 
surgery. As such, our program interventions target major risk factors that are modifiable 
yet rarely addressed in the pre-surgery period (physical function, nutrition, pain, sleep, 
anxiety, and cognition). We also aim to determine how these interventions can best be 
delivered for optimal participation.  
Participants will receive 3 to 4 weeks of exercise training with a physical therapist, nutrition 
education with a registered dietitian, meditation with an experienced meditation teacher, 
and cognitive behavioral intervention to discuss goals, facilitators and barriers to program 
adherence with the goal to enhance motivation and promote self-efficacy. Two (2) follow-
up assessments will additionally be performed at days 30 and 90. Further details of the 
intervention are provided below: 
• Exercise training with home/virtual/in-center physical therapy will take place on 
average twice a week for 1 hour per session over 3-4 weeks. The participant will be 
encouraged to exercise on their own for 30 minutes per day for 4 or more days a week 
and track exercise in a diary (number of minutes achieved per day). They will also be 
asked to wear a physical activity tracking device (Fitbit Fitness tracker) to measure 
daily number of steps, active minutes, and heart rate. This device will also remind the 
participant to get up and move throughout the day. 
• Nutrition class with a licensed nutritionist (registered dietitian) will take place on 
average once a week for 1 hour per session over 3-4 weeks. The participant will also 
be asked to drink/consume 1 high calorie, high protein nutritional supplement per day 
which will be provided to them by the study. They will be asked to write down their 
approximate daily food intake in a diary (3 days/week) – this will be an informal 
accounting of their intake with the primary focus being on protein-containing food 
items. This information will be used to measure their protein intake during their 
participation in the study.  
• Meditation with a yoga/meditation teacher will take place once a week for 1 hour per 
session over 3-4 weeks. The participant will also be asked to practice meditation on 
their own for at least 12 minutes each day and track in a diary (number of minutes 
achieved each day).  
• Weekly check-in calls will take place once a week for about 30 minutes per sssion 
over 3-4 weeks. During these calls the participant will talk about their goals, discuss 
personal motivation, and review their progress. They will be asked about any potential 
adverse events (such as sore muscles or falls).  
• A 30 minute telephone interview will take place at the end of the intervention (in weeks 
3 or 4). The participant will be asked to provide feedback discussing what parts of the 

 
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intervention worked well and what did not. We will use this information for protocol 
refinement. 
The primary outcome is the feasibility of the prehabilitation protocol, defined as the 
proportion of patients to whom we can deliver an adequate dose (≥50% of the planned 
sessions) of the 3 core interventions: physical therapy (≥4/8 sessions), nutrition (≥2/4 
sessions), and meditation (≥2/4 sessions).  Secondary outcomes include 1) adherence to 
exercise, protein intake and meditation; 2) changes in 5-chair stand time, dominant 
handgrip strength, patient-centered outcomes, measured using PROMIS scores in 
physical function, cognitive function, participation in social roles/activities, depression, 
anxiety, sleep disturbance, pain and fatigue domains at baseline, following completion of 
the prehabilitation (before surgery), and on postoperative days 30 and 90; 3) clinical 
outcomes (3-D Confusion Assessment Method,1 a composite complication score,2 length 
of stay, and 30-day readmission and death); and 4) Postoperative Quality of Recovery 
Scale3 to be obtained around postoperative day 3; 5) adverse events. 
 
The proposed research will provide necessary information for a larger randomized 
controlled trial (RCT). 
 
3. STUDY OBJECTIVES 
 
The objective of this pilot study is to evaluate feasibility of a prehabilitation program in 
frail older adults undergoing major surgery. Our central hypothesis is that optimizing risk 
factors before surgery with a multicomponent prehabilitation protocol will improve 
postoperative outcomes in high-risk older adults undergoing major elective abdominal, 
gynecological oncologic, and urologic surgery. By utilizing a patient-centered 
multicomponent protocol, the most effective intervention strategies of the protocol can be 
refined for a larger-scale randomized controlled trial. This research has four (4) 
intervention components: 1) physical therapy; 2) nutrition; 3) meditation; and 4) cognitive 
behavioral strategies will additionally be utilized to enhance motivation and support self-
efficacy. We will accomplish the following two (2) specific aims: 
 
3.1 Objective/Aim 1. To evaluate the feasibility of and adherence to the 
prehabilitation program. We will estimate the duration of preoperative geriatric 
assessment screening; enrollment rate; feasibility of and adherence to the prehabilitation 
program; attrition rate; and extent of missing outcome data. We expect that we will be 
able to deliver our prehabilitation program to ≥50% of patients.  
 
Feasibility is defined by proportions of enrollment, refusal, and adherence to intervention 
components as a whole and individually, potential barriers to adherence, and self-
reported and objective measures of adherence including diaries, wearable sensors, and 
physical performance tests. As secondary outcomes, we will collect clinical outcomes 
(e.g., Postoperative Quality of Recovery Scale, surgical complications, and length of stay) 
and Patient-Reported Outcomes Measurement Information System (PROMIS) measures.  
 

 
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3.2 Objective/Aim 2. To identify barriers and facilitators of prehabilitation program 
and refine protocol accordingly. After the prehabilitation program, we will interview 
patients and their caregivers to identify facilitators, barriers, and areas for improvement. 
After completing all qualitative interviews, we will refine the intervention components 
based on participant feedback. This information will inform the design of a future, larger 
RCT which will target frailty using the most effective intervention components.  
 
By completing this research, we hope to generate evidence that rehabilitation 
interventions are feasible and effective for optimizing risk factors before surgery. Based 
on our review of literature, we concluded that the success of an RCT would depend on 
having a feasible and acceptable prehabilitation program in the preoperative period.  
Therefore, we chose to focus on intervention refinement to provide necessary information 
to design a large RCT to compare a multicomponent prehabilitation program versus usual 
care on clinical and patient-centered outcomes among high risk older adults undergoing 
major elective surgery.  
 
4. BACKGROUND 
 
Current practice of preoperative evaluation does not consider the intrinsic capacity of 
older adults to tolerate stress related to surgery. Frailty is a measure of intrinsic capacity.4 
Individuals with frailty have decreased physiologic reserve to tolerate stressors,5 and thus 
they are more likely to experience poor surgical outcomes, such as complications, 
mortality, readmission, functional decline, and discharge to an institution.6,7 While it is a 
reliable measure of surgical risk, frailty is not part of the preoperative assessment of older 
adults. Frailty assessment within the context of a comprehensive geriatric assessment—
a multi-domain assessment of medical history, functional status, cognition, mood, 
physical performance, and nutritional status8—provides not only risk stratification but also 
opportunities to optimize modifiable risk factors to improve surgical outcomes. 
 
Optimizing risk factors before surgery may improve outcomes. Interventions to increase 
reserve through physical activity and nutritional interventions before surgery are 
biologically plausible ways to improve surgical outcomes, but they are not routinely done 
in practice. To date, studies on prehabilitation have mostly been on gastrointestinal,9-13 
cardiothoracic,10,14 and orthopedic surgeries15 with physical activity and nutrition as single 
or dual interventions.9-12,14 There are only a small number of RCTs on a multicomponent 
prehabilitation (≥3 interventions).16-21 Some studies have shown that prehabilitation may 
decrease length of stay and postoperative complications, and improve function, while 
others did not show benefits.9,11,12,14,22,23 Systematic reviews concluded insufficient 
evidence for prehabilitation for clinical use due to significant limitations of studies, 
including small sample sizes,11,13,15,24,25 increased risk of bias (e.g., single-arm studies),9-
11,14,23,26 and lack of attention to adherence.13,14,21,24,26 Little is known about facilitators of 
and barriers to adhering to prehabilitation interventions, particularly among frail 
patients.27,28 Moreover, evidence as to which patients will most benefit from 
prehabilitation10,29 and the effect of prehabilitation on patient-centered outcomes14 are 
lacking.  

 
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The efficacy and potential mechanisms of interventions are supported by evidence (Table 
1). Short duration (3-4 week) intensive exercise and protein-focused nutrition programs 
have also previously been shown to improve physical measures30,31 and outcomes18,19,32-
34; however, a robust RCT of a multi-component prehabilitation program addressing the 
aforementioned gaps is still needed.  
 
Table 1. Evidence and potential mechanisms for multi-component prehabilitation program 
 
 
To accomplish this, we are planning to conduct an RCT of a multi-component 
prehabilitation program versus usual care on patient-centered outcomes in older adults 
undergoing major surgery (Figure 1).  
 
Figure 1. Conceptual model for an RCT of prehabilitation program. Abbreviation: CGA, comprehensive geriatric 
assessment. 
 
 
In this future RCT, we will identify candidates for prehabilitation based on the patient’s 
frailty level, which represents the physiologic reserve to tolerate stress from surgery and 
hospitalization. We will provide a multicomponent intervention which not only addresses 
the body but also the neurobehavioral aspect of a frail patient, given the link between 
frailty and cognition.28 We will measure patient-centered outcomes using validated 
Patient-Reported Outcomes Measurement Information System (PROMIS) measures.29 
Therefore, we propose this pilot study to assess the feasibility of key steps of this ideal 
RCT and refine a multicomponent prehabilitation protocol to ensure its feasibility and 
adherence. 
Day -30
Surgery 
(Day 0)
Discharge
Day 90
Day 30
CGA 
Assessment of risk factors
Prehabilitation 
Interventions for modiﬁable risk factors
䢖 Muscle strength
䢖 Muscle mass
䢖 Pain threshold
䢖 Improve sleep
䢗 Anxiety
䢖 Cognitive reserve
䢗 Postoperative 
complications
䢖 Patient-Reported 
Outcomes
䢖 Early readiness 
for discharge

 
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5. STUDY POPULATION  
 
We will review schedules to identify patients who meet the following inclusion (5.1) and 
exclusion criteria (5.2). A trained research assistant will perform preoperative geriatric 
assessment—which consists of 1) medical history (automated in EHR), 2) self-reported 
functional status (a questionnaire of 22 daily activities and physical tasks), 3) tests of 
cognitive function (Mini-Cog or MoCA test) and physical function (gait speed, chair stands, 
and grip strength), and 4) nutritional status (automated in EHR)—and calculate a frailty 
index using our EHR calculator.  For eligible patients, we will explain the purpose of our 
study to the patients and their surgeon and ask whether they are willing to participate in 
3 to 4 weeks of prehabilitation. Remote or e-consent will be obtained. Screening of 
potential participants will take place during the surgeon’s office visit.  The assessment of 
eligibility will take place by telephone.  Our target enrollment is 30 patients (2 patients per 
week for 15 weeks).  See the detailed inclusion and exclusion criteria provided below: 
 
5.1 Inclusion Criteria: 
 
• Patient is ≥70 years 
• Patient is ≥65 years old AND high risks per surgeon’s clinical judgement 
• Patient is scheduled to have a gastrointestinal, gynecological oncologic,  
urologic, and cardiovascular procedure 
• Patient provides an informed e-consent or remote consent  
 
5.2 Exclusion Criteria: 
 
• Surgery is scheduled less than 21 days from the expected start date of the 
prehabilitation intervention 
• Patient is considered an inappropriate candidate per the surgeon’s assessment. 
• Non-English speaking 
• Patient has a major cognitive impairment, which will be defined as telephone 
Montreal Cognitive Assessment (MoCA) <18 or Brief Capacity Assessment 
Questionnaire 
• Patients with chronic kidney disease stage 3 or higher will be excluded from 
receiving protein supplement of the prehabilitation intervention. 
 
6. ENROLLMENT 
 
As stated above, patients who are scheduled to undergo a gastrointestinal, gynecological 
oncologic, and urologic surgery, meet inclusion criteria, and have approval from their 
surgeon to participate will be contacted by a study clinician who will assess eligibility, 
including a telephone-based preoperative frailty assessment (only patients with frailty will 
be eligible). This assessment includes the following domains: 

 
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• Medical history 
• Self-reported functional status (activities of daily living [ADL], instrumental 
activities of daily living [IADL], and physical tasks without another person’s help) 
• Tests of cognitive function (Telephone MoCA)  
• Nutritional status (BMI and self-reported weight loss)  
 
Most of these assessments are already available or routinely collected and entered in 
BIDMC Online Medical Record (OMR). The study clinician will verify the existing 
information in OMR with the patient and fill in any missing information if needed. The OMR 
frailty index calculator calculates the frailty index based on information available in OMR 
(Figure 2). The index ranges from 0 to 1; frailty is defined as ≥0.25. 
 
Figure 2. Example report of OMR frailty index calculator and assessment report. The frailty index calculator (A) 
will use the latest information available in OMR to calculate a deficit-accumulation frailty index.  The report shows the 
assessment domain-specific impairment and comparison of the frailty index against a reference population of Medicare 
beneficiaries.  
 
 
6.1 Baseline Assessment 
 
Once informed e-consent or remote consent is signed, trained research personnel will 
administer additional measurements that are not collected as part of preoperative 
assessment. These measurements (provided below) may be conducted 1) during the 
telephone call during which informed consent is obtained; 2) during a separate call (if 

 
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requested by the patient or caregiver); 3) email survey; 4) during an in-person physical 
therapy session (for gait speed, chair stands, and handgrip strength); or 5) a combination 
of these modalities. 
 
• Usual walking speed from 4-meter walk (if not already measured) 
• Time to complete 5 chair stands (if not already measured) 
• Dominant handgrip strength: average of 3 measurements (if not already 
measured) 
• 3-day diet recall (done by telephone) 
• PROMIS Profile CAT v1.0 is a 29-item, computer adaptive, patient-reported 
outcome measure of social roles/activities, anxiety, depression, fatigue, pain 
interference/intensity, physical function, and sleep disturbance domains (may be 
done by telephone or email) 
• PROMIS v2.0 Cognition CAT is a 12-item, computer adaptive, patient-reported 
outcome measure of cognitive function domain (may be done by telephone) 
 
PROMIS (available at https://www.healthmeasures.net/index.php) is a publicly available, 
validated system of highly reliable, precise measures of patient-reported health status for 
physical, mental, and social well-being for general population as well as people with 
chronic conditions. It is designed to enhance communications between clinicians and 
patients in diverse clinical and research settings. Computer adaptive test (CAT) allows 
accurate assessment with a limited number of questions from the PROMIS item bank, 
thereby reducing participant burden. 
 
6.2 Medical Record Review: 
 
Trained research personnel will obtain the following data from the OMR and record them 
in REDCap database: 
 
• Demographic information: age, sex, race, ethnicity 
• Chronic comorbidities 
• Self-reported functional status: ADL, IADL, physical tasks by Nagi and Rosow-
Breslau  
• Cognitive function: telephone MOCA  
• Physical function: gait speed, dominant handgrip strength, and chair stands 
• Nutritional status: height, weight, BMI, weight loss in the past year, serum 
albumin level 
 
7. STUDY INTERVENTION 
 
All participants will be enrolled in a prehabilitation program that will start 3-4 weeks prior 
to the date of scheduled surgery. The intervention will target three principal components 
(physical activity, nutrition, and meditation) and deliver cognitive behavioral interventions 

 
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(Table 3). Each intervention has 1) instructional or training components, delivered by our 
study team, and 2) self-directed components.  
 
Table 3. Multicomponent prehabilitation program and measures of feasibility and adherence for each 
component 
Target 
Intervention 
Measures of Feasibility or Adherence 
Exercise:  
Increase muscle 
function 
• Physical therapy (home, in-person, hybrid 
or virtual) 
• By physical therapists 
• Average two 1-hour individual sessions per 
week (delivered in patient’s home, in-
person center, hybrid, or virtual) 
• Goal: 6-8 total PT sessions  
• Endurance, strengthening, flexibility 
• Self-directed exercise 
• Goal: 30 mins/day x 4 days per week 
• Number of sessions delivered (feasibility) 
• Number of days with ≥30 min exercise per self-
report diary 
• Step count from a wearable activity tracker  
(Fitbit Fitness tracker): provision of weekly 
feedback based on step count 
• Change in 5-chair stands and grip strength pre- 
and post- intervention 
Nutrition:  
Preserve lean 
body mass 
(Patients with 
CKD will be 
excluded) 
• Nutrition counseling 
• By registered dietitian 
• Average one 1-hour group session per 
week 
• Goal: 3-4 total nutrition education sessions 
• Self-directed protein consumption  
• Goal: 1-2 ONS (20 gram)/day x 4 days per 
week 
• Number of sessions delivered (feasibility) 
• Number of ONS consumed per self-report 
• Change in protein intake per 3-day dietary 
recall pre- and post- intervention 
• Change in quadriceps thickness by ultrasound 
pre- and post- intervention 
Meditation:  
Increase 
cognitive 
resilience 
• Mindfulness meditation 
• By meditation teacher 
• Average one 1-hour group session per 
week 
• Goal: 3-4 total guided meditation sessions  
• Self-directed meditation 
• Goal: 12 mins/day 
• Number of sessions delivered (feasibility) 
• Number of days with ≥12 min meditation per 
diary 
Cognitive 
behavioral 
interventions:  
Improve 
adherence to the 
above 3 core 
interventions 
• Cognitive behavioral interventions 
• By research staff certified in cognitive 
behavioral therapeutic techniques 
• Education about frailty, discussion about 
barriers, writing down individualized goals, 
and weekly progress review 
• Average one 30-min individual session per 
week 
• Goal: 3-4 total cognitive behavioral 
sessions 
• Number of sessions delivered (feasibility) 
Abbreviation: CKD, chronic kidney disease; ONS, oral nutritional supplement; PROMIS, Patient-Reported Outcomes 
Measurement Information System. * Participants living within a 20-mile radius from HSL will be offered home in-person, 
center based, or hybrid physical therapy. 
 
7.1 Component 1: Exercise  
 
The instructional part will be delivered via average twice weekly, one-hour, in-person 
home, center-based, or virtual (via HSL’s Zoom video-conferencing software) physical 
therapy sessions, depending on the patient’s preference, familiarity with technology, 
availability of transportation, and other contingencies (e.g., COVID-19 based restrictions, 
incremental weather). Evidence suggests that virtual sessions offer similar benefits to in-
person home sessions30 or in-clinic sessions.31 Although a twice-weekly schedule is 
aimed, the schedule will be adjusted flexibly to deliver a total of 6-8 sessions. 
 

 
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Exercises targeting flexibility, strength, and endurance will be adopted mainly, though not 
exclusively, from the NIA Go4Life guide (https://go4life.nia.nih.gov/). Sample exercises 
are shown in Table 4.  
 
Before each in-person or virtual physical therapy session, the study physical therapist will 
review safe areas for exercise, safety techniques and warning signs (such as chest pain 
or pressure, severe dyspnea, left shoulder or arm pain, indigestion, heart palpitations, 
lightheadedness, dizziness, and headache). Participants will begin at a low level of effort 
and incrementally increase exercise intensity according to the therapist’s guidance. For 
virtual sessions and self-directed exercise, we will ask caregivers, family members, or 
home health personnel to provide supervision for safety and development of adverse 
events, whenever possible. During the in-person session, blood pressure, heart rate, and 
blood oxygen level will be monitored by the physical therapist. 
 
The self-directed part will include self-directed exercise (any types of exercise) at least 
30 minutes per day for 4 or more days per week. Step count data from a wearable device 
(Fitbit Fitness Tracker) will monitor progress and provide feedback, which improves 
adherence in older adults. Fitbit Fitness tracker will either be provided at the pre-
admission testing visit or mailed to the patient’s home.  
 
Table 4. Sample exercises for flexibility, strength, and endurance (source: Go4Life) 
Flexibility (stretching) 
Strength 
Endurance 
• Neck 
• Hand grip 
• Walking 
• Shoulder 
• Wrist curl 
 
• Shoulder and upper arm 
• Arm raise 
 
• Upper body 
• Arm curl 
 
• Chest 
• Seated row 
 
• Back 
• Wall push-up 
 
• Ankle 
• Elbow extension 
 
• Back of leg 
• Chair dip 
 
• Thigh 
• Leg raise 
 
• Hip 
• Knee curl 
 
• Calf 
• Leg straightening 
 
• Chair stand 
 
• Toe stand 
 
 
7.2 Component 2: Nutrition 
 
The instructional part will be delivered in once-weekly (on average), one-hour, virtual 
group sessions (via HSL Zoom software) by co-investigator/registered dietitian, Ms. 
Newmeyer, (the virtual sessions will be offered at three different days/times to 
accommodate participants’ schedules). This nutrition counseling will focus on optimal 
protein intake (1.2 gram per kg of body weight) for lean body mass preservation (from 
food sources and oral nutritional supplements). Sessions will focus on nutrition for muscle 
gain and lean body mass preservation with topics including: 
 
• Session 1: Good sources of protein and total needs (1.2 grams x weight in kg) 
• Session 2: Protein intake timing: rule 15/30 (at least 15 grams within 30 minutes 
of exercise) 

 
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• Session 3: Protein for muscle gain  
• Session 4: Tips to increase protein intake 
 
The self-directed part will include consumption of oral nutritional supplements (20-30 
grams of protein/day and between 150-350 calories/day, such as Think! High Protein Bar 
(20 grams protein, 22 grams carbohydrate, 150 calories) or Ensure Enlive (20 grams 
protein, 45 grams carbohydrate, 350 calories) , which will be provided by our study team. 
Oral nutrition supplements (ONS) will be ordered directly from the product manufacturer 
in bulk and mailed to the patient’s home by a research assistant. Due to ongoing supply 
chain shortages of popular nutrition supplements, we have identified multiple that meet 
the above macronutrient parameters. All supplements will be purchased in bulk for each 
participant with enough to last the entirety of the study. Supplements will not be changed 
unless the patient reports an adverse event such as GI distress (please see section B5 
for more detailed information).   Protein supplements are shelf-stable and can be stored 
at room temperature until use by date when unopened. Once opened, product should be 
refrigerated within 4 hours. After opening, any remaining product should be discarded 
within 48 hours – though patients will be encouraged to consume product in its entirety 
within 24 hours per study protocol.     
 
Patients with chronic kidney disease stage 3 or higher will not receive this intervention 
because high protein intake may accelerate kidney function decline. This will be 
determined by medical record review (medical history of chronic kidney disease or 
elevated creatinine value within the last 6 months) and/or lab results obtained before the 
start of the study intervention.                                                                                                                   
 
7.3 Component 3: Meditation  
 
The instructional part will be delivered in once-weekly (on average), one-hour, virtual 
group sessions by a meditation teacher, Ms. Tulsi Chase, at BIDMC Sadhguru Center 
(the virtual sessions will be offered by BIDMC Zoom video-conferencing at three different 
days/times to accommodate participants’ schedules). Classes will focus on breathing 
techniques, yoga, and mindful meditation practices.  
 
The self-directed part will include practicing self-directed meditation for a minimum of 12 
minutes daily. 
 
7.4 Component 4: Cognitive Behavioral Interventions 
 
A trained co-investigator will have (on average) once weekly 0.5-hour telephone-based 
sessions with individual patients to deliver cognitive behavioral strategies to increase 
adherence to the prehabilitation program. These strategies will include: 
 
• Education about frailty and surgery 
• Increase positive beliefs of the benefits of exercise and nutrition  
• Discuss barriers  

 
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• Set individualized goals for surgery and recovery 
• Develop a detailed exercise and nutrition plan (including logistics) 
• Self-monitoring of progress using weekly exercise, diet, and meditation logs 
• Enhance self-efficacy through the celebration of small wins  
 
This co-investigator has completed the Professional Education Systems Cognitive 
Behavioral Therapy Intensive Training Course in preparation for this intervention. This 
course is designed for health professionals without formal cognitive therapy training. 
 
8. STUDY ENDPOINTS/OUTCOMES 
 
8.1 Primary Outcome For the primary outcome we will measure the following:  
 
Feasibility of the prehabilitation program 
o Measurement: proportion of patients to whom we can deliver an adequate 
dose (≥50% of the planned sessions) of the 3 core interventions: physical 
therapy (≥4/8 sessions), nutrition (≥2/3-4 sessions), and meditation (≥2/3-4 
sessions).  
o Range: 0-100% (higher values indicate higher feasibility). 
 
8.2 Secondary Outcomes For secondary outcomes, we will measure the following: 
 
• Change in 5-chair stand test (time) 
o Measurement: time to complete 5 chair stands (seconds), post-
prehabilitation minus pre-prehabilitation 
o Range: -60 to 60 seconds (higher values indicate worsening performance) 
 
• Change in dominant handgrip strength (kg) 
o Measurement: average of 3 measurements of dominant handgrip strength, 
post-prehabilitation minus pre-prehabilitation 
o Range: -50 to 50 kg (higher values indicate improved performance) 
 
• Change in protein intake (grams) 
o Measurement: 3-day average protein intake from dietary recall, post-
prehabilitation minus pre-prehabilitation 
o Range: -100 to 100 grams higher values indicate greater intake) 
 
• Adherence to exercise 
o Measurement: proportion of days with ≥30 minutes of exercise out of 21-
28 days per self-report 
o Range: 0-100% (higher values indicate better adherence) 
 
• Adherence to protein intake 
o Measurement: proportion of oral nutritional supplement consumed over 
the total number of supplements provided per self-report 

 
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o Range: 0-100% (higher values indicate better adherence) 
 
• Adherence to meditation 
o Measurement: proportion of days with ≥12 minutes of meditation out of 21-
28 days per self-report 
o Range: 0-100% (higher values indicate better adherence) 
 
• Adverse events 
o Measurement: proportion of patients who experience any adverse events 
per self-report 
o Range: 0-100% (higher values indicate more adverse events) 
 
8.3 Exploratory Outcomes For all other outcomes, we will measure the following: 
 
• 3-D Confusion Assessment Method34 
o Measurement: proportion of patients who develop delirium according to 3-
D Confusion Assessment Method, a clinically validated algorithm of 
delirium diagnosis, on any of the postoperative days 1 to 3. 
o Range: 0-100% 
 
• Postoperative Quality of Recovery Scale35 
o Measurement: a clinically validated scale that includes physiologic, 
nociceptive, functional, cognitive, emotional recovery domains assessed 
as well as overall patient perspective on postoperative day 3. 
o Range: 40-200 (higher values indicate better recovery) 
 
• Comprehensive complication index36 
o Measurement: a composite complication grading system by Clavien-Dindo 
Classification after an intervention 
o Range: 0-100 (higher values indicate more severe complications) 
 
• Length of stay (time to readiness to discharge) 
o Measurement: number of hospital days from surgery until a patient 
becomes medically stable for discharge based on clinical notes  
o Range: ≥1 day 
 
• 30-day readmission from all causes 
o Measurement: proportion of patients who were readmitted within 30 days 
of surgery 
o Range: 0-100% 
 
• 30-day mortality from all causes 
o Measurement: proportion of patients who died within 30 days of surgery 
o Range: 0-100% 
 
• 90-day mortality from all causes 

 
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o Measurement: proportion of patients who died within 90 days of surgery 
o Range: 0-100% 
 
• Change in PROMIS-CAT score in participation in social roles/activities (4 
questions) 
o Measurement: self-reported measure of participation in social 
roles/activities 
o Range: 0-100 (higher values indicate higher participation) 
 
• Change in PROMIS-CAT score in Anxiety (4 questions) 
o Measurement: self-reported measure of anxiety 
o Range: 0-100 (higher values indicate more anxiety) 
 
• Change in PROMIS-CAT score in Depression (4 questions) 
o Measurement: self-reported measure of depression 
o Range: 0-100 (higher values indicate more depression) 
 
• Change in PROMIS-CAT score in Fatigue (4 questions) 
o Measurement: self-reported measure of fatigue 
o Range: 0-100 (higher values indicate more fatigue) 
 
• Change in PROMIS-CAT score in Pain interference (4 questions) 
o Measurement: self-reported measure of pain interference 
o Range: 0-100 (higher values indicate more interference) 
 
• Change in PROMIS-CAT score in Pain intensity (1 question) 
o Measurement: self-reported measure of pain intensity 
o Range: 0-10 (higher values indicate more severe pain) 
 
• Change in PROMIS-CAT score in Physical function (4 questions) 
o Measurement: self-reported measure of physical function 
o Range: 0-100 (higher values indicate better physical function) 
 
• Change in PROMIS-CAT score in Sleep disturbance (4 questions) 
o Measurement: self-reported measure of sleep disturbance 
o Range: 0-100 (higher values indicate more sleep disturbance) 
 
• Change in PROMIS-CAT score in Cognitive function (12 questions) 
o Measurement: self-reported measure of cognitive abilities 
o Range: 0-100 (higher values indicate better cognitive abilities) 
 
The timing and modality of outcome measurements is shown in Table 5.  
 
Baseline functional assessments with physical therapy staff from Hebrew SeniorLife’s 
outpatient clinic and at the conclusion of the prehabilitation program (before surgery) will 
be in-person assessments (though some baseline functional assessments may be done 

 
18 
virtually via Zoom). In-hospital outcomes will be assessed via in-person interview or 
review of medical records. Postoperative assessment on post-op day 30±7 and 90±7 will 
be conducted via telephone interview, email survey, or medical record review. 
 
Table 5. Timing of outcome measurement.  Day 0 is defined as the date of surgery. 
Outcome 
Baseline 
functional 
assessment 
(In-person or 
may be done 
virtually) 
Before surgery 
(In-person) 
Hospitalization 
(In-person /  
medical record) 
Postop Day 30±7 
(Telephone /  
e-mail survey / 
medical record) 
Postop Day 90±7 
(Telephone /  
e-mail survey / 
medical record) 
Feasibility 
 
X 
 
 
 
Change in chair stands 
X 
X 
X (if not done)* 
 
 
Change in handgrip strength 
X 
X 
X (if not done)* 
 
 
Change in protein intake 
X 
X 
X (if not done)* 
 
 
Adherence to exercise 
 
X 
X (if not done)* 
 
 
Adherence to protein intake 
 
X 
X (if not done)* 
 
 
Adherence to meditation 
 
X 
X (if not done)* 
 
 
Adverse events 
 
X 
X (if not done)* 
 
 
3-D CAM 
 
 
X 
 
 
PQRS 
 
 
X 
 
 
Surgical complications 
 
 
X 
 
 
Length of stay 
 
 
X 
 
 
Readmission  
 
 
 
X 
X 
Death 
 
 
 
X 
X 
PROMIS-CAT scores 
X 
X 
 
X 
X 
Abbreviations: CAM, Confusion Assessment Method; PQRS, Postoperative Quality of Recovery Scale; PROMIS-CAT, 
Patient-Reported Outcomes Measurement Information System-Computer Assessment Test. 
* We will try to measure these outcomes before surgery near the conclusion of the prehabilitation program; if not 
measured before surgery, we will measure them during the hospitalization. 
 
9. QUALITATIVE INTERVIEWS 
 
Near the end of the prehabilitation (from the last week of prehabilitation to hospital 
discharge), a trained co-investigator will conduct semi-structured qualitative interviews of 
patients and their caregivers (if they are involved in preoperative care).  
 
An interview guide has been developed under qualitative expert consultant guidance. The 
questions have been grounded in the Behavioral Change Wheel framework to assess 
factors influencing capability (physical and psychological), opportunity (physical and 
social), and motivation (reflective and automatic).36 The co-investigator will also ask 
participants about areas for improvement within our prehabilitation program.  
 
Qualitative data analysis will seek to identify facilitators of and barriers to adhering to our 
prehabilitation program. We will conduct hybrid deductive and inductive thematic analysis 
based on the 3 components (capability, opportunity, and motivation) of the Behavioral 
Change Wheel framework, while also allowing new insights to emerge from the data. The 
interviews will be audio-recorded and transcribed verbatim. A coding framework to all 
transcripts will be applied via a collaborative approach through an iterative process. 
Codes and subsequently derived themes will be refined by the research team.  
 

 
19 
10. DATA AND SAFETY MONITORING 
 
10.1 Adverse Events 
 
Definition and Classification of Adverse Events 
 
For this study, the following standard adverse event definitions are used: 
• Adverse events: Any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of the study intervention, regardless of whether 
it is considered related to the study intervention. 
• Serious adverse event: Any adverse event that result in death, life-threatening 
experience, hospitalization or prolonged hospitalization, persistent or significant 
disability or incapacity. 
• Unanticipated problems: Any experience that 1) is unexpected in terms of nature, 
severity, or frequency, given the research procedures described in the protocol 
document and the characteristics of the study population; 2) is related or possibly 
related to participation in the research; 3) suggests that the research places 
participants or others at a greater risk of harm than was previously recognized. 
 
Adverse events are graded according to the following scale: 
• Mild: An experience that is transient and requires no special treatment.  The 
experience does not generally interfere with usual daily activities. 
• Moderate: An experience that is alleviated with simple therapeutic treatments.  The 
experience impacts usual daily activities. 
• Severe: An experience that requires therapeutic intervention.  The experience 
interrupts usual daily activities.  If hospitalization (or prolongation of hospitalization) 
is required for treatment, it becomes a severe adverse event. 
 
The study uses the following adverse event attribution scale: 
• Not related: The adverse event is clearly not related to the study procedures (i.e., 
another cause of the event is most plausible and/or a clinically plausible temporal 
sequence is inconsistent with the onset of the event). 
• Possibly related: An event that follows a reasonable temporal sequence from the 
initiation of study procedures, but that could readily have been produced by a 
number of other factors. 
• Definitively related: The adverse event is clearly related to the study procedures. 
 
10.2 Adverse Event Monitoring 
 
Monitoring adverse events will be primarily performed in two ways: 1) unsolicited report 
from study interventionists (physical therapist, dietitian, and meditation teacher); and 2) 
weekly assessments by telephone using a standardized checklist. 
 
• Unsolicited reporting: Any adverse events that occur during the in-person or virtual 
sessions will be assessed for severity by the study interventionists (in conjunction 

 
20 
with PI or an MD co-investigator). In the event of a serious adverse event, the 
participant or caregiver will be instructed to contact emergency medical services 
to receive immediate medical attention. All adverse events will be reported to the 
PI. 
• Standardized assessment: At the beginning of cognitive behavioral intervention 
telephone calls, co-investigator Ms. Newmeyer will assess adverse events using a 
standardized checklist that includes the following expected adverse events (see 
below). 
 
Expected Adverse Events 
 
• Exercise: fall or injury (expected risk is low); new or worsening musculoskeletal pain 
(expected risk is moderate); cardiovascular events including angina, arrhythmia, 
myocardial infarction, heart failure, or stroke (expected risk is very low); other 
symptoms including chest pain, dizziness/lightheadedness, dyspnea, palpitation, or 
syncope (expected risk is low). 
• Nutrition: gastrointestinal distress such as diarrhea, nausea, constipation (expected 
risk is moderate); electrolyte imbalance or dehydration (expected risk is low), renal 
injury from increased renal solute load (expected risk is very low)38 Meditation: 
psychological distress (expected risk is very low/rare)39 
• Outcome measurement: possibility of incidental finding (such as suicidal ideation) 
through the Patient-Reported Outcomes Measurement Information System 
(PROMIS) surveys (expected risk is very low) 
 
10.3 Interim Analysis 
 
Since this is a pilot study, no interim analysis will be performed. Data analysis will be 
performed after study enrollment is complete. 
 
10.4 Data Safety Monitoring Plan 
 
The PI will assure that informed consent is obtained prior to performing any research 
procedures, that all participants meet eligibility criteria, and that the study is conducted 
according to the IRB-approved research plan. Because this is a pilot study, a formal Data 
and Safety Monitoring Board will not be formed; instead, a safety officer will oversee and 
review adverse events during the study period. Please see below regarding the roles of the 
safety officer. 
 
Frequency of Data and Safety Monitoring 
 
Study data are accessible at all times for PI to review. The PI will review study progress 
weekly initially (bi-weekly once the study procedures are established), including the number 
of potential patients screened and provided informed consent, the number of drop-outs, 
protocol deviations, and adverse events. The PI will review serious adverse events in real-
time and consult each other when needed for determination of the relatedness to the study 
interventions. The PI will ensure that all protocol deviations, adverse events, serious 

 
21 
adverse events, and unanticipated problems are reported to IRB. Serious adverse events 
and unanticipated problems that are definitively related to the study interventions will be 
reported to IRB within 48 hours from when we learn about the event. 
 
Content of Data and Safety Monitoring Report 
 
The content of the data and safety monitoring report will include accrual, baseline 
characteristics, efficacy data on primary and secondary outcomes, and adverse events. 
 
DSMB/Safety Officer 
 
A formal Data Safety Monitoring Board will not be established for this pilot study; however, 
a physician not directly involved in the study has been identified to fill the safety officer 
role: Dr. Sarah D. Berry, a geriatrician and clinical investigator at HSL Marcus Institute 
and Associate Professor of Medicine, HMS. 
 
Conflict of Interest of DSMB/Safety Officer 
 
The safety officer will have no direct involvement with the study investigators or 
intervention.  The safety officer will sign a conflict-of-interest statement which includes 
current affiliations, if any, with pharmaceutical and biotechnology companies, and any 
other relationship that could be perceived as a conflict of interest related to the study 
and/or associated with commercial interests pertinent to the study objectives. 
 
DSMB/Safety Officer Responsibility 
 
• Assess the research protocol, informed consent documents, and plans for data 
safety and monitoring 
• Recommend initiation of subject recruitment after review of the protocol 
• Evaluate trial progress quarterly, including recruitment, accrual and retention, 
participant risk versus benefit, and other factors that can affect study outcomes 
• Consider factors external to the study when relevant, such as scientific or 
therapeutic developments that may impact the safety of the participants or the 
ethics of the trial 
• Provide recommendations and assist in the resolution of problems reported by 
the PI 
• Protect the safety of the study participants 
• Provide recommendations to the PI regarding continuation, termination, or other 
study modifications based on the observed beneficial or adverse effects of the 
treatment under study 
• Ensure the confidentiality of study data and monitoring results 
 
11. ANALYSIS PLAN 
 

 
22 
11.1 Statistical Analysis for Feasibility 
 
We will estimate the feasibility of the entire prehabilitation program and each component; 
mean time for preoperative geriatric assessment; proportion of participants who enroll in 
the prehabilitation program; proportion of participants who drop out; and rate of missing 
outcome data.  No statistical testing will be performed. 
 
Sample Size Justification: We anticipate that the 3 core components of our prehabilitation 
program would be completed for 70% of the eligible patients9-15 (feasibility of ≥50% would 
be needed for a large RCT). Assuming a 20% margin of error and a lower bound of the 
95% confidence interval of 0.50, we will need 30 patients.  
 
11.2 Statistical Analysis for Qualitative Research 
 
There is no statistical analysis for qualitative research. 
 
Sample Size Justification: In most qualitative studies, interviews of 16-24 participants are 
needed to achieve thematic saturation of data.40 Our target enrollment of 30 patients (2 
patients per week for 15 weeks), ensures we meet that threshold, and our sample size is 
sufficient to reach thematic saturation to fully understand the “meaning” of the data. 
 
12. HUMAN SUBJECT PROTECTION AND PROTECTION OF 
CONFIDENTIALTY 
 
12.1 Risks to Human Subjects 
 
The potential risks to study participants include modest risk of physical harm, such as 
musculoskeletal pain, falls, cardiovascular or pulmonary events from low-intensity 
exercise; diarrhea, nausea, constipation, electrolyte imbalance, dehydration, or renal 
injury due to hyperosmolar content of some oral nutrition supplement formulations 
(Ensure Enlive). There is potential risk for increased anxiety or psychological distress 
from meditation. Lastly, while none of the PROMIS questions specifically ask about 
suicide, some of the possible questions through the computer-adaptive test may indicate 
that the patient is at risk. As such, there is potential risk to uncover suicidal ideation in 
patients. Loss of confidentiality is another potential risk. We do not anticipate any financial 
or legal risks. 
 
12.2 Protection Against Risks  
 
To minimize physical harm, the physical therapist will adapt the exercise program 
according to the participant’s physical capacity, their level of confidence, and the home 
environment. Prior to participation in exercise, the therapist will encourage participants to 
express any concerns. Participants will be taught safe exercise techniques. To minimize 
gastrointestinal (GI) distress, only participants with clinically significant weight loss (>5% 

 
23 
x 1 month; >7.5 x 3 months; 10% x 6 months; 20% x 1 year)or who have a history of 
taking calorically-dense supplements without issue (confirmed by patient) will be provided 
the hyperosmolar protein supplemental shake (Ensure). All other participants will be 
provided with a high protein bar or powder (for patients with swallowing or chewing 
difficulty, powder can be mixed with a solid puree). Those receiving the shake will be 
instructed to consume no more than one high calorie, high protein supplement per day 
and to drink adequate fluids before and after taking supplement. In the event of 
gastrointestinal distress (nausea, diarrhea or constipation), patient will be instructed to 
consume supplement in divided doses (no more than 50% in one sitting) or to dilute 
formula 1:1 with water. If gastrointestinal distress continues, patient will be switched to 
the protein bar or powder. Due to the lower calorie  content, those participants may be 
instructed to consume an additional high-calorie snack, if needed. . In the event that an 
incidental finding such as depression or suicidal ideation (SI), a specific protocol is 
outlined below in Figure 3 to ensure patient safety: 
 
Figure 3 - Incidental Finding: Depression and suicidal risk 
 
 
In the case of adverse events, the physical therapist or the participant will be instructed to contact 
a study physician (for any adverse events) and emergency medical services (for serious adverse 
events). These procedures will prevent or mitigate the consequences of adverse events. 
 
12.3 Potential Benefits to Human Subjects and Others  
 
The proposed research will provide essential information for the future design of a large 
clinical trial that examines the impact of a multi-component prehabilitation program on 
post-operative outcomes in frail older adults undergoing major surgery. Under the current 
standard of care, frail patients continue to experience complications such as mortality, 

 
24 
readmission, functional decline, and discharge to an institution. The potential benefits to 
study participants include receiving our study intervention, which targets major risk factors 
that are modifiable yet rarely addressed in the preoperative period (physical function, 
nutrition, pain, sleep, anxiety, and cognition), at no cost. These interventions address 4 
of the 8 target areas identified by the American College of Surgeons “Strong for Surgery” 
quality initiative to improve surgical outcomes. Moreover, each component of the 
intervention was studied to have some level of benefit based on biological plausibility and 
clinical findings. It is thus reasonably expected that the intervention will provide some 
benefits to the participants that are more likely to outweigh the modest risk of physical 
harms from exercise. 
 
12.4 Importance of Knowledge to be gained 
 
We will proceed with a large RCT if all of the progression criteria are met: 1) enrollment (we can 
enroll ≥1.5 patients per week); 2) feasibility (we can deliver an adequate dose of the core 
interventions to ≥50% of participants); 3) adherence (≥50% of participants adhere to the core 
interventions: ≥4 days with 30 minutes of exercise per week, ≥4 days with protein intake per week, 
and ≥4 days with 12 minutes of meditation per week); 4) follow-up (≥65% of surviving participants 
can complete PROMIS assessment on postoperative day 90). If these are not met, we will use 
information from qualitative interview to revise our study interventions before proceeding to an 
RCT. We will submit an NIH R01 application in 18 months. 
 

 
25 
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