Nutritional (High Protein) Perihabilitation in Older Veterans Undergoing Surgery
Phase: NA
Conditions: Malnutrition, Nutritional Risk, Abdominal Surgery
Sponsor: VA Office of Research and Development

 
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Nutritional (High Protein) Perihabilitation Intervention in Older Veterans Undergoing Surgery 
 
Funding Agency: United States (U.S.) Department of Veterans Affairs Rehabilitation R&D (Rehab RD) Service 
 
Principal Investigator: Kathryn N. Starr, PhD, RD 
 
NCT03073811 
 
5/13/21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Research Protocol: Nutritional (High Protein) Perihabilitation Intervention in Older Veterans Undergoing 
Surgery 
Principal Investigator: Kathryn Starr, Ph.D., R.D.  
 
 
Purpose 
The purpose of this research is to evaluate the feasibility, fidelity, and acceptability of a perioperative protein-
enhanced intervention compared to a standard protein intervention. The successful completion of the 
proposed research will provide preliminary data to test this hypothesis in a large scale randomized controlled 
trial. Such findings would be of considerable importance, providing a patient-centered viewpoint that will 
inform the development of nutrition interventions that meet the standards and needs of high-risk Veteran 
Populations.  
 
Specific Aims 
 Specific Aim 1.1 - Use a pilot trial to evaluate the feasibility, fidelity, and acceptability of a perioperative 
protein-enhanced intervention compared to an educational, normal protein control. 
 
 
Introduction. Malnutrition is recognized as a major concern by healthcare providers, as well as by 
patients, families, and caregivers. In a very recent survey, 28% of 1,035 patients, families and caregivers 
reported that malnutrition was a very significant problem, while 55% reported it was a somewhat significant 
problem in older adults 65 and older.26 This response aligns with reports that up 65% of older adults admitted 
to the hospital are malnourished (National Resource Center on Nutrition, Physical Activity, and Aging, 2015). 
Thus, it is essential to establish systematic malnutrition screening in the clinical setting and to develop 
intervention models and standards of nutritional care. The objective of this aim is to investigate the feasibility, 
fidelity and acceptability of a nutrition intervention protocol providing higher protein intakes before and after 
surgery in malnourished Veterans. To achieve the objective of this aim, we will test our working hypotheses 
that recruitment in clinic will have a high yield and that intervention fidelity (adherence, retention) and 
acceptability (attrition, patient satisfaction) will be predominantly satisfactory. The rationale for this aim is 
that successful completion of the proposed research will provide necessary knowledge to begin to identify 
feasible and acceptable interventions for community-dwelling Veterans who are preparing for surgical 
procedures. When the proposed studies for Aim 1.1 have be completed, it is our expectation that 75% of 
patients approached for recruitment will agree to participate, 75% of the time patients will adhere to the 
intervention, 80% of the participants will remain in the study, and that 80% of participants will find the 
intervention to be acceptable. Such findings would be of considerable importance, providing a patient-
centered viewpoint that will inform the development of nutrition interventions that meet the standards and 
needs of high-risk Veteran Populations.  
 
Specific Aim 1.2 – To determine the effect size for planned future studies of enhanced protein supplementation 
in malnourished Veterans, with physical function as the primary outcome of interest. Of secondary interest are: 
biomarkers of inflammation (albumin, hsCRP, TNF-α, IL-6), dietary intake, hospital readmission, discharge 
location, length of skilled care, and ED admission, and physical activity. 
Introduction. Older adults have reduced adaptive and regenerative capacities to recovery from a 
surgical insult.27 Thus, when coupled with insufficient energy intake, malnutrition becomes the driver that 
leads to further deterioration of functional abilities, reduction in lean muscle mass, and inability to maintain 
physical reserve. A generous and balanced intake of high quality protein (~30 grams) is essential for achieving 
optimal protein synthesis in older adults28 and is linked to lean mass retention.29 The essential amino acids 

 
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found in complete (animal) proteins stimulate translation initiation of the mTOR signaling pathway and 
increase muscle protein synthesis in older individuals.29 The objective of this aim is to research the effects of a 
meal-based protein enhanced perihabilitation intervention in malnourished older Veterans undergoing 
elective surgery on the primary outcome physical function and secondary outcomes, inflammatory biomarkers 
(albumin, hsCRP, TNF-α, IL-6), dietary intake, hospital readmission, discharge location, length of skilled care, 
and ED admission, and physical activity. To achieve the objective of this aim, we will test the working 
hypothesis that Veterans consuming the enhanced protein supplementation will have superior improvements 
in function compared to the control arm. Approach: We will further refine our working hypothesis in a two-
armed pilot trial comparing a high protein nutrition supplement for two weeks pre and post-surgery to an 
education control arm. We will assess physical function (SPPB) and secondary outcomes two weeks before, 
the day of surgery, and four weeks post-surgery. The successful completion of the proposed research will 
provide preliminary data to test this hypothesis in a large scale randomized controlled trial. When the 
proposed studies for Aim 1.2 have be completed, it is our expectation that the protein intervention will prove 
to provide higher functional and physiological benefits relative to the control treatment, illustrating the 
importance of nutritional perihabilitation prior and following surgery in high-risk, vulnerable populations.   
 
 
Design 
This is a Randomized Controlled Study. Veterans will be enrolled until 84 participants have completed the 
study.  
 
Setting: The POSH Clinic is an interdisciplinary collaboration between surgery, anesthesiology, geriatrics, 
nursing, and physical therapy to provide perioperative surgical care for high-risk Veterans at the Durham 
VAMC. The clinic opens with a conference to review patients to be seen that day. The surgery chief resident 
presents and the team covers technical issues with the surgery and selection of anesthesia, as well as covering 
a list of specific care points. The POSH clinic estimates 200 – 400 patients enrolled annually.  
 
VAPOSH Veterans who are malnourished or at risk of being malnourished will be randomly assigned on a 1:1 
ratio by computer-generated random numbers to either an education (nutritional counseling) control 
(PoshControl) arm or high-protein perihabilitation (PeriHab) arm. All will receive nutrition education. 
Participants in the PeriHab arm will also be provided with high quality protein supplements that will bring their 
protein intakes to at least 30 grams for each of the 3 meals per day. 
 
Study Arms: 
• PoshControl; n = 42: During their VAPOSH clinic visit, participants will be provided nutrition counseling 
and prescribed to consume protein at 1.0 g/kg of body weight in the form of educational handouts 
explained by a Registered Dietitian. Participants will also be instructed to consume 1 oral nutrition 
supplement per day two weeks before surgery. 
• PeriHab; n = 42: PeriHab will be provided nutrition counseling and prescribed to consume protein at 
1.6 g/kg of body weight) as well as provided 30 g of high quality protein to some 3 times per day for 2 
weeks before and 4 weeks after surgery. 
 

 
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Measurements: 
 After the participant has been consented and HIPAA Authorization forms have been signed, a Registered 
Dietitian will administer the NRS-2002 screening tool, the PG-SGA, and nutrition focused physical exam. A 
patient screening “nourished” on the NRS-2002, PG-SGA, and nutrition focused physical exam will not be 
included in the study.  For study candidates who are malnourished or at nutritional risk we will then proceed 
with baseline assessments (described below). Upon the completion of all baseline assessments, the participant 
will be randomized to PeriHab or PoshControl. The following variables will be blocked in this order: 1) surgery 
type and 2) American Society of Anesthesiology (ASA) Physical Status Classification System (≥3 versus <3). An 
equal number of participants will be randomized across the two arms. 
 
Measures and Data Collection Points 
Measure 
When Collected 
NSR-2002  
Baseline (T1), T2, T3 
PG-SGA 
T1, T2, T3 
Nutrition Focused Physical Exam 
T1, T2, T3 
Cognition 
T1 
Medical History 
T1 
Demographic  
T1 
Anthropometrics 
T1, T2, T3 
Comorbidity Status 
T1 
Bristol Stool Chart 
T1 
Short Physical Performance Battery 
T1, T2, T3 
Handgrip strength 
T1, T2, T3 
Biological Markers 
T1, T2, T3 
Postoperative outcomes 
T3 
 

 
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Physical Activity 
T1, T2, T3 
PROMIS and PROMIS GLOBAL QUESTIONNAIRES 
T1, T2, T3 
Three-day Food Record 
T1, T2, T3 
Protein Checklist 
Daily  
24-Hour Dietary Recall 
Weekly between time points 
Participant Satisfaction Questionnaire  
T3 
Participant Acceptability 
T3 
 
Risk/Benefit Assessment 
There are no known psychological hazards or risks associated with completing the nutrition screen and 
assessment questionnaires.  The nutrition-focused physical exam will involve palpation of the Veteran to 
identify edema, skin or muscle changes, fat loss, and muscle wasting and muscle strength that may be 
uncomfortable or cause some distress. To minimize this risk, the Registered Dietitian conducting the nutrition-
focused physical exam will have completed a hands-on workshop offered by the Academy of Nutrition and 
Dietetics prior to administering the physical exam. The physical performance tests include activities such as 
walking, standing, and stepping. These activities reflect common activities of daily living and as such, are 
associated with minimal risk for injury. However, there is a small risk of falls or muscle soreness with physical 
testing. To minimize risk, trainer personnel will oversee physical performance testing at all times. There is 
potential risk associated with venipuncture, taking blood from a vein in the arm by needle stick. Risks 
associated with drawing blood from the arm include momentary discomfort and/or bruising. Infection, excess 
bleeding, clotting, or fainting are also possible, although unlikely. Blood draws will be done by a trained 
phlebotomist and every effort will be made to prevent discomfort. There is a potential risk associated with the 
loss of confidentiality of the study data. However, of primary importance in all study activities will be the 
security and protection of Veterans’ private health information (PHI). All staff will complete educational 
modules designed to improve good clinical practices, improve protection of participant privacy, and promote 
information security and research compliance. 
 
Participants may benefit from this study by improving their nutritional status and functional status during the 
perioperative period. Additionally, participants may benefit from knowing that their participation in research 
will provide valuable information regarding the nutritional status of older Veterans preparing for surgery, and 
will allow for better identification and management of Veterans at nutritional risk before and after surgery. 
 
Selection of Subjects 
The inclusion, exclusion criteria are outlined below:  
 
Table 2. Inclusion/Exclusion Criteria  
Inclusion Criteria  
Exclusion Criteria  
• Referred to VAPOSH (at increased risk for 
post-operative complications) 
• Abdominal surgery (upper GI, colorectal, 
hepatobiliary, pancreatic, intra-abdominal, 
• Living in skilled nursing facility 
• Having any surgery other than abdominal surgery 
• A score of <21 (high school edu.) or <20 (less than high school edu.) 
on the Montreal Cognitive Assessment (MoCA) or Saint Louis 

 
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bladder, VATS/lobectomy and abdominal 
aortic aneurysm) 
•  Age > 60 years 
• Malnourished or at nutritional risk (PG-
SGA and Nutrition Focused Physical Exam)  
• English speaking 
University Mental Status (SLUMS) and inability to preform 1 or 
more activities of daily living (ADL).   
• A diagnosis of Galactosemia, a rare genetic metabolic disorder that 
affects an individual's ability to metabolize the sugar galactose 
properly.  
 
 
Only participants scheduled for a POSH clinic visit will be eligible for study participation. Dr. Starr or study staff 
will meet with the coordinator of the POSH clinic, weekly to identify eligible patients. We will screen and 
consent individuals until we meet the desired sample size of 84 subjects. The POSH clinic has over 300 visits 
annually.  
 
To protect vulnerable populations or those subjects who may be susceptible to coercion or undue influence 
against, any Veteran who is approached by staff will be told that their participation is voluntary, and they may 
choose not to answer any questions that they find too sensitive. Also, Veterans will be told that their 
participation will not affect their care at the VA. The study staff member will explain the study in detail. No 
study procedures will begin until formal, written informed consent has been obtained.  
 
Subject Recruitment 
This study will utilize a Request for HIPPA waiver of Authorization and waiver or alteration of informed 
consent process to identify potential participants for this research study. This study will be conducted in the 
context of the POSH clinic and will only include patients who participate in the POSH clinic. Identification of 
POSH patients: patients scheduled to be seen in general surgery clinic will be screened for candidacy for a 
POSH referral through CPRS.  Specific referral criteria are based on established risk factors for post-operative 
complications and include age ≥ 60, multiple comorbid conditions, falls, mobility limitation or documented 
functional impairment.  In addition to an alert being sent to the surgical team, a notice will be sent to the PCP, 
with information about the program and an invitation to contact the program manager with any questions or 
additional information.  Patients will receive a single appointment to see the POSH team.  
 
Once patients are referred to the POSH clinic, the POSH clinic coordinator, will contact the study staff. At that 
time, a chart review will be conducted to assess initial eligibility (abdominal surgery, surgery date is at least 
two weeks after to POSH clinic visit). Potential participants identified will then be sent an introductory letter 
signed by the PI that describes the study and informs them that they will be called regarding participation. In 
the letter, potential participants will be given an “opt-out” number to call in order to decline participation 
and/or further contact regarding participation. Five business days after the mailing, Veterans who have not 
called the study number to decline participation will be called by a study staff member to request their 
participation in the research study (see telephone screen script). In the telephone contact, the study staff 
member will inform the Veteran that he/she was selected for recruitment because he/she is an older Veteran 
who is been seen at the POSH Clinic and is having abdominal surgery and may be at nutritional risk.   
 
Any Veteran who contacts or is contacted by study staff will be told that their participation is voluntary, and 
they may choose not to answer any questions that they find too sensitive. Also, Veterans will be told that their 
participation will not affect their care at the VA. The study staff member will explain the study in detail, 
including compensation. No study procedures will begin until formal, written informed consent has been 
obtained. 

 
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Consent Process  
On the day of their POSH clinic visit, potential participants identified we will be informed again that he or she 
is being recruited because he/she is having abdominal elective surgery and is a patient in the POSH clinic. The 
participant will be told that their participation is voluntary, and they may choose not to answer any questions 
that they find too sensitive. Also, Veterans will be told that their participation will not affect their care at the 
VA. The study staff member will explain the study in detail. The participant will be will be given as long as they 
need to read through the consent form and HIPAA Authorization. Study staff will answer all questions and 
concerns. No study procedures will begin until formal, written informed consent has been obtained.  
 
Study Interventions 
 
Caloric Intake and Monitoring Protocol for Both Arms: Caloric needs will be prescribed for each participant 
using an established standard of 30 to 35 kcal/kg41 at the VAPOSH clinic. To assure adequacy for all enrollees, 
calculated protein needs will be higher than the recommended 0.8 g/kg of body weight for both arms, 
PoshControl protein prescription = 1.0 g/kg of bodyweight and PeriHab protein prescription = 1.6 g/kg of 
bodyweight. Participants will be monitored by weekly phone calls during which study staff will ask the 
participant to recall their intake from the day before (24-hour dietary recall). This information will be used to 
ensure that both arms are meeting their calorie needs. If a participant in either arm has an inadequate intake 
they will be counseled on how to increase their current intake. Based on our previous assessment of similar 
populations, it is unlikely that the PeriHab arm will be able to meet the 1.6 g/kg of body weight protein 
prescription on their own and for that reason we are providing protein supplement to be consumed 3 times a 
day (as described below). The PoshControl arm will be given one ONS to consume every day prior to surgery.  
 
PeriHab Arm Protein Perihabilitation Protocol: The protein supplementation protocol provides for three daily 
supplements of 30 g of high quality protein in the form of a liquid nutritional supplement (30 g).  Subjects will 
receive sample menus to help the participants incorporate the increased protein into their daily intake.  
Individually packaged portions of the liquid supplement will be supplied at the VAPOSH clinic visit (T1). 
Participants will be given a two-week supply of supplement. Included will be a printed check-off sheet for 
participants to record protein supplement use. The protein check-off sheet, three-day food record, Actigraph 
log, and lids from the protein drink will be turned in on the day of surgery (T2). Following their surgery, 
participants will be given an additional four week supply of the same supplement at discharge and the same 
materials as at the VAPOSH clinic visit (T1). The protein check-off sheet, three-day food record, Actigraph log, 
and lids from the protein bottles will be turned in at the follow-up appointment (T3).  
 
Participants will be contacted weekly by study staff and queried with a standard set of open-ended questions 
designed to identify problems with compliance. Participants who are having difficulty will be provided 
additional counseling to ensure they are able to achieve 30 grams of high quality protein three times a day.  
 
PoshControl Arm Protocol: Participants in the PeriControl arm will be asked to consume 1 ONS protein 
supplement per day prior to surgery. They will be provided education on the role of nutrition to prepare for 
and heal from surgery with the following main messages, 1) complications associated with malnutrition; 2) the 
benefits of good nutrition; 3) tips for dietary intake when not hungry; 4) easy food preparation; and 5) what to 
eat. The study Registered Dietitian will instruct the participant to follow the information on the handout. 
Study staff will call the PoshControl arm participants once a week to identify problems with compliance, 

 
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answer any questions and also remind participant to complete their 3-day food records. The ONS check-off 
sheet, three-day food record, and lids from the Ensure Plus bottles will be turned in on the day of surgery (T2). 
Four weeks following surgery, PoshControl participants will return for a follow-up appointment and will bring 
Ensure Plus checklist, three-day food record, and Actigraph log.  
 
 
Adverse Events 
Given the study population of older Veterans undergoing surgery we anticipate adverse events that are not 
related to the study, including ER readmission following surgery, poor would healing, and surgical 
complications. Perioperative nutrition intervention should enhance rather than jeopardize the health status, 
and potential serious adverse events (SAE) for participants in this project are not expected. Regardless, we will 
minimize potential risk by careful screening of potential participants. All adverse events will be reported per 
Durham VAMC requirements. All Serious, Unanticipated and Related adverse events will be reported to IRB 
within 5 business days of hearing of the event. All other adverse events will be reported at continuing review. 
 
Costs and/or Payments to Subjects 
Study participants in both arms may receive up to $160 for full participation in the study. This payment 
information is provided in the informed consent document. Participants will receive $40.00 for time points 1 
and 2, since these are times in which they would be coming to the VA for their preoperative care and surgery. 
They will receive $80.00 for time point 3.  
 
Data and Safety Monitoring 
The individuals responsible for data safety and monitoring will be the PI, the Registered Dietitian, project 
coordinator, and the study Co-Investigators. 
 
Further data safety and monitoring will be provided by the PI. There will be several ongoing mechanisms for 
monitoring and reporting of adverse events: 1) ongoing participant contact via study personnel, 2) study 
telephone number provided to participants to report concerns related to study participation; and 3) weekly 
meetings between the PI and study personnel. 
 
The PI will meet at least weekly with study personnel to discuss participants’ reactions to outcome measures 
and assessments, weekly telephone calls, and any adverse events or unanticipated problems. Monthly 
meetings between the investigators and the project coordinator will allow for ongoing progress reports, 
including the number of participants currently involved in the study and scheduled data collection from 
participants, as well as notification and review of any AEs. Safety monitoring for adverse events (AEs) will be 
conducted in real time by the PI and/or project coordinator. The following information about adverse events 
will be collected: 1) the onset and resolution of the AE, 2) an assessment of the severity or intensity (use 
existing grading scales whenever possible), 3) an assessment of the relationship of the event to the study 
(definitely, probably, possibly or not related), and 4) action taken (e.g., none, referral to physician, start or 
increase concomitant medication). The PI will determine the severity of the event, will assign attribution to 
the event, and will monitor the event until its resolution. All adverse events will be reported per Durham 
VAMC requirements. All Serious, Unanticipated and Related adverse events will be reported to IRB within 5 
business days of hearing of the event. All other adverse events will be reported at continuing review.  
 
Withdrawal of Participants 

 
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Subjects who do not have surgery will be withdrawn from the study. Additionally, if a subject has to have 
emergency surgery, rather than elective surgery during the two weeks between the POSH clinic visit and their 
scheduled surgery date they will be withdrawn from the study. Finally, subjects who refuse to consume 
protein supplement will be withdrawn from the study.  
 
If a participant decides to withdraw from the study, they will be instructed to contact the PI and discuss the 
reason for withdraw. This information will be documented to help better understand the reasons that the 
participant was unable to complete the study.  
 
Data Analysis and Statistical Considerations 
 
Data management and quality control:  We will employ REDCap (Research Electronic Data Capture) for data 
entry. Key components of this activity include data entry screen programming and database testing and 
validation.  The database will include study default parameters and ranges for database, protocols, users, and 
access rights. Access and data entry to the database will be controlled by login permissions, and the database 
will be backed up daily, with full backups occurring weekly, and quarterly backups retained for perpetuity. The 
database will be routinely checked for data integrity and quality.  In addition, since some data will require 
direct download from computerized databases (e.g. VA patient information, lab findings) a final relational 
database will be built to be used for analysis in SAS, combining data from all data sources. This process will 
include quality control, developing an appropriate query, validation, and justification procedures, auditing, 
developing a manual of procedures and documentation, interim reporting of data flow, and maintaining 
security and patient confidentiality of the data base. The analysis database derived from this source data will 
be de-identified. Identifying information will be viewed and managed only by the data manager and 
appropriately consented data collection staff.   
 
Quality control procedures will be established for each component of the study. At each level of data 
management, and for each subject contact, strict adherence to VHA policy will be observed regarding HIPAA, 
IRB and other VHA patient quality controls. These procedures include not identifying any patient or provider 
on any of the reports generated from this study. All computer files will be password protected. Files containing 
names and addresses will have a separate password, will be accessible only to personnel who need to contact 
the subjects, and will be stored separately. Ultimately, a de-identified file appropriate for analysis will be 
produced for report generation and analysis. All analysis and Data management personnel are current with all 
VA mandated security training.  
 
Aim 2.1 Analysis Plan: 
Feasibility proportions for future screening and recruitment will be calculated at the end of the intervention 
using the following: 
1. Proportion of patients recruited will be calculated as the number of patients deemed potentially 
eligible and contacted for enrollment divided by the total number of patients enrolled. 
• Feasibility Hypothesis:  75% of patients approached for recruitment will agree to participate 
Fidelity proportions will be calculated for adherence and retention at the end of the intervention using the 
following: 
1. Proportion adherent to nutrition intervention will be computed by the number of empty supplement 
containers divided by the number of possible supplement containers that could be consumed.  

 
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2. Proportion adherent to nutrition intervention will also be computed by the number of meals 
consumed that are 25 grams of protein divided by the number of possible meals that could be 
achieved. For the PoshControl arm, adherence will be assessed by the number of dietary changes they 
make based on the educational handout provided to them at baseline. These will be determined by 
using diet records for 3 days prior to surgery and 3 days following surgery. Diet food records are valid 
method for collecting dietary intake data and have been administered in Veteran populations.42 We 
have experience administering and analyzing this data.1 
• Adherence Hypothesis: 75% of the time PeriHab participants will adhere to the intervention 
and >75% of the time controls will show at least one recommended dietary change in their 3-
day diet record 
3. Proportion retention will be computed by dividing the number of retained subjects at the end of the 
intervention by the total number randomized into the study. 
• Retention Hypothesis: 80% of participants will remain in the study for the duration of the trial 
We will calculate these rates of retention and adherence and their respective confidence intervals overall and 
by group. While non-powerful, we will assess if these rates differ by chi-square test of proportion and Poisson 
regression respectively. In a series of sensitivity tests, we will assess if adherence overall was impacted by 
demographic or symptomatic variables (such as chronic health conditions, living arrangements, surgery, 
functional status, and nutrition status). 
Acceptability will be assessed by: 
1. Calculating levels of attrition.  
• Patient satisfaction will be assessed by a brief 5-item questionnaire: a) satisfaction with 
participating in the study; b) satisfaction with directions on how and when to consume the 
protein supplement, c) satisfaction of the taste of the protein supplement, d) satisfaction with 
functional status after protein e) satisfaction with interactions with the registered dietitian. 
80% of participants will report satisfaction with participating in the study.  
2. Qualitative semi-structured interviews in a subset of the participants. A qualitative analytical approach 
is well suited to exploring concepts related to a complex process (malnutrition and nutrition 
intervention). We anticipate we will achieve thematic saturation by enrolling 20 participants. The data 
in the interview transcripts will be coded using Atlas software. Perform the analysis using the skills 
obtained in my proposed coursework and with the assistance from my co-investigators. Data analysis 
will include summarizing the major topics of discussion, synthesizing recurring themes, and selecting 
exemplars of these themes from individual comments. In concert with the quantitative results, these 
data will be used to inform the design of a larger trial aimed at improving outcomes for older, 
malnourished Veterans.  
• Patients will be selected using maximum variation purposive sampling including to include a mix 
of ages, genders, races, surgical procedures, and nutrition status.  
• Each semi-structure interview will be conducted at the endpoint visit and will last 
approximately 15 minutes. The interviews will be conducted according to a script developed in 
close collaboration with my co-investigators. 
• All interviews will be tape-recorded and transcribed. The interviewer will also take written 
notes to capture changes in emotion or enthusiasm related to the response to each question 
that will not be captured in transcribed reports.  
 
 
 

 
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Aim 1.2 Analysis Plan: This design is a two-armed clinical trial, with replicate measures at three time points: 
baseline, two, and six weeks. Since subjects are randomized to either PeriHab or PoshControl arm, and the 
groups are presumed equal at baseline, the analysis is straightforward. Following the Good Clinical Practice 
Guidelines for the analysis of a clinical trial, we will employ mixed models,43 analyze under an Intent to Treat 
(ITT) criteria, and control for baseline and assess the impact of Time, Treatment Group and the interaction of 
these variables on the outcomes. Relative to the usual repeated measures designs, mixed models have several 
advantages: 1) missing values present no particular difficulties in estimation and the estimates are unbiased as 
long as the set of variables leading to MAR are estimated, 2) the usual assumption of conditional 
independence (compound symmetry) used in standard repeated measures need not be made, and 3) the 
actual times of measurement need not be equivalent across subjects. Controlling for the individual baseline 
values for the particular outcomes, the trajectories over time and differences in those trajectories will be 
assessed. Following the statistical principles section from the International Conference on Harmonization, we 
will select covariates (e.g., age, race, number of comorbidities) for the primary models a priori, but we also will 
conduct auxiliary sensitivity analyses that evaluate whether potential group imbalances bias the treatment 
effect estimate. These analyses will be performed using conventional testing for confounding. 
 
For any particular outcome, the general form of the model will be: 
Yit = β0+ β 1(group) + β 2(timet) + β 3(group*timet) + β 4(covariates) + εit 
Where i is an indicator of person, and time is defined as t=1, 2 (measuring week 2 or 6), and the β’s are 
regression coefficients connecting the predictors to the outcome. For brevity, we list β4 as a vector of K 
regression coefficients linking the K covariates to the outcome. As defined, the overall test of the intervention 
effect will be the joint effect of group and group*time on 2 df (β1 and β2) assessing an overall effect of group, 
and if this group effect is constant over time. If significant, follow-up tests will assess where group differences 
lie. In particular, we note that if the time by group interaction is rejected, we will test if the groups differ at the 
end of 6 weeks (a test of effect at the completion of the intervention). 
We will carefully examine model assumptions, including the distribution of model residuals, additively, 
linearity, and influential observations, and will, if necessary, re-parameterize the models or transform the 
outcomes accordingly. 
 
We note that we have listed numerous measures to be analyzed as outcomes, but have listed only 2 
domains of outcomes as primary (physical function and a biological index of nutrition status and 
inflammation). We will not adjust for Type-I error rate for these primary outcomes. Rather, we will warn the 
reader of the multiple outcomes tested and the chance for a Type-I error. 
 
Secondary Outcomes: At the conclusion of the study, we will have a rich database with which to conduct 
follow-up exploratory analyses. We will perform multiple exploratory analyses of the remaining measures.  In 
addition to the impact of the intervention on the secondary outcomes, we will assess mediation of the group 
effect on the primary outcome by demographic, comorbid and adherence variables. Subjects may differ in 
their process of change depending on baseline demographic and functional status values. Second, we will 
assess the functional form of the change over time, by looking at non-linear functions of change.  For example, 
change in function and performance is likely to be non-linear, initially changing quickly and leveling at points 
distal from baseline.  It would be important to note if this change differed by group. Finally, we will assess 
whether the trajectories of change, irrespective of group assignment, are similar for individuals. In this 
application, we have listed several variables, which we expect to change as result of the intervention.  We 
further hypothesize that all these variables will change in the same pattern. To test this hypothesis, across the 

 
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range of outcome measures, we can look at overall change through the use of multivariate tests (Bock44 or 
Anderson45) for the singly measured functional items, and by assessment of correlated trajectories for those 
outcomes measured repeatedly.  With appropriate weighting for number of observations per individuals, the 
correlation between individual trajectories can assessed. A positive correlation between the trajectories for 
any two outcomes will indicate that the subjects changed similarly for the 2 outcomes, and will provide 
additional support for the notion that the intervention had a generalized effect across the outcomes. 
Significant correlations would perhaps indicate mechanistic/causal linkage between variables over time, or, 
from a reliability standpoint, may indicate that the subsequent trial may want to employ summary measures 
aggregating across outcome measures, or, alternatively, employ multivariate tests across several outcomes to 
assess the group differences, reducing the chance of Type-I error inherent in the testing of multiple variables. 
 
The results of these analyses will provide invaluable information regarding the process and functional forms 
and, potentially, the causal pathways of the intervention process.  For example, one important analysis will 
enter 'level of compliance to the intervention' into the analysis, allowing for a 'per protocol' analysis of the 
results. 
 
Power Estimate: Estimate effect sizes for the physical function between-group comparisons and the power 
available to detect effect with two-tailed tests are provided below for the total N= 80. The objective of this 
pilot study is to perform preliminary evaluation of a nutrition perihabilitation program in malnourished 
Veterans, in preparation for a larger grant submission. This pilot work will allow us to conduct sample size, 
effect sizes, and power analyses for a larger clinical trial. To date, no randomized controlled nutrition 
perihabilitation study has been conducted in malnourished Veterans. As such, we turned to the literature. 
Gillis et al.,46 reported that older adults undergoing colorectal resectioning surgery who were given nutrition 
supplementation 3 weeks before surgery improved by 23.7 meters on the 6 minute walk test while the arm 
given nutrition supplement following the surgery declined by -21.3 meters. The pooled standard deviation of 
these changes was 67.75. Thus, a standard difference of 0.66 = (23.7 - (-21.3))/67.75 was observed. 
Differences of this magnitude have been labeled as ‘medium’ in the statistical power literature (70). Assuming 
a standard deviation in the change scores of 67.75, n=40 per group, power=80% and alpha=0.05 (two-tailed), 
we are powered to detect a difference in changes scores of a standardized magnitude of 0.634, in line with the 
results of Gillis et al.46  
 
 
 
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