Clinical trial NCT02459275
Conditions: Critically Ill
Keywords: feeding protocol enteral nutrition protocol critically ill surgical ICU enteral nutrition nutrition therapy
Sponsor: Clinical Evaluation Research Unit at Kingston General Hospital
Start date: 2015-07-01; Completion date: 2017-09-01
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this project is to asses for safety, feasibility and effectiveness of an aggressive feeding protocol, PEP uP (Enhanced Protein-Energy Provision via the Enteral Route Feeding Protocol) in increasing protein and energy delivery to critically ill surgical patients. Our hypothesis is that an aggressive feeding protocol, PEP uP will be safe, acceptable, and effectively increase protein and energy delivery to critically ill surgical patients.

Detailed description:
Gross underfeeding or iatrogenic malnutrition is prevalent in intensive care units throughout the world. Critically ill patients only receive, on average, 40-50% of their prescribed nutritional requirements. Inadequate provision of nutrition to these patients is associated with increased complications, prolonged length of stay in the ICU and hospital, and increased mortality. There are good data from large scale observational studies and randomized trials that suggest better fed patients have better clinical and economic outcomes and there are ICUs that consistently reach an average of 80-90% nutritional adequacy (amount of nutrition received over amount prescribed) thus it appears to be a feasible goal.

The PEP uP protocol (Enhanced Protein-Energy Provision via the Enteral Route Feeding Protocol) includes a new, innovative approach that protocolizes an aggressive set of strategies to providing enteral nutrition (EN) and shifts the paradigm from reactionary to proactive followed by de-escalation if nutrition therapy is not needed. The key components of this new PEP uP protocol are the following:

1. Starting feeds at the target rate based on increasing evidence that some patients tolerate starting nutrition at a higher rate of delivery and that slow start ups are not necessary.
2. Allowing "trophic feeds" a low volume of a concentrated feeding solution for 24 hours or longer, designed to maintain gastrointestinal structure and function for those patients who are deemed unsuitable for high volume intragastric feeds.
3. Prescribing semi-elemental feeding solution instead of a standard polymeric solution.

   These can then be changed to more traditional polymeric solution once the patient is tolerating adequate amounts of nutrition.
4. Prescribing protein supplements at initiation of EN and then discontinue if EN is well tolerated and protein requirement are met through their standard EN.
5. Starting motility agents at the same time EN is started with a re-evaluation in the days following to see if it is necessary.

This PEP uP protocol has been previously studied in two published studies enrolling primarily medical patients. In the first study, a pilot before and after trial, the protocol seemed to be feasible, safe, and acceptable to critical care nurses. No incidents compromising patient safety were observed. (Heyland 2010) Rates of vomiting, regurgitation, aspiration, and pneumonia were similar and the PEP uP group received significantly more energy and protein (when they were prescribed to receive full volume as opposed to "trophic"). A subsequent multi-center cluster randomized trial involving low-performing ICUs likewise demonstrated that intervention sites had improvements in energy and protein delivery as well as a decrease in average time from ICU admission to start of enteral nutrition compared to the control group. (Heyland 2013).

Arms: arm 1: Participants will receive the PEP uP protocol with the pro motility agent. The intervention will be provided until the tube feeds are stopped or patient is fed meals orally and will be tracked until hospital discharge or 60 days which ever occur first. arm 2: Standard formula polymeric tube feeds started at a rate of 20 ml/hour. Gastric residual volume (GRV) will be checked every 4 hours. GRV is reinfused to the patient each time it is checked. GRV threshold is 200-500 ml. If the patient is tolerating tube feeds as determined by measuring the GRV, the rate is advanced by 20 ml/hour every 4 hours up to the goal rate. Participants will be followed until the tube feeds are stopped or patient is fed meals orally and will be tracked until hospital discharge or 60 days which ever occur first.
Interventions: intervention 1: PEP uP Protocol intervention 2: Metoclopramide
Intervention descriptions: intervention 1: Semi-elemental tube feeds are started at the hourly goal rate as determined by the 24 hour volume goal. Protein supplements will be started at the initiation of tube feeds to target a daily delivery of 2 g/kg/day. intervention 2: Metoclopramide 10mg Intravenous (IV) every 6 hours (q6h) or 5mg IV q6h for renal failure will be started empirically concomitant with EN initiation. Gastric Residual Volume (GRV) will be checked every 4 hours and will be reinfused to the patient each time it is checked.

Protocol documents:
Prot_SAP_000.pdf: 
PRINCIPAL/OVERALL INVESTIGATOR 
Daniel Dante Yeh, MD 
PROTOCOL TITLE 
PEP uP Protocol(Enhanced Protein-Energy Provision via the Enteral 
Route Feeding Protocol) in Surgical Patients 
FUNDING 
Nestle HealthCare 
VERSION DATE 
02/11/2017 
SPECIFIC AIMS 
Our hypothesis is that an aggressive feeding protocol, PEP uP (Enhanced 
Protein-Energy Provision via the Enteral Route Feeding Protocol) will be 
safe, acceptable, and effectively increase protein and energy delivery to 
critically ill surgical patients. 
BACKGROUND AND SIGNIFICANCE 
Critically ill patients are often hypermetabolic and can rapidly become nutritionally 
compromised. Pre-existing malnutrition is prevalent in these patients and has been 
associated with increased morbidity and mortality, particularly in the surgical 
population. Consequently, the goals of nutrition therapy in critically ill patients are 
to attenuate the metabolic response to stress or injury by providing nutrition 
consistent with the patient’s condition, preventing or treating nutrient deficiencies, 
and avoiding complications related to the route of nutrition delivery. 
Gross underfeeding or iatrogenic malnutrition is prevalent in intensive care units 
throughout the world. 
Critically ill patients only receive, on average 40-50% of 
their prescribed nutritional requirements. Inadequate provision of nutrition to these 
Filename: Protocol Summary 
1 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
Concisely state the objectives of the study and the hypothesis being tested. 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
 
 
N
NCT# 02459275 


patients is associated with increased complications, prolonged length of stay in the 
ICU and hospital, and increased mortality. There are good data from large scale 
observational studies and randomized trials that suggest better fed patients have 
better clinical and economic outcomes. 
There are some ICUs that consistently reach an average of 80-90% nutritional 
adequacy (amount of nutrition received over amount prescribed) and thus we 
believe that this is a feasible goal. 
Historically, feeding protocols have been used to guide the delivery of enteral 
nutrition (EN) and they frequently utilize conservative, reactionary approaches to 
optimizing nutrition that are not grounded in evidence but rather, seem to have 
evolved over time. We propose a new, innovative approach that protocolizes an 
aggressive set of strategies provide EN and to shift the paradigm from reactionary 
to proactive followed by de-escalation if nutrition therapy is not needed: PEP uP 
(Enhanced 
Protocol). 
Protein-Energy 
Provision 
via the Enteral Route Feeding 
The key components of this new PEP uP protocol are the following: 
1) Starting feeds at the target rate based on increasing evidence that some patients 
tolerate starting nutrition at a higher rate of delivery and that slow start ups are not 
necessary. For patients who are hemodynamically stable, we propose to shift from 
an hourly rate target goal to a 24 hour volume goal and give nurses guidance on 
how to make up this volume if there was an interruption for non-gastrointestinal 
reasons. 
2) For patients who are deemed unsuitable for high volume intragastric feeds, we 
provide an option to initiate “trophic feeds” to provide a low volume of a 
concentrated feeding solution for 24 hours or longer, designed to maintain 
gastrointestinal structure and function rather than meet their protein and caloric 
goals. 
3) To optimize tolerance in the early phase of critical illness, we propose to use a 
semi-elemental feeding solution instead of a standard polymeric solution. These 
can then be changed to more traditional polymeric solution once the patient is 
tolerating adequate amounts of nutrition. 
4) Rather than wait for a protein debt to accumulate because of inadequate delivery 
of EN, protein supplements are prescribed at initiation of EN and can be 
discontinued if EN is well tolerated and they are receiving all their protein 
requirements through their standard EN. 
5) Rather than wait for a problem with gastrointestinal tolerance to develop, we 
propose to start motility agents at the same time EN is started with a re-evaluation 
in the days following to see if it is necessary. 
This PEP uP protocol has been previously studied in two published studies enrolling 
primarily medical patients. 
In the first study, a pilot before and after trial, the 
Filename: Protocol Summary 
2 
 


protocol seemed to be feasible, safe, and acceptable to critical care nurses. 
No 
incidents compromising patient safety were observed. (Heyland 2010) 
Rates of 
vomiting, regurgitation, aspiration, and pneumonia were similar and the PEP uP 
group received significantly more energy and protein (when they were prescribed to 
receive full volume as opposed to “trophic”). 
A subsequent multi-center cluster 
randomized  trial  involving  low-performing  ICUs  likewise  demonstrated  that 
intervention sites had improvements in energy and protein delivery as well as a 
decrease in average time from ICU admission to start of enteral nutrition compared 
to the control group. (Heyland 2013) 
Heyland et al. Enhanced protein-energy provision via the enteral route in critically ill 
patients: a single center feasibility trial of the PEP uP protocol, Crit Care 2010 
Heyland et al. Enhanced Protein-Energy Provision via  the Enteral Route Feeding 
Protocol in Critically Ill Patients: Results of a Cluster Randomized Trial, Crit Care Med 
2003 
RESEARCH DESIGN AND METHODS 
This will be a prospective, randomized study which will be analyzed by 
“intention-to-treat.” All patients admitted to the two SICUs at Massachusetts 
General Hospital (Blake 12 and Ellison 4) on the Trauma and Emergency 
General Surgery (Churchill team) service and to the SICU at Brigham and 
Women’s Hospital on the Trauma and Emergency General Surgery service in 
whom initiation of tube feeds is currently planned by the intensivist will be 
screened for the study. Additional recruitment sites include: Jamaica 
Hospital Medical Center (Jamaica, NY), Carilion Clinic (Roanoke, VA) and 
Parkland Memorial Hospital (Dallas, TX). Those patients who are eligible and 
enroll will be randomized into two groups: 
1) Standard of Care 
2) PEP uP 
The inclusion criteria are: 
1) 
2) 
3) 
Age ≥ 18 years 
ICU admission within past 48 hours 
Initiation of tube feeds currently planned by the SICU team and 
primary surgical team 
4) 
Admitted by a surgical service to the SICU 
patient) 
(not a MICU or neurology 
Filename: Protocol Summary 
3 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the  
eligibility criteria (for example, age range, gender, medical condition). Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.” 
 


5) 
Expected to remain mechanically ventilated for > 24 h and expected 
to require ICU care for > 72 h after screening 
The exclusion criteria are: 
1) 
2) 
Pregnancy 
Attending surgeon preference (they 
must agree to feeding their 
patient according to the protocol in either arm using the goal rate 
determined by the SICU team and the nutritionist) 
3) 
Contraindication 
to enteral nutrition 
(bowel obstruction, 
bowel 
discontinuity, 
syndrome) 
proximal enterocutaneous fistula, and short gut 
4) 
DNR  status  or  goals  of  care  that  specify  limitations 
therapies 
Death expected within 24 hours 
in  medical 
5) 
The  primary outcome for  this study is  nutritional adequacy. 
To assess 
nutritional adequacy, the total amount of energy or protein received from 
either EN or parenteral nutrition (PN), inclusive of propofol, will be divided 
by the amount prescribed as per the baseline assessment and expressed as 
a percentage. For the purposes of evaluating these enteral feeding protocols, 
our primary comparison will be adequacy from EN sources between the two 
groups over the first seven ICU days. Categorical variables will be reported 
as counts and percents and compared between cohorts by the Fisher's Exact 
test. Length of stay variables will be described by medians and quartiles and 
compared by the log-rank test. Other continuous variables will be described 
by their means and standard deviations or medians and IQR, and compared 
by the Wilcoxon-Mann-Whitney or the Fisher’s Exact test accordingly. 
Statistical analysis will be done using SAS v9.1.3 (SAS Institute Inc., Cary, 
NC, USA). All tests will be two-sided with statistical significance considered 
as a P-value <0.05 
Sample Justification 
From our prior work, we know the standard deviation is 31%. We aim to 
detect a small but clinically meaningful increase in nutritional adequacy of 
about 20%. For 90% power, we would need 50 patients per group. 
Therefore, our sample size will be 100 patients total. 
Filename: Protocol Summary 
4 
Briefly describe study procedures. Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.” Describe 
study endpoints. 
 


Once consent is obtained and necessary baseline data collected, the study 
co-coordinator will log on to the web-based randomization system at the 
Clinical Evaluation Research Unit (http://www.ceru.ca/) at Kingston General 
Hospital. The system will confirm eligibility prior to allowing randomization. 
The system will then provide the study co-coordinator with a patient study 
number. The randomization system, which has proven reliable in several 
prior RCTs, has a robust audit trail and will maintain concealment and 
blinding. 
However, due to the nature of the intervention, post- 
randomization concealment and blinding will not be possible. 
Once a patient is randomized, tube feeds will be started through an existing 
naso-enteric or oro-enteric tube after proper placement is confirmed by 
radiograph. If a feeding tube is not already present, then it will be placed 
and location confirmed by radiograph. The goal rate for feeding will be set 
by the intensivist and SICU nutritionist to a rate that will approximate the 
patient’s nutritional needs. This may vary significantly based on estimations 
of the patient’s caloric and protein requirements, additional nutrition that the 
patient could be receiving such propofol, and restrictions in fluid such as in 
patients on dialysis. The intensivist may change the goal rate at any time, 
based on changes in the patient’s nutritional demands. 
For  patients  assigned  to  the  standard  of  care  group,  feeds  will  be 
delivered as follows: 
Standard formula polymeric tube feeds will be started at a rate of 20 
ml/hour. Gastric residual volume (GRV) will be checked every 4 hours. 
GRV will be reinfused to the patient each time it is checked. If the 
patient is tolerating tube feeds as determined by measuring the GRV, 
the rate will be advanced by 20 ml/hour every 4 hours up to the goal 
rate. 
If the GRV is: 
< 200 ml 
- Tube feeds will be continued to advance to goal 
200 – 500 ml 
- Tube feeds will be continued to advance to goal 
- Metoclopramide will be started at 10 mg IV every 6 hours for 3 
days (or 5mg IV q6h for renal failure) 
> 500 ml 
- Tube feeds will be held 
- GRV will be rechecked every 4 hour and Tube feeds will be 
restarted at half of the previous rate (rounded up to the nearest 
10 ml/hour) once GRV < 500 ml. 
If the patient is tolerating tube 
feeds as determined by GRV<500mL, the rate will be advanced 
by 20 ml/hour every 4 hours back up to the goal rate. 
Filename: Protocol Summary 
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For patients assigned to the PEP uP group, feeds will be delivered as 
follows: 
Semi-elemental tube feeds (Peptamen Bariatric) will be started at the 
hourly goal rate (as determined by the 24 hour volume goal). For 
example, if the 24 hour volume goal is determined to be 1200cc, then 
the initial starting PEP uP feeding rate will be 50 
supplements 
(ProSource 
or Beneprotein) 
will be 
initiation of tube feeds to target a daily delivery of 
cc/hr. 
Protein 
started 
at the 
2 g/kg/day. 
A 
promotility agent (metoclopramide 10mg IV q6h or 5mg IV q6h for 
renal failure) will be started empirically concomitant with EN initiation. 
GRV will be checked every 4 hours and will be reinfused to the patient 
each time it is checked. 
If the GRV is: 
< 500 ml 
- Tube feeds will be continued at goal 
> 500 ml 
- Tube feeds will be held 
- GRV will be rechecked every 4 hours feeding will be restarted 
at half the previous rate (rounded up to the nearest 10 ml/hour) 
once GRV < 500 ml. If this half-rate is tolerated for 4 hours (as 
evidenced by GRV <500mL), then Tube feeds will be returned to 
full goal rate. 
Once the patient shows tolerance of semi-elemental formula, the tube feeds 
will then be converted to standard polymeric formula.  Daily, the patient will 
be reassessed for the need to continue promotility agents (metoclopramide). 
In the SICU, renal failure is usually assessed according to the RIFLE criteria 
(Risk, Injury, Failure, Loss, ESRD). Our threshold for adjusting 
metoclopramide dose will be Injury, or twofold increase in the serum 
creatinine, or GRF decrease by 50 percent, or urine output <0.5 mL/kg per 
hour for 12 hours. For patients with chronic renal insufficiency, we will use 
an absolute cutoff of GFR <30. 
Patients  in  both  groups  will  be  closely  monitored  for  clinical  signs  of 
intolerance to enteral nutrition. The feeding tube will be placed to suction 
and feeds will be held for: witnessed aspiration, nausea (in awake patients) 
or emesis, or abdominal distension. After being held for these clinical signs 
of intolerance, tube feeds will be restarted 4 hours after resolution of the 
symptoms at half of the previous rate. If the intensivist, surgeon or PI does 
not feel that the patient cannot tolerate the full volume PEP uP feeding 
protocol to which they are assigned, the patient will be assigned to “trophic” 
rate of 20cc/hr. 
Filename: Protocol Summary 
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The intervention will end when tube feeds are stopped and the patient is fed 
meals orally. At this point, the patient will not resume the intervention, even 
if tube feeds are restarted due to inadequate oral nutrition. The intervention 
will also end whenever a patient is transferred out of the SICU. Patients will 
be tracked until discharge from the hospital or 60 days (whichever occurs 
first) in order to collect follow-up data. 
Within  24  hours  of  enrollment  in  the  study  the  following  data  will  be 
collected (see attached Data Collection Sheet): age, gender, APACHE 2 
score, baseline SOFA score, hospital admission, ICU admission, mechanical 
ventilation, 
ICU diagnosis, 
operation, 
comorbidities, 
laboratory 
baseline nutritional assessment. 
values, 
While receiving enteral feeds, the following data will be collected: feeding 
glucose 
prescription 
monitoring, 
episodes of 
(formula and goal rate), if a motility agent was given, 
insulin, propofol, location of feeding tube, oral nutrition, any 
intolerance to feeding, calories and protein received, enteral 
nutrition interruptions. 
From the time of enrollment in the study until discharge from the hospital 
(or day 60), the following data will be collected: mortality, ICU length of 
stay, hospital length of stay, ventilator days. 
As part of the data collection to assess feasibility and acceptability, nurses 
caring for patients randomized to the PEP uP arm will be given a survey to 
complete. A study investigator will distribute paper copies of the survey to 
the nurse and they will be asked to fill it out anonymously and return it to a 
collection envelope. 
The standard of care protocols for both institutions are described in the 
above section. 
Patients who enroll in our study will not undergo any additional diagnostic or 
therapeutic 
intervention 
that 
they 
would 
not 
otherwise 
undergo. 
Filename: Protocol Summary 
7 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes. 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care. 
Provide information on available alternative treatments, procedures, or methods of diagnosis. 
 


Furthermore, no diagnostic or therapeutic interventions will be withheld as a 
result of enrolling in our study. 
The most common foreseeable risk of providing a larger volume of enteral 
nutrition prior to confirming that a patient can tolerate a smaller volume is 
the risk of vomiting. However, the risk of vomiting has been described to 
better correlate with elevated GRVs rather than the feeding protocol TF 
provided. Vomiting has been described to occur in as many as 27% of the 
cases where GRV is continuously monitored and can reach even higher rates 
(39%) if no monitoring takes place. 
In this study, the vomiting rate is a group phenomenon based on individual 
subject data blocked into 12-hour periods, where if a subject vomits once or 
more during a 12-hour period, this counts as one vomiting occurrence, and 
the vomiting rate is the incidence of such occurrences as a percentage of 
total 12-hour periods observed. 
As stated above, patients in both groups will be closely monitored for clinical 
signs of intolerance to enteral nutrition. The feeding tube will be placed to 
suction and feeds will be held for: witnessed aspiration, nausea (in awake 
patients) or emesis, or abdominal distension. After being held for these 
clinical signs of intolerance, tube feeds will be restarted 4  hours after 
resolution of the symptoms at half of the previous rate. Furthermore, if 
either the intensivist, surgeon or PI does not feel that a patient could 
tolerate the feeding protocol to which they are assigned, the patient will be 
labeled as a protocol violation. 
Additionally, the risk of refeeding syndrome could potentially be increased by 
our intervention. Refeeding syndrome is a rare complication that can lead to 
life-threatening metabolic derangements upon feeding a patient who has 
taken minimal nutrition for 5 days. Any patient that shows evidence of the 
refeeding syndrome based on a significant drop in the serum potassium, 
magnesium or phosphorus or other abnormalities as determined by the 
intensivist, surgeon or PI, the patient will be changed to the “trophic rate” 
feeding protocol until the electrolytes have improved enough to return to full 
feeding rate. This is consistent with our usual practice in the SICU. Because 
electrolytes are assessed frequently and aggressively replaced, we expect 
the actual incidence of refeeding syndrome to be very low. 
Filename: Protocol Summary 
8 
Describe explicitly the methods for ensuring the safety of subjects. Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events. The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups. 
 


We have recruited a surgeon at Partners, Dr. Janey Pratt, to act as a Medical 
Monitor. She is not involved in the study and will review the safety data 
after every 25 subjects. Stopping criteria include: 
a) Vomiting in >10% of the subjects assigned to the PEPuP arm or 
b) Macroaspiration in 20% of the subjects assigned to the PEPuP arm or 
c) 50% more pneumonia in the PEPuP arm than the control group. 
FORESEEABLE RISKS AND DISCOMFORTS 
The foreseeable risks and discomforts of starting tube feeds at a greater rate 
before confirming that patients can tolerate a lower rate of tube feeds are 
abdominal pain, nausea, vomiting, and diarrhea. These events could be 
distressing to patients or their families and could require additional medical 
treatments 
such 
as pain medications, 
antiemetics, 
after enteral 
ill patients at 
or 
antidiarrheal 
medications, but are likely to resolve soon 
decreased in rate. Vomiting places critically 
feeding is held or 
risk for aspiration 
which could lead to pneumonitis and pneumonia. 
In the single-center feasibility trial of the PEP uP protocol, Heyland et al. 
reported a 6.7% (n=2) rate of vomiting after implementation of the 
protocol, compared to 15% (n=3) before implementation. In the follow- 
up cluster randomized trial, Heyland et al. reported an average of 5.6% 
vomiting, which was not significantly different from 4.4% baseline rate. 
Aspiration is a common event in the ICU, but it has been repeatedly shown 
that the majority of aspirations and aspiration pneumonia result from 
aspiration 
of oropharyngeal 
secretions, 
not gastric regurgitations. 
Recently it was demonstrated that despite an increased rate of vomiting 
episodes (39.6% vs. 27.0%) there was no significant difference in any 
other outcomes such as ICU-acquired infections or duration of mechanical 
ventilation. (Reignier et al.) Similarly, in a recent study Williams et al 
demonstrated that despite an increased rate of vomiting, there was no 
increased rate of ventilator-associated pneumonia or any other clinical 
outcome. 
In the event of witnessed aspiration or vomiting, the decision to perform 
additional interventions will be left to the clinical team. 
Filename: Protocol Summary 
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Provide a brief description of any foreseeable risks and discomforts to subjects. Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality. When applicable, describe risks to a developing fetus or nursing infant. 
 


Finally, vomiting or diarrhea could place patients at risk for electrolyte 
abnormalities which will be counteracted by the constant assessment and 
replacement protocols active in the SICU. 
EXPECTED BENEFITS 
We expect that patients participating in our study and randomized to the PEP 
uP arm will receive a greater quantity of nutrition than those receiving 
standard of care. We believe that infectious complications, ICU length of 
stay, hospital length of stay and even mortality could be decreased by 
providing early and adequate nutrition. Starting tube feeds at the goal rate 
and decreasing due to intolerance has been shown to decrease infectious 
complications in traumatic brain injury patients. If its benefits are found to 
be generalizable, it could potentially benefit all surgical patients who require 
enteral nutrition since it takes no additional equipment to implement. 
EQUITABLE SELECTION OF SUBJECTS 
Pregnant women are rarely admitted to our SICUs. They have significant 
issues related to the effects of progesterone and the space occupying gravid 
uterus on the stomach and other GI organs. We could not enroll enough 
pregnant women to appropriately generalize our results to this population. 
Children are admitted to our SICUs in only the rare occasion when their age 
is unknown and incorrectly estimated to be over 18 years. We would not be 
able to enroll enough children to appropriately 
population. 
generalize our results to this 
Filename: Protocol Summary 
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When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so. Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present. 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it. No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so. Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research. 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study. Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.” 
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 


We will not exclude patients who do not speak English. Our research does 
not target a non-English speaking population and we do not anticipate more 
than incidental cases of non-speaking subjects. In cases of unexpected 
encounters with non-English speakers, the Partners Human Research 
Committee policy on obtaining and documenting informed consent of 
subjects who do not speak English will be followed and we will make sure 
that potential subjects are provided with both; a written translation in a 
language understandable to them of the ‘short form’ and an interpreter 
fluent in both English and the subject’s spoken language. 
RECRUITMENT PROCEDURES 
The enrollment sites are: Massachusetts General Hospital (MGH), Brigham 
and Women’s Hospital (BWH), and Jamaica Hospital Medical Center (JHMC). 
MGH and BWH are conducting the research under the Partners IRB approval 
and JHMC is conducting research under their own local IRB approval. 
Twice daily, the Study Coordinator will screen the SICU census and identify 
newly admitted eligible patients (based on the inclusion and exclusion criteria) 
prior to initiating enteral nutrition. The patient’s SICU attending will be notified 
to obtain approval to approach the subject for enrollment. At this point a 
licensed physician investigator will be introduced by a physician from the SICU 
team in order to obtain consent. 
If the potential subject is NOT a patient of a study investigator, then the 
primary health care provider (attending surgeon and intensivist) will be 
contacted first by an investigator. That provider must then give approval for 
his/her patient to be contacted for research purposes, initially introduce the 
study to the patient, AND verbally obtain the patient’s (or surrogate’s) 
permission to be contacted by study staff. 
If the potential subject is among the investigator’s own patients, that 
investigator will reinforce with the patient (or surrogate) that participation is 
voluntary, that they do not have to participate, and the decision not to 
participate will not affect their care, now or in the future. 
Filename: Protocol Summary 
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Explain in detail the specific methodology that will be used to recruit subjects. Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation. Include any specific recruitment methods used to enhance recruitment of women 
and minorities. 
For guidance, refer to the following Partners policy: 
Obtaining and Documenting Informed Consent of Subjects who do not Speak English 
http://healthcare.partners.org/phsirb/nonengco.htm 
 


Hospital interpreters will be used for the enrollment of non-English speaking 
subjects. 
No remuneration will be provided 
CONSENT PROCEDURES 
Consent will be obtained by a licensed physician investigator (not a member 
of the clinical team) from the subject or surrogate after it is confirmed that 
the patient meets all eligibility criteria for the study. If the patient’s physician 
is a member of the study staff, they will introduce another licensed physician 
investigator from the study staff who will obtain informed consent. 
It is expected that many patients will be incapable of providing informed 
consent since a common indication for enteral nutrition is mechanical 
ventilation 
via endotracheal intubation, and mental status is commonly 
impaired in critically ill patients. If the physician investigator is unable to 
determine if the patient has capacity to consent for our study, a physician on 
the SICU team will assist in making this evaluation. 
In cases where a patient is deemed incapable 
of providing consent, 
surrogate consent will be sought from 
 
legally authorized representatives. 
Filename: Protocol Summary 
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Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation). For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided. 
 For guidance, refer to the following Partners policies: 
Recruitment of Research Subjects 
http://healthcare.partners.org/phsirb/recruit.htm 
Guidelines for Advertisements for Recruiting Subjects 
http://healthcare.partners.org/phsirb/advert.htm 
Remuneration for Research Subjects 
http://healthcare.partners.org/phsirb/remun.htm 
Provide details of remuneration, when applicable. Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation. Investigators may wish to consider providing reimbursement for such 
expenses when funding is available 
 


The PHRC preferred order of surrogates will be followed and consent will be 
obtained accordingly: 
1) 
Court appointed guardian with specific authority to provide consent 
for participation in research, or authority to make health care 
decisions for a class of diagnostic and therapeutic decisions inclusive 
of the proposed research. 
Health care proxy/person with durable power of attorney, with 
specific authority to make healthcare-related decisions inclusive of 
the proposed research 
2) 
3) 
Spouse, adult child, or other close family member 
subject well and has been involved in their care. 
who knows the 
DATA AND SAFETY MONITORING 
The PI will review the data each month. If at any time, he is concerned that 
the study is unsafe, he may stop the study or temporarily suspend the 
study. Additionally an independent medical monitor, Dr. Janey Pratt, will 
review the data after every 25 enrolled subjects (study-wide) for safety. 
Filename: Protocol Summary 
13 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports. Describe the plan for reporting adverse events to the sponsor 
Describe the plan for monitoring the data to ensure the safety of subjects. The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped. Include a brief description of any stopping 
rules for the study, when appropriate. Depending upon the risk, size and complexity of the  
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity. 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision- 
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
 
http://healthcare.partners.org/phsirb/newapp.htm#Newapp 
 
 
For guidance, refer to the following Partners policy: 
Informed Consent of Research Subjects  
http://healthcare.partners.org/phsirb/infcons.htm 
 


In accordance with the Partner policy “Reporting Unanticipated Problems 
including Adverse Events”, all unanticipated problems, adverse events, and 
serious adverse events will be reported electronically to the IRB within 7 
calendar days of any investigator in the study becoming aware  of the 
occurrence. 
An investigator will round on the subjects daily while they are undergoing 
the study intervention in the SICU, and weekly thereafter until the patient is 
discharged from the hospital. They will meet with the PI weekly to review 
the data confirm that no unanticipated problems, adverse events, or serious 
adverse events are overlooked. 
MONITORING AND QUALITY ASSURANCE 
At all enrollment sites, a research 
electronic database stored in a secure 
computer system. The consent forms will 
fellow will maintain the data in an 
location on a password-protected 
be kept in files which will be stored 
in a secure location. De-identified data will be uploaded to the coordinating 
center (see below). 
The local site PI will meet with the research fellow 
weekly to confirm that each new patient enrolled in the study has a valid 
consent form. The PI will confirm the completeness of data being entered in 
the electronic database. For the first 2 patients in each group and every 10 
patients, a patient randomly selected by the PI, the PI will review the source 
documents with the research fellow in order to assure that the protocol is 
being collected and reported 
being followed accurately and that data is 
Filename: Protocol Summary 
14 
 Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol. Specify who 
will be responsible for monitoring, and the planned frequency of monitoring. For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent. 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB. 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites. 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting 
 


accurately in the electronic database. If any deviation is encountered that 
could place the study subjects at increased risk, an ad-hoc meeting of the 
Steering Committee will be convened to evaluate the problem. If only minor 
issues are discovered, the study staff 
the problem. 
will meet to troubleshoot and resolve 
PRIVACY AND CONFIDENTIALITY 
No identifiable information will be revealed to any third party. All subjects’ 
identifiable 
information 
will be saved on Partners 
password 
protected 
computers with limited access to the study staff only. 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
The coordinating center for this study is located at the Clinical Evaluation 
Research Unit (CERU) at the Kingston General Hospital, Ontario, Canada. 
CERU consists of a staff with experience and resources to support the 
successful completion of all phases 
 
of the design, conduct, monitoring, and 
Filename: Protocol Summary 
15 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects. 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected. This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location. 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors. 
For guidance, refer to the following Partners policies: 
Data and Safety Monitoring Plans and Quality Assurance 
http://healthcare.partners.org/phsirb/guidance.htm#13 
Reporting Unanticipated Problems (including Adverse Events) 
http://healthcare.partners.org/phsirb/guidance.htm#7 
 


interpretation of multicenter clinical studies. Dr. Daren Heyland, the Director 
of CERU is a Professor of Medicine and Epidemiology at Queen’s University, 
Kingston, Ontario Canada. He is trained in Internal Medicine, Critical Care 
Medicine, and Clinical Epidemiology.  Dr. Heyland is the originator of the PEP 
uP protocol. The study was designed by PI Dr. Yeh under the guidance and 
mentorship of Dr. Heyland. 
The data manager at Partners sites will be responsible for all aspects of data 
collection and processing, while the statistician at CERU will be responsible 
for all aspects of the data analysis and reporting of data. The data manager 
for the non-Partners sites (JHMC) will be responsible for all aspects of data 
collection and processing at their local site.  All sites will send data directly 
to CERU. 
CERU’s proprietary central randomization system (CRS) is a 
modular web-based tool used to monitor patient enrollment, accrual and/or 
randomization. CERU uses REDCap as an electronic data capture system for 
capturing, managing, and reporting clinical research data for trials. The 
REDCap system will run on the SOLARIS 10 operating system and the data 
will be hosted on a MySQL server database. 
Accessing the servers from the CERU offices is done via Virtual Private 
Network.  HPCVL  provides  an  encrypted 
ensure only authorized users can access 
connect to the virtual private network are 
of CERU’s IT staff. 
connection  to  their  network  to 
the servers. The permissions to 
granted by HPCVL at the request 
End users will access the CRS and REDCap using a Secure Socket Layer 
connection (SSL) and secure passwords provided by CERU’s IT staff. Access 
to the CRS and REDCap is only possible with previous authorization by CERU 
IT staff. 
All data pertaining to the research participant are transmitted to CERU in an 
anonymized fashion. At the time of data entry participants will be identified 
in the CRS and REDCap with a 
randomization number). 
unique identifier 
(i.e. enrollment 
or 
All these resources are compliant 
regulatory authorities worldwide. 
with Good Clinical Practice and other 
Filename: Protocol Summary 
16 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol. Include whether subjects can withdraw 
their specimens/data, and how they would do so. When appropriate, submit documentation of 
IRB approval from the recipient institution. 
 


RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Filename: Protocol Summary 
17 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects. When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.