Clinical trial NCT03298945
Conditions: Colorectal Cancer
Keywords: colonoscopy colorectal cancer bowel preparation regimen pragmatic trial
Sponsor: VA Office of Research and Development
Start date: 2018-12-13; Completion date: 2024-06-30
Enrollment: 2239 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
From the patients' perspective, the most formidable part of the colonoscopy experience is the process of bowel cleansing. A poorly tolerated bowel preparation regimen often leads to incompletion of scheduled colonoscopies which in turn undermines the effectiveness of colonoscopy, increases cost, and decreases patient satisfaction. The current standard bowel preparation in the VA is of larger volume and less palatable than another commonly used bowel preparation regimen. The investigators propose to compare these two commonly used bowel preparations with respect to the overall completion rate of scheduled colonoscopies in a real-world VA practice setting. The results of the study can be immediately applied to maximize the effectiveness of colonoscopy and increase patient satisfaction in the VA.

Detailed description:
Anticipated Impacts on Veterans Health Care: by identifying a colonoscopy bowel preparation regimen which is the most effective in real-world VA practice and can be immediately implemented on a VA-wide scale, the proposed study will maximize the effectiveness of colonoscopy in reducing colorectal cancer (CRC) risk among Veterans, increase Veteran satisfaction, and reduce VA healthcare cost. Background: CRC is a leading cause of cancer-related death among Veterans. Colonoscopy can effectively reduce CRC incidence and mortality. However, non-adherence to screening colonoscopy substantially undermines this benefit. Existing evidence indicates that a disagreeable bowel preparation is a leading barrier to completing a colonoscopy from the patients' perspective. The taste and the volume of the bowel preparation determine patient tolerability and compliance to the preparation instructions, which in turn affects the incompletion (e.g., cancellation/no-show/reschedule) rate of scheduled colonoscopies as well as the effectiveness of the completed colonoscopies and patient satisfaction. The two most commonly used preparations currently in the US are the split-dose 4L polyethylene glycol (PEG) and the split-dose 2L MiraLAX/Gatorade preparations. While a high-volume regimen may in theory be more effective than a lower volume one, it may be associated with lower tolerability and adherence in real-world practice. Three small trials have compared these two preparations. However, data from these explanatory trials cannot inform policy decisions because they were conducted under artificial conditions, restricted among narrow patient populations, and most importantly not designed to capture the full impact of bowel preparation on the completion rate or effectiveness of colonoscopy. To address this critical knowledge gap, the investigators are proposing a pragmatic trial to determine the optimal split-dose bowel preparation in the general Veteran population. Objectives: to compare the real-world effectiveness of the two most commonly used split-dose colonoscopy bowel preparation regimens in the US (i.e., 4L PEG and 2L MiraLAX/Gatorade) with respect to the completion rate of scheduled colonoscopies, adenoma detection rate and secondarily preparation quality, cancellation/no-show rate and patient-oriented outcomes (e.g., willingness to repeat the preparation).

Arms: arm 1: 4-L split-dose Golytely bowel prep arm 2: 2-L split-dose Miralax-Gatorade bowel prep
Interventions: intervention 1: Miralax-Gatorade Prep intervention 2: Golytely
Intervention descriptions: intervention 1: 2-L split-dose Miralax-Gatorade bowel prep for colonoscopy intervention 2: 4-L split dose Golytely is the current standard prep at the VA

Protocol documents:
Prot_SAP_000.pdf: 
 
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CMCVAMC SPECIFIC PROTOCOL SUMMARY 
Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center (CMCVAMC) 
Institutional Review Board (IRB) 
 
 
Section 1. General Information 
 
Protocol Title:   Comparative Effectiveness of Split-dose Colonoscopy Bowel Preparation Regimens   
 
CMCVAMC Protocol Version Number and Date:  Version #3 6/17/2018  
 
NCT number: NCT03298945 
 
Principal Investigator (PI) Name:  Yu-Xiao Yang   
 
PI’s Academic Degree(s):   MD 
 
Is the study funded?   YES    If “yes”, specify funding agency:  VA 
 
Is a grant application requesting funds for the study currently being reviewed?    NO 
 
CMCVAMC is the only institution involved: YES 
 
CMCVAMC is the coordinating center in which the PI is the lead investigator: Choose an item.       
If this answer is yes, complete the next two sections: 
➢ List the name(s) of the other site(s) involved.        
➢ Provide the FederalWide Assurance (FWA) numbers for each site.        
 
State name of coordinating center if this is not CMCVAMC.          
 
Describe PI’s qualifications to conduct this project, and attach a copy of PI’s VA or NIH 
biosketch.  Be specific in regard to PI’s research experience. NOTE:  If PI does not have any prior 
research experience, indicate what provisions are being made to provide oversight or mentoring.  As a 
staff gastroenterologist at the Corporal Michael J. Crescenz VA Medical Center for the past 10 years, Dr. 
Yang has intimate knowledge about the veteran population, the clinical and administrative operations of 
the VA and the GI endoscopy services.  
 
Dr. Yang is a core investigator of the VA Center for Health Equity Research and Promotion (CHERP) 
and a staff gastroenterologist at the Corporal Michael J. Crescenz VA Medical Center, an Associate 
Professor of Medicine and Epidemiology in the Gastroenterology Division and a Senior Scholar in the 
Center for Clinical Epidemiology and Biostatistics (CCEB) at the University of Pennsylvania. He is 
board-certified in Internal Medicine and in Gastroenterology. He has had extensive formal training in 
epidemiology and clinical research methodology and holds a Master of Science degree in Clinical 
Epidemiology from the University of Pennsylvania. His research program has been supported by highly  
competitive venues including the NIH (K08, R01), AHRQ (R01), VA (CSR&D Merit Review Award), and 
GI foundations.  


 
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A major theme of his highly productive and independent research program in GI epidemiology focuses  
on gastrointestinal epithelial cancer epidemiology, specifically colorectal cancer (CRC) prevention and 
risk assessment. He recently completed an AHRQ R01 project that investigated the risk of CRC 
following normal colonoscopies among elderly patients and those with diabetes. This project provided 
crucial data for determining the optimal screening colonoscopy frequency at a population level. Funded 
by a VA Merit review award (R01 equivalent), he is currently leading a prospective study investigating 
the role of insulin therapy on colorectal adenoma recurrence. The results of this study will guide the 
effort to optimize the CRC screening/surveillance policy in people with diabetes. This VA Merit project 
and his other NIH R01 project involved enrolling and following a large cohort patient both at the Corporal 
Michael J. Crescenz VA and the University of Pennsylvania. He has also conducted a randomized 
controlled trial testing the effectiveness of a physician-targeted intervention on optimizing medication 
prescribing in the University of Pennsylvania Health System. 
 
Does any research staff member have an actual and/or perceived conflict of interest with this 
study?   NO         If yes, explain.        
 
Is this study a clinical trial?  YES         If yes, specify the type. Phase IV 
 
State the estimated length of time to complete enrollment of subjects.  3 years 
 
State the expected duration of participation by individual subjects (including any follow-up, e.g., 
need to re-contact subject for follow-up questions prior to closure of the study). 6 months  
 
Specify the projected date of completion of the study.   7/1/2021 
 
Section 2:  Participating Site Specifications 
2.1. 
Where will the research project be conducted?  (Check all that apply)  
  VA Inpatient Setting 
  VA Outpatient Clinic/Office 
  
  VA Laboratories 
  Participant Homes 
 
 
  University of Pennsylvania 
  Community Based Outpatient Clinics (CBOCs)   
 
  Other (Specify):       
 
2.2. 
If research is conducted at a non-VA site, please specify where and how much of the 
project will be conducted at that location.     
          
 
Section 3:  Introduction 
3.1. 
Provide scientific background and rationale for study.  Including summary of gaps in 
current knowledge, relevant data, and how the study will add to existing knowledge.   
                B.1 Colonoscopy and colorectal cancer risk 
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US.7 Colonoscopy  
is now the main tool used for CRC screening and prevention. It has been shown to effectively reduce 
CRC incidence and mortality.8-17 However, the effectiveness of colonoscopy in preventing CRC 
depends on adherence to guideline recommended colonoscopy schedules and identification and 


 
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removal of precancerous polyps at the time of the colonoscopy. Unfortunately, compliance with 
colonoscopy screening recommendations has been suboptimal, including in the VA population.18 
Furthermore, up to 7% of CRCs are diagnosed within 3-5 years of a prior colonoscopy, with many of 
these being a consequence of missed lesions.19   
B.2 Role of colonoscopy bowel preparation  
Bowel preparation before colonoscopy is one of the most important determinants of the effectiveness of 
colonoscopy and is recognized as the major impediment contributing to a patient’s hesitancy to accept 
colonoscopy as a screening examination for CRC.5 Pre-colonoscopy bowel cleansing generally  
involves having patients ingest a large volume of often unpalatable liquid bowel preparation agent prior 
to the procedure, ideally leading to effective purging of the colon to allow adequate examination. This 
process may cause significant disruption to the patients’ daily routine (e.g., sleep disturbance, need for 
fasting or a restricted diet), while the large volume and unpleasant taste of the bowel preparation 
regimen may cause physical discomfort (e.g., nausea, vomiting, abdominal bloating/discomfort, fecal 
incontinence). Indeed, the bowel preparation process rather than the colonoscopy itself is the most 
formidable part of the colonoscopy experience from the patient’s standpoint.  
B.3 Adverse consequences of a poorly tolerated bowel preparation  
Existing data indicate that concern over the volume and taste of the bowel preparation is the most 
common factor that deters patients from undergoing screening colonoscopy.5 Our pilot data also 
indicate that poor tolerability of bowel preparation is a leading cause of no-shows or last-minute 
cancellations of scheduled colonoscopies (see D.2). A substantial proportion of patients do not initiate 
or complete the bowel preparation secondary to the large volume and/or poor palatability of the 
preparation.20 The resulting cancellations, no-shows, or inadequate bowel preparation has a number of 
undesirable downstream consequences affecting the patients, the providers and the health system. For 
the patients, cancellations and no-shows represent missed opportunity to reduce CRC risk; inadequate 
bowel preparation is associated with reduced adenoma detection21 and increased risk of procedure-
related complications,22 thus compromising the effectiveness and safety of the procedure. Poor bowel 
preparation often leads to aborted colonoscopy examination, necessitating a repeat colonoscopy within 
a few weeks to months and compounding the negative experience for the patient. From the 
endoscopist’s standpoint, inadequate bowel preparation adds technical difficulty to the procedure and 
increases procedure time.23 Even in cases where the endoscopist is able to reach the cecum, 
suboptimal bowel preparation is a common reason for the provider to recommend an interval for the 
follow-up colonoscopy much shorter than suggested or recommended by current practice guidelines  
(e.g. 5 years for patients without polyps rather than 10 years, 3 years rather than 5-10 years for patients  
with low risk polyps, or 1 year rather than 3 years for patients with high risk polyps).25 For the VA 
health system, the need to reschedule for cancellations/no-shows and increased colonoscopy  
frequency for inadequate preparation quality put additional strain on service capacity (e.g., longer 
backlogs) and entail substantially increased health care cost.24  
B.4 Bowel preparation quality in VA below benchmark  
Recognizing the critical importance of bowel preparation quality, the US Multi-Society Task Force 
(USMSTF) on Colorectal Cancer set the minimal rate of adequate bowel preparation before 
colonoscopy at 85%, and recommended that improvement initiatives be undertaken for anything below 
that target.3 Considerable efforts have been implemented in the VA system to enhance patient 
compliance with bowel preparation including implementation of novel patient educational tools and 


 
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routine pre-procedure telephone call by a GI nurse. However, the rate of adequate bowel preparation 
within the VA is still below the acceptable benchmark based on limited published data25 and our own 
pilot data (see D.2). Furthermore, the colonoscopy screening uptake rate is low among VA patients, 
particularly among African Americans;18 the anticipated negative experience of bowel preparation 
associated with colonoscopy could be a contributing factor for such disparities. These observations  
indicate an urgent need to improve colonoscopy bowel preparation quality within the VA system. 
B.5 Guideline recommendations on bowel preparation  
Patient tolerability of the bowel preparation regimen is associated with the characteristics of the 
regimen (e.g., the chemical compound used, volume, palatability, and the timing of ingestion relative to 
the time of the procedure [e.g., single- versus split-dose]).  Because tolerability is associated with 
compliance, the same variations among the existing bowel regimens also influence the quality of the 
bowel preparation.  Based on high-quality evidence from a current systematic review, the USMSTF on 
Colorectal Cancer strongly recommends the split-dose preparations (i.e., roughly half of the bowel 
cleansing dose given on the day of colonoscopy). However, it does not make a recommendation from 
among the several available split-dose options.3 These split-dose regimens have substantial 
differences in palatability and volume (i.e., large [≥3 liter] and low [<3 Liter]). Among these the most 
commonly used preparations currently in the US are 4L polyethylene glycol with balanced electrolyte 
solution (PEG-ELS) and 2L MiraLAX-Gatorade (M-G).  
B.6 PEG 
PEG is a non-absorbable solution that passes through the bowel without net absorption or secretion. 
Significant fluid and electrolyte balance shifts are therefore avoided. High-volume lavage solutions  
containing PEG-ELS such as GoLytely have been the mainstay of bowel preparation in many 
institutions including the VA system. However, these agents are not well-tolerated by many patients  
because of the large volume (4L) of solution to be consumed over a short time and its salty taste. 
Patient acceptance is poor.20, 26, 27 Reducing the volume and improving the taste of the preparation 
may be an important driving force to improved compliance.  
B.7 Guideline recommendations regarding MiraLAX-Gatorade preparation  
In this context, one agent that has been widely used in clinical practice in the US is MiraLAX (PEG 3350 
powder) in combination with 64 oz of Gatorade sports drink. The USMSTF stated that “These OTC 
medications or combinations (M-G preparation included) can be recommended by physicians as part of 
a bowel-cleansing regimen in preparing patients for… endoscopy”, but strongly recommended using the 
split-dose schedule to enhance tolerability and efficacy.3 A survey of a random sample of members of 
the American College of Gastroenterology in 2013 showed 37.4% of the gastroenterologists  
recommended the M-G preparation.4 Although hyponatremia is a potential risk theoretically when using 
a hypotonic lavage solution such as PEG powder. There have been no reports of hyponatremia with 
split-dose M-G regimens. In fact, based on its own review of the literature, the USMSTF concluded that 
“widespread use of PEG-3350 for bowel preparation seems to have been remarkably safe”.3  
B.7.1 Efficacy and safety data on MiraLAX-Gatorade preparation  
Five small randomized controlled trials (RCTs) have compared PEG-ELS to M-G bowel 
preparations.28-32 However, only 3 of these compared split-dose regimens, which is the current 
standard.28, 29, 31 Enestvedt et al. compared split-dose 4L PEG-ELS to 2L M-G in an RCT that was 
terminated early. They observed that PEG-ELS was associated with a higher rate of adequate bowel 


 
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preparation (i.e., Boston Bowel Preparation score [BBPS] ≥ 7). A higher proportion of MiraLAX users 
were willing to take their preparation again (P = 0.006). Hjelkrem et al. reported a prospective,  
randomized, single-blinded controlled trial comparing the efficacy and tolerability of a 2-L M-G 
preparation (with and without bisacodyl or pubiprostone) with a standard 4-L PEG-ELS preparation 
using split-dose administration to individuals undergoing screening colonoscopy.29 The PEG-ELS was 
associated with a better Ottawa Bowel Preparation Score (OBPS) than each of the M-G preparations  
(5.1 vs 6.3-6.9, p<0.001). However, because the OBPS downgrades the quality for retained fluids, 
which can be easily removed, the current USMSTF on CRC recommends against the use of this scale 
for assessing bowel preparation quality. Despite the difference in mean Ottawa scores, the authors did 
indicate that “All 4 of the bowel preparation regimens studied displayed adequate bowel cleansing”.  
Furthermore, there was no difference in procedural time, polyp detection rate or adverse events among 
the 4 comparison groups. However, those in the M-G arm rated the overall experience significantly  
better compared to the GoLytely group (P< .001). Finally, Samarasena et al. conducted an RCT at a 
single VA center, comparing single-dose and split-dose 4L PEG-ELS against single-dose and split-dose 
2L M-G. 31 They found that both split-dose regimens had comparably high BBPS scores (8.33 for PEG-
ELS vs. 8.01for M-G, p >0.05). Bother split-dose regimens were more efficacious than the single-dose 
preparations. In addition, 96.8 % of the M-G group were willing to repeat the same preparation vs. 75 % 
in the PEG-ELS group (P < 0.01). There were no clinically significant electrolyte changes from baseline 
in any subject in any group after bowel preparations. A recent meta-analysis of these 3 trials showed 
that pooled rates for satisfactory bowel preparations were 83% for the M–G group and 89% for the PEG 
group, and there were no statistically significant differences between the two split-dose preparations for 
polyp detection.6 Overall, the published RCTs reported inconsistent results regarding the efficacy of the 
M-G regimen in bowel preparation quality compared to the 4L PEG-ELS preparation. However, it is 
worth noting that the only trial conducted among the VA population showed split-dose the M-G 
preparation to be at least as good as the split-dose 4L PEG-ELS preparation in bowel cleanliness.31 
With regard to patient-related outcomes, M-G regimen appears strongly and consistently favored by the 
patients in all published studies. No safety signals with respect to electrolyte abnormalities were 
detected from the trials that collected data on this endpoint.30-32  
B.8 Existing explanatory trial data on MiraLAX-Gatorade preparation cannot inform clinical decision 
The data from the 3 existing explanatory trials cannot be used to support VA system-wide policy 
decisions. These 3 trials all tested how well 2L M-G and 4L PEG “can” work in narrow populations and 
artificial conditions. With regard to the study population, collectively the 3 explanatory trials included 
only 288 patients receiving split-dose M-G. In addition, these trials had extensive exclusion criteria. 
Most of the factors used for exclusion are associated with poor bowel preparation (e.g., non-screening 
indications, diabetes mellitus, constipation and narcotics use), limiting the generalizability of the findings  
from these trials. These data demonstrate that the results of these explanatory trials do not reflect real-
world clinical practice and thus cannot be used to inform VA wide policy decisions.   
Most importantly, the published explanatory trials narrowly focused solely on preparation quality among 
patients who actually consumed the bowel preparation and showed up for a colonoscopy. However, 
poor tolerability of bowel preparation has been reported by patients (both those who have [57%] and 
have not [66%] undergone screening) as the most important factor that deters them from undergoing 
screening colonoscopy.7 The majority of patients (59% of those having and 69% of those not having 
undergone screening) also indicated that a smaller volume bowel preparation was the most preferred 


 
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solution to improve their chance of undergoing screening colonoscopy.5 Indeed, our pilot data (See 
Section D.2) indicated that with the current VA standard split-dose 4L PEG, 44% of the scheduled 
colonoscopies were not completed due to cancellations, no-shows and inadequate preparation quality. 
Furthermore, poor tolerability and non-compliance of the current standard preparation was a leading 
determinant of incompletion of scheduled colonoscopies which adds substantial financial and logistical 
strain on endoscopy services in the VA. Therefore, in addition to preparation quality, a comparison of 
the existing bowel preparation options intended to inform policy decisions must also evaluate the effect 
of bowel preparation regimen on the rate of non-compliance and no-shows among all scheduled 
colonoscopies. Based on these considerations, there is no adequate comparative effectiveness data 
currently regarding the relative advantage of the split-dose low volume M-G versus the current VA-
standard of split-dose high volume PEG-ELS that can be used to inform real-world clinical and policy  
decisions regarding the optimal bowel preparation regimen in the VA system.  
B.9 Rationale for the proposed pragmatic clinical trial design 
The overarching goal of the proposed project is to address this critical knowledge gap. Specifically, we 
propose to conduct a pragmatic point-of-care (POC) clinical trial to generate the necessary comparative 
effectiveness data to directly inform policy and clinical decision-making regarding the optimal choice of 
standard colonoscopy bowel preparation in real-world VA clinical practice. This trial will answer novel 
questions not addressed by any of the prior trials – whether completion rates of scheduled colonoscopy  
and population-level adenoma detection rate differ between these two strategies when used in routine 
clinical practice. We hypothesize that owing to its superior tolerability and solid efficacy in producing 
adequate bowel preparations, the split-dose 2L M-G regimen is a better option than the current 
standard split-dose 4L PEG-ELS regimen in the VA population. To maximize pragmatism of the trial, 
key design features of the study will include direct comparison against current VA standard bowel 
preparation and broad patient inclusion criteria such that the study population offers the maximum 
opportunity for generalization of study results to the general VA population. Most importantly, by 
focusing on the overall completion rate of scheduled colonoscopy and population-level ADR as the 
primary endpoints, the proposed study will be the first to determine the full spectrum of downstream 
impact of a lower-volume and better-tolerated bowel preparation on the efficiency and effectiveness of 
colonoscopy. Furthermore, all the study procedures including enrollment, randomization, and 
administration of the treatments and data collection will be seamlessly integrated into the point of care 
with virtually no interference to the flow of usual clinical care. Also, the implementation of these 
procedures will take advantage of the existing VA electronic medical records system to maximize 
efficiency and minimize cost. These innovative design features will reduce study costs, enhance 
external validity of the study and accelerate the translation of research findings to practice. They are 
consistent with the VA’s commitment to learning through the integration of research and practice.  
C. Significance 
The poor tolerability of the current standard colonoscopy bowel preparation is contributing to the 
unacceptably low colonoscopy uptake and completion rate within the VA population. Split-dose M-G 
preparation is a lower-volume and more palatable alternative which has been widely used in non-VA 
clinical settings with better patient acceptance than the current VA standard and a good safety profile. 
The few small and narrowly focused explanatory RCTs comparing the two regimens cannot be used to 
support policy and clinical decisions. The proposed pragmatic clinical trial will fill this critical evidence 
gap by generating comparative effectiveness data in the real-world VA setting regarding the 


 
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effectiveness of the split-dose M-G regimen in maximizing the overall effectiveness of VA colonoscopy  
services. If the M-G bowel preparation regimen is found to be the superior option compared to the 
current standard, it would improve patient satisfaction, reduce CRC risk and promote more efficient use 
of VA endoscopy resources. This innovative study leverages the existing features of the VA electronic  
medical records system to seamlessly integrate the research procedure into the routine clinical care 
activity, minimizing cost and intrusiveness to routine care while maximizing the efficiency and 
pragmatism of the study. As such, the proposed project will contribute to the current mission to 
transition the VA into a learning health care system in which research and practice are intertwined to 
enable systematic learning from ongoing clinical care that will constantly improve clinical practice. 
 
Section 4:  Objectives Section  
4.1. 
Describe the study’s purpose, specific aims, or objectives.     
   Primary Aim: To compare split-dose 4L PEG to split-dose 2L MiraLAX/Gatorade bowel 
preparation regimen with respect to the rate of completion of scheduled colonoscopy and 
population-level adenoma detection rate (ADR) among veterans scheduled for colonoscopies.  
Hypothesis: the 2L split-dose Miralax/Gatorade is better than 4L split-dose PEG with regard to 
completion of scheduled colonoscopy and adenoma detection.  
Secondary Aim #1: To compare split-dose 4L PEG to split-dose 2L MiraLAX/Gatorade bowel 
preparation regimen with respect to cancellation/no-show rate, the bowel preparation quality and 
patient willingness to repeat the bowel preparation among veterans undergoing colonoscopies.  
Hypothesis: the 2L split-dose Miralax/Gatorade is better than 4L split-dose PEG with regard to 
bowel cleanliness and patient preference.  
Secondary Aim #2: To compare split-dose 4L PEG to split-dose 2L MiraLAX/Gatorade bowel 
preparation regimen with respect to the rate of completion of scheduled colonoscopy,  
population-level ADR, bowel cleanliness and willingness to repeat the bowel preparation in 
subgroups defined by sex, diabetes status, history of constipation and age (≥65 and <65), 
indication of colonoscopy, timing of colonoscopy (AM vs. PM). 
Hypothesis: the 2L split-dose Miralax/Gatorade is better than 4L split-dose PEG with regard to 
completion of scheduled colonoscopy, ADR, bowel cleanliness and patient preference 
regardless of sex, age, diabetes status, timing of colonoscopy, indication of colonoscopy or 
constipation.  
Exploratory Aim: To quantify and compare the average staff/physician time and cost spent on 
completing a round of colorectal examination per patient using split-dose 4L PEG versus split-
dose 2L MiraLAX/Gatorade.  
Hypothesis: the 2L split-dose Miralax/Gatorade is associated with lower average staff/physician 
time and cost spent on completing a round of colonoscopy examination per patient than split-
dose 4 L PEG. 
 
4.2. 
State the hypotheses to be tested.     
   See above 
 


 
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Section 5: Study Procedures 
5.1. 
Study Design 
5.1.1. 
Describe in detail the experimental design, i.e. from recruitment 
procedures to study closure.            
    E.1 Overview The proposed study will be a pragmatic, open-label, randomized 
trial comparing 4L split-dose PEG to 2L split-dose M-G bowel preparation regimen 
among veterans scheduled to undergo a colonoscopy at the CMCVAMC. The 
colonoscopy bowel preparation ordering workflow in the VA computerized patient 
record system (CPRS) will be slightly modified to allow the ordering provider to 
give permission for the patient to be enrolled into the trial. The study will be 
conducted with a waiver of documentation of informed consent. Enrolled patients  
will be randomized in the CPRS at the point of care to one of the two bowel 
preparations, and the order for the assigned preparation will be generated  
automatically for provider signature. Study patients will undergo the colonoscopy  
as usual. The providers performing the colonoscopy are requested to document in 
their routine pre-procedure note the patients’ willingness to repeat the bowel 
preparation regimen they received as well as their assessment of the clarity and 
completeness of the bowel preparation instructions. There are no study-related 
diagnostic procedures and no study-specific follow-up events required. Outcomes  
and covariate data will be collected directly from the CPRS. The primary 
endpoints are completion rate of scheduled colonoscopy and population-level 
ADR, and the secondary endpoints are cancelation/no-show rate, bowel 
preparation quality and patient-oriented outcomes (e.g., willingness to repeat). 
Analysis will be based on intention-to-treat (ITT).  
E.2. Study Site and Data Source  
The proposed project will be performed at the CMCVAMC. CMCVAMC is the 
largest VA facility in the southeastern Pennsylvania, New Jersey and Delaware 
Tri-state area, providing comprehensive care for nearly 40,000 patients annually. 
The facility is staffed by more than 1,500 employees and supports more than 150 
acute beds and a 240-bed Nursing Home Care Unit. The CMCVAMC houses a 
number of primary care and subspecialty clinics. About 16,000 patients are seen 
annually in primary care clinics. CPRS is a comprehensive electronic medical 
record system that has been implemented since 1998 at all VA medical centers  
nationwide and at VA outpatient clinics, nursing homes, and other sites of care. It 
is well integrated with other Veterans Health Information System and Technology  
Architecture (VistA) applications, such as pharmacy, radiology, laboratory and 
histologic data, inpatient and outpatient progress notes, discharge summary, 
consult notes, all endoscopic procedure notes, problem list, VistA imaging, billing, 
and patient administration. Information in the CPRS is retrievable through 
database query of the VISN 4 data warehouse on a large scale or by individual 
chart review when more detailed or comprehensive information in a specific  
patient is needed.  


 
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E.3 Study Population 
Our goal in selecting study patients for this pragmatic trial is to enroll all patients  
who meet the basic entry criteria and reflect the full range of patients undergoing 
bowel preparation for colonoscopies found in regular VA clinical practice. The 
study population will consist of all veterans seeking healthcare at the CMCVAMC. 
E.3.1. Inclusion criteria 
The inclusion criteria for potentially eligible subjects are: 
1.  > 18 years of age, and  
2.  being scheduled for outpatient elective screening, surveillance or diagnostic  
colonoscopies, and  
3.  the provider ordering the colonoscopy giving permission to enroll the patient. 
E.3.2. Exclusion criteria  
Patients who are <18 years, undergoing inpatient colonoscopy, those with contra-
indications to receiving the standard 4L PEG-ELS colonoscopy bowel preparation 
(e.g., allergy to PEG) will be excluded. We are excluding inpatient colonoscopies  
because they account for a very small fraction of the total colonoscopies  
performed. Also, inpatient colonoscopies are often performed for urgent reasons  
such that rapid bowel preparation procedures are followed. In addition, because 
the objective of inpatient colonoscopy is often not to look for small polyps, the 
threshold for “adequate” bowel preparation quality might be different from that for 
outpatient procedures. In addition, for patients undergoing more than 1 
colonoscopy during the study period, only their first colonoscopy will be included 
in the primary analysis. Patients who are undergoing a repeat colonoscopy for to 
a recent inadequate colonoscopy examination with poor bowel preparation will be 
excluded. 
E.4 Recruitment Strategies  
The CAC at CMCVAMC will change the existing CMCVAMC colonoscopy bowel 
preparation order workflow in CPRS slightly to incorporate an option for the 
ordering provider to allow the patient to be enrolled into the proposed trial.  
Specifically, the only difference is that after the provider submits the colonoscopy  
consult request, a pop-up CPRS window (Step B) will briefly introduce the  
proposed trial to the providers (who should already be aware of the study because 
the study team will present the study to all PCPs before the enrollment initiation) 
and ask if they believe the patient would be appropriate for consideration of 
enrollment. If they believe it is, they will ask the patient whether he/she would like 
to opt out of being approached for consideration of enrollment in the trial (see 
script template).  Those who do not opt out will be given an information sheet (see 
letter template). If either the provider or the patient does not agree to having the 
patient approached for the study, the provider will document this by clicking a 


 
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radio button in the window indicating “No. The patient may not be approached.  
Proceed with usual care” and  s/he will continue with the current workflow 
proceeding with ordering the default 4L Golytely (PEG). A health factor is 
automatically created to allow the study team to track the number of refusals  
generated at this stage in the process. If both the provider and the patient agree 
that the patient may be contacted for consideration of enrollment in the trial, the 
provider will select the radio button indicating “Yes. Patient agreed to be 
contacted. The research team may approach this patient for consideration of 
enrolment”. Selecting that the patient may be approached will automatically  
prepopulate and send a research consult to the study staff. The provider is then 
directed back to the order entry menu to place an order for 4L Golytely (PEG) until 
the patient can be consented and randomly assigned. This “holding order”  
ensures that care is not disrupted in the event that the study nurse is unavailable. 
On receiving the research consult, the study staff calls the patient and explains  
the study to the patient and obtains verbal informed consent. If the patient 
consents to the study, the study staff will discontinue the “holding order” and 
activate the randomization procedure built in the prepopulated reminder dialog 
progress note, which will return the randomization assignment instantaneously. 
This reminder dialog progress note will also serve the purpose of documenting the 
participant's consent, as well as date, and the name of the person conducting 
consent in the EMR. If the patient declines to participate in the study, a pre-
populated progress note is automatically entered into the EMR, which is 
forwarded to the colonoscopy ordering clinician, along with prepopulated order for 
Golytely (the current standard prep), for review and signature. Progress notes for 
both patients accepting and declining participation are automatically created for 
and forwarded to the provider ordering colonoscopy. Medication orders are 
prepopulated according to treatment assignment and must be signed by 
clinicians. A CPRS/VISTA alert is therefore used to prompt the provider to sign 
and complete the randomized order. The study staff also verifies that the order 
has been ‘released’ by the provider and contacts the provider directly if 
necessary. Finally, a health factor is created that documents which of the two 
arms the patient is randomly assigned to. This allows the study team to identify  
subjects and their interventions quickly in the CPRS/VISTA database. 
HIPAA authorization will be obtained in subjects who present to CMCVAMC Gi 
endoscopy suite to have a colonoscopy to be performed by Dr. Yang. Dr. Yang 
will routinely check CPRS notes before every outpatient colonoscopy procedure to 
determine whether his patient is enrolled in the current study. We will request a 
HIPAA waiver for all other patients who will have no face-to-face interaction with 
the study team.  
The proposed project meets the requirements for a waiver of documentation of 
informed consent. The oral consent will be read to the subject. The research 
presents no more than minimal risk of harm to participants and involves no 


 
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procedure for which written consent is normally required outside of research 
context. Existing literature suggests that extensive disclosure in pragmatic trials  
that compare low-risk standard-of-care interventions may confuse potential 
subjects into thinking that the research differs substantially from standard care 
and that they face a critical decision.33  Furthermore, such unnecessary  
disclosure can be associated with low satisfaction and increased anxiety and may 
introduce substantial selection bias and clinical disruption.33   
E.4.1 Measures to ensure high referral rate for providers  
We expect that VA PCPs will be responsible for the vast majority of the referrals 
and will thus implement multiple measures to ensure a high referral rate. First, the 
Chief of Primary Care will serve as a consultant for the proposed study and meet 
with the PI at least monthly. He will champion the study among the PCPs, actively  
solicit their concerns and feedback regarding the study implementation and 
communicate these to the PI, and help the PI develop strategies to address any 
concerns. Second, prior to the start of the study, the PI will give in-person 
presentations to all PCPs and GI providers during monthly faculty meetings  
regarding the purpose and the details about the study, particularly those aspects  
relevant to the providers work flow (e.g., the one choice they need to make, etc.). 
He will also answer any questions about the M-G prep option with which some VA 
providers might not be familiar. The PI will also contact individual providers who 
cannot attend the faculty meetings to set up one-on-one meetings. The goal will 
be to proactively convey the importance of the study, explain the specific actions  
required of the PCPs and resolve any questions and concerns from the PCPs. 
The PI will also regularly attend the faculty meetings after the implementation of 
the trial to address any new concerns. Third, any planned changes in the CPRS 
study-flow and order menu change will first be piloted among a sample of PCPs 
and Dr. Tzanis to ensure readability and usability and modified based on their 
feedback. Further modifications will also be performed based on feedback  
solicited after the initiation of the trial. Fourth, the design and the implementation 
of the study procedures will benefit from the expertise of Charlene Weir, PhD from 
the Salt Lake VA IDEAS COIN who will serve as a consultant on this project. Dr. 
Weir is a renowned expert on real-world implementation and formative evaluation 
of EMR-based interventions in VA practices. Of particular relevance to the  
proposed trial, she led the only study that assessed VA providers’ beliefs and 
attitudes toward pragmatic trials embedded at the point of care. 34 She will 
ensure that the study-related procedures are responsive to these provider factors. 
E.7 Study procedure  
E.7.1 Randomization  
The randomization procedure will be carried out based on an approach recently  
developed in the VA CPRS system.2 This method takes advantage of a random 
number generator ($RANDOM) feature of CPRS/VISTA to generate a random 


 
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integer between 0 and 999. The returned integer is used by a CPRS feature 
called “computed finding” to randomly generate a bowel preparation order for 
each patient. Patients will be randomly assigned to the 4L PEG-ELS or 2L M-G 
regimen at a 1:1 ratio. A template progress note activated by the study  
coordinator will document randomization.32 This template progress note will 
generate ‘health factors’ in CPRS that will serve to identify patients as subjects in 
the trial for tracking purposes in VISTA.  
E.7.2. Bowel preparation regimens  
The bowel preparation regimens being compared are split-dose 4L PEG-ELS, 
which is the current standard bowel preparation regimen within the VA system, 
and split-dose 2L MiraLAX-Gatorade preparation. We will use a treatment 
schedule that mirrors real-world practice. To that end, the patients will receive 
either regimen (i.e., GoLytely or GlycoLAX [generic of MiraLAX]) from the VA 
central pharmacy via postal mail. The currently-used instructions for the 4L PEG-
ELS will be used (see Appendix 1). The instructions for the 2L M-G preparation 
will be adapted from the one used at the University of Pennsylvania Health 
System (where it is the standard colonoscopy bowel preparation) or other premier 
academic medical centers. The patients in the M-G preparation arm will be 
instructed to mix the entire 238g bottle of the generic form GlycoLAX in 32 ounces 
of Gatorade or any other clear non-carbonated liquid. Patient with diabetes will be 
instructed to use sugar-free Crystal Lite solution instead of Gatorade. Those who 
are randomized to the M-G preparation arm will need to purchase 64 oz. of 
Gatorade (~$2) or Crystal Lite on their own. Based on our consultation with VA 
PBM leadership as well as local and central VA pharmacy, VA is unlikely to 
provide Gatorade as a VA pharmacy item even if the M-G bowel preparation 
becomes the standard bowel preparation. Therefore, we designed the M-G arm of 
our trial to reflect how the intervention would eventually be implemented in real-life 
practice. This is consistent with the pragmatic nature of the trial. 
The 4L PEG and 2L M-G regimens are the two dominant forms of bowel 
preparation regimen used in the US. Although there are other formulations, their 
use is limited in clinical practice due to potential safety issues (e.g., sodium 
phosphate, picosulfate), limited supporting evidence (e.g., picosulfate, oral sodium 
sulfate), or high cost (e.g., 2L PEG preparation such as MoviePrep). Therefore, 
we chose not to include these regimens. 
E.7.3 Follow-up  
Since information regarding main outcomes will be collected via VA administrative 
records (e.g., cancelations/no-shows) and VA electronic medical records, there 
will be no need for any patient follow-up.  
E.7.4 Blinding 


 
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Blinding of the patients is impossible in this trial. Since endoscopists routinely ask 
the patient about their experience with bowel cleansing in usual practice, blinding 
of the endoscopists would also be difficult and more importantly would not reflect 
usual practice. Therefore, to maximize pragmatism in the trial design, no blinding 
will be implemented.  
E.7.5 Outcomes  
E.7.5.1. Primary Outcomes 
Because the objective of the proposed pragmatic trial is to generate data that can 
directly inform system-wide policy decision regarding the optimal bowel 
preparation choice, it is critical that the primary outcomes capture the full-
spectrum of the down-stream effects of bowel preparation. Published evidence 
indicates that the tolerability of the bowel preparation is regarded by patients (both 
those who have and have not undergone CRC screening) as the most important 
factor that deters them from undergoing colonoscopy.5 Therefore, poorly tolerated 
bowel preparation can not only compromise patient compliance with bowel 
preparation instructions, but also their likelihood of undergoing scheduled 
colonoscopies. For these reasons, our primary outcomes will be the completion 
rate of scheduled colonoscopy and population-level ADR. The completion rate of 
scheduled colonoscopy will be defined as the proportion of patients who show up 
for their scheduled colonoscopy and have endoscopist-rated “adequate” bowel 
preparation quality, among those scheduled for a colonoscopy. The colonoscopy  
reporting software from Endosoft® allows documentation of the following ratings  
for quality of bowel preparation: poor, fair, good and excellent.  We will consider a 
rating of “good” or “excellent” as adequate preparation quality. We recognize the 
4-category rating scale is an imperfect instrument, but elect to use it to define our 
outcome measure for several reasons. The 4-category rating scale is the most 
commonly used rating scale in clinical practice both within and outside of the VA. 
In this scheme, excellent and good are widely viewed as adequate.3 VA 
endoscopists use this scale to make clinical decisions regarding need for repeat 
colonoscopy or follow-up intervals. We recognize that there are three other 
commonly used bowel preparation quality rating scales (OBPS, BBPS and 
Aronchick). However, based on its review of these scales, the USMSTF 
recommends against the use of Aronchick or Ottawa scales because they 
downgrade the score for retained fluids.3 It further concluded that none of the 
existing scales satisfactorily captures the operational definition of adequate 
preparation (i.e., the one in which the colonoscopist can and does recommend a 
follow-up screening or surveillance interval for the next colonoscopy that is 
appropriate for the examination findings), although the USMSTF regarded BBPS 
as being closer to this concept compared to the other scales. BBPS is an 
available option in the Endosoft® colonoscopy procedure note template. However, 
to implement this scale would necessitate education and training of the 
endoscopists and impose substantial additional documentation burden on the 


 
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providers which is outside of usual clinical care, and would compromise the 
“pragmatic” nature of the study design.  
The population-level ADR in this trial will be calculated as the proportion of 
patients who are found to have at least 1 adenoma, among those scheduled for a 
colonoscopy. This definition of ADR differs from the conventional concept of ADR 
which is calculated among those having undergone colonoscopies. While poor 
bowel preparation quality may decrease the probability of polyp detection among 
patients having undergone colonoscopies, patients who cancel or fail to show up 
for their scheduled colonoscopies because they do not want to go through with 
the poorly tolerated bowel preparation will have zero probability of having his/her 
polyp(s) detected. Therefore, it is imperative that we examine the ADR among all 
patients scheduled for a colonoscopy so that we can capture the full effect of 
bowel preparation on the overall effectiveness of colonoscopy service. 
E.7.5.2. Secondary Outcomes  
Our secondary outcomes will be the rate of cancellations/no-shows, the proportion 
of patients with endoscopist-rated “adequate” (i.e., Excellent or Good) bowel 
preparation quality among patients who show up for their colonoscopy, which 
reflects the immediate effect of bowel preparation and patient-reported outcomes: 
patient’s self-reported willingness to repeat the bowel preparation and patients  
reported clarity and completeness of the bowel preparation instructions. The 
patient’s self-reported willingness to repeat the bowel preparation is an 
established patient-reported outcome measures to assess patient preference in 
this setting.  
The patient-reported endpoints will be defined dichotomously based on the 
patient’s response (i.e., Yes/No) to the following questions immediately before the 
colonoscopy: 1). If you had a choice of products, would you be willing to repeat 
the same bowel preparation in the future? 2). Were the bowel preparation 
instructions written in a way that is clear to you? and 3). Did the bowel preparation 
instructions fail to include any relevant information? For quality improvement  
purposes, those patients answering “No” to the latter two questions will be asked 
to elaborate on which aspect(s) of the instructions is(are) unclear or missing. In 
order to obtain information for these outcomes, we will add the above questions to 
the mandatory pre-procedure note by the endoscopist immediately before each 
colonoscopy (see example in Appendix) and request the endoscopists to ask the 
patients these questions and document the responses in the routine mandatory  
pre-procedure note. Since the endoscopists are already required to document 
several related data elements in the pre-procedure note including last per oral 
take of clears and food of any form, adding these simple yes/no questions should 
not lead to excessive burden to the endoscopists. 
As an exploratory endpoint, we will also determine the proportion of patients with 
inadequate bowel preparation who are recommended to have earlier-than-usual 


 
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follow-up colonoscopy. This is a clinical outcome with resource utilization 
implications. It is consistent with the USMSTF operational definition of adequate 
preparation quality. Ideally, the endoscopist who performed the procedure should 
provide this information in each case. However, requiring the endoscopists to 
uniformly and consistently provide written justification of all their recommendations  
and document the impact of bowel preparation on each of their follow-up 
recommendations is outside the standard practice and may represent undue 
burden. More importantly, such burden might alter their behavior in grading or 
documenting the bowel preparation quality (e.g., they may upgrade the 
preparation quality to avoid such burden). For these reasons, the information for 
this outcome will be assessed by the PI and the co-investigator (Dr. Khan) by 
reviewing CPRS. Any disagreement between the PI and co-investigator (Dr. 
Khan) will be resolved by a discussion between the two to reach a consensus. It is 
expected that endoscopists deviate from guideline recommended follow-up 
colonoscopy intervals for a variety of reasons other than the quality of bowel 
preparation. Such reasons may not be apparent based on a chart review even by 
an expert gastroenterologist. Given the potential for misclassification for this 
outcome, we will include it as an exploratory outcome.  
Although the primary focus of the trial is to evaluate the impact of bowel 
preparation on colonoscopy completion, the trial presents an opportunity to collect 
information on all health factors that could affect the outcome. Such data would 
help us interpret the findings of the main trial and inform the design of future trials 
by identifying potentially modifiable factors. Therefore, we will collect information 
on the reasons for non-shows/cancellations among a sample (e.g., all non-
shows/cancellations in the first month of each quarter during the study) of eligible 
patients.  
Although hyponatremia has not been associated with split-dose M-G regimen, as 
an exploratory safety endpoint, we will track incident cases of hyponatremia or 
renal failure over the 6 month period following the ingestion of the bowel 
preparation within among our study patients. In order to efficiently collect such 
data, the CHERP programmer will perform electronic query within VISN 4 data 
warehouse using ICD-9 codes for these two diagnoses within the 6-month time 
frame. 
E.8 Data Collection  
We will collect all study data regarding baseline characteristics or covariates (i.e., 
sex, age, race, DM status, history of renal failure, history of heart failure, history of 
hyponatremia, history of constipation or current use of laxatives, history of colon 
resection, history of inflammatory allergy history, history of mental health issues, 
use of narcotics, indication for colonoscopy, baseline creatinine level, total 
procedure time, timing of procedure [AM/PM], colonoscopy examination aborted 
[yes/no], cecal intubation [yes/no]) and all outcomes (i.e., colonoscopy completion 


 
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rate, bowel preparation quality rating by endoscopist, patient willingness to repeat, 
number of polyps removed and the corresponding pathology report, endoscopist  
recommended timing of next colonoscopy, incident renal failure and hyponatremia 
within 6 months after the bowel preparation).  
Information on scheduled colonoscopies as well as procedure cancellations/no-
shows is routinely collected by the GI section nurse manager on a daily basis for 
administrative purpose and will be used for this study. To minimize interference 
with routine care, we will first search for reasons for cancellations/no-shows in 
CPRS because this information is usually documented for cancellations based on 
our pilot data. If the underlying reason cannot be identified in CPRS, we will 
conduct a telephone survey of the patients to collect such data. In order to  
encourage honest answers, the survey will be conducted as a part of an on-going 
QI initiative in the GI section of CMCVAMC, analogous to the survey described in 
D.2. 
Information on all other variables is expected to be available for all patients in 
CPRS. As described above, the information on baseline comorbidity status and 
incident cases of hyponatremia and renal failure will be collected through 
electronic query of the VISN 4 data warehouse using ICD-9 codes on structured 
fields including all visit-associated diagnoses and problem list. Medication use at 
baseline will be collected by VISN 4 warehouse query for the corresponding drug 
class. Information from colonoscopy report and associated pathology report will 
be collected by manual chart review of the CPRS. Finally, endoscopist 
recommendations regarding timing of next colonoscopy and the impact of bowel 
preparation on such recommendation will be collected by manual chart review by 
the PI and co-investigator.    
E.9.4 Exploratory Cost Analysis 
A dedicated full economic analysis would be necessary to comprehensively  
quantify the short-term and long-term financial impact of adopting the superior 
regimen in the VA. Given the complexity of such a dedicated economic analysis  
(e.g., the need for extensive modeling of long-term health utility, etc.), it would be 
beyond the scope of the current project. We intend to apply for addition funding to 
perform such an analysis as a future step. Nevertheless, along side of the 
proposed trial, we will conduct an exploratory economic evaluation prospectively.  
Our exploratory economic analysis will focus on quantifying staff/physician time 
and cost for the completion of the scheduled colonoscopies associated with each 
of the two bowel preparation options during the 3 years of follow-up and compare 
these costs between the two options.  
Counts of the four possible outcomes for scheduled colonoscopies -- 
cancellations, no-shows, colonoscopies with inadequate bowel prep, and 
colonoscopies with adequate bowel prep -- will be derived from the clinical data 
collected during the trial. For the patients included in the economic analysis, we 


 
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will collect additional information from CPRS to take into account repeated  
cancellations, no-shows, and colonoscopies with inadequate bowel prep for the 
same round of colorectal examination over the period of follow-up. Per-patient 
counts of outcomes will be multiplied by estimates of the average cost per 
outcome and the sum of these costs will represent the per-patient cost devoted to 
completion of a scheduled colonoscopy. The cost of these outcomes will be 
derived from either self-timing/self-report35 (cancellations and no shows) or direct 
observation time-and-motion estimation35 (colonoscopies with inadequate bowel 
prep, and colonoscopies with adequate bowel prep) of the average staff/physician 
time required for each of these outcomes and staff/physician wages (including 
benefits).  
For the cancellation and no-show outcomes, we will collect data on the time GI 
staff spend contacting the patients and rescheduling colonoscopies (staff self-
report)as well as the time a GI nurse spends providing bowel prep instructions for 
the rescheduled colonoscopy (Staff self-report). Because our pilot data suggest 
that cancellations and no-shows occur on the day of the procedure and because 
colonoscopy requires specific bowel preparation with dietary restrictions as well 
as arrangement for an escort ahead of the procedure, the vacated colonoscopy  
slots can rarely be filled by another patient, We thus conservatively assume that 
the idle resources from a cancellation or no-show will be equivalent to that for a 
colonoscopy with adequate bowel prep (see below). In a separate sensitivity  
analysis we will exclude the costs of the staff/physician time due to a vacated and 
unfilled colonoscopy slot. 
For the 2 colonoscopy outcomes, staff/physician time will include bowel prep 
instructions (staff self-report), for colonoscopies with inadequate bowel prep it will 
include time spent rescheduling repeat colonoscopy (staff self-report), plus 
staff/physician time spent performing the colonoscopy (direct observation, time-
and-motion study). Separate time estimates will be developed for colonoscopies  
with and without adequate bowel prep.  
In performing the time and motion study, each of the services provided to perform 
a colonoscopy will be enumerated. The average time needed to perform these 
services will be estimated by use of direct observation. Separate estimates will be 
made for colonoscopies with and without adequate bowel prep. We will perform 
direct observation in a random sample of at least 100 scheduled colonoscopies in 
each of three years of the trial. Assuming that 20-25% of colonoscopies  
performed are associated with inadequate bowel prep, we anticipate observing 20 
such colonoscopies per year for a total of 60 colonoscopies. If in any year we fail 
to observe 20 colonoscopies with inadequate bowel prep, we will continue to 
directly observe a random sample of colonoscopies until 20 colonoscopies with 
inadequate bowl prep have been observed.  


 
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Data on the average annual salary plus benefits (by grade and step) for personnel 
like the ones who are observed will be obtained from the GI section nurse 
manager and the section Director. Issues of confidentiality will be minimized by 
working with average wages and benefits by grade and step rather than by use of 
wages and benefits for individual VA staff/physicians. 
In addition to estimating the average cost per patient in each arm of the trial, we 
will also estimate the average cost saving per annum by multiplying the average 
cost saving per scheduled colonoscopy completed by the total number of 
colonoscopies scheduled per year at CMCVAMC. We will also incorporate the 
cost difference between the preparations in calculating the net savings. One 
potential issue is that the cost of MiraLAX may decrease if it becomes a part of 
the standard preparation at the VA. We will perform the analysis using its current 
price. If the cost of MiraLAX tips the balance in the overall cost comparison, then 
we will calculate the threshold price that would make the M-G preparation cost-
saving. 
We will be tracking costs over multiple years of the study. To avoid having to 
inflation-adjust the annual cost data, we will use salary, benefits, and preparation 
costs that are appropriate for the last year of follow-up. Some patients may have 
repeated scheduled exams over a period of time that exceeds 1 year. In these 
cases we will discount follow-up costs at 3% per year. 
E.10 Logistics   
E.10.1. Dissemination of research findings   
Dissemination activities will be coordinated through the VA CHERP program. The 
CHERP Dissemination and Communication Core supports CHERP investigators  
in disseminating research results, developing policy recommendations, and 
delivering information to target audiences. CHERP will regularly update VA HSRD 
about opportunities to disseminate appropriate updates about the progress and 
findings of the study on their Web site and through their other communications  
vehicles, including cyber seminars for VA clinicians. In Year 4, CHERP will 
produce a Research Bulletin summarizing the project and its findings. It will be 
distributed electronically to Office of Quality and Performance leaders, VISN 
Network and Primary Care Service Line directors at all VA medical centers. 
Furthermore, as the chairperson for the Medical Advisory Panel for Pharmacy  
Benefits Management for VA and the Co-Director of the VA Center for Medication 
Safety, the consultant for the project, Dr. Chester B. Good, will help facilitate the 
implementation and dissemination of the study findings within the VA system. 
This research has potential for application outside the VA. The progress and 
findings will be presented at national meetings and published in peer-reviewed 
medical journals. In Year 4, Dr. Yang and designated members of the 
investigative team will apply to HSRD for travel funds to present the project’s 


 
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findings at the national conferences of scientific societies, including the annual 
HSRD conference.  
E.11.2.Project Management Plan  
We have assembled an outstanding multi-disciplinary team.  
Principal Investigator: Dr. Yang is a Core Investigator with the Center for Health 
Equity Research and Promotion (CHERP), a VA HSR&D Center of Innovation 
(COIN) with offices in Philadelphia and Pittsburgh. He has extensive experience 
conducting VA and non-VA clinical research studies. He will be responsible for the 
completion of all aspects of the study aims. He will also be responsible for the 
fiscal, administrative and regulatory aspects of the study, including all regulatory 
affairs, data collection and management, adherence to all policies and 
procedures, coordinating meetings and email/telephone communications among 
the contracted Divisions, consultants and the primary team at the CMCVAMC, 
and maintenance of study protocol to ensure that the specific aims of the study  
are being met. Dr. Yang will develop Manual of Procedures.   
Co-investigators and supporting staff at CMCVAMC: Dr. Khan is the Director of 
the GI section at the CMCVAMC. He is a clinical gastroenterologist with extensive 
experience conducting clinical research including clinical trial within the VA 
system. He will provide support to all aspects of the study. Dr. Hubbard, a 
biostatistician in the Center for Clinical Epidemiology and Biostatistics at the 
University of Pennsylvania, will provide statistical support. Dr. Glick is an expert in 
performing economic analysis embedded in clinical trials and will oversee all 
aspects of the prospective economic evaluation.  
Consultant: As the chairperson for the Medical Advisory Panel for Pharmacy  
Benefits Management for VA, and as the Co-Director of the VA Center for 
Medication Safety, Dr. Chester B. Good will share his experience in national 
formulary issues, drug safety issues and optimizing prescribing practice within the 
VA. He will help with design of the intervention and facilitate the implementation 
and dissemination of the study findings within the VA. Dr. James Lewis, Professor 
of Medicine and Epidemiology at the University of Pennsylvania, is a board 
certified gastroenterologist and prolific clinical investigators. He has been the PI 
for 4 NIH funded clinical trials and is on the steering committee for a 5th NIH 
funded trial. These studies have used a variety of designs to facilitate recruitment,  
data collection, and retention while not altering practice patterns in real world 
settings. We will adapt these methods for this trial given the importance of 
studying the different regimens as practiced in usual care. Dr. Charlene Weir will 
provide her expertise to help ensure the study procedures are acceptable to VA 
providers. 
The entire project will require 4 years to complete. 
5.1.2. 
What research methods will be used in the project? Check all that apply. 
 Surveys/Questionnaires 
 Interviews               
 Audio Taping 


 
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 Behavioral Observations        
 Chart Reviews        
 Video Taping 
 Focus Groups 
       
 Randomization       
 Double-Blind 
 Control Group 
       
 Placebo 
          
 Withhold/Delay Treatment 
 Specimen Collection 
       
 Deception 
          
 Telephone Survey 
 Other (Describe) time-in-motion study for exploratory cost analysis 
 
5.1.3. 
Provide description of the study population (delineate all categories of 
subjects – male, female, inpatients, outpatients, providers, family 
members, employees, etc.).   Include anticipated initial enrollment 
numbers (and number of subjects anticipated to complete all aspects of 
the protocol).    
   Our goal in selecting study patients for this pragmatic trial is to enroll all 
patients who meet the basic entry criteria and reflect the full range of patients 
undergoing bowel preparation for colonoscopies found in regular VA clinical 
practice. The study population will consist of all veterans seeking healthcare at the 
CMCVAMC. 
E.3.1. Inclusion criteria 
The inclusion criteria for potentially eligible subjects are: 
1.  > 18 years of age, and  
2.  being scheduled for outpatient elective screening, surveillance or diagnostic 
colonoscopies, and  
3.  the provider ordering the colonoscopy giving permission to enroll the patient.  
E.3.2. Exclusion criteria  
Patients who are <18 years, undergoing inpatient colonoscopy, those with contra-
indications to receiving the standard 4L PEG-ELS colonoscopy bowel preparation 
(e.g., allergy to PEG) will be excluded. We are excluding inpatient colonoscopies 
because they account for a very small fraction of the total colonoscopies 
performed. Also, inpatient colonoscopies are often performed for urgent reasons 
such that rapid bowel preparation procedures are followed. In addition, because 
the objective of inpatient colonoscopy is often not to look for small polyps, the 
threshold for “adequate” bowel preparation quality might be different from that 
for outpatient procedures. In addition, for patients undergoing more than 1 
colonoscopy during the study period, only their first colonoscopy will be included 
in the primary analysis. Patients who are undergoing a repeat colonoscopy for to 
a recent inadequate colonoscopy examination with poor bowel preparation will be 
excluded. We project to randomize 10,000 eligible patients with scheduled 
colonoscopy. We expect all 10,000 eligible patients to complete the study (i.e, 
allow us to determine primary outcome of completion of scheduled colonoscopy). 


 
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5.1.4. 
As applicable, provide rationale and information on any added protections 
and safeguards for vulnerable populations (children, prisoners, pregnant 
women, physically or mentally-disabled persons, and economically or 
educationally disadvantaged persons).      
N/A 
 
5.1.5. 
Does this project target a specific race or ethnic group as participants? NOT 
APPLICABLE         If yes, check all that apply.  
Race 
                                                        Ethnicity 
American Indian or Alaska Native 
 
Hispanic or Latino 
Asian 
 
Not Hispanic or Latino 
 
Black or African American 
 
 
 
Native Hawaiian or other Pacific Islander 
 
 
 
 
White 
 
 
 
 
Other       
 
 
 
 
5.1.6. 
Will this study bank data and/or specimens?  NO        
5.1.6.1. 
 If yes,  include information on data and specimen banking.   
             
5.1.6.2. 
IF BANKING SPECIMENS, IT MUST BE AT A VA APPROVED FACILITY. 
(For additional information, go to the following website 
http://www.research.va.gov/programs/tissue_banking/, or contact the 
IRB office.) 
5.1.6.3. 
If specimens will be banked, specify banking location.   
             
5.1.6.4. 
If the location is a non-VA site, has the mandatory approval from VA 
Central Office been obtained through submission of a tissue banking 
application?   Choose an item.          
5.1.6.4.1. If yes, provide a copy of the response from VA Central Office. 
5.1.6.5. 
If applicable, explain how destruction of banked samples will be 
substantiated.   
                
5.1.6.6. 
Do you anticipate using the banked specimens for other studies beyond 
the defined study period and defined study parameters?    Choose an 
item. 
5.1.6.6.1. If yes, will you need to re-contact subjects?  How will this be 
done? 
      
5.2. 
Participant Recruitment Methods 
5.2.1. 
State how many subjects will be needed.    
10,000  
5.2.2. 
Who will be responsible for recruiting potential participants?   Provide 
titles of individuals.  
PI, research coordinator, research assistant  
5.2.3. 
How will initial contact with potential participants be made? (e.g., local 
clinics, physician referrals, letters to prospective participants) NOTE: VA 


 
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policy prohibits “cold calls” to potential VA research participants. Provide an 
introductory letter and telephone script.    
The providers who order the colonoscopy will introduce to the patient the 
opportunity to be considered for enrollment and an information sheet will be 
presented to them so there will be no cold calling. The study team will only 
contact the patient after the primary care providers indicate that patient agrees 
to be approached for consideration of enrolment in the study.    
5.2.4. 
Will you be using any of the following methods to recruit participants? 
(Check all that apply.) 
  N/A 
  Local database for which participants have NOT given prior permission 
to be contacted for Research.  NOTE:  If this option is checked, please 
submit a Waiver of Individual Authorization for Disclosure of Protected Health 
Information.      
  Personal contact with patients over whom you have direct/indirect 
oversight 
  Provider (Clinician) Referrals of potential participants 
5.2.5. 
Indicate the types of recruitment/advertisement materials that will be used:  
Check all that apply.  Submit copies of recruitment materials, for IRB 
review. 
     
Not applicable; none to be used 
     
Fliers       
Newspapers      
Letters      
Websites      
Television 
     
Radio      
Audio      
Video      
Surveys 
     
Other (Specify, e.g. employee newsletters)  Information Sheet  
5.2.6. 
Participants will be given a copy of the Notice of Privacy Practice.   NOT 
APPLICABLE 
 
5.3. 
Compensation for Participation -   NOT APPLICABLE        If yes, complete the following. 
5.3.1. 
Summarize any financial compensation that will be offered to subjects.     
          
5.3.2. 
Provide the schedule for compensation.  
5.3.2.1. 
Per study visit or session.      
             
5.3.2.2. 
Total amount for entire participation.   
             
5.3.3. 
State how compensation will be provided:  Choose an item.  
 
5.4. 
Informed Consent Procedures 
5.4.1. 
Indicate if informed consent will be obtained and/or if you are requesting a waiver 
of informed consent or waiver of documentation of informed consent. Because 
the research presents no more than minimal risk and involves no procedures for 
which written consent is required, we are requesting Waiver to Obtain 
Documentation of Informed Consent 
5.4.2. 
If the research involves multiple phases, specify for which phases of the research 
the waiver(s) is/are being requested.   


 
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                            n/a 
5.4.3. 
Describe circumstances, if any, that may need to be addressed in seeking 
informed consent (e.g., subjects with impaired decision making ability and the 
use of a legally authorized representative, etc.)      
     Because we only approach patients deemed suitable for consent by their primary care 
providers, we do not expect such special needs. Regardless, we will ensure that 
consents are obtained only from an adult capable of providing consent.  
5.4.4. 
If applicable, indicate how study personnel will be trained regarding human 
subjects protections requirements and how to obtain and document informed 
consent.   
     All study personnel will receive annual VA Privacy and HIPAA training as well as 
Collaborative Institutional Training Initiative training. Study personnel will be required to 
follow the consent document, explain the details such a way that the patient or 
representative can understand, invite and answer patient/representative’s questions.  
5.4.5. 
Inclusion/Exclusion Criteria:  Describe the criteria that determine who will be 
included in or excluded from the study.  
5.4.5.1. 
Inclusion Criteria 
           The inclusion criteria for potentially eligible subjects are: 
1.  > 18 years of age, and  
2.  being scheduled for outpatient elective screening, surveillance or diagnostic  
colonoscopies, and  
3.  the provider ordering the colonoscopy giving permission to enroll the patient. 
5.4.5.2. 
Exclusion Criteria 
           Patients who are <18 years, undergoing inpatient colonoscopy, those with 
contra-indications to receiving the standard 4L PEG-ELS colonoscopy bowel 
preparation (e.g., allergy to PEG) will be excluded. We are excluding inpatient 
colonoscopies because they account for a very small fraction of the total 
colonoscopies performed. Also, inpatient colonoscopies are often performed for 
urgent reasons such that rapid bowel preparation procedures are followed. In 
addition, because the objective of inpatient colonoscopy is often not to look for 
small polyps, the threshold for “adequate” bowel preparation quality might be 
different from that for outpatient procedures. In addition, for patients undergoing 
more than 1 colonoscopy during the study period, only their first colonoscopy will 
be included in the primary analysis. Patients who are undergoing a repeat 
colonoscopy for to a recent inadequate colonoscopy examination with poor 
bowel preparation will be excluded. 
 
5.5. 
Withdrawal of Subjects 
5.5.1. 
Describe how a subject can withdraw from the study.   
n/a   
5.5.2. 
Describe any anticipated circumstances under which subjects will be 
withdrawn from the research without their consent. 
                n/a 
5.5.3. 
Describe the consequences of a subject's decision to withdraw from the 
research and the procedures for orderly termination of participation by the 


 
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subject (e.g., the subject contacting the investigator for an end-of-study 
visit).   
                n/a 
 
5.6. 
Potential Risk/Benefit Analysis 
5.6.1. 
Potential Study Risks 
5.6.1.1. 
Describe and assess all of the following risks that may be associated 
with the research: 
5.6.1.2. 
Physical (Physical risks include physical discomfort, pain, injury, illness or 
disease brought about by the methods and procedures of the research. A 
physical risk may result from the involvement of physical stimuli such as 
noise, electric shock, heat, cold, electric magnetic or gravitational fields, etc. 
Engaging a subject in a social situation which could involve violence may also 
create a physical risk.) 
                 The risks associated with participating in the study are less than minimal to 
the patients involved in the project.  
Other than being randomized to one of the two bowel preparation regimens, there is no 
change in the care the patients receive. In addition, the two bowel preparation 
regimens used represent the most commonly used split-dose bowel regimens in 
routine clinical practice in the US. No clinically significant adverse effects have been 
reported to be associated with their extensive use. They are recommended by the 
current US Multi-Society Task Force (USMSTF). The 4L split-dose PEG group is the 
current standard bowel preparation in the VA. The 2L split-dose MiraLax/Gatorade 
preparation is the standard bowel preparation in many if not the majority of GI practices 
in the US (including the University of Pennsylvania Health System) and has been used 
by millions of patients worldwide. MiraLax is available over-the-counter, and Gatorade 
is a common sports drink. In addition, patients with diabetes are instructed to use 
Crystal Lite instead of Gatorade. Like any colonoscopy bowel preparations, these 
preparations would lead to diarrhea, urgency and bloating, but these should not be 
more than what the patient would have experienced with the usual preparation regimen 
and should not lead to clinically important adverse effects. Of course, allergic reactions  
can occur to any medication but are extremely rare. 
5.6.1.3. 
Psychological (Psychological risks include the production of negative 
affective states such as anxiety, depression, guilt, shock and loss of self-
esteem and altered behavior. Sensory deprivation, sleep deprivation, use of 
hypnosis, deception or mental stresses are examples of psychological risks.) 
None  
5.6.1.4. 
Social/Economic (Social/Economic risks include alterations in relationships 
with others that are to the disadvantage of the subject, including 
embarrassment, loss of respect of others, labeling a subject in a way that will 
have negative consequences, or in some way diminishing those opportunities 
and powers a person has by virtue of relationships with others. Economic 
risks include payment by subjects for procedures not otherwise required, loss 
of wages or other income and any other financial costs, such as damage to a 
subject's employability, as a consequence of participation in the research.) 
Those randomized to the MG prep will need to purchase 2L of Gatorade 
because it is a sports drink .                


 
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5.6.1.5. 
Legal (Legal risks exist when the research methods are such that the subject 
or others will be liable for a violation of the law, either by revealing that the 
subject or others have engaged, or will engage, in conduct for which the 
subject or others may be criminally or civilly liable, or by requiring activities for 
which the subject or others may be criminally or civilly liable.) 
                 none  
5.6.1.6. 
Loss of Confidentiality (In all research involving human subjects, 
confidentiality of identifiable information is presumed and must be maintained 
unless the investigator obtains the express permission of the subject to do 
otherwise. Subjects have the right to be protected against injury or illegal 
invasions of their privacy and to preservation of their personal dignity. The 
more sensitive the research material, the greater the care that must be 
exercised in obtaining, handling, and storing data. In order to minimize the 
risk for loss of confidentiality, investigators should only collect personal 
information that is absolutely essential to the research activity. If personal 
data must be collected, it should be coded as early in the activity as possible 
and securely stored so that only the investigator and authorized staff may 
access it. Identities of individual subjects must never be released without the 
express consent of the subject. In addition, if an investigator wishes to use 
data for a purpose other than the one for which it was originally collected and 
the data are still identifiable (e.g., a code list for the data still exists), the 
investigator may need to obtain consent from the subjects for the new use of 
the data.) 
                 Every effort will be made to reduce the risk of loss of confidentiality in this 
study.  Research files containing confidential material will be stored in a locked file 
cabinet in the PI’s locked office at the Philadelphia VA Medical Center.  Security during 
data extraction and management will follow the standard operating procedure of the 
CHERP.  Specifically, data obtained to fulfill the information needs of IRB-approved 
studies or QI efforts are housed on a secure server physically located within the FITS 
computer room of the Philadelphia VA Medical Center and networked within the VA 
Intranet.  As a result, the servers have the same degree of physical and electronic  
protection afforded other VA computer systems, including antiviral protection and 
routine back-ups.  FITS is responsible for managing the server hardware and software, 
including its physical and network security and connectivity, backup processes, 
operating system patches, and application management.  Study data will be stored in 
one of two places – either within tables on a Philadelphia VAMC SQL Server (the 
CHERP4 machine), or in data files stored within protected directories on the server 
(CHERP NAS).  CHERP file folders will be created by the CHERP Dataset 
Administrator (DSA) and stored on the CHERPNAS server with read and write access  
to study files restricted by the operating system to authorized persons only for the time-
frame designated during the IRB and R&D approval. At the end of the timeframe the 
folders will be locked. By using this approach, access to the data will be under the strict 
surveillance and control of the CHERP data administrator (Christopher Roberts or a 
CHERP assigned programmer with equivalent experience).  
To ensure subject confidentiality and comply with HIPAA regulations, none of the 18 
HIPAA identifiers will be stored in the database, e.g.no personal information, such as 
names, dates, contact information, social security/medical record numbers, etc. All 


 
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research files containing protected health information will be stored in a locked file 
cabinet in a locked office or on a secure VA server on a password protected computer 
in a locked office at Philadelphia VA Medical Center. All VA data will be appropriately  
kept behind the VA firewall and in compliance with all VA data security guidelines. All 
members of the research team will maintain up-to-date training on HIPAA, patient 
oriented research, and data security measures at the VA. 
5.6.1.7. 
Other, e.g. radiation, placebo, washout of medications  
                  none 
5.6.1.8. 
Assess the likelihood and seriousness of such risks. 
                   The likelihood of the risks described above is extremely. Also, the risks are 
not serious. 
 
5.6.2. 
Include a description of how anticipated risk will be minimized and include 
an analysis of risk vs. potential benefit.  
     Every effort will be made to reduce the risk of loss of confidentiality in this 
study.  Research files containing confidential material will be stored in a locked 
file cabinet in the PI’s locked office at the Philadelphia VA Medical Center.  
Security during data extraction and management will follow the standard operating 
procedure of the CHERP.  Specifically, data obtained to fulfill the information 
needs of IRB-approved studies or QI efforts are housed on a secure server 
physically located within the FITS computer room of the Philadelphia VA Medical 
Center and networked within the VA Intranet.  As a result, the servers have the 
same degree of physical and electronic protection afforded other VA computer 
systems, including antiviral protection and routine back-ups.  FITS is responsible 
for managing the server hardware and software, including its physical and network 
security and connectivity, backup processes, operating system patches, and 
application management.  Study data will be stored in one of two places – either 
within tables on a Philadelphia VAMC SQL Server (the CHERP4 machine), or in 
data files stored within protected directories on the server (CHERP NAS).  
CHERP file folders will be created by the CHERP Dataset Administrator (DSA) 
and stored on the CHERPNAS server with read and write access to study files 
restricted by the operating system to authorized persons only for the time-frame 
designated during the IRB and R&D approval. At the end of the timeframe the 
folders will be locked. By using this approach, access to the data will be under the 
strict surveillance and control of the CHERP data administrator (Christopher 
Roberts or a CHERP assigned programmer with equivalent experience).  
To ensure subject confidentiality and comply with HIPAA regulations, none of the 
18 HIPAA identifiers will be stored in the database, e.g.no personal information, 
such as names, dates, contact information, social security/medical record numbers, 
etc. All research files containing protected health information will be stored in a 
locked file cabinet in a locked office or on a secure VA server on a password 


 
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protected computer in a locked office at Philadelphia VA Medical Center. All VA 
data will be appropriately kept behind the VA firewall and in compliance with all 
VA data security guidelines. All members of the research team will maintain up-
to-date training on HIPAA, patient oriented research, and data security measures at 
the VA. 
 
5.6.3. 
Potential Study Benefits 
5.6.3.1. 
Indicate potential benefits to be gained by the individual subjects, as 
well as benefit(s) that may accrue to society in general as a result of the 
planned work. If the subject will not receive any direct benefit, this fact 
must be stated here and in the consent form.  
                 According to VHA Handbook 1108.04 (research): 12. CO-PAYMENTS, item 
a. Title 38 U.S.C. 1722A, Co-Payment for Medications, and 38 CFR § 17.110, Co-
Payment for Medications, VA medication co-payments must be waived if the 
medication is provided to the subject as part of a VHA-approved research protocol. 
This waiver applies whether or not the sponsor of the investigational study provides the 
medication. This benefit applies to all patients who would be responsible for co-pay for 
the 4L PEG regimen. Finding an effective and better tolerated bowel preparation could 
benefit all future VA patients undergoing colonoscopies. Overall, the minimal risks to 
the study patients and providers are reasonable in relation to the anticipated benefit. 
 
5.6.4. 
Alternative Treatments Outside the Study 
5.6.4.1. 
Describe alternatives available to the subject outside the research 
context. If there are no such alternatives, state that the alternative is not 
to participate in the research study.  
Alternative is not to participate in the study 
 
5.7. 
Data Monitoring (Monitoring plans describe how a monitor, independent of the study team, 
regularly inspects study records to ensure the study is adhering to the study protocol and applicable 
research regulations and CMCVAMC requirements.  Monitoring plans do not necessarily require the 
use of an independent Data and Safety Monitoring Board (DSMB).  Such independent boards are 
usually reserved for high-risk phase I studies, or large, multi-center phase III trials.  Federally funded 
studies may require the use of an independent DSMB.) 
5.7.1. 
Will a Data and Safety Monitoring Board (DSMB) or Data Monitoring Committee 
(DMC) oversee the project?   NO 
5.7.1.1. 
If yes, provide contact information for the DSMB or DMC representative. 
             
5.7.1.2. 
If the project will not be overseen by a DSMB or DMC, describe the data 
and safety monitoring plan to be followed. 
       A data and safety monitoring plan will be implemented to ensure that there 
are no changes in the benefit/risk ratio during the study and that confidentiality of 
research data is maintained.  Investigators and personnel involved in the study  
will meet twice annually to discuss the study (e.g., study goals, progress, 
modifications, documentation, recruitment, data analysis and confidentiality).  
Minutes will be kept for these meetings and will be on file.  These meetings will 
be overseen by the PI, Dr. Yang.  The PI will meet with individual study team 
members as needed in order to address specific issues and concerns in the 


 
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team members’ area of expertise.  Any instances of adverse events, protocol 
deviations, or other problems identified will be reported within the required  
reporting time-frames using standard forms and/or procedures set forth by the 
IRB.  In addition, clinical research coordinators may review study documentation 
to ensure that participants’ confidentiality is maintained. 
 
This minimal risk study does not warrant the establishment of a Data Safety  
Monitoring Board.  
 
5.8. 
Reporting of Protocol Deviations, Adverse Events (AEs), Serious Adverse Events (SAEs), 
Breaches of Confidentiality, Unanticipated Adverse Device Effects (UADEs), and 
Unanticipated/Unexpected Problems  
5.8.1. 
Include procedures for reporting these events to the CMCVAMC IRB and 
sponsor.  (Note: Except for AEs, all other events must be reported to the 
CMCVAMC IRB within 5 business days of discovery. Use the CMCVAMC 
Serious-Adverse Event form for reporting SAEs, UADEs, and 
unanticipated/unexpected problems.  Use the CMCVAMC Protocol Deviation 
form for reporting protocol deviations.  On-site AEs should be reported at the 
time of continuing review.) 
                The primary potential adverse events associated with this study would be due to 
breach of confidentiality.  Such events will be reported to the PVAMC IRB within 24 hours in 
writing.  In addition, any protocol deviation will also be reported to the PVAMC IRB in writing. 
Except for AEs, all other events will be reported to the CMCVAMC IRB within 5 business days 
of discovery. We will use the CMCVAMC Serious-Adverse Event form for reporting SAEs, 
UADEs, and unanticipated/unexpected problems.  We will use the CMCVAMC Protocol 
Deviation form for reporting protocol deviations.  On-site AEs will be reported at the time of 
continuing review.   
 
5.9. 
Privacy and Confidentiality 
5.9.1. 
Describe whether the study will use or disclose subjects’ Protected Health 
Information (PHI). 
                The study will use PHI. 
5.9.2. 
Check the PHI to be collected on all subjects for this research protocol. 
 Name 
 All geographic subdivisions smaller than a State, including street address, city, 
county, precinct, ZIP code, and their equivalent geographical codes, except for 
the initial three digits of a ZIP code if, according to the current publicly available 
data from the Bureau of the Census: 
a. The geographic unit formed by combining all ZIP Codes with the same three 
initial digits contains more than 20,000 people; and 
b. The initial three digits of a ZIP Code for all such geographic units containing 
20,000 or fewer people are changed to 000. 
 All elements of dates (except year) for dates directly related to an individual, 
including birth date, admission date, discharge date, date of death; and all ages 
over 89 and all elements of dates (including year) indicative of such age, except 
that such ages and elements may be aggregated into a single category of age 90 
or older.   


 
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 Telephone numbers 
 Fax numbers 
 Electronic mail addresses 
 Social Security/Medical Record Number 
 Health plan beneficiary numbers 
 Account Numbers 
 
 Certificate/license numbers  
 Vehicle identifiers and serial numbers, including license plate numbers 
 Device identifiers and serial numbers  
 Web universal resource locators (URLS) 
 Internet protocol (IP) address numbers 
 Biometric identifiers, including fingerprints and voiceprints 
 Full-face photographic images and any comparable images 
 Any other unique identifying number, characteristic, or code, unless otherwise 
permitted by the Privacy Rule for re-identification. 
 HIV (testing or infectious disease) records 
 Sickle cell anemia 
 Drug Abuse Information 
 
 
 Alcoholism or Alcohol Use 
 
5.10. Information Security  (Contact the Information Security Officer for additional assistance 
regarding confidentiality (storage/security) of research data.) 
5.10.1. 
List the data/information that will be stored (including signed, original informed 
consent and HIPAA authorization forms, if applicable, case report forms, etc.)  
                We will use electronic case report forms to collect information regarding patient 
demographics, comorbidity information, as well as study outcomes (e.g., colonoscopy prep 
quality , completion rate and colorectal adenoma detection rate). 
5.10.2. 
Describe the steps that will be taken to secure the data (e.g., training, 
authorization of access, password protection, encryption, physical controls, 
Certificates of Confidentiality, and separation of identifiers and data). 
     Every effort will be made to reduce the risk of loss of confidentiality in this study.  
Research files containing confidential material will be stored in a locked file cabinet in the 
PI’s locked office at the Philadelphia VA Medical Center.  Security during data extraction 
and management will follow the standard operating procedure of the CHERP.  
Specifically, data obtained to fulfill the information needs of IRB-approved studies or QI 
efforts are housed on a secure server physically located within the FITS computer room 
of the Philadelphia VA Medical Center and networked within the VA Intranet.  As a result, 
the servers have the same degree of physical and electronic protection afforded other 
VA computer systems, including antiviral protection and routine back-ups.  FITS is 
responsible for managing the server hardware and software, including its physical and 
network security and connectivity, backup processes, operating system patches, and 
application management.  Study data will be stored in one of two places – either within 
tables on a Philadelphia VAMC SQL Server (the CHERP4 machine), or in data files  


 
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stored within protected directories on the server (CHERP NAS).  CHERP file folders will 
be created by the CHERP Dataset Administrator (DSA) and stored on the CHERPNAS 
server with read and write access to study files restricted by the operating system to 
authorized persons only for the time-frame designated during the IRB and R&D 
approval. At the end of the timeframe the folders will be locked. By using this approach, 
access to the data will be under the strict surveillance and control of the CHERP data 
administrator (Christopher Roberts or a CHERP assigned programmer with equivalent 
experience).  
To ensure subject confidentiality and comply with HIPAA regulations, none of the 18 
HIPAA identifiers will be stored in the database, e.g.no personal information, such as 
names, dates, contact information, social security/medical record numbers, etc. All 
research files containing protected health information will be stored in a locked file 
cabinet in a locked office or on a secure VA server on a password protected computer in 
a locked office at Philadelphia VA Medical Center. All VA data will be appropriately kept 
behind the VA firewall and in compliance with all VA data security guidelines. All 
members of the research team will maintain up-to-date training on HIPAA, patient 
oriented research, and data security measures at the VA. 
5.10.3. 
Indicate how and where data/information will be stored, and specify pertinent 
security systems.  
                Every effort will be made to reduce the risk of loss of confidentiality in this study.  
Research files containing confidential material will be stored in a locked file cabinet in the PI’s 
locked office at the Philadelphia VA Medical Center.  Security during data extraction and 
management will follow the standard operating procedure of the CHERP.  Specifically, data 
obtained to fulfill the information needs of IRB-approved studies or QI efforts are housed on a 
secure server physically located within the FITS computer room of the Philadelphia VA 
Medical Center and networked within the VA Intranet.  As a result, the servers have the same 
degree of physical and electronic protection afforded other VA computer systems, including 
antiviral protection and routine back-ups.  FITS is responsible for managing the server 
hardware and software, including its physical and network security and connectivity, backup 
processes, operating system patches, and application management.  Study data will be stored 
in one of two places – either within tables on a Philadelphia VAMC SQL Server (the CHERP4 
machine), or in data files stored within protected directories on the server (\\vhaphicherpnas).  
CHERP file folders will be created by the CHERP Dataset Administrator (DSA) and stored on 
the CHERPNAS server with read and write access to study files restricted by the operating 
system to authorized persons only for the time-frame designated during the IRB and R&D 
approval. At the end of the timeframe the folders will be locked. By using this approach, 
access to the data will be under the strict surveillance and control of the CHERP data 
administrator (Christopher Roberts or a CHERP assigned programmer with equivalent 
experience).   
To ensure subject confidentiality and comply with HIPAA regulations, none of the 18 HIPAA 
identifiers will be stored in the database, e.g.no personal information, such as names, dates, 
contact information, social security/medical record numbers, etc. All research files containing 
protected health information will be stored in a locked file cabinet in a locked office or on a 


 
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secure VA server on a password protected computer in a locked office at Philadelphia VA 
Medical Center. All VA data will be appropriately kept behind the VA firewall and in compliance 
with all VA data security guidelines. All members of the research team will maintain up-to-date 
training on HIPAA, patient oriented research, and data security measures at the VA. 
5.10.4. 
Will PHI be transmitted or transported outside of CMCVAMC?      NOT 
APPLICABLE                            If yes, complete sections 5.10.4.1 through 5.10.4.4.  
If no, go directly to section 5.11. 
5.10.4.1. Does the informed consent document and Authorization for Use & 
Release of Individually Identifiable Health Information for Veterans 
Health Administration (VHA) Research form disclose entities/individuals 
to which/whom PHI will be transported or transmitted?    Choose an 
item. 
5.10.4.2. Specify entities/individuals outside CMCVAMC to which/whom data will 
be disclosed, the justification for such disclosure and the authority, and 
how they will access it.   
            
5.10.4.3. List the data/information that will be transmitted or transported, and  
specify how data will be transported or transmitted from one location to 
another and how it will be protected during transmission or 
transportation outside of CMCVAMC. 
                        
 
5.11. Communication Plan  
5.11.1. 
Include plan for ensuring that the study is conducted according to the IRB-
approved protocol. 
We will ensure all members of the study team are up-to-date on clinical research 
conduct training. We will develop a manual of operations according the IRB approved 
study protocol. The study team will promptly report any AEs, SAEs, and unanticipated 
problems, protocol violations to the IRB according to IRB guidelines.  
5.11.2. 
If a multi-site study, include information on 
• 
ensuring that all required local site approvals are obtained and notifying the 
Director of any facility where the research is being conducted but the facility is 
not engaged, and 
• 
keeping all engaged sites informed of changes to the protocol, informed 
consent, and HIPAA authorization, and 
• 
informing local sites of any Serious Adverse Events, Unanticipated Problems, 
or interim results that may impact conduct of the study, and 
• 
notifying all local facility directors and local site investigators (LSI) when a 
multi-site study reaches the point that it no longer requires engagement of the 
local facility (e.g., all subsequent follow-up of subjects will be performed by 
the PI from another facility). 
                          
 
5.12. Investigational Drug   NO       If yes, complete the rest of this section.  If no, go directly to 
section 6. NOTE:  If this study involves an investigational drug, investigator must contact the 
Pharmacy and Therapeutics (P&T) Committee and provide its approval to IRB. 
5.12.1. 
Specify if the drug or biological agent is:   
5.12.1.1. FDA approved:   Choose an item. 
5.12.1.2. Used for off-label purposes:   Choose an item. 


 
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5.12.2. 
Include the FDA Investigational New Drug (IND) number for all non-FDA approved 
and off-label drugs, biological agents or nutritional supplements.  If not 
applicable state, “Not Applicable.”  
             
5.12.3. 
Provide all relevant information about the drug, including pre-clinical data. 
             
5.12.4. 
Explain any wash-out periods, rescue medications permitted and any type of 
medications not permitted while enrolled in the study.   
             
5.12.5. 
Describe blinding and un-blinding procedures.  
             
5.12.6. 
Include the dosage, route of administration, previous use, and the safety and 
efficacy information on any drug used for research purposes. 
            
5.12.7. 
Describe rationale for the dosage in this study. 
            
5.12.8. 
Justify why the risks are reasonable in relation to anticipated benefits and/or 
knowledge. 
           
5.12.9. 
Describe where drug preparation will be done. 
           
5.12.10. All drugs for CMCVAMC subjects must be dispensed through the VA 
investigational pharmacy. 
           
5.12.11. Describe where the study treatment will be administered. 
           
5.12.12. Describe plan for tracking a non-compliant treatment study subject. 
          
5.12.13. Describe the process for the storage, security, dispensing and return of an 
investigational drug. 
           
 
5.13. Investigational Device - NOT APPLICABLE        If yes, complete the rest of this section. 
5.13.1. 
The Investigational Device Exemption (IDE) number must be submitted for all 
significant risk devices and if an IDE exists for a non-significant risk device. 
            
5.13.2. 
Significant Risk or Non-significant Risk - If a device is not approved by the FDA, 
specify whether or not the sponsor has determined this device to be a 
“significant risk” or “non-significant risk” as defined by the FDA. 
             
5.13.3. 
Provide all relevant information about the device. 
             
5.13.4. 
Describe blinding and un-blinding procedures. 
              
5.13.5. 
Specify if device is:   
5.13.5.1. FDA approved:  Choose an item. 
5.13.5.2. Used for off-label purposes:   Choose an item. 
5.13.6. 
Explain if the investigational device will be delivered and/or stored by the 
Principal Investigator or Pharmacy Service. 


 
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5.13.7. 
Describe the process for the storage, security, dispensing and return of an 
investigational device. 
           
5.13.8. 
For research involving an investigational device, describe the SOP or plan for 
device control. 
           
5.13.9. 
Address how the device will be stored in such a way that only research staff 
associated with the protocol will have access to the device. 
           
5.13.10. Describe measures that will be put into place to ensure that the device will only 
be used in subjects of this research protocol. 
                        
 
Section 6:  Resources and Personnel 
6.1. 
Include where and by whom the research will be conducted.  
                The entire study will be conducted at the CMCVAMC. We have assembled an 
outstanding multi-disciplinary team.  
Principal Investigator: Dr. Yang is a Core Investigator with the Center for Health Equity  
Research and Promotion (CHERP), a VA HSR&D Center of Innovation (COIN) with offices in 
Philadelphia and Pittsburgh. He has extensive experience conducting VA and non-VA clinical 
research studies. He will be responsible for the completion of all aspects of the study aims. He 
will also be responsible for the fiscal, administrative and regulatory aspects of the study, 
including all regulatory affairs, data collection and management, adherence to all policies and 
procedures, coordinating meetings and email/telephone communications among the contracted 
Divisions, consultants and the primary team at the CMCVAMC, and maintenance of study 
protocol to ensure that the specific aims of the study are being met. Dr. Yang will develop 
Manual of Procedures.   
Co-investigators and supporting staff at CMCVAMC: Dr. Khan is the Director of the GI section 
at the CMCVAMC. He is a clinical gastroenterologist with extensive experience conducting 
clinical research including clinical trial within the VA system. He will provide support to all 
aspects of the study. Dr. Hubbard, a biostatistician in the Center for Clinical Epidemiology and 
Biostatistics at the University of Pennsylvania, will provide statistical support. Dr. Glick is an 
expert in performing economic analysis embedded in clinical trials and will oversee all aspects  
of the prospective economic evaluation.  
Consultant: As the chairperson for the Medical Advisory Panel for Pharmacy Benefits  
Management for VA, and as the Co-Director of the VA Center for Medication Safety, Dr. 
Chester B. Good will share his experience in national formulary issues, drug safety issues and 
optimizing prescribing practice within the VA. He will help with design of the intervention and 
facilitate the implementation and dissemination of the study findings within the VA. Dr. James 
Lewis, Professor of Medicine and Epidemiology at the University of Pennsylvania, is a board 
certified gastroenterologist and prolific clinical investigators. He has been the PI for 4 NIH 
funded clinical trials and is on the steering committee for a 5th NIH funded trial. These studies  


 
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have used a variety of designs to facilitate recruitment, data collection, and retention while not 
altering practice patterns in real world settings. We will adapt these methods for this trial given 
the importance of studying the different regimens as practiced in usual care. Dr. Charlene Weir 
will provide her expertise to help ensure the study procedures are acceptable to VA providers.  
Joyce Askew (Clinical Applications Coordinator/Program analyst)  
Ms. Askew is a full-time health informatics specialist at the Corporal Michael J. Crescenz VA 
Medical Center. Ms. Askew is familiar with the functionality of clinical and administrative 
applications and the interrelationships of those applications to the operations of clinical 
services, particularly with regard to Veterans Health Information Systems and Technology  
Architecture (VistA) and the Computerized Patient Record System (CPRS). Using her expert 
knowledge for the VA electronic health record and associated clinical software applications, she 
routines provides technical support to develop, generate, deploy, validate, maintain and modify  
major CPRS clinical application components including Order Entry/Results Reporting, TIU 
documents, Consult Request Tracking, Health Summary, Problem List, Care Management,  
VISTA Web and Clinical Reminders. She routinely engages in projects in process improvement  
and reengineering business process for clinical efficiency and documentation, including several 
changes to the GI endoscopy consultation and the colonoscopy bowel preparation ordering 
menu. In preparation for the current project, she has obtained from her counterpart from Boston 
VA Medical Center the programming codes for the implementation of linking the ordering menu 
change with study randomization procedure and tested these in a pilot environment in CPRS. If 
the grant is funded, she will be responsible for modifying the colonoscopy bowel preparation 
menu, linking the ordering menu to implementation of study randomization procedure as well as 
auto-population of associated progress notes, health alerts and consultations in CPRS. She will 
also be responsible for maintaining this system in CPRS and troubleshooting during the study  
period. Her responsibility in the proposed project will be a part of her formal job responsibilities,  
and no additional salary support is requested.  
 
Roberts, Christopher B. (Dataset Administrator non-2210).  
Christopher B. Roberts MPH, is a Dataset Administrator for CHERP and will assume the 
Dataset Administrator position for the project, a non-2210 position. His Salary totals reflects 2% 
COLA and anticipated step increases during each project year The Dataset Administrator will 
establish a study folder for the proposed project on a secure CHERP server. He will be 
responsible for developing electronic query algorithms for extracting patient lists and other 
study participant data such as patient demographics and all the other baseline characteristics 
from the VISN4 regional data warehouse. He will set up prospective execution of the queries 
and store the collected data in a secure and accessible manner for the PI and the study  
coordinators. In concert with the Sr. Research Coordinator and the PI, he will develop the 
electronic CRFs, project database and will interface for data entry and project tracking/report  
generation.  Working closely with the biostatistician and the PI, he will develop, test, and 
implement data cleaning, data quality monitoring procedures and will be responsible for 
creation of analytic databases for all data analyses.  The Dataset Administrator will have 


 
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oversight responsibility for data storage on the secure research data server and will maintain 
documentation of IRB approval to support data use and access by study staff.  
 
TBN  (Sr. Research Coordinator)  
We are requesting funds for a full-time MS- level senior clinical research coordinator for each of 
the 4 years of the project. He/she will be responsible for the following: working with the CHERP 
dataset programmer to setup study database for collection of study data; creating a manual of 
operation procedures for the study; performing EHR chart review for initial screening; 
contacting patients, obtaining consent, and obtaining patient procedure cancellation/no-show 
data; forwarding procedure ordering request to the PI; supervising the abstraction of patient 
randomization data and progress notes from CPRS, recording and entering the study data into 
the study database, ensuring that subject data are secure and kept confidential; assisting the 
CHERP programmer with setting up and updating patient tracking spreadsheet, monitoring 
study financial expenditures, ordering supplies/subject recruitment materials, troubleshooting 
study data collection and/or study participant-related issues. 
 
The senior research coordinator will also support the activities of the investigators including 
conducting library and computer searches for relevant study literature; assisting with document 
and correspondence production; creating, updating and maintaining project files in a 
confidential manner. In addition, he/she will assist Dr. Yang with preparation of progress and 
study milestone reports and publications, adverse event tracking and reporting, IRB 
correspondence and renewals and regulatory auditing of the study. He/she will document 
proceedings of team meetings and teleconferences and process project-related forms. This 
senior research coordinator will have the added the responsibility of supervising the junior 
research assistant.  
 
TBN (Research Assistant)  
We are requesting funds for a full-time research assistant for each of the 4 years of the project.  
Given the large sample size (10,000 patients) and the need to complete the study procedures  
and data collection in a timely manner, a second junior level research assistant will be required 
to complete study tasks. He/she will be responsible for the following: documentation in CPRS, 
ensuring patient follow-up and retention, and preparation of data for analysis at the 
CMCVAMC/Philadelphia site. The research assistant will also assist the senior research 
coordinator in the preparation of data for reports and IRB submissions. The junior research 
assistant will work under the supervision of the Sr. Research Coordinator to maintain study  
database for collection of study data; assist with creating a manual of operation procedures for 
the study; assist with EHR chart review for initial screening; contact patients, obtain consent, 
and collect patient procedure cancellation/no-show data; forward ordering request to the PI; 
collecting randomization data and progress notes from the CPRS, recording and entering the 
study data into a study database, ensure that subject data are secure and kept confidential;  


 
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assist the Sr. Research Coordinator with updating patient tracking spreadsheet. The research 
assistant will also support the activities of the investigators including assisting with document 
and correspondence production; creating, updating and maintaining project files in a 
confidential manner.  
 
Carson Clark 8/8th  (Dissemination Manager) (CHERP Communications Coordinator)  
Ms. Clark has over 20 years of experience in public relations, marketing, advertising and 
publication. She has led the communications activities on numerous prior studies conducted by 
researchers at CHERP. Ms. Clark will have primary responsibility for all strategic  
communication and public relations activities related to the dissemination of study findings to 
VA and non-VA researchers and policymakers, the media and the general public. She will 
handle the development of all electronic and print communications for the study. This project 
will require 5% effort of Carson Clark’s time in year 4 of the project only. 
6.2. 
Provide a brief description of each individual’s role in the study.   Indicate who will have 
access to protected health information and who will be involved in recruiting subjects; 
obtaining informed consent; administering survey/interview procedures; and performing 
data analysis.  
                See above section. The PI, the research coordinators and the dataset administrator will have 
access to PHI 
6.3. 
If applicable, provide information on any services that will be performed by contractors, 
including what is being contracted out and with whom.  
                None 
6.4. 
If applicable, provide information on any Memoranda of Understanding (MOUs) or Data 
Use Agreements (DUAs) that are being entered into, including with whom and for what 
reason.  
    n/a 
 
Section 7: Genetic Testing 
7.1. Does the project involve genetic testing?  Not Applicable, SKIP TO SECTION 8 
7.2. Will specimens be kept for future, unspecified use? Choose an item. 
7.3. Will samples be made anonymous to maintain confidentiality? Choose an item.  (If there is a 
link, it is not anonymous.  Coding is not anonymous.) 
7.4. Will specimens be destroyed after the project-specific use is completed? Choose an item. 
7.5. Will specimens be sold in the future? Choose an item. 
7.6. Will subjects be paid for their specimens now or in the future? Choose an item. 
7.7. Will subjects be informed of the results of the specimen testing? Choose an item. 
7.8. Are there any implications for family members based on specimen testing results? Choose 
an item. 
7.8.1. If answer to section 7.8 is yes, they may be participants. 
7.9. Will subjects be informed of results obtained from their DNA? Choose an item. 
7.10. Explain if the study is looking for an association between a genetic marker and a specific 
disease or condition, but at this point it is not clear if the genetic marker has predictive 
value.  
                 
7.11. Describe if the study is based on the premise that a link between a genetic marker and a 
specific disease or condition is such that the marker is clinically useful in predicting the 
development of that specific disease or condition.  


 
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7.12. Will the subject be notified of the results and the provision for genetic counseling?  Choose 
an item. 
 
Section 8:  International Research 
8.1. 
Does this study involve international research?   NOT APPLICABLE    If no, go directly to 
section 9. 
8.1.1. For further instructions, refer to VHA Directive 2005-050, Requirements for 
Conducting VA-Approved International Research Involving Human Subjects, 
Human Biological Specimens, or Human Data 
8.1.2. VHA Handbook 1200.05 definition of international research - VA international 
research is any VA-approved research conducted at international sites (not within 
the United States (U.S.), its territories, or Commonwealths); any VA-approved 
research using either human biological specimens (identified, de-identified, or 
coded) or human data (identified, de-identified, or coded) originating from 
international sites; or any VA-approved research sending such specimens or data 
out of the U.S.  NOTE: For the purposes of the VHA Handbook 1200.05, research 
conducted at U.S. military bases, ships, or embassies is not considered 
international research. 
 
Section 9:  Statistical Analysis 
9.1. 
Include statistical power calculations and the assumptions made in making these 
calculations.  
   The GI section is expected to perform 10,500 colonoscopies over the 3-year recruitment 
period. Based on our pilot data, the 10,500 colonoscopies performed will entail approximately  
15,000 colonoscopies scheduled during the same period. Again based on our preliminary data, 
11% of the scheduled colonoscopies during the period will be expected to represent repeat 
examinations for the same patients during the 3-year period and will thus be excluded. Due to 
the low risk of the intervention and minimal burden on the provider and participant, we expect to 
have very high enrolment rates among eligible patients. We therefore project to randomize 
10,000 eligible patients with scheduled colonoscopy. Following the ITT analysis design, all 
10,000 randomized patients will be included in the primary analysis with 5,000 allocated to each 
treatment arm. Based on preliminary data, we anticipate that in the 4L PEG-ELS arm 74% of 
patients will show up for their scheduled colonoscopy and undergo the examination, and 75% will 
have adequate bowel preparation. We therefore anticipate that 56% will satisfy our composite 
primary outcome of colonoscopy completion. At α=0.025, we will have 99.8% power to detect a 
5% improvement, or 90.3% power to detect a 3.5% improvement in the colonoscopy completion 
rate. Assuming an ADR of 28% in the 4L PEG-ELS arm, we will have in excess of 99.9% power 
to detect a 5% improvement in ADR at the  = 0.025 level in the 2L M-G arm.  
Analyses of cancellation/no-show rate will be similar to the analyses for primary outcomes. At 
α=0.017, we will have 95.4% power to detect a 3.5% difference in cancellation/no-show rate. The 
analyses of other secondary outcomes will be conducted in the sub-group of patients who show 
up for their scheduled colonoscopy. We thus anticipate a sample size of 7,400 for these 
secondary analyses. Assuming 3,700 patients in each arm, we anticipate that in the 4L PEG-ELS 
arm 75% will have adequate bowel preparation. At α=0.017, we will have in excess of 99.7% 
power to detect a 5% improvement in the rate of adequate bowel preparation in the 2L M-G arm. 


 
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Assuming the proportion of patients in the 4L PEG-ELS arm willing to repeat the preparation is 
66.7%,6 we will have 98.8% power to detect a 5% improvement in the rate of patients willing to 
repeat their bowel preparation regimen at the  = 0.017 level in the 2L M-G arm. 
We have designed our study to be overpowered for the primary comparisons in order to improve 
power for subgroup analyses. For instance, in a sub-group consisting of 10% of the total sample 
(N = 1,000 patients) we will have 80% power to detect a difference between treatment arms at 
the  = 0.05 level of 8.7% in the completion rate, 8.3% in ADR, and 9.3% in the proportion willing 
to repeat their bowel preparation regimen. Note that we have used an -level of 0.05 in 
exploratory analyses in order to maximize power, as exploratory analyses are fundamentally  
hypothesis-generating. We thus deem type II errors more severe in exploratory analyses than 
type I errors and accordingly set a less conservative  level. Results of such hypothesis-
generating analyses must be confirmed, however, in subsequent studies. 
Within-endoscopist correlation in our outcomes of interest will result in decreased power relative 
to the nominal power computed above under independence. Although we anticipate that within-
endoscopist correlation will be minimal due to the largely patient-oriented nature of our 
outcomes, we have designed our study to have sufficient power under a moderate level of within-
endoscopist correlation. Specifically, as correlation among observations increases, the effective 
sample size decreases according to the relationship Neff = N/(1+ (b-1)), where N is the total 
number of patients sampled, b is the average number of patients per endoscopist, and  is the 
intraclass correlation coefficient. In primary analyses in which the nominal sample size is 10,000, 
our study will have 80% power to detect a 5% difference in the colonoscopy completion rate at 
the  = 0.025 level for effective sample sizes as small as 3,703 and a 5% difference in ADR at 
the  = 0.025 level for effective sample sizes as small as 3,222. For our secondary analysis of 
the cancellation/no-show rate with nominal sample size of 10,000, our study will have 80% power 
to detect a 5% difference at the  = 0.017 level for effective sample sizes as small as 3,009. For 
secondary analyses in which the nominal sample size is 7,400, our study will have 80% power to 
detect a 5% difference in the adequate bowel preparation rate at the  = 0.017 level for effective 
sample sizes as small as 2,919 and a 5% difference in the rate of willingness to repeat the 
regimen at the  = 0.017 level for effective sample sizes as small as 3,567. Across all primary 
and secondary outcomes, we will thus have at least 80% power as long as our effective sample 
size is 48.2% (3,568/7,400) of the nominal sample size or larger.  
9.2. 
Define plans for data and statistical analysis, including key elements of the statistical plan, 
stopping rules and endpoints. 
 E.9.2.1  Descriptive statistics   
The initial analyses will utilize descriptive statistics to describe the characteristics of the study 
cohort. Continuous variables will be described as medians and interquartile ranges. Categorical 
variables will be described using proportions. Formal statistical comparisons of these descriptive 
variables between study arms will be performed comparing the two arms of the study using the 
Wilcoxon rank sum test for continuous variables and the chi squared or Fisher’s exact test for 
categorical variables. Because any imbalance in the two groups is by definition a chance 
occurrence, these analyses will be used to highlight areas of substantial imbalance between the 
study arms. 
E.9.2.2  Primary Effectiveness Analysis   


 
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Our study will have two primary effectiveness outcomes. The first primary outcome is the 
colonoscopy completion rate, a composite binary indictor based on patient attendance at 
scheduled colonoscopy and having adequate (i.e., excellent or good) quality bowel preparation 
as rated by the endoscopist. The corresponding parameter of interest is the proportion of 
patients in each arm of the trial who both show up for their colonoscopy and are rated as having 
adequate bowel preparation. The second primary outcome is the ADR estimated as the 
proportion of patients with at least one adenoma detected among all patients scheduled for 
colonoscopy. We hypothesize that patients using the 2L M-G regimen will have a higher 
colonoscopy completion rate and higher ADR than patients using the 4L PEG-ELS regimen. 
Analyses will be based on intention-to-treat (ITT) principles, with all randomized patients included 
in the primary analysis and analyzed according to the regimen to which they were randomly  
allocated. At the conclusion of the trial we will report the primary outcome measures (i.e., 
colonoscopy completion rate and ADR) for each preparation regimen group with 95% confidence 
intervals as well as the difference in outcome rates between arms with their 95% confidence 
intervals.  Because of the very large sample size and fixed-design 1:1 randomization, we 
anticipate minimal imbalance in baseline characteristics between study arms. Adjustment for 
baseline patient characteristics is therefore not anticipated to be necessary in the primary 
analysis. Treatment arms will be compared using two-sample tests of proportions. To account for 
the multiple primary outcomes, hypothesis tests will be conducted at the 2-sided  = 0.025 level 
in order to control the type I error rate at the family-wise 0.05-level using a Bonferroni correction 
to account for the two hypothesis tests. 
E.9.2.2 Secondary Effectiveness Analysis   
Our study will have three secondary effectiveness outcomes. The first secondary outcome is the 
rate of cancellation or no-show in each bowel prep arm. The second secondary outcome is 
adequate bowel preparation, a binary indictor based on endoscopist rating of excellent or good 
quality bowel preparation. The corresponding parameter of interest is the proportion of patients in 
each arm of the trial rated as having excellent or good quality bowel preparation, computed 
among the subset of patients in whom the colonoscopy examination was started regardless of 
the extent of the examination. The third secondary outcome is a binary outcome based on 
patients’ self-reported willingness to repeat the bowel preparation regimen among patients 
attending their scheduled colonoscopy. The corresponding parameter of interest is the proportion 
of patients reporting willingness to repeat the bowel preparation regimen in each arm of the 
study, computed from among those patients in whom the colonoscopy examination was 
attempted regardless of the extent of the examination. We hypothesize that patients using the 2L 
M-G regimen will have lower cancellation/no-show rate, higher adequate bowel preparation rates 
and a higher proportion willing to repeat the regimen than patients using the 4L PEG-ELS 
regimen. 
Analyses for cancellation/no-show rate will mirror those for the primary outcomes. However, 
since the other two secondary outcomes will be estimated among the subset of patients in whom 
the colonoscopy was performed, we will exclude all patients not attending their scheduled 
procedure or the few patients who showed up but do not undergo the colonoscopy (e.g., having 
fever, non-compliance with dietary instruction, etc.). At the conclusion of the trial we will report 
the secondary outcome measures (i.e., cancellation/no show rate, adequate bowel preparation 


 
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rate and proportion willing to repeat the regimen) for each preparation regimen group with 95% 
confidence intervals as well as the difference in outcome rates between arms with their 95% 
confidence intervals among patients attending their colonoscopy. Treatment arms will be 
compared using two-sample tests of proportions. To account for the multiple secondary  
outcomes, hypothesis tests will be conducted at the two-sided  = 0.017 level in order to control 
the type I error rate at the family-wise 0.05-level using a Bonferroni correction to account for the 
three hypothesis tests. 
E.9.2.3 Exploratory Sub-group Analyses  
We will conduct additional exploratory analyses to examine the comparative effectiveness of the 
two bowel prep regimens within subgroups of trial participants.  We will compare three 
effectiveness outcomes, colonoscopy completion rate, ADR, and proportion willing to repeat the 
regimen, in pre-specified sub-groups defined by patient gender, advanced age (≥ 65 or <65), 
DM, timing of colonoscopy (AM vs. PM), and history of constipation, narcotic use or laxative use. 
These factors have been associated with bowel preparation quality. Within strata defined by 
each sub-group, we will compute outcome measures as described above and compare treatment 
arms using two-sample tests of proportions. Because of the potentially limited sample size within 
some patient sub-groups, this analysis will be primarily descriptive. However, we believe it will 
provide useful information to inform the design of future studies including implementation of 
primary trial results. 
E.9.2.4 Safety Analysis 
To ensure safety of the 2L M-G regimen, we will evaluate one safety outcome, incidence of 
hyponatremia or renal failure in the 6-month period following colonoscopy. We will report the 
number and proportion, with 95% confidence intervals, in each treatment arm experiencing 
hyponatremia or renal failure in the 6-month period following the colonoscopy.  
 E.9.2.5 Accounting for Within Endoscopist Correlation  
While some of our outcomes are largely dependent on patient behavior and preferences,  
provider-specific ADR and rate of adequate bowel preparation may potentially exhibit some 
within-endoscopist correlation. Correlation within clusters defined by endoscopists will tend to 
decrease the effective sample size and power of our study. Because we anticipate that variability  
attributable to endoscopist will constitute a small proportion of the overall variability, our primary 
analyses will be conducted at the patient-level without accounting for endoscopist. However, we 
will conduct sensitivity analyses to ensure that within-endoscopist correlation does not affect our 
inference. Because of the small number of endoscopists included in this trial (an estimated n = 8 
endoscopists), we will use fixed effects logistic regression models including terms for treatment 
arm and a separate fixed effect for each endoscopist to account for this source of correlation. By 
conditioning on endoscopist, the resultant fixed effects regression model satisfies the assumption 
of conditional independence among observations from the same cluster. We have selected this 
approach because alternative approaches to accounting for within-cluster correlation, including 
generalized estimating equations and mixed effects models, are unsuitable in the context of 
small numbers of clusters. We will compare the statistical significance of the treatment arm term 
in these regression models to the significance from our primary and secondary analyses using 
two-sample tests of proportions to ensure that within-cluster correlation does not affect our 
inference.  


 
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9.3. 
Provide sample size determination and analysis (include anticipated rate of screen 
failures, study discontinuations, lost to follow-up, etc.) 
 The GI section is expected to perform 10,500 colonoscopies over the 3-year 
recruitment period. Based on our pilot data, the 10,500 colonoscopies performed will 
entail approximately 15,000 colonoscopies scheduled during the same period. Again 
based on our preliminary data, 11% of the scheduled colonoscopies during the period 
will be expected to represent repeat examinations for the same patients during the 3-
year period and will thus be excluded. Due to the low risk of the intervention and 
minimal burden on the provider and participant, we expect to have very high enrolment 
rates among eligible patients. We therefore project to randomize 10,000 eligible 
patients with scheduled colonoscopy. Following the ITT analysis design, all 10,000 
randomized patients will be included in the primary analysis with 5,000 allocated to 
each treatment arm. Based on preliminary data, we anticipate that in the 4L PEG-ELS 
arm 74% of patients will show up for their scheduled colonoscopy and undergo the 
examination, and 75% will have adequate bowel preparation. We therefore anticipate 
that 56% will satisfy our composite primary outcome of colonoscopy completion.  
9.4. 
Describe how, where and by whom the data will be analyzed.   
The data analysis for the primary and secondary aims will be performed by the 
biostatistician (Dr. Hubbard) and the PI. The exploratory cost analysis data will be 
analyzed by Dr. Glick and the PI. 
 
Section 10:  References - Bibliography of cited literature