Investigation of Medical Management to Prevent Episodes of Diverticulitis (IMPEDE) Trial
Phase: NA
Conditions: Diverticulitis
Sponsor: University of Washington

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Investigation of Medical Management to Prevent Episodes of Diverticulitis (IMPEDE) Trial 
Protocol  
Developed by  
David R. Flum, MD MPH and Lisa Strate, MD MPH 
 
 
Study Funder: 
National Institute of Diabetes and Digestive and Kidney Diseases  
 
Version Number and Date: 
Version 5: August 7, 2023 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1.0 Key Personnel 
……………………………………………………………………………………5 
2.0 Background and Rationale ........................................................................................................6 
2.1 Rationale ...........................................................................................................................6 
3.0 Study Aims and Methods ...........................................................................................................7 
3.1 Study Aims ........................................................................................................................7 
3.2 Methods ............................................................................................................................8 
4.0 Study Flow, Participant Screening and Enrollment ...................................................................8 
4.1 Overview of Study Flow ....................................................................................................8 
4.2 Participant Screening........................................................................................................9 
4.3 Inclusion Criteria ...............................................................................................................9 
4.4 Exclusion Criteria ..............................................................................................................9 
4.5 Consent Process............................................................................................................ 10 
4.5.1 Randomization Procedures ............................................................................ 10 
4.5.2 Those who decline randomization .................................................................. 10 
4.6 USDA Mediterranean-stye Food Pattern/ Medi for all .................................................. 10 
4.7 High Fiber Diet Arm ....................................................................................................... 11 
5.0 Study Schedule Overview, Research Assessments, Medical Record Review, Call Triggers, 
Withdrawal, Compensation, and Retention ......................................................................... 11 
5.1 Study Schedule Overview ............................................................................................. 11 
5.2 Research Assessments ................................................................................................. 12 
5.2.1 Baseline Assessment (Index Encounter) ....................................................... 12 
5.2.2 Bi-Weekly Check-in ........................................................................................ 13 
5.2.3 Follow-up Assessments (3, 6, 9, and 12 months) .......................................... 13 
5.2.7 Participant Burnout and Optimizing Data Collection ...................................... 14 

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5.3 Medical Record Review ................................................................................................. 14 
Time points ............................................................................................................... 14 
Data Collection ......................................................................................................... 14 
5.4 Adverse Event Reporting ................................................................................... 15 
5.5 Reasons for Withdrawal................................................................................................. 15 
5.5.1 Handling of Withdrawals ................................................................................. 15 
5.6 Compensation ................................................................................................................ 15 
5.6.1 Participant Compensation .............................................................................. 15 
5.7 Retention Activities ........................................................................................................ 16 
5.7.1 Maintaining Contact ........................................................................................ 16 
6.0 
Outcome Assessments ........................................................................................................ 16 
6.1 Primary and Secondary Outcomes ............................................................................... 16 
6.2 Clinical Complications........................................................................................ 17 
7.0 Data Management and Information Security ......................................................................... 18 
7.1 Data Management ......................................................................................................... 18 
7.1.2 Data Quality Monitoring  ................................................................................. 19 
7.2 Information Security ....................................................................................................... 19 
8.0 Statistical Analysis Plan and Stopping Rules ......................................................................... 20 
8.1 Allocation and Randomization ....................................................................................... 20 
8.2 Study Feasibilities Measures ......................................................................................... 20 
8.3 Treatment Fidelity and Adherence: ............................................................................... 20 
8.4 Signal Assessment for Biomarkers:  ............................................................................. 21 
8.5 Secondary Statistical Analyses ..................................................................................... 21 
8.6 Missing Data .................................................................................................................. 22 
8.7 Sample Size and Statistical Power ................................................................................ 22 

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8.8 Data and Safety Monitoring Plan (DSMP)..................................................................... 22 
9.0 Study Related SAEs ............................................................................................................... 23 
9.1 Identification of SAEs..................................................................................................... 23 
9.2 SAE Reporting ............................................................................................................... 23 
9.3 Assignment of SAEs as Treatment Related .................................................................. 23 
10.0 Reporting Procedures ........................................................................................................... 23 
11.0 Protocol Violations and Deviations .............................................................................. 23 
12.0 Protection of Human Participants ......................................................................................... 24 
13.0 References ............................................................................................................................ 25 
 
 
 

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1.0 Key Personnel 
 
Principal Investigators 
 
David R. Flum, MD MPH  
University of Washington  
Department of Surgery 
1959 NE Pacific Street, Box 356410 
Seattle, WA 98195 
Phone: 206-616-5440 
Email: daveflum@uw.edu 
 
Lisa Strate 
University of Washington 
Department of Medicine 
Phone: 206-744-7058 
Email: lstrate@uw.edu 
 
 
Director, Data Coordinating 
Center 
 
 
 
 
 
 
Key Personnel  
 
 
 
 
 
 
 
Bryan Comstock, MS 
University of Washington 
Department of Biostatistics 
4333 Brooklyn Avenue NE, Box 359461 
Seattle, WA 98105 
Phone: 206-543-1882 
Email: bac4@uw.edu  
   
Adam Drewnowski, MA PhD 
UW School of Public Health 
Box 353410 
Nutritional Sciences 
Raitt Hall 305B 
Seattle, WA 98195 
Phone: 206-543-8016 
Email: adamdrew@uw.edu 
 
Joshua Liao 
University of Washington 
Department of Medicine 
1959 NE Pacific Street  
Seattle, WA 98195 
Email: joshliao@uw.edu 
 
 

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2.0 Background and Rationale 
Diverticulitis is one of the most common gastrointestinal indications for inpatient hospital 
admission, outpatient clinic and emergency room visits, and colon surgery.1, 2 At least 20% of 
individuals with an initial episode of diverticulitis will have one or more painful and unpredictable 
recurrences.3 The risk of recurrence increases with each subsequent episode.3 Unfortunately, 
there is no proven pharmacologic means to decrease the risk of diverticulitis.4 Currently, 
secondary prevention relies on segmental colectomy, which is associated with a ~10% risk of 
major complications and does not eliminate the possibility of future attacks.5-8 In the face of the 
enormous burden of recurrent diverticulitis, secondary prevention is a high priority.  
Diet and lifestyle factors are modifiable targets for prevention of diverticulitis. Multiple large, 
prospective cohort studies, including work from our group, have identified low dietary fiber, high 
red-meat intake, and a Western dietary pattern as risk factors for incident diverticulitis.9-13 Physical 
inactivity, obesity, smoking, and nonsteroidal anti-inflammatory drug use also increase risk.14-19 
An observational study of 51,000 men examining the joint contribution of multiple modifiable risk 
factors found a linear relationship between number of low-risk factors and diverticulitis incidence. 
Adherence to a low-risk profile (<51g/day red meat, >23g/day fiber, 2 hours exercise/week, 
normal BMI and never smoked) decreased the risk of incident diverticulitis by nearly 75% (RR 
0.27, 95% CI 0.15-0.48).20 However, these modifiable risk factors have not been evaluated for 
secondary prevention. Based on the indirect nature of the evidence, U.S. guidelines conditionally 
recommend diet and lifestyle changes in individuals with a history of diverticulitis.  As part of the 
Dietary Guidelines for Americans, the USDA developed a Healthy Mediterranean-style Food 
Pattern21 that includes the main dietary components associated with primary prevention of 
diverticulitis and may be effective for secondary prevention. However, barriers to adherence 
relating to cost, cultural preferences, and food restrictions need to be addressed to consider it a 
practical intervention in a clinical setting.  
Growing evidence suggests an interaction between diet, lifestyle, the gut microbiota, chronic 
inflammation, and episodes of diverticulitis. Cross-sectional studies indicate that gut microbial 
composition differs in patients with diverticulitis compared with controls,22-25 and diet and lifestyle 
are known to influence the gut microbiome.26-29 Prediagnostic inflammatory markers (interleukin-
6 [IL-6]) and a diet with high inflammatory potential were associated with increased risk of 
diverticulitis.30 Thus, serum and stool biomarkers may identify high-risk individuals who are likely 
to respond to preventative interventions. Greater use of the Mediterranean diet decreases dietary 
inflammation scores and levels of circulating biomarkers of inflammation31, 32 and it is effective in 
the prevention of cardiovascular disease33, 34 and certain cancers.35 
 
2.1 Rationale 
 
As our preliminary data indicate, diets that promote inflammation increase the risk of 
diverticulitis, and are therefore potential targets for secondary prevention. Dietary patterns 
account for the combined influence of multiple dietary components on disease risk, more closely 
resemble real world dietary practices, and are more readily translated into public health 
interventions.130 A Mediterranean diet is more strongly associated with reduced CRP and other 
cardiometabolic risk factors than other diet patterns such as AHEI and DASH,72 and is inversely 
associated with inflammatory diet scores. It also shares many features with other diets that are 
inversely associated with incident diverticulitis, including the AHEI and prudent pattern. A USDA 
Med-style Food Pattern is prominently featured in the widely disseminated Dietary Guidelines 
for America 2020-2025 and is well known to health professionals.131 Therefore, we hypothesize 
that a USDA Med-style Food Pattern diet will reduce the risk of recurrent diverticulitis and the 
level of inflammatory markers more than a high- fiber diet or fiber supplementation and will be 

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feasible to implement in a large-scale RCT, as well as clinical practice and public health 
interventions. 
 
We will study three biomarkers involved in systemic inflammation and implicated in 
chronic disease. Our prior work linked diet, CRP and IL-6 (but not TNFR1B) to incident 
diverticulitis.30 CRP and IL-6 are major inflammatory markers implicated in chronic disease and 
are associated with the inflammatory potential of diet.30 In this study, we will measure IL-6, IL-1β 
and IL-10 primary pro and anti-inflammatory cytokines, respectively.132-134 We will also collect 
blood samples for future biomarker studies that are outside the scope of this pilot feasibility 
study. Future biomarker work could explore additional inflammatory cytokines such as CRP, fat 
derived hormones such as adiponectin and markers of intestinal permeability such as 
lipopolysaccharide (LPS), as well as repeat multiplex assays (e.g., of IL-6, IL-1b, IL-10) and 
blood-based metabolome to examine various pathways that are hypothesized to link diet, 
chronic inflammation, and diverticulitis. 
Fecal calprotectin is a protein found in the cytoplasm of neutrophil granulocytes that is released 
in the stool when the intestinal tract—the colon in particular—is inflammed.135  It is resistant to 
bacterial degradation and is easily measured in stool.136, 137 It is a more sensitive and specific 
marker of intestinal inflammation when compared with plasma erythrocyte sedimentation rate 
(ESR) and CRP,136, 138 and can detect subclinical inflammation. It is commonly used to diagnose 
and monitor inflammatory bowel disease.139, 140 Fecal calprotectin is also elevated in acute 
diverticulitis,141 and in a study of 48 patients followed every 2 months after recovery, it was 
predictive of recurrence.142 In this study, a semi-quantitative test was used (<15µg/g, ≥15µg/g-
60µg/g, >60µg/g). Seventeen (37%) of patients had increased fecal calprotectin (>15µg/g) after 
a normal test following treatment for acute diverticulitis; 7 of 8 (88%) of patients with recurrence 
had an elevated fecal calprotectin during follow-up. Studies of healthy controls and patients with 
inflammatory bowel disease indicate that fiber intake and the Mediterranean diet are associated 
with decreases in fecal calprotectin.137, 143  Therefore, we have selected fecal calprotectin as an 
innovative and plausible biomarker that may predict risk of recurrent diverticulitis and be more 
sensitive than plasma biomarkers. Collection of samples will provide data on the feasibility of 
stool collection within a larger diet trial. We also plan to collect and store stool for future work on 
the gut microbiome and metabolome in diverticulitis that is outside the scope of this pilot study. 
3.0 Study Aims and Methods 
3.1 Study Aims 
Aim 1. Conduct a randomized trial (n=75) of the USDA Healthy Med-style Food Pattern 
intervention versus standardized guidance on fiber intake for patients with diverticulitis to 
determine feasibility of a larger-scale effectiveness trial focused on long-term clinical outcomes 
(recurrence and complications). We will examine willingness to randomize and assess 
adherence to USDA Healthy Med-style Food Pattern. 
Aim 2. Explore plasma inflammatory markers in a subset of participants (n=40) (IL-6, IL-1, IL-1β) 
and fecal calprotectin as short-term, intermediate inflammatory biomarkers of response to 
treatment and collect samples for future biomarker study. 
The hypotheses underlying the IMPEDE trial include 1) A large-scale trial of the USDA Med-
style Food Pattern will be feasible (high rate of patient willingness to be randomized, high rate of 
adherence to the intervention, improvement in Med-style food pattern scores assessed by a 
well-characterized food frequency questionnaire (FFQ) [measure of extent of use of the 
Mediterranean diet], acceptability of study survey burden and follow-up). 2) A USDA Med-style 
Food Pattern reduces serum and fecal biomarkers of inflammation more than standardized 

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recommendation to encourage a high-fiber diet. Based on prior studies, we expect reductions in 
these biomarkers will correlate to lower rates of recurrent diverticulitis. 
3.2 Methods  
This is a feasibility-focused, patient-level randomized trial of an intervention promoting the 
USDA Healthy Med-Style food pattern versus standardized guidance on fiber intake (standard 
educational materials related to a high-fiber diet) in patients with a history of diverticulitis. This 
trial will assess and address barriers to the eventual large-scale trial and lay groundwork for that 
trial that will focus on the risk of recurrent diverticulitis and other clinical outcomes. We will also 
compare changes in serum and stool biomarkers of inflammation that are proximal endpoints in 
the causal path relating a Mediterranean diet pattern’s anti-inflammatory properties and 
recurrence of diverticulitis. 
Research Setting 
The proposed work will use the infrastructure of the Comparative Effectiveness Research 
Translation Network (CERTAIN), a collaborative of dozens of health systems across the US with 
a successful track record of conducting large-scale randomized and observation cohort studies. 
The CERTAIN diverticulitis research network, described in more detail in the UW Facilities and 
Resources description, supports our diverticulitis studies (e.g., DEBUT and COSMID) and will 
provide the setting for the conduct of IMPEDE.  
The University of Washington’s (UW) Surgical Outcomes Research Center (SORCE) will lead a 
Clinical Coordinating Center (CCC). The UW Center for Biomedical Statistics (CBS) will serve 
as the Data Coordinating Center (DCC).  
 
4.0 Study Flow, Participant Screening and Enrollment 
4.1 Overview of Study Flow 
Figure 1: IMPEDE Trial Design 
 
 
 
 

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4.2 Participant Screening  
Patients presenting to University of Washington Medicine gastroenterology and surgery clinics 
at UWMC and Harborview will be screened, remotely and/or in-person, by the research team. 
Patient-facing flyers will be posted at the clinic locations to allow potential participants to ask 
their clinician about the study or to access study information via a link/QR code/study contact 
information. Patients deemed eligible via initial clinician/research team pre-screening will have 
eligibility confirmed. They will then be given time to ask questions about the study to determine 
whether they are interested in participating.  
 
Patients will also be able to begin a self-screening process on the Surgical Outcomes Research 
Center (SORCE) website, guiding them through simple yes/no eligibility questions to determine 
if the trial might be right for them (study eligibility from screening form). Patients will have the 
opportunity to review a consent form but will be contacted by a research team member for a 
consent call before they are able to sign and provide consent to participate. A study investigator 
will confirm eligibility before randomization, but no clinic visit will be required of those patients 
interested in enrolling in this manner. To be considered for participation, patients must have had 
a confirmed diagnosis of diverticulitis by a physician, with medical records to be accessed by 
study physician(s) to confirm. 
 
The study team will also contact patients previously seen for diverticulitis and screened for other 
trials. Basic eligibility information will be visible to the research team through medical record 
screening. 
4.3 Inclusion Criteria  
1. Adult ≥18 years; 
2. Patients presenting (or recently presented) to gastroenterologist or surgeons or 
accessing study website after recovery from an episode of diverticulitis (within the prior 
18 months), either the index episode or recurrent.  
3. Ability to provide written informed consent in English. 
4.4 Exclusion Criteria 
Participants must not have any of the following exclusion criteria:  
1. Unable or unwilling to return for specimen collection visits or be contacted for and/or 
complete research surveys;  
2. Currently incarcerated in a detention facility or in police custody (patients wearing a 
monitoring device can be enrolled) at baseline/screening; 
3. Last episode of acute diverticulitis currently unresolved (i.e., on antibiotics for 
diverticulitis; drain in place)  
4. Intolerance/allergy to the main components of the Med-style food pattern; 
5. Surgery for diverticulitis within past 6 months without an episode of diverticulitis post-
surgery 
6. Planned elective surgery in next 6 months 

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4.5 Consent Process 
The research coordinator and a representative from the medical team will confirm the patient’s 
eligibility for the study based on inclusion and exclusion criteria. Patients will be given time to 
ask questions about the study to determine whether they are interested in participating. Our 
research team will utilize both in-person recruitment and remote/eConsents as applicable. The 
research coordinator will review the study and its risks with the patient and those interested in 
participating will sign informed consent and complete a Health Insurance Portability and 
Accountability Act (HIPAA) form in accordance with institutional guidelines.  
 
For the remote consent option, access to the consent forms will be available digitally or via 
paper copies of the consent forms sent through the mail. A member of the study team will 
contact the patient via phone or over a HIPAA-compliant tele/videoconference line to verbally 
review the consent process with the patient. The patient will be granted time to consider and 
discuss the study before deciding to participate. If the patient decides to participate, they can 
either provide their electronic signature in an electronic consent platform, or they can sign a 
paper copy of the consent form that has been mailed to them. If the patient chooses to sign a 
paper copy of the consent, the patient will be mailed two copies of the consent form along with a 
self-addressed stamped envelope (SASE). One copy of the consent form will be to sign and for 
the patient to keep for themselves, and the second will be signed and mailed back to the study 
team. 
4.5.1 Randomization Procedures 
After consent is obtained, participant information will be entered into an electronic study portal to 
complete enrollment and perform randomization. Participants will be randomized to either the 
USDA Mediterranean-style Food Pattern or to standardized guidance on fiber intake in a 2:1 
allocation ratio, respectively. Randomization failures, defined as a patient who agreed to 
randomization but whose treatment was allocated in a non-random fashion or was randomized 
under inaccurate information and occurring within the first week of randomization will be 
recorded as protocol violations, described in detail in 11.0.   
 
4.5.2 Those who decline randomization 
Participants who decline randomization and participation may be asked to complete a short 
survey assessing their interest in participating in a future trial of medical management. 
 
4.6 USDA Mediterranean-stye Food Pattern/ Medi for all 
Participants randomized to the USDA Mediterranean-style Food Pattern Arm (called Medi for 
all) will have access to a “toolbox” that includes education materials (e.g., food pattern tables 
according to daily caloric intake), recipes, grocery lists, group-based online dietary support, 
feedback, and reminders to encourage dietary change. Recipes and grocery lists can be 
individualized to a participant’s food budget and preferences. Materials will be available in print 
and Web-based. This state-of-the art intervention will then use electronic feedback in the form of 
nudge messages designed to motivate participants to sustain or improve adherence to the Med-
style Food Pattern. Every two weeks, participants in the intervention arm will be prompted via a 

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digital online platform96 (analog also available) to complete the 14-item Mediterranean Diet 
Assessment Score (an adapted version of the MEDAS Score145 previously used in the 
PREDIMED34 study) for the purpose of providing timely, individual feedback on diet adherence 
(not for assessing adherence to the diet pattern). The MEDAS score will be calculated via the 
online digital platform and ranked according to 3 cutpoints: ≤7, 8–9, or ≥10.145 Patients will be 
encouraged to achieve a score of ≥10 which is considered high adherence. The platform will 
then offer feedback based on the levels of self-reported adherence to the diet including self vs. 
peer comparisons and support resources. Nudge messages will utilize information from a 
baseline assessment of participants’ dietary attitudes and beliefs about which food groups within 
a Med-style food pattern they perceive to be most within their control. Ultimately, this approach 
will enable us to provide participants with dietary information and services that support 
adherence by accounting for attitudes, norms, and perceived control.146-148 The extent of 
interaction with the online platform will be assessed bi-weekly; degree of adherence to the 
USDA Med-style food pattern; and engagement in dietician services will be assessed at 
quarterly intervals. 
4.7 High Fiber Diet Arm 
Participants randomized to the High Fiber Diet Arm will be given commonly used patient 
education pamphlet,149 describing fiber and high-fiber foods, the rationale for increasing fiber 
intake, and ways patients can promote greater intake. Based on prior observational studies of 
incident diverticulitis, at least 25 grams/day of fiber will be recommended for participants.  
 
5.0 Study Schedule Overview, Research Assessments, Medical Record Review, Call 
Triggers, Withdrawal, Compensation, and Retention 
5.1 Study Schedule Overview 
Consented and randomized participants will be asked to complete research assessments on the 
topics and at the time points described in Table 1. Research coordinators (RCs) or study team 
members will offer baseline and follow-up assessments in multiple modalities in order of 
participant preference (e.g., online, on paper, or over the phone). Participants randomized to the 
USDA Healthy Med Style food pattern (Medi for All) will receive electronic nudges to support 
behavior change. Additionally, the study dietitian will provide online group counseling sessions 
and office hours for participants to schedule individual online follow up counseling sessions 
which will provide additional content related to wellness, self-efficacy and motivation.    
Table 1. Participant Assessment Schedule. 
Item 
 
 
Baseline 
 
 
Bi-
Weekly 
Monthly 
Follow-Up Time Point 
Month 
3 
6 
9 
12 
Contact Information 
x 
 
 
x 
x 
x 
x 
Food Frequency 
Questionnaires 
x 
 
 
 
x 
 
x 
Online Diet Program 
x 
x 
 
x 
  
  
x 
Blood and Stool 
Sample* 
x 
 
 
  
x 
  
 x 
DVQOL 
x 
 
 
  
x 
  
x 

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IPAQ 
X 
 
 
 
x 
 
x 
Gastrointestinal Quality 
of Life (GIQLI)22 
x 
 
  
 
 x 
  
x 
Mediterranean Diet 
Assessment Score 
(MEDAS) 
 
x 
  
x 
x 
x 
x 
Adverse Events 
 
 
  
x 
x 
x 
x 
Self-Reported Weight 
x 
 
 
 
x 
 
x 
Diverticulitis Symptoms 
& HCU 
x 
 
 
x 
x 
x 
x 
Beyond Demographics 
x 
 
 
 
 
 
 
*Up to 40 participants will be also invited to submit a stool sample for fecal calprotectin analysis. 
This will be collected at baseline, 6 months, and 12 months.  
To ensure successful retention of participants and completion of research assessments through 
the follow-up period, detailed contact information including name, address, phone numbers, 
email addresses, as well as alternate contact persons and phone numbers will be requested 
from participants at baseline (and updated at subsequent time points). While complete contact 
information is ideal to optimize future retention, only one means of contacting the participant is 
required for enrollment. For participants with upcoming travel plans abroad or who may live 
internationally, it is preferred that they provide phone and email contact information as mailed 
contact is slow and costly for the short windows around each research assessment.  
5.2 Research Assessments 
5.2.1 Baseline Assessment (Index Encounter)  
The Baseline Assessment as listed in Table 1 should be completed in-person or online and prior 
to revealing the participant’s random treatment assignment; however, research coordinators are 
asked to document when the participant became aware of their assignment, should it be 
revealed prior to completion of the Baseline Assessment.  
• 
Survey questions will be presented in the order of importance in the event that 
the participant is unable to complete the full battery of questionnaires.  
• 
Collection and Measurement of Inflammatory Markers: We will collect and store 
blood samples on all participants. For the exploratory aim of this pilot study, we 
will measure inflammatory markers in plasma drawn in up to 40 participants. 
Blood samples will be collected in purple top EDTA tubes (EDTA plasma will be 
collected and stored for future studies) and immediately processed at room 
temperature.  
• 
Collection of Stool for Measurement of Fecal Calprotectin and Future Studies: 
Participants may collect stool samples for future microbiome and metabolome 
analyses using an easy-to-use kit including catchment materials placed under the 
toilet lid and a small spatula/spoon. For stool collection, the spatula/spoon will be 
dipped into the fecal material and 1-5 g (peanut sized sample) will be obtained 
and placed in a clean, screw-top vial. Another small sample will be obtained and 
placed in another identical vial containing ethanol with instructions to screw lid 
tightly and shake. To optimize stability of the specimens, the vials should be 
refrigerated until shipping or transport.  

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• 
Participants randomized to Medi For All will participate in an introductory session 
regarding a USDA Healthy Med-style Food Pattern. Participants will have access 
to a “toolbox” that includes education materials (e.g., food pattern tables 
according to daily caloric intake), recipes, grocery lists, group-based online 
dietary support, feedback, and reminders to encourage dietary change. Recipes 
and grocery lists can be individualized to a participant’s food budget and 
preferences. Materials will be available in print and Web-based.  This state-of-the 
art intervention will then use electronic feedback in the form of nudge messages 
designed to motivate participants to sustain or improve adherence to the 
intervention. They will also be offered 6L of extra virgin olive oil (EVOO) over the 
12-month study period, free of charge, if interested. Participants randomized to 
the fiber arm will be offered 6L of EVOO at the end of the 12-month study period, 
free of charge, if interested. 
5.2.2 Bi-Weekly Check-in 
Participants in the Medi For All intervention will be prompted every other week via a digital 
online platform (analog also available) to complete the 14-item Mediterranean Diet Assessment 
Score (MEDAS Score), slightly adapted for a US population, for the purpose of providing timely, 
individual feedback on diet adherence. The MEDAS Score will be calculated via the online 
digital platform and ranked according to 3 cutpoints; ≤7, 8–9, or ≥10. Patients will be 
encouraged to achieve a score of ≥10 which is considered high adherence. The platform will 
then offer feedback based on the levels of self-reported adherence to the diet including self vs. 
peer comparisons and support resources (such as group sessions and recipes). Nudge 
messages will utilize information from a baseline assessment of participants’ dietary attitudes 
and beliefs about which food groups within a Med-style food pattern they perceive to be most 
within their control.   
 
The extent of interaction with the online platform will be assessed bi-weekly; degree of 
adherence to the USDA Med-style food pattern; and engagement in dietician services will be 
assessed at quarterly intervals. Study staff will utilize a multi-modal (email, phone call, text, etc.) 
outreach for participants who fail to complete the MEDAS Score when prompted.  
 
5.2.3 Follow-up Assessments (3, 6, 9, and 12 months) 
In-person follow-up assessments will be prioritized around the participant’s clinical 
appointments. UW study staff will contact the participant to complete assessments prior to their 
scheduled blood draw/fecal specimen collection. This outreach will include a combination of 
phone, mail, and email as determined by the contact information provided by the participant. If a 
participant hasn’t completed their scheduled follow up assessment at the time of their visit, the 
study staff will attempt to complete it in person. The follow-up assessments are listed in detail in 
Table 1.  
In addition to the survey assessments, participants’ specimens will be collected at 6 and 12 
months following the same guidelines as in the baseline visit. Specimen collection will 
coordinate with clinical appointments whenever possible.  
 

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See section 5.2.1 for specimen collection instructions, which remain the same for follow-up time 
points. Participants will be reminded that they are welcome to contact their research coordinator 
at any time if any questions or concerns should arise. UW study staff will communicate with the 
research coordinator to ensure appropriate reporting is completed should an AE or complication 
be reported to them.  
Self-reported complications or AEs will be recorded. Any serious adverse events (SAEs) will be 
communicated to the relevant site study team to ensure appropriate reporting is completed. 
5.2.7 Participant Burnout and Optimizing Data Collection  
Participants may experience research assessment burnout due to the frequency and number of 
questions asked of them. To optimize complete data collection, research personnel should 
recognize a participant’s reluctance to complete the research assessment and request that the 
participant instead complete a sub-set of survey responses (minimal research assessment). In 
the event that a participant prefers to complete a minimal research assessment, research 
personnel should prioritize asking the research participant questions related to signs and 
symptoms of diverticulitis and aim to complete the Food Frequency Questionnaires. Study staff 
will be provided with a prioritization model to clarify what questions are high versus medium 
priority. Study staff should use their best judgment to determine how many additional survey 
questions should be asked. It is preferred to miss some responses at one research assessment 
time point rather than risk the participant withdrawing altogether due to research assessment 
burnout. 
5.3 Medical Record Review 
Time points 
Participants will have their EMR reviewed at ad-hoc time points if triggered by a survey 
response or if they have a diverticulitis event. Study staff will conduct an EMR review to assess 
the following: 
1. Complications for patients using the National Surgical Quality Improvement Program 
(NSQIP) definitions and protocol; and 
2. The following information related to diverticular disease:  
a. Indication for healthcare utilization  
b. Length of stay (if hospitalized);  
c. Surgery type, if applicable.  
 
 
As needed, chart review will be conducted if a patient reports an adverse event and further 
documentation is needed. 
 
Data Collection 
Data  will be  collected using the following forms: 
Form 
Description 

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Form Information  
Captures information about when the form was filled out (time point), and 
by whom  
Enrollment Form  
Completed at index visit only; captures basic demographics and treatment 
assignment data; medical history and cohort designation  
Healthcare Utilization Form  
Captures information about any visit (date, setting, treatments, 
medications)  
Adverse Events Form  
Captures information about adverse events at any time point  
If a participant seeks care at an outside hospital, the study team will work with the participant to 
obtain relevant information.  
5.4 Adverse Event Reporting 
The research coordinator will recommend that the participant contact their clinician for any 
worrisome concerns or symptoms.  
The study team will be responsible for initiating the Serious Adverse Event (SAE) reporting 
process if the reported patient concern is an SAE. See Section 9.0. 
5.5 Reasons for Withdrawal 
Participants may be withdrawn from the study for the following reasons: 
1. Participant desires withdrawal (reasons for withdrawal will be recorded); and 
2. Study investigator(s) deems it in the participant’s best interest to be withdrawn (reason 
for withdrawal recorded). 
3. Participant decides to pursue a different dietary plan that conflicts with study 
5.5.1 Handling of Withdrawals 
If the participant requests to be withdrawn from the study, they will be given appropriate 
treatment, but will not continue with scheduled study follow-ups. If the participant withdraws 
from the study and withdraws consent for disclosure of future information, no further evaluations 
will be performed and additional data will not be collected. The investigators may retain and 
continue to use data collected before withdrawal of consent.  
5.6 Compensation 
5.6.1 Participant Compensation 
Participants will be paid up to $150 for completing the research assessments described in Table 
1 (Section 5.0). Payment will be provided on a pro-rated, weighted fashion: $25 for the Baseline 
Assessment, up to $20 for Quarterly Assessments through 12 months. Participants will receive 
$10 for the biospecimen collection at baseline, $15 at 6 months and $20 at 12 months. 
Compensation will be distributed to participants by UW research staff unless other 
arrangements have been made.  

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5.7 Retention Activities 
5.7.1 Maintaining Contact 
Participants will be asked to confirm their contact information before beginning each research 
assessment. They will also be asked to confirm the contact information of family members, 
friends, and employers who may be asked to update the participant’s contact information should 
they be otherwise lost to follow-up. 
6.0 Outcome Assessments  
6.1 Primary and Secondary Outcomes  
Patient Reported Outcomes (PROs) will be assessed for adults using both generic and disease-
specific surveys utilizing the QoL instruments in Table 2. 
Table 2. Primary and secondary outcomes and intervention related process measures.  
Primary or Secondary 
Name of Outcome 
Specific Measure to Be Used 
Time Point 
Primary 
Willingness to enroll 
Enrolled/approached 
Baseline 
Primary 
Adherence to USDA Med-
Style Food Pattern 
USDA Med-style Pattern score 
calculated from the NASR FFQ.161 
Baseline, 6, 12 months 
Primary 
Participant retention 
Proportion enrolled and retained at 3, 6, 
9 and 12 months 
3, 6, 9 and 12 months 
Primary 
Interaction with on-line 
program 
Number of times accessed  
Bi-weekly 
Primary 
Engagement with nutrition 
services 
Number of sessions with dietician 
Quarterly 
Secondary 
Plasma, IL-6, IL-10, IL-1, 
fecal calprotectin 
Concentration 
Baseline, 6, 12 
months 
Secondary 
Diverticulitis events 
Self-reported (presumed), subset of 
those resulting in healthcare utilization 
(e.g., hospitalization, surgery).  
Quarterly 
Secondary  
NSQIP-defined 
complications, a subset of 
which are serious adverse 
events to be reported to 
ISM 
Standardized assessment-serious 
events defined as death, cardiac 
arrest, myocardial infarction, 
pneumonia, progressive renal 
insufficiency, acute renal failure, 
pulmonary embolism, deep vein 
thrombosis, return to operating 
room, serious site infections 
Quarterly 
Secondary 
DVQOL65 
A 17-item questionnaire that assesses 
four domains: symptoms, concerns, 
emotions, and behavior changes related 
to diverticulitis.  
Baseline, 6, 12 months 
Secondary  
GIQLI159 
A 36-item questionnaire that assesses 
five domains: gastrointestinal symptoms, 
physical function, emotional well-being, 
social well-being, and perception of 
medical treatment measured by a single 
item question.  
Baseline, 6, 12 months 

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Secondary 
IPAQ Short Form169 
A validated 7-item questionnaire: 
moderate and vigorous physical activity, 
walking, and sitting in the past 7 days 
Baseline, 6, 12 months 
Secondary  
Time in healthcare 
Days missed from work/school, 
ED/hospital encounters, diverticulitis-
related diagnostic/therapeutic 
interventions 
3, 6, 9 and 12 months 
Secondary 
Self-reported weight 
Self-reported weight 
Baseline, 6, 12 months 
6.2 Clinical Complications 
Death, SAEs, and complications (reported as AEs via EMR review) will be assessed and 
recorded through the study surveillance period. Complications (reported as AEs) will incorporate 
NSQIP standards and definitions as well as events related to antibiotic-related complications.  
Table 3: Summary of SAE/AEs 
 
Serious Adverse Events 
 
Adverse event 
Death 
 
 
Life-threatening event 
 
CVA or stroke 
 
MI requiring treatment or cardiac arrest 
Myocardial infarction 
Atrial arrhythmia 
Unplanned admit to ICU 
 
Acute Renal Failure (requiring dialysis) 
Major UTI (e.g., pyelonephritis) 
Urinary retention 
Acute Renal Failure (no dialysis) 
Progressive renal insufficiency 
C. difficile colitis (requiring colon resection) 
 
Pulmonary embolism requiring therapy 
DVT/PE requiring treatment 
Coma >24 hours 
 
Septic shock (requiring pressors) 
Sepsis 
Bleeding requiring transfusion 
 
Newly infected prosthetic graft infection  
 
Mechanical ventilation >48 hours 
Tracheal reintubation/tracheostomy 
Colostomy or ileostomy 
NG tube replacement (non-routine) 
Bowel obstruction 
Ileus 
 
Organ/space infection (including peritonitis) 
Surgical site infection 
Intra-ab Abscess 
Severe dehydration 
Hernia 
Malignant hyperthermia 
Pneumonia 
Other infection 
Other post-op occurrence: unspecified 
Other non-operative intervention: unspecified 
Unplanned (re)operative intervention during index 
C. difficile colitis (not requiring colon resect) 

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Other life threatening event 
 
 
Hospitalization* 
 
*Exception to hospitalizations that do not need to be reported as an SAE: 
• 
Planned, elective surgical procedures 
• 
Labor and delivery 
• 
Psychiatric hospitalizations 
7.0 Data Management and Information Security 
7.1 Data Management 
Data management will be almost exclusively web-based, with paper-based surveys available as 
needed for mailing. The UW CCC will support an https-secured web page that 
provides a centralized location for public information about the project for potential subjects, 
investigators, and institutional agencies. The web page will contain a link to the project portal 
(https://uwdcc.org/portal/impede). Study personnel will log on to the private portal on the 
study web page with individual single sign-on (SSO) authentication usernames and 
passwords to securely perform study data management activities. An overview of the DCC 
responsibilities and data management system is presented below. 
 
Study Integration: The UW DCC team has extensive experience developing Application 
Programming Interfaces (APIs), which allow multiple software programs to seamlessly interact 
and communicate with one another in a simple and intuitive interface. The web portal API will 
serve as the wrapper for all data management tools and software utilized in the IMPEDE Trial, 
including: study ID assignment, screening, centralized image storage (if needed), prospective 
data collection forms and surveys, and study operations reporting. Screening and eligibility will 
be determined centrally through the portal and all subjects screened under the trial protocol 
will be assigned a sequentially generated study participant ID. The DCC will maintain a 
REDCap database to centrally and securely store patient information, with distinct data 
access groups for clinical recruitment sites. 
 
Electronic Data Capture: The UW DCC supports its own installation of REDCap, which is 
software specifically designed for electronic data capture that we have used successfully in 
several multi-site clinical trials. REDCap features include differentiated user roles and 
privileges, password and user authentication security, electronic signatures, SSL encryption, 
and comprehensive auditing to record and monitor access and data changes 
(http://www.project- redcap.org/software.php). REDCap will serve as the architectural 
backbone for all data captured prospectively in this study, with all data linked by study subject 
ID. The web-based data management portal allows for three participant contact methods: 
research coordinator data entry; electronic survey; or computer-assisted telephone 
interviewing (CATI). All survey modalities are customized to incorporate project logos and 
information to increase participant recognition and response rate. Furthermore, surveys may 
be distributed on any time schedule (e.g., monthly for pain and disability), and in any 
designated survey format. 
 
All study questionnaires completed on paper will be reviewed by study staff for accuracy and 
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7.1.2 Data Quality Monitoring  
The CCC and DCC will review participant enrollment, reasons for exclusion, 
participant demographics, and follow-up rates by site in order to assess proximity to enrollment 
targets, site performance, and protocol adherence.  
The DCC will perform in-line quality assurance checks by using field masking, range 
checks, and real-time warning messages. Missing data reporting and other customized 
reports will be developed by the DCC in collaboration with the CCC and recruitment team in 
order to facilitate efficient work- flow and high-quality data capture. A subset of key 
personnel from the DCC and CCC will serve as an operations committee and review quality 
control reports on a weekly or biweekly basis, though quality control reports will be made 
available on a daily basis. CRF-specific follow-up rates will be tabulated on a nightly basis 
and reviewed during the weekly check-in meeting with each clinical recruitment site. 
Nightly, the DCC will generate graphs that monitor CRF-specific follow-up rates over time 
as well as data quality trigger rates over time to prospectively monitor potential issues that 
may develop gradually or acutely over time. A data query resolution dashboard will be 
available to each site on a continuous basis. In similar studies, we have found that 
establishing a fixed-day for a monthly review of all unresolved queries is an adequate 
balance of time to resolution and alert fatigue.  
On a nightly basis, the DCC will also generate a comprehensive data quality report to flag 
unusual data and will be made broadly available to the study team. Research staff at the 
recruitment sites will be asked to review each outstanding query and respond with “confirmed” 
or “corrected” and may provide a comment beside each query to note relevant details. Each 
query will be closed by the DCC protocol operations specialist. 
7.2 Information Security 
All participant data collected on paper will be stored in locked file cabinets located in the site 
research offices.  
All data entered onto UWMC laptop/desktop computers sites will be secured via our Information 
Security infrastructure.  Information Security at UWMC is multi-layered and includes physical 
security measures, network security measures, managed servers, and desktop/laptop 
computers with authentication and authorization controls. All systems are designed and 
implemented to properly secure restricted or confidential information, including PHI, from 
inadvertent or unauthorized disclosure. All policies and procedures adhere to federal, state, and 
health system requirements. Servers, desktops, and laptops are under active management by 
an Integrated Technology Services Group (ITSG) at each participating site. In addition to 
maintaining anti-virus and firewall installations, the ITSG audits patch status of systems 
connected to the network and installs any missing updates or patches found. Servers have 
defined change control periods for operating system maintenance but are patched or updated 
outside the schedule as necessary to address threats. Anti-virus software is configured to 
update daily. The host-based firewalls restrict inbound connections to only the subnets where 
department workforce resides or that are needed for firewall administration. The firewall rule set 
on the dedicated server is further restricted to the network subnets. A specific Windows domain 
account is required to access computers. Domain passwords must be at least 8 characters in 
length, conform to complexity rules, and be changed at least every 120 days. Database systems 
and security policies are established and overseen by administrative staff members who do not 
require research funding. 
 

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REDCap: 
All data, including PHI, names, and contact information will be entered onto a HIPAA and 21 
CFR Part 11- compliant database. Participant PHI, including names, contact information, health 
information, will be entered onto this database. Only study staff will have access to the database 
and each study staff member will be given separate access only after completing study-required 
trainings.   
 
8.0 Statistical Analysis Plan and Stopping Rules  
The IMPEDE Trial is based on the Practice-Based conceptual model for comparative 
effectiveness;162 “there is a comprehensive set of patient, treatment, and outcome variables, 
and [that by] analyzing them we identify treatments associated with better outcomes for specific 
types of patients”.  The strategy for utilizing this model is that a lack of evidence related to the 
effectiveness of interventions to prevent recurrent diverticulitis is limiting treatment options and 
leading to excessive use of preventative colon resections. Also, structural barriers (e.g., 
affordability of Medi For All) may result in differential acceptance of medical management 
among historically disadvantaged groups.   
8.1 Allocation and Randomization 
The Data Coordinating Center (DCC) will generate and maintain randomization 
assignments. Randomization assignments (2:1 randomization; N=50 to USDA Med-style Food 
Pattern (Medi For All): N=25 to standardized guidance on fiber intake) will be generated 
separately by site using block randomization randomly permuted block sizes for each site. 
Research coordinators will randomize eligible patients using a web-based portal that provides the 
next available assignment once an eligible patient consents for study participation. Study 
participants will be unblinded to the assigned intervention group (USDA Med-style Food Pattern 
or standardized guidance on fiber intake), but CERTAIN investigator team and research staff 
involved in data collection will be blinded to intervention status.  
 
8.2 Study Feasibilities Measures  
We will assess willingness to randomize as the number of eligible patients that randomized 
divided by the number of eligible patients (Aim 1). We will provide descriptive statistical 
summaries of time to complete survey materials, time interacting with the USDA Med-style Food 
Pattern platform, and changes in estimated weekly meal expenses. These data will be used to 
inform the future large-scale trial including the number of study sites, recruitment rate/study 
duration and amount of coordinator effort. The rate of willingness to randomize is unknown but 
as long as it is at least 20% our study will be successful. We would also want at least 50% of 
those willing to randomize to be willing to give a blood sample and at least half of those to give 
stool. 
8.3 Treatment Fidelity and Adherence:   
The Fred Hutch FFQ is a standard method of dietary intake assessment that has been used in 
several large-scale cohort studies including the Women’s Health initiative.153, 154 The degree of 
adherence with the USDA Healthy Med-style Food Pattern (Aim 1) will be ascertained by 
assigning point scores based on the estimated daily amounts of the recommended food groups 
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recommendations and partial points to diets that do not. Given that the USDA Healthy Med-style 
Food Pattern provides recommended amounts for relevant food groups, the adherence score 
will be based on food consumption data normalized per 100 kcal, much along the lines of the 
Healthy Eating Index (HEI). The HEI is a 100-point score that measures adherence to the DGA 
and is the standard measure of diet quality in the US. This approach represents an advance 
over the 14-item food frequency MEDAS score, which ranks adherence to the Med-style diet 
pattern using 3 cutpoints: ≤7, 8–9, or ≥10 (maximal adherence).145 The data derived will help us 
understand the central tendency and variability in Med-style food pattern scores which is critical 
for determining the sample size of a future trial. Degree of adherence to the different aspects of 
the medical management regimen will also be used to define per-protocol analysis and be 
considered as potential mediators and/or effect modifiers in explanatory regression models 
8.4 Signal Assessment for Biomarkers:  
We will use a linear mixed effects regression model to compare IL-6, IL-10, IL-1, and fecal 
calprotectin measures at baseline, 6, and 12 months after randomization between the two groups. 
We focus our statistical analysis on IL-6 for which there are preliminary data specific to 
diverticulitis. The linear mixed effects model will be structured as a longitudinal analysis of 
covariance, allowing for both cross-sectional and longitudinal comparisons of serum biomarkers 
between intervention groups. From the model, we will estimate the mean difference and 95% 
confidence interval in time-averaged IL-6 by averaging the time-specific intervention group 
differences. The longitudinal analysis of covariance model will adjust for intervention (USDA Med-
style pattern versus standardized guidance on fiber intake), recruitment site, and baseline IL-6 as 
fixed effects: IL6 (𝑡)~ 𝛽0 + 𝛽1 ∙𝐼𝑛𝑡𝑒𝑟𝑣𝑒𝑛𝑡𝑖𝑜𝑛 + 𝛽2 ∙𝑆𝑖𝑡𝑒+ 𝛽3 ∙𝐼𝐿6(𝑡= 0), for t = 6 and 12  
months. Follow-up time-point specific differences in mean IL-6 between intervention groups will 
be estimated by a statistical interaction term between time and intervention status in a second 
model. Finally, experience in other ongoing trials has shown that serum biomarkers are often 
positively skewed. We will therefore log-transform IL-6 measurements (and all skewed serum 
biomarkers) throughout all statistical analyses, and exponentiate model coefficients (as 
appropriate) for interpretation. Sex and gender (if different from sex assigned at birth) will be 
considered as exploratory variables in assessing the relationship of the diet-behavioral 
intervention and the primary and secondary outcomes. Analyses of IL-10, IL-1, and fecal 
calprotectin and patient-reported outcomes will mirror the analyses of IL-6, with the primary goal 
of estimating plausible intervention effect sizes and standard deviations with the goal of informing 
a larger phase 3 clinical trial. Formal statistical testing will not be conducted and therefore no 
multiple testing correction will be employed for analyzing multiple serum biomarkers. Sex as a 
biological variable will be included in an exploratory analysis of all biomarker models. The study 
of serum and stool biomarkers will also inform the feasibility of performing a biomarker sub-aim 
within a future phase 3 trial.  
8.5 Secondary Statistical Analyses 
Binary and categorical endpoints (e.g., adverse events and complications) will be tabulated by 
intervention group. Time in healthcare will be summarized by group using medians and 
interquartile ranges, and differences between intervention groups will be summarized using 95% 
confidence intervals generated from generalized linear regression models appropriate for each 
type of outcome (e.g., binary, count, continuous, etc.). To examine the sensitivity of adherence 
to the Med-style Food Pattern on changes in serum biomarkers, we will modify the primary 
analytic model described for Aim 2 by separately adjusting for a binary indicator of adherence 
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mediation analyses to explore the extent to which changes in serum biomarkers over time are 
mediated through intervention-induced changes in weight and physical activity. 
  
8.6 Missing Data  
Participants who do not complete some or all of the baseline and follow-up questions will 
have missing data points.  As summarized in the NEJM guidance,163 we will employ three primary 
strategies that are recommended to address missing data. First, the DCC will work in conjunction 
with the CCC to minimize the amount of missing data since prevention of missing data is 
preferable to any attempted analysis correction.  We will document all reasons for missing data.  
Second, we will use inverse probability weighting164 to inflate the weights of cases that are under-
represented in the analysis due to selective attrition and/or non-participation. A descriptive 
analysis that characterizes enrolled participants who do not provide data due to attrition will be 
conducted, and we will use observed covariates to construct a weighted model using logistic 
regression. Third, the strategy that we used for two recent primary trial publications102, 165 and 
which we will adopt for our primary analysis is the use of 10-fold multiple imputation to assess the 
robustness of the results when missing data are imputed and allowing all participants to be 
included in intent-to-treat analysis. Our primary approach is to use multiple imputation since it 
provides flexibility in inclusion of relevant baseline and follow-up data. We will also impute missing 
data under both pessimistic and optimistic scenarios to provide bounds on the statistical 
uncertainty.  
8.7 Sample Size and Statistical Power  
Using 2:1 randomization, we will enroll 50 patients into a USDA Med-style Food Pattern and 25 
patients to receive standardized guidance on fiber intake. The analytic aim of this study is to 
inform potential effect sizes and variance estimates toward the ultimate goal of conducting a 
definitive phase 3 randomized trial. While 1:1 randomization is more statistically efficient when 
group variances in outcome are similar, we plan to enroll more participants into the USDA Med-
style food pattern intervention to strengthen the precision of estimates of adherence and patient-
reported response. Since statistical testing will not be formally conducted, statistical power was 
not a primary motivation for sizing for this pilot study.166 However, enrollment of 50 study 
participants in the USDA Med-style Food Pattern intervention allows a 95% one-sided confidence 
interval for the intervention adherence rate to exclude rates less than 0.70 if the observed 
adherence rate is 0.80 or higher in this pilot study. 
8.8 Data and Safety Monitoring Plan (DSMP) 
Given the minimal risk nature of this study, monitoring will be conducted by the DCC and an 
Independent Safety Monitor (ISM). The ISM will review patient-reported outcomes as they 
accrue over time but will not be responsible for making interim decisions based on observed 
efficacy (or lack thereof). ISM and the DCC will put together a report according to accrual (at 
50%, 75%, and full enrollment). The study team will review and report to the IRB and sponsor 
as required.   

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9.0 Study Related SAEs 
9.1 Identification of SAEs 
Randomized participants will be monitored for SAEs throughout their study surveillance period 
(enrollment through twelve months). The occurrence of an SAE may come to the attention of 
study personnel during study follow-up phone interview or by a study participant calling the 
study team or presenting for medical care. Study staff will use the EMR to fill out the SAE form. 
The PI will then complete the form and sign the form. The SAE form will then be submitted to 
the DCC who will provide it to the ISM. The ISM will review the SAE form and ask the study 
team for additional clarification or specification as he/she sees necessary.  
9.2 SAE Reporting 
Life-threatening complications or SAEs are a very rare possibility with both intervention arms. 
SAEs are defined as one of the following conditions (also listed in section 6.2.): 
1. Death during the period of protocol-defined surveillance; 
2. Life-threatening event related to the treatment or significant disability/incapacity related 
to the treatment; or  
3. Inpatient hospitalization except for:  
o Planned, elective surgical procedures 
o Labor and delivery 
o Psychiatric hospitalizations 
 
All SAEs will be: 
1. Recorded on the appropriate SAE case report form; 
2. Adjudicated by the ISM; 
3. Followed until satisfactory resolution or until the study investigators deem the event to be 
chronic or the participant to be stable;  
4. Reported to the study team and IRBs per their reporting guidelines; and 
5. The study investigators will also report SAEs to the funder when appropriate. 
9.3 Assignment of SAEs as Treatment Related 
The determination of whether an SAE is related to the treatment will be assessed by the ISM 
and site lead, based on supporting documentation provided by the research coordinators case 
reports or in consultation with the treating physician, as needed.  
10.0 Reporting Procedures 
SAEs will be captured on the appropriate source document. Information to be collected includes 
event description, date event occurred, date study personnel became aware of the event, 
investigator assessment of event severity, event outcome, and relationship to study treatment. 
All SAEs will also have information on action taken at time of report, date SAE resolved, 
outcome at time of SAE report, and, depending on the site, whether the IRB has been notified.  
For SAEs, the date of resolution (or when the event is deemed stable/chronic) will be noted on 
the appropriate case report form.  
11.0 Protocol Violations and Deviations 
A protocol violation is any non-compliance with the clinical trial protocol or Good Clinical 
Practices. The noncompliance may be either on the part of the participant, the investigator, or 
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are 1) Participant enrolled but did not meet inclusion criteria, 2) Participant enrolled but 
exclusion criteria present or eligibility criteria not met, 3) Consent not obtained in accordance 
with IRB guidelines, 4) Randomization failure  
A protocol deviation is a smaller digression from study protocol. Deviations are monitored with 
consideration for protocol amendment should it become clear that the original protocol was too 
inflexible.  
It is the responsibility of the research staff to use continuous vigilance to identify and report 
violations and deviations within 5 working days of identification of the protocol 
violation/deviation.  
All violations and deviations from the protocol will be addressed in study participant source 
documents. A completed copy of the Protocol Violations and Deviation Form will be maintained 
in the regulatory file, as well as in the participant’s study chart. Protocol violations and 
deviations will be sent to the local IRB per their guidelines. The study staff will be responsible for 
knowing and adhering to their IRB requirements. 
12.0 Protection of Human Participants 
We expect that most patients will have good baseline health but will not exclude patients with 
most stable and chronic medical conditions, other than those characteristics described in the 
exclusion criteria.   
Patients of childbearing potential will be excluded if they have a positive pregnancy test 
documented prior to enrollment. Incarcerated patients will be excluded. There is no evidence 
from prior studies to suggest there will be differences in intervention effect among sex/gender or 
racial/ethnic subgroups.  
The risks and benefits for participants enrolled in this trial are appropriately balanced and 
minimal. The primary risks of this study are loss of patient privacy, loss of confidentiality, study 
burden, and risk of bleeding, bruising, or discomfort during the specimen collection.  
Loss of confidentiality could occur if the study database were breached. This risk will be low 
because of numerous steps to protect confidentiality. Approaching patients about enrollment in 
the clinic poses a risk to privacy. We anticipate this risk to be low. Patients will be approached in 
a private clinic room. To avoid threats of coercion, providers will be educated but not directly 
involved with recruitment of patients. We expect the risks of discomfort or anxiety related to 
study questionnaires to be low. There is a small risk of bleeding, bruising, or discomfort at the 
site of the blood collection. Attention will be taken to apply pressure following the procedure to 
reduce bleeding. There is also a small risk of fainting or feeling faint during a blood draw. There 
is minimal discomfort associated with collection of the fecal (stool) sample. We expect these 
specimen collection risks to be low.  
Study participants could benefit from participation in this study by learning how to increase their 
dietary fiber intake or how to integrate tools from the Medi For All diet and behavioral 
intervention, potentially helping their diverticulitis symptoms.  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of both interventions will be provided to the participants using 
standardized materials. Consent forms describing in detail the study procedures and risks will 
be given to the participant and documentation of informed consent will be required prior to 
completing study assessments.  

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Consent forms will be IRB-approved and the participant will be given sufficient time to read and 
review the document. They will be specifically asked if they have any questions or concerns, 
which will be addressed, or would like more time to consider their participation, which will also 
be provided. The study team will explain the research study to the participant and answer any 
questions that may arise. The participants will sign the informed consent prior to completing any 
study related activities. The participants may withdraw consent at any time throughout the 
course of the study. A copy of the informed consent will be given to the participants for their 
records. The rights and welfare of the participants will be protected by emphasizing to them that 
they will still be able to receive medical care at the facility if they decline to participate in this 
study. 
Participant confidentiality is strictly held in trust by the participating investigators and their staff.  
 
13.0 References 
 
1. 
Peery AF, Crockett SD, Barritt AS, et al. Burden of Gastrointestinal, Liver, and Pancreatic 
Diseases in the United States. Gastroenterology 2015;149:1731-1741 e3. 
2. 
Peery AF, Dellon ES, Lund J, et al. Burden of Gastrointestinal Disease in the United 
States: 2012 Update. Gastroenterology 2012;143:1179-1187 e3. 
3. 
Bharucha AE, Parthasarathy G, Ditah I, et al. Temporal Trends in the Incidence and 
Natural History of Diverticulitis: A Population-Based Study. Am J Gastroenterol 
2015;110:1589-96. 
4. 
Stollman N, Smalley W, Hirano I, et al. American Gastroenterological Association Institute 
Guideline on the Management of Acute Diverticulitis. Gastroenterology 2015;149:1944-9. 
5. 
Gervaz P, Inan I, Perneger T, et al. A Prospective, Randomized, Single-Blind Comparison 
of Laparoscopic Versus Open Sigmoid Colectomy for Diverticulitis. Ann Surg 2010;252:3-
8. 
6. 
Klarenbeek BR, Veenhof AA, Bergamaschi R, et al. Laparoscopic Sigmoid Resection for 
Diverticulitis Decreases Major Morbidity Rates: A Randomized Control Trial: Short-Term 
Results of the Sigma Trial. Ann Surg 2009;249:39-44. 
7. 
Raue W, Langelotz C, Paolucci V, et al. Problems of Randomization to Open or 
Laparoscopic Sigmoidectomy for Diverticular Disease. Int J Colorectal Dis 2011;26:369-
75. 
8. 
Strate LL, Peery AF, Neumann I. American Gastroenterological Association Institute 
Technical Review on the Management of Acute Diverticulitis. Gastroenterology 
2015;149:1950-1976 e12. 
9. 
Aldoori WH, Giovannucci EL, Rockett HR, et al. A Prospective Study of Dietary Fiber 
Types and Symptomatic Diverticular Disease in Men. J Nutr 1998;128:714-9. 
10. 
Cao Y, Strate LL, Keeley BR, et al. Meat Intake and Risk of Diverticulitis among Men. Gut 
2018;67:466-472. 
11. 
Crowe FL, Appleby PN, Allen NE, et al. Diet and Risk of Diverticular Disease in Oxford 
Cohort of European Prospective Investigation into Cancer and Nutrition (Epic): 
Prospective Study of British Vegetarians and Non-Vegetarians. BMJ 2011;343:d4131. 
12. 
Ma W, Nguyen LH, Song M, et al. Intake of Dietary Fiber, Fruits, and Vegetables and Risk 
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