Scaling Colorectal Cancer Screening Through Outreach, Referral, and Engagement (SCORE): A State-Level Program to Reduce Colorectal Cancer Burden in Vulnerable Populations
Phase: NA
Conditions: Colorectal Cancer
Sponsor: UNC Lineberger Comprehensive Cancer Center

LINEBERGER COMPREHENSIVE CANCER CENTER 
Health Services Research 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
December 3, 2021 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC2056:  Scaling Colorectal Cancer Screening Through Outreach, Referral, and 
Engagement (SCORE): A Program to Reduce Colorectal Cancer Burden in 
Vulnerable Populations 
 
 
Principal Investigator 
Daniel Reuland, MD, MPH 
UNC Lineberger Comprehensive Cancer Center 
200 N Greensboro Street, Suite C-1, Campus Box 3345 
Carrboro, NC  27510 
919-391-7775 (phone)  
Email: daniel_reuland@med.unc.edu 
 
Principal Co-Investigator  
N/A 
 
Co-Investigator(s) 
Alison Brenner, PhD, MPH 
Seth Crockett, MD, MPH 
Leah Frerichs, PhD 
Kristen Hassmiller Lich, PhD, MHSA 
Jennifer Leeman, DrPH, MPH 
Shana Ratner, MD, FACP 
Catherine Rohweder, DrPH 
Karyn Stitzenberg, MD, MPH, FACS 
Xianming Tan, PhD 
Stephanie Wheeler, PhD, MPH 
 
Biostatistician  
Xianming Tan, PhD 
 
 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source:  Colon Cancer Coalition and National Cancer Institute 
 
Version Date:   v5 11/18/2021 

LINEBERGER COMPREHENSIVE CANCER CENTER 
Health Services Research 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
December 3, 2021 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC2056:  Scaling Colorectal Cancer Screening Through Outreach, Referral, and 
Engagement (SCORE): A Program to Reduce Colorectal Cancer Burden in 
Vulnerable Populations 
 
 
Principal Investigator 
Daniel Reuland, MD, MPH 
UNC Lineberger Comprehensive Cancer Center 
200 N Greensboro Street, Suite C-1, Campus Box 3345 
Carrboro, NC  27510 
919-391-7775 (phone)  
Email: daniel_reuland@med.unc.edu 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name:__Daniel Reuland_____________________ 
 
PI Signature: ___________________ 
 
Date:___11/18/2021_________________ 
 
 
 
Version Date:__v5 11/18/2021_____________________ 
 

LCCC2056 
 
CONFIDENTIAL 
PI:  Reuland 
 
UNIVERSITY OF NORTH CAROLINA 
Version/Date:  v5 11/18/2021 
 
December 3, 2021 
 
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TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE .................................................................1 
1.1 
Study Synopsis .....................................................................................................1 
1.2 
Background ..........................................................................................................2 
1.3 
Purpose and Rationale ..........................................................................................3 
2.0 
STUDY OBJECTIVES AND ENDPOINTS ........................................................4 
2.1 
Primary Objective (Aim 1) ..................................................................................4 
2.2 
Secondary Objectives ...........................................................................................4 
3.0 
PATIENT ELIGIBILITY .....................................................................................5 
3.1 
Inclusion Criteria .................................................................................................5 
3.2 
Exclusion Criteria ................................................................................................6 
4.0 
STUDY PLAN ........................................................................................................6 
4.1 
Schema .................................................................................................................7 
4.2 
Duration of Study ...............................................................................................10 
4.3 
Study Details ......................................................................................................10 
4.3.2 
Randomization ...................................................................................................10 
4.4 
Expected Risks ...................................................................................................15 
4.5 
Removal of Patients from Protocol ....................................................................15 
5.0 
TIME AND EVENTS TABLE ............................................................................15 
5.1 
Time and Events Table ......................................................................................16 
6.0 
UNANTICIPATED PROBLEMS ......................................................................17 
6.1 
Definition ...........................................................................................................17 
6.2 
Reporting............................................................................................................17 

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7.0 
STATISTICAL CONSIDERATIONS ...............................................................17 
7.1 
Study Design ......................................................................................................17 
7.2 
Sample Size and Accrual ...................................................................................18 
7.3 
Data Analysis Plans ...........................................................................................19 
7.4 
Data Management/Audit ....................................................................................22 
8.0 
STUDY MANAGEMENT ...................................................................................22 
8.1 
Institutional Review Board (IRB) Approval and Consent .................................22 
8.2 
Required Documentation ...................................................................................23 
8.3 
Registration Procedures .....................................................................................23 
8.4 
Adherence to the Protocol ..................................................................................23 
8.5 
Amendments to the Protocol ..............................................................................24 
8.6 
Record Retention ...............................................................................................24 
8.7 
Obligations of Investigators ...............................................................................25 
9.0 
REFERENCES .....................................................................................................25 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
Main Trial (ages 50-75) 
This study assesses the effectiveness, feasibility, acceptability, and cost-
effectiveness of mailed fecal immunochemical test (FIT) screening, compared to 
usual care, among patients aged 50-75 served by Roanoke Chowan Community 
Health Center (RCCHC) and Blue Ridge Health (BRH) who are due for colorectal 
cancer screening (CRC) according to US Preventive Services Task Force 
(USPSTF) guidelines for improving CRC screening rates. It includes formative 
work to develop and refine the intervention implementation and outcomes 
measurement, as well as a randomized controlled trial. We will work with 
RCCHC and BRH to identify up to 4,000 patients who are potentially eligible for 
CRC screening. Patients will be randomized to the following two arms: usual care 
(Arm 1) and mailed FIT plus up to two mailed reminders to complete the FIT 
(Arm 2). Current usual care at RCCHC and BRH consists of a visit-based FIT 
distribution approach. We hypothesize that we will observe higher CRC screening 
completion rates among patients assigned to study Arm 2. Our economic 
outcomes are the per-arm total costs and the incremental cost-effectiveness of 
intervention versus usual care arms, measured in cost per person screened for 
CRC.  
 
Additional sub-study (ages 45-49)  
This sub-study also will identify approximately 450 additional patients aged 45-
49 served by RCCHC who are newly eligible for CRC screening because of 
updated USPSTF recommendations, which were recently revised in May 2021 to 
include this age group.We will work with RCCHC to identify the sample of 
patients aged 45-49 who are potentially eligible for CRC screening under these 
new recommendations. In this sub-study we will examine CRC screening (as 
measured by mailed FIT return rates), but not economic outcomes.  
 
We will evaluate our mailed outreach intervention in this newly eligle age group 
in two ways: First, we will compare screening rates in this age group cohort at a 
single clinic before and after conducting mailed FIT outreach intervention. 
Second, we will conduct a nested trial conducted in this single site cohort to 
assess the impact of the appearance of the envelope that contains the FIT on FIT 
return. Patients will be randomized to one of two arms: an experimental arm 
(padded envelope with tracking label and sticker message) and an active 
comparator arm (plain envelope without tracking label or sticker message). Both 
arms will receive the same envelop contents (FIT and instructions) as described 
above. We hypothesize that we will observe higher FIT completion rates among 
patients assigned to the experimental arm.  
 

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1.2 
Background 
CRC is the third most common cancer diagnosis and the second leading cause of 
cancer death in the United States (U.S. Cancer Statistics Working Group, 2013). 
Screening is effective in reducing CRC incidence and mortality (United States 
Preventive Services Task Force et al., 2016), but CRC screening is underused. 
Although CRC screening has increased since 2002, current screening rates remain 
modest, with only 68% of age-eligible adults in North Carolina up-to-date with 
screening in 2012 (Centers for Disease Control and Prevention [CDC], 2013). 
 
In North Carolina, as in many parts of the United States, screening is substantially 
underused in vulnerable and marginalized populations (CDC, 2013). CRC burden 
is particularly high in certain regions of the state. A recent study identified one 
such region (“hotspot”) in northeastern North Carolina with elevated CRC 
mortality rates compared to national averages (Siegel et al., 2015). Hertford 
County, in which RCCHC is located, is one of 11 counties in North Carolina that 
is included in this “hotspot.” This “hotspot” is a priority area for interventions to 
increase CRC screening. The western region of North Carolina, in which BRH is 
located, is a mountainous area characterized by rural, largely white, Appalachian 
communities as well as large and growing communities of Hispanic immigrants 
who work in the agricultural sector (e.g., the Christmas tree industry). Both 
regions afford a critical opportunity to address disparities in CRC screening and 
disease burden.  
 
Increasing CRC screening among vulnerable populations will be crucial to reach 
the Healthy People 2020 and National Colon Cancer Roundtable goals of having 
70.5-80% of the age-eligible population up-to-date with CRC screening (National 
Colorectal Cancer Roundtable, n.d.; Office of Disease Prevention and Health 
Promotion, 2014). 
 
The United States Preventive Services Task Force (2016) recommends several 
stand-alone tests to screen for CRC, including colonoscopy every 10 years and 
fecal blood tests such as fecal immunochemical testing (FIT) annually, for 
patients ages 50-75 years, and more recently, patients ages 45-49 years (USPSTF, 
2021). Further, the CDC Community Guide to Prevention recognizes several 
effective and cost-effective means of increasing CRC screening, including 
interventions to decrease structural barriers (such as mailed, at-home stool testing) 
(Sabatino et al., 2012). Mailed programs of FIT have shown promise as an 
effective means of increasing screening use, including for vulnerable populations. 
One program showed that a mailed FIT-based outreach program could increase 
screening by nearly 30 percentage points among vulnerable patients in a safety net 
system in Texas (Gupta et al., 2013). Several other studies have found mailed 
fecal testing programs to be effective in increasing screening rates in insured 
populations (Church et al., 2004; Kempe et al., 2012; Levy et al., 2012).  
However, researchers and experts attending a CDC-sponsored Mailed FIT 
Summit in June 2019 identified the challenge of getting patients to “open the 
envelope” (Gupta et al., 2020). Summit participants suggested making the 

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packaging eye-catching to increase the likelihood that patients will open the 
packet and respond. Additional research is needed to better understand how best 
to engage patients in mailed FIT outreach and prompt them to “open the envelope. 
To date, such programs have not been implemented and tested in North Carolina’s 
vulnerable populations. 
 
Through this study, we will work with federally qualified health centers (FQHCs; 
RCCHC and BRH) to help increase the rate of CRC screening completion among 
their screening-eligible patients, including underserved adults. Approximately 
54% of screening-eligible patients aged 50-75 at RCCHC are up-to-date with 
CRC screening, leaving about 46% (n = ~3,100) patients aged 50-75 due for 
screening and thus potentially eligible to be randomly selected for this study. 
Approximately 67% of screening-eligible patients aged 50-75 at BRH are up-to-
date with CRC screening, leaving about 33% (n = ~2,600) patients eligible to be 
selected for this screening study.  
 
In addition, we will work with RCCHC to promote uptake of CRC screening 
among their screening-eligible patients aged 45-49. We will enroll all patients 
who are aged 45-49 and meet study eligibility criteria. Based on a recent query of 
RCCHC’s EHR, there are approximately 450 patients aged 45-49 who currently 
are eligible for CRC screening. We will compare screening completion before and 
after mailed FIT outreach and will assess the impact of envelope appearance on 
FIT return. 
1.3 
Purpose and Rationale 
Main Trial (ages 50-75) 
Although the effectiveness of mailed FIT-based screening programs has been 
demonstrated within organized health systems (Daly et al., 2010; Levy et al., 
2012), it is unclear whether this approach is effective, feasible, acceptable, and 
cost-effective in community health centers, which tend to be under-resourced. The 
purpose of this study is to assess whether a mailed FIT outreach program can 
improve CRC screening completion among patients aged 50-75 served by 
RCCHC and BRH. Using a randomized controlled trial study design, our study 
team will randomly assign patients to the following arms:  
 
 
Arm 1 (control): Usual care 
 
Arm 2 (intervention): Mailed FIT plus up to 2 reminder letters  
 
We will compare the two arms on CRC screening completion rates. We will also 
assess and compare implementation outcomes for the intervention arm (Arm 2), 
including whether the mailed FIT outreach program was feasible, acceptable, and 
cost-effective. 
 
Sub-study (ages 45-49) 

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In patients aged 45-49 (newly eligible per updated USPSTF 
recommendations), we will evaluate: 1) screening completion before and 
after the mailed FIT outreach, and 2) FIT return comparing two types of 
envelopes for the mailed FIT outreach.  
To assess the effect of the two types of envelopes on FIT return, we will 
randomly assign patients to one of two arms as described below. 
Arm 1 (experimental arm): FIT is packaged in a padded envelope with a 
sticker message (e.g., “Important information from your doctor”) and a 
United States Postal Service tracking label. 
 
Arm 2 (active comparator arm): FIT is packaged in a plain white envelope 
without a sticker message or tracking label. 
 
We will also conduct exploratory subgroup analyses to assess program reach, 
defined as the proportion and representativeness of patients who complete a FIT. 
2.0 
STUDY OBJECTIVES AND ENDPOINTS  
2.1 
Primary Objective (Aim 1) 
 
Main Trial (ages 50-75) 
The primary objective of this study is to assess the effectiveness of a mailed FIT 
outreach program on CRC screening completion in a community health center 
context in both northeastern and western North Carolina, by comparing the 
proportion of patients aged 50-75 years screened (as indicated by FIT or 
colonoscopy completion, assessed in the electronic health records [EHRs]), in the 
intervention arm and the control arm, 6 months post-intervention. Because both 
FIT and colonoscopy are viable CRC screening options and some patients may 
opt for a colonoscopy instead of the FIT, our measure of CRC screening 
completion includes both FIT and colonoscopy completion. We hypothesize that 
CRC screening completion rates will be higher among patients in Arm 2, 
compared to patients who received usual care in Arm 1.  
2.2 
Secondary Objectives  
Main Trial (ages 50-75) 
Other objectives of this study are to assess implementation determinants and 
outcomes to inform plans for sustaining and scaling the CRC screening program. 
Our aims are to: 
 
Aim 2: Assess the logistical feasibility and patient and provider acceptability of 
the mailed FIT outreach program (Arm 2), and 
 
Aim 3: Estimate the cost and cost-effectiveness per person screened in each arm, 
as well as the level of resource investment required to scale-up the program 
statewide. 

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Sub-study (ages 45-49) 
A new, secondary objective of this trial is to assess screening completion of a 
mailed FIT outreach program in patients aged 45-49 who are patients at the clinic.  
 
We will: 
1. Compare the proportion of patients who are current with any CRC screening 
prior to mailed FIT outreach and within 60 days of FIT mailing per electronic 
health record (EHR) query 
2. Compare the proportion of patients who complete FIT within 60 days of the 
mailed FIT date, by experimental and active comparator arms 
3. Describe the demographic characteristics of patients who complete FIT 
including, but not limited to, patient race, ethnicity, sex, and insurance status.  
 
3.0 
PATIENT ELIGIBILITY 
 
We will use the inclusion and exclusion criteria below to guide our electronic 
health record (EHR) query to identify eligible patients for the main trial and 
added cohort of patients ages 45-49. 
3.1 
Inclusion Criteria 
Individuals must meet all of the following inclusion criteria to participate in this 
study: 
3.1.1 Main trial: Age 50-75 years; Sub-study: Age 45-49 years 
3.1.2 At average risk for CRC (“average risk” is defined as those patients who do not 
have any of the following: history of CRC, colonic adenomas, family history of 
CRC, or diagnosis of inflammatory bowel disease) 
3.1.3 No record of fecal occult blood test (FOBT)/FIT within the past 12 months or 
colonoscopy within 10 years, sigmoidoscopy within 5 years, barium enema within 
5 years, or computed tomography (CT) colonography within 10 years of the EHR 
query date 
3.1.4 No record of any CRC diagnosis or total colectomy 
3.1.5 Active patient (seen within the past 18 months) of RCCHC or BRH 
 
Patients invited to participate in an interview will meet three additional inclusion 
criteria: aged 50-75; be assigned to study Arm 2 in the Main Trial; and have a 
positive (abnormal) FIT result as a participant in the screening program. We will 
not interview participants who are aged 45-49. 

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3.2 
Exclusion Criteria 
All individuals meeting any of the exclusion criteria at baseline will be excluded 
from study participation: 
3.2.1 Main trial: Age younger than 50 years or older than 75 years; Sub-study: Age 
younger than 45 years or older than 49 years 
3.2.2 Not at average risk for CRC (“average risk” is defined as those patients who do 
not have any of the following: history of CRC, colonic adenomas, family history 
of CRC, or diagnosis of inflammatory bowel disease) 
3.2.3 Record of FOBT/FIT within the past 12 months or colonoscopy within 10 years, 
sigmoidoscopy within 5 years; barium enema within 5 years, or CT colonography 
within 10 years of the EHR query date 
3.2.4 Record of any CRC diagnosis or total colectomy 
3.2.5 Not an active patient (not seen within the past 18 months) of RCCHC or BRH 
 
Patients will not be invited to participate in an interview if they meet additional 
exclusion criteria: be assigned to study Arm 1, do not return a FIT as a participant 
in the screening program, or have a negative (normal) FIT result as a participant 
in the screening program.  
4.0 
STUDY PLAN 

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4.1 
Main Trial Schema 
 
 
    
This trial will enroll up to 4,000 patients aged 50-75 years who are not up-to-date 
with CRC screening. The primary purpose of this study is to assess the 
effectiveness of mailed FIT outreach on CRC screening completion in a 
community health center context in both northeastern and western North Carolina, 
by comparing the proportion of patients screened across two study arms. 
 
All participants assigned to Arm 2 will be eligible to receive two intervention 
rounds, scheduled about 54 weeks apart. These two intervention rounds will allow 
us to longitudinally assess adherence to the United States Preventive Services 
Task Force recommendations for annual screening with FIT (see 1.2). Arm 
assignment will remain the same across both intervention rounds. Patients will be 

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included in the second intervention round if they continue to meet the study’s 
IRB-approved inclusion criteria for age, risk, screening history, CRC or 
colectomy history, and active patient status (seen within the past 18 months). In 
accordance with clinical recommendations, patients who receive a positive 
(abnormal) FIT result in the first round will not be included in the second round 
of FIT mailings (they will not be mailed a FIT). 
 
We anticipate that the approximate time for the study team to complete each of 
the two rounds of study mailings will be 3 months, and patients’ active 
participation during each round will last from 4 weeks (for patients with a FIT 
negative result and needed few, if any, reminders to complete the FIT) up to 6 
months (for patients with a positive FIT result who need a follow-up colonoscopy, 
and needed several reminders to complete the FIT). For each round, we will 
assume that patients who have not completed screening (FIT, screening 
colonoscopy, or follow-up colonoscopy) after 6 months following the FIT kit 
mailing, do not intend to do so. We will randomly select an equal number of 
control group participants to correspond to each mailing wave for intervention 
participants, and will track both intervention and control participants for the same 
time period (from Introductory Letter mailing to 6-months post-mailing). 
 
Provider surveys: All FQHC providers who deliver care to patients who received 
a mailed FIT (Arm 2) will be invited to complete a brief (about 18 items) survey 
to assess their perceptions of the appropriateness, feasibility, and fit of the 
program. We also will administer a brief (about 13 items) Contextual 
Determinants Survey to representatives of each FQHC to assess organizational 
climate, culture, and communication patterns that may affect the implementation 
of the project. The Contextual Determinants Survey will be administered to 
providers with leadership roles FQHC, such as the Chief Medical Officer, project 
champion, Clinic Nurse Managers, and Lead Referral Coordinators. Contextual 
Determinants Survey participants all have had direct contact with the UNC 
project team as we collaboratively developed the program. 
 
Provider interviews: Approximately 2-3 months after administering the provider 
surveys, we will invite a cross-section of up to 20 providers to participate in a 
semi-structured interview. We will recruit providers who recommend or provide 
CRC screening to patients of each FQHC (10 providers from each FQHC region). 
The interviews will allow us to better understand contextual factors that may 
affect adoption, maintenance, and scalability of the SCORE CRC screening 
program. 
 
Patient interviews: We will invite up to 30 intervention arm patients (up to 15 
from each FQHC) to participate in a semi-structured interview to better 
understand factors that affect completion of a follow-up colonoscopy following a 
positive (abnormal) FIT result. A member of the project team will invite patients 
to participate in an interview least 2 weeks after their final telephone contact with 
a patient navigator. We will sample purposively to ensure that we include 

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important and representative perspectives within each FQHC, based on sex, age, 
race, ethnicity, English/Spanish fluency, and whether the patient completed a 
follow-up colonoscopy. 
 
Sub-study Schema for Experimental Comparison of Envelope Type (ages 45-
49) 
 
 
 
All patients enrolled in the sub-study will be eligible to receive 1 round of annual 
mailed FIT. We anticipate that the approximate time for the study team to 
complete 1 round of the study mailings (introductory letter, FIT packet, and up to 
2 reminder letters) will be about 6 weeks, and patients’ active participation will 
last from 4 weeks (for patients with a FIT negative result and needed few, if any, 
reminders to complete the FIT) up to 6 months (for patients with a positive FIT 

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result who need a follow-up colonoscopy, and needed several reminders to 
complete the FIT). 
4.2 
Duration of Study 
Main Trial 
We anticipate that the entire active data collection phase, from randomizing the 
cohort to assessing screening outcomes via EHR and completing interviews with 
a subset of patients (see 4.3.6), will be approximately 36 months. 
 
Sub-study (ages 45-49) 
We anticipate that the entire active data collection phase, from randomizing the 
cohort to assessing screening outcomes via EHR will be approximately 6 months. 
4.3 
Study Details 
4.3.1 Cohort Ascertainment 
 
Our study team will work with RCCHC and BRH to identify the population of 
patients at each site who meet study inclusion criteria (see section 3.1), using an 
automated query of the EHR at each site. Per protocols from two similar projects, 
all patients meeting inclusion criteria will be initially included in the study cohort. 
Because EHR records are based on best available information and may not reflect 
screenings performed at another facility, our study materials will include a phone 
number for patients to contact the study team to self-identify as ineligible. We 
will select patients for inclusion randomly from the cohort and replace as needed 
to reach the goal of up to 4,000 Main Trial participants from RCCHC and BRH 
and an additional 450 sub-study participants from RCCHC. Each FQHC will 
query their own EHR to identify patients who meet eligibility criteria. Designated 
staff at each FQHC will securely transfer the queried patient information from 
their EHR to a folder accessible only to IRB-approved study team members on a 
secure UNC server (UNC Teams folder designated specifically for each FQHC). 
The data set will contain, but not necessarily be limited to, patient name, age, sex, 
race/ethnicity, email address, mailing address, primary care provider, and the date 
of the most recent visit with one of the FQHC’s primary care providers. Only 
authorized clinic and UNC project team representatives will be able to upload or 
remove data to UNC Teams. Each FQHC site will have its own folder, which will 
prevent access to data of patients not seen at their clinic. A member of the UNC 
project team will then transfer the patient data from UNC Teams to a REDCap 
database accessible only to UNC project team members. 
4.3.2 Randomization 
 
Main Trial (ages 50-75) 
At baseline, patients will be randomized 1:1 to Arm 1 (usual care) and Arm 2 
(mailed FIT outreach), stratified by site (RCCHC, BRH) and insurance status 
(Medicare, Medicaid, commercial/private, self-pay/uninsured). The 

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randomization list will be generated by the study biostatistician using a SAS 
program for stratified (by site and insurance status) randomization. 
 
Sub-study (ages 45-49) 
At baseline, patients will be randomized 1:1 to Arm 1 (experimental arm) and 
Arm 2 (active comparator arm). The randomization sequence will be generated by 
the study biostatistician using a SAS program. 
 
4.3.3 FIT Kit Packet Contents and Mailing 
 
Main Trial (ages 50-75) 
All FIT kit construction and mailing will be done by UNC project staff. For 
patients in Arm 2 (intervention arm), we will mail an introductory letter alerting 
patients to expect a free CRC screening test in the mail. Approximately two 
weeks later, we will mail a FIT Kit, which consists of  a(n): 1) cover letter from 
RCCHC or BRH reminding the patient s/he is due for CRC screening; 2) study 
information sheet; 3) education sheet about CRC screening; 4) instructions for 
completing the FIT; 5) one-sample FIT kit; and 6) pre-paid return mailer for the 
completed FIT kit (this return mailer includes a lab test form with the patient’s 
name, address, date of birth, and medical record number). For pragmatic reasons, 
FIT kits will be mailed across multiple waves (rather than to all patients at once) 
over the course of several months. The FIT mailing materials were developed and 
tested during the pilot phase of this study. They have now been adopted by each 
clinic as their standard of care for mailed FIT outreach. 
 
The mailing schedule is depicted in the Main Trial Schema (section 4.1). Patients 
in Arm 2 who do not return the FIT kit within 2-3 weeks, will receive Reminder 
Letter 1. If they do not return the FIT kit within 2-3 weeks after Reminder Letter 
1, they will receive Reminder Letter 2. 
 
Sub-study (ages 45-49) 
 All FIT kit construction and mailing will be done by UNC project staff. 
For patients in both arms, we will follow the same mailing schedule that applies 
to Arm 2 in the Main Trial. The mailing schedule is depicted in the Sub-study 
Schema (section 4.1). Arms will differ as follows: Arm 1 (experimental arm): FIT 
kit is packaged in a padded envelope with a message (e.g., “Important information 
from your doctor”) and a United States Postal Services tracking label, and Type 2 
(active comparator arm): FIT is packaged in a plain white envelope without a 
sticker message or tracking label.  
4.3.4 FIT Return and Sample Processing 
 
Main Trial 

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As described in section 4.3.3, participants in Arm 2 will be provided with a pre-
paid return mailer for their completed FIT kit. This pre-paid mailer is addressed to 
the laboratory. Patients may mail the completed kit directly to the laboratory or 
can bring it to the FQHC, who will send the sample to the laboratory for 
processing. The laboratory will relay the test results to the appropriate FQHC. 
Each FQHC assigns appropriate FQHC staff members to ensure test results of all 
patients, regardless of study participation, are entered into the EHR per their usual 
protocols.  
 
Sub-study (ages 45-49) 
For all patients in the sub-study (Arms 1 and 2), the FIT return and sample 
processing procedures will be exactly the same as those described above for Arm 
2 participants in the Main Trial.  
 
4.3.5 Notification of Results and Follow-up on Positive FITs 
 
Negative FIT result: BRH patients with a negative FIT result, per BRH current 
clinical protocol, will receive a letter from their primary care provider. For 
RCCHC patients with a negative FIT result, IRB-approved UNC research staff 
will send patients a letter (approved by RCCHC) to notify them of the negative 
result. The letter will include a reminder that the test should be repeated in 12 
months. 
 
Positive FIT result: For patients with a positive (abnormal) FIT result, the 
patient’s primary care provider or the provider’s designee will call the patient, per 
current standard protocol at each FQHC. The primary care provider or primary 
care provider’s designee will inform the patient of the positive result and need for 
a follow-up colonoscopy. After a patient is notified of a positive result, the patient 
navigator (employed by UNC and credentialed by each FQHC) will call the 
patient to offer information and support, including navigation services to access 
colonoscopy. Navigation services include, but are not necessarily limited to, 
referral and assistance with registering for charity care programs operating in each 
region (Hertford Health Access program for RCCHC and Digestive Health 
Partners-Hendersonville or Pardee Hospital Charity Care program for BRH) 
including no-cost colonoscopy (for uninsured patients) and, if available, 
transportation services to and from the colonoscopy appointment (for all patients). 
Patients who do not qualify for charity care may receive no-cost colonoscopy, 
supported using study funding and/or donated colonoscopy services. The patient 
navigator will help navigate the patient to these services, if needed. 
 
4.3.6 Data Collection 
 
 

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REDCap database: RCCHC and BRH will securely transfer patient information 
from the EHR to a secure SharePoint folder at UNC. A UNC research assistant 
will then upload the data to a REDCap database (developed based on two 
previous completed or ongoing studies). Data will include, but not necessarily be 
limited to, patient name, age, sex, race/ethnicity, mailing address, identified 
primary care provider, and if possible, the number of visits within the past 18 
months with that provider. The study team has fully executed data use agreements 
in place with each FQHC. Designated approved members of the research team 
members will use the REDCap database to document whether patients were 
mailed a FIT kit and to track the status of FIT kit completion (yes or no), test 
result (positive or negative), contact with patients who have positive results (yes 
or no), and receipt of navigation support for colonoscopy (yes or no), including 
referrals for no-cost follow-up colonoscopy (yes or no) and transportation services 
(yes or no). Approved members of the UNC research team will also document in 
the REDCap database whether patients call to report they are ineligible for FIT 
screening per their screening and relevant medical history (e.g., already 
completed CRC screening elsewhere, have a medical history that places them at 
higher than average risk for CRC). 
 
EHR: Each CHC will specify, train, and credential members of the UNC research 
team to conduct a manual review of participant EHRs 6 months or more after 
randomization to determine whether patients completed any CRC screening test 
(FIT, colonoscopy, flexible sigmoidoscopy, Cologuard) and, if so, the test result. 
As mentioned in the preceding paragraph, these data will be entered directly into 
the REDCap database by IRB-approved UNC staff members for analysis. 
 
Charity Care Program: Hertford Health Access will oversee no-cost follow-up 
colonoscopy and transportation service to and from medical appointments for 
RCCHC patients. Digestive Health Partners-Hendersonville and Pardee Hospital 
Charity Care program provide no-cost colonoscopy services for BRH patients. 
The patient navigator will contact the local charity care program (Hertford Health 
Access, Digestive Health Partners, or Pardee Hospital) to acquire data on whether 
patients from our cohort (who had a positive FIT result) received no-cost follow-
up colonoscopy and transportation service. The patient navigator will store these 
data in the secure REDCap database. 
 
Surveys and interviews (applicable only to participants ages 50-75 in the Main 
Trial): We will use brief surveys and semi-structured interviews to assess 
providers’ perceptions about the acceptability, appropriateness, and feasibility of 
the mailed reminder plus FIT kit program. We also will recruit up to 15 patients 
from each FQHC (RCCHC and BRH) to participate in a 30-45-minute interview 
to better understand factors that affect their completion of a follow-up 
colonoscopy following a positive (abnormal) FIT result. Spanish-speaking patient 
participants will be eligible to participate in the interviews. Patient interviews will 
be conducted by phone or in person. For provider interviews we will recruit up to 
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will be conducted in person or by phone depending on the providers’ preference. 
Interviews will be audio recorded and transcribed verbatim. Personally 
identifiable information will be redacted from the transcripts prior to analysis. 
Patients aged 45-49 will not be invited to participate in interviews.  
4.3.7 Number and Duration of Contact with Patients 
4.3.7.1 CRC Screening 
 
Patients in the Main Trial control arm (ages 50-75) will not be contacted.  Patients 
in the Main Trial intervention arm (ages 50-75) and patients the Sub-study (ages 
45-49) intervention arm and comparator arm will receive an Introductory Letter 
(first contact) that notifies the patient to expect a FIT kit in the mail. This mailing 
will allow the study team to identify patients with incorrect addresses before 
mailing the FIT kit.  
 
After mailing the FIT kit (second contact), the study team will make up to two 
reminder attempts to follow up with patients in the intervention arm (Arm 2) who 
have not returned a completed FIT kit. If the FIT kit is undeliverable and returned 
to the study team because of an incorrect address, the patient will be removed 
from future Reminder Letter mailings.  
 
Main Trial Patients (ages 50-75) in Arm 2 will receive up to two reminder letters 
(third and fourth contact). All sub-study patients (ages 45-49) in the intervention 
and comparator arms also will receive up to two reminder letters (third and fourth 
contact). 
 
For patients who complete a FIT kit and have a negative result: The patient will 
be notified of the test result by letter (see section 4.3.5). 
 
For patients who complete a FIT kit and have a positive (abnormal) result: The 
patients’ primary care provider or the primary care provider’s designee will notify 
the patient of the results. After the patient is notified of their positive result, the 
patient navigator (employed by UNC and credentialed by RCCHC and BRH) will 
contact the patient by phone or, if phone contact is not successful, by mail to offer 
information and support for accessing follow-up colonoscopy. Communication 
will include information about no-cost colonoscopy (for uninsured patients) and 
transportation service to and from the colonoscopy appointment (for all patients). 
The patient navigator will call the patient up to three additional times to support 
the patient in scheduling an appointment for a follow-up colonoscopy, preparing 
for the colonoscopy procedure, accessing transportation, and financial services, 
and understanding colonoscopy results. The approximate duration of each phone 
call will be 5-15 minutes.  
 
The total number of contacts initiated by the study team will range from 3 
(Introductory Letter + FIT kit mailing + results letter/call) to 9 (Introductory 

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Letter + FIT kit mailing + up to 2 reminder letters + results letter/call + up to 4 
navigation calls for patients with a positive FIT). The study team may have 
additional contact with patients if the patients reach out to the study team or 
indicate they require additional contact (e.g., questions or requests for navigation 
assistance). 
4.3.7.2 Provider Surveys  
Survey completion will entail a minimum of 2 contacts at each of the 2 time 
points. The first contact will be a recruitment email and the second contact will be 
an online survey. Additional contacts may include up to 4 recruitment emails and 
a brief presentation during a standing provider meeting, to invite participation. 
The brief survey will require 10 minutes or less.   
4.3.7.3 Provider Interviews  
Interview completion will entail a minimum of 4 contacts at each of 2 time points. 
The first contact will be a recruitment email, the second contact will an interview 
scheduling call or email, the third contact will be an interview reminder, and the 
fourth contact will be an interview. Additional contacts may include up to 6 
recruitment emails and/or phone calls and a brief presentation during a standing 
provider meeting, to invite participation. The interview will require approximately 
20 minutes. 
4.3.7.4 Patient Interviews (applicable to Main Trial participants ages 50-75) 
We expect at least 5 contacts including a recruitment letter, a recruitment phone 
call to schedule the interview, an interview reminder, the interview, and a post-
interview contact to mail the gift card. We also will call patients up to 5 times for 
interview recruitment. Interviews will last approximately 30-45 minutes. Patients 
aged 45-49 will not be invited to participate in interviews.  
 
4.4 
Expected Risks 
It is possible that patients may experience emotional distress or feelings of 
embarrassment of completing a home-based stool test. However, given that CRC 
screening using FIT is a part of usual care at the participating FQHCs, these risks 
are not substantially increased as a result of study participation. The letters 
included with the mailed FIT intervention emphasize the benefits of the screening, 
that participation is voluntary, they may choose not to answer questions, there will 
be no effects on care received by the FQHC or providers based on decision about 
participation, and information collected will be confidential and securely stored.   
4.5 
Removal of Patients from Protocol  
We have not identified any factors a priori that would lead the Principal 
Investigator to remove a patient from the study. 
5.0 
TIME AND EVENTS TABLE 

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5.1 
Time and Events Table 
         
 
Main Trial 
The timeline of activities for our study is shown in Table 1. 
 
 
 
 
 
 
Sub-study (ages 45-49) 
The timeline of activities for the sub-study is shown in Table 1. Participants in the 
sub-study will only receive one round of mailed FIT outreach because we are in 
Year 4 of a 6-year award and will not have sufficient time to conduct two rounds 
of annual FIT with outcome assessment. 
 
 
Table 2. Substudy Timeline 
 
 
 
 
 
 
 
 
 
Month 
Activity 
1 
2 
3 
4 
5 
6 
7 
Identify eligible patients (query EHR) 
 
  
  
  
  
  
  
Transfer patient data to UNC and REDCap 
 
 
 
 
 
 
 
Randomly assign patients to study arms 
 
 
 
 
 
 
 
Mail introductory letters 
 
 
 
 
 
 
 
Mail FIT packets 
 
 
 
 
 
 
 
Mail reminder letter 1 
 
 
 
 
 
 
 

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Mail reminder letter 2 
 
 
 
 
 
 
 
FIT results notification 
 
 
 
 
 
 
 
Patient navigation for patients with a positive FIT result 
 
 
 
 
 
 
 
FIT tracking and other data collection 
 
 
 
 
 
 
 
FIT return and CRC screening outcomes assessment 
 
 
 
 
 
 
 
Program evaluation 
 
 
 
 
 
 
 
 
6.0 
UNANTICIPATED PROBLEMS 
6.1 
Definition 
As defined by UNC’s IRB, unanticipated problems involving risks to study 
subjects or others (UPIRSO) refers to any incident, experience, or outcome that: 
• 
Is unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
• 
Is related or possibly related to a subject’s participation in the research; 
and  
• 
Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) related 
to the research than was previously known or recognized. 
6.2 
Reporting 
Any UPIRSO that occurs during the conduct of this study and that meets all three 
criteria listed in 6.1 must be reported to the UNC IRB using the IRB’s web-based 
reporting system.   
 
7.0 
STATISTICAL CONSIDERATIONS 
7.1 
Study Design 
 
Main Trial 
This study includes a two-arm, multi-center, randomized controlled trial. The 
primary objective of the trial is to assess the effectiveness of a mailed FIT 
outreach program on CRC screening completion in a community health center 
context in both northeastern and western North Carolina, by comparing the 
proportion of patients screened in the intervention arm to the control arm. Arm 1. 
Participants receive usual care (no change from the original study protocol). Arm 
2. Participants receive the following already IRB-approved intervention 
components: (1) Introductory Letter to let patients know they should expect a FIT 
kit in the mail; (2) Cover Letter and FIT kit with instructions; (3) Reminder Letter 
1 for patients who have not returned the FIT kit; and (4) Reminder Letter 2 for 
patients who still have not returned the FIT kit (added in protocol version 2). 

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The secondary objective of this study is to develop and refine implementation 
outcomes to inform a large, multi-site implementation study. As part of this 
secondary objective, our aims are to test the logistical feasibility and patient and 
provider acceptability of a mailed reminder plus FIT outreach program (Aim 2), 
and estimate the cost per person screened of the mailed reminder plus FIT 
outreach program, as well as the level of resource investment required to scale-up 
the program statewide (Aim 3). 
 
Sub-study (ages 45-49) 
Objective 1 of this sub-study is to compare CRC screening rates before and after  
mailed FIT outreach to patients aged 45-49 in a community health center context 
in northeastern North Carolina. All participants will receive the same intervention 
components as are described above for the Arm 2 in the Main Trial: 1) 
introductory letter to let patients know they should expect a FIT kit in the mail; 2) 
cover letter and FIT kit with instructions; 3) reminder letter 1 for patients who 
have not returned the FIT kit; and 4) reminder letter 2 for patients who still have 
not returned the FIT kit. 
 
Objective 2 of this sub-study is to assess the impact of varying FIT packet 
appearance on FIT return. Patients will be randomized to receive FIT materials in 
either a: 1) padded envelope with a sticker message (e.g., “Important information 
from your doctor”) and a United States Postal Service tracking label, or 2) plain 
white envelope without a sticker message or tracking label. We will compare the 
proportion of participants in each arm who complete a FIT. 
 
7.2 
Sample Size and Accrual 
 
Main Trial 
Our project funding supports a sample size of up to 4,000 patients at two clinical 
sites who are eligible for CRC screening. Using a 1:1 randomization approach, up 
to 2,000 RCCHC patients and up to 2,000 BRH patients will be randomized to the 
two study arms. For each FQHC, up to 1,000 patients will be randomized to each 
of the two arms. Our statistician performed formal power calculations for our 
primary study outcome comparing CRC screening completion for the intervention 
arm vs. the control arm, stratified by patient insurance status (4 strata: Medicare, 
Medicaid, commercial/private, and self-pay/other). Based on previous research, 
we anticipate that 25% of those receiving the intervention will complete CRC 
screening, and 17% of patients in the usual care arm will complete screening (8% 
difference between arms). We need 492 participants per arm, per strata to have at 
least 80% power to detect an 8% difference between study arms at 1-sided alpha 
level 0.0125 (3,936 participants total, which can be rounded up to 4,000). We 
calculated power by SAS PROC Power (SAS Institute, Cary, NC). 
 
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Sample size in this additional substudy is determined by feasibility and resource 
constraints. We have the resources to do intervention testing in this new age group 
(45-49) in a single clinic site.  We will identify the cohort of participants who are 
eligible for screening on a given index date. We estimate 500 patients are in this 
age group and eligible for screening.  We estimate that approximately 10%, i.e., 
50 individual patients, will be current with screening at baseline. We  will conduct 
the mailed intervention on the approximately 450 patients who are not current and 
then assess the screening rate at 60 days in same cohort. For outcome 2, we will 
use a 1:1 randomization approach to randomize patients the patients who are not 
current with screening to the two experimental study arms (envelope type). 
 
Our statistician performed formal power calculations for our study outcomes of 
change in CRC screening rate (pre-post) for this age group, as well as FIT return 
compared across the two arms. Outcome 1:  We will observe baseline and post-
intervention status of CRC for subjects who are not screened at baseline. For 
those who screened at baseline, we will not observe post-intervention CRC status, 
but we assume a high post-intervention screen rate for such subjects if they 
receive intervention before they receive screening. This leads to a paired binary 
data problem, and we test if the conversion rate (from not screened to screened) is 
high enough. A sample size of 500 achieves 80% power to detect an odds ratio of 
2.922 using a two-sided McNemar test with a significance level of 0.05. This 
calculation is based on a difference between two paired proportions of 0.034 
(P10-P01), where P10 (about 0.052) refers to the proportion of subjects who not 
screen at baseline but screen after intervention) and the proportion (P01) of screen 
at baseline but not screen after intervention. This is an assumed number because 
we are not able to observe it but assume it's a very small number) is 0.018. The 
proportion of discordant pairs is 0.07. We will report baseline screening rate and 
post-intervention screening rate. Outcome 2: With 225 patients per arm, we reach 
80% power, with 1-sided alpha 0.05, to detect a difference between the group FIT 
mail back rates of 0.102. The FIT mail back rate in Group 1 (the treatment group) 
is assumed to be 0.20 under the null hypothesis and 0.302 under the alternative 
hypothesis. The rate in Group 2 (the control group) is 0.20. We calculated power 
using SAS PROC Power (SAS Institute, Cary, NC). 
 
7.3 
Data Analysis Plans 
Main Trial 
Our main statistical test for primary and secondary outcomes will be a Mantel-
Haenszel chi-squared test, adjusted for recruitment site (FQHC). If there are 
important differences between the control and intervention arms across baseline 
variables known to be associated with the outcome being tested, we will also then 
use multiple logistic regression, adjusting for the additional baseline variables. 
One-sided tests will be used for the primary and secondary outcomes because we 
expect active interventions will lead to more favorable results compared to usual 
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7.3.1 Aim 1  
For Aim 1, the main outcome of interest is the proportion of the sample 
completing FIT kits among those to whom the materials are mailed. We refer to 
this metric as the “proportion screened.” Using a 1:1 randomization approach, up 
to 2,000 RCCHC patients and up to 2,000 BRH patients will be randomized to 
each study arm (Arm 1-usual care; Arm 2-introductory letter + mailed FIT + 2 
follow-up reminder letters). 
 
Aim 1 analytic approach: Our primary analysis will be a crude comparison of 
proportions of completed CRC screening at 6 months post-FIT mailing for the 
mailed FIT plus reminder arm vs. the usual care arm using a one-sided Mantel-
Haenszel chi-squared test, controlling for recruitment site (FQHC) and insurance 
status. As stated in the overview, we will also, if necessary, conduct a multiple 
logistic regression analysis. We will also compare the proportion screened 
between the mailed FIT plus reminder arm vs. the usual care arm for each of the 
four insurance status groups, using a one-sided Mantel-Haenszel chi-squared test, 
controlling for recruitment site, conducted at the 0.0125 significance level. 
7.3.2 Aim 2 
For Aim 2, we will examine intervention implementation outcomes, including the 
logistical feasibility, patient acceptability, and provider acceptability of a mailed 
FIT outreach program. To accomplish this aim, we will track and report feasibility 
and acceptability metrics. For feasibility, we will measure the proportion of bad 
addresses using the REDCap database. To assess patient acceptability and 
perceptions of program appropriateness, we will conduct semi-structured 
interviews with up to 30 patients who had a positive (abnormal) FIT result, were 
referred for follow-up colonoscopy, and were offered patient navigations services. 
Invitations will be made on a rolling basis until a sufficient number of patients 
complete the interviews. Invitation letters will be sent after no more than 6 
months after the FIT kit was mailed. To assess acceptability and feasibility from 
the providers’ perspectives, we will conduct surveys and semi-structured 
interviews at two time points. For the interviews, the RCCHC or BRH medical 
director will send an email to the clinician listserv to invite clinicians at the target 
clinic to participate in a follow-up interview. If this approach does not yield 
enough clinician participants, UNC project staff will attend regularly scheduled 
provider meetings to enhance recruitment. Clinician interviews will be conducted 
in study months 6-12. We will also track and report the proportions of patients 
who inform us of ineligibility in response to the Introductory Letter and 
subsequent mailings. 
 
Aim 2 analytic approach: For quantitative assessments, we will use descriptive 
statistics (e.g., proportions and associated 95% confidence intervals) to 
characterize feasibility and acceptability measures. For qualitative assessments 
(i.e., semi-structured interviews), we will perform a thematic analysis of 
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7.3.3 Aim 3 
For Aim 3, the main outcome of interest is the total cost (sum of fixed and 
variable costs) and the incremental cost-effectiveness of the intervention arm 
versus the usual care arm, measured in cost per person screened for CRC. We will 
document all fixed and variable costs associated with implementing the 
intervention, based upon personnel time tracking, invoices, receipts paid, test kit 
and processing costs, postage and other mailing costs, and other means. Fixed 
costs (i.e., costs absorbed by the screening program irrespective of the number of 
participants screened) include those of program administration and setup, 
materials design, and database development and analytics. Variable costs (i.e., 
those that are determined by the number of participants engaged or screened) 
include the costs of the intervention materials, FIT kits, postage and mailing costs, 
and costs of patient navigation and other personnel involved in the screening and 
follow-up process. For personnel time (e.g., in-reach follow-up of non-
responders; navigation to colonoscopy), we will record the amount of time in 
minutes spent on each participant interaction, and calculate cost by multiplying 
total time spent in minutes with the average hourly salary of participating clinic 
nurses, administrative staff, and other staff, as relevant. Time spent in training, 
handling samples, and data management will be monitored using a similar time-
audit approach. Mailing-associated costs will be recorded for the intervention 
arm. We will also assess costs associated with additional health care utilization 
post-screening (e.g., follow-up colonoscopy). We will not assess fixed costs 
common across the arms, such as overhead operating costs of clinics, or costs 
related to the conduct of the study alone, such as costs associated with data 
collection. For secondary analyses using the societal perspective, we will also 
attempt to estimate patient time costs associated with the intervention arm versus 
usual care arm. 
 
Aim 3 analytic approach: We will describe total costs associated with each of the 
intervention arms for the trial. We will then calculate the incremental cost-
effectiveness ratio (ICER) defined as cost per additional person screened, 
comparing intervention arms to usual care. We will also perform sensitivity 
analyses to examine the effect of different prices (potentially negotiable for larger 
programs assuming volume-based economies of scale). For alternate analyses 
from the societal perspective, we will estimate patient time costs using the human 
capital method (Jonas et al., 2008). 
 
7.3.4 Sub-study (ages 45-49)  
Our main statistical test for outcomes 1 and 2 will be a Mantel-Haenszel chi-
squared test. If there are important differences between the arms across baseline 
variables known to be associated with the outcome being tested, we will also then 
use multiple logistic regression, adjusting for the additional baseline variables. 
 

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7.4 
Data Management/Audit 
Study team members will enter data into separate REDCap databases. Study data 
will be stored securely and managed through the REDCap databases.  
 
As an investigator-initiated study, the trial will also be audited by the Lineberger 
Cancer Center audit committee every six or twelve months, depending on the 
participation of affiliate sites. 
8.0 
STUDY MANAGEMENT 
8.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
For mailed outreach participants (Main trial (ages 50-75) and sub-study (ages 45-
49)): We will request a waiver of informed consent for mailed outreach 
participants because: 1) the research involves no more than minimal risk to the 
subjects; 2) the waiver will not adversely affect the rights and welfare of the 
subjects; and 3) the research could not practicably be carried out without the 
waiver. 
 
 
 
For patient interview participants (patients 50-75): Before recruitment and 
enrollment onto this study, the patient will be given a full explanation of the study 
and will be given the opportunity to review the consent form. Each consent form 
must include all the relevant elements currently required by the FDA Regulations 
and local or state regulations. Once this essential information has been provided 
to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent 
to participate in the study by signing an IRB-approved consent form.  
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. Patients aged 45-49 will not be 
invited to participate in interviews. 
 
For provider survey participants: The online survey will include a study 
information page. Providers will indicate consent by proceeding to the online 
survey after reviewing the study information page. The brief survey asks 
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program and implementation of CRC screening at their clinic. The questions do 
not request sensitive information.  
 
For provider interview participants: We will request verbal consent only because 
we are inquiring about participants’ jobs, not personal information about 
themselves. 
8.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• CVs and medical licensure for the principal investigator and any 
associate investigators who will be involved in the study 
• A copy of the IRB-approved consent form 
8.3 
Registration Procedures 
Please describe how you will keep track of patient enrollment. 
8.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
8.4.1 Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior UNC IRB 
approval.  
 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
8.4.2 Single Patient/Subject Exceptions 
Eligibility single subject exceptions are not permitted for Lineberger 
Comprehensive Cancer Center Investigator Initiated Trials under any 
circumstances. Other types of single subject exceptions may be allowed if proper 
regulatory review has been completed in accordance with Lineberger 
Comprehensive Cancer Center’s Single Subject Exceptions Policy. 
8.4.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 

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• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore® (or 
other appropriate database set up for the study), and report to any sponsor or data 
and safety monitoring committee in accordance with their policies.  Deviations 
should be summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report UPIRSO.   
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO: 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB (see section 6.1) must be reported by the Study Coordinator using the 
IRB’s web-based reporting system.   
8.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC. It should also be 
noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
8.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 

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logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator. In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
8.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification 
of proper entry of data. At the completion of the study, all case report forms will 
be reviewed by the Principal Investigator and will require his/her final signature 
to verify the accuracy of the data. 
9.0 
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