Pilot Feasibility Testing of a Small Randomized Controlled Trial to Evaluate a Telemedicine Stress Management and Lifestyle Group Intervention for Patients With Symptomatic Chronic Hepatitis C
Phase: NA
Conditions: Chronic Hepatitis C
Sponsor: University of North Carolina, Chapel Hill

VC-CBCS Study protocol v7.0—16Nov2021 
 
 
 
A Pilot Feasibility Testing of a Small Randomized Controlled Trial to Evaluate a 
Telemedicine Stress Management and Lifestyle Group Intervention for Patients 
with Symptomatic Chronic Hepatitis C 
 
Study Protocol: Version 7.0, 16Nov2021 
 
NCT Identified Number: NCT04198584 
 
Primary Investigator: 
Donna M. Evon, PhD 
 
 
Professor of Medicine 
8010 Burnett-Womack, CB#: 7584 
Division of Gastroenterology and Hepatology 
Department of Medicine 
University of North Carolina 
Chapel Hill, NC 27599-7584 
Telephone: (919) 966-6732 
Email: Donna _Evon@med.unc.edu 
 
Sponsor: The University of North Carolina at Chapel Hill 
 
 Grant Number: 1R21NR017908 - 01A1 
 
Funded by: National Institutes of Health –National Institute of Nursing Research (NINR) 
 
Version Number:  v.7.0 
 
Version Date: 16 Nov 2021 
 
 
 
 
 
 
 
 
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
STUDY PROTOCOL 
DOCUMENT HISTORY 
 
Document 
Date of Issue 
Summary 
Original Version 
of Protocol, 
Version 1.0 
22Sept2019 
• 
First version of the protocol : 22Sept2019 
• 
Submitted to UNC IRB: 22Sept2019 
• 
Approved by IRB 
• 
Submitted to NINR  
Version 2.0 
07Feb2020 
The following changes have been made: 
• 
Updated: 
o exclusion criteria 
o reimbursement procedures 
o randomization procedures  
o salivary cortisol procedures 
o research team information 
• 
Removed: 
o use of study website; replaced with a Google drive 
o use of Zoom; study will only utilize WebEx 
• 
Clarified research staff roles in study procedures 
Version 3.0 
20Mar2020 
**During the COVID-19 outbreak, Wave 1 is allowed to forego saliva 
sample testing, if necessary, pending allowed research operations** 
 
Additionally, the following changes have been made: 
• 
Recruitment and consenting procedures clarified and 
updated to include verbal telephone consent  
• 
Changed randomization groups so that Group 1 will consist 
of 7 patients and Group 2 will consist of 9 patients; total 
number of participants remains the same (n=32)  
• 
Updated location of some study procedures to be conducted 
in a private area and for study documents to be stored in 
locked, secure area 
• 
Minor updates to IT’s role and responsibility   
• 
Typographical and grammatical errors corrected throughout 
 
Version 4.0 
18May2020 
The following changes have been made: 
• 
Removed: 
o use of Google drive; replaced with UNC OneDrive 
• 
Typographical, formatting, and grammatical errors corrected 
throughout 
Version 5.0 
09Jul2020 
Replacing UNC OneDrive with Google Drive due to technical issues.  
Version 6.0 
15Dec2020 
The following changes have been made: 
• 
Updated order of study outcomes  
• 
Typographical, formatting, and grammatical errors corrected 
throughout 
 
Version 7.0 
16Nov2021 
Updated study outcomes  
 
 
 
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
 
Table of Contents 
 
1 BACKGROUND AND RATIONALE ......................................................................................................................... 5 
2 STUDY AIMS ............................................................................................................................................................... 6 
3 STUDY DESIGN .......................................................................................................................................................... 7 
3.1 Study Design .......................................................................................................................................................... 7 
3.2 Study Participants................................................................................................................................................... 7 
3.3. Inclusion/Exclusion Criteria .................................................................................................................................. 7 
3.3.1. Inclusion .........................................................................................................................................................     7 
3.3.2. Exclusion ............................................................................................................................................................ 7 
4 RECRUITMENT ........................................................................................................................................................... 7 
5 INFORMED CONSENT PROCESS............................................................................................................................. 8 
6 SCREENING FOR VC-CBCS ELIGIBILITY ............................................................................................................. 8 
6.1 Phase I Screen ........................................................................................................................................................ 9 
6.2 Phase II Screen: ...................................................................................................................................................... 9 
6.3 Screening Data: ...................................................................................................................................................... 9 
7 REIMBURSEMENT ..................................................................................................................................................... 9 
8 RANDOMIZATION ................................................................................................................................................... 10 
9 STANDARD CARE .................................................................................................................................................... 10 
10 VC-CBCS GROUP INTERVENTION ..................................................................................................................... 10 
10.1 Tentative Conceptual Model of the VC-CBCS .................................................................................................. 10 
Figure 1: Conceptual Model of VC-CBCS Intervention ............................................................................................ 11 
10.2 Conducting the VC-CBCS Group Intervention ................................................................................................. 11 
Table 1: Content and structure of 14 VC-CBCS group modules ................................................................................... 12 
Figure 2: How does the VC-CBCS help to improve Liver Health and Wellness?..................................................... 12 
10.3 Technology Training and iPads and Review of Rules of Group Engagement and Privacy ............................... 13 
10.4 Iterative changes to VC-CBCS intervention ...................................................................................................... 13 
11 DATA COLLECTION ASSSEMENT SCHEDULE ................................................................................................ 13 
11.1 PRO Assessments............................................................................................................................................... 13 
11.2 Salivary Cortisol................................................................................................................................................. 13 
11.3 VC-CBCS Process Assessments ........................................................................................................................ 13 
Table 2: Data Collection Schedule ............................................................................................................................. 14 
12 MEASURES TO EVALUATE FOUR SPECIFIC AIMS......................................................................................... 14 
12.1 Study and Intervention Feasibility (Aims #1, #2) .............................................................................................. 14 
12.2 Patient Satisfaction (Aim #3) ............................................................................................................................. 14 
12.3 Patient-Reported Outcome Measures (Aim #4) ................................................................................................. 15 
13 PRIMARY FEASIBILITY OUTCOME MEASURES ........................................................................................ 15 
14 PRIMARY PATIENT-REPORTED OUTCOME MEASURES .......................................................................... 15 
14.1 PROMIS Global Health Status Mental Health Mean T-Score ........................................................................... 15 
14.2 PROMIS Global Health Status Physical Health Mean T-Score ......................................................................... 15 

VC-CBCS Study protocol v7.0—16Nov2021 
 
14.3 PROMIS Depression Mean T-score ................................................................................................................... 15 
14.4 PROMIS Anger Mean T-score ........................................................................................................................... 15 
14.5 PROMIS Anxiety Mean T-score ........................................................................................................................ 15 
14.6 PROMIS Fatigue Mean T-score ......................................................................................................................... 15 
14.7 PROMIS Sleep Disturbance Mean T-score ....................................................................................................... 15 
14.8 PROMIS Pain Interference Mean T-score ......................................................................................................... 15 
15 SECONDARY PATIENT-REPORTED OUTCOME MEASURES .................................................................... 15 
16 SECONDARY CLINICAL OUTCOMES ............................................................................................................ 16 
17 EXPLORATORY PATIENT-REPORTED OUTCOME MEASURE ................................................................. 17 
18 EXPLORATORY STRESS BIOMARKER OUTCOME ..................................................................................... 17 
20 PATIENT SOCIODEMOGRAPHICS .................................................................................................................. 17 
21 PROTOCOL FIDELITY ....................................................................................................................................... 17 
22 ELECTRONIC DATA CAPTURE AND SECURE STORAGE .............................................................................. 18 
23 DATA ANALYSIS ................................................................................................................................................... 18 
23.1 Statistical Analysis Overview ............................................................................................................................ 18 
23.2 Aim 1: Feasibility of conducting a RCT ............................................................................................................ 18 
23.3. Aim 2: Feasibility of intervention delivery ....................................................................................................... 18 
23.4 Aim 3: Patient satisfaction and acceptability ..................................................................................................... 19 
23.5 Aim 4: Explore changes in patient outcomes, mediators and intervention targets, as well as temporal 
associations and strength of associations among variables in a preliminary conceptual model, to inform a future 
efficacy trial ........................................................................................................................................................ 19 
24 STUDY CONDUCT ................................................................................................................................................. 19 
25 DATABASE RETENTION ...................................................................................................................................... 19 
26 DATA AND SAFETY AND MONITORING PLAN............................................................................................... 20 
26.1 Procedures for Adverse Events (from DSMPv2.0 - 27Sept2019) ...................................................................... 20 
27 RESEARCH TEAM .................................................................................................................................................. 20 
28 GLOSSARY OF TERMS .......................................................................................................................................... 21 
29 REFERENCES .......................................................................................................................................................... 22 
 
 
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
1 BACKGROUND AND RATIONALE 
 
Hepatitis C viral (HCV) infection has a tremendous impact on individual and public health. HCV 
affects over 3 million Americans, leading to 15,000 deaths per year from liver failure, cirrhosis, and liver 
cancer.48 Up to 20% of patients will develop cirrhosis49,50 and 10-20% will develop decompensated 
cirrhosis or cancer. Though typically associated with the liver, HCV is a multi-faceted systemic disease 
also affecting multiple organs and systems51 and associated with many extrahepatic disorders (EHDs) 
including musculoskeletal, endocrine, neuropsychiatric, and cardiac disorders.13,52 Our PROP UP data 
suggest that HCV patients have an average of 4 comorbidities (range: 0-15), the most prevalent being 
musculoskeletal pain and high blood pressure (50%), psychiatric (44%), sleep disturbance (31%), and 
diabetes (20%).53 Patients report clinical distress from somatic and neuropsychiatric symptoms with 
fatigue, depression, sleep issues and chronic pain most common.16-20,54 Not surprisingly, HRQOL is 
impaired.21,22  While HCV may lead to chronic systemic inflammation with neuropsychiatric and somatic 
sequalae,13,54,55 other factors also contribute to poor health including social determinants of poor 
health.27 Unhealthy lifestyle habits also perpetuate chronic illness56-58 and confer greater risk for liver 
disease, metabolic syndrome, and death.28,59 Even in patients cured of HCV, many remain symptomatic 
and at risk for cirrhosis or liver cancer if healthier lifestyles not adopted.24 The economic burden of HCV 
is >$10 billion annually when accounting for costs of liver disease, EHDs, low HRQOL and loss of work 
productivity.60 
 
People who have been infected with HCV may benefit from comprehensive multi-modal 
interventions to improve important patient outcomes. Comprehensive multi-modal psychosocial 
interventions that provide stress management, coping skills, and lifestyle modification for the HCV 
population are nonexistent. Despite chronic health risks, multi-morbidities, life stress and unhealthy 
behaviors, all of which amplify illness, virtually no psychosocial interventions have been developed for 
the HCV population. However, evidence-based psychosocial interventions have improved diverse 
health outcomes in people with other chronic illnesses (e.g., cancers, diabetes, chronic fatigue, pain, 
HIV). Group-based psychosocial interventions that emphasize cognitive behavioral (CB) stress 
management (SM) coping skills improve psychological and physical health outcomes30,31,35-37,61 and are 
associated with change in multiple stress-related immunological indices (e.g., CD4 viral count, cortisol 
patterns, proinflammatory cytokines).31-34 Improvements in immune functioning often correlate with 
symptom reduction.62-65 In one of the only psychoneuroimmunological studies conducted in HCV, 
associations were found between patients’ depression, anxiety, fatigue, and pain levels and high levels 
of inflammatory proteins, accounting for up to 40% of the variance in symptoms.14  
 
Extrapolating from this strong empirical base built in other chronic diseases, liver disease researchers 
need to determine if psychosocial interventions confer similar benefits to liver patients. Given the 
prevalence of HCV and the number of patients who remain symptomatic or may progress to advanced 
liver disease, comprehensive, holistic liver care should integrate health promotion interventions into 
current practice, over and above a myopic focus on just viral eradication and medical management of 
cirrhosis. The ideal intervention would include stress management, coping skills, and health behavior 
modifications, which, in turn, may improve symptoms, 66 HRQOL, and disease markers.29,67,68 Within 
this secondary prevention model, modifying psychological and physiological stress and lifestyle 
behaviors in symptomatic or at-risk liver patients, may yield substantial health benefits. As such, we 
sought to tailor evidence-based psychosocial interventions to the needs of HCV patients to improve 
physical and psychological health outcomes.  
 
Multiple patient barriers exist to attending in-person interventions. Patient-level barriers to 
accessing traditional face-to-face healthcare services are enormous and include travel, geographical, 
financial, transportation, and illness barriers.69 This dilemma is particularly salient in rural areas where 
healthcare access is poor.39,70 During pilot-testing of the in-person group-based Cognitive Behavioral 
Coping Skills (CBCS-HCV) intervention developed for patients infected with chronic HCV, patients who 
declined participation cited travel distance and transportation barriers.6,38 No patients declined due to 
lack of interest. Many commented that the intervention seemed valuable, but that in-person sessions 
were impractical. Other psychosocial interventions for patients with HCV that require in-person 
sessions have also suffered from low recruitment,71,72 convincing us that alternative modes of delivery 

VC-CBCS Study protocol v7.0—16Nov2021 
 
must be explored to increase access to treatment, especially in rural states like North Carolina (85 out 
of 100 counties are designated rural). 
 
Delivering interventions via videoconferencing (VC) technology is a cutting-edge alternative to 
in-person delivery. Healthcare delivery is moving rapidly in the direction of utilizing innovative 
technologies to overcome myriad inefficiencies costs, and barriers that currently stymy the US 
healthcare system.39-42  “Telehealth” is a burgeoning sector of healthcare delivery in the US. VC 
technology has numerous potential advantages for delivering interventions directly from providers to 
patients situated in their own homes.73 Geographical, financial, and unreliable transportation barriers 
are eliminated. Patients who are too ill to travel can participate.74 Reducing patient barriers may lead to 
higher rates of study enrollment and attendance. Recruitment for in- person interventions is often lower 
than 40%71, while recruitment for phone- or web-based interventions can range from 57-94%.7,75-77 
Higher attendance may increase intervention “dose,” which in turn, may increase clinical 
effectiveness.75,78 Patient satisfaction with VC has been shown to be very high and often is preferred 
over in-person sessions due to overcoming many obstacles.5,75,78,79 Importantly, skill-based 
psychosocial treatments are commonly delivered in a group format, and can be highly economical and 
efficient for providers and healthcare systems. Delivering psychosocial skill-based interventions in 
group formats also capitalize on positive therapeutic processes such as group cohesion, peer support, 
bonding and social persuasion.80 In order to retain cost-efficiency and beneficial processes of group-
based therapy, an ideal telehealth version of the CBCS-HCV would be delivered via VC technology to a 
group of HCV patients, participating from the comfort of their own home. While many telehealth 
modalities are being investigated, most are 1:1 provider-to-patient; very few have investigated 
delivering a group-based intervention to multi-end-user patients in their own separate homes. 2-5 
 
Since the CBCS-HCV is a skill-based intervention and group format is often the standard of care for 
these types of interventions, multi-user VC delivery may be a cutting edge and efficient system to 
deliver holistic interventions to patients who might not otherwise have access to services due to illness 
or transportation barriers. Pilot testing the CBCS group-based intervention via a state-of-the-art VC 
multipoint platform is a highly innovative and a logical extension of our previous work. Delivering the 
CBCS-HCV via VC may decrease patient barriers, increase access to care, and be clinically effective. 
However, the feasibility, technical issues, patient satisfaction, and preliminary outcomes require pilot-
testing to determine if a larger efficacy trial is warranted. 
 
We propose to conduct a pilot feasibility study of a small randomized controlled trial (RCT) to evaluate 
the CBCS delivered via videoconferencing (herein referred to as “VC-CBCS”) compared to patients in 
standard of care (SC) with a representative sample of 32 symptomatic HCV patients, to address the 
following specific aims:  
 
2 STUDY AIMS  
 
Aim 1: Evaluate the feasibility of conducting a RCT of the VC-CBCS, quantified as the proportion of 
patients (a) approached vs. consented vs. enrolled/randomized vs. retained, and (b) who complete data 
collection;  
Aim 2: Evaluate the feasibility of intervention delivery via VC, quantified as (a) the proportion of 
sessions attended by participants and (b) frequency and nature of technical, logistical, or participant 
problems; 
Aim 3: Evaluate patient acceptability and satisfaction;  
Aim 4: Explore changes in patient outcomes, mediators and intervention targets, as well as temporal 
associations and strength of associations among variables in a preliminary conceptual model, to inform 
a future efficacy trial. 
 
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
3 STUDY DESIGN  
 
3.1 Study Design 
This pilot feasibility study was designed as a preparatory two-arm small randomized controlled trial 
(RCT) with a total enrollment of 32 participants assigned by randomization to VC-CBCS (n=24) or SC 
(n=8) to address the specific aim.  
 
3.2 Study Participants 
Participants (n=32) will be a representative sample of adult patients, age 21 or older, who have or had 
a diagnosis of chronic HCV 
 
3.3. Inclusion/Exclusion Criteria 
 
 
3.3.1. Inclusion 
• 
Age 21 and older; 
• 
Medically cleared by hepatology; 
• 
Patients who are currently or were previously diagnosed with chronic HCV; 
• 
Evidence of ongoing symptoms, stress, or unhealthy lifestyle habits, defined as a score of 
greater than or equal to 4 on a scale 0(none) - 10 (severe) on two or more numeric rating scale 
questions (see Screening Form 1); 
• 
Able to read and speak English. 
3.3.2. Exclusion 
• 
Decompensated liver disease (Childs Pugh C) judged by hepatologist or recorded in patient 
medical record; 
• 
Life expectancy of <12 months estimated by hepatologist; 
• 
Has had a liver transplant or is on the waitlist for a transplant; 
• 
Severe alcohol or substance use disorder, psychiatric disorder or cognitive impairment that is 
likely to interfere with the ability to participate in telehealth groups and follow guidelines about group 
participation as judged by the Hepatology provider or research staff using a two-tiered research 
screening process (See Section 6); 
• 
Lack of private, quiet space in home in which to participate in VC-CBCS sessions; and 
• 
Unwilling to have group sessions audio-recorded.  
4 RECRUITMENT 
 
A two-pronged recruitment strategy will be utilized (primary: in person in liver clinic; secondary: over the 
phone). Patients will be recruited from the outpatient liver clinics or by phone if referred by a hepatology 
provider.   
 
For every patient approached for recruitment, a minimal amount of data will be stored in a REDCap 
Screening Database, separate from the REDCap Research Database. The Screening Log will include: 
name, MRN, phone number, race, sex, age, and reason for exclusion or not proceeding forward with 
consent process. Name, MRN and phone number will be deleted after recruitment ends. De-identified 
race, sex, and age are retained to satisfy CONSORT guidelines for future publications.  
 
Patients will be recruited in 4 waves. Although we seek to enroll/randomize a total of 32 patients with 24 
randomized to VC-CBCS and 8 randomized to SC, we will over-consent to accommodate for patients 
who are deemed ineligible during the screening process or who withdraw consent prior to enrollment. 
The overall 3:1 randomization scheme allows us to examine feasibility of randomization while allowing 
us to intensively examine the VC-CBCS group.  
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
 
5 INFORMED CONSENT PROCESS 
 
The informed consent process will take place in person in the GI liver clinic or over the phone.  
1. In-Person Consent: Interested patients will be introduced to study staff and taken to another private 
room to engage in the informed consent process and screening assessment. Interested and eligible 
patients will sign and date/time the consent forms, staff signs/dates and the patient will be provided a copy. 
The informed consent process will be documented for each consented patient. After written consent is 
obtained, staff can begin to screen and collect data from the patient. 
2. Over-the-Phone Consent: When a prospective patient is referred by a hepatology provider to the 
study team, the staff will pre-screen the patient using a limited waiver of HIPAA approved by the UNC IRB. 
Study staff will access patient medical records for contact information and conduct a brief eligibility 
assessment (e.g., HCV diagnosis, > age 21, English speaker). Staff will contact patients via phone to 
discuss the study and consent documents. Interested patients will be consented with a verbal telephone 
consent and then be emailed or mailed a HIPAA authorization with a pre-paid envelope for return. The 
study team will then review the HIPAA authorization with the participant and instruct the participant to sign 
and date and return to study in provided envelope. Participants will be considered consented if and when 
they agree to the telephone verbal consent, but their medical records will not be accessed until signed 
HIPAA authorization is received by the study team.  
Whether consented in-person or over the phone, all components of the informed consent process will be 
reviewed and documented per federal (https://www.hhs.gov/ohrp/regulations-and-
policy/regulations/finalized-revisions-common-rule/index.html) and institutional guidelines 
(https://www.hhs.gov/ohrp/regulations-and-policy/regulations/finalized-revisions-common-
rule/index.html) and relevant Good Clinical Practice Guidelines from the International Conference on 
Harmonisation. Issues of privacy, confidentiality, and time commitment will be discussed. Patients will 
verbalize understanding that research participation in voluntary and they can choose to stop or decline 
at any time without penalty. They can refuse to participate, and this decision will not affect their medical 
care at UNC. They can refuse to answer any study or interview question. The study staff obtaining 
consent will allow ample time for patients to ask questions and express full understanding of the study.  
 
A checklist of the informed consent process will be retained for all consented patients. All signed 
consent forms will be uploaded to the REDCap database and hard copies retained in a secure location. 
Data collection, enrollment, randomization will not commence until all necessary consents have been 
obtained.  
  
Patients will consent to participate in the following:  
1) review of electronic medical records for clinical data;  
2) undergo screening process and collection of screening data; 
3) participation in a 14-week VC-CBCS group intervention delivered via home technology or study-
loaned tablets that patients may return at the end of the study; 
4) participation in a group exit interview following participation in the intervention; 
5) completion of self-report surveys throughout the study; 
6) collection of saliva samples at pre- and post-intervention; and  
7) REDCap storage of email address, mailing address, phone numbers for self and a loved one in case 
of lost to follow-up. This information is required for REDCap data collection of surveys, reimbursement 
to patients and communication throughout the study.  
 
6 SCREENING FOR VC-CBCS ELIGIBILITY 
To enhance intervention fidelity, group cohesion/dynamics, and adherence to the protocol, a two-tiered 
screening process will be conducted to enroll eligible patients. Patients will be consented prior to 
engaging in the screening assessment. Phase I of screening will occur with study staff in-person in the 
liver clinic or over the phone. Phase II is conducted by the study PI.  

VC-CBCS Study protocol v7.0—16Nov2021 
 
6.1 Phase I Screen: Staff will conduct the initial screening for I/E criteria using three Screening Forms 
located in a separate REDCap database for screening data only. The patient must meet all inclusion 
criteria including "evidence of ongoing symptoms, stress, or unhealthy lifestyle habits as defined by a score 
of ≥ 4 on a rating scale from 0 – 10, for ≥ 2 symptoms, perceived stress, or lifestyle habits" and must not 
meet exclusion criteria, including severe current alcohol, substance use or psychiatric disorder likely to 
interfere with group dynamics or adherence to study protocol. The Screening Forms will include items to 
determine inclusion/exclusion criteria, including assessment of physical and mental symptoms, stress level, 
and lifestyle habits. Alcohol, substance use, and psychopathology will be assessed using questions from 
validated instruments, including the Alcohol Use Disorders Identification Test (AUDIT), the Substance 
Abuse and Mental Illness Brief Symptom Screener (SAMISS) and additional screening items developed by 
the PI. Screening will take place in-person in private exam room in clinic, or over the phone. 
 
6.2 Phase II Screen: The second phase of the two-tiered screening process will be conducted by the PI (a 
licensed clinical psychologist at UNC Healthcare) who will review the Phase I screening forms and discuss 
the prospective participant with the screening coordinator who conducted the consent and screen. If the 
patient meets I/E criteria and screens negative for severe current alcohol, substance use or psychiatric 
disorders, the patient will be approved for enrollment into the study based on Phase I screening data. 
When ambiguity or uncertainty arises regarding the patient’s eligibility related to current alcohol, substance 
use or psychiatric disorders, the PI will conduct a brief clinical interview with a prospective participant over 
the phone. Based on the two-tiered screening process, the PI will adjudicate final decisions regarding study 
eligibility.  
 
The goal of the two-tiered screening process is to ensure that patients (1) are appropriate for a group 
therapeutic setting; (2) are at low risk for verbal behaviors that will interfere with or sabotage group 
cohesiveness/support which is critical to the success of psychosocial interventions; (3) are able to adhere 
to the study protocol and rules of engagement; and (4) with active and severe psychiatric or substance use 
disorders are referred for more appropriate individual treatment in their local community.  
 
Patients judged to have untreated or more severe psychopathology will receive a referral from the PI to 
more appropriate mental health/addiction services in their local community. 
 
6.3 Screening Data: Data from the three Phase I Screening Forms will be stored in a REDCap screening 
database separate from the Research Data. For patients who are ineligible or decline to participate, their 
name, MRN, age, sex, race, and reason for ineligibility/refusal will be retained in the screening REDCap 
database. All other screening data will be deleted at the end of the study. Name and MRN are retained 
during the study for staff to identify previously recruited but ineligible patients. Name and MRN of non-
enrolled patients will be deleted from the screening database after recruitment ends. The hard copy Phase 
II Brief Clinical Interview forms will be shredded after recruitment ends. Once the screening data are 
deleted or de-identified, only sex, race, age, and reason for non-enrollment patients will be retained until all 
data are published, to satisfy CONSORT guidelines. Once final data are published, the REDCap Screening 
database will be deleted. For patients who are eligible and enrolled, data from the three Screening Forms 
will be exported into the Research REDCap database to describe characteristics of the cohorts. 
 
7 REIMBURSEMENT 
 
Participants in both conditions will be reimbursed $25 for four patient-reported outcomes (PROs) 
assessments and two days of salivary sample collection. Completion of PROs during each assessment 
period will take 20-30 minutes. Patients randomized to VC-CBCS will be reimbursed $25 to participate in 
an exit focus group. For reimbursement of VC-CBCS sessions, participants will be reimbursed for cellular 
and wi-fi data plans, if needed for iPad use, and will be given two options: (1) retain the iPad (worth $300) 
after the study ends; (2) receive a rechargeable Visa gift card at the beginning of the study that will be 
recharged with $300 after the intervention ends and iPad is returned.  Participants will check their 
preference for one of these two options on the consent form. Participant preferences will be tracked in a 
Reimbursement Log to inform reimbursement options for a future RCT. 

VC-CBCS Study protocol v7.0—16Nov2021 
 
 
8 RANDOMIZATION  
 
Four groups of patients will be randomized and will consist of 7-9 patients each. The groups are as follows:  
 
• 
Group 1 - 7 patients with 5 randomized to VC-CBCS and 2 to SC;  
• 
Group 2 - 9 patients with 7 randomized to VC-CBCS and 2 to SC;  
• 
Groups 3 and 4 - 8 patients each with 6 randomized to VC-CBCS and 2 to SC each group.  
 
Once each group meets their respective necessary number of patients, they will be randomized. We will 
use these randomization procedures for a total of 24 participants randomized to VC-CBCS and 8 
randomized to SC and overall 3:1 ratio. A computer-based procedure for permuted-block randomization 
and concealment will be implemented by non-study staff. No study personnel will have access to the 
randomization schedule. The computer-generalized randomization scheme will automatically randomize 
patients who are enrolled to one of the two group assignments after each wave is enrolled. Participants will 
be subsequently called and informed of group assignment. 
 
9 STANDARD CARE 
 
Patients randomized to the SC condition will be managed per standard HCV and liver disease 
management guidelines by the UNC hepatologists. Clinic appointments, lab tests and procedures will be 
conducted at the provider’s discretion. Depending on severity of liver disease, patients are typically 
followed every 6-12 months by Hepatology. Research staff will have minimal contact with SC participants 
except during PRO assessment windows and two saliva sample collections. Study staff will extract clinical 
data from electronic medical records up to 6 months post-intervention.   
 
10 VC-CBCS GROUP INTERVENTION 
 
The CBCS is based on Cognitive Behavioral Theory (CBT) and the Informational-Motivation-Behavioral 
skills (IMB) theoretical framework.83,97,101 The intervention modules will be delivered over 14 sessions, each 
with a duration of 90 to 120 minutes to allow for the practice of a newly introduced skill. Each session will 
incorporate comprehensive information on evidence-based skills for health behavior change and stress 
management. The modules will also incorporate CBT skills and educational materials developed by federal 
agencies.102-104 Sessions will include background information and rationale, recommended behavioral skills 
and will utilize strategies such as peer discussion and support, goal-setting and motivational enhancement 
techniques to increase commitment and motivation for positive lifestyle changes.  
 
10.1 Tentative Conceptual Model of the VC-CBCS 
As a pilot feasibility study, we are not testing the intervention model depicted in Figure 1 below. We are 
mapping out a hypothetical model to gather preparatory information to inform a subsequent efficacy trial: 
The model helps to identify survey items that need to be developed or used to measure intervention targets 
and mediators. Pilot-testing will help determine the optimal frequency of data collection of targets and 
mediators while balancing patient burden. Pilot-testing will help with exploration of preliminary associations 
(aim #4) among variables to understand their temporal relationships and strength of associations. Figure 1 
describes how each intervention session will attempt to target information-motivation-behavioral skills 
(CBT, stress management, health behaviors). Didactic information is provided to build ‘buy-in’. Behavioral 
skills are taught and practiced during session and as homework. Sessions wrap up with round robin 
discussion of patients’ SMART goals for the week and why a patient is motivated to work on this goal 
(fosters personal and social motivational enhancement, commitment, social persuasion, and healthy 
norms). Intervention targets may improve both psychological and physiological stress, healthy behaviors, 
and medication adherence, which may operate as mediators/mechanisms of change, but may also serve 
as intermediate outcomes in and of themselves. These mediators or intermediate outcomes may in turn, 
improve health outcomes, including overall health status and  symptoms. It is plausible that behavioral 
changes and stress reduction may improve clinical disease outcomes. In this pilot study, we will attempt to 
collect aspartate aminotransferase (AST) and alanine aminotransferase (ALT) from patients electronic 
health records (EHRs) to determine the feasibility of collecting standard clinical data from the EHRs, and if 

VC-CBCS Study protocol v7.0—16Nov2021 
 
feasible, explore potential pre-post change in these two markers of liver inflammation. We will also extract 
additional clinical variables of interest that may be relevant to a future efficacy trial, such as hemoglobin 
A1C in diabetic patients (~ 20% of sample), body weight (kg) and other laboratory tests.  If a future efficacy 
trial finds the VC-CBCS to have short-term benefits on patient outcomes, it would behoove us to 
investigate the potential for longer-term benefits on subjective health, liver disease, and other comorbid 
conditions, as has been shown in other medical populations.106-109 
 
Figure 1: Conceptual Model of VC-CBCS Intervention 
 
 
 
 
10.2 Conducting the VC-CBCS Group Intervention 
Sessions will be delivered using the UNC School of Medicine’s University-approved, HIPAA-compliant 
WebEx® videoconferencing system. WebEx® is an application that is widely used for web and 
videoconferencing meetings and includes multi-point audio and video communication, screen sharing, 
video and audio recording, and telephone bridging. The research team will work closely with the UNC 
School of Medicine Information Technology Security Team on all aspects of delivering the VC-CBCS 
including patient instructions, iPad set up, and remote data cleaning. Each group member will join the 
virtual group from their home using their choice of home audio-visual technology or study-provided iPads to 
simultaneously observe and interact with the group facilitator and other group members (“Brady Bunch” 
style).  
 
All modules follow the same three-part organization (Table 1):  
(1) Introduction and practice of new relaxation skill 
(2) Review of previous weeks’ information, skill, and SMART goals 
(3) Information, acquisition, and practice of new skills. Didactic information is followed by practicing skills to 
aid in cognitive behavior change. Motivational enhancement strategies are used to increase personal and 
social motivation.97,101 SMART goals are used to promote achievement of weekly goals that are specific, 
measurable, action-oriented, realistic, and time-based.  
 
VC-CBCS sessions will be led by a Masters-level therapist with experience in facilitating groups, protocol-
based and evidence-based treatments, and adept at motivational enhancement strategies.  
 
VC-CBCS patient materials will be stored on iPads and uploaded to a secure Google Drive shared drive 
containing no identifying information. Materials include the Patient Workbooks, relaxation audio-recordings, 
technical instructions, and link to unique REDCap application system. Hard copy Patient Workbooks will 
also be mailed to each participant prior to the first session for use during sessions.   
 
 
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
 
 
Table 1: Content and structure of 14 VC-CBCS group modules 
 
Figure 2: How does the VC-CBCS help to improve Liver Health and Wellness? 
 
 
Mod 
Part 1: 
 Relaxation Training 
Part 2:  
Review and Application of Previous 
Skills 
Part 3: 
Training in New Topic and Skills 
1 
Progress. Muscle Relax. 
(PMR-6) 
Introductions, Group Expectations; 
Confidentiality 
Overview of Liver Functions, Liver 
Conditions, and Targets of the VC-CBCS 
Intervention  
2 
Diaphragmatic Breathing & 
PMR-4 
Overview of Liver Functions, Liver 
Conditions, and Targets of the VC-CBCS 
Intervention 
Love Your Liver: Healthy Nutrition and 
Hydration 
3 
Diaphragmatic Breathing & 
Mindfulness 
Love Your Liver: Healthy Nutrition and 
Hydration 
Physical Activity for the Liver 
4 
PMR-4 & Healing Wellness 
Imagery 
Physical Activity for the Liver 
Sleep Hygiene & Managing Sleep 
Problems 
5 
Diaphragmatic Breathing & 
Light Imagery 
Sleep Hygiene & Managing Sleep 
Problems 
Taking medications as prescribed & 
Maintaining Healthy Lifestyle 
6 
Deep Breathing & Immune 
Guided Imagery  
Taking medications as prescribed & 
Maintaining Healthy Lifestyle 
Stress Awareness & Appraisal 
7 
Diaphragmatic Breathing & 
Autogenic Training 
Stress Awareness & Appraisal  
Automatic Thoughts & Cognitive 
Distortions 
8 
PMR-4 & Self-Forgiveness 
Affirmation Script 
Automatic Thoughts &  
Cognitive Distortions 
 
Cognitive Restructuring 
9 
Counting Breaths & Passive 
PMR 
Cognitive Restructuring 
Coping with Stress & Symptoms 
10 
4-7-8 Breath & Mindful 
Movement 
Coping with Stress & Symptoms 
Cognitive-Behavioral Skills for 
Depression - Behavioral Activation & 
Pleasurable Events 
11 
Short Body Scan 
Cognitive-Behavioral Skills for Depression 
– Behavioral Activation & Pleasurable 
Events 
Activity-Rest Cycles 
12 
Mini Practices & Self-
Acceptance Affirmation 
Script 
Activity-Rest Cycles 
Anger Prevention & Management 
13 
Mindfulness Meditation & 
Deep Breathing 
Anger Prevention & Management 
Assertive Communication; 
Interpersonal Effectiveness 
14 
Group Choice 
Assertive Communication; Interpersonal 
Effectiveness 
Maintenance of Positive Lifestyle 
Changes & SMART Goals;  
Group Program Review 

VC-CBCS Study protocol v7.0—16Nov2021 
 
10.3 Technology Training and iPads and Review of Rules of Group Engagement and Privacy 
If patients do not have appropriate audio-visual technology on home computers/laptops, they will be 
provided a study iPad and funding for cellular or internet data plans during the duration of the study. The 
UNC School of Medicine Information Technology Services (ITS; https://its.unc.edu/) staff and the 
national broadband map (https://www.broadbandmap.gov/) will be used to determine best data plans for 
each participant. The iPads will be set-up and secured by SOM ITS. Participants will receive iPad, 
internet, and REDCap data collection training from the research staff with ITS support prior to the initial 
session. A conference line will be available if VC disconnection occurs. All technical issues will be 
tracked as part of reporting feasibility outcomes. Our consultants will share best practices for delivering 
tele-mental health.45,105 An SOM ITS expert will be available during each cohort launch to troubleshoot. 
Although patients will be provided iPad and data plans, WebEx® is available for Android and iOS smart 
phones. A few patients may be allowed to participate via smartphone to examine patient satisfaction and 
outcomes using smartphones, which could be more scalable in future projects. They can complete their 
post-session surveys at the conclusion of each session or at their convenience during the assessment 
window (7 days).  
 
During the WebEx® training with study staff, privacy and confidentiality issues related to engagement in 
home-based virtual groups with other participants will be thoroughly discussed. A copy of group rules 
will be reviewed. Participants will need to provide verbal assurance that they will respect the group 
privacy rules.  
 
10.4 Iterative changes to VC-CBCS intervention 
Based on patient feedback and lessons learned, the research team will modify aspects of the VC-CBCS in-
between the four waves. Changes may be made based on feasibility data, patient satisfaction ratings, and 
impromptu feedback, feedback from exit focus groups and overall experiences and lessons learned. 
Consideration for making substantial changes during the trial would occur if major issues were identified 
that seriously jeopardize recruitment, attendance, retention, or data collection efforts. Otherwise, we will 
carefully track issues during each wave, making minor changes to improve performance, and solicit 
feedback about issues during exit focus groups. If recruitment, attendance, and retention are not hugely 
jeopardized, the team may wait to make substantive changes until after all the feasibility, patient 
acceptability, and exit focus group data are analyzed.  
 
11 DATA COLLECTION ASSSEMENT SCHEDULE 
 
The data collection assessment schedule is shown in Table 2.  
 
11.1 PRO Assessments 
In both conditions, PRO survey data will be collected directly from patients during the following assessment 
periods:  
 
T1: Pre-intervention (time period: Within 30 days prior to start of 1st intervention session); 
T2: After the 5th intervention session (time period: Within 21 days after the 5th session); 
T3: After the 10th intervention session (Time period: Within 21 days after the 10th session); and 
T4: At post-intervention after the 14th session (Time period: within 14 days after the 14th session). 
 
11.2 Salivary Cortisol 
Saliva samples will be collected from participants in both conditions pre-intervention and post-intervention 
as described below. Pre-intervention time period is within 7 days prior to 1st intervention session. Post-
intervention time period is within 7 days after final 14th intervention session.  
 
11.3 VC-CBCS Process Assessments 
In participants assigned to the VC-CBCS condition, they will submit self-report data directly into REDCap 
after each of the 14 intervention sessions to collect process data. Data collected will include Patient 
Satisfaction/Acceptability Ratings; S-M-A-R-T (specific, measurable, action-oriented, realistic, and time-
based) goals; Ratings of Importance, Motivation and Self-Confidence related to each SMART goal. 
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
Table 2: Data Collection Schedule 
 
 
12 MEASURES TO EVALUATE FOUR SPECIFIC AIMS 
 
12.1 Study and Intervention Feasibility (Aims #1, #2) 
To address specific aims #1 and #2, several feasibility measures will be collected from all participants. To 
evaluate the feasibility of conducting a larger RCT of the VC-CBCS, we will collect data on the proportion of 
patients who are approached/contacted by study staff (Napproached) vs. consented (Nconsented) vs. 
randomized/enrolled (NR/E) vs. retained (Nretained). Feasibility of data collection, EHR extraction of clinical 
data, and frequency and patterns of missing data on various outcomes will be evaluated (i.e., PROs, 
process/intermediate outcomes, salivary samples, clinical/disease outcomes). To evaluate the feasibility of 
delivering the intervention via video technology, we will collect feasibility data on the proportion of sessions 
attended by VC-CBCS participants, have patients complete a telehealth satisfaction survey, and track the 
frequency and nature of technical, logistical, and participant problems.  
 
12.2 Patient Satisfaction (Aim #3) 
To address specific aim #3, several measures of patient satisfaction will be collected. VC-CBCS patients 
will complete a Patient Acceptability/Satisfaction survey after each of the 14 sessions.6 They will complete 
a survey on satisfaction with therapist and group dynamics midway through and at end of the 
intervention.6,99,110,111 Reasons for drop out and attrition will be evaluated in both conditions. Exit group 
interviews will be conducted with each VC-CBCS cohort after the intervention ends and will be audio-
recorded. The audio recording will be stored on a secure network server housed by UNC. The qualitative 
data will be analyzed to understand likes/dislikes, pros/cons, and solicit feedback on optimizing the 
intervention (e.g., number and duration of sessions, modules, relaxation skills, structure, group format, data 
collection). For the Patient Acceptability/Satisfaction Survey, items are scored on a scale from 1= not at all 
to 5=extremely. Data across all patients and all sessions will be averaged into a Total Patient Satisfaction 
Table 2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 
1. Study Feasibility 
# approached to consented 
X 
# consented to eligible 
X 
# eligible to enrolled/randomized 
X 
# enrolled/randomized to retained 
X 
X 
Randomization 
X 
Session Attendance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Data Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Technology/Logistical Problems 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2. Patient Satisfaction 
Patient Acceptability  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reasons for drop out 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Group Dynamic Survey 
X 
X 
Exit Focus Groups 
X 
3. Protocol Fidelity 
Facilitator Adherence 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
     Facilitator Competence 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4. Patient Features 
NINR sociodemographic data 
X 
Screening information 
X 
X 
Clinical / lab data   
X 
X 
5. Intervention Targets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6a. Intermediate Outcomes/Mediators X 
X 
X 
X 
6b. Salivary Cortisol 
X 
X 
7a. PROs 
X 
X 
X 
X 
7b. Liver enzymes / clinical data 
X 
X 

VC-CBCS Study protocol v7.0—16Nov2021 
 
score that could range from 1 to 5 with higher scores indicating greater satisfaction. One secondary 
outcome is the overall Patient Acceptability/Satisfaction survey mean score from all patients over all 14 
sessions. 
 
12.3 Patient-Reported Outcome Measures (Aim #4) 
To address specific aim #4, several PRO measures will be collected to evaluate primary, secondary and 
exploratory outcomes to examine the temporal associations and strength of associations among variables 
in the preliminary conceptual described in Figure 1. PROs will be collected from all participants at four PRO 
time points (T1-T4). Collection of PRO data serves several preparatory functions for the efficacy trial 
including making final selection of PROs, contributing to sample size calculations, and exploring 
preliminary relationships with other variables in the causal pathway.  
 
13 PRIMARY FEASIBILITY OUTCOME MEASURES 
 
13.1 Percentage of Patients Consented Versus Approached 
13.2 Percentage of Participants Consented Versus Randomized 
13.3 Percentage of Standard of Care Condition Participants Retained vs Enrolled 
13.4 Percentage of VC-CBCS Intervention Condition Participants Retained vs Enrolled 
13.5 Percentage of Surveys Completed by Participants Who Completed the Study 
 
14 PRIMARY PATIENT-REPORTED OUTCOME MEASURES 
Several of the NIH Patient-Reported Outcomes Measurement System (PROMIS®) short forms will be used 
to measure primary outcomes such as health status, mental health symptoms, and physical health 
symptoms. We have found the PROMIS® surveys to have good psychometrics in HCV patients.124 The 
primary patient-reported outcomes will be the mean T-scores at T1 (Baseline) and T4 (end of intervention): 
14.1 PROMIS Global Health Status Mental Health Mean T-Score 
14.2 PROMIS Global Health Status Physical Health Mean T-Score 
14.3 PROMIS Depression Mean T-score 
14.4 PROMIS Anger Mean T-score 
14.5 PROMIS Anxiety Mean T-score 
14.6 PROMIS Fatigue Mean T-score 
14.7 PROMIS Sleep Disturbance Mean T-score 
14.8 PROMIS Pain Interference Mean T-score 
 
15 SECONDARY PATIENT-REPORTED OUTCOME MEASURES 
 
15.1 The Perceived Stress Scale Mean Score (PSS) measures perceived stress in all participants at four 
PRO time points (T1-T4) and covers 30 days prior to assessment.115 The PSS is a widely used survey to 
measure stress perception. The scale includes 10 items, rated using a 5-point scale, from 0 (never) to 4 
(very often) where patients report the frequency of stress symptoms in the past month. Higher PSS scores 
reflect higher subjective stress.  
15.2 Sleep Behaviors 
15.2.1 Pittsburgh Sleep Quality Index (PSQI) measures sleep behaviors and issues.117 All participants 
complete this measure at PRO time points T1 and T4 that covers 30 days prior to assessment. "During 
the past month, how would you rate your sleep quality overall?" The response set ranges from a 
minimum of 0 (Very Good) to a maximum of 3 (Very Bad). Higher mean scores indicate worse sleep 
quality. 
15.2.2 Pittsburgh Sleep Quality Index (PSQI) Sleep Efficiency Composite Mean Score. Items 1, 3 and 4 
from the Pittsburgh Sleep Quality Index (PSQI) were used to create a Sleep Efficiency composite 
score. All participants completed this measure at T1 and T4 that covered 30 days prior to assessment. 
The sleep efficiency score = (# hours slept/# hours in bed) X 100% .The sleep efficiency composite 

VC-CBCS Study protocol v7.0—16Nov2021 
 
score ranged from: 0 = >85% efficiency,1 = 75-84% efficiency, 2= 65-74% efficiency, and 3= <65%. 
Lower scores indicate better sleep efficiency. 
15.2.3 Healthy Sleep Behaviors Mean Score. One item "In the last month, how often did you engage in 
healthy sleep behaviors before bedtime?" evaluated healthy sleep behaviors. All participants completed 
this measure at T1 and T4. The response set ranged from 0 (not at all) to 4 (almost every night). Higher 
scores indicated better sleep behaviors. 
15.3 Medication Adherence Visual Analog Scales evaluate medication adherence for up to five daily 
medications for multiple comorbidities in the past 7 days in participants who were prescribed medications 
at baseline. Participants report the average adherence over the course of 7 days for each medication on a 
scale from 0% to 100% adherence for each medication.  
15.4 Coping Skills Confidence Mean Score: Items from the Measure of Current Status (MOCS)-Part A 
will measure patient confidence in performing multiple skills including stress awareness, relaxation, 
assertiveness, and coping skills.114 The Measure of Current Status (MOCS)-Part A will measure patient 
confidence in performing multiple skills including stress awareness, relaxation, assertiveness, and coping 
skills. The scale contains 13 items rated on a scale from 0 = I cannot do this at all to 4 = I can do this 
extremely well. A Total Coping Skills score is created by taking the average of the 13 items where the Total 
Coping Skill score can range from 0 to 4.  
15.5. Alcohol and Drug Use:  Items from the Substance Abuse and Mental Illness Symptoms Screener 
(SAMISS) Survey evaluate self-reported alcohol use (3 items), non-prescription street drug use(1 item), 
and prescription drug misuse (1 item) in all participants. Individual scores could range from 0 to 4, with 
higher reported mean scores indicating higher consumption. 
15.6 Behavioral Risk Factor Surveillance System (BRFSS)116 items measure health behaviors such as 
exercise; fruit, vegetable, added sugar and sweet beverage consumption; meals prepared at home in all 
participants at T1 (baseline) and T4 (Week 14) and will cover 30 days prior to assessment. BRFSS items 
were used to measure the following secondary outcomes: 
15.6.1 Percentage of Participants Who Improved Fruit Consumption by One or More Categories 
15.6.2 Percentage of Participants Who Improved Vegetable Consumption by One or More Categories 
15.6.3 Percentage of Participants Who Complete Moderate Activity for at Least 10 Minutes at a Time 
15.6.4 Mean Number of Minutes of Moderate Activity Per Week 
15.6.5 Percentage of Participants Who Complete Vigorous Activity for at Least 10 Minutes at a Time 
15.6.6 Mean Number of Minutes of Vigorous Activity Per Week 
15.6.7 Mean Time Spent Sitting on the Weekdays 
15.6.8 Mean Time Spent Sitting on the Weekends 
15.6.9 Percentage of Participants Who Reduced Regular Soda Intake by One or More Categories 
15.6.10 Percentage of Participants Who Reduced Diet Soda Intake by One or More Categories 
15.6.11 Percentage of Participants Who Reduced Meals from Fast Food Restaurants by One or More 
Categories 
15.6.12 Percentage of Participants Who Increased Dinners Prepared at Home by 1 or More Days 
 
15.7 Participant Satisfaction With VC-CBCS Intervention Mean Score: After each VC-CBCS 
intervention session, participants complete a 14-item acceptability/satisfaction survey about their 
impressions with the current intervention session. Items are scored on a scale from 1= not at all to 
5=extremely useful. Data across all VC-CBCS participants and all intervention sessions are averaged into 
a Total Patient Satisfaction score that could range from a minimum of 1 to a maximum of 5 with higher 
scores indicating greater satisfaction. 
 
15.8 Weight Changes. Change in raw weight, percent weight change, and BMI evaluated among those 
who had pre-intervention BMI > 24.9 (overweight and above) from T1 to T4. 
 
16 SECONDARY CLINICAL OUTCOMES 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are extracted from all participants 
electronic health records (EHRs) who had already achieved viral cure at baseline and who were not on 
HCV treatment at baseline in order to determine feasibility of extracting these data from the medical record 

VC-CBCS Study protocol v7.0—16Nov2021 
 
and explore pre and post intervention mean scores in these two markers of liver inflammation. Mean AST 
and ALT levels are compared in both females and males. 
 
17 EXPLORATORY PATIENT-REPORTED OUTCOME MEASURE 
 
17.1 Satisfaction with Telehealth Session Mean Score. After session 1 and session 14, participants 
complete a 15-item acceptability/satisfaction survey about their satisfaction with using telehealth sessions. 
Items are scored on a scale from 1= strongly disagree to 5=strongly agree. The average Total Telehealth 
Satisfaction score is analyzed from session 1 and session 10, which could range from 1 to 5 with higher 
scores indicating greater satisfaction.  
 
18 EXPLORATORY STRESS BIOMARKER OUTCOME 
Participants in both conditions collect saliva samples at baseline (T1) and post-treatment (T4). Cortisol 
secretions follow a diurnal pattern, but physiological and psychological stress disrupt normal rhythms, 
dysregulate the sympathetic nervous system and HPA axis and are associated with poor health. 
Conversely, stress management skills regulate cortisol patterns.32,92,118-120 Participants will be given two 
salivary collection kits to provide salivary samples pre- and post-intervention. Participants will provide 
salivary samples four times: immediately upon wakening, 30 minutes after awakening, in the late afternoon, 
and at bedtime. Research staff will contact patients the day prior to collection to remind them of the 
protocol. Samples will be stored in participants’ home refrigerators within 30 minutes of collection and 
mailed to UNC in pre-paid gel wrap mailers. Samples will be stored at −80°C until assayed. Collection and 
storage methods have been validated.121 Saliva samples will be stored de-identified using subject ID 
number only. Mean log10 cortisol as a diurnal function of time of day and summary values such as the area 
under the curve (AUC), AUC minus ground will be compared from T1 to T4. Lower cortisol levels indicate a 
lower level of stress.  
 
19 INTERVENTION TARGETS 
VC-CBCS participants will complete a weekly Post-Intervention Form after each of 14 sessions directly into 
REDCap on their iPad or home technology.  
 
19.1 SMART Goals related to health changes, stress management, and cognitive-behavioral skills. After 
each new session, each patient will describe at least one new SMART goal related to the session topic 
such that after session one, they describe one goal…after session 14, they describe 14 goals, one per 
topic. 
 
19.2 For each SMART goal, patients will rate the Importance/Relevance of the particular goal, their 
Motivation to achieve the goal, and their Self-Efficacy to achieve the particular goal. The three ratings will 
be on a Numeric Rating Scale ranging from 0% to 100%. 
 
20 PATIENT SOCIODEMOGRAPHICS 
At baseline (T1), all participants will self-report the following NINR data elements: age, sex, race, ethnicity, 
marital status, income, education level, employment status, caregiver type, household member total count, 
and health comorbidities.112-114 History of psychiatric, alcohol and substance use issues will be obtained 
during the screening process and transferred to the research database for enrolled patients. All data will be 
cross-validated with data reviewed in patients’ EHRs. 
 
21 PROTOCOL FIDELITY 
To examine the Group Facilitator’s competency and fidelity to the intervention protocol and 14 modules, we 
will utilized two observer-rating forms to evaluate Facilitator Adherence and Facilitator Competency to 
manage group dynamics. A research staff member will observe VC-CBCS sessions and complete the 
observer-rating Facilitator Adherence form, rating the proportion of sections completed on scale of 0-100%. 
The staff member will also complete the Facilitator Competency observer-rating form, a 14-item Likert 

VC-CBCS Study protocol v7.0—16Nov2021 
 
scale (1=not at all; 4=extremely). The Facilitator will not have access to these ratings until completion of 
each cohort. 
 
22 ELECTRONIC DATA CAPTURE AND SECURE STORAGE 
 
Data will be directly entered and stored in the web-based research electronic data capture system, 
REDCap (https://projectredcap.org/). The REDCap system is a secure, HIPAA-compliant web-based 
application to support distributed data collection governed by standard University, School of Medicine, and 
Federal information security policies and standards. The REDCap application is hosted and monitored on a 
secure server located within the UNC CTSA-funded NC TraCS Institute’s Bioinformatics Core. Access to 
the REDCap database for this study will be restricted to authorized research team members as needed to 
perform their job functions. Research staff who access the REDCap system will use a unique user ID 
provided by the Bioinformatics Core. Research staff will enter EHR data into clinical forms on REDCap. 
Each time research staff access REDCap, a unique electronic signature (login) is required, and REDCap 
maintains an audit trail of all activity. Participants will be given the choice of providing PRO data (a) directly 
into REDCap from a weblink set up on their iPad, (b) from an automated email from the REDCap system 
that contains a URL link to the survey or (c) through phone-delivered surveys with study staff who enter 
responses directly into REDCap. Each REDCap link is unique to each subject and each assessment 
period. Patients will be sent electronic reminders from REDCap to approved email addresses when PRO 
data entry is needed.   
 
For each consented patient, their consent documents will be uploaded and stored in REDCap. Hard copy 
consent documents will be stored in a secure location.  
 
While the research data will be stored in REDCap, other study materials (e.g., SAE/AE forms, 
reimbursements, audio-video recordings) will be securely stored on VPN- and password protected CGIBD 
secure server in a study folder. The server and study folders are maintained and monitored by UNC SOM 
ITS. ITS will provide access only to staff working on this project. No study-related documents containing 
patient PHI or identifiers will reside on desktop or laptop computers.   
 
23 DATA ANALYSIS 
 
23.1 Statistical Analysis Overview 
The analysis strategies are designed to inform the feasibility and planning of a subsequent efficacy RCT. 
No hypothesis tests will be conducted. Statistical estimates will be reported with 95% confidence intervals 
(CIs) or standard deviations. Collectively, the results of this preparatory study will allow us to formulate 
reasonable expectations for the subsequent RCT. A publicly available PROMIS® scoring system is 
available for computing PROMIS T-scores. Statistical computations will be performed in SAS software 
(SAS Institute, Cary, NC). 
 
23.2 Aim 1: Feasibility of conducting a RCT 
Frequencies will be tabulated for the following: patients approached/called, consented, 
randomized/enrolled, retained, completed surveys, and salivary cortisol samples. We will examine reasons 
for refusal, causes of dropout, session attendance, causes and patterns of missing data, and technical and 
logistical difficulties with delivering the intervention via VC. We anticipate that >50% of approached/called 
patients will consent; >75% of consented patients will be randomized and enroll; >80% will be retained; and 
>90% of PRO and cortisol data will be collected. 
 
23.3. Aim 2: Feasibility of intervention delivery 
Technical and logistical issues with VC technology, internet, and software will be recorded. Descriptive 
methods will summarize the proportion of sessions attended. We anticipate >75% of VC-CBCS participants 
will attend >75% of sessions. 
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
23.4 Aim 3: Patient satisfaction and acceptability 
Qualitative data from each exit focus groups will be obtained to help improve the structure and content of 
the future VC-CBCS and study methods. The Patient Acceptability/Satisfaction survey will be analyzed as 
an average for the 14 sessions.6 Items on the group dynamics survey will be evaluated at both time 
points.6,99,110,111  Reasons for drop out will be evaluated in both conditions. We anticipate that patients will 
find the VC-CBCS highly acceptable and useful, as measured by the Patient Acceptability survey and 
information provided during the exit focus groups. If 19 of the 24 VC-CBCS participants find the 
intervention acceptable (overall score ≥3.5 out of 5.0), the point and interval estimate will be 79% [95% CI: 
61, 100]. 
 
23.5 Aim 4: Explore changes in patient outcomes, mediators and intervention targets, as well as 
temporal associations and strength of associations among variables in a preliminary conceptual 
model, to inform a future efficacy trial 
For each outcome measured before, during and after the intervention, we will obtain estimates of specific 
mean changes, treatment effects, standard deviations, serial correlations, corresponding confidence 
intervals indicating levels of precision or standardized effect size estimates (Cohen’s d) of change. We 
anticipate that mean changes will favor the VC-CBCS intervention relative to SC.  
 
Various exploratory methods may be used to fully examine the data and generate hypotheses to be 
evaluated in a future RCT. We may explore the weekly repeated measures for intervention targets and 
potential mediators/intermediate outcomes to identify targets rated as strongest by patients, and to identify 
the timing and magnitude of changes in mediators/intermediate outcomes during the VC-CBCS. To better 
understand potential causal pathways and refine the conceptual model, we may explore temporal 
correlations among targets, mediators (intermediate/secondary outcomes) and primary patient-reported 
and clinical outcomes. For example, we may explore associations of mediators with intervention-induced 
changes in health status, physical and mental symptoms, salivary cortisol, ALT and AST. We will estimate 
mean log10 cortisol as a diurnal function of time of day and compute summary values such as the area 
under the curve (AUC), AUC minus ground, and cortisol awakening.  
 
24 STUDY CONDUCT 
 
This study will be conducted in accordance with federal and institutional guidelines 
(https://www.hhs.gov/ohrp/regulations-and-policy/regulations/finalized-revisions-common-rule/index.html;  
(https://www.hhs.gov/ohrp/regulations-and-policy/regulations/finalized-revisions-common-rule/index.html) 
and relevant Good Clinical Practice (GCP) Guidelines described by the International Conference on 
Harmonization (ICH). The study will be conducted in compliance with this version of the study protocol. The 
protocol and any amendments will receive UNC Institutional Review Board (IRB) approval prior to initiation 
of the study. Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
 
We will apply all standard protections of patient confidentiality and data integrity during this study. Consent 
forms will be uploaded to REDCap and hard copies stored in a secure, locked location. All research data 
will be stored on a secure electronic server, behind a firewall at UNC, maintained and monitored by the 
UNC SOM ITS. Study documents will be stored in locked and secure file cabinets and on the CGIBD 
secure server in a folder accessible only to study staff. Audio-video files of the intervention will be uploaded 
to the CGIBD secure server to the private research folder.  
 
25 DATABASE RETENTION 
 
The REDCap database and all study-related materials will be maintained until all data are published and up 
to 5-7 years after the end of the study at UNC by the PI in collaboration with the NC TraCS Institute and 
SOM ITS. Hard copy data will be securely stored on the secure server and in locked cabinets. Access to 
electronic folders and REDCap will be terminated for staff no longer working on the project. Data initially 
stored on screened patients who were not enrolled will be deleted at the end of the study. If datasets are 
exported for analysis, no identifiers or contact information will be exported.  
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
26 DATA AND SAFETY AND MONITORING PLAN 
 
This study has a full DSMP that has been reviewed and approved by the NIH National Institute of Nursing 
Research (NINR)  and is in accordance with the Policy of the NINR for Data and Safety Monitoring of 
Extramural Clinical Trials. Available in supplementary attachment. Study staff will adhere the guidelines in 
the DSMP.  
 
26.1 Procedures for Adverse Events (from DSMPv2.0 - 27Sept2019) 
In brief, we will identify, review, and report study-related serious adverse events (SAEs) according to UNC 
regulatory guidelines and OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving 
Risks to Subjects or Others and Adverse Events. The UNC IRB Standard Operating Procedures (dated: 
6/2/2017) defines a reportable serious adverse events (SAE) as any event temporally associated with the 
subject’s participation in research that meets any of the following criteria: 1) results in death, 2) is life 
threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in 
persistent or significant disability/incapacity, 5) results in congenital anomaly/birth defect, or 6) any other 
adverse event that, based on appropriate medical judgement, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the outcomes listed above (UNC SOP 1401: 
3.2.2.1.1). These SAEs will be reported immediately to the PI and Dr. Lechner, the Independent Safety 
Monitor (ISM), within 48 hours of notification. The PI and ISM will review the SAE and determine if the SAE 
is partially or fully related to study participation. (Note: We do not anticipate any study-related SAEs or AEs 
based on prior experience conducting these interventions and as this is a minimal risk behavioral 
intervention including no drugs, devices or procedures). Based on SAE review and ISM, the SAE 
outcome/conclusion will be recorded with study records. If the SAE is determined to be study-related, an 
ISM summary will be reported to the UNC IRB within 7 calendar days. If not study-related, it will be tracked 
but not reported. Unanticipated study-related AEs or problems will be reported within 14 days to the IRB. 
We will record SAEs and unanticipated study-related AEs in a regulatory binder. The NINR Program Officer 
will be notified of study-related SAEs or study-related unanticipated AEs within one month of reporting the 
event to the UNC IRB (per OHRP Guidance recommendations).  
 
The target population has a higher prevalence of medical, psychiatric, and substance use disorders and 
conditions. Therefore, we anticipate learning about non-study related patient issues related to liver, 
cirrhosis, psychiatric, or substance use issues due to the natural history or these disorders and higher risk 
of these disorders in the target population. Under this protocol, the PI and ISM will not report non-study 
related events such as inpatient hospitalizations for medical conditions or symptoms (e.g., complaints of 
fatigue, nausea, pain) to the IRB or sponsor, although reports of these events will be tracked in a regulatory 
binder. We will follow a SOP to handle non-study related medical or psychiatric issues.  
 
Dr. Evon will provide oversight and direct patient care commensurate with good clinical practice as a 
clinical psychologist and member of the UNC Liver Program. We do not anticipate any events that would 
halt accrual. If an event should occur, it would be discussed with ISM, staff and telemental health 
consultants. A review of eligibility criteria, patient monitoring, assessments, or the intervention may occur 
but is unlikely to halt accrual. 
 
27 RESEARCH TEAM 
NAME 
DEPARTMENT NAME 
ROLE 
Donna Evon 
UNC Department of Medicine 
Principal Investigator 
Michael Fried 
UNC Department of Medicine 
Co-Investigator 
Susan Girdler 
UNC Department of Psychiatry 
Co-Investigator 
Dawn Harrison 
UNC Gastroenterology and Hepatology 
Co-Investigator 
Deborah Tate 
UNC Department of Health Behavior and 
Department of Nutrition 
Co-Investigator 
Chip Bailey 
Duke University School of Nursing 
Co-Investigator 
Suzanne Lechner 
n/a Independent Contractor 
Independent Safety Monitor 

VC-CBCS Study protocol v7.0—16Nov2021 
 
Cathryn Mainville 
n/a Etheridge Private Practice 
Group Facilitator 
Leslie Morland 
University of California, San Diego 
Department of Psychiatry 
Director, San Diego Regional Telemental 
Health Program, San Diego VA Health Care 
System 
Telemental health 
Consultant 
Jeremy Simpson 
UNC School of Medicine 
Information Technology Security (ITS)  
AV Support  Engineer 
 
Paul Stewart 
UNC Department of Biostatistics 
Biostatistician 
Ashley Arrington 
NC TraCS Institute, RCMU 
Project Manager 
Taylor Caron 
Center for Gastrointestinal Biology and 
Disease 
Research Coordinator 
Ginny Sharpless 
Center for Gastrointestinal Biology and 
Disease 
Data Management 
Consultant 
28 GLOSSARY OF TERMS 
 
A1C – Hemoglobin A1C 
AE- adverse event 
ALT - alanine aminotransferase  
AST - aspartate aminotransferase  
BRFSS - Behavioral Risk Factor Surveillance System  
CB – cognitive behavioral 
CBCS - cognitive behavioral coping skills 
CBSM – cognitive behavioral stress management 
CBT – cognitive behavioral treatment 
CGIBD- Center for Gastrointestinal Biology and Diseases 
CTSA – clinical and translational science awards 
CONSORT – Consolidated Standards for Reporting of Trials 
DSMP – data safety monitoring plan 
HCV- hepatitis C virus 
HCV-PEG – Hepatitis C Virus Patient Engagement Group 
HCV RNA – HCV RNA PCR test 
IMB - informational-motivation-behavioral skills  
IRB – Internal Review Board 
MOCS - Measure of Current Status-Part A 
NC TraCS- North Carolina Translational & Clinical Sciences Institute 
NIH- National Institutes of Health 
NINR – National Institute of Nursing Research 
PRO- patient-reported outcomes 
PROMIS- Patient Reported Outcomes Measurement System 
PROP UP – patient reported outcomes project of HCV-TARGET 
PSS – perceived stress scale 
HRQOL- health-related quality of life  
RCT - randomized controlled trial 
REDCap - research electronic data capture system 
SAE – serious adverse event 
SAMISS - Substance Abuse and Mental Illness Brief Symptom Screener 
SC – standard of care 
SM – stress management 
VC - videoconference 
 
 
 

VC-CBCS Study protocol v7.0—16Nov2021 
 
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