Stepped-Wedge Randomized Control Trial to Compare Integrated, Co-located, Telemedicine-based HCV Management for Individuals on Opiate Agonist Treatment Versus Usual Care Treatment of HCV of Individuals on Opiate Agonist Treatment
Phase: NA
Conditions: Hepatitis C
Sponsor: Andrew Talal

 
 
Official Title: 
Comparison of Telemedicine to Usual Care for HCV 
Management for Methadone‐maintained Individuals 
NCT number: 
NCT02933970 
Document Type:  
Study Protocol  
Date of the Document: 
October 20, 2023 
 
 

 
  
University at Buffalo Institutional Review Board (UBIRB)  
Office of Research Compliance | Clinical and Translational Research Center Room 5018  
875 Ellicott St. | Buffalo, NY 14203  
UB Federalwide Assurance ID#: FWA00008824  
  
Complete Research Protocol (HRP-503)  
  
Table of Contents  
Template Instructions.......................................................................................................... 2  
1.0  
Objectives ................................................................................................................ 4  
2.0  
Scientific Endpoints ................................................................................................. 5  
3.0  
Background .............................................................................................................. 6  
4.0  
Study Design ............................................................................................................ 9  
5.0  
Local Number of Subjects ..................................................................................... 10  
6.0  
Inclusion and Exclusion Criteria ............................................................................ 11  
7.0  
Vulnerable Populations .......................................................................................... 13  
8.0  
Eligibility Screening .............................................................................................. 14  
9.0  
Recruitment Methods ............................................................................................. 15  
10.0   Procedures Involved............................................................................................... 17  
11.0   Study Timelines ..................................................................................................... 24  
12.0   Setting .................................................................................................................... 25  
13.0   Community-Based Participatory Research ............................................................ 26  
14.0   Resources and Qualifications ................................................................................. 27  
15.0   Other Approvals ..................................................................................................... 29  
16.0   Provisions to Protect the Privacy Interests of Subjects .......................................... 29  
17.0   Data Management and Analysis ............................................................................ 30 
18.0   Confidentiality ....................................................................................................... 33  
A. 
Confidentiality of Study Data ............................................................................ 33  
B. 
Confidentiality of Study Specimens ................................................................... 36  
19.0   Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 38  
20.0   Withdrawal of Subjects .......................................................................................... 39  
21.0  
Risks to Subjects ................................................................................................  40 
22.0   Potential Benefits to Subjects ................................................................................ 42  
23.0   Compensation for Research-Related Injury ........................................................... 42  
24.0   Economic Burden to Subjects ................................................................................ 42  
25.0   Compensation for Participation ............................................................................. 43  
26.0  Consent Process ..................................................................................................... 44 
27.0 Waiver or Alteration of Consent Process ............................................................... 48 
28.0 Process to Document Consent ............................................................................... 50 
29.0 Multi-Site Research (Multisite/Multicenter Only).............................................. .  51....           
30.0  Banking Data or Specimens for Future Use ....................................................52         
31.0 Drugs or Devices........................................................................................................54 
32.0   Humanitarian Use Devices .................................................................................... 55  
  
  
  

  
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Page 1 of 58  
  
Template Instructions  
Sections that do not apply:  
• 
In several sections, the addition of checkboxes for Not Applicable have been 
added to the template as responses.   o If an N/A checkbox is present, select the 
appropriate justification from the list.    
o If an N/A checkbox is not present, or if none of the existing 
checkboxes apply to your study, you must write in your own 
justification.  
• 
In addition:  
o For research where the only study procedures are records/chart 
review:  Sections 19, 20, 22, 23, 24, 25, 31, and 32 do not apply. o 
For exempt research:  Sections 31 and 32 do not apply.  
  
Studies with multiple participant groups:  
  
• 
If this study involves multiple participant groups (e.g. parents and children), 
provide information in applicable sections for each participant group. Clearly 
label responses when they differ.  For example:  
Response:   
Intervention Group: management of hepatitis C virus (HCV) infection via 
telemedicine  
  
Control Group:  
Usual care treatment of HCV.  
Formatting:  
• 
Do not remove template instructions or section headings when they do not apply 
to your study.  
If you are pasting information from other documents using the “Merge Formatting” 
Paste option will maintain the formatting of the response boxes.  
Amendments:  
• 
When making modifications or revisions to this and other documents, use the 
Track Changes function in Microsoft Word.  
• 
Update the version date or number on Page 3.  
  
  
PROTOCOL TITLE:  
Include the full protocol title.  

  
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Response:   
  
Stepped-Wedge Randomized Control Trial to Compare Integrated, Co-located,  
Telemedicine-based Treatment Approach for Hepatitis C Virus (HCV)  
Management for Individuals on Opiate Agonist Treatment and Usual Care  
Treatment of HCV of individuals on Opiate Agonist Treatment  
  
  
PRINCIPAL INVESTIGATOR:  
Name  
Department  
Telephone Number  
Email Address  
Response: Andrew Talal MD.  
University at Buffalo Department of Medicine   
Clinical and Translational Research Center  
716 888-4737 
ahtalal@buffalo.edu  
  
  
VERSION:  
Include the version date or number.  
Response: October 20, 2023  
Version 22  
  
  
GRANT APPLICABILITY:  
Indicate whether this protocol is funded by a grant (e.g. NIH, foundation grant).  
For a grant with multiple aims, indicate which aims are covered by this research 
proposal.  
NOTE: This question does not apply to studies funded by a sponsor contract.  
 Include a copy of the grant proposal with your submission.      
Response: This protocol is funded by an award from the Patient Centered 
Outcomes Research Institute (PCORI).  
  
  
RESEARCH REPOSITORY:  
Indicate where the research files will be kept, including when the study has been 
closed.  The repository should include, at minimum, copies of IRB 
correspondence (approval, determination letters) as well as signed consent 

  
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documents.  This documentation should be maintained for 3 years after the study 
has been closed.    
Response: All study documentation will be kept at the Clinical and 
Translational Research Center for a minimum of 3 years after the study 
has been completed.   
Location: University at Buffalo Dept. of Medicine   
Address: 875 Ellicott St. Buffalo, N.Y. 14203 Rm 6035  
Department: Dept. of Medicine  
1.0 Objectives  
1.1 Describe the purpose, specific aims, or objectives of this research.  
Response: This study aims to implement information technology 
(telemedicine) for improvement in health care delivery to the difficult to 
reach and underserved patient population of people with substance use 
disorders (PWSUD) who are on opiate agonist treatment (OAT).   
Primary specific aim: To compare the effectiveness of a patient-centered, 
OAT-integrated telemedicine-based approach for management and delivery 
of HCV treatment to PWSUD versus usual carereferral to an offsite location 
for HCV management. The effectiveness will be expressed through the 
primary patient centered and clinical outcome, achievement of viral 
eradication or sustained virologic response (SVR), defined as undetectable 
HCV RNA 12 weeks post treatment cessation.   
Our secondary aims are:  
a. Comparison of treatment initiation rates between the two arms, as 
measured by the proportion of patients that take an initial medication dose. b. 
Comparison of treatment completion rates between the two arms.  
c. 
Comparison of patient satisfaction with health care delivery between 
the two arms as assessed through the Hepatitis C Patient Satisfaction 
Questionnaire, Mini Mental Health Screen, National Institute on Drug Abuse 
Quick Screen, Drug Abuse Screening Test and Socio-demographics Survey.   
d. 
Comparison of treatment adherence rates between the two arms, as 
measured by attendance at scheduled specialists, telemedicine visits, and 
medication adherence.  
e. Resource utilization between the two arms  
f.  Association between social determinants of health and pursuit of HCV 
 
treatment in both arms. 
 
  
 
Interview substudy: 
  
g) Understand from the patient point-of-view the barriers and facilitators 
 
 
  

  
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for pursing telemedicine treatment of HCV. 
 
 
h) Understand the role that knowledge of new treatments or innovative 
 
 
technologies play in patient’s willingness to be treated for HCV. 
  
i) From the staff point of view, what are the barriers and facilitators of 
 
 
establishing telemedicine as a method to integrate behavioral and medical 
 
treatment. 
 
  
  
 
1.2  State the hypotheses to be tested, if applicable.  
NOTE:  A hypothesis is a specific, testable prediction about what you expect to 
happen in your study that corresponds with your above listed objectives.  
Response:   
The primary hypothesis is a patient-centered OAT-integrated, telemedicine-
based approach for delivery of HCV care that addresses PWSUDs’ specific 
needs will lead to improved treatment outcomes compared to usual care, 
which in most cases we assume will be referral to an offsite location for 
HCV management.   
2.0 Scientific Endpoints  
  
2.1    Describe the scientific endpoint(s), the main result or occurrence under 
study.    
  
NOTE:  Scientific endpoints are outcomes defined before the study begins to determine 
whether the objectives of the study have been met and to draw conclusions from the data.  
Include primary and secondary endpoints.  Some example endpoints are:  reduction of 
symptoms, improvement in quality of life, or survival.  Your response should not be a 
date.    
Response:    
o  Achievement of viral eradication defined as undetectable HCV RNA for  
12 weeks post treatment cessation for those patients treated via 
telemedicine  
o  Improvement in quality of life  
o  Restore hepatic function  
o  Decrease hepatic failure and incidence of transplants  
o  Diminished pool of HCV-infected people and consequently future HCV 
incidence and prevalence.  
3.0 Background  
3.1 Provide the scientific or scholarly background, rationale, and significance of the 
research based on the existing literature and how it will contribute to existing 

  
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knowledge.  Describe any gaps in current knowledge.  Include relevant 
preliminary findings or prior research by the investigator.   
Response:   
HCV infection is a leading cause of chronic liver disease affecting more 
than 120 million people globally1 and ~5 million in the United States 
(US)2. Approximately 80% of HCV-exposed individuals develop chronic 
infection that can progress to cirrhosis, liver cancer, and death. As 50% to 
75% of those infected are unaware of their status3, the impetus to diagnose 
and to treat chronic HCV is tremendous. Currently, HCV is the leading 
indication for liver transplantation in the US4. The prevalence of HCV-
related liver cirrhosis is predicted to increase from 25% in 2010 to 45% by 
2030 and liver-related deaths are projected to increase by 175% over the 
next decade5. Injection drug use is the primary route of HCV transmission; 
estimated HCV prevalence among PWSUD is 30% to 70% while incidence 
ranges from 16% to 42% per year6,7. Of those with chronic HCV infection, 
56% have a history of injection drug use8.   
Recent therapeutic advances have radically improved HCV treatment.  
Using a combination of orally administered, direct acting antivirals 
(DAAs), treatment is curative in more than 90% of individuals with 
virtually no side effects and substantially shortened treatment duration (i.e., 
8 to 12 weeks)9,10,11. Previously, interferon (IFN) was prescribed for HCV 
and had significant, frequently treatment-limiting side effects12,13.  
Despite these advances, DAA dissemination to PWSUD has been limited. 
Consequently, new patient-centered approaches are critical to deliver these 
medications to those most desperate for treatment. PWSUD referral to an 
HCV specialist is the current usual HCV management strategy. 
Unfortunately, despite the majority (>70%) of PWSUD indicating 
willingness to pursue HCV treatment, only 21% to 65% of HCV 
seropositive PWSUD have been evaluated for HCV and only a minor 
percentage (1% to 6%) actually receives therapy14,15,9,10. The importance 
of HCV treatment among PWSUD will only increase as a result of an 
increase in acute HCV cases among injection drug users < 30 years11.   
Treatment of substance use: Of treatments available for opiate dependence, 
methadone maintenance when combined with medical, psychiatric, and 
socioeconomic support services has the highest probability of 
effectiveness16. Because of a concern of illegal sale and distribution of 
methadone, most patients receiving methadone through an OAT program 
are required to attend clinic appointments 3 to 6 days per week16. The 
frequency of required OAT program visits provides an opportunity for 
otherwise hard-to-reach patients to access health care services, an 
important consideration as many PWSUDs experience multiple health 
problems, including higher rates of viral hepatitis, HIV and sexually 
transmitted infections compared to the general population17. Many OAT 
programs also represent a primary health care site for their patients.   
For this study we are implementing and evaluating a patient centered, OAT 
program-integrated telemedicine approach for the management and delivery 
of HCV care to diverse PWSUD populations compared with usual care 

  
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(referral). The patient-centered telemedicine approach, based on diffusion 
of innovations theory (DOI), is key for the intervention and treatment of 
HCV, and ultimately other frequent co-morbid conditions that affect 
PWSUD18.  
  
Interview substudy:  
Patients: As part of our ongoing PCORI study, we have collected patient 
surveys that assess their responses and reactions to telemedicine or referral 
-based care for HCV. We have also recently completed a study that 
identified themes derived from case managers’ stories of HCV treatment. 
We identified three themes as being important for pursuit of HCV care: 1) 
trust in the opioid treatment program (OTP), 2) identification of competing 
priorities, and 3) personalizing care so that identified priorities are 
addressed. Satisfactorily addressing these issues enables pursuit of HCV 
care (Talal, Jaanimägi, et al., 2020; Zeremski et al., 2014).  
We now propose to pursue a study of patient interviews and focus groups 
for a more in depth assessment of their reactions to telemedicine and 
referral-based care. Our experiences have shown that direct patient contact 
is the most effective method to assess reactions to an intervention in this 
population (Talal et al., 2019). We will utilize the interviews to pursue a 
mixed qualitative/quantitative manuscript combining the patient reaction 
data with the already collected survey data.  
Staff – In 2013, we published a paper on clinical staff attitudes toward 
onsite HCV treatment within the OTP (Talal et al., 2013). In other work, we 
have shown that knowledge of HCV natural history and treatment improves 
the likelihood of primary care providers pursuing HCV screening (Samuel, 
Martinez, Chen, Markatou, & Talal, 2018).Our goal now is to update our 
knowledge of barriers and facilitators to HCV treatment pursuit among staff 
at substance use treatment programs, to identify barriers to telemedicine 
and how they have been overcome, and considerations and lessons learned 
about telemedicine implementation from the point of view of the staff 
working at or leading OTPs (Talal, Sofikitou, et al., 2020).  
3.2 Include complete citations or references.   
Response:   
1. 
World Health Organization. Hepatitis C.  Fact Sheet No. 164.   
http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed August 21, 2013.  
2. 
Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in 
USA: an estimate of true prevalence. Liver Int. 2011;31(8):1090-1101.  
3. 
Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the 
identification of chronic hepatitis C virus infection among persons born during 
1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.  
4. 
Brown RS. Hepatitis C and liver transplantation. Nature. 2005;436(7053):973978.  
5. 
Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C 
virus (HCV)-infected persons in the United States: a multiple cohort model of 

  
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HCV prevalence and disease progression. Gastroenterology. 2010;138(2):513521, 
521 e511-516.  
6. 
Amon JJ, Garfein RS, Ahdieh-Grant L, et al. Prevalence of hepatitis C virus 
infection among injection drug users in the United States, 1994-2004. Clin Infect 
Dis. 2008;46(12):1852-1858.  
7. 
Edlin BR, Carden MR. Injection drug users: the overlooked core of the hepatitis C 
epidemic. Clin Infect Dis. 2006;42(5):673-676.  
8. 
Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. 
The prevalence of hepatitis C virus infection in the United States, 1999 through 
2002. Ann Intern Med. 2006;144(10):705-714.  
9. 
Grebely J, Raffa JD, Lai C, et al. Low uptake of treatment for hepatitis C virus 
infection in a large community-based study of inner city residents. J Viral Hepat. 
2009;16(5):352-358.  
10. 
Schackman BR, Teixeira PA, Beeder AB. Offers of hepatitis C care do not lead to 
treatment. J Urban Health. 2007;84(3):455-458.  
11. 
Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus infection related 
to injection drug use among persons aged </=30 years - Kentucky, Tennessee, 
Virginia, and West Virginia, 2006-2012. MMWR Morb Mortal Wkly Rep. 
2015;64(17):453-458.  
12. 
Fried TR, Bradley EH, Towle VR, Allore H. Understanding the treatment 
preferences of seriously ill patients. N Engl J Med. 2002;346(14):1061-1066.  
13. 
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus 
ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of 
chronic hepatitis C: a randomised trial. Lancet. 2001;358(9286):958-965.  
14. 
Mehta SH, Genberg BL, Astemborski J, et al. Limited uptake of hepatitis C 
treatment among injection drug users. J Community Health. 2008;33(3):126-133.  
15. 
Grebely J, Genoway KA, Raffa JD, et al. Barriers associated with the treatment of 
hepatitis C virus infection among illicit drug users. Drug Alcohol Depend. 
2008;93(1-2):141-147.  
16. 
Vocal-NY. Beyond Methadone:  Improving Health and Empowering Patients in 
Opioid Treatment Programs.  www.methadonemaintenance.net, 2011.  
17. 
Masson CL, Sorensen JL, Batki SL, Okin R, Delucchi KL, Perlman DC. Medical 
service use and financial charges among opioid users at a public hospital. Drug 
Alcohol Depend. 2002;66(1):45-50.  
18. 
Rogers EM. Diffusion of innovations. 5th ed. New York: Free Press; 2003.  
19.    Samuel, S. T., Martinez, A. D., Chen, Y., Markatou, M., & Talal, A. 
H. (2018). Hepatitis C virus knowledge improves hepatitis C virus 
screening practices among primary care physicians. World Journal 
of Hepatology, 10(2), 319.   
20.   Talal, A. H., Dimova, R. B., Seewald, R., Peterson, R. H., Zeremski, 
M., Perlman, D. C., & Des Jarlais, D. C. (2013). Assessment of 
methadone clinic staff attitudes toward hepatitis C evaluation and 
treatment. Journal of Substance Abuse Treatment, 44(1), 115-119.   
21.   Talal, A. H., Jaanimägi, U., Davis, K., Bailey, J., Bauer, B. M., 
Dharia, A., 
. . . Dickerson, S. S. (2020). Factors Affecting Persons with Opioid 
Use  

  
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Disorder Engagement in Treatment for Hepatitis C Virus Infection 
via Telemedicine. Journal of Substance Abuse Treatment, 
Manuscript in Preparation.   
22.   Talal, A. H., McLeod, A., Andrews, P., Nieves-McGrath, H., Chen, 
Y., Reynolds, A., . . . Brown, L. S. (2019). Patient reaction to 
telemedicine for clinical management of hepatitis C virus integrated 
into an opioid treatment program. Telemedicine and e-Health, 25(9), 
791-801.   
23.   Talal, A. H., Sofikitou, E. M., Jaanimägi, U., Zeremski, M., Tobin, 
J. N.,  
& Markatou, M. (2020). An Implementation Framework for 
PatientCentered Telemedicine for Vulnerable Populations. Journal 
of Biomedical Informatics, Invited Revision.   
24.   Zeremski, M., Dimova, R. B., Zavala, R., Kritz, S., Lin, M., Smith, B. D., . 
. . Talal, A. H. (2014). Hepatitis C virus-related knowledge and willingness 
to receive treatment among patients on methadone maintenance. J Addict 
Med, 8(4), 249-257. doi:10.1097/ADM.0000000000000041  
  
4.0 Study Design  
4.1 Describe and explain the study design (e.g. case-control, cross-sectional, 
ethnographic, experimental, interventional, longitudinal, observational).  
Response:   Our study will be conducted as a non-blinded Stepped Wedge 
Cluster Randomized Controlled Trial with two arms: Onsite HCV 
management through telemedicine versus HCV management through 
usual care, which in most cases will be referral to an offsite liver specialist 
(Referral). The arm assignment will be at the cluster (clinic) level. After an 
initial period 9 months) in which all OAT clinics implement the control 
intervention (usual care), at regular intervals (i.e., the “steps”) of 9 months 
duration each, one group of OAT clinics will be randomized to cross over 
from the Usual Care arm to the Telemedicine arm. In this way, there will 
be enough time for implementation and assessment of the intervention 
within each time period. The process continues until all OAT clinics have 
crossed over to implement telemedicine, and thus the clinics contribute 
data to both interventions. Board-eligible or certified providers will 
manage HCV treatment. All sites are allocated to a single cluster. 
Therefore, no participant cross-over between the arms is permitted. 
  
Interview substudy:  
This is an observational study consisting of interviews and focus groups.  
5.0 Local Number of Subjects  
5.1 Indicate the total number of subjects that will be enrolled or records that 
will be reviewed locally.  

  
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Response: The University at Buffalo Dept. of Medicine is the Sponsor of the 
study initiating the study design and managing its implementation as well as data 
analysis. Therefore, UB staff  will not be directly consenting or enrolling subjects. 
Screening, consenting and enrollment of subjects will be at each participating  
OAT clinic. Our target sample size is 624 OAT program-maintained patients from 
12 clinics throughout the state of NY Interview substudy:  
Patients-We will plan to interview up to 25 patients who participated in the 
parent study (approximately 2 per clinic).   
Staff: We will plan to interview/conduct focus groups with up to 200 
individuals across the study clinics.   
We may also contact sites that declined to participate in the parent study to assess 
the reasons for non-participation. These individuals would likely represent the 
leadership at these sites, including administrators, providers, lawyers or clinic 
directors.  
We are also trying to interview patients who were invited to participate in the 
study but declined.  
  
  
5.2 If applicable, indicate how many subjects you expect to screen to reach your 
target sample (i.e. your screen failure rate).   
Response: We estimate that approximately 2534 patients (~130 patients/clinic) 
will be screened.  
  
5.3 Justify the feasibility of recruiting the proposed number of eligible subjects 
within the anticipated recruitment period. For example, how many potential 
subjects do you have access to? What percentage of those potential subjects do 
you need to recruit?  
Response:   
Currently, there are 126 OAT programs in New York State. Estimated HCV 
(antibody) prevalence among PWID ranges from 30% to 70%, depending on 
frequency and duration of use, while incidence ranges from 16% to 42% per 
year.  
Interview Substudy  
Most of the potential participants are subjects from the parent study, so many 
of them are either still in regular contact with the study staff or have contact 
information available.   
For staff, we will work closely with the clinic leadership at each site to tailor 
staff recruitment to be consistent with local procedures. We have been 
working with all sites since late 2016, and the parent study is very well 
known to clinic leadership and staff. Many staff have been involved in either 
HCV medication dispensing, supporting patients through their treatment, or 
identifying patients for recruitment.   
  

  
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We will also seek to conduct interviews or focus groups with staff at sites 
that might have declined study participation. Additional interviews or focus 
groups might be conducted with state agencies that oversee telemedicine or 
substance use treatment, such as New York State Dept of Health and the 
Office of Addiction Services and Supports (OASAS). The goals of these 
discussions will be to understand facilitators and barriers to telemedicine 
implementation and how these might have changed as a result of the 
COVID-19 pandemic.  
  
6.0 Inclusion and Exclusion Criteria  
6.1 Describe the criteria that define who will be included in your final study sample.   
NOTE:  This may be done in bullet point fashion.  
Response: The inclusion criteria:  
1. HCV antibody detected  
2. Ability and willingness of subject or legal representative to provide written 
informed consent.  
3. 18 years of age or older  
4. A minimum of 6-month enrollment in the OAT program  
5. Likely to be adherent to the therapeutic regimen  
6. Treatment must be covered by medical insurance  
  
Interview Substudy:  
Subjects from the parent study or staff that worked at the study site clinics 
during the study period will be eligible. We also may approach current 
or former members of our.patient advisory committee that is operational 
at each site and ask them to participate in focus groups or interviews.   
Additional interviews may be conducted with staff from other substance use 
treatment facilities or governmental agencies that participate in telemedicine 
or substance use treatment  
Patients at the clinic who were invited to participate in the study but declined are 
eligible to be interviewed in a single session, but will not participate in any 
other aspect of the study.  
6.2 Describe the criteria that define who will be excluded from your final study 
sample.    
NOTE:  This may be done in bullet point fashion.   
Response:  
1. Mental instability or incompetence, such that the validity of the informed 
consent or ability to be compliant with the study is uncertain.  
2. <18 years of age  
3. < 6 months enrolled in OAT program.  

  
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4. Non-compliance with methadone therapeutic regimen at the Opiate Agonist 
Treatment program, defined as three consecutive missed appointments that 
will result in a discussion between the principal investigator at the site and 
the study participant to determine the reason for the missed appointments. 
Continuation in the study for the participant will be assessed on a case-
bycase basis between the study PI and the site sub-PI.  
5. Lack of medical insurance coverage  
6. Ineligibility for HCV treatment  
7. Active treatment for HCV at the time of the study enrollment  
8. HIV positive- not on stable antiviral therapy  
9. Enrolled subjects will be withdrawn if they are discharged from their clinic 
or their HCV medication administration lapses for 1 month or more  
6.3 Indicate specifically whether you will include any of the following special 
populations in your study using the checkboxes below.    
  
NOTE:  Members of special populations may not be targeted for enrollment in your 
study unless you indicate this in your inclusion criteria.  
Response: we will not enroll any special populations in our study   
☐  
Adults unable to consent  
☐  
Individuals who are not yet adults (infants, children, teenagers)  
☐  
Pregnant women  
☒  
  
 Prisoners  
6.4 Indicate whether you will include non-English speaking individuals in your 
study.  Provide justification if you will exclude non-English speaking 
individuals.   
In order to meet one of the primary ethical principles of equitable selection 
of subjects, non-English speaking individuals may not be routinely excluded 
from research as a matter of convenience.  
In cases where the research is of therapeutic intent or is designed to 
investigate areas that would necessarily require certain populations who 
may not speak English, the researcher is required to make efforts to recruit 
and include non-English speaking individuals.  However, there are studies 
in which it would be reasonable to limit subjects to those who speak 
English.  Some examples include pilot studies, small unfunded studies with 
validated instruments not available in other languages, studies with 
numerous questionnaires, and some non-therapeutic studies which offer no 
direct benefit.  
Response:   
Study materials will be offered in both English and Spanish, the two languages that are 
spoken by the vast majority of OAT program patients in NY State.   

  
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At least one of the patients who declined participation and will be invited to 
participate in a single interview is Spanish speaking.  
7.0 Vulnerable Populations  
If the research involves special populations that are considered vulnerable, 
describe the safeguards included to protect their rights and welfare.    
NOTE: You should refer to the appropriate checklists, referenced below, to ensure you 
have provided adequate detail regarding safeguards and protections. You do not, 
however, need to provide these checklists to the IRB.  
7.1 For research that involves pregnant women, safeguards include: NOTE 
CHECKLIST: Pregnant Women (HRP-412)  
Response:  
   
☒  
N/A:  This research does not involve pregnant women.  
7.2   For research that involves neonates of uncertain viability or non-viable 
neonates, safeguards include:  
NOTE CHECKLISTS: Non-Viable Neonates (HRP-413), or Neonates of Uncertain 
Viability (HRP-414)  
Response:   
  
☒  N/A:  This research does not involve non-viable neonates or neonates of 
uncertain viability.  
7.3   For research that involves prisoners, safeguards include: NOTE 
CHECKLIST: Prisoners (HRP-415)  
Response: We do not plan to study prisoners specifically, but since many 
methadone-maintained patients cycle through the correctional system quite 
frequently, there will be instances when we have study subjects who become 
incarcerated.  No study related procedures will occur during the time of the 
incarceration, but will resume if possible after the subject is released.  No data 
will be collected on the subject during the time of incarceration.  Subjects will not 
be recruited while incarcerated.  If a subject is incarcerated while being treated for 
HCV, the treatment may be continued as standard of care during the incarceration. 
Subjects will only be withdrawn from the study for incarceration if it causes them 
to meet the overall criteria for withdrawal from the study:  they are discharged 
from the clinic or if their HCV medication administration lapses for 1 month or 
more.  
If incarcerated subjects are withdrawn from the study, the study data collected on 
them up to the point of withdrawal will still be used for the study.  
  
  
☐  
N/A:  This research does not involve prisoners.  
6.5 7.4 For research that involves persons who have not attained the legal age for 
consent to treatments or procedures involved in the research (“children”), 
safeguards include:    

  
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NOTE CHECKLIST: Children (HRP-416)  
Response:   
  
☒  
N/A:  This research does not involve persons who have not attained the 
legal age for consent to treatments or procedures (“children”).  
6.6 7.5 For research that involves cognitively impaired adults, safeguards include: 
NOTE CHECKLIST: Cognitively Impaired Adults (HRP-417)  
Response:   
  
☒  
N/A:  This research does not involve cognitively impaired adults.  
7.6 Consider if other specifically targeted populations such as students, 
employees of a specific firm, or educationally or economically disadvantaged 
persons are vulnerable.  Provide information regarding their safeguards and 
protections, including safeguards to eliminate coercion or undue influence.  
Response: there will not be students, employees of a specific firm or 
educationally or economically disadvantaged persons targeted 
Interview substudy:  
Subjects from our PCORI study and staff at the OTP clinics will be targeted, but 
the voluntary nature of participation will be stressed during the consent process. 
This will also be stressed to sites that may not be participating in or who declined 
participation in the PCORI study as well.  
  
8.0 Eligibility Screening   
8.1 Describe screening procedures for determining subjects’ eligibility.  
Screening refers to determining if prospective participants meet inclusion and 
exclusion criteria.   
 Include all relevant screening documents with your submission (e.g. screening 
protocol, script, questionnaire).   
Response: By New York State regulation, all OAT programs are required to screen for the 
presence of HCV antibody on an annual basis. Consequently, potential subjects in this 
study will be identified from the health record at each of the participating clinics for the 
presence of HCV antibody. In the case that a clinic does not screen for HCV, we will 
provide HCV antibody and HCV RNA screening as part of this protocol, and provide the 
necessary screening kits to the clinic.  
  
☐  
N/A:    
9.0 Recruitment Methods  
☐  
N/A:  This is a records review only, and subjects will not be 
recruited.  NOTE:  If you select this option, please make sure that 
all records review procedures and inclusion/exclusion screening 
are adequately described in other sections.  

  
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9.1 Describe when, where, and how potential subjects will be recruited.   
NOTE:  Recruitment refers to how you are identifying potential participants and 
introducing them to the study.  Include specific methods you will use (e.g.  
searching charts for specific ICD code numbers, Research Participant Groups, 
posted advertisements, etc.).  
Response:  By regulation, all OAT programs in NYS are required to screen 
for the presence of HCV antibody on an annual basis.  
Consequently, potential subjects in this study will be identified from the 
health record at each of the participating clinics for the presence of HCV 
antibody. A partial HIPAA waiver will be obtained to allow for review of 
potential subjects HCV antibody status. We will offer screening for HCV 
antibody and HCV RNA for any patients or clinics that have not had access 
to these tests. A brochure and flyer will be distributed to all sites to enhance 
recruitment. A video simulating a telemedicine visit within a methadone 
clinic will be available for patients to view when deciding on participation 
within the telemedicine arm. The goal is to enhance understanding how 
telemedicine can be incorporated into the daily flow of the subject’s routine 
when coming for dosing of methadone. The video produced by the 
University at Buffalo Center for the Arts will be completed using actors and 
clinic setting not involved in the study.  
Recruitment of subjects to participate in the dissemination of results 
(interviews and public speaking opportunities) will be done either with a 
phone call or at the subject’s study visit. Interview substudy:  
Patients  
We will plan to interview up to 25 patients who participated in the parent 
study (approximately 2 per clinic) utilizing purposive sampling. We will 
approach PCORI parent study participants who have had particularly 
interesting or meaningful experiences as a result of the treatment modality of 
telemedicine.  Potential subjects will be contacted by the case manager  who 
intereacted with them in the parent study, either in person or by text or phone 
call or email, depending on the known preferences of the individual.  
Staff  
We will plan to interview up to 200 staff who participated in or were involved 
with the parent study utilizing purposive sampling. We will approach staff 
who have had particularly interesting or meaningful experiences as a result of 
their engagement with the study and treatment modality of telemedicine.    
Administrators  
We will plan to interview all administrators – one to two, depending on a site 
or organization.   
For the staff members, the case manager will also contact them either in 
person, or phone or by email.  
Non-subjects  
Patients at the clinics who were invited to be part of the study but declined to 
participate and are still going to the same clinic may be approached during 
their clinic visit with an invitation to be interviewed.  Eligible patients will be 

  
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found based on screening records from the main study or study staff 
recollections.  
9.2 Describe how you will protect the privacy interests of prospective subjects 
during the recruitment process.    
NOTE:  Privacy refers to an individual’s right to control access to him or herself.    
Response: Protection against privacy breach by participants will be 
ensured by discussions of study enrollment done in a private setting, 
between the study case manager at each participating site and the potential 
study participant. Similarly, for patients in the telemedicine arm, HCV 
therapies will be dispensed at the methadone dispensing window at the 
same time as methadone to minimize the chance that other patients from 
the OAT program might observe a study subject taking HCV medications. 
As part of the informed consent, we will also request consent from patients 
to contact their medical providers and HCV specialists in order to follow 
up on the referral requests to determine if the patient actually went for the 
referral from their primary provider to an off-site Liver specialist.   
Data security. Stored data protections will be designed in collaboration 
with the Information Technology Departments at each of the participating 
institutions as well as with the data management systems, My Own Med 
(MoM) and Breadcrumb Analytics, we will employ for this protocol. 
Protections employed in this study will be similar to those that have been 
enacted in similar clinical research studies. Data will be stored on 
password protected servers. Patient identity will not be shared with anyone 
other than the staff at participating sites and the physicians who are 
treating the patients. Each participating site will be assigned a site number, 
with each patient provided a single study identification number in 
ascending order by the study coordinator for all study related data 
pertaining to the subject. This information once de-identified will be 
stored additionally on a data management server housed at the Institute for 
Healthcare Informatics or similar university-designated server at the 
University at Buffalo and monitored by study staff at UB Research. 
Additionally, in all participating OAT clinics, all study personnel will be 
trained and certified in human subject studies protection. Furthermore, 
training in human subject’s protection and research methodology will be 
part of the engagement process for any study related procedures to be 
conducted as part of this protocol.  
9.3 Identify any materials that will be used to recruit subjects.   
NOTE:  Examples include scripts for telephone calls, in person announcements / 
presentations, email invitations.   
For advertisements, include the final copy of printed advertisements with your 
submission. When advertisements are taped for broadcast, attach the final  
audio/video tape.  NOTE:  You may submit the wording of the advertisement prior 
to taping to ensure there will be no IRB-required revisions, provided the IRB also 
reviews and approves the final version.  
 Response: At present, we will not rely on advertisements or video production but 
will recruit people from the electronic health record or through the screening 
process described in sect.7.1 Eligibility Screening   

  
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10.0 Procedures Involved  
10.1 Provide a description of all research procedures or activities being 
performed and when they are performed once a subject is screened and 
determined to be eligible. Provide as much detail as possible.    
NOTE:  This should serve as a blueprint for your study and include enough detail 
so that another investigator could pick up your protocol and replicate the research.  
For studies that have multiple or complex visits or procedures, consider the 
addition of a schedule of events table in in your response.  
Response: All participating OAT clinics will screen patients for HCV Antibody as 
required by New York State. At each participating OAT clinic, the designated study 
manager will meet privately with each patient identified as HCV Antibody positive to 
discuss the study. Once consented, blood specimens would be obtained (up to 44 ml) to 
determine HCV RNA, geno-typing, Drug sensitivity, HIV RNA, CD4 count (to be 
offered if in not in patient’s chart), HBsAb, HBsAg, complete blood count, 
comprehensive metabolic panel with estimated glomerular filtration rate, international 
normalized ratio, prothrombin time, and a referral either directly to a specialist or to their 
primary care physician (if HCV RNA detected). Once a referral has been issued, the 
designated study case manager of the OAT clinic will interact with the patient on a 
monthly basis to determine whether they have complied with the referral as well as 
medication adherence. HIPAA consent and contact information of the primary care 
physician as well as the liver specialist will be obtained. In the case of one-step referral 
process, the coordinator will be able to follow up directly with the liver specialist. In the 
case of a two-step referral process, the coordinator will follow up with both the primary 
care provider as well as the liver specialist. Some payers may require the two-step 
process as they may require that all referrals be completed by the PCP. We will 
administer the Hepatitis C Patient Satisfaction Questionnaire, Modified Mini Mental 
Health Screen, National Institute on Drug Abuse Quick Screen, Drug Abuse Screening 
Test (DAST), and Sociodemographic Survey to patients who are referred for HCV 
management at an offsite location. Similarly, in both arms, subjects will be given a 
standardized brochure about HCV produced by SAMHSA.  
After 9 months, 4 randomly selected clinics will begin consenting and enrolling 
patients into the telemedicine arm. This randomization will continue every 9 months 
until all clinics have been transitioned into the telemedicine arm. Screening and 
consent will be conducted in the same manner described for the referral arm. We will 
offer HCV-related interactive educational sessions to the patients enrolled in 
telemedicine treatment of HCV at each clinic during its telemedicine period. These 
sessions will cover the specifics of telemedicine as a means for delivery of healthcare 
and will address the concerns, such as privacy and confidentiality. During the 
telemedicine visits, patients will be linked with the provider via two-way 
videoteleconferencing, which may be, depending upon a visit, facilitated by an onsite 
OAT program staff member. The educational sessions will also include the principles 
of telemedicine as well as an introduction, including the credentials of the physician 
conducting telemedicine-based appointments and the privacy of medical data. Family 
members and patient caregivers will be invited to participate in the initial session so 
that they may be a means of moral support to the patient during HCV treatment. 

  
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During this appointment, patients will be evaluated for liver fibrosis that only requires 
a routine blood sample (Fibrosure)   
Two weeks later, patients will have a second telemedicine appointment when their results will be 
discussed with the liver specialist. If the patient meets treatment eligibility criteria and is willing 
to undergo HCV therapy, medications will be prescribed using the standard format requested by 
our specialty pharmacy partner. This telemedicine visit will be concluded with specific 
information provided to the patient concerning the medication regimen to be followed and side 
effects. The patient will then be instructed on how to take the HCV medications and the 
importance of adherence to the HCV treatment regimen will be emphasized. HCV medication 
will be administered as directly observed therapy (DOT) dispensed through the methadone 
dispensing counter in the OAT program. Subjects in both arms will be given Hepatitis C 
Treatment Satisfaction Questionnaires at the time of the first visit, and three months post 
treatment cessation.   
In the Telemedicine arm, HCV RNA will be obtained at baseline, treatment week 2, treatment 
week 6, at the end of treatment, post treatment week 4, and at 12 weeks posttreatment cessation. 
The blood will also be obtained at 6, 12, 18, and 24 months posttreatment to monitor for HCV 
reinfection. Follow up tests for reinfection may be done by standard blood draw or by dry blood 
spot testing, which involves a finger prick.    
DBS (dried blood spot) testing is used to assess HCV RNA (Hep C viral load). If the test 
comes back positive, we would confirm HCV RNA with venipuncture. At the same time, we 
would likely check the genotype for genotype switching. A different genotype would likely 
indicate reinfection.  
All telemedicine appointments will occur online with the liver specialist. The OAT Program staff 
clinician (MD/NP/PA) will be requested to be present based on the clinical need (e.g., non-
compliance with therapeutic regimen, issues related to substance use). Telemedicine 
appointments will occur at the initial evaluation, when the HCV medication is ordered, and 2 
weeks into treatment. Post-treatment, telemedicine appointment will occur at week 12. Other 
visits are optional and are based on the clinical need. Counseling sessions aimed at preventing 
reinfection will be offered to both arms at post treatment week 12 visit. Finally, we will 
administer the Hepatitis C Patient Satisfaction Questionnaire, Drug abuse Screening Test three 
months post treatment cessation. Among patients in both arms who achieve viral eradication, 
HCV RNA, toxicology screens will be obtained at week 4 post treatment, week 12 post treatment 
and months 6, 12, 18 and 24 post treatment cessation. This blood may be shipped from the clinic 
to SUNY at Buffalo, where it may be assayed for HCV RNA and HCV genotyping. We may also 
store an aliquot of blood for future reference including sequencing for new viruses. We may also 
decide to sequence the baseline virus to investigate for viral genetic diversity.   
If a patient is found to again test positive for HCV during their follow up period, we 
will collect data about their new infection, and draw up to 3 tbsp of blood at 2 and 6 
weeks after the beginning of retreatment, at the end of treatment and at 4 and 12 weeks 
after the end of treatment.  We may also decide to sequence samples obtained from any 
patients who have a positive HCV RNA sample after successful viral eradication in 
order to differentiate those who have reinfection versus relapse.  We may also measure 
the HCV core antigen on these samples.   
Collecting of HCV reinfection data occurs only during the subject’s study period, that 
is, up to 24 months from the end of their first study-related HCV treatment. If the 
subject is not retreated, we will continue monitoring him/her for a potential treatment 
start date during the study period and if s/he starts new treatment, we will collect 
follow-up data until the end of their study period. If the subject is reinfected at the end 

  
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of his/her study period, i.e., Visit 11 in the Usual Care Arm and Visit 12 in the 
Telemedicine Arm of the study, there will be no further data collection.  
For the collection of social determinants of health (SDOH) data:  Information from the 
subject’s initial intake forms (local to each site: Comprehensive assessments ), as well as 
any follow-up assessments done in subsequent years, will be entered into a data 
collection spreadsheet.  
Then the PAS-44 and certain PAS-26s will be collected as follows:  
1. Following instructions sent from OASAS, data from the PAS-44, administered at 
patient’s admission to the opioid treatment program, and specified PAS-26s, will be 
downloaded into an Excel spreadsheet from OASAS’s website (this is a secure 
download through their system). The data will be extracted by a member of the study 
team.   
2. The spreadsheet is generated by OASAS’s program based on entering a date range of 
up to a year.  A spreadsheet is created that contains the information for all the clinic’s 
patients that filled out the PAS form for that date range.    
3. After the spreadsheet is created, without opening the file, it will be dropped into a 
computer program created by Breadcrumb Analytics that has been downloaded onto 
the local computer. The program will allow the user to enter a set of patient identifiers  
(which will include some of the following identifiable data points: Provider Client ID, 
Birth Date, Last 4 SSN, Last Name-First 2 Letters, First Name-First 2 Letters) to 
select only the data related to the study subjects.  The program will extract the data 
for the selected patients, and remove the identifying columns (All data points in 
TRS61 and TRS-49 sections,, please see screenshot below).  It will also change the 
date of admission and date of assessment completion to just month and year.  All 
other records of non-study subjects will be discarded and deleted.    
4. The program will then allow the user to inspect the other fields to verify that there is 
no identifying information.  Once the records have been verified as containing no 
identifiable information except for the Study ID#, the program will allow the user to 
send the files to the UB study team over secure FTP.  
5. The time sequence of requested PAS-26 is as follows:  
The first one administered (that is, the first annual update), 4 years prior to the study, and 
every year after that until the participant completes the study or is otherwise discontinued 
from the study (up to approximately 10 PAS-26).  
  
  
  
Patient Advisory Committee: Patient Advisory Committee members and study 
participants may be requested to speak on behalf of their experiences participating in the 

  
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study, their experiences with HCV treatment, or on the dissemination of results of the 
study. These appearances may consist of media interviews, one-on-one interviews, or 
public speaking engagements.  
The purpose of these interviews and speaking engagements is not for recruitment into 
the study. The purpose of the dissemination of results is to spread the word about the 
benefits of telemedicine to a wide variety of stakeholders including patients, clinic staff, 
and insurance companies. The goal is to familiarize patients with the procedures, to 
encourage financial sustainability through appropriate telemedicine reimbursement, and 
to promote the growth of the modality as a method to deliver healthcare.  
Interview substudy:  
Some of the subjects from the parent study will be invited to be interviewed about their 
experiences, opinions and feelings about the study, medical care in general, and their 
OTP clinic and community.  The interviews will take place over videoconferencing, the 
phone, or in person.  All interviews will be recorded and transcribed.     
Subjects will be interviewed by someone on the study staff who does not work in the 
subject’s OTP.    
The questions will fall under the following general categories:  
• 
Trust in the OTP clinic and community (Example: How would you describe 
your relationship with clinic staff, i.e., counselor, physician?)  
• 
Experience with the research study (Examples:  What attracted you to being in 
the PCORI study?  Features that made you skeptical about being in the study?)  
• 
Challenges with receiving medical care outside of the study (Example: What are 
the barriers or problems you do have or have encountered in general medical settings?)  
• 
Experiences with personalized care in the OTP (Example: What are some of the 
helpful things that clinic staff does to manage your treatment plan and prioritize your 
needs (including addiction, comorbidities, mental health issues, insurance/finances, 
transportation)?)  
Some of the staff who have been working at the clinic during the conduct of the study 
will be interviewed, about their feelings, opinions and experiences with telemedicine in 
general, as well as specifically their observations about the use of telemedicine to 
implement HCV treatment.  
Interview guides are included in this submission.  
Contacts at sites that did not choose to participate in the parent study will be interviewed 
about the reasons why and their opinion about telemedicine.  
  
Patients at the clinics who were invited to participate in the main study and declined and 
agree to be interviewed will participate in a single interview either by Zoom, telephone, 
or in person.  They will be asked questions in the following categories:  
  
1) Why did you decide not to pursue HCV treatment and/or participate in the study?  
2) Is there anything that we could do to get you ready for treatment?  
3) Are there any areas where you think education or knowledge could be helpful?  

  
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4) Do you have any other recommendations for us?  
  
  
  
10.2 Describe what data will be collected.    
NOTE:  For studies with multiple data collection points or long-term follow up, 
consider the addition of a schedule or table in your response.  
Response: The following data will be collected from patients enrolled in the 
study:  
1. Demographic information (age, sex, race, ethnicity)  
2. Height  
3. Weight  
4. Body Mass Index  
5. Marital status  
6. Type of residence  
7. Employment status  
8. Legally disabled   
9. Highest level of educational attainment  
10. Type of insurance  
11. Co-morbid medical and psychiatric diagnoses  
12. Medications with current dose  
13. CD4 cell count and HIV RNA level on patients chart- if status unknown HIV 
testing to be offered  
14. Data related to HCV including HCV RNA, HCV genotype, fibrosis level, 
inflammatory grade, HCV resistance associated variants, complete blood 
count, comprehensive metabolic panel with estimated glomerular filtration 
rate, international normalization ratio, and prothrombin  
15. Data related to hepatitis B virus infection-HBV DNA level, HBsAb, HBsAg   
16. Opiate agonist specific variables-methadone peak and trough levels, type of 
treatment, dose and duration.  
17. Illicit drug use and behavior  
18. For sites that have access to FibroScan, we will collect fibrosis measurements 
and steatosis level.   
19. Model of end-stage liver disease (MELD)  
20. Drug Abuse Screening Test (DAST)  
21. Billing and claims data such as CPT code, gross charges, payment, patient 
cost share (co-pay or co-insurance), reason for denial of payment by the 
insurance company.  
  
  

  
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22. Patient stories and events will be collected from study case managers and 
study staff to illustrate how the telemedicine model with accompanying 
medication dispensing facilitates HCV treatment.  No identifiable patient 
information will be included.  
Information to be collected includes patient-reported outcomes, such 
as how the onsite treatment delivery facilitated treatment completion, 
overcoming stigma barriers, obtaining secure housing in a homeless 
shelter, and obtaining treatment in the case of physical immobility.  
23.    Social determinants of health – behavioral, environmental, and 
demographic characteristics that can affect a patient’s health.  Please 
see Comprehensive Assessment and SDOH in  
Supporting Documents.  These may be from the versions done at the 
subject’s initial admission to the clinic, or during follow up 
administrations of the same and/or similar forms over the time since 
the initial admission.  We will also collect the data from the PAS-44 
and PAS-26s (see section 10.1 for schedule) minus the identifiable 
fields.  The PAS forms are the SDOH variables collected by OASAS 
from each clinic, and overlap the local clinic’s forms.  
Interview substudy:  
General demographics from staff will be collected (age, gender, ethnicity), job 
title, and degrees received. (See data collection instrument). Everything else 
that will be collected from both patients and staff will be qualitative data such 
as opinions and experiences from recorded and transcribed interviews and 
focus groups. No quantitative data will be collected from patients as all 
required quantitative data have been collected as part of the parent study.  
General demographics will be collected from the non-participants as 
well – age, gender, ethnicity and educational level completed.  
  
  
  
10.3 List any instruments or measurement tools used to collect data (e.g. 
 
questionnaire, interview guide, validated instrument, data collection form).    
  
Include copies of these documents with your submission.  
Response:  All participants will complete a Modified Mini Mental Health Screen, 
National Institute Drug Abuse Quick Screen and Sociodemographic Survey at the 
first study visit. We will also administer the Drug Abuse Screening Test (DAST) 
at screening, and Patient Satisfaction Questionnaire at 3 months post treatment 
cessation.   
If a subject is found to be reinfected with HCV, the information about the new 
treatment episode will be collected on an Excel spreadsheet (attached).  
  
Interview substudy:  

  
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Videoconference recordings and transcripts or digital voice recordings and 
transcripts will be used to collect the interview and focus group data.   Interview 
guides are included in this submission. Please see attached Excel file for the 
quantitative data to be collected from staff.  
  
  
  
Describe any source records that will be used to collect data about subjects (e.g. 
school records, electronic medical records).  
Response: Data will be collected from Electronic Medical Records using an 
electronic file transfer through MoM. Additionally this de-identified information 
will be stored on a data management server, housed at the Institute for Healthcare  
Informatics or similar university-designated server at the University at Buffalo and 
monitored by study staff at UB Research.  Financial data for the telemedicine 
subjects and usual care subjects that were treated by the PI will be extracted from 
the UBMD or START financial reports that the PI receives as the rendering 
provider.  
Financial data for usual care subjects not treated by the PI will be requested from 
subjects’ insurance companies or treating physician/practice.  
Social Determinants of Health may be accessed in paper medical records if the 
information has not been added to the clinic’s EMR.  The PAS-44 and PAS-26 
will be downloaded from the OASAS servers through an online portal at each 
clinic.  
  
Interview substudy: NA  
  
10.4 Indicate whether or not individual subject results, such as results of 
investigational diagnostic tests, genetic tests, or incidental findings will be 
shared with subjects or others (e.g., the subject’s primary care physician) and if 
so, describe how these will be shared.  
Response: Each subject will be privately given all test results at screening and at 
each visit. Consents will be obtained to share collected information with primary 
physicians and/or liver specialists.  
10.5 Indicate whether or not study results will be shared with subjects or others, 
and if so, describe how these will be shared.  
Response: Presentations will be done at participating clinics in order to 
share our findings with study participants as well as with other patients 
who might be interested in the study results. Similar presentations will 
also be organized in other methadone clinics. We plan to engage the 
Patient Partners (a group of patient volunteers who have gone through 
HCV treatment via telemedicine) in the dissemination of the results within 
their own clinics and to outlaying clinics.  Many patients seen in these 
clinics are HCV infected and may be very interested in the study findings 
and embrace alternative strategies for HCV management and treatment 

  
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other than usual care, referral to an offsite location. Results of this study 
will be made available on ClinicalTrials.gov  
Information collected from study case managers and other study staff (see 
10.2 #23) will be used to create a manuscript of interesting patient stories 
or events to illustrate how the telemedicine model with accompanying 
medication dispensing facilitates HCV treatment. We have had a variety of 
instances where patients have reported that the model directly or indirectly 
facilitated their overcoming obstacles to healthcare access and delivery 
related to HCV. The manuscript will be an opportunity to capture these 
events to illustrate ancillary benefits of integrated addiction and HCV 
treatment in our telemedicine model. 
Study results will be shared with stakeholders at the national, state, and local 
levels to obtain their input and perspectives for drafting a variety of manuscripts 
based on the study. These stakeholders, who were involved in the implementation 
and conduct of the study, may include patient-participants, case managers, and 
clinic administrators and staff. No identifiable information will be shared.  
11.0 Study Timelines  
11.1 Describe the anticipated duration needed to enroll all study subjects.  
Response: The anticipated duration to enroll all study subjects is 36 months.  
Interview substudy:  
3 months for patients, staff 6 months.  
11.2 Describe the duration of an individual subject’s participation in the study. 
Include length of study visits, and overall study follow-up time.  
Response: Subjects will be enrolled for approximately 32 months in the study. 
This would encompass time of initial screen to the last visit 2 years post 
treatment.  
Each visit is expected to require an average of 1 hour of subject’s 
time.Interview substudy:  
Interviews will take about an hour.  PCORI subjects and staff will be interviewed 
once, and some may be invited to participate in a one time focus group, which 
would also take about an hour. Non-participants, i.e., individuals who declined to 
participate in the parent study, will be invited to participate in a one-time 
interview.  
11.3 Describe the estimated duration for the investigators to complete this study 
(i.e. all data is collected and all analyses have been completed).  
Response: The estimated time for the investigator to complete the study is 5.5 
years.   
Interview substudy:  
Approximately 6 months to collect the data and an additional 6 months to analyze 
it.  
12.0 Setting  
12.1 Describe all facilities/sites where you will be conducting research 
procedures.  Include a description of the security and privacy of the facilities 

  
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(e.g. locked facility, limited access, privacy barriers).  Facility, department, and 
type of room are relevant.  Do not abbreviate facility names.    
NOTE:  Examples of acceptable response may be: A classroom setting in the 
Department of Psychology equipped with a computer with relevant survey 
administration software,” “The angiogram suite at Buffalo General Medical 
Center, a fully accredited tertiary care institution within New York State with 
badge access,” or, “Community Center meeting hall.”  
Response: All participating OAT clinics must provide a patient-friendly, private 
examination room for discussion of HCV detection, study information, and 
consenting. For telemedicine they must employ two-way, face to face 
communication using a HIPAA- compliant, secure web – connected computer 
equipment with digital camera.  
 
Interview substudy:  
Interviews will happen over the phone, over videoconferencing, or in a private 
room in the OTP clinic.    
  
12.2 For research conducted outside of UB and its affiliates, describe:  
• 
Site-specific regulations or customs affecting the research  
• 
Local scientific and ethical review structure  
NOTE:  This question is referring to UB affiliated research taking place outside 
UB, i.e. research conducted in the community, school-based research, 
international research, etc.  It is not referring to multi-site research.  UB affiliated 
institutions include Kaleida Health, ECMC, and Roswell Park Cancer Institute.    
Response: Submission, review and approval of the protocol will be at the local  
IRB level.  Those sites without a local IRB sites 01 and 11, will follow UB-IRB 
guidelines and approvals. All sites will meet state regulations and licensing 
requirements for treatment of substance abuse patients.  UB is acting as the main 
coordinating site.  All the other sites will submit their clinical data to UB through 
MyOwnMed (MoM), and the billing data and SDOH data through other secure 
means.  There is no data sharing between sites laterally.  Data Use Agreements 
are in place between UB and the participating sites.   
  
☐  
N/A:  This study is not conducted outside of UB or its affiliates.  
13.0 Community-Based Participatory Research  
13.1 Describe involvement of the community in the design and conduct of the 
research.   
NOTE:  Community-Based Participatory Research (CBPR) is a collaborative 
approach to research that equitably involves all partners in the research process 
and recognizes the unique strengths that each brings.  CBPR begins with a 
research topic of importance to the community, has the aim of combining 
knowledge with action and achieving social change to improve health outcomes 
and eliminate health disparities.  

  
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Response: This research will be conducted in a largely medically disenfranchised, 
largely under-represented minority group of patients in substance use treatment.  
In addition to protocol reviews by local IRBs, a patient-partner group led by a 
patient advocacy manager, will meet every month or quarterly to discuss the 
details of treatment practice and to provide feedback on the study conduct to share 
with participating sites and within their own communities. As this study is 
supported by the Patient-Centered Outcomes Research Institute (PCORI), patient 
and community engagement of interested stakeholders is a crucial part of the 
entire study. Meetings will occur at least annually with patient and stakeholder 
advisory groups where feedback will be ascertained on mechanism by which to 
improve the study conduct.    
  
☐  
N/A:  This study does not utilize CBPR.  
13.2 Describe the composition and involvement of a community advisory board.  
Response: For this study, the “community advisory board” will be comprised of 
two separate committees, a patient advisory board and a sustainability committee 
comprised of stakeholders. The objective of each will be to educate and to 
advocate for treatment and support services for individuals with viral hepatitis. 
Patient partner groups will consist of a patient advocate acting as facilitator and 3 
patients who have completed or who are undergoing HCV treatment at a 
participating site. The Sustainability Committee will be comprised of 
representatives of New York State and City Departments of Health, leading 
pharmaceutical manufacturers of HCV treatments and diagnostic companies, third 
party payers, HCV educational foundations, medical providers, telemedicine 
implementation expert, and federal agencies involved in treatment of patients with 
substance use disorders.   
  
☐  
N/A:  This study does not have a community advisory board.  
14.0 Resources and Qualifications  
14.1 Describe the qualifications (e.g., education, training, experience, expertise, 
or certifications) of the Principal Investigator and staff to perform the research.  
When applicable describe their knowledge of the local study sites, culture, and 
society.  Provide enough information to convince the IRB that you have 
qualified staff for the proposed research.   
NOTE:  If you specify a person by name, a change to that person will require prior 
approval by the IRB.  If you specify a person by role (e.g., coordinator, research 
assistant, co-investigator, or pharmacist), a change to that person will not usually 
require prior approval by the IRB, provided that the person meets the 
qualifications described to fulfill their roles.  
Response: The Principal Investigator (PI) of this study, Dr. Andrew Talal is a 
board-certified gastroenterologist who has been treating patients with HCV 
infection for the past 25 years, and who has been conducting a pilot study of HCV 
treatment via telemedicine for the past 5 years at one of the participating sites 
(START Treatment and Recovery Centers). At the European Association for the 
Study of Liver Diseases annual meeting in April 2016, Dr. Talal illustrated the 

  
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results of the first 19 methadone-maintained patients treated for HCV via 
telemedicine that showed excellent efficacy, medication adherence, and 
acceptance of the modality. The research teams, at each participating site consist 
of experts in addiction medicine, infectious diseases, implementation science, 
epidemiology, biostatistics, and addiction psychiatry. All will be responsible for 
general study oversight as delegated and supervised closely by the PI. 
Describe other resources available to conduct the research.   
14.2 Describe the time and effort that the Principal Investigator and research 
staff will devote to conducting and completing the research.  
NOTE:  Examples include the percentage of Full Time Equivalents (FTE), 
hours per week.  The question will elicit whether there are appropriate resources to conduct 
the research. Response:  
 Principal Investigator (20% Effort each year)  
  
  Co-Investigator: (10% Effort Y1-4, 5% Effort Y5).  
  
  Co-Investigator: (5% Effort Y1 and 5, 10% Effort Y2-4).  
  
  Biostatistician: (20% Effort Y1, 10% Y2-3, 30% Y4-5)  
  
TBN Project Coordinator/Managed care coordinator:   
(50% Effort Y1-4, 25% Y5)  
  
  
  
TBN - Recruiter:   
(50% Effort Y1-4)  
  
  
TBN - Telehealth IT support:   
(20% Effort Y1-3, 10% Y4)  
  
  
TBN - Clinician trainer:   
(40% Effort Y1-4, 20% Effort Y5)  
  
   
  
14.3 Describe the availability of medical or psychological resources that 
subjects might need as a result of anticipated consequences of the human 
research, if applicable.  
NOTE:  One example includes: on-call availability of a counselor or psychologist 
for a study that screens subjects for depression.  
Response: The study will be conducted at sites that have familiarity with the treatment 
of mental health disorders in patients in substance use treatment as well as 24-hour 

  
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medical coverage for emergencies. Secondly, in the case that a particular site does not 
have the requisite expertise to address a medical issue, each participating site could 
contact other sites that could support patient management in specific areas that may 
be lacking at the individual clinic. Thirdly, each individual site study staff will be 
available 24 hours a day, 7 days a week to address issues that may not be readily 
addressed by the above mentioned methods.   
  
14.4 Describe your process to ensure that all persons assisting with the 
research are adequately informed about the protocol, the research procedures, 
and their duties and functions.  
Response: Clinicians, staff, and administrators from the participating OAT clinics will 
be engaged at the outset of the project by convening multiple information and staff 
training sessions given by UB Research staff to introduce the study, to explain the 
rationale and background for the initiative, and to review the protocol. Update 
meetings will be conducted to share progress and to address challenges.  
  
15.0 Other Approvals  
15.1 Describe any approvals that will be obtained prior to commencing the 
research (e.g., school, external site, funding agency, laboratory, radiation 
safety, or biosafety).  
Response: Participating OAT sites must have all state required licenses prior to 
consideration of participating in research study. Protocols will be submitted, 
reviewed and approved by local IRBs. Those sites without a local IRB will use 
UB-IRB approved protocol. Physicians delivering telemedicine must be licensed 
in the state where services are delivered and versed in the state and payer-specific 
reimbursement processes. The sponsor, PCORI, has already approved the study 
concept.   
Interview substudy:  
All study sites not depending on UB IRB will obtain IRB approval at their 
institutions.  
☐  
N/A:  This study does not require any other approvals.  
16.0 Provisions to Protect the Privacy Interests of Subjects  
  
16.1 Describe how you will protect subjects’ privacy interests during the course 
of this research. NOTE:  Privacy refers to an individual’s right to control access to 
him or herself.  Privacy applies to the person.  Confidentiality refers to how data 
collected about individuals for the research will be protected by the researcher from 
release.  Confidentiality applies to the data.    
Examples of appropriate responses include: “participant only meets with a study 
coordinator in a classroom setting where no one can overhear”, or “the 
participant is reminded that they are free to refuse to answer any questions that 
they do not feel comfortable answering.”    

  
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Response: During visits, clinicians and specialist will meet with patients in 
private, comfortable, closed examination rooms to discuss lab results, plans of 
care and progress.   
Subjects who agree to be interviewed in an external setting for study 
dissemination activities will sign a separate consent form and will be asked about 
each interview opportunity separately.  These subjects will be reminded that any 
information that they share, as well as their status as active participants in a study 
about hepatitis C treatment conducted in an OAT clinic, will no longer be private.  
Interview substudy:  
During videoconference or phone interviews, privacy on both sides of the call will 
be ensured, with the interview being rescheduled if privacy is not possible.  
Participants will be reminded that they are free to refuse to answer any questions 
that they do not feel comfortable answering.  
16.2 Indicate how the research team is permitted to access any sources of 
information about the subjects.    
NOTE:  Examples of appropriate responses include:  school permission for review 
of records, consent of the subject, HIPAA waiver.  This question does apply to 
records reviews.  
Response: Subjects will be asked to sign a HIPAA consent and a study-specific 
informed consent to allow primary providers, liver specialists, and their particular 
substance use treatment site to share patient information pertaining to treatment of 
HCV and as required for the conduct of the study. A Partial HIPAA Waiver will 
be submitted at each site for review of potential subject’s medical records at 
screening.  
A HIPAA waiver is being requested to analyze the billing data for the subjects in 
the telemedicine arm and those in the usual care arm who were treated by the PI.  
Modification 5/8/2020 -  A HIPAA waiver is also being requested to collect the 
billing data for the usual care arm subjects who were treated elsewhere, by 
requesting the billing data from the insurance companies or from the treating 
physician.     
A HIPAA Waiver is also being requested to collect retrospective data from the 
subject’s clinic records and the OASAS server on their SDOH.  This will apply to 
the subjects from the two sites covered by UB-IRB only.  All other sites will 
submit to their own IRBs.  
17.0 Data Management and Analysis  
17.1 Describe the data analysis plan, including any statistical procedures.  This 
section applies to both quantitative and qualitative analysis.   
Response: In this study, we will implement a stepped wedge cluster randomized controlled 
trial with two arms (intervention and control). The statistical analysis will be performed 
using SAS (SAS Institute Inc., Cary, NC, USA) and R (http://www.r-project.org/). The 
data collection will be conducted over 4 time points with 3 steps with 4 clinics switching 
(in a random order) from control to intervention at each step. The analysis set will include 
all patients who satisfy the patient level eligibility criteria (6 months active OTP 

  
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enrollment, HCV RNA positivity, and medical insurance; exclusion criteria are HCV 
medication contraindications and HCV treatment elsewhere) and consent to participate.  
We will follow the intention to treat principle. Enrolled subjects’ characteristics will be 
summarized by their arm and by time period. In addition to demographic data (sex, age, 
race, ethnicity, education, employment), we will also collect data on opiate agonist therapy-
specific variables (type of treatment, duration, therapeutic regimen), illicit drug use 
behavior (frequency, abstinence), HCV-specific variables (HCV RNA, HCV genotype, 
fibrosis, ALT, AST, hemoglobin, platelet count, sodium, total bilirubin, creatinine, 
estimated glomerular filtration rate, prothrombin, international normalized ratio,  previous 
HCV treatment) and co-morbidities (HIV, HBV, psychiatric). Continuous variables will be 
presented by their mean (and standard deviation) and median (and interquartile range 
[IQR]).  Categorical variables will be presented by their frequencies. We will assess 
comparability between the two arms. Categorical variables will be compared through 
Fisher’s exact test, and continuous variables will be compared through Wilcoxon’s 
ranksum test.   
 
The primary outcome of the study is achievement of SVR, which is defined as undetectable 
HCV RNA 12 weeks post treatment cessation. For the primary analysis, the SVR rate will 
be evaluated based on all study patients (HCV RNA+, age ≥18, at least 6months of OTP, 
insurance coverage) who consent to referral (usual) care or telemedicine management of 
HCV. Primary analysis will be individual-level based with binary outcome, corresponding 
to successful treatment outcome (achievement of SVR), using GLMM or GEE modelling 
to account for the clustering. The GLMM model will include a random effect for each 
cluster, as well as a fixed effect for each time period and for the cluster (clinic) intervention 
assignment at each time point. We will check for interaction between time and intervention 
and will adjust as necessary for covariates to account for potential differences between the 
two arms. The intervention effect will be expressed as odds ratio and will be reported 
together with its 95% confidence interval and p-value, and both unadjusted and adjusted 
odds ratios will be reported. Model assumptions will be checked at every level of the 
analysis through graphical and analytical tools. Additionally, for patients assigned to the 
telemedicine arm who do not adhere to at least one telemedicine appointment, we will also 
account, by subgroup analysis, for the actual management strategy for HCV treatment that 
each patient utilized (i.e., whether at least one telemedicine appointment was completed).  
As secondary outcomes, we will collect information on Hepatitis C patient 
satisfaction surveys, National Institute on Drug Abuse Screen, Modified Mini Mental 
Health Screen, Drug Abuse Screening Test and Sociodemographic Survey, treatment 
initiation rate, treatment adherence rate, treatment completion rate and HCV reinfection 
rate at the end of the study. We will assess for the questionnaire’s internal consistency by 
calculating the Cronbach’s alpha. We will compare patient satisfaction with the delivery of 
health care between the two arms using linear mixed effects model or GEE. For the 
comparison of the treatment initiation and treatment completion rates between the two 
arms, we will apply the same methodology as for the analysis of the SVR rate (above). 
Adjustment for covariates will be incorporated as appropriate. HCV reinfection will be 
represented by a binary variable indicated as HCV RNA positivity and will be modeled 
using GLMM or GEE. All tests will be two sided with level of significance of 0.05. Most 
covariates for adjustment of the analyses for potential confounding will be assessed during 
the screening process of the study either directly from the patient or from the patients’ 
medical record. We will use graphical and analytical methods for detection of outliers in 
the data and conduct sensitivity analysis by fitting the model with and without the 
suspicious observations. The suspicious observations will be checked for accuracy.  

  
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We will be evaluating the resource utilization used in treating Hepatitis C via 
telemedicine as a way to minimize the long term complications of the virus, such as liver 
transplants, liver cancer and cirrhosis.  Resource utilization will be analyzed for regional 
differences and other socioeconomic variables.    
  
SDOH will be analyzed for any association with the pursuit of HCV treatment. For the 
analysis of SDOH data, we may use large language models provided by Open AI using 
their application programming interface (API) to pre-process the data for statistical 
analysis. We will abide by Open AI’s procedures for processing data following their 
terms, conditions, and protocols. The UB Purchasing Department and the Office of 
Medical Computing are carefully reviewing the terms and conditions associated with 
procuring the Open AI large language model API access.  Terms and Policies associated 
with the program are located at https://openai.com/policies. Policies related to an 
addendum for Personal Data Processing is located at https://openai.com/policies/data-
processing-addendum. The following form will be completed as required for compliance 
with the personal data processing: Data Processing Addendum Form -
https://ironcladapp.com/public-launch/63ffefa2bed6885f4536d0fe. 
  
Interview substudy:  
Topic areas of interest for both patients and staff will be developed by a group of 
experts in the area of qualitative research including a clinical psychologist with 
significant experience with substance use research in the criminal justice system, a 
UB Professor of Nursing, and an Infectious Diseases physician who has 
conducted research in OTPs for the past two decades. Combined with experienced 
case managers and the PI of the parent study, we will develop interview/focus 
group/survey topics to be assessed. We anticipate asking these topics in sections...  
For qualitative research, we will analyze the data using Hermeneutic phenomenology to 
interpret and to explicate common meanings and shared practices of the phenomena.  
17.2 If applicable, provide a power analysis.    
NOTE:  This may not apply to certain types of studies, including chart/records 
reviews, survey studies, or observational studies.  This question is asked to elicit 
whether the investigator has an adequate sample size to achieve the study 
objectives and justify a conclusion.   
Response: Please see below for the sample size calculations for the primary 
(Table 1) and secondary (reinfection) (Table 2) endpoints.   
Table 1. Effect Size, Sample Size and Statistical Power for Primary Aim of Viral  
Eradication  
  
Telemedicine Arm  
 
Referral Arm (Usual Care)  
80% 
power  
90% 
power  
Treatment  
Initiation  
SVRa  
SVRb  
Treatment  
Initiation  
SVRa  
SVRb  
N  
Total  
N   
Total  
25%  
80%  
20%  
15%  
80%  
12%  
518  
681  
30%  
80%  
24%  
15%  
80%  
12%  
257  
336  
30%  
80%  
24%  
18%  
80%  
14.4%  417  
548  

  
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IRB Version: JAN2016  
30%  
80%  
24%  
20%  
80%  
16%  
613  
808  
35%  
80%  
28%  
15%  
80%  
12%  
160  
207  
35%  
80%  
28%  
18%  
80%  
14.4%  228  
297  
35%  
80%  
28%  
20%  
80%  
16%  
297  
389  
35%  
90%  
31.5%  18%  
90%  
16.2%  195  
256  
35%  
90%  
31.5%  20%  
90%  
18%  
256  
334  
38%  
80%  
30.4%  15%  
80%  
12%  
126  
164  
38%  
80%  
30.4%  18%  
80%  
14.4%  172  
225  
38%  
80%  
30.4%  20%  
80%  
16%  
216  
283  
38%  
80%  
30.4%  20%  
70%  
14%  
163  
212  
38%  
80%  
30.4%  20%  
60%  
12%  
126  
164  
  
a  Among those who initiate treatment; b Among those who are eligible for treatment  
  
Table 2: Power of Test and Effect Size by Follow-up Time for Reinfection  
Follow-up 
Time Period  
Re-infection  
Rate  
Reduction  
Power (1-β)  
Total Sample 
Size Required  
6 months  
50%  
70%  
480  
 
80%  
 
624  
12 months  
25%  
70%   
480  
80%  
624  
18 months  
20%  
80%  
480   
24 months  
15%  
>85%  
480  
  
17.3 Describe any procedures that will be used for quality control of collected 
data.  
Response: OAT site study case managers will review data collected on a case by 
case basis to ensure all required patient data, lab reports, surveys and 
questionnaires are completed and documented in patient electronic files. In 
addition, the data collected during the study will be entered using double data 
entry by experienced data operators into a database and will be monitored for 
accuracy and completeness using the data management system. We will conduct 
continuous data quality checks using the data management system. Participant 
medical information will be entered into a password protected electronic medical 
record.   
Interview substudy:  
The transcripts will be compared against the videoconference or voice recordings 
for accuracy.    
  
18.0 Confidentiality  
  

  
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A. Confidentiality of Study Data  
  
Describe the local procedures for maintenance of confidentiality of study data 
and any records that will be reviewed for data collection.    
  
18.1 A.  Where and how will all data and records be stored?  Include 
information about:  password protection, encryption, physical controls, 
authorization of access, and separation of identifiers and data, as applicable.  
Include physical (e.g. paper) and electronic files.  
Response: We are using My OWN MED (MoM) as the data management system 
for this protocol.  All study data is entered into MoM, which utilizes end-to-end 
data encryption, SHA384Managed hash algorithm, and password authentication 
with 24/7/365 network monitoring. All participating institutions have been made 
aware of MOM data security practices. A copy of the MOM Functional 
Requirements document is being included in this submission. MoM contains 
identifiable information.  The data can be sent to UB either de-identified or with 
identifiers.  Any database with identifiers will be kept on a secure server accessed 
by study team members with password protected access. Identifiers will be used 
as necessary to link billing data to the correct subject, but the data will be 
deidentified before the analysis stage. Additionally coded information will be 
stored on a data management server, housed at the Institute for Healthcare 
Informatics at the University at Buffalo.  IHI staff are responsible for routine and 
continuous monitoring of the network, servers, and overall data security, and our 
data analytics team also monitors the data for integrity and completeness via data 
queries and checks.  Protections employed by this study will be similar to those 
that have been enacted in similar clinical research studies. Data will be stored on 
password protected servers. Passwords will only be available to the study case 
manager and to the Principal Investigator. Patient identity will not be shared with 
anyone other than the staff involved in the clinical management of the patient 
including the physicians who are treating the patients. Patients will be provided a 
study identification number for all study related data.  
Answers from questionnaires and surveys will be entered into MoM.  Any paper 
copies will be kept in locked file cabinets in the clinic where they were done. 
Billing data will be stored in an excel spreadsheet, under the subject’s study 
identification number, on password protected computers.    
The intake forms containing the SDOH information, or excel sheets that the 
information from the intake forms has been entered into, or that contain the 
downloaded PAS data, will be sent to the UB study team either by fax, secure 
email or through UB Box or secure file transfer.  The information will reside in 
appropriate computer files (i.e., excel, pdfs, cvs) under study IDs, and will be 
stored on secure servers at Breadcrumb Analytics, or on secure servers at UB 
including the IHI and CCR.  The data needed for biostatistics will be sent to the 
IHI server and combined with the main study data under study IDs.  Any paper 
copies of the forms will be kept in a locked drawer in a key card protected office 
in the CTRC.  The electronic files will be stored in a password protected file on 
the S drive.   
Interview substudy:  

  
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All recordings and transcripts will stored on a password protected secure server.   
  
18.2 A.  How long will the data be stored?  
Response: Data related to the study will be stored for three years after study 
completion.  
All identifiable data in the billing data will be destroyed at the end of the study, 
defined as the successful publication of a manuscript.  
The intake forms (both paper and electronic) and excel sheets that contain the 
SDOH data will be destroyed/ deleted upon successful publication of that portion 
of the study.   
Interview substudy:  
Recordings and complete transcripts will be kept until successful publication.  
After publication, transcripts will be de-identified and stored indefinitely for 
future research, and recordings will be deleted.    
18.3 A.  Who will have access to the data?  
Response: Because HCV treatment will be a part of the subject’s routine care, 
identifiable data regarding individual subjects will be available to study staff and 
providers directly involved in the clinical management of the patients enrolled in 
the study. Subject data will be de-identified and assigned a study identification 
number prior to transmission of data for study analysis.  Aggregate data will be 
shared with stakeholders, patient- partners and patient advocates as well as with 
local IRBs, as appropriate.  
The non-coded SDOH information (in the form of the intake forms or downloaded 
PAS data) will only be accessed by the PI and the study team member(s) at the 
study site doing the data entry or the downloading and coding of the PAS data.  
The information will never be in the database in a non-coded form.  The coded 
SDOH data will be combined with the coded data in the main study database for 
analysis by the biostats team listed on the study.  No one who is not currently part 
of the study team will see the coded database and have access to the code key or 
identifiable data.   
Interview substudy:  
Only the study staff at UB will have access to the data.  
18.4 A.  Who is responsible for receipt or transmission of the data?  
Response: Ultimately, the principal investigator is responsible for receipt and 
transmission of all samples and data. Clinical data will be transmitted over web-
secured, HIPAA-compliant data management system (MoM) to the Principal 
investigator and biostatistician responsible for this project. Additionally, this 
coded information will be stored on a data management server, housed at the 
Institute for Healthcare Informatics at the University at Buffalo and monitored by 
study staff at UB Research for the sake of generating reports to identify 
incomplete or missing data within the MoM system.  
The intake forms that contain SDOH data, or the excel sheets that contain the 
intake forms and PAS data, will be transmitted by fax or electronically. Once 

  
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entered into the database built for this purpose on the Breadcrumb Analytics 
server, the data will be securely transferred to the server in IHI, where they can be 
accessed by the biostatisticians.  
Interview substudy:  
The study coordinator and PI will be responsible for receipt,  The study team 
member doing the interviews will be responsible for transmission.  
18.5 A.  How will the data be transported?  
Response: Data will be transported via electronic documentation to web secure, password 
protected servers through MoM, a clinical trial management system that will enable us to 
perform clinic randomization electronically and data collection and transfer from the 12 
participating sites to UB research staff for data analysis. All sites enter data into 
MyOwnMed and the aggregate data is only accessible to UB study staff.  Sites do not 
share their data with any other site, just Dr. Talal and the UB study staff.  MOM will also 
provide consulting and technical support on regulatory and compliance issues related to 
data sharing throughout the study and will offer resources, such as business associate 
agreements to permit data sharing between the system and each clinic partner. Data Use 
Agreements are in place.   
SDOH data will be sent via fax or electronically through secure email or Box.  
Interview substudy:  
All data will be transported electronically.  
B. Confidentiality of Study Specimens  
  
Describe the local procedures for maintenance of confidentiality of study 
specimens.    
  
 
☐  
N/A:  No specimens will be collected or analyzed in this research.    
(Skip to Section 19.0)  
  
18.1B.  Where and how will all specimens be stored?  Include information 
about:  physical controls, authorization of access, and labeling of specimens, as 
applicable.    
Response: The primary purpose of this study is to compare efficacy of HCV treatment 
between traditional referral and telemedicine. Therefore, handling of specimens will 
be managed through each individual OAT site with proper labeling of specimens. 
Patients will be provided a study identification number for all study related data and 
specimens. Processing, reporting and storing of Standard of Care specimens will be 
dictated by the commercial vendor laboratory standards of practice. We will also 
collect 4 vials of blood (60ml) for viral diversity among patients who relapse after 
treatment and subject to future research. (See Sec.8) These coded specimens will be 
sent to the biorepository at UB and will be maintained indefinitely. All samples will 
be labeled with the participant’s study number.   
  
18.2 B.  How long will the specimens be stored?  

  
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Response: specimens for biorepository (if the subject agreed on the ICF to have 
additional blood drawn for the biorepository) will be stored indefinitely in a 
biorepository located at 875 Ellicott St Buffalo, N.Y. 14203. A 2ml de-identified 
aliquot maybe stored at Abbott laboratories in Abbott Park, IL. for possible 
genome sequencing in the future.    
18.3 B.  Who will have access to the specimens?  
Response: For specimens housed at the UB biorepository, the PI and study staff associated 
with the biorepository will have access. Samples sent to commercial vendor laboratories 
for Standard of Care laboratory assessments will be accessed by employees of these 
laboratories and will not be used or accessed for future research purposes.   
The following is a description of a possible substudy to happen in the future if 
scientific questions merit.  A new protocol would be submitted for approval if this 
were to happen.  A request to Abbott Laboratories is for a sub-study to that funded through 
PCORI. Although patient follow up for two years post treatment cessation was part of the 
requirements for the PCORI award, no additional funding was provided to enable us to 
collect and sequence viral isolates. The assumption was that the HCV RNA measurements 
would be completed by clinical laboratories routinely utilized by each clinic. However, we 
are interested in increasing the scientific value of the project through the fulfillment of the 
following specific aims:  
1) To assess genetic differences in viral isolates between those patients who have viral 
recurrence.   
2) To identify baseline relatedness between HCV isolates obtained from patients on OAT 
from different parts of New York State.  
3) To identify “hot spots” of viral transmission among PWSUD.  
4) To conduct new virus discovery to assess for novel isolates among symptomatic OAT 
patients from throughout NYS.   
Aims related to HCV core antigen  
1) 
Cross-sectional assessment of relationship between HCV core antigen (HCVcAg) 
and HCV RNA at baseline among OAT patients.  
2) 
Longitudinal assessment of HCVcAg declines in a cohort of PWID on DAA-
based therapy.   
3) 
Decline in HCV core antigen for up to 2 years post-treatment completion in a 
cohort of PWSUD.   
1) HCV RNA and HCV genotyping will be performed on the M2000 at Kaleida’s 
Flint Road facility in a GCP lab.  
Whole genome sequencing will be performed at Abbott Laboratories in Abbott Park, IL.  
  
18.4B.  Who is responsible for receipt or transmission of the specimens?  

  
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Response: Individual sites will be responsible for shipping of specimens 
according to commercial lab. A lab manual with standard operational procedure 
and shipping supplies will be provided to each individual clinic for biorepository 
specimens (sect.16.6). Specimens will be delivered to:   
Biorepository- Dr. Andrew Talal  
875 Ellicott St 6th fl. Rm.6047  
Buffalo, N.Y. 14203 Via 
FedEx.  
Staff at the University of Buffalo with prior IRB authorization to maintain 
specimens in the Biorepository, will ship via courier from this repository, a de-
identified specimen to the Kaleida lab at Flint Rd. Amherst, N.Y. where the 
Abbott Lab M2000 is  
housed, for HCV RNA and genotyping, and a 2 ml aliquot of de-identified blood 
product will be sent to Abbott Laboratories in Abbott Park, IL. for genome 
sequencing via shipping supplies provided by Abbott Lab.  
  
18.5B.  How will the specimens be transported?  
Response: In the case of shipment of specimens to the UB biorepository, ambient 
specimens will be shipped daily to the biorepository using the designated courier 
(FedEx). Staff at the University of Buffalo with prior IRB authorization to 
specimens in the Biorepository, will ship via courier from this repository, a 
deidentified specimen to the Kaleida lab at Flint Rd. Amherst, N.Y. where the 
Abbott Lab M2000 is housed, for HCV RNA and genotyping, and a 2 ml aliquot 
of de-identified blood product will be sent to Abbott Laboratories in Abbott Park, 
IL. for genome sequencing via shipping supplies provided by Abbott Lab.  
  
 Standard of Care samples sent to commercial laboratories will be sent using the 
standard procedure identified by each laboratory at each site.   
  
19.0 Provisions to Monitor the Data to Ensure the Safety of Subjects  
☐  N/A:  This study is not enrolling subjects, or is limited to records review 
procedures only.  This section does not apply.  
  
NOTE:  Minimal risk studies may be required to monitor subject safety if the research 
procedures include procedures that present unique risks to subjects that require 
monitoring.  Some examples include:  exercising to exertion, or instruments that elicit 
suicidality or substance abuse behavior.  In such cases, N/A is not an acceptable 
response.  
  
19.1 Describe the plan to periodically evaluate the data collected regarding 
both harms and benefits to determine whether subjects remain safe.  
Response: During the study start–up phase, a Data Safety Monitoring Board  
(DSMB) will be established and meet at a minimum annually. The DSMB will 
include experts in liver disease, infectious diseases, epidemiology, biostatistics, 

  
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bioethics and a patient representative, all of whom are independent of the study 
and institutions. The DSMB will meet initially to review the study aims and 
protocol, to select variables and procedures for monitoring, and to establish early 
stopping rules in the case of subject harm. Subsequently, the DSMB will have the 
opportunity to review trial outcome data at scheduled interim analyses to be 
conducted in months 24, 36, 48 and 60. Similarly, the IRB at each of the 
participating institutions could request review of the study in case of concern for 
patient safety. Rules for early study termination will be established prior to 
participant engagement.  
  
19.2 Describe what data are reviewed, including safety data, untoward events, 
and efficacy data.  
Response: Data to be reviewed will be that involved with direct patient care 
management by the liver specialists and physician extenders. Data review will include 
lab values obtained during the clinical management of HCV infection, such as 
hemoglobin, chemistries, renal and liver function tests as well as HCV RNA. Also, 
day to day communications with the patient to address patient’s concerns and side 
effects of treatment will be reviewed on a regular basis by the study team at the 
participating OAT sites.  
  
19.3 Describe any safety endpoints.  
Response:  Any evidence of serious adverse events and/or death related to 
telemedicine.   
  
19.4 Describe how the safety information will be collected (e.g., with case 
report forms, at study visits, by telephone calls with participants).  
Response: Safety information will be collected by day to day communication with the 
patient, completion of patient satisfaction surveys, and review of lab reports.  
  
19.5 Describe the frequency of safety data collection.  
Response: Subjects on methadone maintenance must report to clinics at a frequency 
that ranges from once daily to once weekly for dosing of methadone. Therefore, any 
patient concerns or safety laboratory signals may be addressed quickly with the 
patient by study staff and/or clinical personnel at the OAT clinic.  
  
19.6 Describe who will review the safety data.  
Response: Data on the study and particularly any safety concerns will be reviewed 
and discussed by study and clinic staff including the PI as appropriate. Similarly, the 
IRB at each of the participating clinics and of the participating institutions may 
request review of the study in case of concern for patient safety. The DSMB will 
review data annually at a minimum.   
  
19.7Describe the frequency or periodicity of review of cumulative safety data.  

  
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Response: Cumulative safety data will be reviewed at monthly meetings of Steering 
committee and at least annually by the DSMB.  
  
19.8 Describe the statistical tests for analyzing the safety data to determine 
whether harm is occurring.  
Response: Providers, nurse practitioner/physician assistants will continuously monitor 
lab results and patient reports of symptoms for assessment of adverse events, and if 
necessary use disproportionality measures of analysis to assess for potential harm.  
  
19.9 Describe any conditions that trigger an immediate suspension of the 
research.  
Response: Evidence of serious adverse events and death related to telemedicine.  
  
20.0 Withdrawal of Subjects  
 
☐  
N/A:  This study is not enrolling subjects.  This section does not apply.  
  
20.1 Describe anticipated circumstances under which subjects may be 
withdrawn from the research without their consent.  
Response: If, in the opinion of the PI continued participation in the study of any subject 
might lead to undue harm, the subject may be withdrawn without consent. Three 
consecutive missed appointments will result in a discussion between the principal 
investigator at the site and the study participant to determine the reason for the missed 
appointments. Continuation in the study for the participant will be assessed on a case-by-
case basis between the study PI and the site PI. Continued HCV treatment will not be 
affected by study withdrawal and subject to local institutional policy and procedure.  
Participants in both arms who do not undergo an HCV evaluation within 5 months of 
enrolling in the study will be withdrawn and will be considered as treatment failuresAny 
subject will be discontinued from the study if they are discharged from the clinic or if 
their HCV medication administration lapses for 1 month or more.  
  
20.2 Describe any procedures for orderly termination.    
NOTE:  Examples may include return of study drug, exit interview with clinician.  
Include whether additional follow up is recommended for safety reasons for 
physical or emotional health.  
Response: Orderly termination will proceed as follows. Sites will contact the 
patient advising of the potential need to terminate participation in the research 
protocol. If subject is agreeable, a visit may be scheduled at the site to discuss 
subjects concerns and or reasons for poor adherence.    
20.3 Describe procedures that will be followed when subjects withdraw from the 
research, including retention of already collected data, and partial withdrawal 
from procedures with continued data collection, as applicable.  
Response: Subjects will be informed at the time of informed consent that should 
they choose to withdraw prematurely from the study, they will be asked to 

  
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complete a last survey and agree to last blood draw to determine viral load status, 
subsequently, any new and all data collected to date will be included in study 
results.  
  
21.0 Risks to Subjects  
21.1 List the reasonably foreseeable risks, discomforts, hazards, or 
inconveniences to the subjects related to their participation in the research. 
Consider physical, psychological, social, legal, and economic risks.  Include a 
description of the probability, magnitude, duration, and reversibility of the 
risks.   
NOTE:  Breach of confidentiality is always a risk for identifiable subject data.  
Response: The primary risk potential is breach of participant confidentiality and 
privacy and injury due to blood drawing. Blood obtained for HCV RNA levels 
will be drawn by experienced laboratory personnel who have been trained in 
phlebotomy. Data protections will be designed in collaboration with the 
information technology departments at each of the participating sites throughout 
the study to minimalize the risk of breach of confidentiality.   
Interview substudy:  
Breach of confidentiality is a risk.  Subjects may feel uncomfortable with some 
interview questions.  
For the focus groups:  While we are not specifically looking for information that 
may be damaging, we are asking about experiences from the staff and 
administrators’ places of employment, and due to the free form nature of the focus 
groups, participants may offer opinions and information that may be damaging to 
their employment and/or reputation.  Due to the nature of the focus groups, 
multiple people from each clinic may be present, as well as other professionals 
from other clinics, and therefore participants would not have confidentiality from 
other participants.  No content from the focus groups will be published or shared 
in an identifiable manner.  
21.2 Describe procedures performed to lessen the probability or magnitude of 
risks, including procedures being performed to monitor subjects for safety.  
Response: To minimize risk, blood will be drawn in medical settings with 
protections such as bandages and immediate access to medical personnel in case 
of severe injury. Discussions of study enrollment will be done in a private setting, 
between the study case manager and the potential study participant at the 
individual participating OAT clinic site. Similarly, for patients in the telemedicine 
arm, HCV therapies will be dispensed at the methadone dispensing window at the 
same time as methadone to minimize the chance that a person might be observed 
taking HCV medications. Consent will be obtained to disclose medical 
information to their medical providers and HCV specialists in order to follow up 
on referral requests. Participants will also be asked to sign a confidentiality 
statement acknowledging the importance of not disclosing personal information to 
other participants. Participant medical information will be entered into a password 
protected electronic medical record. Data collected during the study will be 
entered using data entry by experienced data operators into MoM, or a secure 

  
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database created by Breadcrumb Analytics. This de-identified data will be 
monitored for accuracy and completeness via reports generated by the Institute for 
Healthcare Informatics Department at the University at Buffalo  
Interview substudy:  
Subjects’ names will not be included in recordings or transcripts.  All recordings and 
transcripts will be stored electronically on a password protected server.    
  
21.3 If applicable, indicate which procedures may have risks to the subjects 
that are currently unforeseeable.  
Response: While measures will be taken to avoid breach of confidentiality, 
technology at all levels is at risk for corruption of data servers as well as cyber 
hacking of information.  
  
21.4 If applicable, indicate which research procedures may have risks to an 
embryo or fetus should the subject be or become pregnant.  
Response: N/A  
  
21.5 If applicable, describe risks to others who are not subjects.  
Response: N/A  
  
22.0 Potential Benefits to Subjects  
22.1 Describe the potential benefits that individual subjects may experience by 
taking part in the research.  Include the probability, magnitude, and duration of 
the potential benefits.  Indicate if there is no direct benefit.    
NOTE:  Compensation cannot be stated as a benefit.  
Response: For those participants who follow through with treatment from referral to a 
liver specialist or via telemedicine intervention, the expected benefit will be sustained 
virologic response. Additionally, many patients who have resolved HCV report 
improved quality of life, diminished fatigue, a more positive attitude toward life in 
general with the knowledge that they have eliminated a chronic viral infection.   
  
23.0 Compensation for Research-Related Injury  
☐  
N/A:  The research procedures for this study do not present risk of 
research related injury (e.g. survey studies, records review studies).  This 
section does not apply.    
23.1 If the research procedures carry a risk of research related injury, 
describe the available compensation to subjects in the event that such injury 
should occur.    
Response: Since this is a study of telemedicine-based treatment approaches for 
HCV, we do not anticipate a great deal of risk associated with the protocol.  

  
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Therefore, no compensation will be available to subjects in the event of injury. 
We do acknowledge, however, that we are assessing a treatment delivery 
modality that will involve the use of FDA-approved medications at indicated 
doses and durations; these medications may have their own associated adverse 
events. Although not part of the research, per se, in the event of injury to the study 
subject, immediate medical attention will be provided at the clinic where they 
customarily receive treatment or by referral from the study participating clinic to a 
local hospital.   
  
23.2 Provide a copy of contract language, if any, relevant to compensation for 
research related injury.  
NOTE:  If the contract is not yet approved at the time of this submission, submit the 
current version here.  If the contract is later approved with different language regarding 
research related injury, you must modify your response here and submit an amendment 
to the IRB for review and approval.  
Response: There is no specific contract language from PCORI related to 
compensation for research related injury.   
  
24.0 Economic Burden to Subjects  
24.1 Describe any costs that subjects may be responsible for because of 
participation in the research.    
NOTE:  Some examples include transportation or parking.  
Response: Inclusion criteria require that all subjects must be covered by medical 
insurance as is the case for 95% of patients on OAT in New York State. Subjects 
consenting to participate in either arm will be responsible for any and all 
copayments identified by medical insurers. We will attempt to have visits for 
subjects managed by telemedicine scheduled during their regularly scheduled 
methadone visits. However, there may be some costs related to travel for 
unscheduled visits. Therefore, we do not anticipate significant added financial 
burden incurred due to transportation required to travel to the methadone clinic 
for study-related visits.  
  
☐  
N/A:  This study is not enrolling subjects, or is limited to records review 
procedures only.  This section does not apply.  
25.0 Compensation for Participation  
25.1  Describe the amount and timing of any compensation to subjects, 
including monetary, course credit, or gift card compensation.  
Response: Subjects will receive $25 each for completion of consent and blood 
draw, and $15 for completion of each survey as well questionnaire/survey. 
Participants in the telemedicine arm will be reimbursed a total of $130 and in the 
usual care arm a total of $130.  

  
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Item 
administered 
Cost 
per 
admini-
stration 
# of times 
administe
red 
Total 
admini-
stration 
cost 
Informed 
consent and 
blood draw 
$25 
1 
$25 
Sociodemo-
graphics 
$15 
1 
$15 
Mini mental 
$15 
1 
$15 
DAST 
$15 
2 
$30 
NIDA Quick 
Screen 
$15 
1 
$15 
HCV patient 
satisfaction 
$15 
2 
$30 
Total 
 
 
$130 
DAST-10, drug abuse screening test; NIDA, National Institute on Drug Abuse; 
HCV, hepatitis C virus.  
 
Subjects will be compensated with petty cash at the end of each visit and per 
survey completed.  
Subjects who participate in study dissemination interviews and media 
appearances will be compensated $25 per hour with petty cash at the end of each 
interview.  
If a subject is reinfected and agrees to have additional blood draws, they will 
receive $25 for the genotyping blood draw visit, and if they begin retreatment, 
$25 for each blood draw visit, up to 5.  
Interview substudy:  
PCORI Study subjects and non-participants will be compensated $25 per 
interview or focus group session. Compensation may be in the form of gift card or 
cash.  It will be available immediately after the interview at the substance use 
treatment facility for the subject to pick up at their convenience, or mailed in a 
secure fashion.  If possible (depending on union/site rules) staff will be 
compensated $25 for interviews.  
☐  
N/A:  This study is not enrolling subjects, or is limited to records 
review procedures only.  This section does not apply.  
☐  
N/A:  There is no compensation for participation.  This section 
does not apply.  
26.0 Consent Process  
26.1 Indicate whether you will be obtaining consent.    

  
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NOTE:  This does not refer to consent documentation, but rather whether you will 
be obtaining permission from subjects to participate in a research study.   Consent 
documentation is addressed in Section 27.0.  
 
☒  
Yes  
(If yes, Provide responses to each question in this Section)  
 
☐  
No  
(If no, Skip to Section 27.0)  
  
26.2 Describe where the consent process will take place.  Include steps to 
maximize subjects’ privacy.  
Response: Consenting of subjects will be completed at the individual participating 
clinic sites by designated study staff. Discussions of study enrollment and 
consenting will be done in a private setting between the study case manager at the 
participating OAT clinic and the potential study participant. All participating OAT 
clinics must provide a patient-friendly, private examination room for discussion of 
HCV detection, study information, and consenting.   
Subjects who are found to be reinfected will be asked to sign an ICF addendum 
for the collection of additional blood draws.  
Interview substudy:  
For interviews, the consent process will take place in a private room, or over the 
phone or videoconference while both parties are in a private room.  
26.3 Describe how you will ensure that subjects are provided with a sufficient 
period of time to consider taking part in the research study.    
NOTE:  It is always a requirement that a prospective subject is given sufficient time 
to have their questions answered and consider their participation.  See “SOP: 
Informed Consent Process for Research (HRP-090)” Sections 5.5 and 5.6.  
Response: Patients identified as HCV antibody positive will be given their results 
and information regarding HCV infection in the form a brochure provided by 
SAMHSA. At that time, the case study manager will inform the patient of the 
study and will provide them with a copy of the consent for their review. Potential 
subjects will be given as much time as required to review the consent, including 
taking it home with them for consideration of signing at another visit. As patients 
attend the OAT program several times per week, asking them to return on a 
subsequent day should not pose an undue burden on patients. All patients will be 
encouraged to ask questions and to discuss potential enrollment with family 
members, friends, and other providers. Patients may enroll at any time during the 
control or intervention time frames.  
Interview substudy:  
Subjects may take their time deciding whether they would like to participate.  
  
26.4 Describe any process to ensure ongoing consent, defined as a subject’s 
willingness to continue participation for the duration of the research study.    
Response: Subjects will be informed of their right to withdraw from the study at 
any time without risk of jeopardizing ongoing participation in the OAT program.  
Interview substudy:  

  
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If subjects seem uncomfortable with a question, they will be reminded that they 
may skip any questions, or stop the interview at any time.  
26.5 Indicate whether you will be following “SOP: Informed Consent Process 
for Research (HRP-090).” If not, or if there are any exceptions or additional 
details to what is covered in the SOP, describe:  
• 
The role of the individuals listed in the application who are involved in 
the consent process  
• 
The time that will be devoted to the consent discussion  
• 
Steps that will be taken to minimize the possibility of coercion or 
undue influence  
• 
Steps that will be taken to ensure the subjects’ understanding  
Response: Subjects who are interested in participating in interviews and speaking 
engagements during study dissemination activities will sign a separate consent 
addendum.  
  
☒  
We have reviewed and will be following “SOP: Informed Consent Process 
for Research (HRP-090).”  
  
Non-English Speaking Subjects   
☐  N/A:  This study will not enroll Non-English speaking subjects.   
(Skip to Section 26.8)  
26.6 Indicate which language(s) other than English are likely to be 
spoken/understood by your prospective study population or their legally 
authorized representatives.  
  
NOTE: The response to this Section should correspond with your response to 
Section 6.4 of this protocol.  
Response: English and Spanish are the two most common languages spoken 
by a great majority of methadone maintained patients in New York  
State.    
If subjects who do not speak English will be enrolled, describe the process to 
ensure that the oral and written information provided to those subjects will 
be in that language.  Indicate the language that will be used by those 
obtaining consent.  
NOTE:  Guidance is provided on “SOP:  Informed Consent Process for Research 
(HRP-090).”  
Response: Study materials (including informed consent) will be available in 
both English and Spanish, the two languages that are spoken by the great 
majority of methadone-maintained patients in NYS. In most circumstances, 
Spanish-speaking clinic staff at participating OAT clinics are available to 
reach out to non- English speaking patients so that they may be given the 
opportunity to consider enrollment.  

  
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Cognitively Impaired Adults  
 
☒  N/A:  This study will not enroll cognitively impaired adults.    
(Skip to Section 26.9)  
 26.7 Describe the process to determine whether an individual is capable of 
consent.   
Response: N/A  
  
  
Adults Unable to Consent  
 
☒  
N/A:  This study will not enroll adults unable to consent.   
(Skip to Section 26.13)  
When a person is not capable of consent due to cognitive impairment, a legally 
authorized representative should be used to provide consent (Sections 26.9 and 
26.10) and, where possible, assent of the individual should also be solicited 
(Sections 26.11 and 26.12).  
 26.8 Describe how you will identify a Legally Authorized Representative (LAR).  
Indicate that you have reviewed the “SOP: Legally Authorized Representatives, 
Children, and Guardians (HRP-013)” for research in New York State.   
NOTE:  Examples of acceptable response includes: verifying the electronic medical 
record to determine if an LAR is recorded.  
Response: N/A  
  
☐  
We have reviewed and will be following “SOP: Legally Authorized  
Representatives, Children, and Guardians (HRP-013).”   
 26.9 For research conducted outside of New York State, provide information 
that describes which individuals are authorized under applicable law to consent 
on behalf of a prospective subject to their participation in the research.  One 
method of obtaining this information is to have a legal counsel or authority 
review your protocol along with the definition of “legally authorized 
representative” in “SOP: Legally Authorized Representatives, Children, and 
Guardians (HRP-013).”  
Response: This study will be conducted only in New York State.  
  
26.10 Describe the process for assent of the adults:  
• 
Indicate whether assent will be obtained from all, some, or none of the 
subjects.  If some, indicate which adults will be required to assent and 
which will not.  
Response:   

  
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• 
If assent will not be obtained from some or all subjects, provide an 
explanation of why not.  
Response: N/A  
26.11 Describe whether assent of the adult subjects will be documented and the 
process to document assent.    
NOTE:  The IRB allows the person obtaining assent to document assent on the 
consent document using the “Template Consent Document (HRP-502)” Signature 
Block for Assent of Adults who are Legally Unable to Consent.  
Response:   
  
Subjects who are not yet Adults (Infants, Children, and Teenagers)  
☒  N/A:  This study will not enroll subjects who are not yet adults.   (Skip 
to Section 27.0)  
 26.12Describe the criteria that will be used to determine whether a prospective 
subject has not attained the legal age for consent to treatments or procedures 
involved in the research under the applicable law of the jurisdiction in which 
the research will be conducted (e.g., individuals under the age of 18 years).  
For research conducted in NYS, review “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013)” to be aware of which 
individuals in the state meet the definition of “children.”   
NOTE:  Examples of acceptable responses include: verification via electronic 
medical record, driver’s license or state-issued ID, screening questionnaire.  
Response: Verification of a subject’s age will be achieved via electronic medical 
records and/or photo ID.   
26.13 For research conducted outside of New York State, provide information 
that describes which persons have not attained the legal age for consent to 
treatments or procedures involved the research, under tctedhe applicable law of 
the jurisdiction in which research will be conducted.  One method of obtaining 
this information is to have a legal counsel or authority review your protocol  
along the definition of “children” in “SOP: Legally Authorized Representatives, 
Children, and Guardians (HRP-013).”  
Response: This study will be conducted entirely in NYS.  
 26.14 Describe whether parental permission will be obtained from:  
Response: there will not be children under the age of 18 enrolled in this study.  
☐   One parent even if the other parent is alive, known, competent, reasonably 
available, and shares legal responsibility for the care and custody of the 
child.  
☐  Both parents unless one parent is deceased, unknown, incompetent, or not 
reasonably available, or when only one parent has legal responsibility for the 
care and custody of the child.  
☐  Parent permission will not be obtained.  A waiver of parent permission is 
being requested.  

  
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NOTE:  The requirement for parent permission is a protocol-specific determination 
made by the IRB based on the risk level of the research.  For guidance, review the  
“CHECKLIST: Children (HRP-416).”   
26.15Describe whether permission will be obtained from individuals other than 
parents, and if so, who will be allowed to provide permission.  Describe your 
procedure for determining an individual’s authority to consent to the child’s 
general medical care.  
Response: No subjects under the age of 18 years of age will be enrolled in this study.  
  
 26.16Indicate whether assent will be obtained from all, some, or none of the 
children.  If assent will be obtained from some children, indicate which children 
will be required to assent.  
Response: N/A   
26.17 When assent of children is obtained, describe how it will be documented.  
Response: N/A  
  
27.0 Waiver or Alteration of Consent Process  
Consent will not be obtained, required information will not be disclosed, or the 
research involves deception.  
 
☐  
N/A:  A waiver or alteration of consent is not being requested.  
27.1 If the research involves a waiver or alteration of the consent process, 
please review the “CHECKLIST: Waiver or Alteration of Consent Process 
(HRP-410)” to ensure that you have provided sufficient information for the IRB 
to make the determination that a waiver or alteration can be granted.    
NOTE:  For records review studies, the first set of criteria on the “CHECKLIST: 
Waiver or Alteration of Consent Process (HRP-410)” applies.   
Response:   (Modification 2/27/2020) We are requesting a waiver of consent only 
for the analysis of the subjects’ financial data for those in the telemedicine arm 
and the subset of usual care arm subjects who were treated by the PI.  The 
workforce and resource analysis was not planned at the beginning of the study, so 
permission to collect billing data was not included in the consent. At this point in 
the timeline of the study, it is impracticable to re-consent everyone that the PI 
treated.  Approximately 5% of the subjects are deceased or lost to follow up, and 
many of the subjects are in long term follow up, with study visits only every 6 
months.  Given the nature of the study population, with approximately 15% 
discontinuation from the methadone treatment program annually, the rate of 
subjects who will be lost to follow up during the long term follow up period is 
expected to be higher than the average patient population.    
The major point is that long term follow up lasts for two years.  With patients who 
have discontinued from the study because they no longer have follow up, as well 
as those who have transferred, expired or been imprisoned, approximately 30% of 
telemedicine patients are no longer in contact with the study team.    

  
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As the provider of the telemedicine or usual care, the PI and his practice plan 
(UBMD) are already in possession of the data for non-research purposes, so no 
further patient records would have to be accessed to gather the data.  In addition, 
the use of these data would not require any patient interactions.  
In order to properly analyze socioeconomic variable differences by region and 
cost benefit measures by liver disease stages, we would like to include the entire 
telemedicine population and the few usual care subjects treated by the PI, and not 
just the smaller subset of those from whom we can get consent from at this point.  
(Modification 5/8/2020)  Based on the initial analysis of the billing data that was 
collected in our previous modification, we are asking for a waiver of consent to 
try to collect the retrospective billing data for the remainder of the usual care arm 
subjects who were not treated by the PI.  This study is a comparison of 
telemedicine vs usual care, and usual care in the vast majority of cases is offsite 
referral. We would request the billing data from the subject’s insurance company, 
or secondarily, from their treating physician or clinic.  
  
We are also asking for a waiver of consent to retrospectively collect data points 
from the subjects’ medical records at the substance use treatment facility and 
OASAS’s servers to analyze their social determinants of health (SDOH).  SDOH 
are behavioral, environmental, and demographic characteristics that can affect a 
patient’s health. Upon admission to a substance use treatment facility, all patients 
are requested to complete a form that originates from the New York State Office 
of Addiction Services and Supports (OASAS) and collects a variety of 
psychosocial and economic information. A copy of the form from the 01 clinic, a 
powerpoint showing the site 11clinic, and the PAS-44 and PAS26 have been 
added to Supporting Documents and all clinics in NYS collect similar information 
as part of their admission process. The clinics have their own forms, and then the 
clinic fills out the PAS-44 and PAS-26 for OASAS. The original award that funds 
the study was recently amended by PCORI to include this analysis.  
  
  
27.2 If the research involves a waiver of the consent process for planned emergency 
research, please review the “CHECKLIST: Waiver of Consent for Emergency Research 
(HRP-419)” to ensure you have provided sufficient information for the IRB to make these 
determinations.  Provide any additional information necessary here:  
Response: N/A  
  
28.0 Process to Document Consent  
 
☐  
N/A:  A Waiver of Consent is being requested.    
(Skip to Section 29.0)  
28.1Indicate whether you will be following “SOP: Written Documentation of 
Consent (HRP-091).” If not or if there are any exceptions, describe whether and 
how consent of the subject will be obtained including whether or not it will be 
documented in writing.    

  
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IRB Version: JAN2016  
NOTE:  If your research presents no more than minimal risk of harm to subjects 
and involves no procedures for which written documentation of consent is normally 
required outside of the research context, the IRB will generally waive the 
requirement to obtain written documentation of consent.  This is sometimes 
referred to as ‘verbal consent.’  Review “CHECKLIST: Waiver of Written 
Documentation of Consent (HRP-411)” to ensure that you have provided sufficient 
information.   
If you will document consent in writing, attach a consent document with your 
submission.  You may use “TEMPLATE CONSENT DOCUMENT (HRP- 
502)”.  If you will obtain consent, but not document consent in writing, attach the 
script of the information to be provided orally or in writing (i.e. consent script or 
Information Sheet).    
Response:   
Interview substudy:  
If the subject is consented in person, a written, signed consent form will be 
available.  If the subject is consented remotely, either over the phone or over 
videoconference, the person obtaining consent will document the subject’s verbal 
consent. A hard copy of the consent will be left in participant’s OTP for them to 
pick up or emailed/mailed to them in a secure manner. No matter which of these 
methods are used, consent to be recorded for interviews and/or focus groups will 
be reitereated at the beginning of the activity and prior to recording.  
 
 ☐  
We will be following “SOP:  Written Documentation of Consent” (HRP-
091).  
29.0 Multi-Site Research (Multisite/Multicenter Only)  
☐  
N/A:  This study is not an investigator-initiated multi-site study.  This 
section does not apply.  
  
29.1 If this is a multi-site study where you are the lead investigator, describe 
the processes to ensure communication among sites, such as:  
• 
All sites have the most current version of the IRB documents, 
including the protocol, consent document, and HIPAA authorization.  
• 
All required approvals have been obtained at each site (including 
approval by the site’s IRB of record).  
• 
All modifications have been communicated to sites, and approved 
(including approval by the site’s IRB of record) before the 
modification is implemented.  
• 
All engaged participating sites will safeguard data as required by local 
information security policies.  
• 
All local site investigators conduct the study appropriately.  
• 
All non-compliance with the study protocol or applicable requirements 
will be reported in accordance with local policy.  
Response:  

  
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IRB Version: JAN2016  
• 
As the lead site, the UB Research Center will ensure that once an IRB 
amendment is approved by the UB IRB, the revised protocol, consents, 
and HIPAA authorization (if applicable) is distributed to all of the study 
sites.  
• 
As the lead-site, we will maintain documentation that all required 
approvals will have been obtained at each site prior to implementation 
of any study related procedures, including approval by the site’s IRB of 
record.  
• 
As the lead site, we will ensure that all modifications have been 
communicated to sites and approved (including approval by the site’s 
IRB of record) before the modification is implemented.  
•  
As the lead site we will ensure all engaged participating sites 
will safeguard data as required by local information security 
policies.  
•  
As the lead site we will ensure all local site investigators 
conduct the study appropriately.  
•  
All non-compliance with the study protocol or applicable 
requirements will be reported in accordance with local policy.  
29.2 Describe the method for communicating to engaged participating sites:  
• 
Problems  
• 
Interim results  
• 
Study closure  
Response: Communication to engaged participating sites will be achieved through 
a Governance Plan. A management structure will be organized through a Steering 
committee and four standing committees.    
The Governance Plan consists of:  
Steering committee: will set priorities, oversee timely completion of tasks 
and monitor the overall budget for the study. They will also supplement 
the Data and Safety Monitoring Plan and will review project data in that 
capacity as needed.  
Implementation Committee: This committee will oversee intervention 
activities, monitor quality of interventions, and make adjustments as 
needed.  
Evaluation Committee: Will oversee all aspects related to data 
management and analysis, including the preparation of study instruments 
and development of the evaluation tool for capturing data from the 
electronic chart reviews.  
Patient Advisory Committee: Will review procedures to permit patients an 
opportunity to discuss their concerns, and to maintain the patient 
centeredness of the study. All case managers will attend the regular 
meeting with the PAC at each clinic site to ensure timely resolution of  
patient-centered ongoing concerns or obstacles to study recruitment.  
Sustainability Committee: will include all stakeholders and will meet 
annually to review study progress and to provide advice on sustainability.  

  
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29.3 Indicate the total number of subjects that will be enrolled or records that 
will be reviewed across all sites.  
Response: The total sample size is projected to be 624 patients enrolled from 12 
participating OAT programs throughout New York State.  
  
29.4If this is a multicenter study for which UB will serve as the IRB of record, 
and subjects will be recruited by methods not under the control of the local site 
(e.g., call centers, national advertisements) describe those methods.   
Response: We will seek to engage a local IRB at each individual site for review and 
approval of the study protocol. In the case that a site does not have a local IRB, 
University at Buffalo IRB will be acting as the IRB of record.  
  
30.0 Banking Data or Specimens for Future Use  
☐  
N/A:  This study is not banking data or specimens for future use or 
research outside the scope of the present protocol.  This section does not 
apply.  
30.1 If data or specimens will be banked (stored) for future use, that is, use or 
research outside of the scope of the present protocol, describe where the 
data/specimens will be stored, how long they will be stored, how the 
data/specimens will be accessed, and who will have access to the 
data/specimens.   
NOTE:  Your response here must be consistent with your response at the “What 
happens if I say yes, I want to be in this research?” Section of the Template 
Consent Document (HRP-502).  
Response: A separate check box will be included in the informed consent to 
enable the collection of blood specimens at the time of enrollment (baseline), 
during treatment and up to two years after treatment for storage in the 
biorepository for viral genetic testing.  Patients will be given a copy of the 
consent and will be counselled that their participation in this aspect of the study is 
voluntary and will not disqualify their enrollment should they choose not to 
participate in donating a serum specimen. Similarly, should they choose to request 
that their sample be discarded at any time, study personnel will adhere to their 
request. Samples will be stored indefinitely and only study personnel at UB will 
have access to them. From this repository a de-identified specimen will be sent to 
the Kaleida lab at Flint Rd. Amherst, N.Y. where the Abbott Lab M2000 is 
housed for HCV RNA and genotyping. A 2ml de-identified aliquot will be stored 
at Abbott laboratories in Abbott Park, IL. for genome sequencing.     
Interview transcripts will be de-identified and banked indefinitely for future 
research purposes.  
30.2 List the data to be stored or associated with each specimen.  
Response:  Medical information captured within the MoM system will be 
transferred from the subject’s electronic medical record to our database by 
secure transfer from MoM to University at Buffalo’s secure Data base housed 

  
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IRB Version: JAN2016  
at the Institute for Healthcare Informatics.  The specimen will be deidentified 
and assigned a sequential number and site code identifying each specimen.  
The data to be collected are  as follows: Gender, age at start of study, 
Diagnosis, Co-morbidities, smoking history, height, weight, fasting status, 
social history including drug and alcohol use and frequency, race, 
geographical location of residence and primary language.    
  
  
30.3 Describe the procedures to release banked data or specimens for future 
uses, including: the process to request a release, approvals required for release, 
who can obtain data or specimens, and the data to be provided with specimens.  
Response:  Storage and release of the specimens will be under the auspices of the PI,  
Andrew H. Talal, MD and based upon submission of a written request to Dr. Andrew 
Talal, MD, 875 Ellicott St., Buffalo, NY 14203, and an IRB approved protocol.  The 
specimens and associated data (stated in 28.2) will then be released by the director of the 
biorepository.  The specimens will be packaged and shipped on dry ice to the designated 
recipient via chain of custody. A de-identified specimen will be sent via courier to the  
Kaleida lab at Flint Rd. Amherst, N.Y. where the Abbott Lab M2000 is housed for HCV 
RNA and genotyping. A 2ml de-identified aliquot will be stored at Abbott laboratories in 
Abbott Park, IL. for genome sequencing using shipping supplies provided by Abbott labs. 
 
All future use of data from this study outside the scope of this protocol will be submitted 
to the IRB for review.   
  
  
31.0 Drugs or Devices  
☒  
N/A:  This study does not involve drugs or devices.  This section does not 
apply.  
31.1 If the research involves drugs or devices, list and describe all drugs and 
devices used in the research, the purpose of their use, and their regulatory 
approval status.   
Response: N/A. We will be using FDA approved medications for HCV treatment 
consistent with standard approval.  
  
31.2 Describe your plans to store, handle, and administer those drugs or 
devices so that they will be used only on subjects and be used only by authorized 
investigators.  
Response: N/A. All drugs patients receive are standard of care, not part of the research 
study. All medications will be stored according to the manufacturer’s 
recommendations, and distributed to subjects enrolled in the study, along with dosing 
of methadone by authorized personnel.    
  
If the drug is investigational (has an IND) or the device has an IDE or a claim of 
abbreviated IDE (non-significant risk device), include the following information:  

  
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IRB Version: JAN2016  
31.3 Identify the holder of the IND/IDE/Abbreviated IDE.  
Response: N/A. No investigational drugs will be utilized in this study. All drugs used 
for HCV treatment in this study are FDA approved used as Standard of Care.  
  
31.4 Explain procedures followed to comply with FDA sponsor requirements for 
the following:    
  
  
 
Applicable to:  
 
FDA Regulation  
IND Studies  
IDE studies  
Abbreviated 
IDE studies  
21 CFR 11  
X  
X  
  
21 CFR 54  
X  
X  
  
21 CFR 210  
X  
  
  
21 CFR 211  
X  
  
  
21 CFR 312  
X  
  
  
21 CFR 812  
  
X  
X  
21 CFR 820  
  
X  
  
Response: This study will only use FDA approved medications for HCV treatment.  
  
32.0 Humanitarian Use Devices  
☒  
N/A:  This study does not involve humanitarian use devices.  This does 
not apply.  
32.1 For Humanitarian Use Device (HUD) uses provide a description of the 
device, a summary of how you propose to use the device, including a description 
of any screening procedures, the HUD procedure, and any patient follow-up 
visits, tests or procedures.  
Response:   
  
32.2 For HUD uses provide a description of how the patient will be informed of 
the potential risks and benefits of the HUD and any procedures associated with 
its use.  
Response: N/A  
  
  

1 
 
 
Official Title: 
Comparison of Telemedicine to Usual Care for HCV 
Management for Methadone-maintained Individuals 
NCT number: 
NCT02933970 
Document Type:  
Statistical Analysis Plan 
Date of the Document: 
May 31, 2023 
 
 
 

2 
 
I.  
STATISTICAL ANALYSES 
 
The primary outcome of interest is the sustained virological response (SVR) rate in the two arms as well as the comparison 
of the SVR rates between usual care and telemedicine. Other outcomes of interest include: 1) treatment initiation rates 
as measured by the proportion of individuals who take an initial medication dose; 2) treatment completion rates; 3) 
patient satisfaction with the telemedicine-based hepatitis C virus (HCV) care scores using the adapted Patient Satisfaction 
Questionnaire (PSQ) [1, 2]; and 4) reinfection rates.  
 
For an explanation of the study scope, aims, setting, description of the population, and implementation strategies, please 
see [3]. We analyzed treatment initiation and completion rates graphically. Details on the analysis of patient satisfaction 
scores are reported below as are the analysis of reinfections. We have followed the CONSORT statement for reporting of 
stepped wedge trials [4].  
 
Ia. 
Primary Aim Analysis Plan 
 
Ia1. 
Data Collection: Per guidance of the New York State Office of Addiction Services and Supports (OASAS), HCV 
antibody levels are assessed on admission to the opioid treatment program (OTP) and on an annual basis. Thus, we 
obtained a list of potentially eligible participants who were then approached regarding study entry. If HCV seropositive 
individuals consented to study participation, they were scheduled for a screening visit where the laboratory parameters 
mentioned in Table 1 were obtained.  Those individuals who had detectable serum HCV RNA were enrolled in the study 
and had their levels of fibrosis and inflammation subsequently assessed.  
 
Table I.2: Laboratory parameters collected at Baseline 
Lab test  
Reason 
HCV antibody 
Assess exposure to HCV  
HCV RNA  
Assess active HCV infection 
HCV genotype 
Assess type of hepatitis C 
CBC 
Assess hemoglobin concentration 
CMP 
Assess metabolic, renal, hepatic parameters 
INR 
Assess coagulation parameters 
Toxicology screen 
Assess use of illicit substances 
HIV antibody 
Assess exposure to HIV 
HBV surface antigen 
Assess exposure to HBV 
HBV surface antibody 
Assess immunity to HBV 
FibroSure® 
Assess liver fibrosis and inflammation levels 
HIV RNA 
Assess active HIV infection 
CD4 cell count 
Assess immune system status in HIV infection 
Abbreviations: CBC, complete blood count; CMP, complete metabolic panel; HCV, hepatitis C virus; INR, 
international normalized ratio; HBV, hepatitis B virus; HIV, human immunodeficiency virus; RNA, ribonucleic acid 
 
Ia2. 
Missing data: Missing data can occur in any study design and with any data source. In clinical trials, missing data 
often arise when participants drop out of the study before its conclusion [5]. Li et al (2014) indicate that the single best 
approach to deal with missing values is to prospectively prevent their occurrence [6]. To this end, the study personnel 
attempted to minimize the amounts of missing values by following the study participants closely. The case managers were 
provided with a list of strategies to avoid missing values, and issues surrounding missing data were reviewed weekly during 
conference calls.  
 

3 
 
Specifically, the following strategies were implemented to limit the amount of missing data. Adherence to the treatment 
schedule was monitored very closely by the case managers at each site. At the level of the overall study, the Biostatistics 
and Data Management Team monitored the trial weekly. Study participants were informed at the consent stage of the 
importance of completing all surveys, and case managers facilitated their completion by administering the surveys onsite 
within the OTP. During the time of COVID-19 restrictions and because recruitment had been completed, the impact of 
COVID on the study was minimal. Additional strategies we implemented included frequent reminders to study participants 
for study visits, education of participants of the importance of continuous engagement, keeping participant contact 
information current, providing monetary incentives to participants, utilizing OTP staff support to promote participant 
engagement, and collecting information on participants at risk of dropout.  
 
To adequately address statistical challenges around missing data, we collected detailed information on the reasons for 
missingness when missing data occurred. Whenever a participant discontinued all or some type of study participation, we 
documented the following: 1) the reason for discontinuation, 2) type(s) of participation that the discontinuation involved, 
and 3) who decided to discontinue the participant from the study. For example, in the case of ongoing non-adherence 
with OTP attendance requirements or prolonged absence from the OTP, such as in the case of incarceration, the OTP may 
“administratively discontinue” an individual. If a study participant was discontinued from the OTP, their study participation 
ceased. Therefore, opportunities for follow up blood draws and obtaining study-related information were not possible.  
 
When we encountered missing data, we took the following steps. 1) We filed a report documenting the occurrence of 
missing data, its potential resolution, and the expected resolution date. 2) The case manager at each site investigated 
whether data retrieval was possible. If not retrievable, we supplemented the report with the reasons for missing data. We 
requested that each site report the percentage of missing data for each participant on a weekly basis.  
 
The above strategies severely limited the quantity of missing data. When we encountered missing data, the explanations 
that accompanied the missing data guided the adjudication of the missing data mechanism. We used valid statistical 
methods, such as multiple imputation, to impute missing data. In our study, the maximum percentage of missing data is 
5.814%, and the missing mechanism is missing at random. To perform multiple imputation, we used Multivariate 
Imputation by Chained Equations (MICE) since the estimated intra-cluster correlation is 0.099, sufficiently low to allow the 
use of MICE. We generated 20 imputed data sets that were used in the analysis.   
 
To estimate the effect of facilitated telemedicine, we used two methods of analysis. Generalized linear mixed effects 
models, adjusted for the time effect, were used in an intention to treat analysis. An alternative robust, nonparametric, 
within period, cluster-level method was also used.  
 
I2 
Secondary Aim Analyses 
 
I2a  
Heterogeneity of Treatment Effects: Analysis of heterogeneity of the intervention effect, that is, estimation of the 
intervention effects in subgroups, can be challenging (see [7]). We defined “a priori subgroups of interest”, at the request 
of the sponsor, by the following variables: 1) comorbid medical conditions (specifically anxiety and depression), 2) liver 
fibrosis stage (binary with one level including F3, F3-F4, and F4 participants versus all other stages), 3) location of residence 
(specifically urban/rural classification). Our goal is the identification of whether or not these factors influence the decision 
to initiate and adhere to HCV treatment in the telemedicine and usual care arms.   
 
The percentage of people with opioid use disorder with comorbid medical conditions ranges from 20% to 85% based upon 
findings reported by others [7, 8].  We included depression and anxiety disorders as a specific diagnosis among those with 
co-morbid conditions since the prevalence varies from 24.5% to greater than 50% [7-9]. The sample size of our study was 
sufficient to permit stratification by the comorbid conditions variable to allow exploratory analyses.  
 
Despite the tremendous therapeutic advances in HCV treatment over the past several years, fibrosis stage remains an 
important factor to explore for its importance as a determinant of successful HCV cure. We based our estimates of advance 
fibrosis and cirrhosis from our previous study [10] in which the percentage of participants with advanced fibrosis (F3 and 

4 
 
F3-F4) was 16% and 12% had cirrhosis (F4).  Correspondingly, we estimated that 28% of the participants in each study arm 
would have advanced fibrosis or cirrhosis, thereby permitting evaluation of the variable’s influence on virologic outcomes. 
We also evaluated the percentage of study participants residing in urban or rural areas.   
 
Univariate subgroup analyses were conducted by incorporating a treatment by factor interaction in all relevant models 
and adjusting for multiplicity of testing. People with opioid use disorder have been substantially affected by opioid-related 
deaths. As our secondary analyses are largely exploratory, we followed Wang et al, (2007) in interpreting and reporting 
the results [11].  
 
I2b  
Patient Satisfaction Analysis: Our mixed-methods analysis of patient satisfaction with HCV treatment delivery 
comparing in-person and telemedicine has recently been published [12]. Generalized linear mixed models were used to 
account for the time effect on the Patient Satisfaction Questionnaire that was administered at two timepoints, 
incorporating adjustments for the clustering effect and the study arm. We modeled the survey response rate as a function 
of demographic and other relevant covariates.  
 
I2c  
Other Secondary Aims: One proposed analysis, designed to understand the stability of people with opioid use 
disorder, analyzed variables collected on methadone adherence and retention. These include the characterization of 
longitudinal profiles of study participants to illustrate adherence in the telemedicine and usual care arms. For these 
analyses, continuous variables were summarized by means/medians and discrete type variables were summarized by 
percentages. 
 
I2d  
Analysis of Reinfection Study: An exploratory aim of the trial was the follow up of study participants for up to 24 
months after achieving an SVR to evaluate for HCV reinfection. We compared the reinfection rates between the usual care 
and telemedicine arms by calculating the cumulative incidence density for both arms.  
 
I2e 
Analysis of Social Determinants of Health: We conducted a separate analysis of data obtained on admission to the 
opioid treatment program as well as annual updates for up to four years preceding participants entry into the study. The 
goal of this analysis was to understand the non-medical factors, specifically social determinants of health, on a 
participant’s willingness to pursue HCV treatment. We have recently published an overview of the methods we employed 
to collect, aggregate, and integrate data collected clinically for research purposes [13]. We used multiple correspondence 
analysis, k-means algorithm, and logistic regression to identify variables and clusters associated with uptake of HCV 
management. 
 
I2f 
Implementation Characteristics of Facilitated Telemedicine: We evaluated organizational characteristics and 
implementation variables associated with patient satisfaction with HCV care through facilitated telemedicine and an SVR. 
We initially used random forests and configurational comparative methods to identify combinations of factors associated 
with high levels of patient satisfaction and successful HCV treatment outcomes. We subsequently used thematic analysis 
to identify themes associated with successful implementation based upon guidance from an advisory board comprised of 
staff members who were involved with the study. We used the Reach, Effectiveness, Adoption, Implementation, and 
Maintenance (RE-AIM) framework to understand the factors that led to successful implementation.  
 
 
I2g.  
Qualitative methods: As part of the study, we sought to understand the impact of the case managers’ perceptions 
and obstacles of conducting research with people with opioid use disorder [14].  In a separate manuscript, to understand 
the implementation process, we investigated clinical and administrative staffs’ experiences toward integrated clinical care 
through onsite telemedicine for HCV [15]. We also sought to understand their recommendations regarding scaling and 
sustaining facilitated telemedicine for HCV [16]. In both aforementioned manuscripts, we utilized hermeneutic 
phenomenology, a qualitative approach to interpreting texts to study a phenomenon. In our initial work, we requested 
texts of stories and held a focus group of case managers facilitating HCV care in people with opioid use disorder. The case 
managers’ experiences provided unique perspectives as they were the primary conduits between the participants, 
investigative team, clinicians, and the OTP staff. We also interviewed study participants to understand their reactions 
more fully to integrated HCV and OUD treatment [17].  

5 
 
 
A.2.3 
Exploratory Analysis 
 
Distribution of all variables was examined using graphical methods and descriptive statistics. Continuous variables are 
presented by their means and standard deviations or medians and associated interquartile ranges. Categorical variables 
are presented by the associated counts and percentages. Distributional assumptions were checked via boxplots, qq-plots 
or other appropriate graphical techniques, and outliers were identified via the aforementioned graphical analysis. All 
statistical analyses were conducted using SAS (SAS Institute, Cary, NC) and/or R. The estimated intraclass correlation 
coefficient (ICC) was .099.  
 
Demographic description of the population was provided in terms of characteristics such as age, gender, race, and 
ethnicity. Other variables that contributed to the descriptions included residence type (i.e., urban versus rural), Drug 
Abuse Screening Test (DAST)-10 scores [18], and variables incorporated within the NIDA Quick Screen questionnaire [19]. 
We also incorporated variables collected on methadone and HCV adherence.     
 
References 
1. 
Marshall, G.N. and R.D. Hays, The patient satisfaction questionnaire short-form (PSQ-18). 1994, RAND, Santa 
Monica, CA. 
2. 
Yip, M., et al., Development of the Telemedicine Satisfaction Questionnaire to evaluate patient satisfaction with 
telemedicine: a preliminary study. J Telemed Telecare, 2003. 9(1): p. 46-50.DOI: 10.1258/135763303321159693. 
3. 
Talal, A.H., et al., Patient-centered HCV care via telemedicine for individuals on medication for opioid use 
disorder: Telemedicine for Evaluation, Adherence and Medication for Hepatitis C (TEAM-C). Contemp Clin Trials, 
2022. 112: p. 106632.DOI: 10.1016/j.cct.2021.106632. 
4. 
Hemming, K., et al., Reporting of stepped wedge cluster randomised trials: extension of the CONSORT 2010 
statement with explanation and elaboration. BMJ, 2018. 363: p. k1614.DOI: 10.1136/bmj.k1614. 
5. 
Little, R., et al., The design and conduct of clinical trials to limit missing data. Stat Med, 2012. 31(28): p. 3433-
3443. 
6. 
Li, T., et al., Standards should be applied in the prevention and handling of missing data for patient-centered 
outcomes research: a systematic review and expert consensus. J Clin Epidemiol, 2014. 67(1): p. 15-32.DOI: 
10.1016/j.jclinepi.2013.08.013. 
7. 
Varadhan, R., et al., A framework for the analysis of heterogeneity of treatment effect in patient-centered 
outcomes research. J Clin Epidemiol, 2013. 66(8): p. 818-25.DOI: 10.1016/j.jclinepi.2013.02.009. 
8. 
El-Serag, H.B., et al., Psychiatric disorders among veterans with hepatitis C infection. Gastroenterology, 2002. 
123(2): p. 476-82.DOI: 10.1053/gast.2002.34750. 
9. 
Ho, S.B., et al., Integrated Care Increases Treatment and Improves Outcomes of Patients With Chronic Hepatitis C 
Virus Infection and Psychiatric Illness or Substance Abuse. Clin Gastroenterol Hepatol, 2015. 13(11): p. 2005-14 
e1-3.DOI: 10.1016/j.cgh.2015.02.022. 
10. 
Talal, A.H., et al., Integrated, co-located, telemedicine-based treatment approaches for hepatitis C virus 
management in opioid use disorder patients on methadone. Clin Infect Dis, 2019. 69(2): p. 323-331.DOI: 
10.1093/cid/ciy899. 
11. 
Wang, R., et al., Statistics in medicine--reporting of subgroup analyses in clinical trials. N Engl J Med, 2007. 
357(21): p. 2189-94.DOI: 10.1056/NEJMsr077003. 
12. 
Talal, A.H., et al., High Satisfaction with Patient-Centered Telemedicine for Hepatitis C Virus Delivered to 
Substance Users: A Mixed-Methods Study. Telemed J E Health, 2023. 29(3): p. 395-407.DOI: 
10.1089/tmj.2022.0189. 
13. 
Markatou, M., et al., Social determinants of health derived from people with opioid use disorder: Improving data 
collection, integration and use with cross-domain collaboration and reproducible, data-centric, notebook-style 
workflows. Front Med (Lausanne), 2023. 10: p. 1076794.DOI: 10.3389/fmed.2023.1076794. 

6 
 
14. 
Talal, A.H., et al., Facilitating engagement of persons with opioid use disorder in treatment for hepatitis C virus 
infection via telemedicine: Stories of onsite case managers. J Subst Abuse Treat, 2021: p. 108421.DOI: 
10.1016/j.jsat.2021.108421. 
15. 
Dickerson, S.S., et al., Integrating Facilitated Telemedicine for Hepatitis C Virus Treatment Within Opioid 
Treatment Programs: Staff Experiences [poster #31]. , in 2023 American Telemedicine Association Conference 
and Expo. 2023: San Antonio, TX. 
16. 
Ventuneac, A., et al., Scaling and Sustaining Facilitated Telemedicine to Expand Treatment Access Among 
Underserved Populations: A Qualitative Study. Telemed J E Health, 2023.DOI: 10.1089/tmj.2022.0534. 
17. 
Talal, A.H., et al., Patient Experiences of Hepatitis C Virus Treatment Access Through Facilitated Telemedicine 
[poster #35], in 2023 American Telemedicine Association Conference and Expo. 2023: San Antonio, TX. 
18. 
Skinner, H.A., The drug abuse screening test. Addict Behav, 1982. 7(4): p. 363-71.DOI: 10.1016/0306-
4603(82)90005-3. 
19. 
National Institute on Drug Abuse, NIDA Drug Screening Tool. Available at: 
https://archives.drugabuse.gov/nmassist/. Accessed July 3, 2021.