Addressing Loneliness and Substance Use With Telehealth CBT
Phase: NA
Conditions: Substance Use Disorders
Sponsor: VA Office of Research and Development

Version  8/3/2022 
Telehealth CBT-L for Veterans using substances 
Funding Agency: HSR&D 
Principal Investigator: Lisham Ashrafioun, Ph.D
1&7 

 
Page 2 of 24 
 
Abstract 
Loneliness—a subjective emotional state characterized by the perception of social isolation—is 
a psychosocial factor that is associated with increased mortality, substance use, and is 
associated with precipitants of relapse among individuals with substance use disorders (SUD). 
Importantly, there are effective interventions that can be used to decrease loneliness; however, 
these have not been tested on Veterans with SUD who are lonely. 
There are no studies that have tested a loneliness intervention in Veterans with SUD who are 
lonely, which may neglect a broader impact on mental and physical health. This study is ideally 
situated to generate new and important knowledge on the association of loneliness and SUD. 
This study seeks to address a transdiagnostic factor, which may improve engagement with 
social support thereby reducing substance use. An additional innovative aspect of this study is 
recruitment being conducted outside the VHA. This may increase access to care among those 
Veterans who are especially isolated. 
We will initially conduct a small single-arm trial (n = 6) for further refinement. This trial will allow 
us to collect feasibility of treatment delivery, and treatment satisfaction and acceptability data to 
further refine the manual. With the refined manual Veterans with SUD reporting loneliness will 
be randomized to either CBT-L/SUD (n = 15) or CBT-SUD (n = 15). We will assess: (1) 
treatment acceptability, (2) participant adherence to treatment, and (3) therapist fidelity. We will 
also assess outcome measure completion percentage, means and standard deviations, and 
level of correlation of repeated measurement of primary loneliness outcomes and secondary 
substance use outcomes. 
 

 
Page 3 of 24 
 
List of Abbreviations 
CBT-LS: Cognitive-behavioral therapy for Loneliness 
SUD: Substance Use Disorders 
 
 

 
Page 4 of 24 
 
Contents 
Study Protocol ............................................................................................................................... 5 
Protocol Title: Telehealth CBT-L for Veterans using substances ................................................. 5 
1.0 
Study Personnel ................................................................................................................. 5 
2.0 
Introduction ........................................................................................................................ 7 
3.0 
Objectives .......................................................................................................................... 8 
4.0 
Resources and Personnel .................................................................................................. 9 
5.0 
Study Procedures ............................................................................................................... 9 
5.1 Study Design ....................................................................................................................... 9 
5.2 Recruitment Methods ........................................................................................................ 11 
5.3 Informed Consent Procedures .......................................................................................... 12 
5.4 Inclusion/Exclusion Criteria ............................................................................................... 12 
5.5 Study Evaluations .............................................................................................................. 12 
5.6 Schedule of Assessments ................................................................................................. 13 
5.7 Data Analysis .................................................................................................................... 14 
5.8 Withdrawal of Subjects ...................................................................................................... 16 
6.0 
Protection of Human Subjects .......................................................................................... 16 
7.0 
References ....................................................................................................................... 21 
 
 
 

 
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Study Protocol 
Protocol Title:  Telehealth CBT-L for Veterans using substances 
1.0 
Study Personnel 
 
Principal Investigator: 
Lisham Ashrafioun, PhD 
Health Science Specialist 
Center of Excellence for Suicide Prevention 
VA Finger Lakes Healthcare System 
Lisham.ashrafioun@va.gov 
Co-Investigators: 
Tracy Stecker, PhD 
Co-Research Director 
Center of Excellence for Suicide Prevention 
VA Finger Lakes Healthcare System 
Tracy.stecker@va.gov 
 
Nicholas P. Allan, PhD 
Health Science Specialist 
Center of Excellence for Suicide Prevention 
VA Finger Lakes Healthcare System 
Nicholas.Allan@va.gov 
Research Staff: 
Caitlin Titus 
Center of Excellence for Suicide Prevention 
VA Finger Lakes Healthcare System 
Caitlin.Titus@va.gov 
 
Park Bogan 
Project Coordinator 
Center of Excellence for Suicide Prevention 
VA Finger Lakes Healthcare System 
park.bogan@va.gov 
 
Monae James 
Research Assistant 
Center of Excellence for Suicide Prevention  
Monae.james@va.gov 
 
Shelby Neureuter 
Research Assistant  
Center of Excellence for Suicide Prevention 
ShelbyLynn.Neureuter@va.gov  
 
Tyler Webb 
Project coordinator 

 
Page 6 of 24 
 
Center of Excellence for Suicide Prevention  
Tyler.Webb@va.gov 
 
Brady Stephens  
Analyst 
Center of Excellence for Suicide Prevention 
Brady.Stephens@va.gov 
 
Jennifer Kelly 
Analyst 
Center of Excellence for Suicide Prevention 
Jennifer.Kelly5@va.gov 
 
Martin Hoover  
Analyst 
Center of Excellence for Suicide Prevention  
Martin.Hoover@va.gov 
 
Sponsor: HSR&D  
 
Sites: 
Center of Excellence for Suicide Prevention/Canandaigua VA Medical Center

Version  8/3/2022 
2.0 
Introduction 
Substance use is a significant public health concern. Life expectancy in the United 
States had increased for over 50 years before slowing more recently and having a three-year 
decline from 2015-2017.1 This decline is largely attributed to staggering increases in deaths of 
despair—drug overdoses, alcohol-related mortality, and suicide.1,2 The rate of drug overdoses in 
2017 was nearly 5 times higher than in 1999. The death rate from alcoholic liver disease 
increased 40%, with age-specific increases as high as 158% among adults ages 25 to 34 
years.1 Alcohol is estimated to be involved in nearly one-third of all suicides,3 and the number of 
suicides involving opioids nearly tripled from 1999 to 2014.4 The suicide rate among Veterans 
with opioid use disorders is now quadruple the overall rate of Veterans.5  
The Veterans Health Administration (VHA) has taken an aggressive and comprehensive 
approach to respond to substance use-related morbidity and mortality.6 This includes 
decreasing opioid analgesic  prescribing, increasing non-pharmacological pain treatment, 
establishing clinical dashboard tools (e.g., REACHVET, STORM), and increasing access to 
effective medications for opioid use disorders and opioid overdose reversals among many 
others.6-10 These approaches are significant, and at the same time, developing treatments 
focusing on novel therapeutic targets are critical in addressing substance use disorders (SUD) 
as Veterans with SUD continue to suffer from comorbidity and premature mortality. Social 
factors, such as loneliness and social isolation, continue to plague people with SUD. Greater 
emphasis addressing these social stressors are essential to curb substance use-related 
morbidity and mortality.   
The 21st century has brought advances in technology improving our ability to connect 
and communicate with people from around the world. Despite advances to improve connection, 
there has been a global increase in loneliness.11 The same technology aimed at increasing 
connection may be decreasing it for some.12 Related social factors such as decreases in 
household and social network size, marriage rates, and religious affiliation rates are contributing 
to this through diminished opportunities for social connection.13 Deaths of despair also have a 
large impact on communities through the degradation of social networks and social cohesion.14 
Additionally, with measures aimed at increasing social distancing due to the COVID-19 
pandemic, many people have become further isolated, have fewer economic opportunities, and 
have reduced access to adaptive coping strategies and treatment.15,16  
Loneliness—a subjective emotional state characterized by the perception of social 
isolation11—is a critical social factor that can have a significant impact on substance use. 
Loneliness is evident across the lifespan and occurs at higher rates among those with 
psychiatric disorders, people who are objectively isolated, and people with chronic illnesses.11 
Among a cohort of over 25,000 Veterans, 44% reported feeling lonely at least sometimes in the 
last month, with other studies among civilians estimating the prevalence from 20-33%.17-19 
Loneliness has a profound impact on well-being. A meta-analysis of 70 studies found that 
loneliness increases the odds of mortality by 29% even after accounting for key risk factors.20 
Researchers have estimated that the impact of loneliness on mortality is comparable to that of 

 
Page 8 of 24 
 
obesity or smoking 15 cigarettes a day.21 Loneliness has deleterious effects on physical and 
mental health, increasing the risk for a constellation of chronic diseases and the development 
and exacerbation of psychiatric disorders and substance use.22,23 Loneliness is positively 
associated with suicidal ideation and suicide attempts.22 In a study among Veterans with 
depression being seen in primary care, loneliness (and not other social connection constructs) 
were associated with increased depression, endorsement of suicidal ideation, and reduced 
treatment seeking intentions.24  
Loneliness and social isolation are critical clinical endpoints that must be addressed 
among Veterans with SUD to reduce relapse and preventable deaths. A considerable proportion 
of individuals with SUD experience loneliness. A vicious cycle among people with SUD 
develops as social contact becomes less rewarding and stigma distances people with SUD from 
others, including social support. This social isolation then drives further substance use.25 A 
study among treatment seeking patients with an opioid use disorder showed that nearly three-
fourths of women and over two-thirds of men reported moderate to severe loneliness.26 Nearly 
40% of people with an alcohol use disorder reported feeling lonely and isolated at least 
sometimes.27 Loneliness among those with SUD have increased risk of relapse and other 
negative consequences.28 Relative to patients with SUD who do not report loneliness, those 
reporting loneliness have lower quality of life and life satisfaction, and more mood disorder 
symptoms, non-suicidal self-injury, and suicide attempts.28-32 Loneliness among individuals with 
SUD is also associated with greater pain severity and sleep disturbance, two precipitants of 
relapse.33,34 People with SUD report loneliness as an important reason for craving and among 
the most common reasons for relapse.35,36 Loneliness is higher earlier in recovery and predicts 
shorter length of stay in treatment.28 A qualitative study identified a subgroup of individuals 
using heroin who were characterized as being more socially disconnected and these individuals 
have more cognitive barriers  to engaging in methadone maintenance (e.g., treatment harms 
outweigh the benefits) compared to other subgroups.37 Addressing loneliness among Veterans 
with SUD can reduce risk factors for relapse or continued use and have a significant positive 
impact on how a person develops, maintains, and utilizes social support, including treatment 
seeking—all of which are essential factors in reducing substance use.38-41 
3.0 
Objectives 
The proposed study will provide critical feasibility and acceptability data on telehealth Cognitive-
Behavioral Therapy for Loneliness for SUD (CBT-L/SUD) among Veterans with SUD who report 
loneliness. We will conduct a small single-arm trial (n = 6) for refinement of the intervention and 
study procedure. With the refined manual, Veterans with SUD reporting loneliness will be 
randomized to either CBT-L/SUD (n = 15) or CBT-SUD (n = 15). The specific aims are as 
follows: 
Aim 1: Refine the CBT-L/SUD manual by conducting a one-arm trial among Veterans with 
SUD who report loneliness (n = 6). We will deliver CBT-L/SUD as part of a small, single-arm 
trial. This trial will allow us to collect feasibility of treatment delivery, and treatment satisfaction 
and acceptability data to further refine the manual.  

 
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Aim 2: Randomize participants to receive either CBT-L/SUD (n = 15) or CBT-SUD (n = 15) 
to assess feasibility and acceptability among Veterans with SUD who report loneliness. 
We will assess: (1) treatment acceptability, (2) participant adherence to treatment, and (3) 
therapist fidelity. We will also assess outcome measure completion percentage, means and 
standard deviations, and level of correlation of repeated measurement of primary loneliness 
outcomes and secondary substance use outcomes.  
4.0 
Resources and Personnel 
The study team consists of Drs. Ashrafioun, Allan, Stecker, Mr. Bogan, research therapists 
(TBD) to deliver the intervention, and additional research assistants as needed. Research 
therapists will have at least a master’s degree in a counseling/health-related field and prior CBT 
training Drs. Allan, Stecker, and Ashrafioun will be in charge of executing the scientific 
objectives of this project. Mr. Bogan will serve as project coordinator. Mr. Bogan will assist in 
IRB documentation, participant payment and tracking, advertising, and conducting eligibility 
screening. Mr. Bogan will also complete screening and consent procedures, and complete 
assessment packets by telephone with participants at baseline, post-intervention and the 30-day 
follow-ups. Study therapists will deliver the intervention to 36 participants (6 for one arm trial, 30 
for small RCT). 
5.0 
Study Procedures 
5.1 Study Design 
Study sample: We will initially recruit 6 veterans who screen positive for loneliness and screen 
positive for active substance use disorder to receive CBT-L. Once these 6 veterans have 
completed study procedures, we will recruit an additional 30 to be randomized to either CBT-L 
or CBT-L/SUD. This cohort will be randomized 1:1. The study will take place at the VA Center of 
Excellence for Suicide Prevention. Participants meeting study eligibility criteria will be enrolled in 
the one-arm trial to receive CBT-L.  
 
Screening: The project coordinator will screen by phone following a script. Potential 
participants will provide verbal consent to complete the screening measures. Those individuals 
meeting eligibility who are interested in participating will be scheduled for a phone-based 
consent and baseline assessment appointment. Based on our past experience, we expect 
approximately 25% of all participants who complete the screening to be eligible to and 
interested in participating. Therefore, we expect to screen no more than 500 participants to 
reach our sample of 36. 
 
Assessments and Intervention:  
 
Participants will be enrolled following consent and will complete the baseline assessment. 
Participants will schedule a convenient time for their phone-based intervention sessions. Mid-
treatment, post-treatment and 30-day post-treatment follow-up assessments will also be 
conducted by phone, depending on the phase of the study. Participants will be paid $40 each 
assessment completed. The post-treatment assessment will also include an exit interview for 
participants to describe acceptability of the intervention. Total compensation will be up to $80 for 
the pilot phase, and $120 for the randomized phase.  
 

 
Page 10 of 24 
 
CBT for Loneliness for Substance Use Disorders (CBT-L/SUD):  
The study team recently created a CBT-L/SUD manual (see Appendix) starting from a 
translation of the Kall et al. CBT-L manual as the base.42 We then incorporated relevant content 
and worksheets from the VHA Brief CBT manual and worksheets from CBT-SUD into the CBT-L 
base.43,44 The study team met and discussed ways to integrate content into the CBT-L manual 
based on our conceptual model, existing literature on substance use and loneliness, and other 
pertinent content from the VHA Brief CBT manual (e.g., material from behavioral activation) and 
CBT-SUD manual (examples of negative thoughts; case history).  
The full draft of the manual can be found in the Appendix with a broad overview of session-
by-session content below. CBT-L/SUD is a brief, patient-centered, tailored, one-on-one, 8-
session intervention. Each weekly session is 45-60 minutes delivered via telehealth. 
Participants will initially be presented with education on activating events eliciting thoughts, 
behaviors, and emotions that serve to perpetuate loneliness and substance use (i.e., the CBT 
model). Sessions will then focus on identifying and changing thoughts that contribute to 
loneliness and substance use. If a participant states “No one wants to be around a drunk like 
me,” or “my drug use always makes me feel better when I’m alone.” They would be asked to 
estimate the accuracy of the thought and to dispute it. For example, the original thoughts might 
be altered to “My buddy called me last week, so apparently he wants to be around me,” “there’s 
much more to me than just my drinking,” “Shooting up only made me feel lonelier,” and “I 
enjoyed it more when I got coffee with my brother.” Importantly, CBT-L/SUD encourages 
participants to test these beliefs in safe, but real-world experiences (e.g., going to get coffee and 
noting that it reduced loneliness). Exposure and behavioral activation are used to approach 
avoided behaviors and activities (e.g., social interactions in sober environments) and to increase 
the participant’s general activity level to improve mood. By increasing activity level, particularly 
through engaging in pleasant social activities, the participant’s mood may improve by 
decreasing avoidance, increasing the potential for social contact, reducing risk of substance 
use, and increasing self-efficacy to engage in such activities without the use of substances. In 
the final session, the participant identifies ways to cope with loneliness-related problems by 
identifying strategies, evaluating the potential solutions, and selecting a plan to implement the 
strategies. This discussion will occur in the context of preventing a return to behavioral 
inactivation and allowing maladaptive thinking to drive poor coping, further maladaptive thinking, 
and lack of activity. Throughout the intervention, we emphasize (1) not engaging with individuals 
who will threaten recovery, and (2) not entering situations or contexts that place them at 
unnecessarily high risk of use (e.g., meeting people a bar).  
x 
Session 1: CBT Model & Goal Setting  
o Substance use integrated into CBT model; goals also associated with addressing 
SUD-relevant goals) 
x 
Session 2: Identifying & Challenging Thoughts I 
o Substance-use related thoughts perpetuating loneliness; loneliness-related 
thoughts perpetuating loneliness 
x 
Session 3: Identifying & Challenging Thoughts II 
o Continued focus on substance use- and loneliness-related thoughts perpetuating 
substance use and loneliness 
x 
Session 4: Assertiveness Training 
o Teaching effective communication and conflict resolution 
x 
Session 5: Exposure & Behavioral Activation I 
o Incorporating sober activity into exposure and behavioral activation; considering 
difficulty of exposure when sober 

 
Page 11 of 24 
 
x 
Session 6: Exposure & Behavioral Activation II 
o Incorporating sober activity into exposure and behavioral activation; considering 
difficulty of exposure when sober 
x 
Session 7: Problem Solving 
o Developing a plan to remain sober while implementing or practicing CBT skills 
and increasing social interactions 
x 
Session 8: Review & Relapse Prevention 
o Review is specific to new content, using skills for CBT-L to address and avoid 
slips and/or relapse 
CBT-SUD: We will utilize the DeMarce and colleagues CBT-SUD manual developed for 
Veterans, which is designed for flexibility and individualization.44 In order to maintain 
consistency with CBT-L/SUD, CBT-SUD will be delivered over 8, ~45-60 minute sessions. CBT-
SUD teaches skills to increase awareness and address thoughts, behaviors, and emotions that 
contribute to the maintenance of substance use. There are three phases of treatment: preparing 
and planning for change (1 session), cognitive-behavioral strategies (6 sessions), and 
maintaining change and termination (1 session). Phase 1 includes building support, case 
conceptualization, building motivation, and orientation to CBT. Phase 2 will continue case 
conceptualization and building motivation, while introducing and practicing cognitive-behavioral 
strategies. Sessions include (1) recognizing and dealing with craving, urges, and triggers, (2) 
learning refusal and listening skills, (3) managing mood, (4) social and recreational counseling, 
(5) support for sobriety, and (6) problem solving. Phase 3 involves review of skills to help 
maintain treatment gains and ending treatment. The manual is included as an Appendix. 
5.2 Recruitment Methods 
Recruitment and retention procedure: Participants will be recruited using Internet social media 
websites (e.g., Facebook, craigslist) and select print/web portals that have been used 
successfully in several large studies. Advertisements will include a link to a study landing page 
with study information and blank entry forms for interested Veterans to enter contact information 
through VA Qualtrics on Fedramp, a secure, FISMA-compliant server used across government 
agencies with an authority to operate with the VA. We plan to enroll 36 participants in the 
protocol overall.  
 
Participants will also be recruited through a data access request using data from the Corporate 
Data Warehouse. CDW contains financial, enrollment, demographic, diagnostic, treatment 
utilization, and other data across Veterans from 1979 to present. All study staff will be trained on 
accessing these records by Dr. Ashrafioun. Joint Longitudinal Viewer will be used to access 
medical records to prioritize recruitment of Veterans with an active SUD. This pre-screening will 
help reduce Veteran burden and unnecessary contact of Veterans who would not be eligible. 
Participants identified through this method will be screened using the same criteria as those 
recruited through social media websites and select print/web portals as described above. 
Potential participants will be mailed a personalized letter describing the study and provided with 
a toll-free number so that they can contact study staff if they are interested in participating as 
well as opt out of future contact. Potential participants may be recruited from other studies that 
are IRB approved following completion of those other studies or if deemed ineligible. Only study 
staff that are approved on those studies will recruit those participants. Providers may also refer 
participants to the study by emailing the research staff/team. Providers will be given the 

 
Page 12 of 24 
 
approved recruitment letters that are provided to Veterans as well as the approved study 
landing page for information (content can be found on p. 54 of the approved advertising pdf). 
 
Participants will receive compensation for their participation in the study. The compensation 
amount will be based on the schedule that follows: 
 
 
Baseline Assessment  
 
 
$40  
 
Post-treatment Assessment (w/in a week) 
$40 
 
30-day Assessment (RCT only) 
 
$40 
    
 
Therefore, the total compensation for completing all the study components would be $80 for the 
Aim 1 one-arm trial and $120 for the Aim 2 RCT. Payments will be made via direct deposit or 
check following each study procedure listed above. Participants who do not complete the entire 
study for any reason will receive compensation for the components that were completed per the 
above schedule of payments. 
5.3 Informed Consent Procedures 
There are two phases where informed consent could be obtained, when completing the 
screening for eligibility and when enrolling into the study following the screening and if eligibility 
criteria are met. Verbal consent to participate will be obtained for the screening and baseline 
appointment. Informed consent will be obtained by study personnel trained in human subjects’ 
protections requirements and how to obtain and document informed consent.  
5.4 Inclusion/Exclusion Criteria 
Inclusion criteria: Participants will include men and women who: 
x 
Are English-speaking  
x 
Are 18 years of age or older 
x 
Have access to a phone or computer 
x 
Screen positive for active SUD of at least moderate severity based on the M.I.N.I. 
x 
Screen positive for loneliness by scoring at least a T-score > 60 on the NIH Toolbox 
loneliness scale 
We will use the Veteran Verification screening for Veterans recruited through social media 
advertising to help confirm Veteran status. 
Exclusion: Veterans will be excluded on the basis of: 
x 
Does not understand informed consent  
 
Pregnant women will not be excluded from this study as no invasive medical procedures are 
being performed and there is no known risk to the mother or the fetus of the proposed 
interventions. The study will not include prisoners or institutionalized Veterans. 
 
5.5 Study Evaluations 
 
Loneliness: The 20-item Revised UCLA Loneliness Scale will be our primary outcome 
measure.45 We will use the 5-item NIH Toolbox Loneliness Scale46  as our loneliness screening 
measure. The NIH Toolbox Loneliness Scale is correlated highly (r = .80) with the Revised 

 
Page 13 of 24 
 
UCLA Loneliness Scale.24,46 T-scores >60 indicate loneliness scores 1 standard deviation above 
the mean and will be used to assess eligibility.47 
Quality/Quantity of Social Interactions: The Duke Social Support Index (DSSI) assesses 
several domains of perceived social support, including social network size, social interaction, 
social satisfaction, and instrumental social support. Research supports the psychometric 
properties of the DSSI scales.48-50 Belongingness and Burdensomeness: The Interpersonal 
Needs Questionnaire (INQ-12) assesses thwarted belongingness (i.e., an unmet need to 
belong) and perceived burdensomeness (i.e., feeling like a burden to one’s social support 
network). Research supports the scale’s psychometric properties.51
 
Substance use: We will use the Timeline Follow Back (TLFB)52 to assess quantity and 
frequency of substance use, and percent days abstinent. For the baseline assessment, 
participants will complete the TLFB for the past 3-months. Facilitating participant recall, the 
TLFB will be completed at each assessment so there are shorter intervals. Consequences of 
substance use: The Inventory of Drug Use Consequences (InDUC-2) will be used to assess 
drug use consequences in the following domains: impulse control, social responsibility, physical, 
intrapersonal and interpersonal.53 Consequences will be assessed for the last 3 months at 
baseline and the follow-up will be since the previous assessment.   
 
Other key descriptive variables: Treatment utilization: We will assess participant past and 
current substance use and mental health treatment utilization at baseline and follow-up. We will 
also assess primary care and specialty medical care visits, both within and outside the VA. This 
will be done using a modified version of the Treatment Services Review (TSR).54 Quality of life: 
The PROMIS Profile-29 will be used to assess the following: anxiety, depression, physical 
function, fatigue, sleep disturbance, ability to participate in social roles and activities, and pain 
interference.55 Demographics and military background. At screening, we will assess participants’ 
branch, deployment history, gender, age, educational background, employment, income, race, 
ethnicity, and marital and cohabitation status. 
5.6 Schedule of Assessments 
 
Schedule of Assessments – One Arm Trial 
Measures 
Screening 
Baseline 
Post-Intervention 
Informed Consent - Verbal 
X 
  
  
Eligibility Review 
X 
  
  
Demographics and Military Background 
  
X 
  
Oral Fluid Samples 
  
X 
X 
NIH Toolbox Loneliness Scale 
  
X 
X 
Timeline Follow Back (TLFB) 
  
X 
X 
Revised UCLA Loneliness Scale 
  
X 
X 
Duke Social Support Index (DSSI) 
  
X 
X 
Treatment Services Review (TSR) 
  
X 
X 
PROMIS-29 
  
X 
X 

 
Page 14 of 24 
 
Inventory of Drug Use Consequences -  InDUC-2 
  
X 
X 
Interpersonal Needs Questionnaire-12 
  
X 
X 
Exit Interview 
  
  
X 
 
 
 
 
Schedule of Assessments - Randomized Clinical Trial 
Measures 
Screening Baseline 
Post-
Intervention 
30-day Follow-
up 
Informed Consent - Verbal 
X 
  
  
  
Eligibility Review 
X 
  
  
  
Demographics and Military Background 
  
X 
  
  
NIH Toolbox Loneliness Scale 
  
X 
X 
X 
Timeline Follow Back (TLFB) 
  
X 
X 
X 
Revised UCLA Loneliness Scale 
  
X 
X 
X 
Duke Social Support Index 
  
X 
X 
X 
Treatment Services Review (TSR) 
  
X 
X 
X 
PROMIS-29 
  
X 
X 
X 
Inventory of Drug Use Consequences (InDUC-2) 
  
X 
X 
X 
Interpersonal Needs Questionnaire-12 
  
X 
X 
X 
Exit Interview 
  
  
X 
  
 
5.7 Data Analysis 
We will track rate of recruitment per week, and the percentage of participants who 
complete the protocol, and each follow-up. Participant treatment adherence will be assessed by 
tracking attendance and homework completion. Session-by-session participant feedback will be 
used to examine potential reasons for drop-out and non-adherence to inform our small RCT. 
Therapist adherence scores for the individual sessions and the overall interventions will be 
assessed as the percentage of the content delivered. Interrater reliability for fidelity will be 
assessed using intra-class correlation coefficients. We will assess the internal consistency of 
competence using Cronbach’s alpha. Treatment acceptability will be assessed with the modified 
AARS and exit interview for a richer understanding. For participants who choose to withdraw 
prior to completing the full protocol, attempts will be made to conduct exit interviews to assess 
treatment experiences and reasons for early withdrawal. Interviews will be audio-recorded and 
transcribed. Interview data will be analyzed using matrix analysis,56-58 a systematic technique for 
data reduction to thematically organize and analyze data using rows, columns, and cells of a 
table. This process is time efficient, aligns well with results of in-depth analyses, allows for 
accurate summarizing of data, and facilitates participant comparisons.57Matrices are also an 
effective way to share findings with interdisciplinary team members for discussion.56 Following 

 
Page 15 of 24 
 
the analyses, these matrices will be reviewed by the investigative team and expert panel in 
preparation for finalizing the intervention. 
 
 
Consistent with descriptive analyses for pilot studies,59 measure completion percentage 
and means and standard deviations for outcomes will be calculated at each assessment, 
including change scores and correlations across timepoints. We expect large standard errors 
due to small sample size. Distribution of scores will be examined to better evaluate how to 
analyze these data in future studies (e.g., dichotomizing/ categorizing vs. continuous). For 
continuous outcomes, Hedge’s g will be calculated to identify a range of the pre-post effect size. 
Although such calculations are of limited benefit in determining the effect of the intervention, 
they can be helpful in identifying outcomes that are less sensitive to change. Correlations 
among baseline variables will be calculated to assess the potential for variables to be included 
as covariates in the larger trial. This may also be useful in identifying potential moderators and 
mediators for the future larger trial. For data quality and handling of missing data, descriptive 
statistics will help identify out of range values and outliers. We will examine bias in retention 
rates at both the univariate and multivariate level of analyses 
 
Data storage, security, and confidentiality 
Several procedures for protecting participant confidentiality will be implemented to reduce 
the risk of revealing participant identity. All informed consent forms will contain identifying 
information. In order to ensure confidentiality, each consent form will be labeled with a numeric 
identifier and will be stored in a double-locked file. These will be stored in separate double-
locked files from other study materials. As noted in the Data Transport Memorandum, locked 
courier bags will be used to transport any sensitive study information (e.g., consents) outside 
VA. 
The VA Informatics and Computing Infrastructure (VINCI) will be used for the storage of 
study data. VINCI is a major informatics initiative of the Department of Veterans Affairs (VA) that 
provides a secure, central analytic platform for performing research and supporting clinical 
operations activities. It is a partnership between the VA Office of Information Technology (OI&T) 
and the Veterans Health Administration Office of Research and Development (VHA ORD). 
VINCI includes a cluster of servers for securely hosting suites of databases integrated from 
select national VA data sources. VINCI servers for data, applications and virtual sessions are 
physically located at the VA Austin Information Technology Center (AITC), located in Austin, 
Texas. This secure enclave with 105 high-performance servers and 1.5 petabytes of high-speed 
data storage has multiple layers of security and disaster recovery to prevent data loss. 
Study data will be kept in accordance with the Department of Veterans Affairs Record 
Control Schedule 10-1 (RCS 10-1). Storage and transfer of any Personally Identifiable 
Information (PII) or Protected Health Information (PHI) must be done in accordance with 
applicable VA and VHA policies and directives, state and federal regulations, and applicable 
statutes including the Health Insurance Portability and Accountability ACT (HIPAA). Unless 
explicitly requested and approved by data stewards, all sensitive patient data must remain on 
VINCI project servers and only aggregate data without PII / PHI may be transferred from VINCI. 
Prior to being uploaded to VINCI for analysis, data will be stored on a secure VA server, 
which is password protected, and to which only IRB approved VA research personnel have 
access. Should any identifiable information need to be shared between research sites, research 
teams will utilize a secure, SharePoint site or electronic communication with PKI encryption. Any 
identifiable paper data will stored in two separate locked file cabinets (one for informed consents 
and the other for paper questionnaire data) in the offices of the Center for Excellence for Suicide 
Prevention at the Canandaigua VAMC. After a participant completes the study, any identifiers 
will be removed from the paper questionnaire data immediately. Data analysis will occur in the 
VINCI framework. 

 
Page 16 of 24 
 
 
5.8 Withdrawal of Subjects 
Participants who wish to withdraw may do so at any time without affecting their medical care or 
participation in any other study. Participants will be informed of any new information during the 
course of the study which may affect their condition or influence their willingness to continue in 
this study. Finally, based on decisions made by the Principal Investigator, participants may be 
taken out of the study because of unanticipated circumstances such as extreme distress. That 
is, they may be withdrawn from the study if we judge that participating is not in their best 
interest. 
6.0 
Protection of Human Subjects 
Protection of Human Subjects 
 
Risk to Participants 
  
Human Subjects Involvement and Characteristics. The purpose of this study is to assess the 
feasibility and acceptability of Cognitive-Behavioral Therapy for Loneliness for Substance Use 
Disorders (CBT-L/SUD) among Veterans with SUD who are lonely. After an initial refinement 
phase during which 6 Veterans will complete the study protocol, a total of 30 participants will be 
recruited across the US and randomized to receive either CBT-L/SUD (n = 15) or Cognitive-
Behavioral Therapy for Substance Use Disorders (CBT-SUD; n = 15).  
 
According to 2018 data from the National Survey of Drug Use and Health, 92.9% of 
respondents who had ever served in the military and had SUD were men. We expect to have a 
greater number of women compared to this proportion given that loneliness is more common 
among women and given increased recruitment of women. SUD prevalence increases with age 
as those with SUD who had ever served in the military was least common among ages 18-25 
(1.3%) and 26-34 (6.8%) and most common among those 35-49 (16.4%) and 50+ (52.1%). We 
expect there to be relatively greater proportions of younger age and older age groups (rather 
than middle age groups) because loneliness is more common among those age groups.  
 
Source of Materials. Study materials will include self-report questionnaires. The materials will 
be collected for study purposes only. Information collected will be stored in a locked filing 
cabinet in a locked office at the study sites that can only be accessed by members of the study 
team. All electronic data will be stored on VA Informatics and Computing Infrastructure (VINCI) 
project servers. Only approved study team personnel who will be involved in data entry, 
management and analyses will be granted access to this data. All computers are password 
protected.  
Potential risks.  
Psychological distress. Anticipated risks to the participants from assessment procedures and 
therapy are minimal; however, participants may experience psychological distress, frustration, 
and/or fatigue. The semi-structured interviews, assessments associated with the intervention, 
and therapy sessions may encourage participants to recall personal events and life stressors 
that may evoke distress. Additionally, confidentiality may need to be breached if a participant 
poses a threat to him or herself or others, including child abuse. 
 

 
Page 17 of 24 
 
Adequacy of Protection from Risk  
Recruitment and Informed Consent.  
All research staff will have completed appropriate and up-to-date training in research, research 
ethics and the proper conduct of research that includes common issues related to recruitment 
and informed consent.  
 
Participants will be recruited using Internet social media websites, select web portals, and data 
accessed through the Corporate Data Warehouse. Advertisement will nationally target Veterans 
using opioids and who may be lonely. Targeted recruitment of women Veterans and Veterans of 
ethnic/racial minority status will also be used for advertisements. All sites will send participants 
to a study landing page, which serves as a central location for potential participants to follow-up 
with the study team via phone or completing and submitting an online form. Recruitment and 
informed consent procedures were designed to ensure patients do not feel like participation is 
required. Potential participants unable to understand the informed consent process will be 
excluded from participating. Screening interviews will be completed initially over the telephone 
(using a script) to assess eligibility criteria. Verbal consent will be obtained at this time to 
complete the screening. Participants screening positive for exclusion criteria will not be included 
in the study. For eligible and interested participants, a research coordinator will review the 
consent form and complete a brief questionnaire to ensure the potential participant understands 
the study. Verbal consent will be completed with procedures used by the PI that have been 
approved by our local IRB. Specifically, once eligibility is confirmed through screening, each of 
the essential elements of informed consent will be described to the Veteran to which they can 
provide verbal consent. The Veteran will be enrolled following consent. 
 
Protection Against Risk.  
Psychological distress. The potential risks are negligible. There are no known risks associated 
with interview procedures. Participants will be informed that they may feel slightly uncomfortable 
discussing some of their symptoms. Mild discomfort may be likely during the intervention 
session; however, this is unlikely to have a serious negative impact on the participant’s well-
being. Participants will be told they can withdraw from the study at any time. Participation or 
withdrawal from the study will not affect any benefits to which they are otherwise entitled. 
Special precaution will be taken to safeguard confidentiality. During assessments, if the 
interviewer is concerned about thoughts and planning of a suicide attempt, the interviewer will 
ask two follow-up questions: Do you have a desire to kill yourself that you think you might act on 
and Do you have a plan for killing yourself and intend to carry the plan out? With this information 
and available suicide assessment measures, the interviewer will evaluate the severity of the 
participant’s suicide risk. If the participant is deemed to be at imminent risk, a safety plan will be 
initiated. All study staff will receive adequate training in suicidal ideation and risk assessment, 
and all work will be supervised by Drs. Ashrafioun, who is a licensed clinician. 
 
If the interviewer is concerned about imminent risk, procedure for warm transfers to the National 
Suicide Prevention Lifeline (1-800-273-TALK; 988 by July, 2022). Emergency procedures will be 
initiated if patients are determined to be at imminent risk for suicide using the risk assessment 
described above. Participants determined to be at risk will be asked if they are willing to be 
transferred to the National Suicide Prevention Lifeline. Hotline responders are well trained in 
emergency procedures and have working protocols for locating callers and initiating rescues. All 
telephone sessions will be conducted using protocols to ensure that the clinicians’ telephone is 
set up for transfers to the Crisis Line. Calls can be transferred with a four step process. 
 
 
 
Warm Transfer Process 
1. Press the conference/add caller button. 
2. Dial 1-800-273-8255 press option 1 and a Crisis Line responder will answer. 
3. Describe the participants risk and provide name and telephone number.  
4. Pressing the conference/merge calls button and participants will be linked with Crisis Line 

 
Page 18 of 24 
 
It is possible that participants may refuse to be transferred to the Crisis Line or hang up. As a 
result, participants will be asked to use a landline so that the number can be tracked to an 
address if emergency services are needed. For participants who only have a cell phone,  
 
Interviewers will begin each session by asking the participant for the address from which they 
are calling so that the clinician can send help if it is needed. Because participants may give a 
false address, clinicians will consult with Lifeline responders who have a protocol for emergency 
responses for cell phone callers.  
 
For participants that have a lower risk than imminent for suicide at baseline, our crisis plan will 
be consistent with guidelines employed by Dr. Ashrafioun as well as by the DoD/VA for people 
at low acute risk for suicide. This involves the following, which may or may not already be in 
place at the time the participant is deemed at low acute risk: (1) consider consultation with 
behavioral health specialty, (2) discuss safety and restriction of access to lethal means, (3) treat 
mental health and medical conditions, (4) address psychosocial needs, (5) encourage social 
support from friends, family, and/or community, (6) continue monitoring patient status and 
reassess risk in follow-up contacts, and (7) document risk assessment. 
 
The Project Coordinator, research staff, and Research Therapists will receive extensive training 
in conducting screening for suicide risk assessment by Dr. Ashrafioun in consultation with Drs. 
Allen, Stecker, and Maisto. In addition, the Project Coordinator and Research Therapist will 
complete training webinars and extensive test-outs for fidelity. 
 
Breach of Confidentiality. Statistical electronic data files will be kept VINCI project servers 
maintained by VINCI OI&T personnel and only summarized data without protected health 
information (PHI) will be downloaded from VINCI to local storage media. Research staff will use 
an audited VINCI download utility to move summarized data for reports, presentations and 
publications from VINCI servers to local storage media. The VINCI download utility provides an 
audit path including a copy of the downloaded material. The data extraction tool will be adapted 
for use with software directly available on the VINCI platform (e.g. Microsoft Word and Excel) 
and study data will be stored and maintained on VINCI. All study team personnel with access to 
sensitive patient data will stay current on their VA approved information security training and VA 
approved privacy policy training.  
 
Data Safety & Monitoring Plan 
 
Data Safety. To ensure safety of participants in the study proposed and validity and integrity of 
data collected, the PI (Ashrafioun) will oversee all data and safety monitoring functions and the 
research team will be advised that he will be the primary contact overseeing these activities. 
The investigators will meet regularly to monitor study progress and discuss the implementation 
of monitoring procedures. The PI will also meet regularly with the research staff to review 
monitoring procedures and ensure all efforts are being taken to minimize risks to participants. 
We will have an independent Data Safety & Monitoring Board (DSMB), appointed by HSR&D to 
help monitor safety issues. As indicated below, the PI will track all negative outcomes and 
incidents as well as conduct interim data analysis every 6 months after the study has started. 
The study design will be significantly modified (and even screening stopped) on the suggestion 
of the DSMB if the study is creating potential harm to our participants.  
 
The PI will regularly oversee all aspects of the study, including participant recruitment, informed 
consent, data collection, management, and analysis, as well as regularly assess the risk/benefit 
ratio associated with participation in the study. All research staff will participate in an intensive 

 
Page 19 of 24 
 
training to help them understand the importance of reducing the risk for participants and 
learning how to recognize and report any AE or SAE. SAEs may include: death, hospitalization 
due to worsening psychiatric symptoms or suicidal ideation, or all life threatening or 
disabling/incapacitating events among research participants. AEs may include, but are not 
limited to: physical injuries, worsened physical or mental health, or inadvertent disclosure of 
confidential research information. 
 
If an SAE occurs, the PI will immediately contact the DSMB and IRB, followed by a written 
report in 24 hours. He will make a decision whether there is sufficient evidence to suspend data 
collection, allow for further IRB review, modify the protocol, or make other changes to reduce 
potential risk to participants. The study will resume based on agreement of the PI, the IRB chair, 
and the DSMB. In the event that an AE that is not an SAE is reported to the PI, the PI will 
discuss the event with the DSMB. Immediate evaluation will occur to determine if any extra 
steps can be taken to minimize the likelihood of that type of AE occurring again. If changes can 
be made, a report/amendment will be written and submitted to the DSMB and IRB.  
 
As part of a standard practice, the PI will supervise the implementation of one audit within 4 
months after study recruitment and one regularly per year afterwards of the materials collected 
and produced as part of the study at each site to ensure proper confidentiality and compliance 
with ethical principles, including confirmation of verbal consent, questionnaire data, and to make 
sure that the research staff are following established protocols. The PI will provide an annual 
summary report of all AEs to the IRB and the DSMB as part of the annual review. If no adverse 
events have occurred, the report will state, “No adverse events affecting human participants 
have occurred during this project year.”   
 
Data Monitoring. To ensure adequate participant recruitment and enrollment, each week, the PI 
will discuss the current number of participants contacted, screened, and enrolled from each site 
and compare those numbers to the expected based on our preliminary data. If after the first 4 
months, it appears we are not reaching our expected number of participants, the PI will discuss 
potential barriers/obstacles and solutions with the research team and DSMB. Discussions 
regarding recruitment and enrollment will continue at each meeting with the DSMB to ensure 
proper implementation of the study.  
 
Data Safety & Monitoring Board. The purpose of the DSMB is to review protocols and consent 
documents for this study, monitor safety issues throughout the study, provide an overview of the 
quality of the accumulating data, and provide guidance on interim analyses and stopping rules. 
The DSM will be comprised of individuals appointed with by the funder (VA Health Services 
Research & Development) and will have no direct involvement in the study or conflict of interest 
with the research team conducting the clinical trial. The DSMB responsibilities will include:  
(1) Protect the safety of the participants 
(2) Review, provide approval/disapproval, and provide suggestions to protocols, consent 
documents, and plans for data safety and monitoring. 
(3) Monitor, provide suggestions, and report on ethical issues regarding protection of human 
subjects, and advise on ethical issues regarding AEs. The DSMB will coordinate with the 
PI to report to the IRB any unanticipated problems involving risk. The DSMB will provide 
potential solutions or other appropriate actions (e.g., altering inclusion/exclusion criteria, 
changing consent documents). 
(4) Ensure appropriate balance between clinical care, safety, and patient confidentiality. 
(5) Monitor data the progress of the trial. The DSMB will periodically review outcome data 
for outcomes by treatment condition, including participant recruitment, retention, risks 
and benefits, and other factors that may affect outcomes. If differences in results 

 
Page 20 of 24 
 
between conditions appear to be clinically significant, the DSMB will review whether the 
clinical trial should continue with or without further enrollment of new participants. 
(6) Monitor and review any data relevant to quality control and safety. 
(7) Make recommendations to the HSR&D about the continuation, termination, or changes 
to the trial based on benefits or adverse effects of the treatment. 
(8) Communicate problems with the conduct, enrollment, sample size, and/or data collection 
to HSR&D 
The PI will convene annually with the DSMB for the duration of the study. The meetings will 
be held via video teleconference. The Board Chair and PI will decide on the format of the 
meetings. Additional meetings will be held on the recommendation of the Board Chair and PI 
and meeting logistics will be based on clinical urgency and the availability of the DSMB. The PI 
will submit reports to the DSMB a week prior to the scheduled meeting. Reports will include all 
data up to and including 2 weeks prior to the reporting deadline (except for SAEs, which are to 
be reported within 24 hours of an event). For each meeting at which the study is to be 
considered or monitored, the PI will present an overall progress statement containing the 
assurance that the PI has considered the clinical trial’s progress and that there is/is not 
evidence of safety issues that should be addressed by the DSMB. The reports will also include 
information related to problems in recruitment, biases in attrition, biases with respect to AEs, or 
other operational problems that affect the integrity of the study. At the additional request of the 
DSMB, interim analyses will be conducted to determine whether the emerging findings may lead 
to a discussion of discontinuing the trial early. 
 
The DSMB will be kept apprised of all SAEs and AEs on an ongoing basis and will decide 
whether individual patients should be removed from the protocol. Although research staff, under 
the PI’s supervision, are able to take whatever immediate action is necessary to safeguard the 
welfare of individual patients, the DSMB will be called on whenever possible to make decisions 
as a result of a SAE. There may be rare instances where some unanticipated situations occur 
that may affect participant welfare. In these situations, the Syracuse VAMC IRB or the DSMB 
may be contacted to help resolve the situation. 
 
Adverse Events (AE). AEs may include, but are not limited to: worsened physical or mental 
health, or inadvertent disclosure of confidential research information. Serious Adverse Events 
(SAE) may include: death, hospitalization due to worsening psychiatric symptoms or suicidal 
ideation, or all life threatening or disabling/incapacitating events among research participants. 
Per IRB regulations, SAEs, any event resulting in a deviation from the study protocol (e.g., 
emergency hospitalization to address suicidal behaviors) or death will be reported to the PI 
within 24 hours and to the IRB in 48 hours. This will be completed in order to assess 
significance and determine an appropriate response. AEs that involve temporary distress will be 
noted by interviewers and provided to the IRB in an annual report.  
 
Confidentiality of Records. Numerous protections are in place to reduce the likelihood of loss 
of confidentiality. All research data will be kept in locked filing cabinets in secure areas, absent 
of identifying information, and coded by research number only. Files containing items with 
identifying information will also be kept in locked filing cabinets, but these will be separate from 
cabinets containing data from this study. All electronic files, including therapy notes, will be 
maintained on a secure study folder behind the VA firewall. Only approved study team 
personnel will be granted access to this data. All identifiable information will be stored in a 
separate folder behind the firewall from the de-identified study ID and data. 
 
Potential Benefits of Research to Participants and Others. There may be direct and/or 
indirect benefits of study participation. Participants are receiving a brief intervention that 

 
Page 21 of 24 
 
addresses a transdiagnostic factor that may reduce both loneliness and substance use. 
Because this intervention can be used for both participants who are not engaged in treatment 
and for participants who are engaged in treatment, it may augment current services. 
Dissemination of the findings from the study will contribute to the extant literature, provide data 
to guide implementation, and may contribute to reducing loneliness and substance use.  
 
Importance of Knowledge to be Gained. Understanding how to effectively address loneliness 
among Veterans with SUD is a critical approach to curb substance-related morbidity and 
mortality. Loneliness is associated with increased suicide risk, substance use, and key 
precipitants to relapse among people addicted to substances. Addressing loneliness has the 
potential to reduce substance use. The proposed study tests the 8-session CBT-L/SUD that will 
be refined as part of this study. This telehealth intervention targets cognitive biases, and 
avoidance of social interactions and enjoyable activities. We expect that this intervention will 
reduce loneliness, increase the quality and quantity of social interactions, and reduce substance 
use.  Knowledge gleaned from this study will help inform a fully powered randomized clinical 
trial with the long-term goal of future implementation and dissemination efforts across numerous 
settings.  
7.0 
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