Clinical trial NCT03290391
Conditions: HIV Infection Drug Use
Keywords: Russia Substance use Peer case managers ART HIV
Sponsor: Boston Medical Center
Start date: 2018-09-19; Completion date: 2022-04-06
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study, "Linking Infectious and Narcology Care - Part II (LINC-II)," will implement and evaluate a multi-faceted intervention (LINC-II), via a two-armed randomized controlled trial among 240 HIV-infected PWID in St. Petersburg. LINC-II, comprised of pharmacological therapy (i.e., rapid access to ART and receipt of naltrexone for opioid use disorder) and 12 months of strengths-based case management, will assess HIV outcomes (e.g., HIV viral load suppression), impact on care systems and cost-effectiveness of the intervention.

Detailed description:
Russia and Eastern Europe continue to have one of the fastest growing HIV epidemics in the world, with highest transmission risks among people who inject drugs (PWID) and their sexual partners. While routine HIV testing within addiction treatment systems in Russia (i.e., narcology hospitals) is the norm, links between the narcology and HIV care systems are limited and ineffective. In St. Petersburg 50-60% of PWID are HIV-infected, yet among this population less than 10% are on antiretroviral therapy (ART). For Russia to make progress toward the UNAIDS 90-90-90 targets (i.e., 90% aware of HIV diagnosis, 90% of those diagnosed on ART and 90% of those on ART with suppressed HIV viral load \[HVL\]), a bold new strategy is required. The objective of this study, "Linking Infectious and Narcology Care - Part II (LINC-II)," is to implement and evaluate, via a two-armed randomized controlled trial among 240 HIV-infected PWID, a multi-faceted intervention combining pharmacological therapy (i.e., rapid access to ART and receipt of naltrexone for opioid use disorder) and 12 months of strengths-based case management.

The central hypothesis is that LINC-II will lead to marked progress toward the achievement of the 90-90-90 HIV cascade of care targets among HIV-infected PWID, relative to current standard of care, and that LINC-II will facilitate health system coordination of narcology and HIV care. LINC-II aims to: 1) evaluate the effectiveness of LINC-II on undetectable HVL at 12 months (primary outcome), initiation of ART within 28 days of randomization, change in CD4 count from baseline to 12 months, retention in HIV care (i.e., ≥ 1 visit to medical care in 2 consecutive 6 month periods), and undetectable HVL at 6 months; 2) evaluate the impact of LINC-II on coordinated care across the narcology and HIV health care systems, using mixed methods data from health care providers, administrators, and patients; and 3) evaluate the cost-effectiveness of the intervention to inform policy makers on scaling up the LINC-II approach both within Russia and other countries with HIV epidemics driven by injection drug use.

Arms: arm 1: LINC-II is a multi-faceted intervention combining pharmacological therapy (i.e., ART and naltrexone for opioid use disorder) and 12 months of strengths-based case management delivered to coordinate care across the narcology and HIV health care systems. arm 2: Participants randomized to the control group will receive the narcology hospital's standard of care, which is detoxification with or without stabilization. Prior to discharge, those identified as HIV-infected are given contact details for an HIV clinic, not an appointment. Upon discharge, patients are encouraged to receive outpatient narcology treatment, monthly, for 1 year. For this study, with regard to linkage to HIV medical care, patients will be given printed information about where to obtain HIV medical care and a resource card containing harm reduction information.
Interventions: intervention 1: Rapid ART initiation intervention 2: Pharmacotherapy for opioid use disorder intervention 3: Strengths-based HIV case management
Intervention descriptions: intervention 1: The infectionist will streamline the approval with the ultimate goal of starting participants on ART while they are still hospitalized at the City Addiction Hospital. intervention 2: Thirteen months of naltrexone treatment for opioid use disorder (injection at baseline, followed by 4 implants). intervention 3: Strengths-based case management: 10 sessions over 12 months in which a trained case manager (CM) meets individually with patients to motivate them to engage in HIV medical care by supporting the recognition of their own strengths to make positive changes in their lives and ultimately improve their HIV outcomes.

Protocol documents:
Prot_SAP_001.pdf: 
LINC-II Protocol  
 
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STUDY PROTOCOL 
 
  
Linking Infectious and Narcology Care – Part II 
(LINC-II) 
 Principal Investigator:  Jeffrey H. Samet, MD, MA, MPH – Boston Medical Center  
 
 
 
 NIDA Award Number: R01DA045547 
 Clinicaltrials.gov Registration: NCT03290391 
 Boston University Medical Campus IRB Protocol Number: H-36706 
 Enrollment Start: September 19, 2018 
 Protocol Version: July 22, 2021 
 
Detailed Statistical Plan- see pages 47-49 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. INTRODUCTION 
  #5 
1.1 SUMMARY……………………………………………………………………………………. #5 
1.2 SIGNIFICANCE………………………………………………………………………………...#5 
2. OVERVIEW OF STUDY DESIGN 
#6  
2.1 STUDY AIMS ............................................................................................................................ .#6  
2.2 STUDY HYPOTHESES………………………………………………………………………….#6 
2.3 STUDY OUTCOMES……………………………………………………………………............#6 
2.4 STUDY DESIGN  ........................................................................................................................ #7 
2.5 STUDY SITE…………………………………………………………………..…………..…....#8 
2.6 INCLUSION CRITERIA……………………………………………………..………………..... #9 
2.7 EXCLUSION CRITERIA AT STUDY ENTRY…………………………………………..………... #9 
2.8 RECRUITMENT GOALS……………………………………………….……………………….#10 
 2.8.A. SAMPLE SIZE CALCULATION AND POWER………..…...…..………………….. …………#11 
3. INTERVENTION 
#11 
3.1 INTERVENTION OVERVIEW………………………………………………………………....#11 
3.2 RANDOMIZATION…………………………………………………………………………....#13 
3.3 INTERVENTION……………………………………………………………….......................... #13 
   3.3.A. STRENGTHS-BASED CASE MANAGEMENT……………………………….………….…....#13 
   3.3.B. RAPID ACCESS TO ART ………….……………………………………….…..…….…....#15 
   3.3.C. PHARMACOTHERAPY FOR OPIOID USE DISORDER………………………………..…….....#16 
3.4. CONTROL GROUP………………………………..……........................................................#21 
3.5 MEDICATION CONSIDERATIONS…………………………………………............................#22 
   3.5.A. SYMPTOM MONITORING…………………………..………………………………..........#22 


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   3.5.B. DISCONTINUATION OF STUDY MEDICATION………………………….............................#22 
3.6 SCHEDULE OF DATA COLLECTION……………………………………………………........#22 
   3.6.A. VISIT WINDOWS…………………………………………………………………..……..#24 
3.7 DATA SOURCES……………………………………………………………………….……..#25 
   3.7.A QUESTIONNAIRES…………………………………………………………………...........#25 
   3.7.B. BLOOD …………………………………………………………………………...……...#25 
   3.7.C. URINE…………………………………………………………………………..……......#26 
   3.7.D. MEDICAL RECORD REVIEW……………………...…………………………………….....#26 
4. STUDY PROCEDURES 
#26 
4.1 RECRUITMENT………………………………………………………………………............#26 
4.2 SCREENING………………………………………………………………………….............#28 
4.3 INFORMED CONSENT…………………………………………………………………..........#29 
4.4 VISIT FLOW…………………………………………………………………………….........#29 
4.5 QUALITY ASSURANCE…………………………………………………………….................#31 
4.6 COMPENSATION……………………………………………………………………............. #31 
4.7 RETENTION……...……………………………………………………………………..........#32 
5. ASSESSMENTS 
#33 
5.1 BASELINE ASSESSMENT………………………………………………………………..........#33 
5.2 FOLLOW UP ASSESSMENTS………………………………………………………….............#34 
   5.2.A. MEDICATION VISITS ASSESSMENTS………………………………………….…..............#35 
5.3 SYSTEM-LEVEL ASSESSMENT OF LINC-II IMPACT…………………….………………#35 
5.4 ESTIMATES OF COST AND COST-EFFECTIVENESS…………………………………….#36 
6. PARTICIPANT SAFETY 
#38 
6.1 SPECIFICATION OF SAFETY PARAMETERS…………………………………………………#38 
6.2 THE METHODS AND TIME FOR ASSESSING, RECORDING, AND ANALYZING SAFETY 
PARAMETERS………………………………………………………….......................................#39 
6.3 PROCEDURES FOR ELICITING REPORTS OF AND FOR RECORDING AND REPORTING   


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AND ADVERSE EVENT INTERCURRENT ILLNESSES…………………………………………….#40 
   6.3.A. OTHER EVENTS…………………………………………………………….…….…........#40 
   6.3.B. ADVERSE EVENT REPORTING……………………….…….…..........................................#40 
   6.3.C. SAE REPORTING……………………….…….…..............................................................#41 
6.4 THE TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS AFTER ADVERSE 
EVENTS…………………………………………………………………………………………..#43 
7. DATA MANAGEMENT 
#43 
7.1 DATA COLLECTION…………………………………………………………………….........#43 
7.2 QUALITY CONTROL PROCESS...............................................................................................  #43 
7.3 DATA SECURITY AND CONFIDENTIALITY………………………………………………......#43 
7.4 WEB SYSTEMS…………………………………………………………………………….....#44 
8. STATISTICAL ANALYSIS 
#45 
8.1 PRIMARY ANALYSES……………………………………………………………….……......#46 
8.2 ADDITIONAL EXPLORATORY ANALYSES….………………………………………….….....#46 
9. STAFF TRAINING 
#48 
9.1 TRAINING OF STUDY STAFF………………………………………………………………...#48 
9.2 TRAINING OF INTERVENTIONISTS (CASE MANAGER)….……………………………….....#48 
10. STUDY CONTACTS 
#48 
 
 
 
 
 
 
 


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1. INTRODUCTION 
 
1.1 SUMMARY 
 
Russia and Eastern Europe continue to have one of the fastest growing HIV epidemics in the world, with 
highest transmission risks among people who inject drugs (PWID) and their sexual partners. While 
routine HIV testing within addiction treatment systems in Russia (i.e., narcology hospitals) is the norm, 
links between the narcology and HIV care systems are limited and ineffective. In St. Petersburg 50-60% of 
PWID are HIV-positive, yet among this population less than 10% are on antiretroviral therapy (ART). For 
Russia to make progress toward the UNAIDS 90-90-90 targets (i.e., 90% aware of HIV diagnosis, 90% of 
those diagnosed on ART and 90% of those on ART with suppressed HIV viral load [HVL]), a bold new 
strategy is required. The objective of this study, “Linking Infectious and Narcology Care – Part II (LINC-
II),” is to implement and evaluate, via a two-armed randomized controlled trial among 240 HIV-positive 
PWID, a multi-faceted intervention combining pharmacological therapy (i.e., rapid access to ART and 
receipt of naltrexone for opioid use disorder) and 12 months of strengths-based case management. The 
central hypothesis is that LINC-II will lead to marked progress toward the achievement of the 90-90-90 
HIV cascade of care targets among HIV-positive PWID, relative to current standard of care, and that LINC-
II will facilitate health system coordination of narcology and HIV care.  LINC-II aims to evaluate: 1) the 
effectiveness of LINC-II on undetectable HVL at 6 months and 12 months (primary outcome), initiation of 
ART within 28 days of randomization, change in CD4 count from baseline to 12 months, and retention in 
HIV care (i.e., ≥ 1 visit to medical care in 2 consecutive 6 month periods); 2) the impact of LINC-II on 
coordinated care across the narcology and HIV health care systems, using mixed methods data from 
health care providers, administrators, and patients; and 3) the cost-effectiveness of the intervention to 
inform policy makers on scaling up the LINC-II approach both within Russia and other countries with HIV 
epidemics driven by injection drug use. The study’s goal is to improve upon current seek, test, treat, and 
retain efforts for HIV-positive Russian PWID in narcology care, a group routinely tested for HIV.  If LINC-
II is effective and can be embedded efficiently within the Russian and other medical systems challenged 
by HIV-positive PWID, then it has great potential to favorably impact the HIV epidemic in a key HIV 
population. 
 
 
1.2 SIGNIFICANCE 
 
The LINC-II study will assess the effectiveness and implications of an intervention designed to achieve 
90-90-90 HIV care cascade targets by facilitating coordination of care between the addiction (i.e., 
narcology) and HIV treatment systems in Russia. Potential lessons learned in Russia should be applicable 
to all countries attempting to engage HIV-positive people who inject drugs in HIV care.   


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2. OVERVIEW OF STUDY DESIGN  
2.1 STUDY AIMS 
 
LINC-II’s Specific Aims are the following: 
Aim 1: Evaluate the effectiveness of LINC-II on HIV care and health compared to standard of care via a 
2-armed RCT of 240 HIV-positive Russian PWID on the following outcomes: 
a. Primary: Undetectable HIV viral load at 12 months 
b. Secondary: Initiation of ART within 28 days of randomization; 
Change in CD4 count from baseline to 12 months; 
Retention in HIV care (i.e., ≥1 visit to medical care in 2 consecutive 6 month periods) 
Undetectable HIV viral load at 6 months. 
HVL suppression and past 30-day opioid abstinence assessed at 6 and 12 months 
Aim 2: Evaluate the impact of LINC-II on coordinated care across the narcology and HIV health care 
systems using mixed methods data from health care providers and administrators from both systems, as 
well as with LINC-II study participants (i.e., patients within these systems) to determine trends over time. 
Survey data and interviews will assess perceptions of whether the narcology and HIV care systems 
increased coordination of care over the period of the study, and qualitatively, how and why coordination 
does or does not occur, as well as the system implications of such coordination. 
Aim 3: Evaluate whether LINC-II is an affordable and cost-effective strategy for achieving 
undetectable HVL in HIV-positive PWID. If the intervention is successful, it will be important to 
understand the net cost to be incurred by the health system and patients and LINC-II’s cost-effectiveness 
compared to standard of care. This economic perspective will inform policy makers on scaling up the 
LINC-II approach both within Russia and other countries with HIV epidemics driven by injection drug 
use. 
 
 
2.2 STUDY HYPOTHESIS 
 
 
We hypothesize that participants randomized to the LINC-II intervention will have improved HIV care 
outcomes as compared to the control group, which will receive narcology hospital’s standard of care.  
 
2.3 STUDY OUTCOMES 
 


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Aim 1. The primary outcome for aim 1 is defined as an undetectable HVL at 12 months post 
randomization, assessed by study test within a window of 9–15 months. Secondary outcomes are 
initiation of ART within 28 days of randomization, change in CD4 count between baseline and 12 months 
(assessed by study test), retention in HIV care (at least 1 visit to medical care in 2 consecutive 6 month 
periods within 12 months of enrollment, assessed by medical record review and by self-report), 
undetectable HVL at 6 months post randomization assessed by study test, and a composite outcome for 
achieving both HVL suppression and past 30-day opioid abstinence assessed at 6 and 12 months. 
 
2.4 STUDY DESIGN 
 
LINC-II is a Randomized Controlled Trial (RCT) among 240 HIV+ PWID, which aims to test the LINC-II 
intervention, evaluate its impact on coordinated care and evaluate its cost-effectiveness. Eligible 
participants will be randomly assigned into one of two groups: 1) Control group receiving narcology 
hospital’s standard of care or; 2) LINC-II intervention. The intervention for those randomized to the 
intervention arm starts in the narcology hospital: an HIV case manager (CM) will meet with the 
participant, participant will have accelerated access to ART medication with potential to initiate ART 
right at the narcology hospital, and the participant will receive a dose of injectable naltrexone (i.e., 
Vivitrol) for treatment of their opioid use disorder. Following discharge from the narcology hospital, 
participants will meet with the case manager over 12 months, receive implantable naltrexone 
(Prodetoxon) every 10-12 weeks (4 doses), and ideally start on ART at their first HIV care visit, if ART 
was not initiated at the narcology hospital. Study outcomes will be assessed at 6 and 12 months (Figure 
1). 
Figure 1 illustrates the design of this 2-arm RCT with 120 participants per arm.  


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Throughout the course of the study, participants will be expected to participate in three in-person 
assessments and blood draw visits (baseline, 24 weeks and 52 weeks). Intervention participants will 
receive 4 naltrexone implants while in the study. Ideally, implants will be inserted every 10-12 weeks 
starting at week 4 post-study enrollment (weeks 4, 16, 28, 40). Participants will be invited to come in 
every 4 weeks following implantation for medication visits. Ideally, medication visits will occur at weeks 
4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. Full study assessments occur at weeks 24 and 52 (in 
addition to medication visit procedures). Implant visits 2, 3, and 4 will involve the collection of blood for 
laboratory testing to monitor liver toxicity.  
 
2.5 STUDY SITE 
 
St. Petersburg City Addiction Hospital (CAH) will be the site of participant recruitment. CAH is a 
government-funded 510-bed hospital, providing free addiction care to residents of the city of St. 
Petersburg, who are registered as having a substance use disorder (drug or alcohol). The hospital 
provides detoxification, early stabilization, and inpatient rehabilitation. The typical length of stay for 
hospitalized patients is one to two weeks. 
St. Petersburg City AIDS Center will provide HIV care for the intervention group. A typical initial 
outpatient visit to initiate HIV care includes examination by an infectionist (physician), lab testing (e.g., 
HVL, CD4), and referrals (e.g., psychologist or addiction specialist). Some clinics have a narcologist on 


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staff to refer HIV-positive PWID to drug addiction clinics. HIV case managers, including some HIV-
positive PWID in recovery (i.e., peers) have been introduced at the clinics. ART is available at no cost to 
all patients in Russia; however, only a small percentage of PWID actually receive this treatment.  
Follow up study visits, naltrexone implants, and adverse event monitoring will occur at the Laboratory of 
Clinical Pharmacology of Addictions at the First St. Petersburg Pavlov State Medical University (PSMU) in 
St. Petersburg, Russia. PSMU is the major educational, scientific, and clinical medical institution for 
northwestern Russia.  
Blood specimens for AST/ALT will be processed and analyzed at ImmunoBioService (IBS) under the 
direction of Dr. Sergei Selkov. CD4 and HVL testing will take place at the City AIDS Center.  
 
2.6 INCLUSION CRITERIA 
 
To be eligible to participate in the trial, participants will need to meet the following inclusion criteria: 
1. 18 years or older 
2. HIV-positive 
3. Hospitalized at a narcology hospital 
4. History of injection drug use 
5. Current diagnosis of opioid use disorder 
6. Provision of contact information for 2 contacts to assist with follow-up 
7. Address within 100 kilometers of St. Petersburg 
8. Possession of a telephone (home or cell) 
9. Able and willing to comply with all study protocols and procedures 
2.7 EXCLUSION CRITERIA AT STUDY ENTRY 
 
1. Not fluent in Russian 
2. Cognitive impairment resulting in inability to provide informed consent based on research 
assessor (RA) assessment 
3. Pregnancy, planning to become pregnant, or breastfeeding 
4. ART use in past 30 days prior to hospitalization  


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5. Acute severe psychiatric illness (i.e. ,answered yes to any of the following: past three month 
active hallucinations; mental health symptoms prompting a visit to the ED or hospital; mental 
health medication changes  due to worsening symptoms; presence of suicidal ideations) 
6. Known history of liver failure 
7. Known hypersensitivity to naltrexone 
8. ALT or AST >5 times the upper limit of normal ((ALT > 225 for men and 170 for women; AST > 
185 for men and women) 
9. Known severe thrombocytopenia (<50K) 
10. Known coagulation disorder/taking anticoagulation medications 
11. Body habitus that precludes intramuscular injection (e.g., BMI < 17 or >45) 
12. Known hypersensitivity to naloxone  
13. Known history of Raynaud’s disease  
14. Known history of Itsenko-Cushing syndrome 
15. Known history of generalized mycoses 
16. Known history of glaucoma 
17. Known history of osteoporosis. 
18. Planned surgeries in the next 12 months  
 
2.8 RECRUITMENT GOALS  
 
We aim to randomize 240 participants over 30 months into the trial. Three to five days after City 
Addiction Hospital (CAH) admission and treatment for withdrawal symptoms, patients who have typical 
stays of 1 to 2 weeks will be recruited. This strategy will allow time to obtain HIV results (if not known), 
determine eligibility, obtain informed consent, perform baseline assessment, randomize, and, if 
applicable, schedule and conduct the 1st HIV case manager intervention session, conduct the naloxone 
challenge, and receive injectable naltrexone. This research study will focus on people who inject drugs 
(PWID), who comprise >90% of the CAH HIV-positive population. 
In addition to the 240 RCT participants, we will also recruit up to 50 providers and administrators from 
HIV and narcology care systems to participate in a survey at study launch and up to 26 providers to 
participate in in-depth interviews at study launch and 12, and 24-months post-launch (plus short 
surveys) to explore their perspectives and experiences with care coordination between the narcology 
and HIV care systems.  


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A subset of LINC-II participants (at each time point n=10; 5 from intervention group, 5 from control 
group for a total n of up to 30 with 15 participants from each study arm) will also be invited to participate 
in in-depth interviews to discuss their experiences with care coordination at baseline, 6- and 12-months 
post enrollment.  
 
2.8.A. SAMPLE SIZE CALCULATION AND POWER 
 
We provide power calculations for the key hypotheses to be tested in this RCT. Sample size calculations 
assume an alpha level of 0.05 and 240 patients enrolled into the trial.  
Aim 1: primary study outcome, undetectable viral load at 12-months post randomization: Based 
on data from the LINC study, we expect 10% of controls will have undetectable viral load at 12 months. 
Given this and assuming 20% loss to follow-up (i.e., 192 evaluable subjects) the study will have 80% 
power to detect an absolute difference of 17% (i.e., 27% vs. 10% in the intervention and control arms, 
respectively) using a chi-square test with continuity correction. We anticipate larger effects may be 
observed in our study, which would result in even higher power. 
Aim 1: secondary study outcome, retention in HIV care (within 12 months): Because this secondary 
outcome will be assessed using medical records, we expect loss to follow-up to be minimal and estimate 
10% loss to follow-up due to death and subject withdrawals. Based on data collected from LINC, we 
expect 20% of controls will attend 2 appointments in 12 months. Based on these assumptions and with 
216 evaluable subjects, the proposed study has 80% power to detect an absolute difference of 19% (i.e., 
39% vs. 20% in the intervention and control groups, respectively) in the proportions retained in HIV 
care, based on a chi-square test with continuity correction. 
 
3. INTERVENTION 
 
3.1 INTERVENTION OVERVIEW 
 
 
The study will randomize 240 HIV+ persons with injection drug use. Participants will be recruited from 
St. Petersburg City Addiction Hospital (CAH), an inpatient narcology hospital in St. Petersburg, Russia. 
Three to five days after City Addiction Hospital (CAH) admission and treatment for withdrawal 
symptoms, patients who have typical stays of 1 to 2 weeks will be recruited. 
After consent and enrollment, participants will be randomly assigned to either the LINC-II intervention or 
standard of care. Following randomization, participants in the intervention arm will receive one 
intramuscular gluteal injection of 380 mg of naltrexone for extended-release injectable suspension at 
CAH. Since naltrexone can precipitate withdrawal in participants with a physiological dependence on 
opioids, participants will be given a naloxone challenge prior to receiving naltrexone, as per the protocol 
used by Dr. Krupitsky’s research team on previous research studies. The challenge is done by 
administering 0.8-mg naloxone slowly by IV or IM, and if no withdrawal symptoms occur within 5-20 


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minutes (depending on whether it was administered IV or IM) the absence of physiologic dependence is 
confirmed.  At this point the patient is started on study medication. If participant fails the naloxone 
challenge, it will be repeated the next day.  
Following CAH discharge, participants will come to PSMU to receive a 1000mg dissolvable naltrexone 
implant (IN) at four time points (ideally weeks 4, 16, 28, and 40), unless the participant relapsed. Relapse 
will be examined by self-report, evidence of fresh puncture marks, signs and symptoms of withdrawal or 
intoxication, and a urine drug screen that must be negative for opioids before receiving an implant. Seven 
to eleven days after the implant, participants will again come to PSMU for removal of stitches, and an 
inspection of the implant site. 
Participants randomized to the intervention arm will also be assigned a case manager for 12 months. The 
first LINC-II CM session will be held at the City Addiction Hospital following randomization; the second 
session will be scheduled to take place at the City AIDS Center and subsequent sessions can occur at any 
location of preference, or via phone if necessary. LINC-II will offer SMS messaging between sessions to 
reinforce the CM-patient relationship and contact.  
Participants randomized to the intervention arm will have rapid access to ART at their first HIV visit, 
given that as of 2016, CD4 cell count no longer determines timing of ART initiation in Russia. Participants 
in this study will receive streamlined access to ART through a City AIDS Center infectionist who also sees 
patients at the City Addiction Hospital. The infectionist will facilitate initiation of ART medications either 
while the patient is still hospitalized at the City Addiction Hospital, or at their first visit to City AIDS 
Center following CAH discharge. CMs will work with study participants to arrange for the visit to the City 
AIDS Center (to initiate ART, if not initiated at CAH, or to get the second refill) and will be available to 
accompany participants to this visit. Once the initial HIV visit is made, participants will be able to receive 
follow up care and medication refills at their local HIV outpatient clinic. 
Throughout the course of the study, participants will be expected to participate in three in-person 
assessments and blood draw visits (baseline, 6- [24 weeks], and 12 [52 weeks]-months). Intervention 
participants will receive 4 naltrexone implants while in the study. Ideally, implants will be inserted every 
10-12 weeks starting at week 4 post-study enrollment (weeks 4, 16, 28, 40). Participants will be invited 
to come in every 4 weeks following implantation for medication visits. Ideally, medication visits will 
occur at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. Full study assessments occur at weeks 24 
and 52 (in addition to medication visit procedures). Implant visits 2, 3, and 4 will involve the collection of 
blood for laboratory testing to monitor liver toxicity.  
In addition to the 240 RCT participants, we will also recruit providers and administrators from HIV and 
narcology care systems to participate in surveys and in-depth interviews at study launch and 12, and 24-
months post-launch to explore their perspectives and experiences with care coordination between the 
narcology and HIV care systems. A subset of LINC-II participants will also be invited to participate in in-
depth interviews to discuss their experiences with care coordination at baseline, 6- and 12-months post 
enrollment. 
 
 


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3.2 RANDOMIZATION 
 
Randomization will be stratified based on one factor that could relate to study outcome: ever ART use. 
Blocked randomization using random block sizes will be used within each stratum. A computer-
generated randomization table will be created to allow randomization to occur via a custom web-
application. 
 
 
3.3 INTERVENTION 
 
The LINC-II intervention is comprised of 3 main components: strengths-based HIV case management, 
rapid ART initiation, and pharmacotherapy for opioid use disorder. 
 
3.3.A STRENGTHS-BASED CASE MANAGEMENT 
LINC-II is a behavioral and structural intervention that uses a strengths-based case management 
approach in which a trained case manager (CM) meets individually with patients to motivate them to 
engage in HIV medical care by supporting the recognition of their own strengths to make positive 
changes in their lives and ultimately improve their HIV outcomes.1 This approach is grounded in Social 
Cognitive Theory,2 offering psychoeducational support and counseling to increase knowledge of benefits 
of HIV care services and to build comfort and self-efficacy to acquire those services. It also uses 
Psychological Empowerment Theory,3 supporting patients to recognize their strengths and capacities to 
improve their health and circumstance.  
The CM serves as a coordinator between the narcology and HIV systems of care, utilizing HIV strengths-
based case management delivered via 10 one-on-one sessions by a peer case manager (i.e., HIV-positive 
man or woman in recovery from addiction) over a 12-month period to help motivate and reduce barriers 
to HIV care. The first LINC-II CM session will ideally be held at the City Addiction Hospital following 
randomization; the second session will be scheduled to take place at the City AIDS Center. Sessions will 
be planned to occur with approximately 3-6 weeks between sessions, with a goal of 5 sessions for every 6 
months of intervention, for a total of 10 sessions. Following session 2, subsequent sessions can occur at 
any location of preference, or via phone if necessary.  
The first two sessions will consist of ascertaining the patient’s psychological and resource-related 
strengths and developing goals related to obtaining HIV care, as well as discussing with the patient the 
most recent CD4 count and HVL and the benefits of regular HIV care.  
Follow-up sessions will reinforce prior sessions, reviewing previously set goals and patients’ strengths 
and creating new goals as needed.  
All sessions will be audiorecorded for quality assurance purposes. Case Manager will use discretion to 
turn the recorder off if participant feels uncomfortable disclosing certain sensitive information, and will 


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turn it back on as soon as possible. Audiorecordings of case management sessions will be deleted seven 
years after the completion of study analyses and publication of all study manuscripts. 
LINC-II will also offer SMS messaging between sessions to reinforce the CM-patient relationship and 
contact. SMS will be sent to participants, encouraging them to contact their CM if they so wish. 
Participants can either exchange SMS or have their CM call for additional support when needed, for 
example in a craving crisis. SMS will be sent in-between in-person sessions (i.e., every two weeks to start) 
and case managers will be able to adjust the schedule as needed. The standard script below will be used.   
“Hi this is NAME OF CM. Just checking in on how you are doing and whether I can help you with any 
appointments or care. Would you like to speak about this? If yes, please SMS or call me at this number. 
Stay well!” 
“Добрый день! Это (имя КМ). Как дела и нужна ли помощь в назначении визита к врачу или по 
другим вопросам? Если это надо обсудить, то позвоните мне или напишите смс. До свидания.” 
Process Evaluation Components 
Form 
 
Who 
Completes 
Form  
When is Form 
Completed 
Type of 
Form 
Purpose of 
Form 
How Is Data Processed 
 
 
 
 
 
 
1. Case Manager 
Checklist 
(Intervention 
Sessions 1 – 10) 
and brief tracking 
form 
Case 
Manager 
 
During Each 
Intervention 
Session and 
immediately after 
EVERY contact 
with every 
participant 
Electronic  
Quality control to 
ensure all 
activities are 
covered in each 
session  
Record # of 
contacts with 
Case Manager 
Reviewed by Russian 
coordinator and Case 
Manager Supervisor; 
Feedback provided to 
CMs in meetings; 
Update provided to US 
Team in Monthly 
Meetings   
Used to measure dose 
of intervention; Case 
Manager Supervisor to 
review report to ensure 
that forms are being 
filled out and that 
intervention sessions 
are occurring 
 
 
 
 
 
 
2. Case Manager 
Clinical Records – 
case notes 
Case 
Manager  
Immediately after 
EVERY contact 
with every 
participant 
Electronic 
 
Data is used by Case 
Manager Supervisor for 
clinical supervision; will 
not be evaluated for 
research 


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3. Participant 
Satisfaction 
Survey – 
Intervention and 
Control 
Participant  
Self-administered 
on computer as 
part of the 6 and 
12 month interview 
Electronic 
(part of the 
assessment) 
Participant 
satisfaction with 
(response to) 
case managers 
and case 
management 
linkage to HIV 
care  
Prevalence data used 
for reports  
 
 
 
 
 
 
4. LINC Case 
Manager 
Observer Form  
 
Case 
Manager 
Supervisor  
 
Each CM will have 
their audiotapes 
reviewed/observed 
for the first 3 
sessions and then 
10% of cases after 
that.   
Electronic  
Quality 
assurance to 
ensure 
adherence to 
curriculum and 
CM skill 
Data run every 3 months 
to review fidelity; 
Data team to generate a 
list of study IDs for 
review.  
Case Manager 
Supervisor to listen to 
sessions weekly and to 
provide feedback to 
interventionists in 
individual or group 
meetings every two 
months. 
 
 
 
 
 
 
5. CM Evaluation 
of Intervention 
Form 
Case 
Managers   
 
Every 3 months 
subsequent to 
implementation 
start 
Electronic  
Feasibility of 
replication, how 
useful and 
beneficial is the 
program, how 
easy is it to 
implement 
Reviewed by Case 
Manager Supervisor; 
Feedback provided to 
Interventionists in 
individual/group 
meetings; Update 
provided to US Team in 
Monthly Meetings   
 
 
3.3.B. RAPID ACCESS TO ART  
With all HIV-positive individuals now eligible for ART in Russia, regardless of CD4 count, participants 
randomized to the intervention, will have rapid access to antiretroviral medications. Rapid access to ART 
will be facilitated by the infectionist (HIV physician) employed by the City AIDS Center, who sees patients 
at the St. Petersburg CAH. All participants will meet with the infectionist and have their blood drawn for 
CD4 and HVL testing. The infectionist will order a blood draw for HVL and CD4 for all participants. The 


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blood will be sent to CAC for testing. All ART initiation requests in St. Petersburg must be approved by a 
special committee at the City AIDS Center. For participants randomized to the intervention group, the 
infectionist will streamline this approval with the ultimate goal of starting participants on ART while they 
are still hospitalized at CAH. If participant remains hospitalized at CAH at the time of ART approval, the 
infectionist will deliver the first set of medications (1-month supply) to the patient at CAH. Case Manager 
will help schedule the subsequent visit to the AIDS Center in 1 month to pick up the next refill of 
medication. If a participant is no longer admitted at CAH, CM will help patient schedule his or her visit to 
CAC as soon as possible, where the first set of medications will be provided. Once the initial visit to City 
AIDS Center is made, participants can continue HIV care at one of two possible sites: St. Petersburg AIDS 
Center or their local HIV outpatient clinic, and all subsequent ART refills can be picked up at a local clinic.   
 
3.3.C. PHARMACOTHERAPY FOR OPIOID USE DISORDER 
 
Procedures at CAH – Injectable Naltrexone and Naloxone Challenge 
Participants in the intervention arm will receive one intramuscular gluteal injection of 380 mg of 
naltrexone for extended-release injectable suspension at CAH. Since naltrexone can precipitate 
withdrawal in participants with a physiological dependence on opioids, participants will be given a 
naloxone challenge prior to receiving naltrexone, as per the protocol used by Dr. Krupitsky’s research 
team on previous research studies (e.g. Adherence to HIV Therapy in Heroin Addicts: Oral vs. Extended 
Release Naltrexone study). The challenge is done by administering 0.8-mg naloxone slowly by IV or IM, 
and if no withdrawal symptoms occur within 5-20 minutes (depending on whether it was administered 
IV or IM) the absence of physiologic dependence is confirmed.  If the participant fails the naloxone 
challenge, it will be repeated the next day. The naloxone challenge will only be administered if the 
participant’s urine is negative for opioids. The procedures for the naloxone challenge and Vivitrol 
injection will be facilitated and administered by the participant’s treating narcologist and nurse at CAH.  
Naloxone Challenge Risks 
Discomfort during the naloxone challenge will occur if the participant is physically dependent on opioids. 
Naloxone can induce opioid withdrawal, such as feeling sick, stomach cramps, muscle spasms, feelings of 
coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes, and insomnia. If 
participants have withdrawal after the naloxone test, their symptoms may be treated with clonidine or 
phenazepam and are not anticipated to last more than 45-60 minutes.   
In the unlikely situation that emergency treatment is needed, participants may be treated with clonidine 
[75-150 ug] or diazepam [5 mg].  
The most frequent side effects (which appear to be dose-related) of clonidine are dry mouth, 
occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; 
constipation and sedation, each about 10 in 100. 


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The following less frequent adverse experiences have also been reported in patients receiving 
clonidine tablets, but in many cases patients were receiving concomitant medication and a causal 
relationship has not been established: fatigue, fever, headache, pallor, weakness, and withdrawal 
syndrome. Also reported were a weakly positive Coombs test and increased sensitivity to alcohol, 
bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, 
junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, 
palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and 
atrioventricular block have been reported, both with and without the use of concomitant digitalis, 
agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), 
insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, 
sleep disorder, and vivid dreams or nightmares, alopecia, angioneurotic edema, hives, pruritus, 
rash, and urticaria, abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient 
abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic 
pseudo-obstruction), salivary gland pain, vomiting, decreased sexual activity, difficulty in 
micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention, thrombocytopenia, 
gynecomastia, transient elevation of blood glucose or serum creatinine phosphokinase, weight 
gain, leg cramps and muscle or joint pain, dryness of the nasal mucosa, accommodation disorder, 
blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes. 
The most frequent side effects of phenazepam use are drowsiness, sedation, muscle weakness, and 
ataxia. These side effects generally decrease on continued administration and are a consequence 
of CNS depression. 
Less frequent effects include vertigo, headache, confusion, depression, slurred speech or 
dysarthria, changes in libido, tremor, visual disturbances, urinary retention or incontinence, 
gastrointestinal disturbances, changes in salivation, and amnesia. Some patients may experience a 
paradoxical excitation, which may lead to hostility, aggression, and disinhibition. 
Jaundice, blood disorders and hypersensitivity reactions have been reported rarely. Raised liver 
enzyme values have occurred. 
Procedures at Pavlov – Implantable Naltrexone and Naloxone Challenge 
At this point the participant is started on study medication. Following CAH discharge, participants will 
come to PSMU to receive a 1000mg dissolvable naltrexone implant (IN).  Participants will receive 4 
naltrexone implants while in the study. Ideally, implants will be inserted every 10-12 weeks starting at 
week 4 post-study enrollment (weeks 4, 16, 28, 40), unless the participant relapsed. Relapse will be 
examined by self-report, evidence of fresh puncture marks, signs and symptoms of withdrawal or 
intoxication, and a urine drug screen that must be negative for opioids before receiving an implant. 
Participants will undergo a naloxone challenge at study visits during which the naltrexone implant is 
inserted and only if the participant’s urine is opioid-free. If participant does not pass the naloxone 
challenge due to relapse, they will be referred to detox and will be invited to return upon completion of 
that treatment for a repeat naloxone challenge. Naltrexone implantation is an outpatient procedure to be 
conducted on site by a surgeon with the assistance of a study nurse. The implant will be inserted under 
the skin in the abdomen through a 1cm incision. The site will be treated with a local anesthetic prior to 


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insertion. The implant site will be inspected 7-11 days later when the participant returns for removal of 
sutures. Participants will receive discharge instructions to help care for the insertion site at home.  
Details on the procedure are presented at the end of this section.  
Medication Risks 
The most serious risk of naltrexone (both implant and injection) is the potential for hepatocellular injury 
when taken in excessive doses (the margin of separation between the apparently safe dose of naltrexone 
and the dose causing hepatic injury may be only five-fold or less). Harm is less likely at the dosage 
provided in this study. In alcohol dependence trials, liver enzymes that are initially elevated (likely due to 
excessive alcohol use) decreased in participants taking naltrexone.4 As a precaution, participants will 
have ALT and AST repeated at implant visits 2,3, and 4, and if either liver enzyme is >5 times the upper 
limit of normal, results will be shared with participant during their suture removal visit and a repeat test 
will be done during their next medication visit. If any repeat test result is again >5 times the upper limit 
of normal, or if a patient is symptomatic (e.g. fatigue, anorexia, jaundice, nausea, vomiting, dark urine, 
light stool, abnormal pain), the patient will be referred to a hepatologist for further evaluation and a 
recommendation about continuing study medication. We expect this situation to be rare or non-existent 
based on prior experience with naltrexone.  These precautions, combined with frequent contact with 
study staff, will provide thorough monitoring and appropriate response if evidence of liver damage 
emerges in the course of the study. 
Normal ranges: 
AST: Male: to 38 units/L; Female: to 32 units/L 
ALT: Male: to 41 units/ L; Female: to 31 units/L 
Exposure to naltrexone can precipitate severe withdrawal if the participant is physiologically dependent 
on opioids. To avoid unintended withdrawal, participants will be given a naloxone challenge prior to 
starting naltrexone, as described earlier.   
Though data from the Lucey et al study (2008) using injectable naltrexone showed no effect of 
nonsteroidal anti-inflammatory drugs (NSAIDs) in patients taking naltrexone,5 other studies have shown 
that non-steroidals taken with naltrexone can increase the chances of liver damage. As a precaution, 
participants will be warned of this possibility and advised to take NSAIDs only if necessary, and to take 
low doses if use of these medications is necessary. Non-steroidal use will be recorded so that the 
potential for such interactions can be evaluated. 
There is also the possibility that participants will experience side effects from the antiretroviral 
treatment that they receive as a result of participating in HIV care. The fact that naltrexone is metabolized 
by extra hepatic sites suggests that interactions with antiretroviral medications are unlikely, though the 
possibility for interactions at the level of excretion by the kidneys or other sites exists since no studies 
have been done to examine them. The effect of naltrexone on HIV replication is unknown, though a study 
done by Xu Wang et al did not find an increase in viral replication associated with naltrexone.6 If adverse 
interactions occur, they are likely to be detected quickly since patients will be seen monthly and tested 
for viral load, CD4 count, and liver enzymes at specified intervals.  


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If a participant chooses to try to override the opioid blockade with high doses of illicit opioids, s/he risks 
potentially fatal overdose. Also, after a course of naltrexone treatment, the participant may be more 
sensitive to opioids, which, again, if used, could lead to overdose. These possibilities will be explained to 
participants in the consent form.   
The most common side effects of injectable naltrexone are a reaction at the injection site (could be pain, 
tenderness, swelling, redness, and/or itching) and nausea. Other common side effects are: headache, 
fatigue, dizziness, vomiting, decreased appetite, painful joints and muscle cramps. 
Other common adverse effects of injectable naltrexone (>5%) versus placebo, respectively, include 
nausea (33% vs 11%), vomiting (14% vs 6%), decreased appetite (14% vs 3%), headache (25% vs 18%), 
dizziness (13% vs 4%), asthenia (e.g. malaise and fatigue 23% vs 12%), anxiety (12% vs 8%) and 
depressive symptoms (8% vs 4%). Additional risks are injection site reaction (including pain, tenderness, 
induration, swelling, erythema, bruising or pruritis), joint pain/stiffness (12% vs 5%), and muscle aches 
or cramps (8% vs 1%). These effects are generally mild and are responsive to dose reductions and/or 
symptomatic therapies. Any injection site reaction (vs placebo) occurred in 69% vs 50%, but pruritis 
occurred in 10% vs 0%, nodules/swelling 15% vs 4%, pain 17% vs 7%, induration 35% vs 8%. 
The most common side effect of the implant is mild/moderate local irritation, including pain, redness, 
swelling, bruising, or infection, lasting 2-3 days. A low dose of triamcinolone is part of the implant 
formulation to minimize this risk and local irritation has not been a significant problem. Precautions 
taken to minimize the risk of infection include having a physician insert the implant using sterile 
disposable equipment in a room used only for phlebotomy and minor surgery with thorough cleaning of 
the site before and after the procedure. 
The small dose of triamcinolone added to the naltrexone implant to prevent inflammation has not been 
associated with complications. 
Other potential side effects of implantable naltrexone are: loss of appetite, nausea, vomiting, diarrhea, 
constipation, abdominal pain, liver dysfunction, tachycardia, hypertension, phlebitis, headaches, 
weakness, sleep disorder, anxiety, giddiness, depression, dysphoria, runny nose, coughing, difficulty with 
breathing, edema, acne, itching, retardation of ejaculation, decreased potency, increased or decreased 
libido, shivering, tremor, joint pain, local aseptic inflammation, increase of lymphatic nodes, relapse of 
hemorrhoids. 
For implantable naltrexone, non-surgical side effects were documented among patients who remained in 
treatment and were reported in 15.7% of the patients in the implant group, 3.9% of the patients in oral 
naltrexone group (p<0.01), and 6.9% of the patients in placebo group (no significant difference to other 
groups). The most common adverse events were abdominal discomfort, nausea, and drowsiness; none 
required any medication for treatment. 
The proportion of surgical adverse events (i.e., wound infections or local site reactions) with the number 
of patients as denominator were significantly higher in naltrexone implant group: 10.8% compared to 
1.0% in the placebo group (p=0.02) and 1.0% in the oral naltrexone group (p=0.002). 
The following serious adverse events of lidocaine have been most commonly reported:  


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Central nervous system: lightheadedness, nervousness, apprehension, euphoria, confusion, 
dizziness, drowsiness, ringing in the ears, blurred or double vision, vomiting, sensations of heat, 
cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and 
arrest. 
Cardiovascular system: slow heart rate, low blood pressure, cardiovascular collapse, which may 
lead to cardiac arrest. 
Allergic reactions: skin lesions, rash, edema. Allergic reactions as result of sensitivity to lidocaine 
hydrochloride are extremely rare. 
Naltrexone Implant Procedure 
1. Naloxone Challenge - observe for signs of withdrawal  
2. Local Anesthesia  
a. Wash hands with antimicrobial soap  
b. Apply antimicrobial handcream  
c. Apply non-sterile gloves  
d. Cleanse skin with antimicrobial wipe  
e. Cleanse skin with isopropyl alcohol  
f. Inject area with 2% lidocaine 5cc syringe with a 25g x Ѕ" needle under ~ 1" of skin  
3. Pellet insertion  
a. Apply antimicrobial handcream  
b. Apply non-sterile gloves  
c. Open packet of sterile supplies  
d. Prepare Area with 3 sterile betadine swabs  
e. Apply sterile gloves  
f. Apply sterile drapes  
g. Make ~1cm incision with sterile #15 scalpel  
h. Inject 5cc of 2% lidocaine in 5cc syringe with a 18g x 1 Ѕ" needle through the wound in a 
medial direction anesthetizing a tract through which to insert the pellet insertion device.  
i. Insert sterile pellet within sterile insertion device  
j. Close wound with stitches 


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4. Clean and dress wound  
5. Provide wound care instruction sheet to patient  
 
Implantation Discharge Instructions 
1. Wash hands before touching site. 
2. Keep clear dressing over pellet site for 24 hours. 
3. Pull dressing off after 24 hours. 
4. Clean with soap and water as usual in shower every day. 
5. Make sure stitches stay dry - pat dry after shower. 
6. Pour peroxide over stitches after shower. 
7. Stitches will be removed when you return to Pavlov 7-11 days after implantation.  
For redness or swelling in first 24 hours use ice. May use over the counter pain relievers such as 
Tylenol, Ibuprofen, Naproxen Sodium.  
Bruising may occur on abdomen secondary to numbing medication administration.  
If pellet site bleeds, hold pressure over site. Ice will also help stop bleeding at site.  
If pellet site irritated during working hours - cover with band-aid during day - keep site open to air 
at night (No band-aid).  
Notify office if fever develops, redness or swelling occur, or any discharge occurs.  
Counseling 
Assessors will administer brief counseling (~5 minutes) to participants during the medication visits. The 
brief counseling will be conducted by study RAs (addiction psychiatrists) based on standard clinical 
protocols.   
3.4 CONTROL GROUP  
 
Participants in the control group will receive standard care as normally provided to patients in the 
narcology hospital. This could include detoxification with medications, substance use counseling and 
treatment for comorbid psychiatric conditions, as well as possible inpatient rehabilitation for up to 30 
days. They will also be given printed information, including phone numbers, on places that provide HIV 
medical care and will be referred to outpatient narcology care. Detoxification takes 5-7 days, most 
commonly using clonidine, antidepressants, non-opioid analgesics, hypnotics, and Imodium. Stabilization 
occurs within the same ward, takes 1-2 additional weeks, and includes drug counseling and treatment of 
comorbid psychiatric problems. Upon hospital admission, HIV testing is routinely performed in all 
patients who are not documented to be HIV-positive. Prior to discharge, those identified as HIV-positive 


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are given contact details for an HIV clinic, not an appointment. Upon discharge, patients are encouraged 
to receive outpatient narcology treatment, monthly, for 1 year. If control participants are newly 
diagnosed with HIV infection at the CAH, they will receive HIV post-test counseling consistent with CDC 
recommendations. Participants who visit the AIDS center will be able to receive ART medication 
provided they undergo required pre-ART testing and examinations. Enrollment in the study will not 
preclude participants from receiving any HIV or narcology care that would normally be accessible to 
them. 
3.5 MEDICATION CONSIDERATIONS 
 
3.5.A SYMPTOM MONITORING 
 
The study staff (research clinicians [addiction physicians with extensive experience performing 
pharmacotherapy trials]) have extensive experience administering implantable and injectable 
naltrexone, and specimen collection via prior OUD pharmacotherapy studies. They will be trained to 
assess for adverse medication effects and will follow established protocols for identifying and monitoring 
any ongoing adverse events, including referral to treatment as appropriate. Study participants will be 
actively monitored for adverse events. Symptoms will be monitored every four weeks (and more 
frequently, if necessary) by trained clinical staff, while the participants are administered study 
medications.  
 
3.5.B. DISCONTINUATION OF STUDY MEDICATION 
 
Despite known side effects of naltrexone (both implant and injectable), most people taking the 
medications do not discontinue them due to side effects. Those who discontinue medication will be 
followed and analyzed by intention to treat. 
Participants found to be pregnant during the study will have their study medication (i.e., naltrexone) 
discontinued (including removal of the implant if necessary), but will still be followed-up for the duration 
of the study. Participants who report pregnancy outside of study visits will be requested to come to 
Pavlov for a confirmatory pregnancy test where the need for implant removal will be assessed and the 
implant may be removed if deemed necessary.  
 
3.6 SCHEDULE OF DATA COLLECTION   
Intervention Group  
  
 
Pre-
screen 
Screener and Baseline  
Implant 
visits  
Medication 
Checks  
(every 4 weeks 
post implant) 
6-month 
visit (24 
weeks)  
12 month 
visit (52 
weeks)  


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Screener  
Baseline 
  
  
  
 
Screeni
ng 
Verification of 
HIV, pregnancy, 
AST/ALT 
X 
 
  
  
  
  
 
Screening 
Questions 
  
X 
  
  
  
  
 
Enrollm
ent 
Sign Informed 
Consent  
  
X 
 
  
  
  
 
Complete 
contact 
information/verif
y numbers 
  
  
X 
  
  
  
 
Randomization 
  
  
X 
  
  
  
 
Laborat
ory  
Clinical Values 
  
  
X 
X 
X 
X 
X 
Pregnancy Test 
  
X 
 
X 
X 
X 
X 
Urine Drug Test 
 
 
X 
X 
X 
X 
X 
CD4 
  
  
X 
  
  
X  
X 
HVL 
  
  
X 
  
  
      X 
X 
ALT/AST 
  
  
 
 X 
  
  
 
Assess
ment 
Full Study 
Assessment 
  
  
X 
 
 
X 
X 
Qualitative 
Assessment 
 
 
X 
 
 
X 
X 
Medical Record 
Review 
X 
 
 
 
 
X 
X 
Interve
ntion  
Symptom 
Management/Ad
verse Events  
  
  
X 
X 
X 
X 
X 
Naloxone 
challenge  
 
 
X 
X 
 
 
 
Naltrexone 
Injection 
  
  
X 
 
 
 
 
Naltrexone 
Implant  
 
 
 
X 
 
 
 
Brief Counseling 
  
  
 
X 
X 
X 
X 
Other 
Compensate for 
Participation 
  
  
X 
X 
X 
X 
X 
Provide 
Resource Card 
 
 
X 
 
 
 
 
Report Adverse 
Events 
  
  
X 
X 
X 
X 
X 
Complete 
Tracking Forms 
  
  
X 
X 
X 
X 
X 
 
 
 
 
 


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3.6.A. VISIT WINDOWS 
Research Assessment Windows for Intervention and Control Group  
 
6 Month (24-week) Visit  
• Window open: 120 days post baseline 
• Target date: 180 days post baseline 
• Window close: 270 days post baseline 
• Window length: 150 days 
 
12 Month (52-week) Visit  
• Window open: 271 days post baseline 
• Target date: 365 days post baseline 
• Window close: 455 days post baseline 
• Window length: 184 days 
 
Intervention Group Medication Visit Windows 
 
Implant visits will take place 10-12 weeks apart starting with week 4. Ideally, implant visits will occur 4, 
16, 28, and 40 weeks post enrollment, but we will accommodate the following windows. 
 
 
 
Control Group 
  
Pre-
screen 
Screener and 
Baseline Visit 
6 mo (24 
weeks)  
12 mo 
(52 
weeks)  
  
  
  
Screener  Baseline 
 
 
Screening 
Verification of HIV, pregnancy, AST/ALT 
X 
 
  
 
 
Screening Questions 
  
X 
  
 
 
Enrollment 
Sign Informed Consent  
  
X 
 
 
 
Complete contact information/verify numbers 
  
  
X 
 
 
Randomization 
  
  
X 
 
 
Laboratory  
Clinical Values 
  
  
X 
X 
X 
Pregnancy Test 
 
X 
 
 
 
Urine drug Test 
 
 
 
X 
X 
CD4 
  
  
X 
X 
X 
HVL 
  
  
X 
X 
X 
Assessment 
Full Study Assessment 
  
  
X 
X 
X 
Qualitative Assessment 
 
 
X 
X 
X 
Medical Record Review 
X 
 
 
X 
X 
Other 
Provide Resource Card 
  
  
X 
 
 
Compensate for Participation 
  
  
X 
X 
X 
Complete Tracking Forms 
  
  
X 
X 
X 


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Naltrexone Implant Windows  
 
 
 
 
 
 
 
 
 
 
 
 
Medication visits will take place every 4 weeks following the implant visit, with ideally 2 medication 
visits after each implant 
 
Windows listed above are used as guides for scheduling visits, but early/late visits are expected due to 
participant/laboratory scheduling.  
3.7 DATA SOURCES 
 
3.7.A QUESTIONNAIRES 
 
Questionnaires will be administered at baseline, 6-, and 12-month study visits to collect information 
about participant demographics (e.g., age, gender), general and mental health and health-related 
behaviors such as substance use. 
 
Questionnaires for providers are described in section 5.3 SYSTEM-LEVEL ASSESSMENT OF LINC-II 
IMPACT. 
 
3.7.B. BLOOD 
 
Blood will be collected at baseline, implant visit 2, 3, and 4, and 24 and 52 weeks to assess the following:  
 
1. CD4, HIV-1 RNA 
a. Measured at baseline, 24- and 52-week study visits among control and intervention 
participants. Samples collected at City Addiction Hospital (baseline) and Pavlov University 
(follow-up) are sent to the City AIDS Center for testing. Results from the testing are placed 
in participant medical records at City AIDS Center and provided to the Pavlov University 
research team.  
Weeks 2-9 
Implant Visit 1 
(Week 4) 
Baseline 
Implant Visit 2 
(Week 16) 
Implant Visit 4 
(Week 40) 
Implant Visit 3 
(Week 28) 
Weeks 10-21 
Weeks 22-33 
Weeks 34-46 
12-Month 
 
 
 
 
 
Study Timeline 
(52 Weeks) 


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i. If CD4 and HVL results are already available at the City AIDS Center within the 24- 
and 52-week visit windows, a new study test will not be conducted and existing 
results will be used.    
ii. If recent (within one month) CD4 and HVL results are available at the City AIDS 
Center, a new baseline study test will not be conducted and existing results will be 
used. 
iii. If a participant is unable to provide blood during their 6 or 12 month study visit and 
does not have a blood draw scheduled at the City AIDS Center within the study visit 
window, we will take the following approach: 
1. Control group: Participant will be invited to come in for a second blood draw 
attempt in 4 weeks. Participants will receive compensation in the amount of 
500 rubles to cover costs associated with traveling to the laboratory.  
2. Intervention group: A second attempt at a blood draw will be made in 4 
weeks (at their scheduled 28 week medication visit or after the completion of 
the 12 month visit). At the 28-week visit, participants will receive planned 
compensation for attending the medication visit but will not receive 
additional compensation for the blood draw. For the second attempt after the 
12 month visit, participants will receive compensation in the amount of 500 
rubles to cover costs associated with traveling to the laboratory. 
iv. If a participant is unable to provide blood during their 6- or 12-month study visit 
due to COVID-19 restrictions and does not have a blood draw scheduled at the City 
AIDS Center within the study visit window, we will take the following approach: 
1. Control group: Participants will be invited back to Pavlov for a blood draw 
once restrictions are lifted. Participants will receive compensation in the 
amount of 500 rubles to cover costs associated with traveling to the 
laboratory.  
2. Intervention group: A blood draw attempt may be made during a medication 
check-in visit, if one is scheduled. In which case, participants will receive 
planned compensation for attending the medication visit but will not receive 
additional compensation for the blood draw. If a blood draw does not take 
place during a scheduled medication visit, or if no visit is scheduled, 
participants will be invited to come to Pavlov once restrictions are lifted. For 
the blood draw attempt outside of their scheduled visit, participants will 
receive compensation in the amount of 500 rubles to cover costs associated 
with traveling to the laboratory. 
v. If CD4 and HVL results are available in participant’s medical chart at the CAC, we 
will enter them as part of the Chart Review process.  
2. AST, ALT 
a. AST/ALT will be measured only among intervention participants during implant visits 2, 3, 
and 4 to assess liver toxicity. 
3. HIV Antibody Test  
a. If a participant has an undetectable HIV viral load at baseline, an HIV antibody test will be 
conducted during their next study visit to verify their HIV status. 


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3.7.C. URINE 
A pregnancy test will be administered by trained clinical research staff to all participants at screening and 
at each study visit for intervention participants. Pregnant women will be excluded from the study due to 
some reports suggesting possible adverse events with study medications. Participants found to be 
pregnant may have their implant removed but will still be followed-up for the duration of the study. For 
these participants the naltrexone implant will be removed (if removal is indicated) by clinical staff at 
Pavlov.  
Urine will also be used to conduct urine drug testing on all intervention participants at all study visits and 
for control participants at the 6 and 12-month study visits. Urine drug tests must be negative for opioids 
before participants can receive the implant.  Urine toxicology will test for a range of opioids, specifically 
opiates (products of the poppy plant – morphine, heroin, codeine) and synthetic opioids (specifically 
methadone). If new opioids appear on the scene in Russia, such as fentanyl, then we will begin testing for 
this, but currently that is not thought to be an issue. 
3.7.D. MEDICAL RECORD REVIEW  
Medical chart review will be utilized to obtain HIV and addiction care and treatment history. Medical 
records will be reviewed at screening, 6- and 12-months. All LINC-II participants’ medical records will be 
reviewed including those who have withdrawn from the study unless participant refuses future chart 
review at the time of withdrawal. The timeframe of the chart reviews for the withdrawn participants will 
be done one time at the conclusion of the 12-month study window. At the time of withdrawal, research 
assessor will ask permission to continue to perform chart review at the City AIDS Center and document 
this permission on the Study Conclusion Form.  
 
 
4. STUDY PROCEDURES 
4.1 RECRUITMENT 
 
Participants enrolled in Linking Infectious and Narcology Care – Part II (LINC-II) study will be recruited 
from St. Petersburg City Addiction Hospital (CAH), an inpatient narcology hospital in St. Petersburg, 
Russia.  
Qualitative assessment:  
In addition to the 240 RCT participants, we will also recruit providers and administrators from HIV and 
narcology care systems to participate in surveys and in-depth interviews at study launch and 12-and 24-
months post-launch to explore their perspectives and experiences with care coordination between the 
narcology and HIV care systems. The assessment will consist of a short survey and a qualitative 
interview. At study launch, all available providers and administrators from the CAH and CAC will be 


LINC-II Protocol  
 
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invited to participate in the short survey (approximately 50 participants). A subset of 
providers/administrators will be invited to participate in a qualitative interview, more specifically, we 
will aim to interview the following from each care system: 1 administrator, 3 doctors, 1 social worker or 
other frontline staff. Twelve and 24 months post study launch a subset of providers and administrators, 
who have been exposed to the LINC-II study, will be invited to participate in the survey and a qualitative 
interview. We aim to survey and interview the following from each care system: 1 administrator, 2 
doctors, 1 social worker or other frontline staff. An effort will be made to ensure that the qualitative 
assessment is representative of the whole sample in terms of provider experience, such that we would 
like 50% of the providers to be “junior” (less than 10 years of experiences) and 50% to be senior (>10 
years of experience). We will keep a record of the total number of participants who declines and the 
reasons for declination. Providers and administrators will be approached by a research assessor at their 
place of employment (HIV or narcology care location) and invited to participate in the survey and 
interviews.  
A subsample of LINC-II patient participants (n=30) will be purposively selected by research assessors, 
based on their comfort and capacities to discuss HIV and/or narcology systems of care, to participate in 
in-depth interviews and to ensure representation of a variety of potentially relevant characteristics such 
as gender and duration of HIV infection. We will select 15 from each arm (5 at each time point: baseline, 
6-months, 12-months) to ensure equal representation of control and intervention participants. LINC-II 
participants will be invited to participate in the qualitative component of the study following their 
baseline and follow up study interviews. Study staff will be trained to identify participants who are 1) 
willing and able to communicate appropriately in an interview; and 2) insightful about structural issues 
around narcology and HIV care. At follow up, only participants who reported having an HIV care visit in 
the past 6 months during the study interview are eligible to participate in the qualitative interview. We 
will also monitor recruitment of participants into the qualitative component to ensure that we have 
representation of the whole sample in terms of gender (roughly 2 women and 3 men at each time point). 
We will also keep a record of the total number of participants who decline and the reasons for 
declination. The interview will occur a day or two after their baseline visit (while the participant is 
hospitalized). Efforts will be made to interview participants from the intervention group after the first 
case management session has taken place .Once participants are recruited and consent to study 
participation, they will be assessed in a private location by research staff trained in qualitative methods. 
Interviews at 6 and 12 months will take place at Pavlov State Medical University. 
Qualitative In-Depth Interviews in LINC-II 
 
Baseline, study 
launch 
6 months 
12 months 
24 months post 
launch 
Total 
Participants 
5 intervention 
5 controls 
5 intervention 
5 controls 
5 intervention 
5 controls 
 
30 
Providers 
2 admins (1 
narcology, 1 HIV) 
3 narcologists 
3 infectionists  
2 frontline cadre (e.g., 
nurse, social worker) 
 
2 admins (1 narcology, 
1 HIV) 
2 narcologists 
2 infectionists 
2 frontline cadre  
2 admins (1 narcology, 
1 HIV) 
2 narcologists 
2 infectionists  
2 frontline cadre 
26 
 


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4.2 SCREENING 
 
Recruitment will take place at two or more departments of the City Addiction Hospital where the 
admissions department directs patients who have HIV and an Opioid Use Disorder. To assist the team in 
understanding patient flow, admissions department staff will provide the team with information on the 
number of patients admitted to CAH who have HIV and an Opioid Use Disorder (OUD) out of the total 
number of admissions.  All HIV-positive patients with an OUD admitted to the 
detoxification/rehabilitation departments where study staff are based at the City Addiction Hospital are 
eligible for screening. Patients will be screened three to five days after admission to the narcology 
hospital and after treatment for most severe initial withdrawal symptoms.  
Screening for the LINC-II study will take place in two steps: 1) a pre-screen conducted through chart 
review and 2) in-person screening of participants who are eligible following the pre-screen.  
Pre-screening will be conducted by narcologists (Addiction Physicians) within the department. They have 
access to medical charts and will be trained on the research protocol by the Russian and US study 
investigators. The narcologist will search in the electronic study system for the name of the patient prior 
to screening him/her for the study to see if the patient has been previously enrolled in LINC-II. This is to 
prevent double randomization. If the name does not appear in the system, the narcologist will proceed 
with pre-screening procedures. If HIV status is unknown in the medical record, the narcologist will wait 
until test results conducted at the narcology hospital are completed. 
Research Assessors (RAs) who are Addiction Hospital staff (psychologists not involved in the patient’s 
care) will be conducting the in-person screening process. If a patient is identified by the narcologist as 
meeting criteria based on chart review, the narcologist will notify the RA that the patient in their 
department is available to be screened for the study. RA will be introduced to the patient by the 
narcologist and will then meet with the patient in a private location (e.g. hospital room or exam room) to 
briefly describe the study and conduct in-person screening to confirm the presence of inclusion criteria 
and the absence of exclusion criteria.  We will not write down names and room number of potential 
participants. 
If a patient is sick and/or still in withdrawal when approached for screening, the RA will re-approach that 
person every day (if the person is interested) while the patient is still at the CAH (as in, once the person is 
eligible for screening and/or eligible for the study, they should be enrolled once they are feeling better).  
We will not keep a list of names screened to prevent re-screening. We will include a note in the 
participant’s medical chart that s/he was screened for the study to make sure that s/he is not approached 
again during the same visit.  
Protocol for ensuring double randomization and double enrollment do not occur 


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1. Prior to screening, narcologist must confirm that the patient’s chart does not contain a note that the 
patient was already screened for the LINC-II study during this hospital stay. If such a note has been filed, 
narcologist does not proceed with screening.  
2. Narcologist searches the name of the patient in the LINC-II Tracking Website to confirm that the 
patient has not been previously enrolled in the LINC-II Study. If a match appears, narcologist checks DOB 
and address (this will be done very confidentially, so that the patient does not know that there is 
someone with the same last name already in the study, to protect the confidentiality of the enrolled 
participant). If no match is found, narcologist proceeds with screening. 
 
4.3 INFORMED CONSENT 
 
Research assessors (RA) will conduct the consent process as well as obtain written consent. After 
eligibility and interest in enrollment is determined, an RA will administer and document the informed 
consent of the participant in a private location. If participants are unsure whether they would like to 
participate, they will be allowed any amount of time they need to consider participation in the study. If 
the participant is not able to make a decision on the day of the initial visit, s/he will be invited to contact 
the study team once s/he have made their decision. The study will be explained to eligible participants 
who will be offered participation in the study. Research assessors will answer any questions the patients 
may have including risks, benefits and alternatives (including non-participation) to participation, and will 
provide written materials describing the study. The written informed consent (in Russian), including the 
risks, benefits and alternatives, will be signed and dated by the participant and the research assessors. A 
signed copy of the informed consent will be provided to the participant, and a copy will be maintained by 
the research team. Potential participants will be informed that refusal to participate will not affect their 
medical care in any way and they will be informed of their right to drop out of the study at any time.  
For administrators, providers, and participants invited to participate in in-depth interviews, informed 
consent will be administered by RAs from PSMU in a private location. If participants are unsure whether 
they would like to participate, they will be allowed any amount of time they need to consider 
participation in the study. If the participant is not able to make a decision on the day of the initial visit, 
they will be invited to contact the study team once they have made their decision. The study will be 
explained to eligible participants who will be offered participation in the study. Research assessors will 
answer any questions the participants may have including risks, benefits and alternatives (including non-
participation) to participation, and will provide written materials describing the study. The written 
informed consent (in Russian), including the risks, benefits and alternatives, will be signed and dated by 
the participant and the research assessor. A copy of the informed consent will be provided to participant, 
and a copy will be maintained by the research team. Potential participants will be informed that refusal to 
participate will not affect their medical care or employment in any way and they will be informed of their 
right to drop out of the study at any time. 
 
4.4 VISIT FLOW 
 


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After eligible participants are consented and enrolled, the following will take place at the Baseline visit 
and while participants are still hospitalized at the City Addiction Hospital:  
• Collection of locator/contact information and verify contact phone numbers 
• Collection of clinical data (height, weight, blood pressure)  
• Administration of  assessment questionnaire 
• Randomization  
• Provision of resource card 
• Subset of all participants: In-depth interview  
• Compensation and scheduling next visit  
• Blood draw (CD4, HVL) 
• Intervention procedures (medication procedure, meeting with case manager, ART initiation 
procedures)  
Intervention Group:  
• At the medication visits, the Pavlov RA will perform the following: 
o Review and update locator/contact information, verifying new numbers, as necessary 
o Collect a urine sample to check for pregnancy and conduct drug testing 
o Collect clinical data (weight, blood pressure) 
o Assess opioid use  
o Perform symptom monitoring (including inspection of implant site) and brief counseling  
o Compensate participant and schedule next visit 
 
• In addition to the above, at the implant visits, the Pavlov RA will perform the following: 
o Administer naloxone challenge  
o Provide naltrexone implant 
o Implant visits 2, 3, and 4: send participant for phlebotomy to check ALT/AST levels 
 
• During the 24-, and 52-week assessments, in addition to the medication visit procedures 
described above, the Pavlov RA will: 
o Send participant for phlebotomy (CD4, HVL)  
o Administer assessment questionnaire 
o Subset of all participants: In-depth interview  
Control Group: 
• During the 24-, and 52-week assessments, the Pavlov RA will: 
o Review and update locator/contact information, verifying new numbers, as necessary 
o Send participant for phlebotomy (CD4, HVL), collect clinical data (weight, blood pressure)  
o Administer assessment questionnaire 
o Conduct urine drug test  
o Compensate participant and schedule next visit  
o Subset of all participants: In-depth interview  


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4.5 QUALITY ASSURANCE 
Informed consent quality assurance 
 
The RA will review Informed Consent Forms (ICFs) for completeness with the participant present. Items 
to check will include, but are not limited to: responses/initials collected for all questions, correct version 
of ICF used, signed and dated by both subject and RA. Local Study Coordinator will review all completed 
consent forms weekly and will complete the Consent Form Deviation log if any errors are identified.  
 
Assessment quality assurance 
 
During the assessment, if the participant provides conflicting answers or answers that did not make 
logical sense (either within the same section or between sections), the RA will gently try to help the 
participant arrive at more logical answers. However, the RA will not force the participant to change his or 
her answers. Certain quality assurance checks are built into the assessment. The system will flag any 
inappropriate responses and prevent the RA from continuing until the issue is resolved. The RA will 
review the self-administered section with the participant present. If many “refused” options are selected, 
the RA will offer the participant the opportunity to complete those sections (the RA will accept the 
participant’s refusal if he or she does not wish to complete the section). The RA will never guess to 
correct a mistake. The only instance when a change can be made to the completed assessment is in the 
event that the RA is 100% certain that an error was made in data entry. Local data manager will QC all 
paper forms used for the assessment (i.e., rulers for VAS, TLFB calendar, pain rulers). Upon completion of 
QC of paper forms, the reviewer will write their initials and date of review at the bottom of the forms. 
 
CM intervention quality assurance  
 
We will evaluate fidelity of the intervention through 1) observations of encounters with participants by 
CMs via audiotaped recordings of all sessions, reviewing the first 3 sessions for each CM; and 10% 
thereafter; 2) review of CM session checklists; 3) feedback based on observations and staff meetings, 
provided by the interventionist supervisor, Dr. Toussova, using a strengths-based supervision approach; 
and 4) survey on program satisfaction, completed by the interventionists (every 3 months) and all study 
participants at 6 and 12 months. If concerns between participant and staff arise, reassignment to an 
alternate CM is possible, but efforts will be made to maintain the same CM who initiates contact with each 
intervention participant. Collecting these data will enable quality control by the research team and 
pragmatic feedback for the program staff to maintain high quality and standardization of treatment 
conditions. 
 
4.6 COMPENSATION 
 
Participants will be compensated for their time and travel with 1000 rubles in goods or currency at 
baseline, 500 rubles in cash or goods at medication visits, 1500 rubles at medication visits in which 
implantable naltrexone is inserted, and 2000 rubles for their participation at 24 and 52 week follow-up 


LINC-II Protocol  
 
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visits. Participants who complete phone assessments for the follow-up visits will be compensated 500 
rubles for their participation (this will be offered as a last resort option for 24- and 52-week 
assessments). 
 
In the event that baseline compensation is not received at the City Addiction Hospital due to early 
discharge, it will be provided in full at the next study visit. 
 
If a participant is unable to provide blood during their 6 or 12 month study visit and does not have a 
blood draw scheduled at the City AIDS Center within the study visit window, we will take the following 
approach: 
• Control group: Participant will be invited to come in for a second blood draw attempt in 4 weeks. 
Participants will receive compensation in the amount of 500 rubles to cover costs associated with 
traveling to the laboratory.  
• Intervention group: A second attempt at a blood draw will be made in 4 weeks (at their scheduled 28 
week medication visit or after the completion of the 12 month visit). At the 28-week visit, participants 
will receive planned compensation for attending the medication visit but will not receive additional 
compensation for the blood draw. For the second attempt after the 12 month visit, participants will 
receive compensation in the amount of 500 rubles to cover costs associated with traveling to the 
laboratory. 
 
Providers and administrators will be compensated 500 rubles in goods or currency for completing the 
system-level survey. Participants and providers/administrators will be compensated 1500 rubles for 
their participation in each qualitative interview.   
 
Similar compensation has been used in a previous collaborative Russian-Boston research study and was 
deemed by the PSMU IRB to be an appropriate, non-coercive amount of funds for involvement in a clinical 
research project. 
 
Phone assessments will be completed by participants who are unable to come in to Pavlov due to 
restrictions related to COVID-19. Participants will receive full compensation for these phone 
assessments. Upon the restrictions being lifted, participants will be invited back to Pavlov to complete 6- 
and 12-month blood collection if they did not have a blood draw scheduled at the City AIDS Center within 
the study visit window. Participants will receive full compensation for completing these phone 
assessments. Participants in the control group will receive an additional 500 rubles to cover costs 
associated with traveling to the laboratory. Participants in the intervention group will not receive 
additional compensation for the blood draw if the blood draw takes place during their scheduled visit 
(for which they will already be receiving compensation). For the blood draw attempt outside of their 
scheduled visit, participants will receive compensation in the amount of 500 rubles. 
 
 
4.7 RETENTION 
 
Baseline visit: Retention begins at baseline by ensuring that the participant enjoys the experience of 
participating in the study, by explaining the informed consent and what would happen in the study, and 
by collecting excellent contact information, including both the address where the participant is registered 
and the address where the participant is currently staying.  Participants will be asked to provide contact 
information for 4-5 alternative contacts (although only 2 will be required as per eligibility criteria), who 


LINC-II Protocol  
 
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may know their whereabouts. Alternative contacts can include friends, family members, and social 
workers. Participants will be asked if any of their friends are participating in the study and to include 
them as alternative contacts, if possible. Contact numbers must be verified by calling the numbers with 
the participant present, using the following script:  “I work with a team at Pavlov University. Your 
friend/relative [NAME] is here with me and just enrolled in a study. He/she has listed you as an 
alternative contact. We will only call you if we are having trouble reaching [NAME] to see if you can help 
us connect with them. Today I am just calling to confirm that this number is active.” 
Participants will also be asked for their email address and membership to any social networking 
platforms.  
All visits: Participants will be offered tea, coffee, water, and snacks at each study visit to make their 
experience in the research study more enjoyable. 
RA will offer to help participants add the next scheduled study visit to the calendar in their phone and set 
a reminder in their phone.  
Follow up visits: Contact information for participant and alternatives will be reviewed and updated at 
every visit. 
Other strategies: Participants will be contacted by telephone with appointment reminders and email if 
one is provided. The study team will also utilize social networking to connect with participants. If 
participants are unable to be reached via phone, in addition to attempting to reach them via text 
messaging and email, participants will be sent private messages on Vkontakte (Russian social network) 
utilizing an existing standard script to remind them of their upcoming study visit.  No sensitive 
information will be revealed or ascertained using this method.  
Standard reminder text: This is a reminder that your visit to Pavlov Medical University is scheduled 
for_____at______. Please reply to confirm or call 973-53-96 to reschedule.  
Study participants will be asked to contact the study team if their phone number changes between study 
visits; participants will be compensated 200 rubles in goods or currency for this information. All no-
shows will be followed up to reschedule appointments.  
Transportation will be arranged (i.e., a social taxi or Uber) for participants who are unable to come to 
First St. Petersburg Pavlov State Medical University due to a lack of available transportation.  
 
5. ASSESSMENTS 
5.1 BASELINE ASSESSMENT 
 
The baseline assessment will be conducted immediately following the screening and informed consent. 
The assessment will be interviewer-administered with the exception of sections deemed to ask sensitive 
questions, which will be self-administered by the participant.  
 


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Participants will be assessed as part of this study using validated interview instruments covering the 
following topics: 
• Demographics, modified from the ASI Lite-CF Clinical/Training Version and Addiction Severity 
Index7 
• Opportunistic Infections, using questions adapted from the HIV Cost and Services Utilization Study 
(HCSUS)8  
• HIV Testing and HCV Diagnosis, using the HIV/HCV/STI Testing Status and Organizational Testing 
Practices Questionnaire9 
• Healthcare Utilization, using questions created by the Russian and US teams 
• Barriers to Medical Care 10 
• Perceived Discrimination in Health Care11 
• ART Use and Adherence12, 13 
• Medications 
• Pain Assessments14-16 
• Reproductive Health 
• HIV Sex Risk Behaviors, questions are adapted from the Women’s Health Coop Baseline 
Questionnaire  
• Sexual Partners, created by the US and Russian teams 
• HIV Risk Categories, using questions adapted from the American Red Cross and Navaline et al.17  
• HIV Disclosure, using questions from Stein et al. (1998)18 and Raj et al. (2006)19 
• HIV Stigma, using the Berger et al. HIV stigma scale20 
• Substance Use Stigma21, 22 
• Depressive symptoms through the Center for Epidemiologic Studies Depression Scale (CES-D)23, 24 
• Anxiety by the State Trait Anxiety Inventory (STAI- Short Form)25 
• Partner Violence and Sexual Assault, adapted from the TAJ assessment 
• Tobacco Use, using a shortened modified Fagerstrom Test for Nicotine Dependence26, 27 
• Alcohol Use, via the AUDIT28 
• Opioid use disorder diagnosis via the DSM 5 criteria29 
• Drug use by an adapted version of the Risk Behavior Survey30, 31 
• 30-Day Timeline Followback for Opioid Use32, 33 
• Overdose and Suicide, using adapted questions from Britton et al. (2012)34 
• Social Support, using the harmonized STTR document35, 36  
• VR-12 Health Survey & MOS-HIV37, 38 
• Primary Activity 
• Costs of Illness and Treatment in Last Month 
• Attitudes Toward Care Coordination, using questions from Schang et al. (2013)39 
• Care Continuity, modified from Nijmegen Continuity Questionnaire40 
5.2 FOLLOW UP ASSESSMENTS 
Content of assessments administered at the 6-, and 12- month visits will be subsets of the baseline 
assessment (see table below). Phone assessments will be permitted for 6 and 12 month (24 and 52 


LINC-II Protocol  
 
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weeks) assessments, as a last resort, for participants who are unable to come in-person. Questions about 
COVID-19 will only be asked at one time-point, either the 6- or 12-month assessment. 
 
 
Study Time Point 
Administered Assessment 
Baseline 
Medication 
Check-Ins 
6-
Month 
12-
Month 
Demographics 
X 
 
 
X 
HIV Testing and HCV Diagnosis 
X 
 
 
X 
ART Use and Adherence 
X 
 
X 
X 
Health Care Utilization 
X 
 
X 
X 
Costs of Illness and Treatment in Last Month 
X 
 
X 
X 
Attitudes Toward Care Coordination & Care Continuity 
X 
 
X 
X 
Barriers to Medical Care 
X 
 
X 
X 
Perceived Discrimination in Health Care 
X 
 
X 
X 
DSM-5 Opioid Use Disorder 
X 
 
 
 
Drug Use 
X 
 
X 
X 
TLFB: Opioids  
X 
X 
X 
X 
Tobacco Use 
X 
 
 
 
Alcohol Use: AUDIT 
X 
 
 
X 
Opportunistic Infections 
 
 
X 
X 
Medications 
X 
 
X 
X 
Pain assessment 
 
 
X 
X 
HIV Sex Risk Behaviors and Reproductive Health  
 
 
 
X 
*Sexual Partners 
X 
 
 
X 
*HIV Risk Categories 
X 
 
 
 
*HIV Disclosure 
X 
 
X 
 
*HIV Stigma 
X 
 
 
X 
*Substance Use Stigma 
X 
 
 
X 
*Barriers to Medical Care Part 2 
X 
 
X 
X 
*Depressive Symptoms (CES-D) 
X 
 
 
X 
*Anxiety (GAD-7)  
X 
 
 
X 
*Case Manager Questions 
 
 
X 
X 
*Partner Violence and Sexual Assault 
 
 
X 
 
Overdose and Suicide 
 
 
X 
X 
Social Support Scale 
X 
 
 
 
VR-12 Health Survey – MOS-HIV 
X 
 
 
X 
Primary Activity 
X 
 
X 
X 
Visit Costs 
 
 
X 
X 
COVID-19 Questions 
 
 
X 
X 
 
5.2.A. MEDICATION VISITS ASSESSMENTS 
 
Medication symptoms and opioid use will be assessed during the medication check-in visits.   
 
5.3 SYSTEM-LEVEL ASSESSMENT OF LINC-II IMPACT  


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The system-level assessment will focus on provider, administrator, and patient perspectives and 
experiences with care coordination between the narcology and HIV care systems. System-level variables 
will be assessed from providers, administrators, and study participants (i.e., patients in the narcology or 
HIV care systems). Questions will assess demographics, role in the care system, attitudes toward care 
coordination, level of engagement in coordinated care, stigma toward patients with HIV and substance 
use disorders, and connection, if any, to LINC-II. 
For the purpose of this study, care coordination will be defined as “the deliberate organization of patient 
care activities between two or more treatment settings involved in a patient’s care to facilitate the 
appropriate delivery of health care services,” referring in this case to the narcology and HIV care systems. 
Providers and administrators will also be asked to what extent they are aware of LINC-II, if they have 
worked with a LINC-II CM, and what their experiences have been with LINC-II, including whether the 
presence of LINC-II had any other effects on the system, such as patient flow and patient engagement. 
Surveys will be followed by an open-ended qualitative exploration to obtain details regarding 
perceptions of and experiences with care coordination, including concrete examples of connections 
between narcology and HIV care service delivery. It will explore organizational and systemic challenges 
that impede care coordination and opportunities to improve care coordination. Among LINC-II 
intervention participants, the role of LINC-II in addressing these issues and connecting people to both 
narcology and HIV care will be explored. We will conduct in-depth interviews with all providers and 
administrators and recruit a purposively chosen sub-sample of 30 participants from the LINC-II study. 
Interviews will be audio recorded, translated, and transcribed for analysis. 
For administrators and providers in each system (n=26), all surveys and in-depth interviews will be 
conducted within 20-60 minutes and will occur at study launch, 12, and 24 months post-launch. This will 
not necessarily include the same providers and administrators at each assessment, in event of staff 
turnover. Written informed consent will be obtained prior to each interview. LINC-II study participants 
(N=240) will provide survey data on system perceptions at baseline, 6 and 12 month follow-up as part of 
their RCT study assessment. A subsample of participants selected for in-depth interview (n=30) will be 
interviewed subsequent to survey completion. Interviews will be audio recorded, translated, and 
transcribed for analysis. We will maintain a roster of interview refusals so as to consider potential biases 
in our sample of interviewees. 
 
5.4 ESTIMATES OF COST AND COST-EFFECTIVENESS 
 
Costs will be measured from the provider perspective and will include the cost of all resources utilized 
for each study participant from the date of randomization for a period of 12 months. Average provider 
cost per patient will then be stratified by study arm and outcome to generate cost-effectiveness estimates 
with 95% confidence intervals. 
 


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Resource or 
outcome 
Method for estimating unit cost or cost/outcome 
Resources 
Method for estimating unit costs 
Medications, 
laboratory tests, and 
other supplies 
Types of antiretroviral and narcology medications and other drugs dispensed 
to study participants and types of laboratory investigations performed 
between study enrollment and the primary 12-month endpoint will be 
extracted from individual study records and clinic records for the intervention 
arm and from self-report and clinic records for the control arm. For each 
medication dispensed, a unit cost will be assigned that represents local 
investigators’ best estimate of the procurement prices that study sites would 
have to pay if they adopted the intervention as standard care, using data from 
invoices and local medication price lists. For each type of laboratory test, the 
fee charged to conduct the test will be used as its unit cost. If a fee schedule is 
not available, a cost/test will be estimated using an ingredients costing 
method. Laboratory tests that are done solely for research purposes and are 
not likely to be included if the intervention were adopted as standard care will 
be excluded. Supplies that are used for individual patient care will be assigned 
a unit cost from procurement invoices. 
Outpatient visits 
An average unit cost per outpatient visit to each type of facility will be 
estimated by dividing total clinical staff cost per month by the number of visits 
made to the facility that month. If data are available to stratify this estimate by 
purpose of visit or staff cadre required, this will be done, but the overall 
average has proven to be sufficient for outpatient settings. Clinical staff 
salaries (total cost to the employer) for each staff cadre will be obtained from 
the study sites or the administrative entity responsible for the sites’ payrolls. 
Case manager costs 
As case managers are an intervention-specific resource, costs will be calculated 
from study invoices and expenditure reports and estimated as an average cost 
per session conducted. Case manager transport, SMS fees, and other costs 
associated with this component of the intervention will be included in the 
cost/session estimate. (Although every patient in the intervention arm will be 
assigned a case manager, some patients will complete all ten planned sessions, 
while others will not. As participation in sessions may be associated with 
outcomes, a cost/session attended will be a more useful estimate than a cost 
per patient.) 
Fixed costs--buildings 
and equipment and 
furnishings 
The total floor space that is required for study-related service delivery, 
excluding research-specific activities such as administration of informed 
consent, will be measured in each facility, including a proportion of shared 
spaces such as waiting areas. If the study sites or local administrative entity 
use a standard cost/square meter for clinic space, this will be accepted as the 
cost of buildings. Otherwise, a market-related average rental cost per square 
meter will be applied to estimate the cost of the building. Utilities will be added 
as a percentage mark-up based on site-specific planning documents or other 
local sources. The replacement cost of equipment and furnishings will be 
obtained and an appropriate working life applied to each instrument to obtain 
an average cost/month. If laboratory instrument procurement costs are not 
included in lab fees, these will be estimated in the same way as other 
equipment costs. Total building and equipment and furnishing costs per month 
will be divided by the number of relevant clinic visits made each month to 
estimate a fixed cost/clinic visit. 


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6. PARTICIPANT SAFETY 
 
Participant safety will be monitored by study staff every 4 weeks through in person visits. 
 
6.1. SPECIFICATION OF SAFETY PARAMETERS 
 
An Adverse Event (AE) is defined as any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, whether or 
not considered related to the subject’s participation in the research.  
Resource or 
outcome 
Method for estimating unit cost or cost/outcome 
Resources 
Method for estimating unit costs 
Fixed costs--
management and 
administration and 
general supplies 
Costs of all staff members who do not provide direct patient care but provide 
some support to the delivery of study-related services (e.g. clinic manager, 
data clerks) will be calculated, with salaries obtained from the study sites or 
the administrative entity responsible for the sites’ payrolls. The cost of general 
supplies (e.g. cleaning materials, stationery) will be obtained from facility 
financial reports. Total management, administration and supply costs per 
month will be divided by the total number of clinic visits made each month to 
estimate a fixed cost/clinic visit.  
Outcomes 
Methods for estimate cost/outcome 
Cost/patient served 
Total costs in study period/total number of patients enrolled, stratified by arm. 
This estimate is useful for budgeting purposes, as the difference between the 
arms indicates the additional budgetary resources needed to implement the 
intervention per patient served. 
Cost/patient 
initiating ART 
Total cost from enrollment to 28 days/total number of patients initiating ART 
within 28 days, stratified by arm. This estimate looks at the difference in cost 
between the intervention and standard care up to the point of ART initiation. 
Cost/outcome 
Total costs for patients stratified by arm and outcome. The difference in cost 
between outcomes indicates the anticipated difference in budgetary needs if 
outcomes improve. 
Total cost/patient 
suppressed  
Total cost from enrollment to 12 months/total number of patients achieving 
primary outcome of 12-month viral suppression, stratified by arm. This 
estimate focuses on cost differences between the arms for patients who do 
achieve the primary outcome. It takes into account all costs incurred for all 
patients but divides by only the number with a successful outcome, and 
thereby links the cost of service delivery to the primary outcome. 
Cost-effectiveness 
Incremental cost-effectiveness ratio (ICER) = Difference in costs (intervention 
arm-control arm)/ difference in outcomes (intervention arm-control arm).  
The ICER indicates the incremental additional cost to achieve one additional 
successful outcome. 


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An AE can therefore be any new sign, reaction, symptom, event, disease or a worsening in frequency or 
severity of a preexisting condition that occurs during the course of the study.  
Stable chronic conditions that were present prior to study entry and do not worsen are not considered AEs. 
 
SERIOUS Adverse Event (SAE) – is any adverse event that  
(1) 
results in death; 
(2) 
is life-threatening; 
(3) 
results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) 
results in a persistent or significant disability/incapacity; 
(5) 
results in a congenital anomaly/birth defect; or 
(6) 
based upon appropriate medical judgment, may jeopardize the subject's health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition (examples 
of such events include allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse).  
Life-threatening means that the event places the subject at immediate risk of death from the event as it 
occurred. 
 
Unanticipated Problem (UP) – is defined as an event, experience or outcome that meets all three of the 
following criteria:  
• 
is unexpected; AND 
• 
is related or possibly related to participation in the research; AND 
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
Possibly related means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
• 
the known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol–related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as product labeling and 
package inserts; or 
• 
the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the 
adverse event. 
 


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Suspected Adverse Drug Reaction – Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. Reasonable possibility means there is evidence to suspect a causal 
relationship. It is considered unexpected if it is not consistent with the risk information described in the 
general investigational plan. A suspected adverse drug reaction will be defined as a recorded adverse 
event that is unexpected and deemed to be possibly, probably, or definitely related to the study drug. 
 
6.2 THE METHODS AND TIME FOR ASSESSING, RECORDING, AND ANALYZING SAFETY PARAMETERS 
 
• For participants randomized to the LINC-II intervention, symptoms will be assessed at baseline to 
document any chronic conditions or symptoms that existed prior to introduction of study medication. 
These will be documented on the Baseline AE log. This list will be reviewed and compared to reported 
events throughout the study. If the participant reports the same ongoing symptom (same severity) 
during subsequent visits, the symptom should not be recorded as an Adverse Event (AE). If the event is 
new (not previously reported) or worsened, as determined by RA, then it will be considered an AE and 
recorded and reported as described below. 
 
• During each scheduled visit, the RA will ask the participant how he or she feels and review the 
previously reported symptoms. Any event that meets the above criteria for an AE/SAE/UP must be 
recorded. In the case of unresolved AEs, clinical staff will update the AE log with any follow-up 
information that is gathered during their investigation. 
 
• The site will receive the results of all blood work that is performed on study participants from the 
designated lab. If the lab results meet the criteria described in the protocol as an AE and are 
considered clinically significant by the site clinician then an AE will be recorded.  
 
o Participants will be alerted of abnormal lab results and will receive a recommendation to see 
their local provider (please see section 3.3C for protocol specific to AST/ALT results). All 
abnormal lab results obtained at the baseline visit will be listed on the Baseline AE log.  During 
follow-up visits, abnormal lab results will be listed as an AE only if the abnormal lab results 
meet one of the points below: 
▪ Develop at follow-up (i.e., were not previously recorded at baseline). 
▪ Worsen in severity compared to what was previously recorded at baseline. 
▪ Or are considered clinically significant. 
 
• 
All AEs will be assessed to determine if they meet criteria for a Serious Adverse Event (SAE).  If 
the AE is serious, then the SAE form must be completed and appropriate reporting measures 
followed (see below). Investigators are encouraged to consult with the US team, if they are 
uncertain how to classify an event.  
 
• The list of participant’s current medications will be reviewed and updated at every study visit, 
starting at baseline. 
 


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• If an event is discovered outside of the scheduled study visits, it must still be recorded 
accordingly.  
 
• Action Taken will be determined by the RAs for all AEs that are Mild and Moderate and by Drs. 
Krupitsky or Blokhina for SAEs and AEs that are severe, life-threatening or fatal. 
 
6.3. PROCEDURES FOR ELICITING REPORTS OF AND FOR RECORDING AND REPORTING ADVERSE EVENT AND 
INTERCURRENT ILLNESSES 
 
For any reported side effect: While with the participant, study personnel will listen, identify, and 
document the symptoms. All events will be documented on AE forms.  
 
 
 
6.3.A. OTHER EVENTS 
 
• Any participant who voices current suicidality or is experiencing a psychiatric emergency during the 
interview will be reported to Dr. Krupitsky or his designee immediately. Dr. Krupitsky and the 
assessor (Addiction Psychiatrist at City Addiction Hospital or at Pavlov University) will determine the 
appropriate course of action, which will depend on location of the event and the clinical situation. 
Emergency psychiatric consultation is available on site at the CAH and will be requested as indicated; 
patients will be escorted to receive care by appropriate staff if deemed necessary.   
 
6.3. B. ADVERSE EVENT REPORTING 
 
The following information should be present to complete AE and SAE forms during the initial report (on 
the day of finding out about the event):  
 
• Description of the event 
• Date of onset and resolution (if known) 


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• Severity – based on established criteria: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf * See Box 1 
• Assessment of expectedness (is the event anticipated in terms of nature, severity, or frequency) 
given (a) the research procedures that are described in the IRB protocol and informed consent 
document; and (b) the characteristics of the subject population being studied 
• Assessment of relatedness to Naltrexone 
• Any actions taken 
 
Following the initial report, additional information may need to be gathered to complete the AE 
and SAE forms and to evaluate the event for relatedness. This process may include seeking 
hospital discharge reports, physician records, autopsy records or any other type of records or 
information necessary to provide a complete and clear picture of the SAE and events preceding 
and following the event.  
6.3.C. SAE REPORTING 
 
If the SAE is not resolved or stabilized at this time or new information becomes available after the SAE 
form is completed, the SAE form should be updated as soon as possible. Any changes or updates to the 
SAE form will need to be re-reviewed and re-authorized by the study clinician. 
 
In some cases, the study clinician may be unsure upon first learning of an SAE whether it is study related 
and/or expected, because study staff are awaiting more complete medical records. In such cases, the 
study clinician should make his/her best estimate of relatedness and expectedness, understanding that 
these determinations can be updated later. When updating determinations at a later date, the rationale 
for the change should be included in the SAE narrative. 
Box 1. Guidelines for Severity Grades 
 
*Research assessor will refer to the guide for unique clinical descriptions of severity for each AE, which will 
follow the general guideline below: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only intervention not 
indicated. 
• 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities ADL*. 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self care ADL**. 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for Grade 
selection. Grade 5 (Death) is not appropriate for some AEs and therefore is not an option. 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 


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The site must actively seek information about the SAE until the SAE is resolved, stabilized or until the 
participant is lost to follow-up and terminated from the study.  
 
To summarize: upon determining an Adverse Event is Serious, the following procedures should be 
followed: 
 
•  The study staff, while meeting/talking with the participant or person providing details on the event, 
will gather as much information about the event from these individuals as possible and complete 
the appropriate forms.  
 
•  The completed AE and SAE forms will be reviewed by key personnel on the Pavlov team (e.g. Drs. 
Krupitsky or Blokhina). Any relevant clinical documents (labs, physician notes) available at that 
time will be provided to key personnel on the Pavlov team (e.g. Drs. Krupitsky or Blokhina) within 
24 hours of finding out about the event. 
 
•  After initial notification, the SAE must be updated with any additional information.  
 
Any Adverse Events will be entered on the study website and Dr. Samet will be alerted immediately of 
any SAEs or UPs.  
 
BUMC Reporting Guidelines:  
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems and Adverse 
Events to the BMC/BU Medical Center IRB in accordance with IRB policies: 
• Unanticipated Problems involving a fatal or life-threatening event will be reported to the IRB within 
2 days of the investigator learning of the event. 
• Unanticipated Problems not involving a fatal or life-threatening event will be reported to the IRB 
within 7 days of the investigator learning of the event. 
• Adverse Events (including Serious Adverse Events) will be reported in summary at the time of 
continuing review, along with a statement that the pattern of adverse events, in total, does not 
suggest that the research places subjects or others at a greater risk of harm than was previously 
known. 
 
Pavlov Reporting Guidelines:  
 
What Event is Reported 
When is Event Reported 
Fatal or life-threatening unexpected, suspected serious 
adverse reactions 
Within 7 calendar days of initial receipt of 
information 
Non-fatal, non-life-threatening unexpected, suspected 
serious adverse reactions 
Within 15 calendar days of initial receipt of 
information 


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AEs and UPs 
On a quarterly basis 
 
6.4 THE TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
 
All events will be followed until the event is resolved, stabilized, or until the end of individual’s 
participation in the study. 
Drs. Krupitsky or Blokhina will determine a follow-up plan on a case-by-case basis based on their clinical 
judgment and this plan will be documented. 
 
7. DATA MANAGEMENT 
7.1 DATA COLLECTION 
 
All study data will be captured electronically on netbooks via a secure, web-based data capture system. 
 
7.2 QUALITY CONTROL PROCESS 
 
Quality control measures will include: detailed and unambiguous specifications for completion of data 
forms, including rules for coding skipped questions and missing data, training of study staff responsible 
for data collection and built-in validation rules, error checks, question skips for electronic data capture, 
and computer algorithms to check for out-of-range codes and internal inconsistencies. All data, 
regardless of capture method, will be converted to SAS datasets and reviewed for logic, skip patterns, 
response ranges, out-of-range codes, and internal inconsistencies. The RAs will be queried regarding any 
noted inconsistencies. 
 
 
7.3 DATA SECURITY AND CONFIDENTIALITY 
 
Screening forms and most other research paperwork will not include the participant’s name; instead, a 
unique ID will be assigned to each person screened, and another number assigned to those who enrolled. 
Any documents with identifiable participant data will only be accessible to the Russian Co-Investigators 
(Drs. Krupitsky and Blokhina), the project management staff, and the RAs who recruit and follow 
participants.  
 
Tracking information will be kept similarly. Computer data will be password protected, and accessible 
only to research associates needing the information for follow-up purposes.  
 


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The Boston University Biostatistics & Epidemiology Data Analytics Center (BEDAC) will design, develop 
and maintain the electronic data collection forms, participant and data tracking, and underlying SQL 
database systems, and implement procedures for data quality control, including multiple checks for 
entered data. Electronic data collection forms will be designed to read easily, have clear instructions, 
preprogrammed skip patterns, real-time range checks and internal logic to minimize missing data and 
result in “cleaner” data at capture. The website and accompanying database will be located on secure, 
password-protected servers, behind the BU firewalls. The BEDAC has access to two Unix servers, 
including a Linux Beowulf cluster currently configured with 118 CPUs, as well as an SMP Linux server 
with 4 x Six-Core AMD Opteron processors (a total of 24 cores x 2.4 GHz each), 64 GB of RAM, and 6 TB 
(4TB usable) storage capacity. Additionally, the BEDAC has three dedicated servers, all of which are dual 
processors with 150 gigabytes for data storage: an SQL database server; a server used for Web site 
development and management, running Internet Information Server for web page hosting; and a server 
used for web development pre-production testing environment. The web and database servers will use 
Secure Socket Layering (SSL) to ensure data security and confidentiality. Two fax servers, an additional 
server, and a flatbed scanner comprise the Teleform® system. Servers incorporate RAID hard drives for 
data redundancy. A separate web server dedicated for Cold Fusion applications is also available. 
 
The in-depth qualitative interviews will be recorded, and the clinician's or patient's name could be 
mentioned or their identity could otherwise be revealed during the interview; however sensitive 
information will not be the content of the interviews. Names will not be transcribed and audiorecordings 
will be destroyed after transcription. The audiorecordings will be kept in a locked cabinet when not in 
use. 
 
7.4 WEB SYSTEMS 
 
The study will use two web systems: a computerized tracking system and REDCap. The computerized 
tracking system will contain all participant tracking details. This system will be web-based, allowing 
multiple users to access the system. REDCap is a secure web application for building and managing online 
surveys and databases and will be used for screening and assessment purposes. Study forms will be 
completed according to the schedule below. 
  


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8. STATISTICAL ANALYSIS 
 
This study will use an intent-to-treat analysis that includes all participants according to their randomized 
assignment. Descriptive statistics will be calculated for variables at baseline and each follow-up time to 
assess whether there appear to be any differences across treatment arms.  
 
Our Specific Aims are to compare the effects of LINC-II and standard of care following outcomes:  
a. Primary: Undetectable HIV viral load at 12 months 
b. Secondary: Initiation of ART within 28 days of randomization; 
Change in CD4 count from baseline to 12 months; 
Retention in HIV care (i.e., ≥1 visit to medical care in 2 consecutive 6 month periods) 
Undetectable HIV viral load at 6 months; 
HVL suppression and past 30-day opioid abstinence assessed at 6 and 12 months. 
FORM 
Screen & Baseline Visit 
Implant 
Visits  
Medication 
Checks  
6-
month 
visit (24 
weeks) 
12-
month 
visit (52 
weeks) 
As 
Needed 
Screen  
Baseline 
Screener  
X 
 
 
 
 
 
 
Consent and enrollment form 
X 
 
 
 
 
 
 
Contact info 
 
X 
X 
X 
X 
X 
X 
Phlebotomy form (Paper) 
 
 
X 
 
X 
X 
X 
Full assessment 
 
X 
 
 
X 
X 
 
Short assessment  
 
X 
X 
X 
 
 
 
Contact log 
 
 
 
 
 
 
X 
Baseline Event Form 
 
X 
 
 
 
 
X 
Medication use collection (Paper) 
 
X 
X 
X 
X 
X 
X 
Baseline tracking form 
 
X 
 
 
 
 
 
Follow-up tracking form 
 
X 
X 
X 
X 
X 
 
Participant tracking overview  
 
 
 
 
 
 
X 
Participant tracking entry  
Study conclusion form 
 
 
 
 
 
 
X 
AE/SAE form (paper and Web) 
 
 
 
 
 
 
X 
Incarceration form 
 
 
 
 
 
 
X 
Naloxone challenge tracking form 
 
X 
X 
 
 
 
 
Medication form 
 
 
X 
X 
X 
X 
X 
Detox form 
 
 
 
 
 
 
X 
Qualitative interview tracking 
 
 
 
 
 
 
X 
Provider interview tracking 
 
 
 
 
 
 
X 
Case Manager forms 
 
 
 
 
 
 
X 


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8.1 PRIMARY ANALYSES 
 
The primary outcome for this aim is HIV viral load suppression at 12 months. Initial analyses will be 
performed comparing this binary outcome between groups using a chi-square test. The primary analysis 
will use multivariable logistic regression analyses to control for the stratification factor to improve 
efficiency, (i.e., ever ART use). If there are any baseline factors that appear to differ by randomized group, 
additional sensitivity analyses will be conducted controlling for these factors to assess for potential 
confounding. The secondary outcomes of undetectable viral load at 6 months, ART initiation within 28 
days and retention in HIV care will be analyzed using the same approach described above. Change in CD4 
count between baseline and 12 months will be analyzed using multiple linear regression adjusting for the 
stratification factor. If the distribution of change in CD4 is skewed, transformations of the data will be 
considered. If an appropriate transformation is not identified, a median regression model will be used.41, 
42 
 
8.2 ADDITIONAL EXPLORATORY ANALYSES 
 
Effect Modification 
We will perform additional analyses to explore potential effect modifiers of the LINC-II intervention. The 
3 potential effect modifiers of interest are: gender, ever ART, and 30-day IDU. We will fit separate models 
including 2-way interactions between randomization group and each potential effect modifier. If an 
interaction is significant, subsequent stratified analyses will be conducted to explore and describe the 
effect of the LINC-II intervention by categories of the moderator. 
 
Mediation 
Exploratory analyses will be conducted to assess potential mechanisms that may drive LINC-II’s ability to 
improve HIV care outcomes using the Baron and Kenny approach.43 The 3 potential mediators we will 
explore are decreases in substance use, HIV stigma, and substance use stigma. However, because the 
interpretation of the degree of mediation in logistic models is complicated by their inherent nonlinearity, 
we will conduct additional analyses using the recently developed causal inference approach to mediation 
(also referred to as the counterfactual framework), an approach that allows potential interactions 
between the interventions and mediators and derives direct and indirect effects for binary outcomes.44-47 
We will use the Stata mediation package to conduct these analyses.48, 49 
Aim 2 
The analyses for this aim will be descriptive in nature; formal hypothesis testing will not be conducted. 
Descriptive statistics (e.g., means, medians, interquartile ranges, and confidence intervals) will be 
obtained to assess quantitative data from provider, administrator, and patient surveys over time on 
perceptions and experiences of coordinated care. We will also conduct repeated measures analyses of 


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patients’ attitudes and experiences using mixed effects regression models controlling for randomized 
group to assess overall changes over time and to explore and describe potential differences between 
study arms. Qualitative interview data will be analyzed following a thematic approach.50 Content analysis 
of qualitative data will reveal themes regarding care coordination and will identify best practices for 
LINC-II implementation in similar settings, (e.g., where addiction and HIV care systems are largely 
separate). Qualitative and quantitative results will be triangulated.51  
 
Aim 3 
 
Aim 3 is to estimate cost and cost-effectiveness. For this analysis, we will adapt methods developed by co-
investigator Professor Rosen and colleagues in South Africa.52, 53 When all follow-up to the primary 
outcome (12-month viral suppression) has been completed, patient resource utilization will be extracted 
from patients’ medical records for HIV care and study forms for narcology care in the intervention arm. 
Narcology care (number of outpatient visits and services provided) for patients in the control arm will be 
estimated from patient self-report at the time of 6 and 12-month outcome assessments. Unit costs will be 
obtained from published information, external suppliers, and the study sites’ finance and procurement 
records and applied to the resource usage data to provide an average cost per study patient. Costs will be 
measured from the provider perspective and will include the cost of all resources utilized for each study 
participant from the date of randomization for a period of 12 months, including all drugs, laboratory 
tests, outpatient visits, case manager costs, and fixed costs such as building space, equipment, and 
administrative staff. For patients referred to local clinics, rather than the study hospital, for ongoing HIV 
care after ART initiation and/or for narcology care, fixed costs will be estimated at the facility level for a 
typical local clinic for each type of care. 
 
We will estimate average cost with 95% confidence intervals to the provider per patient enrolled, per 
patient initiating ART, and per patient achieving viral suppression by 12 months. We will also estimate 
total cost per patient achieving the primary outcome, which takes into account all the costs for all the 
patients but divides by only the number with a successful outcome (i.e., 12-month viral suppression) and 
thereby links the cost of service delivery to the primary outcome. The cost-effectiveness of the 
intervention, compared to standard care, will also be estimated as an incremental cost per incremental 
outcome. The cost and cost-effectiveness results will then be evaluated in the context of existing 
healthcare budgets, resource availability (e.g., trained case managers) other relevant interventions that 
have been studied in Eastern Europe, and cost estimates for similar countries to help inform policy 
makers about the affordability and priority of scaling up the program.  
 
In addition to the provider cost estimates described above, the baseline questionnaire will elicit 
information about patient costs of seeking care, such as transport fares, lost wages, and substitute labor 
costs (e.g., for childcare). The average cost to patients by arm and by outcome will be estimated and used 
both to help explain study results (e.g. there may be an association between patient costs and retention in 
care) and as a component of the overall economic evaluation. 
 
 


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9. STAFF TRAINING 
9.1 TRAINING OF STUDY STAFF 
 
All study staff will be trained on the study protocol. Training will take place in-person in St. Petersburg 
and via webinars. 
For baseline study activities, staff at CAH will be trained addiction psychiatrists, who have experience 
administering injectable naltrexone to patients.  In-person screening, enrollment, and baseline 
assessment will be performed by CAH staff who are psychologists who have experience working with this 
population.  
Study staff at PSMU are research addiction physicians and nurses with extensive experience performing 
pharmacotherapy trials, including trials of implantable naltrexone, and are experienced in the surgical 
procedure of naltrexone implantation. The staff are trained to assess for adverse medication effects and 
will follow established protocols for identifying and monitoring any ongoing adverse events.  
 
9.2 TRAINING OF INTERVENTIONISTS (CASE MANAGER) 
 
The LINC-II intervention training was led by Dr. Raj, who has substantial experience conducting 
behavioral intervention trainings internationally and in engaging HIV-positive PWID in medical care. 
Over the course of 2 days, Dr. Raj trained the interventionists in St. Petersburg, providing them with an 
overview of the theoretical framework, assessment techniques and the LINC-II intervention; they 
modeled the intervention delivery to assure the use of a strengths-based approach. As per previous 
trainings in earlier studies, simultaneous translation was used to allow multiple role-playing sessions to 
be critiqued. Booster trainings will be conducted annually and as necessary based on findings from 
quality assurance efforts. These intensive trainings as well as the monitoring and observation for quality 
assurance are designed to limit potential variability due to individual interventionists. 
 
10. STUDY CONTACTS 
 
Dr. Samet will be responsible for the financial management of the study and communication between NIH 
and the rest of the leadership team. He will manage the implementation of the study in Russia and 
oversee all components of the study. He will lead the weekly study team research meetings. He will help 
create the study protocol, oversee its administration, and assist in training interventionists. He will 
participate in analysis and presentation of study results and preparation of papers for publication.  
In Russia, the study will be led by site PI, Dr. Evgeny Krupitsky. The study will be managed by Dr. Elena 
Blokhina in St. Petersburg and Natalia Gnatienko in Boston.  


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ICF_000.pdf: 
Research Consent  Form 
NCT03290391 
Jeffrey Samet, MD MA MPH
jsamet@bu.edu
Linking Infectious and Narcology Related Care Part II-(LINC-II)
Document Date- 2/24/2020


BOSTON MEDICAL CENTER AND THE 
BOSTON UNIVERSITY SCHOOLS OF MEDICINE,
PUBLIC HEALTH AND DENTAL MEDICINE
Version 1(f)
Page 1 of 10
RESEARCH CONSENT FORM 
Basic Information      
Title of Project: Linking Infectious and Narcology Care – Part II (LINC-II) 
IRB Number: H-36706
Sponsor: National Institute on Drug Abuse (NIDA)
Principal Investigator: Jeffrey Samet, MD, MA, MPH
  jsamet@bu.edu
  801 Massachusetts Avenue, Crosstown, 2nd Floor, Boston, MA 02118
Study Phone Number: Regular business hours: 7-812-338-6051
   24 hours: 7-952-097-8173
Background
Russia and Eastern Europe continue to have one of the fastest growing HIV epidemics in the world, with 
highest transmission risks among people who inject drugs (PWID) and their sexual partners. An intervention 
that targets both HIV infection and injection drug use has potential to improve the health of HIV-positive 
people. 
You are being asked to participate in this study because you are HIV-positive, are a patient at a narcology 
hospital, and have a history of injection drug use. If you agree to participate, you will be involved in this 
research study for about 12 months. 
Purpose
The purpose of this study is to test whether combining medications to treat HIV and opioid use disorder with 
case management can improve HIV care outcomes among HIV-infected persons who inject drugs. We call this 
project Linking Infectious and Narcology Care – Part II (LINC-II).
What Will Happen in This Research Study
You will be one of approximately 240 participants to be asked to participate in this study.
The study is being carried out at the following locations in St. Petersburg, Russia: St. Petersburg City Addiction 
Hospital, St. Petersburg City AIDS Center, and First St. Petersburg Pavlov State Medical University.
Although your participation will be at the above mentioned locations in Russia, your data will be transferred to 
Boston, Massachusetts (US): Boston Medical Center and Boston University Campus for evaluation with the 
collaborative Russian-US research team.
Screening Visit:
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
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As part of the screening process, all women will be asked to complete a urine pregnancy test to make sure that 
they are not pregnant. This is because the medications that you may get as part of the study could be 
dangerous for the baby. 
Baseline Visit:
After you are enrolled in the study, you will be asked about your demographics (e.g., age, gender), general 
health, substance use and HIV medical care. The interview will take place in person. Some questions will be 
asked by a research assessor and some questions you will complete by yourself. It will take approximately 75 
minutes to complete. We will also review your medical record to find information about your HIV care and 
treatment history.
We will ask to take a blood sample from you (10-20ml [or 2-4 teaspoons]). It will be used to measure your HIV 
viral load and CD4 count. The testing will be performed at the City AIDS Center. The results of these tests will 
be put in your medical record at the City AIDS Center. We will not need a blood sample if you already have a 
recent (within one month) CD4 and HVL result in your City AIDS Center medical chart. If you are assigned to 
the intervention group the results will be shared with your assigned HIV case manager. 
If you are unable to provide a blood sample or have an undetectable HIV viral load at baseline, we will conduct 
an HIV antibody test during a subsequent study visit to verify your HIV status. 
After completion of the interview, you will be randomly (like flipping a coin) placed in one of two study groups. 
You will have an equal chance of being in either group.
Group 1 – Comparison group:
If you are in the comparison group you will receive standard care as normally provided to patients in the 
narcology hospital. This could include detoxification with medications, substance use counseling and 
treatment for comorbid psychiatric conditions, as well as possible inpatient rehabilitation for up to 30 
days. You will also be given printed information, including phone number, on clinic that provides HIV 
medical care and you will be referred to outpatient narcology care. 
Group 2 – Intervention group:
If you are in the intervention group, you will also receive printed information, including phone numbers, 
on places that provide HIV medical care, as well as these three components:
-
Medication for opioid use disorder: You will receive one intramuscular gluteal injection of 380 mg
of naltrexone for extended-release injectable suspension (vivitrol) while still at the hospital. You will
then come to Pavlov University to receive a 1000mg dissolvable naltrexone implant (prodetoxon).
You will receive 4 naltrexone implants while in the study. Ideally, implants will be inserted every 10-
12 weeks starting at week 4 post-study enrollment (weeks 4, 16, 28, 40). You will be asked to return
7-11 days after the implant for removal of sutures. You will also be asked to come in every 4 weeks
for brief medication check visits, during which you will receive brief counseling.
-
HIV case manager: You will participate in 10 individual sessions with an HIV case manager (ideally
1 during your stay at the narcology hospital and 9 after you are discharged) over a period of 12
months. The remaining  sessions can be held at your convenience at an HIV clinic, a non-
governmental organization, or in the community. The case manager will help you understand the
importance of HIV care, identify barriers to receiving care and to recognize your own strengths and
abilities to reduce self-identified barriers to care. As part of the LINC-II intervention, the case
BMC and BU Medical Campus IRB 
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
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manager will help you attend HIV medical appointments and adhere to HIV treatment. The case 
manager will contact you to remind you about your appointments and you could also communicate 
with your case manager by text messaging or phone. Your individual sessions with the case 
manager will be audiorecorded to make sure the sessions are performed well.
-
Rapid access to antiretroviral therapy (ART): As part of this study, your HIV care will be
streamlined, which may allow you to get rapid access to ART medication.
Before getting your naltrexone injection or implant, you will receive a naloxone challenge to make sure there 
are no opioids in your system, as taking naltrexone with opioids in your system will make you feel sick. 
Naloxone blocks the effects of opioids. It works only if it is injected and lasts about 30 minutes. It is used in 
hospitals and by emergency services to reverse the effects of a heroin or other opioid overdose. It will cause 
withdrawal if injected into someone who is currently physically dependent on opioids and will be administered 
to you as a way of making sure that you are not physically dependent on heroin or other opioids before you 
receive injectable or implantable naltrexone. The naloxone challenge will only be administered if your urine is 
negative for heroin or other opioids. The challenge will be done by administering 0.8-mg naloxone slowly, 
either intravenously or intramuscularly. You will be observed for signs of withdrawal for 5-20 minutes. If you 
experience withdrawal after the naloxone test, your symptoms may be treated with clonidine or phenazepam 
and will go away in 45-60 minutes. You will not be started on the study medication until you pass a naloxone 
challenge, which means that you have no signs or symptoms of opioid withdrawal after naloxone is 
administered. 
You may be one of a small number of participants, who will be asked to take part in an interview that will last 
about 60 minutes after your baseline, 6-, and 12-month LINC-II study visits. A trained member of the research 
team will contact you to complete the interview. During the in-depth individual interviews, among 30 study 
participants, we will ask about your perceptions and experiences with care coordination, including examples of 
connections between narcology and HIV care service delivery. The interview will be audio-recorded if you 
agree to it, or else we will take notes
Follow-Up Visits:
Medication check-ins (for Intervention group only)
If you are in the intervention group you will be invited to come in every 4 weeks following implantation for 
medication visits, where you will be monitored for side effects. Ideally, medication visits will occur at weeks 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52.  Implant visits 2, 3, and 4 will involve the collection of blood for 
laboratory testing, in order to monitor liver toxicity. If your liver enzymes are high (>5 times the upper limit of 
normal), we will collect another blood draw to check your liver status at your next medication visit. The results 
of the tests will not be put in your medical record. If a lab value for a test performed at the time blood is drawn 
is abnormal, the research assessor will share the result with you and will recommend to see your local provider 
to discuss the results. 
You will receive 4 1000mg dissolvable naltrexone implants while in the study. Ideally, implants will be inserted 
every 10-12 weeks starting at week 4 post-study enrollment (weeks 4, 16, 28, 40).The naltrexone implant will 
be inserted by a trained surgeon at Pavlov University. The implant will be inserted under the skin in your 
abdomen through a 1cm incision. The site will be treated with a local anesthetic prior to insertion. The implant 
site will be inspected 7-11 days later. You will receive discharge instructions to help you care for the insertion 
site at home.
At all visits you will be asked to provide a urine sample to check for pregnancy, if female, and to check for 
opioids in your system.
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
Page 4 of 10
If you are randomized to the intervention group and you suspect that you have become pregnant during the 
study, you must notify the study doctor immediately and arrange to have the naltrexone implant removed. If 
you become pregnant while you are participating in this study, it could be dangerous for the baby. You must 
use birth control if you are a woman having sex with men while you are taking study medication and for 8 
weeks afterward. Some of the most effective birth control methods are: oral contraceptives (the pill), 
intrauterine devices (IUDs), contraceptive implants under the skin, contraceptive rings or patches or injections, 
diaphragms with spermicide, and condoms with foam. You should not participate in this study if you are a 
woman who has sex with men and cannot use one of these birth control methods. 
In-person study visits (both comparison group and intervention group)
All participants will be asked to come in for in-person assessments and blood draw visits at 24 and 52 weeks 
after enrollment. The follow-up interviews will occur in-person at the First St. Petersburg Pavlov State Medical 
University with a research assessor. These interviews will take approximately 75 minutes to complete and will 
ask questions about your demographics (e.g., age, gender), general health, substance use and HIV medical 
care. We will also review your medical records to find information on medical appointments, HIV medications, 
and laboratory test results (for example, HIV viral load and CD4 count). You will also be asked to provide a 
urine sample to check for opioids in your system.
We will ask to take a blood sample from you (10-20ml [or 2-4 teaspoons]). It will be used to measure your HIV 
viral load and CD4 count. Your blood will be sent to the City AIDS Center for testing and the results of these 
tests will be put in your medical record at the City AIDS Center. 
If blood cannot be obtained during your 24- or 52-week study visit, you will be invited to come in for a second 
blood draw attempt 4 weeks later. If you are in the intervention group, the second attempt will take place during 
your scheduled 28-week visit and you will not receive additional compensation. If the second draw attempt is 
outside of a planned study visit, you will receive compensation in the amount of 500 rubles to cover costs 
associated with traveling to the laboratory.
We will contact you via phone calls, text message, email, and/or letters to remind you about your follow-up 
appointments. 
1) Data repository
We would like permission to store your research data for future studies. Please indicate below if you will allow 
that.
My research data may be kept for future clinical, virological, and immunological research studies related to HIV 
disease, substance use disorder, and other associated illnesses. Yes [ ]  ________(initial or sign )  No [ ] 
_________(initial or sign) 
If you would like to use my research data for future studies not listed above, I am willing to be contacted about 
those studies for my permission. Yes [ ]  ________(initial or sign)  No [ ] _________(initial or sign) 
2) Future studies
We would like to be able to contact you in the future about additional studies for which you may be eligible.
[ ] Yes, I agree to be contacted after my active participation in this study has ended________(initial or sign )  
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
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[ ] No, I do not give permission to be contacted after my active participation in this study has ended. 
________(initial or sign )  
Risks and Discomforts
You may experience stress from the research assessments, as you will be asked sensitive questions regarding 
substance use and HIV status. The risk of stress from interviews will be minimized by using trained 
interviewers, self-administration for particularly sensitive questions, and a standard interview process. You may 
be stressed by the length of the interviews (estimated 75 minutes). You will be allowed to stop at any time 
during the interviews to take a break and come back to complete them. 
Another risk of taking part in this study is loss of confidentiality. However, the chance of someone seeing the 
responses to your interview assessments is unlikely because specific procedures will be put in place to prevent 
this from occurring. There is a small risk that you may experience a loss of confidentiality when research 
assessors contact you for follow-up. All study staff received training on the protection of human subjects in 
research. Study records are confidential, but there is a very small chance that someone outside the study 
could see them. Paper records are kept locked up and electronic records are in password protected 
computers. 
You may experience bruising and minor pain as a result of the blood draw. Other risks such as infection are 
rare. These risks will be minimized by using trained phlebotomists to draw your blood.
You may experience withdrawal symptoms after the naloxone challenge. The symptoms usually resolve 
untreated within 45-60min, but in rare occasions may require the use of clonidine and phenazepam. The most 
frequent side effects (which appear to be dose-related) of clonidine are dry mouth, drowsiness, dizziness, 
constipation and sedation. The most frequent side effects of phenazepam are drowsiness, sedation, muscle 
weakness, and ataxia. These side effects generally decrease on continued administration and are a 
consequence of CNS depression.
Some people have had side effects while taking these study medications. The most serious risk of naltrexone 
(both implant and injection) is the potential for liver injury when taken in excessive doses. Harm is less likely at 
the dosage provided in this study. As a precaution, you will have liver blood tests (ALT and AST) repeated 
during implant visits 2, 3, and 4, and if any level is >5 times the upper limit of normal, a repeat test will be done. 
If any repeat test result is again >5 times the upper limit of normal, or if you have symptoms such as fatigue, 
anorexia, jaundice, nausea, vomiting, dark urine, light stool, abnormal pain, you will be referred to a 
hepatologist for further evaluation and a recommendation about continuing study medication. We expect this 
situation to be rare or non-existent based on prior experience with naltrexone. These precautions, combined 
with frequent contact with study staff, will provide thorough monitoring and appropriate response if evidence of 
liver damage emerges in the course of the study.
The most common side effects of injectable naltrexone are a reaction at the injection site (could be pain, 
tenderness, swelling, redness, and/or itching) and nausea. Other common side effects are headache, fatigue, 
dizziness, vomiting, decreased appetite, painful joints and muscle cramps. 
The most common side effect of the implant is mild/moderate local irritation, including pain, redness, swelling, 
bruising, or infection, lasting 2-3 days. A low dose of triamcinolone is part of the implant formulation to 
minimize this risk, and local irritation has not been a significant problem. The small dose of triamcinolone 
added to the naltrexone implant to prevent inflammation has not been associated with complications. For 
implantable naltrexone, the most common non-surgical side effects are abdominal discomfort, nausea, and 
drowsiness. Other potential side effects include loss of appetite, nausea, vomiting, diarrhea, constipation, 
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
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abdominal pain, liver dysfunction, rapid heart rate, hypertension, vein swelling, headaches, weakness, sleep 
disorder, anxiety, giddiness, depression, dysphoria, running nose, coughing, difficulty with breathing, edema, 
acne, itching, ejaculation problems, decreased potency, increased or decreased interest in sex, shivering, 
tremor, joint pain, local inflammation, increased size of lymph nodes, and relapse of hemorrhoids.
The local anesthetic (numbing medicine) that is used in order to make the small cut in your skin and place the 
medication implant is safe when given in the small amounts that are used to numb the skin. There are some 
risks that can happen. The most serious is if the needle goes into a blood vessel so the medicine gets into the 
blood stream. Steps are taken routinely to prevent this from happening before injecting the medication.
Serious risks that rarely occur can happen from excessive dosage or injecting into a blood vessel and can 
include light-headedness, dizziness, blurred vision, restlessness, tremors and, occasionally, seizures, passing 
out and stopping breathing and your heart stopping beating. These would not be likely with the amount of 
lidocaine you would get and the steps to prevent serious complications. Allergic reactions may also occur.
If you try to use excessive opioids to override the effect of naltrexone, you risk experiencing a potentially fatal 
overdose. After completion of naltrexone treatment, your body may become more sensitive to opioids, and if 
you use opioids at doses used before treatment, you also risk a potentially fatal overdose.
To minimize medication risks the study team will frequently and regularly monitor you for adverse effects, 
particularly liver enzyme elevation, injection and implant site reactions or infections, and common side effects. 
Please contact the study personnel or another health care provider, if you experience any adverse effects.
In the event of an emergency, in which you may require acute pain management, opioids may not be a 
therapeutic option to address the pain while on the study drug, which is a long-acting opioid antagonist 
medication, an injectable or implantable form of naltrexone. In addition, we will provide you with a wallet card to 
be presented to your provider to indicate that you are receiving naltrexone, which has potential impact on pain 
management.
There may be unknown risks/discomforts involved. Study staff will update you in a timely way on any new 
information that may affect your health, welfare, or decision to stay in this study. If you are harmed as a result 
of your participation in this study First St. Petersburg Pavlov State Medical University has medical and 
professional staff available to help. Also, Dr. Krupitsky, Co-Investigator, or his designee, will be available to 
assist you and make referrals as needed.
Potential Benefits
You may not receive any benefits from participating in the study. However, you may benefit from discussing 
your health with an assessor. If you are enrolled in the intervention group, you may benefit by improving your 
health through work with a case manager, medications for your opioid use disorder, and rapid access to ART 
medication.   
Alternatives
Your alternative is to not participate in the study. If you choose not to participate you will be able to access any 
HIV or narcology services that are currently available to you. You will be able to continue receiving standard 
narcology treatment, such as detoxification with medications, substance use counseling and treatment for 
comorbid psychiatric conditions, as well as possibly inpatient rehabilitation for up to 30 days. You can discuss 
with your doctor the possibility of receiving medications, such as naltrexone, for treatment of your opioid use 
disorder. You can seek HIV care, including ART medications and help from a case manager at the City AIDS 
Center or another HIV treatment provider closer to you.
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
Page 7 of 10
Costs
There are no costs to you for being in this research study. You may incur costs traveling to and from study 
visits. All research procedures will be paid for by the study; these include blood draws, medication, 
assessments, and tests. Outside of the study, you may choose to receive additional health services such as 
medical care, tests and/or medications. Payment for services outside of the study will not be paid for by the 
study.
Payment
You will receive 1000 rubles in cash or goods at baseline, 2000 rubles at 24 and 52-week study visits. If you 
are randomized to the intervention group, you will also receive 1500 rubles for visits in which implantable 
naltrexone is inserted, and 500 rubles for monthly medication check-ins. 
If you leave the City Addiction Hospital early before receiving your baseline compensation, you will receive this 
baseline compensation in full during the next study visit you attend.  
Confidentiality
We will do our best to keep your information safe. However, we cannot guarantee confidentiality. 
Federal and state agencies, if they are required by law or are involved in research oversight, may access 
information about you from this study. Such agencies may include the U.S. Department of Health and Human 
Services, the Food and Drug Administration, the National Institutes of Health, and the Massachusetts 
Department of Public Health.
Research assessment questionnaires will be completed with the majority of data entered directly into laptop 
computers, which will require a username and password to logon. Data will not have your name, only your 
unique study ID number. Locator contact information and the master enrollment list will have participant 
names. Paper forms will be kept in locked filing cabinets and electronic data will be stored on password 
protected computers. Study information will be accessible to study staff for purposes of conducting or 
monitoring the study. Intervention sessions with the case managers will be recorded, and your name could be 
mentioned or your identity could otherwise be revealed during the interview; however, audio files will be stored 
on password protected, secure computers accessible only to Russian study staff. The files will be labeled with 
your study ID number and not with your name or any other identifying information.
If during the interview the assessor determines that there is evidence that you are in clear and imminent 
danger of harming yourself, they will contact Dr. Krupitsky or his designee to decide on the appropriate course 
of action, which will depend on where you are during the interview and on the clinical situation. You may be 
referred to emergency psychiatric consultation, which is available on site at the City Addiction Hospital and 
may be escorted to receive emergency psychiatric care. In such a situation, the assessor may need to reveal 
certain identifiable information about you to the emergency psychiatric clinician.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
We might use your research data in future studies. These future studies might be done by us or other 
investigators. Before we use your data, we will remove any information that shows your identity.
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
Page 8 of 10
This study is covered by a Certificate of Confidentiality (CoC) from the National Institutes of Health. All studies 
funded by the National Institutes of Health that involve identifiable information or biological samples are 
covered by a CoC. The CoC provides how we can share research information or biological samples. Because 
we have a CoC, we cannot give out research information or biological samples that may identify you to anyone 
that is not involved in the research except as we describe below. Even if someone tries to get your information 
or biological samples in connection with a legal proceeding, we cannot give it to them. The CoC does not 
prevent you from sharing your own research information. The Certificate of Confidentiality applies to 
information and samples collected for this study which are sent to or kept in the United States of America.
Information from this study may be reviewed and photocopied by the National Institute on Drug Abuse and/or 
state and federal regulatory agencies such as the Office of Human Research Protection and the Institutional 
Review Board of Boston University Medical Center. Information from this study and from your medical record 
may be used for research purposes and may be published; however, your name will not be used in any 
publications. 
Compensation for Injury
If you think that you have been injured by being in this study, please let the investigator know right away. You 
should seek treatment for the injury at your local medical center. We do not offer a program to provide 
compensation for the cost of care for research related injury or other expenses. Other expenses might be lost 
wages, disability, pain, or discomfort. If you do not go to a state-operated facility you will be responsible for 
paying for the medical treatment you receive. You are not giving up any of your legal rights by signing this 
form.
Protection of Subject Health Information
You have certain rights related to your health information. These include the right to know who will get your 
health information and why they will get it. If you choose to be in this research study, we will get information 
about you as explained below.
You authorize Jeffrey Samet and study staff at Boston Medical Center who are working on this research 
project and their employees to use and disclose information concerning you and your identity, medical history, 
and information collected during this study for the following purpose: to study how combining medication (such 
as rapid access to ART and naltrexone for opioid use disorder) and case management can improve HIV care 
outcomes among HIV-infected persons who inject drugs.  
Such information may also be disclosed to or used by others involved in or overseeing the study including 
Boston University and Boston Medical Center Institutional Review Board and the study's sponsor, the United 
States National Institutes of Health (NIH). We share your health information only when we must. We ask 
anyone who gets it from us to protect your privacy. If you do not want to let us use your health information, you 
cannot be involved with this research study. This is because your health information is necessary to the 
conduct of this research. You may withdraw authorization to collect additional information about you at any 
time by writing to the local Principal Investigator, but information already collected may continue to be used 
and disclosed. This authorization has no expiration date. 
Subject’s Rights
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
Page 9 of 10
By consenting to be in this study you do not waive any of your legal rights. Consenting means that you have 
been given information about this study and that you agree to participate in the study. You will be given a copy 
of this form to keep.
If you do not agree to be in this study or if at any time you withdraw from this study you will not suffer any 
penalty or lose any benefits to which you are entitled. Your participation is completely up to you. Your decision 
will not affect your ability to get health care or payment for your health care. It will not affect your enrollment in 
any health plan or benefits you can get.
You may obtain further information about your rights as a research subject by calling the Ethical Committee of 
First St. Petersburg State Pavlov Medical University at 7-812-338-6617.. 
Questions
The investigator or a member of the research team will try to answer all of your questions. If you have 
questions or concerns at any time, contact EDWIN ZVARTAU at 7-812-338-7023 during the day and EVGENY 
KRUPITSKY at 7-952-097-8173 after hours. Also call if you need to report an injury while being in this 
research. 
You may also call +7(812)3386617. You will be talking to someone at the St. Petersburg State Pavlov Medical 
University IRB. The IRB is a group that helps monitor research. You should call or email 
(spbgmutrials@yandex.ru) the IRB if you want to find out about your rights as a research subject. You should 
also call or email if you want to talk to someone who is not part of the study about your questions, concerns, or 
problems. 
Subject: _____________________________________________
  Printed name of subject
By signing this consent form, you are indicating that you have read this form (or it has been read to you), that 
your questions have been answered to your satisfaction, and that you voluntarily agree to participate in this 
research study.
_____________________________________________
___________
Signature of subject
      Date
Researcher: _____________________________________________
         Printed name of person conducting consent discussion
I have personally explained the research to the above-named subject and answered all questions. I believe 
that s/he understands what is involved in the study and freely agrees to participate. 
_____________________________________________
___________
Signature of person conducting consent discussion
      Date
To be completed by witness if researcher reads this form to the subject
This consent form was read to and apparently understood by the subject in my presence. 
_____________________________________________
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020


Project Title: Linking Infectious and Narcology Care – Part II (LINC-II)
Principal Investigator: Jeffrey Samet
Version 1(f)
Page 10 of 10
Printed name of witness (a person not otherwise associated with the study)
_____________________________________________
___________
Signature of witness
    Date
BMC and BU Medical Campus IRB
IRB NUMBER: H-36706
IRB APPROVAL DATE: 02/24/2020