key: cord-0020859-fudgh1wq
authors: Lee, Joshua D.; Malone, Mia; McDonald, Ryan; Cheng, Anna; Vasudevan, Kumar; Tofighi, Babak; Garment, Ann; Porter, Barbara; Goldfeld, Keith S.; Matteo, Michael; Mangat, Jasdeep; Katyal, Monica; Giftos, Jonathan; MacDonald, Ross
title: Comparison of Treatment Retention of Adults With Opioid Addiction Managed With Extended-Release Buprenorphine vs Daily Sublingual Buprenorphine-Naloxone at Time of Release From Jail
date: 2021-09-08
journal: JAMA Netw Open
DOI: 10.1001/jamanetworkopen.2021.23032
sha: 8f182e09f4e9a37054db298fd5ffa4ecf1e6f008
doc_id: 20859
cord_uid: fudgh1wq

IMPORTANCE: Extended-release buprenorphine (XRB), a monthly injectable long-acting opioid use disorder (OUD) treatment, has not been studied for use in corrections facilities. OBJECTIVE: To compare treatment retention following release from jail among adults receiving daily sublingual buprenorphine-naloxone (SLB) vs those receiving XRB. DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized comparative effectiveness study included 52 incarcerated adults in New York City observed for 8 weeks postrelease between June 2019 and May 2020. Participants were soon-to-be-released volunteers from 1 men’s and 1 women’s jail facility who had OUDs already treated with SLB. Follow-up treatment was received at a primary care clinic in Manhattan. Data were analyzed between June 2020 and December 2020. INTERVENTIONS: XRB treatment was offered prior to release and continued monthly through 8 weeks after release. SLB participants continued to receive daily directly observed in-jail SLB administration, were provided a 7-day SLB supply at jail release, and followed up at a designated clinic (or other preferred clinics). MAIN OUTCOMES AND MEASURES: Buprenorphine treatment retention at 8 weeks postrelease. RESULTS: A total of 52 participants were randomized 1:1 to XRB (26 participants) and SLB (26 participants). Participants had a mean (SD) age of 42.6 (10.0) years; 45 participants (87%) were men; and 40 (77%) primarily used heroin prior to incarceration. Most participants (30 [58%]) reported prior buprenorphine use; 18 (35%) reported active community buprenorphine treatment prior to jail admission. Twenty-one of 26 assigned to XRB received 1 or more XRB injection prior to release; 3 initiated XRB postrelease; and 2 did not receive XRB. Patients in the XRB arm had fewer jail medical visits compared with daily SLB medication administration (mean [SD] visits per day: XRB, 0.11 [0.03] vs SLB, 1.06 [0.08]). Community buprenorphine treatment retention at week 8 postrelease was 18 participants in the XRB group (69.2%) vs 9 in the SLB group (34.6%), and rates of opioid-negative urine tests were 72 of 130 tests in the XRB group (55.3%) and 50 of 130 tests in the SLB group (38.4%). There were no differences in rates of serious adverse events, no overdoses, and no deaths. CONCLUSIONS AND RELEVANCE: XRB was acceptable among patients currently receiving SLB, and patients had fewer in-jail clinic visits and increased community buprenorphine treatment retention when compared with standard daily SLB treatment. These results support wider use and further study of XRB as correctional and reentry OUD treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03604159

research regulations, and institutional research policies and procedures. The Principal 28

Investigator will assure that no deviation from, or changes to the protocol will take place 29 without prior agreement from the sponsor and documented approval from the Institutional 30

Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the 31 trial participants. All personnel involved in the conduct of this study have completed Human 32

Subjects Protection Training. 

Buprenorphine, a partial μ-opioid receptor agonist, was approved by the Food and Drug 210

Administration in 2002 as office-based pharmacotherapy for opioid dependence. As an 211 opioid partial agonist, buprenorphine can produce some opioid-like effects such as euphoria 212

or respiratory depression, however, its maximal effects are less than those of full agonists 213 like heroin and methadone. At low doses Buprenorphine produces sufficient agonist effect to 214 enable opioid-addicted individuals to discontinue the misuse of opioids without experiencing 215 withdrawal symptoms. Buprenorphine's opioid effects increase with each dose until at 216 moderate doses they level off, even with further dose increases. This "ceiling effect" lowers 217 the risk of misuse, dependency, and side effects (1) . 218

Monthly, injectable, buprenorphine extended-release (XRB, Sublocade TM , Indivior) is the 220 most recently approved pharmacotherapy for opioid use disorders in the U.S.(2). XRB is 221

available as of March-2018 in a pre-mixed subcutaneous formulation, administered monthly, 222

and equivalent to a 16-24mg/day maintenance dose of sublingual buprenorphine-naloxone 223

(SLB). In this pilot proposal, Buprenorphine extended-release (XRB) or sublingual 224 buprenorphine (SLB) daily maintenance will be provided per usual Opioid Treatment 225

Program protocols in-jail and prior to release. Both medications will be available through the 226 study and the Bellevue Hospital Addiction Medicine clinic free-of-charge. XRB consists of a 227 once monthly abdominal subcutaneous injection using a pre-filled syringe, per usual 228 package insert instructions. SLB is a delivered daily by observed dosing in-jail (controlled 229

substances are not self-administered in-jail). Post-release, all participants may elect to 230

continue SLB maintenance with the Bellevue Primary Care Addiction Medicine clinic, or may 231 pursue SLB maintenance from non-NYU/Bellevue community providers. SLB is available 232 free of charge to uninsured patients at Bellevue Hospital Center, or participants may fill SLB 233

prescriptions at community pharmacies. SLB medication will not be provided by the study 234

itself. 235

In 2016, opioids were involved in 42,249 deaths and opioid overdose deaths were five times 237 higher than in 1999 (3). On average, 115 Americans die every day from an opioid overdose 238

(4). The opioid and overdose epidemic has intensified efforts to expand and optimize 239 effective medication treatment for opioid use disorder (methadone, extended-release 240 naltrexone, buprenorphine) in criminal justice and primary care populations. Despite the 241 effectiveness of methadone and buprenorphine maintenance as standard of care in NYC 242 jails, only about 30% of individuals initiating buprenorphine maintenance in-jail successfully 243 link to community treatment post-release. XRB is newly FDA approved and its effectiveness 244

in a criminal justice setting is promising but untested. 245 246 247

The opioid epidemic in the United States continues to worsen. New York City currently has a 250 robust methadone and buprenorphine maintenance program for adults with opioid use 251 disorder (OUD). However, despite these standards-of-care, outcomes for all OUD patients, 252

including buprenorphine patients, in NYC following release from jail are in need of 253 improvement. Overdose rates in NYC continue to worsen, including among recently 254 incarcerated individuals (5 

Any relapse to illicit opioid and other drug and alcohol use among any of the two treatment 333 arms after release from jail (or while incarcerated) implies a risk of death and disability, and 334 some proportion of participants in all three arms can be expected not to respond to 335 treatment and resume opioid and/or other drug and alcohol use. All participants relapsing 336

post-release and struggling with on-going drug and alcohol use will be counseled and 337

referred by staff to any appropriate treatment modalities, including the immediately available 338

addiction services available at Bellevue Hospital (emergency detoxification with referral to 339 residential treatment or supportive housing, methadone treatment, buprenorphine, intensive 340 outpatient, dual diagnosis). 341

Sublingual Buprenorphine-Naloxone Treatment Arm. The risks of SLB are the usual risks 342 experienced by any patient as part of standard of care buprenorphine maintenance, which is 343 first-line treatment for opioid use disorders in NYC jails and in the community. Persons 344 receiving SLB may experience several common side effects such as drowsiness, dizziness, 345

constipation, or headaches. The SLB arm will otherwise not be exposed to risks beyond 346 those of usual care, which will be provided by existing jail and community partners. Further, 347

participants in the SLB arm will have already agreed to these risks and benefits of an SLB 348 treatment program prior to recruitment and enrollment, as their choice to engage in jail SLB 349

will have been established well before enrollment, which will occur at the end of the 350 incarceration period. 351

Buprenorphine Extended-Release Treatment Arm. XRB carries the same potential systemic 352

buprenorphine-related side effects as SRB. XRB also carries risks from the injection.

Injection site soreness is possible and usually well tolerated. More severe injection site 354 reactions, although rare, include swelling, itching, and pain. All injections sites will be 355 inspected and monitored by study clinicians. 356

increases the risk of adverse reactions including overdose, respiratory depression, and 358

death. Urine toxicology biometric tests will be used to ensure persons receiving both SLB 359

and XRB have not taken any other substances. Participants will be educated regarding the 360 risks of concomitant use of benzodiazepines, sedatives, opioid analgesics and alcohol. 361

Additionally, if a participant requires opioids for any medical treatment once on 362 buprenorphine, they will likely not have adequate pain relief from usual doses of opioid pain 363 medications. Participants should tell the treating clinician that they are participating in this 364

clinical study and will need non-opioid pain relief or higher doses of opioid pain medications 365 for their condition, which they should receive only in a monitored medical setting, such as an 366 emergency room. As a result, participants may experience higher level of pain. 367

Risk/Benefit Ratio: Most of the risks described are expected adverse events associated with 368 XRB and SLB, or those of baseline opioid dependence and jail-to-community ETAU or MTP. 369

The risks of the active treatment arms, XRB and SLB are likely small compared to the 370 expected benefit of discontinuing opioid use. 371 372 373 

Primary Aim hypothesis: We hypothesize that XRB will be a feasible, effective, and 376 preferred/accepted medication assisted therapy for OUDs in jail as compared to SLB. 377 Secondary Aim 1 hypothesis: We hypothesize that XRB will be more effective in improving 378

rates of community treatment initiation/continuation post-release as compared to SLB. 379

Secondary Aim 2 Hypothesis: We hypothesize that XRB will be more effective in decreasing 380

illicit opioid use post-release as compared to SLB. 381

Secondary Aim 3 Hypothesis: We hypothesize that the use of XRB vs. SLB will lead to 382

better outcomes in the context of XRNTX, ETAU, and Methadone outcomes accrued in the 383 larger SOMATICS-XOR RCT. 384

Feasibility and Implementation: Estimate the feasibility and ease of use of XRB vs. SLB as 386 measured by initial patient preference and acceptability, in-treatment patient satisfaction, 387 patient qualitative interviews, jail visit frequency and program cost estimates, and rates of 388 medication diversion. 

This is a phase IV, 8 week, pilot proof-of-concept randomized controlled trial, open-label and 401

unblinded of XRB vs SLB (N=50) that takes advantage of the existing SOMATICS-XOR U01 402

(NIDA) trial design. 403

This is an 8 week pilot RCT. 405

The study has received 50 doses of in-kind Sublocade TM study medication from the 406 manufacturer, Indivior as of September 13, 2019. With this new stock of medication, we 407

would like to offer all participants the option of a therapeutic treatment extension of 24 408 weeks post study visit 5 week 8. Active treatment will continue after the Week 8 study visit 409

through Week 20 wherein participants will be eligible to receive initial and/or additional XRB 410 injections. A safety visit, in which no medication is administered, will be conducted at Week 411 24 to document safety reporting and provide post-study treatment referrals. 412

This 24 week therapeutic extension will be offered to all interested participants regardless of 413 their treatment assignment after the completion of Visit 5 Week 8. Only Sublocade TM 414

injections will be offered, no additional forms of compensation will be provided. 415

This is a multi-site pilot, RCT. Participants (N=50) will be recruited from Rikers Island NYC 417

Jail and will then complete all follow-up visits at Bellevue Hospital Center in NYC. The NYU 418

School of Medicine Institutional Review Board (IRB) is serving as the IRB of record for 419

Health+Hospitals involvement in this research study. buprenorphine, this pilots target population, and 500-800 daily with methadone maintenance. 431

All follow-up will be conducted at the Bellevue Hospital Center's Adult Primary 432

Care Clinic and its Addiction Medicine clinic, which is currently a routine aftercare referral for 433 jail patients continuing buprenorphine in the community and the site of the current NYU-434 NIDA U01 XOR trial. Patient's lost-to-follow-up and out-of-contact are tracked by study staff 435

in the community whenever possible, including in-person door-knocking by Study Staff 436 throughout the 5 boroughs and northern New Jersey. 437

The primary outcome of in-jail feasibility and acceptability will be measured by the percent of 439 eligible participants who enroll in the study, the mean medical/medication visits per arm and 440 regarding treatment satisfaction and ease of use. Additional qualitative interviews will be 442 conducted with eligible participants to further examine opioid use disorder treatment with 443 extended-release buprenorphine, in-jail and within the community. 444

Secondary Aims 1-3 will be measured utilizing the following assessments: baseline 446 demographics, baseline ASI-Lite, baseline MOUD (medication treatment for opioid use 447 disorder) exposure/preference, Timeline Followback, urine toxicology results, treatment 448 retention, and NYS Prescription Monitoring Data. XRNTX, ETAU, and Methadone outcomes 449 will be taken from the SOMATICS-XOR U01 parent study. 450

Adult jail inmates with upcoming release date, current opioid dependence and currently 452 maintained on sublingual buprenorphine-naloxone (N=50). 453

N=50. A total sample size of N=50 would allow for an estimate of an Odds Ratio of 2.0-3.0 455

for the rate of persons successfully in community buprenorphine treatment at 4 weeks post-456 release (71% vs. 30% success favoring XRB; two-sided alpha of 0.05; 80+% power). 457

Inclusion criteria 459 1) Adults >18yo incarcerated in NYC jails with known release dates. investigator provides to the Board justification in writing for following some other procedures, 500

control subjects must be selected randomly from the group of available prisoners who meet 501 the characteristics needed for that particular research project. Jail authorities have no role in 502 this study or in treatment assignment, which is random. 503

(5) The information is presented in language which is understandable to the subject 504 population. The informed consent and consent quiz are intended to be understandable to 505 adults in jail. 506 (6) Adequate assurance exists that parole boards will not take into account a prisoner's 507 participation in the research in making decisions regarding parole, and each prisoner is 508

clearly informed in advance that participation in the research will have no effect on his or her 509

parole; There is no role for, relationship, or other interaction with parole or probation 510 authorities and this study. 511 participants will be eligible for a 24 week therapeutic extension study wherein they are 519 offered initial and/or additional XRB injections. These will occur monthly post study week 8: 520

week 12, week 16, week 20, week 24, and week 28. A final safety visit, no medication 521 administered, will be conducted at week 32 to document safety reporting and provide post-522 study treatment referrals. 523 completely. Participants in the SLB treatment arm will be provided SLB daily by observed 544

dosing in-jail (controlled substances are not self-administered in-jail) and encouraged to 545

continue SLB treatment in weekly, bi-weekly, or monthly quantities for unobserved, daily, 546

self-administration through week 5. Patients may obtain SLB care free-of-charge from the 547

Bellevue Hospital Center Addiction Medicine clinic or from non-NYU/Bellevue providers and 548 pharmacies per usual care standards. After the completion of Visit 5 Week 8, SLB 549 participants will be offered XRB treatment in the 20 week therapeutic extension. If 550 interested, participants would receive one or more XRB injections during the period of 551

Weeks 8, 12, 16, 20, 24, and 28 followed by a final safety documentation visit at Week 32. 552

This pilot will recruit from within the standard-of-care NYC jail opioid treatment program, led 555 by the program director, Jonathan Giftos, MD. Potential participants currently maintained on 556

sublingual buprenorphine (currently a NYC jail standard of care) will be offered study 557

information and encouraged to enroll. Interested participants will be referred by the Opioid 558

Treatment Program staff to Study Staff for further education about the trial and to schedule 559 written informed consent and a comprehensive screening visit. Consented and eligible 560 participants will be randomized by sealed envelope or a web-based randomizer 1:1 to the 2 561 study cells: XRB and SLB. 562

This is an 8-week, open-label, single site, proof-of-concept randomized controlled trial. 564

There is no blinding of treatment assignment or of outcomes assessments. 100 mg/0.5 mL and 300 mg/1.5 mL buprenorphine. Each dose is provided in a prefilled 568 syringe with a 19 gauge 5/8-inch needle. The recommended dose of XRB following 569 induction and dose adjustment with transmuscosal buprenorphine is 300 mg monthly for the 570 first two months followed by a maintenance dose of 100 mg or 300mg monthly. We will offer 571 both 300mg and 100mg doses pre-release and at week 4 post-release. Each dose is 572 supplied in an individual kit and will be acquired in bulk shipments from the supplier Indivior. 573

At the outset of this study and original IRB approval, it was proposed that each participant 574 randomized to the XRB (SUBLOCADE) treatment arm would receive up to two injections of 575 XRB, each 300mg according to the medication package insert. However, the study has 576 since been modified to include a therapeutic treatment extension of 24 additional weeks 577

post Visit 5 Week 8 in which initial and/or additional XRB injections would be offered to all 578 interested participants (see section 5.1.1). With this therapeutic extension, eligible & 579 interested participants could receive 4+ XRB injections in the community. With this in mind, 580

the study must expand the planned XRB dosage to include the 100mg formulation of XRB. 581

As the XRB package insert states, the recommended dose of XRB following induction is 582 300mg monthly for the first two months followed by a maintenance dose of 100mg or 583 300mg monthly. The study must have the capability to offer eligible participants receiving a 584 third XRB injection the lower, recommended maintenance dose of 100mg in addition to the 585 standard 300mg. 586

Sublingual Buprenorphine (SUBOXONE, Zubsolv, or generic tablets): SLB is administered 587

sublingually or buccally as a single daily dose. Medication should be prescribed in 588

consideration of the frequency of visits. Provision of multiple refills is not advised in early 589 treatment or without appropriate follow-up visits. After treatment induction and stabilization, 590

the maintenance dose of SLB is generally in the range of 4mg/1mg buprenorphine/naloxone 591 to 24mg/6mg buprenorphine/naloxone per day depending on the individual patient and 592 clinical response, as determined by the clinician. Daily doses will vary by individual. The 593

recommended target dose of SLB during maintenance is 16mg/4mg 594 buprenorphine/naloxone. SLB will be prescribed and provided via observed dosing in-jail 595 (controlled substances are not self-administered in-jail) per usual care protocols. Post-596 release, all participants may elect to continue SLB maintenance with the Bellevue Primary 597

Care Addiction Medicine clinic, or may pursue SLB maintenance from non-NYU/Bellevue 598 community providers. SLB is available free of charge to uninsured patients at Bellevue 599

Hospital Center, or participants may fill SLB prescriptions at community pharmacies. SLB 600 medication will not be provided by the study itself. Self-report, BHC EMR records, and NYS 601

Prescription Monitoring Plan audits will document SLB post-release community treatment 602 retention, daily dose, and refill frequencies. (prescription monitoring program) registries will be accessed in order to track participant 639 data related to respective treatments. Additional qualitative interviews will be conducted with 640

eligible XRB participants to further examine opioid use disorder treatment with extended-641 release buprenorphine, in-jail and within the community. 642

The primary outcome of in-jail feasibility and acceptability will be measured by the percent of 644 eligible participants who enroll in the study, the mean medical/medication visits per arm and 645

per participant, the incidence rates of medication diversion, and open-ended interviews with 646 patients regarding treatment satisfaction and ease of use. 647 Secondary Aims 1-3 will be measured utilizing the following assessments: baseline 648 demographics, baseline ASI-Lite, baseline MOUD exposure/preference, Timeline 649

Followback, urine toxicology results, treatment retention, and NYS Prescription Monitoring 650

Data. XRNTX, ETAU, and Methadone outcomes will be taken from the SOMATICS-XOR 651 U01 parent study. 652

XRB and SLB are both FDA approved, safe, efficacious medications for the treatment of 654 opioid use disorder. As with most medications both XRB and SLB carry side effects as 655 detailed above. Participants will be monitored throughout this pilot RCT by study physicians, 656

all adverse events and/or serious adverse events will be documented and medication will be 657 discontinued if necessary. Women who are pregnant or plan to become pregnant will be 658 excluded from this pilot RCT. 659

For the purposes of this pilot, proof-of-concept, RCT and follows a clinically reasonable response on withdrawal (dechallenge). 718

Rechallenge information is not required to fulfill this definition. 719  Possibly Related -There is some evidence to suggest a causal relationship (e.g., 720

the event occurred within a reasonable time after administration of the trial 721 medication). However, other factors may have contributed to the event (e.g., the 722 participant's clinical condition, other concomitant events). Although an AE may rate 723 only as "possibly related" soon after discovery, it can be flagged as requiring more 724

information and later be upgraded to "probably related" or "definitely related," as 725 appropriate. 726  Unlikely to be related -A clinical event, including an abnormal laboratory test result, 727 whose temporal relationship to drug administration makes a causal relationship 728

improbable (e.g., the event did not occur within a reasonable time after 729 administration of the trial medication) and in which other drugs or chemicals or 730

underlying disease provides plausible explanations (e.g., the participant's clinical 731

condition, other concomitant treatments). 732  Not Related -The AE is completely independent of study drug administration, 733

and/or evidence exists that the event is definitely related to another etiology. There 734 must be an alternative, definitive etiology documented by the clinician. 735 Study clinicians will be responsible for determining whether an AE is expected or 736

unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 737 event is not consistent with the risk information previously described for the study agent. 738

The pilot study team will record all reportable events with start dates occurring any time after 739

informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the 740 last day of study participation. At each study visit, the investigator will inquire about the 741 occurrence of AE/SAEs since the last visit. Events will be followed for outcome information 742 until resolution or stabilization. 743 744 745

Not applicable. 747

Not applicable. 749

The study procedures are detailed below. 751

The total number of expected visits per participant is 6 visits. All participants will be given 753 the option to participate in a 24 week therapeutic extension study of XRB treatment 754

following completion of Visit 5 Week 8. If a participant elects to continue and/or initiate XRB 755 treatment, there will be 12 total visits per participant. The average time needed to complete 756 each visit will be approximately one hour. The initial week 0 screening and randomization 757 visit will be conducted in a Rikers Island jail facility in the Opioid Treatment Program. Once 758

consented, enrolled, and randomized, buprenorphine extended-release (XRB) or sublingual 759 buprenorphine (SLB) daily maintenance will provided per usual Opioid Treatment Program 760 protocols in-jail and prior to release. The timing between randomization and release will 761

vary. Typical misdemeanor sentences in NYC are 30-60 days, and participants may 762 randomize at any time during this incarceration period, begin XRB vs. SLB treatment, and 763 then leave jail after weeks-to-months. This variable, naturalistic, in-custody study period 764

remains Study Week 0. Study Week 1 commences with the day of release from jail. Post-765 release, all study visits will be conducted at Bellevue Hospital Center's (BHC) Addiction 766

Medicine clinic. Medical and research visits will be conducted weekly and then bi-weekly for 767

both medication arms post-release (week 1 post-release, week 2, week 4, week 6, week 8).

The medication schedule for both arms is as follows: 769

Buprenorphine Extended-Release: Participants randomized to this arm will receive at least 770 two doses of XRB. The first will be administered at study week 0 in-jail, at least one week 771 prior to release. Participants incarcerated for greater than 4 weeks following randomization 772 will receive 2+ XRB doses prior to release. Post-release, XRB injections will be administered 773

at study week 1-16 in the BHC Addiction Medicine clinic depending on the timing of the 774 previous pre-release/community injections. 775

Sublingual Buprenorphine: Participants randomized to this arm will be provided SLB daily 776 maintenance per usual Opioid Treatment Programs protocols in-jail. Post-release, SLB arm 777 participants will receive follow-up care at Bellevue Hospital's Addiction Medicine or at non-778 BHC/NYU community providers, per their preference. We expect and will encourage most 779 participants to follow-up at Bellevue, though this is not mandated. Typically an initial week's 780 supply of SLB is prescribed within one week of release. At visit 2, week 2, SLB participants 781 typically refill a two week's supply of daily maintenance SLB. SLB participants will continue 782

to receive 2-4 week refill prescriptions for SLB from visit 2, week 2 through visit 6, week 8. 783

Regardless of SLB prescribing patterns, they are encouraged to attend study follow-up visits 784

at BHC per the same study schedule (Weeks 1,2,4,6,8) . After the completion of Visit 5 785

Week 8, SLB participants will be offered XRB treatment in the 24 week therapeutic 786 extension. If interested, participants would receive one or more XRB injections during the 787 procedures, and risks are given to the participant and written documentation of informed 811 consent is required prior to starting intervention/administering study product. Written 812

informed consent including a consent quiz adapted from the parent grant protocol will be 813 used to document informed consent. Participants will have the opportunity to carefully 814 review the written consent form and ask questions prior to signing. The participants may 815 withdraw consent at any time throughout the course of the trial. A copy of the signed 816

informed consent document will be given to the participants for their records. The rights 817

and welfare of the participants will be protected by emphasizing to them that the quality 818 of their medical care will not be adversely affected if they decline to participate in this 819 study. 820

A copy of the signed informed consent document will be stored in the subject's research 821

record. The consent process, including the name of the individual obtaining consent, will be 822 thoroughly documented in the subject's research record. Any alteration to the standard 823 consent process (e.g. use of a translator, consent from a legally authorized representative, 824 consent document presented orally, etc.) and the justification for such alteration will likewise 825 be documented. 826

Potential participants will meet with study staff to learn about study procedures, 828

buprenorphine (XRB and SLB) treatment, and follow-up protocols. A pre-screen checklist 829 will evaluate eligibility. All adult jail inmates with an upcoming release date, current opioid 830 use disorder diagnosis, and currently maintained on sublingual buprenorphine-naloxone will 831 be potential participants. If interested and eligible, participants will complete the informed 832 consent process (ICF and ICF quiz). Once informed consent is obtained, baseline 833 assessments will be administered prior to randomization. Informed Consent and Enrollment/Randomization: Study staff will obtain informed consent 858 via the completion of the informed consent form and informed consent quiz. Consented and 859 eligible participants will be randomized by sealed envelope or a web-based randomizer 1:1, 860 XRB vs. SLB. Medications will be dispensed at the screening/randomization visit in-jail (visit 861 1, week 0) for both arms. All follow-up visits (visit 1-6) will take place at Bellevue Hospital 862

Center's Addiction Medicine clinic and medication (XRB) will be provided free-of-charge. 863 

After completion of the final visit (Visit 5, Week 8), study participation is complete for all 930 participants who do not elect to continue and/or initiate treatment in the 24 week 931 therapeutic extension of XRB treatment. All participants will be provided information on XRB 932

and SLB and will be encouraged to continue treatment with the community opioid treatment 933 provider of their choice. All participants will have the option of accessing services at 934

Bellevue, including buprenorphine and methadone maintenance treatment. It is likely that 935 the majority of participants in both arms will continue on SLB maintenance with the BHC 936

Addiction Medicine clinic. XRB may become a usual care option at BHC during the course 937 of this trial, depending on NYS Medicaid policies and H+H formulary updates. 938

For participants who continue in the 24 week therapeutic extension, after completion of the 939 final safety visit (Visit 11, Week 32), study participation is complete. All participants will be 940 provided the same information as highlighted above. It is likely that the majority of 941 participants in this arm will continue on SLB maintenance with the BHC Addiction Medicine 942

clinic. 943

In-jail feasibility will be assessed during and post study completion as the data is made 944

available. All adverse event and serious adverse event monitoring (SAFTEE) will take place 945 throughout the study and will be documented/reported as necessary. 946

Participation in this pilot, proof-of-concept, RCT is entirely voluntary and participants are free 948

to withdraw at any time. In the event of early study termination, study staff will complete the 949 study termination form, modeled from a CRF of the parent XOR study. Any participant 950

withdrawing from the study prior to full study completion, regardless of study group, stands a 951 risk of relapsing to illicit opioid or other drug/alcohol misuse. The study will assist with 952 treatment referrals for detox services at Bellevue Hospital Center, but will not otherwise 953 directly provide such services or medications. Otherwise any XRB or SLB patient who has 954 relapsed and is not interested in continuing their baseline study condition (i.e., an XRB 955 participant does not wish to continue injections due to side effects or for any other reason) 956

will be encouraged to pursue other appropriate community treatment, the menu of which 957

includes the robust addiction service offerings at Bellevue Hospital Center (BHC). BHC's 958

services are available to all persons, regardless of insurance status or an ability to pay, and 959

include emergency detox inpatient services, methadone treatment, office-based 960 buprenorphine, and intensive outpatient and dual diagnosis programs. These services will 961

consist of usual care occurring outside of the study and will not be directly provided by or 962 paid for by the study. 963 

At the end of a three-year period following study closure, written identifiable data will be 1192 destroyed. De-identified study data will remain in digital and written file storage for a period 1193 of 6 years following study conclusion and protocol close per standard NYU IRB guidelines. 1194 The final de-identifiable digital dataset may be used by the Principal Investigator or Co-1195 Investigator for secondary analysis

Project/Program Manager, and study staff will work to ensure that all information 1199 collected is accurate and properly protected/secured. The Principal Investigator, Dr

will assume responsibility for monitoring of data collection and of participant safety. 1201 Any serious or unexpected adverse event will be reported immediately to: 1) the NYC 1202 DOHMH and NYUSOM-IRBs

Data Safety Monitoring Plan

The DSMB will conduct ongoing protocol 1206 review, including data, protocol compliance, safety and efficacy data, in compliance with 1207 NIDA and NYU IRB guidelines. All board members will meet NIDA requirements regarding 1208 background and experience, and none will have ethical conflicts, including financial interest 1209 related to study outcome. Individuals invited to serve on the board will disclose any potential 1210 conflicts in writing. The board will meet every six months (unless more frequent meetings 1211 are deemed necessary. Dr. Lee and other research personnel will open each meeting with a 1212 report on the trial's status, followed by a closed session under the direction of the DSMB 1213 chairperson, during which time the investigators and research team may be present. This 1214 will be followed by an executive session restricted to DSMB members

Following each DSM Board meeting, 1217 recommendations will be made to Dr. Lee, and a final report (edited by all Board members) 1218 will be prepared for reporting to NIDA, the DOHMH and NYU IRBs. The Data Safety 1219

Monitoring Plan (DSMP) includes stopping rules that specify the outcome differences 1220 detected between groups during an interim analysis that can result in stopping the pilot trial. 1221 In general, stopping rules will reflect one of the following conditions: 1) there is clear 1222 evidence of harm or harmful side-effects of the treatment; 2) there is not likelihood of 1223 demonstrating treatment benefit; 3) there is overwhelming evidence of the benefit of the 1224 treatment. However because we are comparing alternative paradigms involving a study 1225 medication (XRB) or community treatment as usual (SLB) that are already FDA-approved as 1226 opioid treatment and do not suggest significant safety considerations

Study Modification

All modifications will be submitted to the NYU IRB for review. All IRB approved 1231 modifications will be stored in regulatory binders. If the IRB determines changes to the 1232 protocol must be made, the protocol will be edited, submitted for NYU IRB review

The National Alliance of Advocates for Buprenorphine Treatment. What exactly is Buprenorphine 1272

FDA Approves SUBLOCADE TM (Buprenorphine Extended-Release), the First and Only 1274

Once-Monthly Injectable Buprenorphine Formulation to Treat Moderate to Severe Opioid Use 1275

Wide-ranging online data for epidemiologic research (WONDER

Death After Jail 1279 Release

Personal Communication, 2/1/2018. Medical Director, Opioid Treatment Program

Buprenorphine and methadone maintenance in jail and post-release: a randomized clinical trial

Buprenorphine-naloxone maintenance following release from jail

Criminal 1287 justice continuum for opioid users at risk of overdose

1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in this trial, which includes performing any screening procedures, medication washout and any restrictions. 2. HIPAA authorization must be obtained on all patients participating in the study at Visit1. 3. Clinical Assessment must be completed per protocol instructions and by the treating investigator for that specific patient. 4. These instruments will be available for each visit, however they may/may not be filled out depending on participant's interaction with CJS 5. X = XRB, # = SLB; dispensation schedule varies depending on release date 6. Emotional Discomfort: There is a small chance that participants may become upset when 996 discussing their history of addiction problems, criminal justice involvement, family conflict, 997prior trauma, or role failure, etc. We will discontinue administration of research instruments 998if a subject shows great discomfort or asks to terminate an interview. Such events have not 999 been observed in our preliminary studies. 1000

The protocol, informed consent form(s), recruitment materials, and all participant materials 1002will be submitted to the appropriate IRB and institutional research committees for review and 1003approval. Approval of both the protocol and the consent form must be obtained before any 1004 participant is enrolled. Any amendment to the protocol will require review and approval by 1005the IRB before the changes are implemented to the study. All changes to the consent form 1006 will be IRB approved; a determination will be made regarding whether previously consented 1007 participants need to be re-consented. 1008

Participants will be asked to provide information regarding a number of sensitive behaviors 1010 (e.g., alcohol and drug use, sexual history, criminal history and on-going illicit activities).

This type of personal information divulged by participants at study visits may have adverse 1012 social and other unknown consequences for participants if released. Therefore, in addition 1013to the safeguards put in place for the collection and storage of all data as described above 1014(section 11.0 Data Collection and Management), the study team obtained a Federal 1015Certificate of Confidentiality (COC #DA-13-154) to encompass protocol activity and further 1016 safeguard the possible risk of released confidential information. We will provide all staff with 1017 training in their responsibilities for maintaining subject confidentiality; we will use unique 1018identifiers to identify subjects in the database; all data will be kept in locked filing cabinets or 1019 on our secure server to which only the investigators and project manager will have access 1020to. Study findings will utilize only aggregate data and no publication or presentation will 1021involve any use of individual information. 1022

Procedures procedure #26. To satisfy the requirement for prompt reporting, UPs will be reported using the following 1066timeline: 1067UPs that are SAEs will be reported to the IRB and to the DCC/study sponsor within 30 days 1068 of the investigator becoming aware of the event. Any other UP will be reported to the IRB 1071 and to the DCC/study sponsor within 30 days of the investigator becoming aware of the 1072 problem. All UPs should be reported to appropriate institutional officials (as required by an 1073institution's written reporting procedures), the supporting agency head (or designee), and 1074OHRP within 30 days of the IR's receipt of the report of the problem from the investigator. 1075

Study clinicians and research staff will undergo the same baseline training at the inception 1077 of the study. The Program/Project Manager and Data Management staff will ensure the 1078 quality of the clinicians' and the research assistants' administration of study assessments 1079and instruments and of integrity of the data recorded through regular reviews and on-going 1080 data monitoring. 1081

Electronic case report forms (CRFs) will be used to manage the data for this study, and the 1083Project Manager will work with study personnel to ensure the completeness and integrity of 1084 all study data. These electronic CRFs will be taken from the parent XOR U01 NIDA study. 1085All data will be checked in real time, stored in a centralized database, reviewed and 1086 monitored for completeness and accuracy, and undergo a final cleaning following the last 1087 subject visit, following which the study database will be locked. REDCap will be the data 1088 entry and database platform for this study. Health office cabinet. These charts will be accessed to call and follow-up with patients post-1093 release and to maintain the ICF on file. Participants will be assigned sequentially numbered 1094 unique study ID numbers at the time of consent (e.g. #001-50). These ID numbers will be 1095 the only identifier entered on Case Report Forms (CRF) and research assessments to 1096 distinguish one participant from another. Secure laptops will be used for web-based data 1097 entry, CRF variables will be input into a secure central database on an NYULMC server. 1098The laptops themselves will be password-protected, but will not store PHI, study ID number 1099 information or any research assessment data and will be used for web-based data entry 1100only. To maintain a link between the study ID and PHI for purposes of follow-up and record-1101 keeping, individual participant charts and research assessment/CRF data there will be a 1102 master participant ID key that will contain each participant's PHI (name, DOB) and their 1103 corresponding unique study ID number. This master key identifier file (.xls) will be 1104 maintained by the PI and Project Manager on a secure NYULMC desktop file and 1105 accessible only to study staff. 1106At the end of a three-year period following study closure, written identifiable data will be 1107 destroyed. De-identified study data will remain in digital and written file storage for a period 1108 of 6 years following study conclusion and protocol close per standard NYU IRB guidelines. 1109The final de-identifiable digital dataset may be used by the Principal Investigator or Co-1110Investigator for secondary analysis, in which case future IRB-approval would be sought. Participants will be assigned sequentially numbered unique study ID numbers at the time of 1143 consent (e.g. #001-50). These ID numbers will be the only identifier entered on Case Report 1144Forms (CRF) and research assessments to distinguish one participant from another. Secure 1145 laptops will be used for web-based data entry, CRF variables will be input into a secure 1146central database on an NYULMC server. The laptops themselves will be password-1147protected, but will not store PHI, study ID number information or any research assessment 1148 data and will be used for web-based data entry only. To maintain a link between the study 1149 ID and PHI for purposes of follow-up and record-keeping, individual participant charts and 1150research assessment/CRF data there will be a master participant ID key that will contain 1151 Information (PHI) will be collected and stored in the form of each participant's original signed 1157informed consent, informed consent quiz, randomization form, and locator form. These 1158 written documents will be filed as individual charts and locked securely in a private 1159Department of Population Health office cabinet. These charts will be accessed to call and 1160follow-up with patients post-release and to maintain the ICF on file. Participants will be 1161 assigned sequentially numbered unique study ID numbers at the time of consent (e.g. #001-1162 50). These ID numbers will be the only identifier entered on Case Report Forms (CRF) and 1163research assessments to distinguish one participant from another. Secure laptops will be 1164 used for web-based data entry, CRF variables will be input into a secure central database 1165on an NYULMC server. The laptops themselves will be password-protected, but will not 1166 store PHI, study ID number information or any research assessment data and will be used 1167for web-based data entry only. To maintain a link between the study ID and PHI for 1168purposes of follow-up and record-keeping, individual participant charts and research 1169 assessment/CRF data there will be a master participant ID key that will contain each 1170 participant's PHI (name, DOB) and their corresponding unique study ID number. This 1171master key identifier file (.xls) will be maintained by the PI and Project Manager on a secure 1172 NYULMC desktop file and accessible only to study staff. All hard copy CRFs labeled only 1173with ID numbers will be filed in subject files, numbered sequentially. These subject files will 1174 be kept in a securely locked, Additionally, this pilot, proof-of-concept, RCT has been approved by NIDA for the period of 1 1238year only. Study termination may be possible in the event of overwhelmingly significant 1239 efficacy differences between groups or unacceptable adverse events. 1240

The study has an estimated completion date of June 29, 2019. 1242

The independence of this pilot from any actual or perceived influence, such as by the 1244 pharmaceutical industry, is critical. Therefore any actual conflict of interest of persons who 1245 have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 1246 disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 1247 be required to have such conflicts managed in a way that is appropriate to their participation 1248in the trial. The study leadership in conjunction with the NYU IRB has established policies 1249and procedures for all study group members to disclose all conflicts of interest and will 1250 establish a mechanism for the management of all reported dualities of interest. 1251Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 1252 financial gain greater than the minimum allowable by their institution, etc.) must have the 1253 conflict reviewed by the NYU Langone Conflict of Interest Management Unit (CIMU) with a 1254Committee-sanctioned conflict management plan that has been reviewed and approved by 1255 the study sponsor prior to participation in this study. All NYULMC investigators will follow the 1256 applicable conflict of interest policies. 1257

This pilot is supported by a NIDA Administrative Supplement as part of the on-going XOR 1259 U01 award. 1260Study Number s18-00823December 11, 2019 Version 10