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Abstract: Suicide is the tenth leading cause of death in the United States and continues to be a major public health concern. Suicide risk is highly prevalent among individuals with co-occurring substance use disorders (SUD) and mental health disorders, making them more prone to adverse substance use related outcomes including overdose. Identifying individuals with SUD who are suicidal, and therefore potentially most at risk of overdose, is an important step to address the synergistic epidemics of suicides and overdose fatalities in the United States. The current study assesses whether patterns of suicidality endorsement can indicate risk for substance use and overdose. Latent class analysis (LCA) was used to assess patterns of item level responses to the Concise Health Risk Tracking Self-Report (CHRT-SR), which measures thoughts and feelings associated with suicidal propensity. We used data from 2,541 participants with SUD who were enrolled across 8 randomized clinical trials in the National Drug Abuse Treatment Clinical Trials Network from 2012 to 2021 (CTN-0037, -0049, -0051, -0053, -0054, -0064, -0067, -0068). Characteristics of individuals in each class were assessed, and multivariable logistic regression was performed to examine class membership as a predictor of overdose. LCA was also used to analyze predictors of substance use days. Three classes were identified and discussed: Class (1) Minimal Suicidality, with low probabilities of endorsing each CHRT-SR construct; Class (2) Moderate Suicidality, with high probabilities of endorsing pessimism, helplessness, and lack of social support, but minimal endorsement of despair or suicidal thoughts; and Class (3) High Suicidality with high probabilities of endorsing all constructs. Individuals in the High Suicidality class comprise the highest proportions of males, Black/African American individuals, and those with a psychiatric history and baseline depression, as compared with the other two classes. Regression analysis revealed that those in the High Suicidality class are more likely to overdose as compared to those in the Minimal Suicidality class (p = 0.04). Conclusions: Suicidality is an essential factor to consider when building strategies to screen, identify, and address individuals at risk for overdose. The integration of detailed suicide assessment and suicide risk reduction is a potential solution to help prevent suicide and overdose among people with SUD. Related protocols: CTN-0037, CTN-0049, CTN-0051, CTN-0053, CTN-0054, CTN-0064, CTN-0067, CTN-0068

Abstract:

People living with HIV and opioid use disorder (OUD) are disproportionally affected by adverse socio-structural exposures negatively affecting health, which have shown inconsistent associations with uptake of medications for OUD (MOUD). This study aimed to determine whether social determinants of health (SDOH) were associated with MOUD uptake and trajectories of substance use in a clinical trial of people seeking treatment.

Data are from a 2018 to 2019 randomized trial (CTN-0067, CHOICES) comparing the effectiveness of different MOUD to achieve viral suppression among people living with HIV and OUD. SDOH were defined by variables mapping to Healthy People 2030 domains: education (Education Access and Quality), income (Economic Stability), homelessness (Neighborhood and Built Environment), criminal justice involvement (Social and Community Context), and recent SUD care (Health Care Access and Quality). Associations between SDOH and MOUD initiation were assessed with Cox proportional hazards models, and SDOH and substance use over time with generalized estimating equation models.

Participants (N=114) averaged 47 years old, 63% were male, 56% were Black, and 12% Hispanic. Participants reported an average of 2.3 out of 5 positive SDOH indicators (SD=1.2). Stable housing was the most commonly reported SDOH (61%), followed by no recent criminal justice involvement (59%), having a high-school level education or greater (56%), income stability (45%), and recent SUD care (13%). Each additional favorable SDOH was associated with a 25% increase in the likelihood of MOUD initiation during the study period [adjusted HR=1.25, 95% CI=(1.01, 1.55), P=.044]. Positive SDOH were also associated with a decrease in the odds of baseline opioid use and a greater reduction in opioid use during subsequent weeks of the study (P<.001 for a joint test of baseline and slope differences).

Conclusions: Positive social determinants of health, in aggregate, may increase the likelihood of MOUD treatment initiation among people living with HIV and OUD.

Related protocols: CTN-0067

Abstract:

This study was a secondary analysis of two CTN trials comparing buprenorphine (BUP-NX) and extended-release naltrexone (XR-NTX), CTN-0051, X:BOT and CTN-0067, CHOICES. The purpose was to estimate how ongoing stimulant use affects return to illicit opioid use after initiation onto medication for opioid use disorder (MOUD).

A total of 528 participants who initiated MOUD as part of trial participation were included; participants were recruited from 13 opioid treatment programs and HIV clinics across 10 states in the U.S. from 2014-2019. Nearly half (49%) were between 30 and 49 years of age, 69% were male and 66% were non-Hispanic White.

The primary outcome was first self-reported day of non-prescribed opioid use following MOUD initiation, and the exposure of interest was daily stimulant use (methamphetamine, amphetamines or cocaine). Both were defined using time-line follow-back. Among participants reporting at least 1 day of illicit opioid use, we also examined relapse to ongoing use, defined as (1) 7 days of continuous opioid use or (2) 4 consecutive weeks with self-reported opioid use, one or more positive urine drug screens (UDS) for opioids or one or more missing UDS.

Forty-seven per cent of participants reported stimulant use following MOUD initiation, 58% returned to illicit opioid use and 66% of those relapsed to ongoing use. Stimulant use was strongly associated with increased risk of misusing opioids after MOUD initiation when measured daily [adjusted hazard ratio (aHR)=9.23, 95% confidence interval (CI)=6.80–12.50, P<0.001] and over a 7-day period (aHR=1.27 for each additional day, CI=1.18–1.37, P<0.001). Using stimulants weekly or more often was associated with increased likelihood of relapse to ongoing opioid use compared with less than weekly or no stimulant use (adjusted odds ratio=2.30, CI=1.05–5.39, P=0.044).

Conclusions: People initiated on medication for opioid use disorder who subsequently use stimulants appear to be more likely to return to and continue using non-prescribed opioids compared with those without stimulant use. The association appears to be stronger among patients who initiate buprenorphine compared with those who initiate extended-release naltrexone.

Related protocols: CTN-0051, CTN-0067

Abstract:

Co-use of stimulants and opioids is rapidly increasing. Randomized clinical trials (RCTs) have established the efficacy of medications for opioid use disorder (MOUD), but stimulant use may decrease the likelihood of initiating MOUD treatment. Furthermore, trial participants may not represent “real-world” populations who would benefit from treatment.

We conducted a two-stage analysis. First, associations between stimulant use (time-varying urine drug screens for cocaine, methamphetamine, or amphetamines) and initiation of buprenorphine or extended-release naltrexone (XR-NTX) were estimated across two RCTs (CTN-0051 X:BOT and CTN-0067 CHOICES) using adjusted Cox regression models. Second, results were generalized to three target populations who would benefit from MOUD: Housed adults identifying the need for OUD treatment, as characterized by the National Survey on Drug Use and Health (NSDUH); adults entering OUD treatment, as characterized by Treatment Episodes Dataset (TEDS); and adults living in rural regions of the U.S. with high rates of injection drug use, as characterized by the Rural Opioids Initiative (ROI). Generalizability analyses adjusted for differences in demographic characteristics, substance use, housing status, and depression between RCT and target populations using inverse probability of selection weighting.

Analyses included 673 clinical trial participants, 139 NSDUH respondents (weighted to represent 661,650 people), 71,751 TEDS treatment episodes, and 1,933 ROI participants. The majority were aged 30–49 years, male, and non-Hispanic White. In RCTs, stimulant use reduced the likelihood of MOUD initiation by 32% (adjusted HR [aHR]=0.68, 95% CI 0.49–0.94, p=0.019). Stimulant use associations were slightly attenuated and non-significant among housed adults needing treatment (25% reduction, aHR=0.75, 0.48–1.18, p=0.215) and adults entering OUD treatment (28% reduction, aHR=0.72, 0.51–1.01, p=0.061). The association was more pronounced, but still non-significant among rural people injecting drugs (39% reduction, aHR=0.61, 0.35–1.06, p=0.081). Stimulant use had a larger negative impact on XR-NTX initiation compared to buprenorphine, especially in the rural population (76% reduction, aHR=0.24, 0.08–0.69, p=0.008).

Conclusions: Stimulant use is a barrier to buprenorphine or XR-NTX initiation in clinical trials and real-world populations that would benefit from OUD treatment. Interventions to address stimulant use among patients with OUD are urgently needed, especially among rural people injecting drugs, who already suffer from limited access to MOUD.

Related protocols: CTN-0051, CTN-0067

Abstract:

As the U.S. grows more diverse, researchers decide how to include non-English speakers. Budget limitations may not allow for translation of all instruments. Study teams must determine which instruments must receive certified translations. This paper describes the procedures used in one U.S.-based, multi-site clinical trial to decide which study instruments should undergo certified translation and discusses dialect review procedures.

The team for NIDA Clinical Trials Network protocol CTN-0067 (the CHOICES-2 study) determined which instruments (n=31) would be translated using a qualitative evaluation to determine the need to obtain a Spanish-language certified translation: 1) “Could the meaning of these questions change (and potentially elicit a different response) if the translations were not consistent?” and 2) “Is it acceptable to have potential inconsistencies in these data?” Instruments for which question 1 was “yes” and question 2 was “no” (e.g., eligibility, outcomes, safety) were marked for certified translation. A dialect committee reviewed all translated patient-reported outcome measures to ensure that the translations had accounted for different meanings of words based on respondents’ countries or regions of origin and recommended changes where necessary.

Fourteen interview-based instruments underwent certified forward-only translation into U.S. Spanish. The remaining 2 interview-based instruments were translated via real-time conversation with participants by bilingual staff. Six forms were administrative and not translated. Five out of 9 professionally translated patient-reported outcome measures were amended to better reflect relevant dialects.

Conclusions: In the absence of specific guidance, it is feasible for study team members to 1) determine which instruments should undergo certified translation and 2) incorporate dialect into translations.

Related protocols: CTN-0067

Abstract:

Increasing rates of overdose and overdose deaths are a significant public health problem. Research has examined co-occurring mental health conditions, including suicidality, as a risk factor for intentional and unintentional overdose among individuals with substance use disorder (SUD). However, this research has been limited to single site studies of self-reported outcomes.

The current research evaluated suicidality as a predictor of overdose events in 2541 participants who use substances enrolled across eight multi-site clinical trials completed within the National Drug Abuse Treatment Clinical Trials Network between 2012 to 2021 (CTN-0037, -0049, -0051, -0053, -0054, -0064, -0067, and -0068). The trials assessed baseline suicidality with the Concise Health Risk Tracking Self-Report (CHRT-SR). Overdose events were determined by reports of adverse events, cause of death, or hospitalization due to substance overdose, and verified through a rigorous adjudication process. Multivariate logistic regression was performed to assess continuous CHRT-SR score as a predictor of overdose, controlling for covariates.

CHRT-SR score was associated with overdose events (p=0.03) during the trial; the likelihood of overdose increased as continuous CHRT score increased (OR 1.02). Participants with lifetime heroin use were more likely to overdose (OR 3.08).

Conclusions: Response to the marked rise in overdose deaths should integrate suicide risk reduction as part of prevention strategies.

Related protocols: CTN-0037, CTN-0049, CTN-0051, CTN-0053, CTN-0054, CTN-0064, CTN-0067, CTN-0068

Abstract:

This is the primary outcomes paper for CTN-0067.

Opioid agonist medications for treatment of opioid use disorder (OUD) can improve human immunodeficiency virus (HIV) outcomes and reduce opioid use. This study tested whether outpatient antagonist treatment with naltrexone could achieve similar results.

This open-label, non-inferiority randomized trial was set in 6 U.S. HIV primary care clinics, enrolling 114 participants with untreated HIV and OUD (62% male; 56% Black, 12% Hispanic; positive for fentanyl (62%), other opioids (47%), and cocaine (60%) at baseline). Enrollment halted early due to slow recruitment. Participants were randomized into one of two groups: HIV clinic-based extended-release naltrexone (XR-NTX, n=55) or treatment as usual with buprenorphine or methadone (TAU, n=59). Treatment group differences were compared for the primary outcome of viral suppression (HIV RNA =200 copies/mL) at 24 weeks and secondary outcomes included past 30-day use of opioids at 24 weeks.

Fewer XR-NTX participants initiated medication compared with TAU participants (47% vs 73%). The primary outcome of viral suppression was comparable for XR-NTX (52.7%) and TAU (49.2%) (risk ratio [RR] 1.064; 95% confidence interval [CI] 0.748, 1.514) at 24 weeks. Non-inferiority could not be demonstrated, as the lower confidence limit of the RR did not exceed the prespecified margin of 0.75 in intention-to-treat (ITT) analysis. The main secondary outcome of past 30-day opioid use was comparable for XR-NTX vs. TAU (11.7 vs. 14.8 days; mean difference -3.1; 95% CI -8.7, 1.1) in ITT analysis. Among those initiating medication, XR-NTX resulted in fewer days of opioid use compared with TAU in the past 30 days (6.0 vs. 13.6, mean difference -7.6; 95% CI -13.8, -0.2).

Conclusions: A randomised controlled trial found supportive, but not conclusive, evidence that human immunodeficiency virus (HIV) clinic-based extended-release naltrexone is not inferior to treatment as usual for facilitating HIV viral suppression. Participants who initiated extended-release naltrexone used less opioids than those who received treatment as usual.

Related protocols: CTN-0067

Abstract:

CHOICES, CTN-0067, was an open-label, randomized, comparative effectiveness trial of office-based extended-release naltrexone versus treatment as usual in people with untreated opioid use disorder and HIV. This study explored facilitators to recruitment in Miami, a successful recruiting site in the national trial. The mixed-methods study included quantitative surveys of randomized participants, medical record abstraction, and qualitative interviews with study staff. Miami recruited 47 (40.5%) of 116 randomized participants in the six-site national trial. In-depth interviews of study staff (n=6) revealed that Miami had a recruitment approach consisting of street level outreach and a close relationship with the local syringe services program (SSP). Partnership with a local SSP provided access to people living with HIV who inject drugs in Miami.

Conclusions: SSPs’ fundamental trust within the community of people who inject drugs can be leveraged in studies aiming to improve health outcomes in this underserved and high priority population.

Related protocols: CTN-0067

Abstract:

The NIDA Clinical Trials Network protocol CTN-0067, CHOICES, tests implementation of extended-release naltrexone (XR-NTX) versus treatment-as-usual (TAU) for opioid use disorders (OUD) in HIV clinics to improve HIV viral suppression. The study team investigated recruitment strategies to elucidate the barriers and facilitators to recruitment and enrollment in the study.

Semi-structured, in-depth, digitally recorded interviews were completed with study recruitment-related staff and medical providers (n=26) from six participating HIV clinics in the fall of 2018. Interviews probed: 1) factors that might prevent prospective participants from engaging in study recruitment and enrollment procedures, and 2) strategies used by study staff that encourage eligible patient participation. Interviews were transcribed and thematically analyzed using a content analysis approach.

All respondents reported that barriers to recruitment and enrollment included challenging patient social and structural factors (e.g., homelessness or living environments with high substance use, criminal justice involvement), difficulty locating patients with unsuppressed HIV viral load and OUD within the HIV clinic, time-consuming study enrollment processes, and stigma around HIV and OUD which inhibited treatment seeking. Some respondents observed that distrust of research and researchers impeded recruitment activities in the community. A specific medication-related barrier was patient fear of opioid abstinence required prior to XR-NTX induction. Facilitators of recruitment included use of trusted peer outreach/recruitment workers in the community, hospitalizations that offered windows of opportunities for screening and XR-NTX induction, providing participant transportation, and partnerships with harm reduction organizations for referrals.

Conclusions: Though study personnel encountered barriers to recruitment in the CHOICES study, people with untreated HIV and OUD can be enrolled in multisite clinical trials by using enhanced recruitment strategies that extend outside of the HIV clinic. Employing peer outreach workers and collaborating with syringe service programs may be especially helpful in facilitating recruitment and merit inclusion in similar study protocols. Future studies may also want to consider broadening eligibility criteria to include individuals with unsuppressed HIV or targeting the varying drugs of choice in a specific community.

Related protocols: CTN-0067

Abstract:

Institutional Review Boards (IRB) ensure that studies with human subjects are conducted ethically and meet federal standards. When trials include multiple study sites and multiple IRBs, variation in IRB processes and regulatory interpretation may delay implementation. NIH policy now requires that multi-site studies must use a single IRB in order to streamline the review process while maintaining standards for human subjects protection, but little has been documented about the actual use of single IRBs in multi-site trials.

This paper describes the single IRB process used by the Western States Node of the NIDA Clinical Trials Network (CTN) for protocol CTN-0067, a clinical trial testing the use of an opioid antagonist (extended-release naltrexone) versus opioid agonists (buprenorphine or methadone) for opioid use disorders among individuals living with HIV.

Using CTN-0067 as a case study, the authors discuss the processes and challenges associated with using a single IRB. These lessons are also informed by other single IRB experiences within the CTN. The intention of the NIH single IRB policy is to facilitate efficient IRB processes. Advanced planning and transparent communication, however, are critical to avoid stalling IRB approval and protocol implementation. Research teams need to account for local IRB willingness to cede to a single IRB and understand the variations in interpretations of abbreviated reviews.

In order to facilitate the effective use of single IRBs, recommendations include assigning staff at each study site for IRB submission coordination and interaction with the lead site IRB staff, training investigators and key regulatory staff on expectations for working with single IRBs, dedicating a regulatory specialist at the lead site to manage the process, developing a communication plan, and supporting the development of strong working relationships with local regulatory staff and the single IRB. The CTN experiences with single IRBs may provide insights for other investigators.

Related protocols: CTN-0067