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Despite comprising one-fifth of the population, individuals living in rural areas are underrepresented in clinical trials on substance use disorders (SUD). The inclusion of rural residents is critical to reducing disparities in health outcomes and improving adoption of evidence-based interventions for SUDs. The current commentary provides five guiding principles to assist researchers in including rural populations in trials. These principles emphasize including rural communities in the study design phase and throughout the research process, understanding the local rural context, consideration of operationalization of rural in research, suggested adaptions for research, and embracing opportunities for bi-directional and sustainable partnerships. When approached thoughtfully, research funding can catalyze rural capacity, foster durable partnerships, and enrich scientific inference to assist in establishing the evidence-base for SUD research.

This commentary examines methodological and ethical problems encountered when a multi-arm clinical trial loses access to one or more of its arms, using the Retention Phase of the NIDA Clinical Trials Network CTN-0100 study, Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy (RDD) as an example.

RDD is a community-based, multi-site trial testing strategies to reduce dropout from medication treatment for opioid use disorder. Among patients with opioid use disorder initiating buprenorphine treatment, the original design was a 3 by 2 factorial comprising 3 pharmacological conditions (Standard-Dose sublingual buprenorphine–16 mg/day target [SL-BUP 16], High-Dose sublingual buprenorphine–32 mg/day target [SL-BUP 32], or extended-release injectable buprenorphine [XR-BUP]), crossed with 2 behavioral conditions: medical management with vs. without a technology-based digital therapeutic app providing cognitive behavioral therapy lessons and contingency management.

The trial experienced two major disruptions to study interventions: 1) The supply of XR-BUP became temporarily unavailable due to manufacturing problems; and 2) The company supplying the digital therapeutic app went bankrupt, rendering the original app permanently unavailable. Questions considered by the study lead team included: 1) Whether to pause recruitment into the trial altogether or continue recruitment into truncated designs omitting the unavailable interventions; 2) How to account for participants who did not experience full exposure to the halted interventions; 3) Whether to substitute a similar intervention; and 4) The problem of concurrent randomizations, namely that a truncated design does not contain all the concurrent randomizations of the full design, introducing risk of confounding or bias.

This experience from the RDD trial demonstrates how multi-arm clinical trials that lose access to an intervention arm can continue with a truncated design, allowing continued progress on study aims, while balancing methodological purity with the pragmatic imperative to keep the trial running and respect subjects’ participation.

Related protocols: CTN-0100

In addition to the studies underway, CTN participants are planning multi-site clinical trials with emerging results that address HIV/AIDS. The CTN has a HIV/AIDS Special Interest Group (SIG) that meets regularly to discuss study ideas and policy approaches. The SIG provides a supportive place to discuss HIV research related to the CTN, share information with each other about opportunities and developments, promote AIDS ideas and research in the CTN, and link CTN research with the AIDS Research Office of NIDA. The SIG periodically reviews and prioritizes study ideas before they work their way up the organizational hierarchy, and, in the latest CTN Call for Concepts, had developed approximately ten suggestions for HIV-related research studies.

Several studies using the CTN ?platform? have also been fielded with external resources. The term ?platform study? describes extramurally funded research that builds on the CTN infrastructure. Studies can add a dimension to a CTN trial, test an intervention by using the infrastructure of the CTN, focus on CTN programs to understand an issue, include CTN programs in data collection, or provide training or career development in the CTN. Extramurally funded platform studies are addressing such issues as models of care for HIV and hepatitis, integrating medical treatment with addiction treatment, and improving adherence to HIV medications.

The increase in opioid-related overdoses has caused a decrease in average life expectancy, highlighting the need for effective interventions to reduce overdose risk and prevent subsequent overdoses. Peer support specialists (PSSs) offer an appealing strategy to engage overdose survivors and reduce overdose risk, but randomized controlled trials are needed to formalize peer-led interventions and evaluate their effectiveness.

Objective: This National Institute on Drug Abuse Clinical Trials Network (CTN) study is a multisite, prospective, pilot randomized (1:1) controlled trial (CTN protocol 0107) that aims to evaluate the effectiveness of an emergency department (ED)–initiated, peer-delivered intervention tailored for opioid overdose survivors (Peer Intervention to Link Overdose survivors to Treatment [PILOT]), compared with treatment as usual (TAU).

Methods: This study evaluates the effectiveness of the 6-month, PSS-led PILOT intervention compared with TAU on the primary outcome of reducing overdose risk behavior 6 months after enrollment. Adults (aged =18 years; N=150) with a recent opioid-related overdose were identified and approached in the ED. Participants were screened and enrolled, either in the ED or within 7 days of ED discharge at research offices or in the community and then asked to complete study visits at months 1, 3, 6 (end of intervention), and 7 (follow-up). Participants were enrolled at 3 study sites in the United States: Greenville, South Carolina; Youngstown, Ohio; and Everett, Washington. Participants randomized to the PILOT intervention received a 6-month, PSS-led intervention tailored to each participant’s goals to reduce their overdose risk behavior (eg, overdose harm reduction, housing, medical, and substance use treatment or recovery goals). Participants randomized to TAU received standard-of-care overdose materials, education, and services provided through the participating EDs. This paper describes the study protocol and procedures, explains the design and inclusion and exclusion decisions, and provides details of the peer-led PILOT intervention and supervision of PILOT PSSs.

Results: Study enrollment opened in December 2021 and was closed in July 2023. A total of 150 participants across 3 sites were enrolled in the study, meeting the proposed sample size for the trial. Primary and secondary analyses are underway and expected to be published in early 2025.

Conclusions: There is an urgent need to better understand the characteristics of overdose survivors presenting to the ED and for rigorous trials evaluating the effectiveness of PSS-led interventions on engaging overdose survivors and reducing overdose risk. Results from this pilot randomized controlled trial will provide a description of the characteristics of overdose survivors presenting to the ED; outline the implementation of PSS services research in ED settings, including PSS implementation of PSS supervision and activity tracking; and inform ED-initiated PSS-led overdose risk reduction interventions and future research to better understand the implementation and efficacy of these interventions.

Related protocols: CTN-0107

Studies often report estimates of the average treatment effect (ATE). While the ATE summarizes the effect of a treatment on average, it does not provide any information about the effect of treatment within any individual. A treatment strategy that uses an individual’s information to tailor treatment to maximize benefit is known as an optimal dynamic treatment rule (ODTR). Treatment, however, is typically not limited to a single point in time; consequently, learning an optimal rule for a time-varying treatment may involve not just learning the extent to which the comparative treatments’ benefits vary across the characteristics of individuals, but also learning the extent to which the comparative treatments’ benefits vary as relevant circumstances evolve within an individual.

The goal of this paper, part of CTN-0094 (Individual Level Predictive Modeling of Opioid Use Disorder Treatment Outcome), is to provide a tutorial for estimating ODTR from longitudinal observational and clinical trial data for applied researchers. The authors describe an approach that uses a doubly-robust unbiased transformation of the conditional average treatment effect. They then learn a time-varying ODTR for when to increase buprenorphine-naloxone (BUP-NX) dose to minimize return-to-regular-opioid-use among patients with opioid use disorder.

Conclusions: This analysis highlights the utility of ODTRs in the context of sequential decision making: the learned ODTR outperforms a clinically defined strategy.

Related protocols: CTN-0094

A lack of consensus on the optimal outcome measures to assess opioid use disorder (OUD) treatment efficacy and their precise definition and computation has hampered the pooling of research data for evidence synthesis and meta-analyses. This study aimed to empirically contrast multiple clinical trial definitions of treatment success by applying them to the same dataset.

Data analysis used a suite of functions, developed as a software package for the R language, to operationalize 61 treatment outcome definitions based on urine drug screening (UDS) results. Outcome definitions were derived from clinical trials that are among the most influential in the OUD treatment field. Outcome functions testing various medication for OUD (MOUD) options were applied to a dataset (n=2492) derived from the CTN-0094 project, which harmonized data from three large-scale National Drug Abuse Treatment Clinical Trials Network (CTN) studies (CTN-0027, CTN-0030, CTN-0051). Hierarchical clustering was employed to empirically contrast outcome definitions.

The optimal number of clusters identified was three. Cluster 1, comprising eight definitions focused on detecting opioid-positive UDS, did not include missing UDS in outcome calculations, potentially resulting in inflated rates of treatment success. Cluster 2, with the highest variability, included 10 definitions characterized by strict criteria for treatment success, relying heavily on UDS results from either a brief period or a single study visit. The 43 definitions in Cluster 3 represented a diverse range of outcomes, conceptualized as measuring abstinence, use reduction and relapse. These definitions potentially offer more balanced measures of treatment success or failure, as they avoid the extreme methodologies characteristic of Clusters 1 and 2.

Conclusions: Clinical trials using urine drug screening (UDS) for objective substance use assessment in outcome definitions should consider (1) incorporating missing UDS data in outcome computation and (2) avoiding over-reliance on UDS data confined to a short time frame or the occurrence of a single positive urine test following a period of abstinence.

Related protocols: CTN-0094

Hospitalizations involving opioid use disorder (OUD) are increasing. Medications for opioid use disorder (MOUD) reduce mortality and acute care utilization. Hospitalization is a reachable moment for initiating MOUD and arranging for ongoing MOUD engagement following hospital discharge. Despite existing quality metrics for MOUD initiation and engagement, few hospitals provide hospital based opioid treatment (HBOT). This protocol describes a cluster-randomized hybrid type-2 implementation study comparing low-intensity and high-intensity implementation support strategies to help community hospitals implement HBOT.

Four state implementation hubs with expertise in initiating HBOT programs will provide implementation support to 24 community hospitals (6 hospitals/hub) interested in starting HBOT. Community hospitals will be randomized to 24-months of either a low-intensity intervention (distribution of an HBOT best-practice manual, a lecture series based on the manual, referral to publicly available resources, and on-demand technical assistance) or a high-intensity intervention (the low-intensity intervention plus funding for a hospital HBOT champion and regular practice facilitation sessions with an expert hub). The primary efficacy outcome, adapted from the National Committee on Quality Assurance, is the proportion of patients engaged in MOUD 34-days following hospital discharge. Secondary and exploratory outcomes include acute care utilization, non-fatal overdose, death, MOUD engagement at various time points, hospital length of stay, and discharges against medical advice. Primary, secondary, and exploratory outcomes will be derived from state Medicaid data. Implementation outcomes, barriers, and facilitators are assessed via longitudinal surveys, qualitative interviews, practice facilitation contact logs, and HBOT sustainability metrics. We hypothesize that the proportion of patients receiving care at hospitals randomized to the high-intensity arm will have greater MOUD engagement following hospital discharge.

Discussion: Initiation of MOUD during hospitalization improves MOUD engagement post hospitalization. Few studies, however, have tested different implementation strategies on HBOT uptake, outcome, and sustainability and only one to date has tested implementation of a specific type of HBOT (addiction consultation services). This cluster-randomized study comparing different intensities of HBOT implementation support will inform hospitals and policymakers in identifying effective strategies for promoting HBOT dissemination and adoption in community hospitals.

Related protocols: CTN-0098

Pharmacists remain an underutilized resource in the treatment of opioid use disorder (OUD). Although studies have engaged pharmacists in dispensing medications for OUD (MOUD), few studies have evaluated collaborative care models in which pharmacists are an active, integrated part of a primary care team offering OUD care.

This study, protocol CTN-0116 (Pharmacist-Integrated Model of Medication Treatment for Opioid Use Disorder), seeks to implement a pharmacist integrated MOUD clinical model (called PrIMO) and evaluate its feasibility, acceptability, and impact across four diverse primary care sites. The Consolidated Framework for Implementation Research is used as an organizing framework for study development and interpretation of findings. Implementation Facilitation is used to support PrIMO adoption. We assess the primary outcome, the feasibility of implementing PrIMO, using the Stages of Implementation Completion (SIC). We evaluate the acceptability and impact of the PrIMO model at the sites using mixed-methods and combine survey and interview data from providers, pharmacists, pharmacy technicians, administrators, and patients receiving MOUD at the primary care sites with patient electronic health record data. We hypothesize that it is feasible to launch delivery of the PrIMO model (reach SIC Stage 6), and that it is acceptable, will positively impact patient outcomes 1 year post model launch (e.g., increased MOUD treatment retention, medication regimen adherence, service utilization for co-morbid conditions, and decreased substance use), and will increase each site’s capacity to care for patients with MOUD (e.g., increased number of patients, number of prescribers, and rate of patients per prescriber).

Conclusions: This study will provide data on a pharmacist-integrated collaborative model of care for the treatment of OUD that may be feasible, acceptable to both site staff and patients and may favorably impact patients’ access to MOUD and treatment outcomes.

Related protocols: CTN-0116

Preventing progression to moderate or severe opioid use disorder (OUD) among people who exhibit risky opioid use behavior that does not meet criteria for treatment with opioid agonists or antagonists (subthreshold OUD) is poorly understood. The Subthreshold Opioid Use Disorder Prevention (STOP) Trial is designed to study the efficacy of a collaborative care intervention to reduce risky opioid use and to prevent progression to moderate or severe OUD in adult primary care patients with subthreshold OUD.

The STOP trial is a cluster randomized controlled trial, randomized at the PCP level, conducted in 5 distinct geographic sites. STOP tests the efficacy of the STOP intervention in comparison to enhanced usual care (EUC) in adult primary care patients with risky opioid use that does not meet criteria for moderate-severe OUD. The STOP intervention consists of (1) a practice-embedded nurse care manager (NCM) who provides patient participant education and supports primary care providers (PCPs) in engaging and monitoring patient-participants; (2) brief advice, delivered to patient participants by their PCP and/or prerecorded video message, about health risks of opioid misuse; and (3) up to 6 sessions of telephone health coaching to motivate and support behavior change. EUC consists of primary care treatment as usual, plus printed overdose prevention educational materials and an educational video on cancer screening. The primary outcome measure is self-reported number of days of risky (illicit or nonmedical) opioid use over 180 days, assessed monthly via text message using items from the Addiction Severity Index and the Current Opioid Misuse Measure. Secondary outcomes assess other substance use, mental health, quality of life, and healthcare utilization as well as PCP prescribing and monitoring behaviors. A mixed effects negative binomial model with a log link will be fit to estimate the difference in means between treatment and control groups using an intent-to-treat population.

Conclusions: Given a growing interest in interventions for the management of patients with risky opioid use, and the need for primary care-based interventions, this study potentially offers a blueprint for a feasible and effective approach to improving outcomes in this population.

Related protocols: CTN-0101

American Indian and Alaska Native (AI/AN) populations are disproportionately affected by substance use disorders (SUDs) and related health disparities in contrast to other ethnoracial groups in the United States. Over the past 20 years, substantial resources have been allocated to NIDA’s National Drug Abuse Treatment Clinical Trials Network (CTN) to disseminate and implement effective SUD treatments in communities. However, we know little about how these resources have benefitted AI/AN peoples with SUD who arguably experience the greatest burden of SUDs. This review aims to determine lessons learned about AI/AN substance use and treatment outcomes in the CTN and the role of racism and Tribal identity.

The authors conducted a scoping review informed by the Joanna Briggs framework and PRISMA Extension for Scoping Reviews checklist and explanation. The study team conducted the search strategy within the CTN Dissemination Library and nine additional databases for articles published between 2000 and 2021. The review included studies if they reported results for AI/AN participants. Two reviewers determined study eligibility.

A systematic search yielded 13 empirical articles and six conceptual articles. Themes from the 13 empirical articles included: (1) Tribal Identity: Race, Culture, and Discrimination; (2) Treatment Engagement: Access and Retention; (3) Comorbid Conditions; (4) HIV/Risky Sexual Behaviors; and (5) Dissemination. The most salient theme was Tribal Identity: Race, Culture, and Discrimination, which was present in all articles that included a primary AI/AN sample (k = 8). Themes assessed but not identified for AI/AN peoples were Harm Reduction, Measurement Equivalence, Pharmacotherapy, and Substance Use Outcomes. The conceptual contributions used AI/AN CTN studies as exemplars of community-based and Tribal participatory research (CBPR/TPR).

Conclusions: CTN studies conducted with AI/AN communities demonstrate culturally congruent methods, including CBPR/TPR strategies; consideration/assessment of cultural identity, racism, and discrimination; and CBPR/TPR informed dissemination plans. Although important efforts are underway to increase AI/AN participation in the CTN, future research would benefit from strategies to increase participation of this population. Such strategies include reporting AI/AN subgroup data; addressing issues of cultural identity and experiences of racism; and adopting an overall effort for research aimed at understanding barriers to treatment access, engagement, utilization, retention, and outcomes for both treatment and research disparities for AI/AN populations.

This is the second session in a series titled “Research 101,” which will provide basic education about doing clinical research.

This webinar outlines the basics of FDA oversight and reviews other essential regulatory activities to successfully keep a study in compliance, including ongoing management and reporting requirements. The regulatory portion reviews essential regulatory activities, such as IRB approvals and informed consent requirements. Lastly, there is a discussion of current challenges and best practices when working on regulatory compliance.

Extended-release injectable naltrexone (XR-NTX) is an effective treatment for opioid use disorder (OUD), but initiation remains a barrier to implementation. Standard practice requires a 10- to 15-day inpatient admission prior to XR-NTX initiation and involves a methadone or buprenorphine taper followed by a 7- to 10-day washout, as recommended in the Prescribing Information for XR-NTX. A 5- to 7-day rapid induction approach was developed that utilizes low-dose oral naltrexone and non-opioid medications.

The NIDA CTN-0097 Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT) study was a hybrid type I effectiveness-implementation trial that compared the effectiveness of the standard procedure (SP) to the rapid procedure (RP) for XR-NTX initiation across six community inpatient addiction treatment units, and evaluated the implementation process. Sites were randomized to RP every 14 weeks in an optimized stepped wedge design. Participants (target recruitment = 450) received the procedure (SP or RP) that the site was implementing at time of admission. The hypothesis was RP will be non-inferior to SP on proportion of inpatients who receive XR-NTX, with a shorter admission time for RP. Superiority testing of RP was planned if the null hypothesis of inferiority of RP to SP was rejected.

Discussion: This is one of the first community-based, hybrid effectiveness-implementation trials of an inpatient procedure to initiate injectable naltrexone for opioid use disorder relapse prevention treatment. If RP for XR-NTX initiation is shown to be effective, the shorter inpatient stay could make XR-NTX more feasible and have an important public health impact expanding access to OUD pharmacotherapy. Further, a better understanding of facilitators and barriers to RP implementation can help with future translatability and uptake to other community programs.

Related protocols: CTN-0097

This is the first session in a series titled “Research 101,” which will provide basic education about doing clinical research.

As some are new to clinical research, it is important to understand clinical trials, how they are conducted and the roles, responsibilities, participants, and procedures that are involved. For this first presentation in the Research 101 series, there will be a review of the different types of research, study designs, phases, and other key aspects of conducting human subjects research.

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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

Pragmatic primary care trials aim to test interventions in “real world” health care settings, but clinics willing and able to participate in trials may not be representative of typical clinics. This analysis compared patients in participating and non-participating clinics from the same health systems at baseline in the PRimary care Opioid Use Disorders treatment (PROUD) trial (CTN-0074).

This observational analysis relied on secondary electronic health record and administrative claims data in 5 of 6 health systems in the PROUD trial. The sample included patients aged 16–90 years at an eligible primary care visit in the 3 years before randomization. Each system contributed 2 randomized PROUD trial clinics and 4 similarly sized non-trial clinics. We summarized patient characteristics in trial and non-trial clinics in the 2 years before randomization (“baseline”). Using mixed-effect regression models, researchers compared trial and non-trial clinics on a baseline measure of the primary trial outcome (clinic-level patient-years of opioid use disorder (OUD) treatment, scaled per 10,000 primary care patients seen) and a baseline measure of the secondary trial outcome (patient-level days of acute care utilization among patients with OUD).

Patients were generally similar between the 10 trial clinics (n = 248,436) and 20 non-trial clinics (n = 341,130), although trial clinics’ patients were slightly younger, more likely to be Hispanic/Latinx, less likely to be white, more likely to have Medicaid/subsidized insurance, and lived in less wealthy neighborhoods. Baseline outcomes did not differ between trial and non-trial clinics: trial clinics had 1.0 more patient-year of OUD treatment per 10,000 patients (95% CI: – 2.9, 5.0) and a 4% higher rate of days of acute care utilization than non-trial clinics (rate ratio: 1.04; 95% CI: 0.76, 1.42).

Conclusions: Trial clinics and non-trial clinics were similar regarding most patient characteristics, and no differences were observed in baseline measures of trial primary and secondary outcomes. These findings suggest trial clinics were representative of comparably sized clinics within the same health systems. Although results do not reflect generalizability more broadly, this study illustrates an approach to assess representativeness of clinics in future pragmatic primary care trials.

Related protocols: CTN-0074