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Abstract: Introduction and background: The three medications approved to address OUD are effective in decreasing opioid use and morbidity and mortality; however, their utility is limited by high rates of dropout from treatment. The CTN-0100 trial will develop an evidence base for strategies to improve retention on buprenorphine and extended-release naltrexone. Research design and methods: The National Drug Abuse Treatment Clinical Trials Network (CTN) study CTN-0100, “Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy” (RDD), is a multicenter, randomized, non-blinded trial enrolling more than a thousand patients from 18 community-based substance use disorder treatment programs. Participants are adult volunteers seeking to initiate medication treatment for OUD (MOUD). Individuals choose between buprenorphine or extended-release injectable naltrexone. The trial randomizes participants choosing buprenorphine, in a 3 × 2 factorial design, to a medication condition (standard-dose sublingual buprenorphine, high-dose sublingual buprenorphine, or extended-release injectable buprenorphine) and to a behavioral condition (Medical Management or Medical Management plus a digital therapeutic (smartphone) app). Individuals choosing extended-release naltrexone are randomized only to a behavioral condition. Participants receive study medication for 74 weeks and are then followed for a further 24 weeks. The primary outcome is successful retention on MOUD at 26 weeks (six months), with 50- and 74-week retention among the secondary outcomes. Conclusions: Dropout from treatment is a major barrier to the effectiveness of MOUD. The CTN-0100 study will determine whether strategies such as high dose sublingual or extended-release buprenorphine, or an app-based behavioral intervention improve retention on MOUD. Related protocols: CTN-0100

Abstract:

Buprenorphine, and extended-release naltrexone, are effective in decreasing opioid use, morbidity and mortality. The available evidence suggests that these medications should be used for long term treatment; however, patients often ask how long they need to be on medication, and whether it would be safe to discontinue. There are sparse data to guide us. The CTN-0100 trial will address this gap in our knowledge by studying participants who have decided to discontinue buprenorphine and extended-release naltrexone for OUD.

The trial is a multicenter, randomized, non-blinded study. Participants are stable adult volunteers, on sublingual buprenorphine, extended-release buprenorphine, or extended-release naltrexone, expressing an interest in discontinuing medication. Participants on buprenorphine must be stable for at least 1 year and participants on extended-release naltrexone must be stable for at least 6 months. Participants are engaged in the study for up to 96 weeks, including a flexible taper period, and are then transitioned to follow-up within the trial. All participants are randomly assigned to the study Medical Management (MM) or to MM plus Connections (CHESS health) digital smartphone application aimed at recovery and abstinence (MMD). Sublingual Buprenorphine participants are also randomized (2 × 2 design) to a taper using either sublingual or extended-release buprenorphine.

Conclusions: It is hoped that this trial will provide a rich source of data on management of patients discontinuing medication for opioid use disorder (MOUD) to inform future research and practice. The trial will shed light on which strategies are most likely to lead to long-term success (absence of relapse), and what participant characteristics distinguish those who can safely discontinue MOUD from those who remain at risk of relapse should they discontinue.

Related protocols: CTN-0100

Abstract:

This is the Results Article for CTN-0084-A-2.

Multiple digital data sources can capture moment-to-moment information to advance a robust understanding of opioid use disorder (OUD) behavior, ultimately creating a digital phenotype for each patient. This information can lead to individualized interventions to improve treatment for OUD.

This aim of this study, CTN-0084-A-2, was to examine patient engagement with multiple digital phenotyping methods among patients receiving buprenorphine medication for OUD.

The study enrolled 65 patients receiving buprenorphine for OUD between June 2020 and January 2021 from 4 addiction medicine programs in an integrated health care delivery system in Northern California. Ecological momentary assessment (EMA), sensor data, and social media data were collected by smartphone, smartwatch, and social media platforms over a 12-week period. Primary engagement outcomes were meeting measures of minimum phone carry (=8 hours per day) and watch wear (=18 hours per day) criteria, EMA response rates, social media consent rate, and data sparsity. Descriptive analyses, bivariate, and trend tests were performed.

The participants’ average age was 37 years, 47% of them were female, and 71% of them were White. On average, participants met phone carrying criteria on 94% of study days, met watch wearing criteria on 74% of days, and wore the watch to sleep on 77% of days. The mean EMA response rate was 70%, declining from 83% to 56% from week 1 to week 12. Among participants with social media accounts, 88% of them consented to providing data; of them, 55% of Facebook, 54% of Instagram, and 57% of Twitter participants provided data. The amount of social media data available varied widely across participants. No differences by age, sex, race, or ethnicity were observed for any outcomes.

Conclusions: To our knowledge, this is the first study to capture these 3 digital data sources in this clinical population. Our findings demonstrate that patients receiving buprenorphine treatment for OUD had generally high engagement with multiple digital phenotyping data sources, but this was more limited for the social media data.

Related protocols: CTN-0084-A-2

Abstract:

This CTN platform study aimed to examine characteristics associated with disparities in digital access (i.e., access to high speed Internet via a computer or smartphone) in American rural and urban households given that digital access has a direct impact on access to telemedicine-based services.

Using the 2019 American Community Survey, researchers from the Greater Southern California Node analyzed the proportions of geographic area, race/ethnicity, and socioeconomic status according to device and high-speed Internet access. Maximum likelihood logit estimators estimated how these factors influenced device and high-speed Internet access. Of 105,312,959 households, 32.29% were without a desktop or laptop computer with high-speed Internet (WDW), 21.51% were without a smartphone with a data plan for wireless Internet (WSW), and 14.02% were without any digital access (WDA). Nonmetropolitan households were significantly more likely to be WDA than metropolitan households. Relative to non-Hispanic Whites, non-Hispanic Blacks, American Indian or Alaska Natives, or Hispanics were significantly more likely to be WDA. When compared to households with private health insurance coverage, households WDA were significantly more likely to have no insurance or public insurance coverage. Households with any digital access reported higher income and more family members living at home. Using the same predictors, similar findings were reported for households WDW or WSW.

Conclusions: Significant disparities in digital access exist among nonmetropolitan households, racial/ethnic minority households, and lower-income households. The lack of digital access has implications for the accessibility of health care services via telemedicine and thus could exacerbate health disparities.

Abstract:

Presented by: Michael Dennis, PhD

Dr. Dennis describes the trends in smartphone interventions for substance users, how they vary by age, and their significance for adolescent treatment. He also discusses how his research examines the findings of several recent clinical trials, including which parts of the smartphone interventions best predict outcomes. Further, he discusses what it means to adapt smartphones to better target adolescents and young adults.

Abstract:

The emergency department (ED) offers an important opportunity to identify patients with opioid use disorder (OUD) and initiate treatment. However, post-ED follow-up is challenging, and novel approaches to enhance care transitions are urgently needed. Outcomes following ED visits have traditionally focused on overdose, treatment engagement, and mortality with an absence of patient reported outcomes (PROs), for example patient ability to schedule follow-up OUD treatment appointments or pick up a prescription medication, that may better inform evaluation of treatment pathways and near-term outcomes after acute events. In the context of increasing novel secure mobile health (mHealth) platforms, researchers explored the feasibility and acceptability of electronically collecting PROs from ED patients with non-medical opioid use to enhance care in the ED and transitions of care.

ED patients with non-medical opioid use or opioid overdose who endorsed willingness and ability to complete electronic surveys after discharge were enrolled from a tertiary, urban academic ED. Participants were enrolled in an mHealth platform, shared electronic health records with researchers, and completed electronic surveys of PROs at baseline, three- and thirty-days post discharge from the hospital, including questions about ability to schedule a follow-up appointment, pick up a prescription medication and overdose risk behaviors. Primary outcomes were measures of feasibility and acceptability of electronic PRO collection among ED patients with non-medical opioid use.

Among 1,808 patients assessed for eligibility between June-December 2019, 101 of 130 (78%) eligible adult patients consented to participate. Ninety-six (95%) of 101 patients completed registration in the mHealth platform, and 77/96 (80%) were successful in sharing their electronic health data. Completion rates for the baseline, three-day and thirty-day surveys were 97% (93/96), 49% (47/96) and 42% (40/96). Implementation challenges included short engagement window during ED visit, limited access to smartphones/computers, insufficient battery life of participant phone to access email and password, forgotten emails and passwords, multi-step verification processes for account set-up, and complaints about hospital care, most of which were effectively addressed by study personnel.

Conclusions: ED patients with OUD were willing to share electronic health information and PROs, although implementation challenges were common, and more than half of participants were lost-to-follow-up after hospital discharge at 30 days. Efforts to streamline communication and remove barriers to engagement are needed to improve the collection of PROs and pathways of care in ED patients with OUD.

Related protocols: CTN-0081

Abstract:

This article describes how smartphones were used to monitor and encourage medication adherence in a pilot study evaluating the potential efficacy of a combination pharmacotherapy for methamphetamine use disorder. It examines the feasibility, utility, and acceptability of using smartphones to capture dosing videos from the perspectives of participants and staff.

The study, CTN-0054 (“Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT) for Methamphetamine Use Disorder”), was an 8-week, open-label evaluation of extended-release bupropion (BRP, Wellbutrin XL, 450mg/day). Participants attended visits twice weekly for observed BRP dosing, assessments, and medical management. BRP was dispensed once weekly for dosing on nonclinic days. Medication adherence was assessed objectively (by observation at the clinic and smartphone videos for dosing at home) and subjectively (self-reports of dosing). Surveys assessing the smartphone component were completed by participants and study staff.

Participants (N=49) reported taking 93.6% of the dispensed BRP doses while 86.6% of dispensed doses were confirmed via dosing video and in-person observations. Most participants who completed the survey agreed that the smartphone was easy to use (92.6%) and that taking the dosing videos helped them remember to take the study medication (80.5%). Staff agreed that the smartphone helped collect accurate dosing data for most (77.5%) participants.

Conclusions: The use of smartphones for video-based oral medication dosing in this study provided a feasible and acceptable mechanism to encourage, monitor, and confirm medication adherence. Video-confirmed dosing adherence provides an objective numerical indicator of the lowest medication adherence rate participants achieve, allowing investigators to more confidently interpret results.

Related protocols: CTN-0054

Abstract:

This is the primary outcomes article for CTN-0054.

This 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone + bupropion as a pharmacotherapy for methamphetamine (MA) use disorder. The study was conducted in 2 stages of recruitment across 3 sites; 20 participants were enrolled in stage 1 and 29 participants were enrolled in stage 2. Eight weeks of open-label pharmacotherapy with a combination of extended-release injectable naltrexone (XR-NTX; Vivitrol) plus extended-release oral bupropion (BRP, Wellbutrin XL) were provided with a smartphone-assisted medication adherence platform. Participants met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported 20 days or more of MA use in the 30 days prior to consent, and submitted 3 MA-positive urine drug screens (UDS) out of 4 collected during screening. Participants attended clinic twice weekly for observed BRP dosing, UDS testing, assessments, and medical management; XR-NTX was administered at weeks 1 and 5. A BRP taper and follow-up visit occurred in week 9.

Analyses evaluated effects of XR-NTX + BRP to determine the number of “responders” according to a statistically predefined response criterion (6 of 8 MA-negative UDS during the last 4 weeks of medication). The 2-stage design required that stage 1 yield 3 or more responders to continue to stage 2; 11 of the 49 participants met responder criteria across both stages (5 in stage 1, 6 in stage 2).

Conclusions: The primary objective of this single-arm, open-label pilot study was to evaluate the safety and preliminary efficacy of XR-NTX + BRP as a potential treatment for MA use disorder. Under the statistical analysis plan, study “success” required 9 or more responders. With 11 responders, the study demonstrated sufficient potential of naltrexone plus bupropion as a combination pharmacotherapy for MA use disorder to warrant further study. Findings also support the general safety and tolerability of this medication combination in MA users, and had high rates of retention and medication adherence.

Related protocols: CTN-0054

Abstract:

Clinical trials have been slow to incorporate e-technology (digital and electronic technology that utilizes mobile devices of the Internet) into the design and execution of studies. In the meantime, individuals and corporations/organizations are relying more on electronic platforms and most have incorporating such technology into their daily lives. This paper, written by five members of the NIDA Clinical Trials Network, provides a general overview of the use of e-technologies in clinical trials research, specifically within the last decade, marked by rapid growth of mobile and Internet-based tools. Benefits of and challenges to the use of e-technologies in data collection, recruitment and retention, delivery of interventions, and dissemination are provided, as well as a description of the current status of regulatory oversight of e-technologies in clinical trials research. As an example of ways in which e-technologies can be used for intervention delivery, a summary of e-technologies for the treatment of substance use disorders is presented, including the Therapeutic Education System studied in protocol CTN-0044 of the NIDA Clinical Trials Network, making trials more efficient while also reducing costs. However, researchers should be cautious when adopting these tools given the many challenges in uses new technologies, as well as threats to participant privacy/confidentiality.

Conclusions: Challenges of using e-technologies in each stage of a clinical trial can be overcome with careful planning, useful partnerships, and forethought. The role of web- and smartphone-based applications is expanding, and the increasing use of those platforms by scientists and the public alike make them tools that cannot be ignored.

Related protocols: CTN-0044

Abstract:

The growing use of newer communication and internet technologies, even among low income and transient populations, require research staff to update their outreach strategies to ensure high follow-up and participant retention rates. This paper presents the views of research assistants on the use of cell phones and the internet to track participants in a multi-site randomized trial of substance use disorder treatment. Pre-interview questionnaires exploring tracking and other study-related activities were collected from 21 research staff across the 10 sites participating in the National Drug Abuse Treatment Clinical Trials Network study CTN-0044, about an online intervention for substance use disorders (Therapeutic Education System). Data were then used to construct a semi-structured interview guide which, in turn, was used to interview 12 of the same staff members. The questionnaires and interview data were entered in Atlas.ti and analyzed for emergent themes related to the use of technology for participant tracking purposes.

Study staff reported that most participants had cell phones, despite having unstable physical addresses and landlines. The incoming call feature of most cell phones was useful for participants and research staff alike, and texting proved to have additional benefits. However, reliance on participants’ cell phones also proved problematic at times. Even homeless participants were found to have access to the internet through public libraries and could respond to study staff e-mails. Some study sites opened generic social media accounts, through which study staff sent private messages to participants. However, the Institutional Review Board (IRB) approval process for tracking participants using social media at some sites was prohibitively lengthy. Internet searches through Google, national paid databases, obituaries, and judiciary websites were also helpful tool.

Conclusions: Research staff perceive that cell phones, internet searches, and social networking sites were effective tools to achieve high follow-up rates in drug abuse research and should be used in addition to established study procedures. Studies should incorporate cell phone, texting, and social network website information on locator forms; obtain IRB approval for contacting participants using social networking websites; and include web searches, texting, and the use of social media in staff training as standard operating procedures.

Related protocols: CTN-0044