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Abstract: High levels of missing outcome data for biologically confirmed substance use (BCSU) threaten the validity of substance use disorder (SUD) clinical trials. Underlying attributes of clinical trials could explain BCSU missingness and identify targets for improved trial design. We reviewed 21 clinical trials funded by the NIDA National Drug Abuse Treatment Clinical Trials Network (CTN) and published from 2005 to 2018 that examined pharmacologic and psychosocial interventions for SUD. We used configurational analysis-a Boolean algebra approach that identifies an attribute or combination of attributes predictive of an outcome-to identify trial design features and participant characteristics associated with high levels of BCSU missingness. Associations were identified by configuration complexity, consistency, coverage, and robustness. We limited results using a consistency threshold of 0.75 and summarized model fit using the product of consistency and coverage. For trial design features, the final solution consisted of two pathways: psychosocial treatment as a trial intervention OR larger trial arm size (complexity=2, consistency=0.79, coverage=0.93, robustness score=0.71). For participant characteristics, the final solution consisted of two pathways: interventions targeting individuals with poly- or nonspecific substance use OR younger age (complexity=2, consistency=0.75, coverage=0.86, robustness score=1.00). Conclusions: Psychosocial treatments, larger trial arm size, interventions targeting individuals with poly- or nonspecific substance use, and younger age among trial participants were predictive of missing BCSU data in SUD clinical trials. Interventions to mitigate missing data that focus on these attributes may reduce threats to validity and improve utility of SUD clinical trials. Related protocols: CTN-0002, CTN-0003, CTN-0004, CTN-0006, CTN-0007, CTN-0009. CTN-0013, CTN-0014, CTN-0015, CTN-0017, CTN-0021, CTN-0029, CTN-0030, CTN-0031, CTN-0037, CTN-0044, CTN-0046, CTN-0048, CTN-0051, CTN-0053

Abstract:

This webinar, presented by Frankie Kropp and facilitated by Lynn Kunkel, completes a broad overview of the infrastructure of the NIDA CTN, including how Local Nodes interact with the sponsor as well as study sites. A summary of available resources for new nodes and research sites will be provided for a variety of Local Node activities. Lastly, best practices are reviewed as well as ways to avoid common mistakes.

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Abstract:

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

Abstract:

In this presentation, Dr. Curran discusses ways to integrate implementation-focused research concepts and questions into clinical trials. He will cover concepts and approaches such as “design for dissemination/implementation,” “implementability,” and effectiveness-implementation hybrid designs. He will share examples from his own work and from others who combine their efficacy/effectiveness and implementation research.

Abstract:

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.

Abstract:

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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Abstract:

During the conduct of clinical trials, some participants may be lost to incarceration. In the National Drug Abuse Treatment Clinical Trials Network (CTN) particularly, researchers must anticipate prisoner involvement as the study population is susceptible to run-ins with the judicial system. This 90-minute web seminar—divided into five separate recordings–will consider strategies and tools that help research teams prepare prior to the start of a study and coordinate procedures during the study to effectively locate and retain participants lost to incarceration. Topics covered include the following:

Introduction to Prisoner Engagement in Clinical Trials. Dagmar Salazar, MS, CCC Protocol Specialist.

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This introduction provides background on the inclusion of prisoners in clinical research and in relation to the National Drug Abuse Treatment Clinical Trials Network. Additionally, the presenter briefly introduces the tools and strategies that will be addressed in the following presentations.

Prisoner Engagement in Clinical Trials–Considerations for
Study Planning and Pre-Implementation. Sarah Farkas, MA, GNY Node.

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This presentation will address considerations for investigators and their study teams when planning for prisoner involvement in CTN trials and introduce a helpful checklist tool with relevant, critical milestones to address during study pre-implementation.

Developing an Effective Standard Operating Procedure (SOP) for Research Staff Engagement with Participants Lost to Incarceration. Dagmar Salazar, MS, CCC Protocol Specialist.

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This presentation will review the development of an effective SOP outlining procedures for prisoner involvement and management of research staff interactions with incarcerated participants and individuals affiliated with detention facilities.

Locating Participants Lost to Incarceration. Amber Regis, BA, GNY Node.

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This presentation will discuss locating and monitoring participants within the criminal justice system, the importance of utilizing national and local resources in those efforts, and strategies for facilitating contact with incarcerated participants.

You’ve Located an Incarcerated Participant–What’s Next? Peter Greco, MPH, GNY Node.

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This presentation will review how to gain access to a correctional facility, coordinating logistical details of the visit, protecting participant confidentiality, and tips for navigating safely and ethically within a correctional facility setting.

Abstract:

Significant fixed effects of site (main effects of site and/or site by treatment interactions) on primary outcome have been identified in the majority of studies performed by NIDA’s National Drug Abuse Treatment Clinical Trials Network. While rarely explored, identifying patient- and site-level variables that are associated with site effects can provide information about the context in which outcome is optimized.

In a 10-site clinical trial that evaluated the effectiveness of a web-based psychosocial intervention compared to usual treatment of patients (N=507) with substance use disorders (CTN-0044), the primary outcome analysis revealed significant main effect of site, modeled as a fixed effect, on the outcome of abstinence. In the current analysis, researchers used a two-level, hierarchical generalized linear model (HGLM) to identify patient- and site-level variables associated with abstinence outcome, while modeling site as a random factor.

The site-specific percentage of patients abstinent in the last 4 weeks of the study varied from 6.1% to 40%. However, only 6.7% (p=0.08) of variability in end-of-study abstinence was accounted for by site, indicating a small-moderate effect. Among patient-level predictors, older age, abstinence at baseline, and among site-level predictors, higher annual clinic admissions, were significantly associated with increased likelihood of abstinence. When controlling for these three variables in a HGLM, only patient age and abstinence at baseline remained significant, and random factor site explained only 1.4% of variability in end-of-study abstinence, a 79% reduction in magnitude.

Conclusions: These findings suggest that only some amount of variability in abstinence outcomes among sites can be explained by a combination of patient- and site-level variables, supporting the case that variability between sites is a natural phenomenon. The methodological recommendation is that site be modeled as a random factor when analyzing multi-site clinical trials.

Related protocols: CTN-0044

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

Abstract:

This web seminar series had three components:

Introduction to Retention in the NDAT CTN. Presented by Dikla Blumberg, PhD (NDAT CTN Clinical Coordinating Center):

Recruitment and retention are vital aspects of clinical research trials and can factor into the success of a study. Therefore, it is important that researchers understand and identify barriers to meeting recruitment and retention targets and the consequences experienced with poor retention. Additionally, it is helpful to examine historical data available on study retention trends to inform implementation efforts on future studies. Accordingly, this presentation briefly addresses these areas by providing an overview on the topic of study retention, retention within the context of the CTN, and discusses the importance of incorporating strategies and tools for study success.

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The “CHEERS” Principle of Participant Retention: More Than Just Techniques. Presented by Frankie Kropp, MS (OV Node) and Mitra Lewis, MS (NDAT CTN CCC):

Good participant retention involves more than just specific techniques; retention depends on the study staff’s overall philosophy of managing and accommodating study participants. One helpful way to think about participant retention is to insert the “CHEERS” principle into study retention efforts– Customer service, Help overcome barriers, Environment, Excellence, Relationship/Respect, and Search. This 20-minute webinar will provide an overview of the CHEERS principle, including specific examples of what sites can do to maximize participant retention.

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Utilizing a Robust and Comprehensive Locator Form as a Retention Tool. Presented by Phoebe Gauthier, MA, MPH (NE Node) and Dagmar Salazar, MS (NDAT CTN CCC).

Participant recruitment and retention are critical aspects of conducting quality clinical research projects. The National Drug Abuse Treatment Clinical Trials Network (NDAT CTN), which evaluates behavioral, pharmacological, and integrated treatment interventions for substance use disorders, routinely enrolls participants who may be challenging to locate during the treatment and follow-up phase of a trial. This 20-minute presentation will review one tool for increasing retention—an adapted locator form. This locator form is designed to better facilitate locating participants, especially those with unstable living conditions or with limited contact information. Additionally, this presentation will discuss the form elements beyond conventional locator forms and methods for collecting the information to help increase participant retention.

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Abstract:

New regulations have established the expectation of a single Institutional Review Board (sIRB) to provide ethical review of a clinical research study. The measure is designed to maintain appropriate protection of study participants and yet streamline federally-funded research reviews by eliminating redundancy and avoiding unnecessary administrative burden. Accordingly, CTN researchers must understand the considerations to factor into selecting a sIRB for a multi-center study.

This presentation from Julia Collins, MD, Protocol Specialist at the NDAT Clinical Coordinating Center at the Emmes Corporation, will describe such considerations based on experiences and lessons learned from research teams working with a variety of sIRBs on seven CTN clinical studies.

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Learning Objectives:

• Describe types of sIRBs and evaluate suitability for ethical reviews of specific trials.
• Define sIRB selection criteria as applied to studies across disease areas and study designs.
• Discuss other factors to consider and effective processes to implement when selecting a sIRB.

Abstract:

An Institutional Review Board (IRB) provides ethical review of proposed and ongoing clinical research to ensure the rights and welfare of research participants are protected, and that both the study and investigative team adhere to pertinent regulations governing the conduct of clinical trials. Clinical sites wishing to engage in human subjects research must be paired with an IRB registered with the Office of Human Research Protections, thereby ensuring adherence to all tenets of Good Clinical Practice. This pledge is provided in the form of a Federalwide Assurance (FWA) and is one of the central pillars of a clinical trial. This presentation from Eric Hardter, PhD, RAC, Regulatory Affairs Specialist at the NDAT Clinical Coordinating Center, Emmes Corporation, provides an overview of the basis of and need for a FWA as well as the roles and expectations of key stakeholders, including IRBs, institutions, and researchers involved in clinical studies.

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Learning Objectives:

• Describe FWAs and FWA provisions.
• Discuss who needs to obtain FWAs, when, and who is covered.
• Consider the expectations and roles for IRBs, institutions, investigators, and researchers that provide oversight and/or engage in clinical research.

Abstract:

Randomized controlled trials (RCTs) are generally considered the gold standard for establishing the effectiveness of new interventions. However, lack of external validity, which indicates how well findings from one particular setting can apply to the target population, can be an issue with many RCTs. This study aimed to compare characteristics of individuals participating in randomized controlled trials of treatments of substance use disorder (SUD) with individuals receiving treatment in usual care settings, and to provide a summary quantitative measure of differences between characteristics of these two groups of individuals using propensity score methods.

Analyses using data from RCT samples from multiple sites in the NIDA Clinical Trials Network (CTN) and target populations of patients drawn from the Treatment Episodes Data Set-Admissions (TEDS-A) were performed. Participants included a total of 3,592 individuals from 10 CTN samples and 1,602,226 individuals selected from TEDS-A between 2001 and 2009.

Propensity scores for enrolling in the RCTs ere computed based on the following nine observable characteristics: sex, race/ethnicity, age, education, employment status, marital status, admission to treatment through criminal justice, intravenous drug use, and the number of prior treatments. The proportion of those with 12 or more years of education and the proportion of those who had full-time jobs were significantly higher among RCT samples than among target populations (in seven and nine trials, respectively). The pooled difference in the mean propensity scores between the RCTs and the target population was 1.54 standard deviations and was statistically significant at p<.001.

Conclusions: In the U.S., individuals recruited into randomized controlled trials (RCTs) of substance use disorder treatments appear to be very different from individuals receiving treatment in usual care settings. Notably, RCT participants tend to have more years of education and a greater likelihood of full-time work compared with people receiving care in usual care settings. Representativeness of the trial samples in future CTN trials should be carefully considered, particularly because the primary mission of the CTN was to improve the quality of SUD treatment nationwide. Less stringent exclusion criteria may improve generalizability and result in more representative samples in SUD treatment RCTs.

Abstract:

This workshop, led by Carmen Rosa of NIDA’s Center for the Clinical Trials Network, featured three presentations focused on the use of various types of new media in the design and conduct of clinical trials. Over 82% of adults now use internet or email, including 53% of those age 65 and older. Additionally, 67% of online adults use social networking sites. Mobile devices such as smartphones, tablets, netbooks, and laptops are now a primary source of Internet connectivity, and 79% of cell phone owners say they use text messaging. As use of these tools continues to grow, exploring ways to put them to use in clinical trials seems increasingly relevant.

The first presentation, by Erin Winstanley, “Using New Media Tools in the Design and Conduct of Clinical Trials,” provided an overview of the concept of “new media” and ways it can be applied to research, including advertising of studies, recruiting/tracking participants, communicating with participants, and disseminating research findings. An introduction to Facebook and Twitter is provided, as well as a look at the use of blogs, Pinterest, and LinkedIn.

Gloria Miele presented on “Social Media Communication Strategy,” giving participants a look at ways to think about and draft policies regarding the use of social media in your study or workplace. A variety of legal considerations, as well as examples of using social media to recruit study participants is also provided. Sample IRB guidance is included, along with IRB Best Practices for using new media. The presentation ends with a case study based on CTN-0044 (“Web Delivery of Evidence-Based, Psychosocial Treatment for Substance Use Disorders”), which used social media platforms like Facebook, as well as email and texting, to contact and follow-up with participants.

The third presentation, by Lynn Simpson, was a demonstration of the variety of uses for “REDCap, Research Electronic Data Capture, A Data Management and Survey Tool.” REDCap is a web-based application designed to give researchers and clinicians the capacity to create and manage databases and surveys in order to support data capture for research.

Related protocols: CTN-0044

Abstract:

This presentation from the “CTN Design & Analysis” workshop at the 2011 Steering Committee Meeting addresses the problem of missing data from CTN trials. The focus is mostly on primary outcomes data, which may be missing for a variety of reasons, including discontinuation of the study, outcomes undefined for some participants (such as quality of life measures after death), or attrition. Though CTN studies are focused on efficacy, not perfection (that is, it’s not “Does treatment work if perfectly delivered?” but instead “Is this a good treatment strategy?”), researchers should still strive to collect complete data from all participants, even those who do not complete the study, as results will never be believable, no matter how sophisticated the statistical method, if there is too much missing data. A variety of approaches for dealing with missing data are discussed, including ways to design trials to help minimize the likelihood of missing data. Ways to analyze missing data are also provided, including repeated-measure designs, linear and quadratic time trend or spline models, and the importance of sensitivity analysis. The presentation uses protocol CTN-0010 to provide a case study about ways to work with and around missing data.

Related protocols: CTN-0010