Measures of outcome for stimulant trials: ACTTION recommendations and research agenda

Abstract

Background The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. Methods In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. Results and Conclusions Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.

Evaluation of the “Pipeline” for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research

“…We advocate that clinical researchers should transition away from strict reliance on positive-versus-negative urine screens as the sole measure of medication efficacy. Indeed, the process of developing alternative outcome measures has already begun (Kiluk et al, 2016). Furthermore, we encourage the perspective that reducing cocaine use can be a meaningful clinical endpoint.…”

“…New target outcomes, such as reductions in drug use, were recently proposed as potential indicators of success. However, questions about the extent to which reductions in cocaine use result in clinically meaningful changes have prevented widespread adoption of these indicators in clinical trials for cocaine use disorder (Winchell et al, 2012;Carroll et al, 2014;McCann et al, 2015;Kiluk et al, 2016). Cocaine abstinence, verified as observation of urine samples testing negative for cocaine metabolites, thus remains the standard for demonstrating treatment efficacy in clinical trials.…”

“…This understanding is reflected in the endorsement by the FDA of "percent subjects with no heavy drinking days" as a meaningful endpoint in trials for medications for alcohol use disorder (FDA, 2006;see Falk et al, 2010). More recently, some have called for a similar approach in trials of medications for cocaine use disorders (Winchell et al, 2012;McCann et al, 2015;Kiluk et al, 2016). As elucidated by McCann et al (2015), the critical hurdle to adopting such measures is a clear demonstration that reductions in drug use lead to clinically measureable benefits to the patient and a determination of the extent of reduction necessary to produce measureable improvements.…”

“…Furthermore, we encourage the perspective that reducing cocaine use can be a meaningful clinical endpoint. Determining what extent of reduction of drug use is necessary to yield real benefits, and the point in treatment when that occurs, is a formidable task (see Kiluk et al, 2016). Preclinical researchers are well-positioned to assist in this area.…”

Statistical considerations in the choice of endpoint for drug use disorder trials

“…The US Food and Drug Administration (FDA) requires clinical trials developing new medications to use a period of post-treatment abstinence as the clinically meaningful endpoint (Food and Drug Administration, 2013); however, only a relatively small percentage of participants in clinical trials ever achieve enduring abstinence in the 6–12 months following completion of treatment. This has prompted interest in the development of outcome measures, other than sustained abstinence, for use as endpoints in drug use disorder trials (Carroll et al, 2014; Donovan et al, 2012; Kiluk et al, 2016; Tai et al, 1997; Tiffany et al, 2012; Van den Brink et al, 2006; Vocci and de Wit, 1999). …”