Reanalysis of Methamphetamine Dependence Treatment Trial

Abstract

Researchers working in the field of clinical trials for addictive disorders have discussed whether the use of responder analyses (analyses which compare the proportion of patients in each treatment arm who achieve the desired response) in these trials represents "setting the bar too high." These discussions involve assumptions about the relative ease or difficulty of establishing a treatment effect using group means versus doing so using responder analyses. In (placeholder for title of McCann paper, Ref. 1), the authors have shown that using a responder analysis identified a treatment effect in methamphetamine dependence, which an initial analysis of group means did not. This demonstrates that responder analysis may be a more appropriate approach, and depending on the study design, may demonstrate differences not appreciated by group means. Other authors have also identified situations in which a responder approach demonstrates an effect where group means did not [2], or where a comparison of means yielded equivocal results of uncertain clinical significance [3]. In addition, Falk et al. [4] recently compared the use of a responder analysis to customarily used group mean comparisons in alcoholism trials and found that their responder definition was as sensitive as customary measures in detecting treatment effects.Addictions are behavioral disorders, characterized by compulsive self-administration of substances despite physical and psychosocial consequences. Although considerable attention is given in addiction trials to biological measures of drug use as endpoints, cocainuria or methamphetaminuria is only a marker and not the disorder under treatment. The aim of treatment is often expressed as an effort to modifying patients' drug use behavior, but the desired effect is improvement in physical and psychosocial consequences. Changing the behavior only minimally, without having impact on the consequences, would be pointless. Drug-taking behavior observed during the brief window of a clinical trial is a surrogate endpoint, as trials intended to show effects on physical or psychosocial consequences of drug use would need to be very long and very large, and may be impractical. When drug-taking behavior is used as a surrogate endpoint, there should be a demonstration of change in behavior that can be reasonably predictive of improvement, such as avoidance of alcohol-related health and social consequences.

Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research

“…The gold standard of efficacy for clinical trials of pharmacotherapies for stimulant dependence has been for putative treatments to promote sustained abstinence (e.g., three consecutive weeks of biologically verified abstinence from cocaine; [51]. Questions have recently arisen about whether complete drug abstinence “sets the bar too high” and has contributed to our inability to identify an effective pharmacological treatment [43,65,66]. These questions are especially germane to the development of combined treatments because a number of the studies reviewed above only showed efficacy for tested treatments with sub-analysis in adherent patients or at specific time points in the trial [54,58].…”

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

“…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.…”

“…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.…”

Effects of buspirone and the dopamine D3 receptor compound PG619 on cocaine and methamphetamine self-administration in rhesus monkeys using a food-drug choice paradigm

“…Compared to other psychostimulants like cocaine, there is less research involving MA abuse in monkey models. For some compounds, clinical studies have reported opposite effects on cocaine and MA (Kampman et al 2004; Johnson et al 2007; see Winchell et al 2012) which further warrants the evaluation of potential psychostimulant treatment drugs in animals self-administering cocaine and MA (see also Martelle et al 2014). Thus, an additional goal of these studies was to extend this evaluation of PG619 and buspirone from cocaine to MA.…”