Percentage of negative urine drug screens as a clinically meaningful endpoint for RCTs evaluating treatment for cocaine use

Historically, sustained abstinence was considered the only endpoint in clinical trials for substance use disorder that would be acceptable for medication approval by the U.S. Food and Drug Administration (Food and Drug Administration & the Psychopharmacologic Drugs Advisory Committee, 2013). However, a meaningful non-sustained abstinence-based endpoint may facilitate development and approval of new agents by lowering the high bar of sustained abstinence (Volkow et al., 2018), an area of tremendous need given the lack of approved medications for substances such as stimulants. Current FDA guidance indicates drug use patterns other than abstinence can be accepted as endpoints in clinical trials, provided there is an association with better health or psychosocial functioning (Food and Drug Administration, 2020). Various non-abstinence drug use patterns have been examined, with findings suggesting that less frequent drug use during treatment is associated with better long-term outcomes (e.g., Fitzmaurice et al., 2020; Kiluk et al., 2014; Miguel et al., 2019; Roos et al., 2019a, Roos et al., 2019b). However, FDA recommends a comparison of the percentage of “responders” rather than group means to evaluate treatment efficacy, with responders potentially defined as those achieving a given threshold known to be associated with clinical benefit (Food and Drug Administration, 2020). A valid threshold for defining a non-abstinent responder has not been empirically established.

Studies examining the clinical meaningfulness of stimulant use outcomes have emphasized continuous (vs dichotomous) measures of stimulant use/abstinence based on frequency of self-reported abstinence from stimulant use (e.g., percentage of days abstinent, consecutive days of abstinence) and results of urine drug screens (UDS; e.g., percentage of negative UDS) (e.g., Carroll et al., 2014a; Fitzmaurice et al., 2017, Fitzmaurice et al., 2020; Kiluk et al., 2014; Miguel et al., 2019). Outcomes based on a dichotomous measure (yes/no) of achieving a specific duration of stimulant abstinence or a reduction in frequency level have shown promise as potential non-abstinence-based thresholds to define responders (e.g., Carroll et al., 2014a; Roos et al., 2019a), but these have been calculated from self-report. Traditionally, dichotomous measures of UDS-based endpoints in stimulant use disorder clinical trials have been used to measure achievement of abstinence, such that any positive UDS would be deemed as treatment “failures.” A dichotomous measure based on results of UDS that allows for less than complete abstinence may be valuable if deemed to be clinically meaningful (i.e., associated with better psychosocial functioning).

In a recent placebo-controlled trial demonstrating the efficacy of naltrexone and bupropion as a treatment for moderate to severe methamphetamine use disorder, treatment response was defined as at least three methamphetamine-negative UDS out of four samples obtained during the final two weeks of a six-week treatment period (Trivedi et al., 2021). This study is notable not only because it demonstrated efficacy of a medication for methamphetamine use disorder, but because it defined treatment response with UDS results that allowed for less than complete abstinence. To our knowledge, it was the first clinical trial to use three out of four (75%) UDS samples negative for stimulants as the primary outcome. However, it is unclear if this outcome is associated with better health and psychosocial functioning.

We sought to build on our prior work evaluating stimulant use outcome measures using data pooled from clinical trials for cocaine use disorder to examine the clinical meaningfulness of a 75% cocaine-negative (CN) UDS threshold as a treatment endpoint. We chose the 75% threshold based on our prior work evaluating cocaine use outcome measures (Carroll et al., 2014a) and to parallel the urine-based threshold used by Trivedi et al. (2021) for defining treatment response in a clinical trial for stimulant use disorder. However, we considered all UDS collected during a treatment period versus only those collected in the last two weeks of a treatment stage (as used by Trivedi et al., 2021) given the varied UDS collection schedule in the RCTs utilized for the current study.

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