Citalopram for treatment of cocaine use disorder: A Bayesian drop-the-loser randomized clinical trial

Abstract

Background: Medication development research for cocaine use disorder (CUD) has been a longstanding goal in addiction research, but has not resulted in an FDA-approved treatment. Rising cocaine use rates underscore the need for efficient adaptive designs. This study compared differences between two doses of the selective serotonin reuptake inhibitor (SSRI) citalopram (versus placebo) on duration of cocaine abstinence and applied adaptive decision rules to select the 'best efficacy' dose.

Methods: A double-blind, placebo-controlled, randomized Bayesian drop-the-loser (DTL) trial with three arms compared placebo to citalopram 20 mg and 40 mg. Adults (N = 107) with CUD attended thrice-weekly clinic visits for 9 weeks. The primary outcome was longest duration of abstinence (LDA), based on continuous cocaine-negative urine drug screens (UDS). The secondary outcome was probability of cocaine-negative UDS during treatment. A planned interim analysis performed at approximately 50% of recruitment dropped the least-effective active medication. Bayesian inference was used for all analyses with a pre-specified posterior probability (PP) threshold PP ≥ 95% considered statistically reliable evidence RESULTS: Citalopram 40 mg satisfied interim efficacy criteria and was retained for the second half of the trial. For LDA, analyses indicated PP = 82% and PP = 65% of benefit for 40 mg and 20 mg, respectively (each relative to placebo). The odds of having cocaine-negative UDS decreased in all groups over 9 weeks but remained higher for 40 mg (PP = 97.4%) CONCLUSIONS: Neither dose met the 95% PP threshold for the primary outcome; however, 40 mg provided moderate-to-strong evidence for positive effects on LDA and cocaine-negative UDS. The 40 mg dose was declared the "winner" in this DTL trial.

Trial registration: ClinicalTrials.gov NCT01393457.

Keywords: Bayesian adaptive design; Citalopram; Cocaine use disorder; Drop-the-loser; Randomized clinical trial.

Conflict of interest statement

Conflict of Interest: No conflict declared.

Copyright © 2021 Elsevier B.V. All rights reserved.

Figures

Figure 1.

Flow chart of study participants.

Figure 2.. Posterior probability of longest duration of abstinence.

The posterior distributions for the incidence rate ratios for citalopram 20 mg (red) and 40 mg (blue), relative to placebo. The x-axis represents the magnitude of the effect (IRR) and the y-axis represents the density of the posterior distribution. The solid black line at IRR = 1.0 represents a null effect. The chance that the effect of each treatment confers benefit (relative to placebo) is represented by the proportion of each distribution that to the right of the solid black line (PP(IRR > 1); as described above these were 64.8% (C20) and 82.1% (C40). The median and 95% CrI of each distribution are represented by dashed and dotted lines, respectively. For each distribution, the median provides the best single point estimate of the effect and the 95% CrI provides the equal-tailed interval that has 2.5% of the distribution on either side of its limits.

Figure 3.. Posterior probability of cocaine-negative urine drug screens.

The posterior distributions for the odds ratios for citalopram 20 mg (red) and 40 mg (blue), relative to placebo. Interpretation follows from Figure 2.

Figure 4.. Observed probability of cocaine-negative UDS over time.

The green, red, and blue shapes describe observed probability of cocaine-negative urine drug screens for each treatment condition (PLC, C20, and C40, respectively) over time.