A Multisite, Double-blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Vigabatrin for Treating Cocaine Dependence

Somoza, Eugene; Winship, Douglas; Gorodetzky, Charles W.; Lewis, Daniel; Ciraulo, Domenic A.; Segal, Scott; Sheehan, Michael B.; Roache, John D.; Bickel, Warren K.; Jasinski, Donald R.; Watson, Daniella; Miller, Steven R.; Somoza, Peggy; Winhusen, Theresa

doi:10.1001/jamapsychiatry.2013.872

Cited by 40 publications

(25 citation statements)

References 31 publications

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“…However, this high adherence rate was primarily based on data from pill counts and subject self-report. The present study and past reports 10;23;24 indicate that pill counts and self-report greatly overestimate medication adherence relative to PK sampling. Subjects who are financially compensated for their participation in clinical trials may feel compelled to hide medication noncompliance.…”

Section: Discussionmentioning

confidence: 40%

Medication Nonadherence, “Professional Subjects,” and Apparent Placebo Responders

McCann¹,

Petry²,

Bresell³

et al. 2015

Journal of Clinical Psychopharmacology

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Nonadherence is a major problem in clinical trials of new medications. To evaluate the extent of nonadherence, this study evaluated pharmacokinetic sampling from 1765 subjects receiving active therapy across eight psychiatric trials conducted between 2001 and 2011. With nonadherence defined as > 50% of plasma samples below the limit of quantification for study drug, the percentage of nonadherent subjects ranged from 12.8% to 39.2%. There was a trend toward increased nonadherence in studies with greater numbers of subjects but an association with nonadherence was not apparent for other study design parameters or subject characteristics. For two trials with multiple recruitment sites in geographical proximity, several subjects attempted to simultaneously enroll at separate site locations. The construct of “professional subjects,” those who enroll in trials only for financial gain, is gaining attention, and we therefore modeled the impact of professional subjects on medication efficacy trials. The results indicate that enrollment of professional subjects who are destined to succeed (those who will appear to achieve treatment success regardless of study drug assignment) can substantially increase both the apparent placebo response rate and the sample size requirement for statistical power, while decreasing the observed effect size. The overlapping nature of nonadherence, professional subjects, and placebo response suggests that these issues should be considered and addressed together. Following this approach, we describe a novel clinical trial design to minimize the adverse effects of professional subjects on trial outcomes, and discuss methods to monitor adherence.

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Section: Discussionmentioning

confidence: 40%

Medication Nonadherence, “Professional Subjects,” and Apparent Placebo Responders

McCann¹,

Petry²,

Bresell³

et al. 2015

Journal of Clinical Psychopharmacology

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“…Over 1.5 million people in the United States habitually use cocaine (SAMHSA, 2014), but there are no effective treatments for those trying to break the habit (Somoza et al, 2013). This leads to a prolonged cycle of abuse, treatment, and relapse (e.g., Griffin et al, 1989;Vonmoos et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector–Delivered Cocaine Hydrolase

Smethells

Swalve

Brimijoin

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaineinduced locomotion, whereas control rats showed a dosedependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse.

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“…Additionally, those receiving GVG were more likely to report abstinence from alcohol (43.5 vs 6.3%), and treatment retention was significantly higher in the GVG group. In a recent multisite, double-blind, placebo-controlled RCT of 186 cocaine-dependent individuals, however, Somoza et al found that there was no statistically significant difference between GVG and placebo in terms of cocaine abstinence or reduction in cocaine-positive urines [113]. The post hoc analysis of GVG urine concentration levels suggested that 40 --60% of patients in the treatment group may not have been adherent with the medication regimen, raising the question of whether the limited efficacy of the medication was due to nonadherence.…”

Section: Vigabatrin and Its Analoguesmentioning

confidence: 98%

Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy

Shorter

Domingo

Kosten

2014

Expert Opinion on Emerging Drugs

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Research into cocaine pharmacotherapy must continue to show innovation. Given that medications targeting single neurotransmitter systems have demonstrated little efficacy in treatment of cocaine use disorder, the recent focus on pharmacotherapeutic agents with multiple neurobiochemical targets represents an exciting shift in trial design and approach. Additionally, consideration of pharmacogenetics may be helpful in identification of subpopulations of cocaine-dependent individuals who may preferentially respond to medications.

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A Multisite, Double-blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Vigabatrin for Treating Cocaine Dependence

Cited by 40 publications

References 31 publications

Medication Nonadherence, “Professional Subjects,” and Apparent Placebo Responders

Medication Nonadherence, “Professional Subjects,” and Apparent Placebo Responders

Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector–Delivered Cocaine Hydrolase

Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy

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