Cocaine addiction is a devastating disorder that disrupts individuals, families, and communities, and it requires huge public health resources. Unique among addictions, cocaine dependence and other stimulant dependencies do not have a single FDA-approved medication. Modafinil, an atypical alerting and cognitively enhancing agent, has shown promise for the treatment of cocaine dependence in three human laboratory studies (Dackis et al, 2003; Malcolm et al, 2006; Hart et al, 2007) and in one preliminary clinical trial (Dackis et al, 2007). Those results were recently complicated by the findings from a multi-center trial reported at CPDD (Elkashef, 2007). The data indicated that for the overall sample (N=203), modafinil was no better than placebo. A post hoc analysis indicated that the subpopulation of patients who were comorbidly dependent on cocaine and alcohol had non-significant results. When that comorbid group was statistically removed, modafinil indeed did have a reduction in cocaine use days as validated by urine drug screens when compared to placebo condition (p=0.02). The subject population in this present R01 competitive submission, along with the original data set collected over four years, will be analyzed and published on its own, but it will also become part of a larger meta-analysis to determine whether modafinil will be sent forward to the FDA as a possible treatment for cocaine dependence. Recruitment in the first four years of this R01 application has been slowed by increased competition from clinical treatment programs and from a higher-than-anticipated rate of screen failures due to increasingly more subjects with comorbidities with opiates, other stimulants, prescription medications, and exclusionary cardiovascular findings. A blinded futility analysis conducted for our DSMB indicates a promising signal and the need to recruit 45 additional subjects. This two-year competitive renewal seeks to continue the present trial in its same methodology to gain the critical power necessary to evaluate efficacy and continued monitoring of safety. The specific hypothesis of this study continues to be: in treatment-seeking cocaine dependent subjects, cognitive-behavioral therapy plus 200 mg or 400 mg of modafinil orally will have a significantly higher number of cocaine non-use days as compared to subjects receiving cognitive-behavioral therapy coupled with placebo. Non-use days will be confirmed with three-times-a-week quantitative urine benzolecgonine levels. Additional aims of this two-year competitive renewal include: to evaluate the effects of alcohol use on the efficacy and safety of modafinil; to conduct a meta-analysis of the data set from this trial, the current University of Pennsylvania trial, and the recently reported multi-center trial in an attempt to delineate a subpopulation of subjects for which modafinil is both safe and efficacious for the treatment of cocaine dependence. ? ? ?
