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Background: To characterize the alterations of liver function tests (LFTs), aspartate- (AST) and alanine transaminase (ALT) in healthy “normal” (HN) and cocaine experienced (actively using cocaine preadmission; CE) adults participating in long term inpatient clinical trials.Methods: LFT values from screening, admission, inpatient and inpatient discharge from 112 male and female volunteers, aged 18 to 45 years, with body mass index (BMI) from 20 to 30 kg/m2, participating in 3 inpatient Phase 1 trials were analyzed. 90 subjects received active drugs, and 22 subjects received matched placebo. 47 subjects were HN and 65 were CE. ANOVA method was applied to determine significant differences of various factors.Results: Both HN and CE subjects had an increase in LFTs during the studies. Gender, BMI, treatment (placebo or drug) did not predict LFTs changes (both for absolute LFTs values as well as differences (ΔALT, ΔAST) between screening day and during the inpatient period. CE study volunteers were found to have significantly higher AST and ALT values than HN volunteers (p< 0.05). All the subjects with abnormal LFTs were CE; 35.7% of them received placebo.Conclusions: Despite normal LFT values at screening, most subjects demonstrated an increase in the ALT level even on placebo. For CE subjects, ΔALT and ΔAST were significantly higher than for HN subjects. The potential to obscure important signals for hepatotoxicity appears to be higher in the CE study population.Clinical Pharmacology & Therapeutics (2005) 79, P2–P2; doi: 10.1016/j.clpt.2005.12.006 [ABSTRACT FROM AUTHOR]

Aims: RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681., Methods: Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [ 11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose., Results: RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [ 11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA., Conclusion: Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving., (© 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Aims: To evaluate the safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX)., Design: Randomized, double-blind, placebo-controlled trial. Subjects received either four buprenorphine implants (80 mg/implant) (n = 114), four placebo implants (n = 54) or open-label BNX (12-16 mg/day) (n = 119)., Setting: Twenty addiction treatment centers., Participants: Adult out-patients (ages 18-65) with DSM-IV-TR opioid dependence., Measurements: The primary efficacy end-point was the percentage of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF)., Findings: The BI CDF was significantly different from placebo (P < 0.0001). Mean [95% confidence interval (CI)] proportions of urines negative for opioids were: BI = 31.2% (25.3, 37.1) and PI = 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64 versus 26%, P < 0.0001), lower clinician-rated (P < 0.0001) and patient-rated (P < 0.0001) withdrawal, lower patient-ratings of craving (P < 0.0001) and better subjects' (P = 0.031) and clinicians' (P = 0.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P = 0.0016). Minor implant-site reactions were comparable in the buprenorphine [27.2% (31 of 114)] and placebo groups [25.9% (14 of 54)]. BI were non-inferior to BNX on percentage of urines negative for opioids [mean (95% CI) = 33.5 (27.3, 39.6); 95% CI for the difference of proportions = (-10.7, 6.2)]., Conclusions: Compared with placebo, buprenorphine implants result in significantly less frequent opioid use and are non-inferior to sublingual buprenorphine/naloxone tablets., (© 2013 Society for the Study of Addiction.)

Aims: In order to increase the number of investigative teams and sites conducting research on pharmacological treatments for methamphetamine use disorders, the National Institute on Drug Abuse (NIDA) established an infrastructure of clinical sites in areas where methamphetamine addiction is prevalent. This multi-site infrastructure would serve to run multiple Phases II and III protocols effectively and expeditiously., Methods: NIDA collaborated with investigators from the University of California at Los Angeles (UCLA) to set up the Methamphetamine Clinical Trials Group (MCTG). This paper describes the development process, as well as data from a test trial to assess the capability of research-naive sites to recruit research participants and conduct study procedures according to research protocol. Subsequent trials are also described., Results: A total of 151 candidates signed consent; 65 individuals were enrolled and 35 (53.8%) completed the 12 weeks' behavioral trial. Self-reported substance use report (SUR) showed comparable use of methamphetamine across sites with the individual site means ranging from 59% (site 5) to 80% (site 3). Drug use as measured by urinalysis was greatly reduced at week 13 compared to the baseline measure; the average rate of methamphetamine-free urine samples across all participants in sites at week 13 was 53%. The highest percentage of methamphetamine-free samples was 85% at site 5; the lowest was at site 1 (40%). Addiction severity index (ASI) composite scores at baseline and protocol completion for all participants demonstrated improvement in all categories over time, except for the medical composite score. The largest composite score reduction in baseline-protocol completion was in the drug domain (0.23 versus 0.15). The changes in the ASI scores from baseline to week 13 were consistent across all five sites., Conclusions: Outcomes of the behavioral trial indicated that the MCTG recruited well; collected study data accurately and reliably; and created a vehicle that can assess promising pharmacotherapies for methamphetamine addiction treatment medications. The MCTG strategy appears to be a feasible approach to increase NIDA's capacity to conduct clinical trials to evaluate potential pharmacotherapies for methamphetamine addiction.

Aim: To analyze pooled data from the Cocaine Rapid Evaluation Screening Trial (CREST). Pooling data from these small pilot trials into four major drug classes permitted data exploration for treatment and covariate effects with increased sample size., Design: Small pilot trials were conducted to screen fifteen medications as prospective treatments for cocaine dependence. Studies included a flexible 2-week to 4-week screening/baseline period followed by an 8-week randomized treatment condition. Participants were randomized equally to one of up to three active medications or placebo., Setting: Five Medications Development Research Units at the five academic centers of University of Cincinnati, New York University, University of Pennsylvania, University of California Los Angeles and Boston University., Participants: The pooled data set consisted of 357 total subjects. Standardized inclusion and exclusion criteria were employed in subject selection to enhance consistency of cocaine-dependent study participants across all sites (see reports on individual trials in this supplement for details). All participants provided at least two urine samples that were positive for cocaine metabolite during a two-week period prior to being randomized., Intervention: All subjects in these trials, those randomized to placebo and active medications, received active treatment in the form of evidence-based cognitive behavioral therapy., Measures: Quantitative urine benzoylecgonine (BE), self-report of cocaine use, and total Brief Substance Craving Scale (BSCS) scores were compared between each class of medication and its matched-placebo group., Findings: Regression analysis of pooled data did not identify any statistically significant differences between treatment and matched-placebo for any of the four classes. Exploration of the effects of baseline covariates indicated that gender and African American status were associated significantly with outcome. Female gender was consistently associated with poorer outcomes for medication and placebo groups, while the direction of association between African American status and outcome differed by treatment groups. Retention was also examined: dropout rates may have been somewhat higher for placebo than treatment groups during the early active-treatment period. Classification trees were used to identify characteristics of subjects who were abstinent for at least two weeks during the eight-week trial; only 4.0% of females while 17.9% of males achieved this criterion., Conclusions: Results presented here may prove useful for planning future clinical trials for therapies targeting cocaine dependence.

Aims: The Cocaine Rapid Efficacy Screening Trials (CREST) were designed by the National Institute on Drug Abuse Division of Treatment Research and Development (NIDA, DT R&D) to rapidly screen a number of medications potentially useful for the treatment of cocaine dependence., Design: Each CREST trial was designed to compare several medications in a single trial against an unmatched placebo. The placebo group was included in each trial to avoid the nearly universal positive response to medications seen in open-label trials. In addition, a common set of procedures and outcome measures were employed throughout to increase comparability of results obtained from different trials and from different times., Participants: In all, 18 medications were screened in seven different trials, conducted in four different sites throughout the United States involving 398 cocaine-dependent patients., Findings: Three medications were found to be promising enough to include in subsequent larger trials. Common statistical procedures for evaluating medications were developed to facilitate comparisons across sites and across time. A portion of the data were pooled and analyzed, which yielded some useful insights into cocaine dependence and its treatment. Finally, a review of individual trials together with the pooled analysis revealed several potential improvements for future screening trials., Conclusions: Overall, the CREST trials proved to be useful for rapidly screening medications for treatment of cocaine dependence, but several modifications in design should be made before this framework is applied further.

Aim: Development of effective medications for the treatment of cocaine dependence remains a major priority for the National Institute on Drug Abuse (NIDA) at the National Institutes of Health. The Cocaine Rapid Efficacy Screening Trial (CREST) paradigm was developed by the Division of Treatment Research and Development (DT R&D) at NIDA with the goal of enhancing pilot clinical trial validity when systematically assessing a range of medications and drug classes for potential utility in treatment of cocaine dependence., Design: CREST utilizes a randomized, controlled, parallel group, blinded methodology for comparing one or more marketed medications against a standard, pharmaceutical grade placebo. The trial design is comprised of a flexible 24-week screening/baseline period followed by randomization to an 8-week treatment period., Measures: Standard measures of outcomes for the CREST included urinary benzoylecgonine (primary metabolite of cocaine), retention, cocaine craving, depression, clinical global impression and HIV-risk behaviors. In order to facilitate comparisons of data from the CREST studies across sites, drug classes and time, standardized procedures, measures and psychosocial counseling were used., Results: A total of 19 medications were evaluated in out-patient treatment research clinics in Boston, Cincinnati, Los Angeles, New York and Philadelphia., Conclusions: Findings supported decisions to move forward three medications (cabergoline, reserpine, tiagabine) using full-scale, adequately powered, randomized placebo-controlled trial designs. Lessons learned from the CREST experience continue to shape cocaine pharmacotherapy trial design and execution.

The search for effective medications for cocaine addiction has been elusive. The failure to find such medications so far could be due to poor understanding of the underlying biology both in the premorbid condition and following the disease state of chronic cocaine use. Population heterogeneity could be a major factor in response to medications. In an attempt to highlight the issue of biomarkers we reviewed physiological, neuroendocrine and neuroimaging studies to identify specific biological changes/markers that could be used to characterize subgroups among chronic cocaine users. Merging the biology within medications studies of cocaine abusers could prove useful for targeting specific pharmacological agents to subgroups of patients, prediction of response to medication and relapse to use.