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DBH gene as predictor of response in a cocaine vaccine clinical trial.

ABSTRACT: We examined a pharmacogenetic association of the dopamine ?-hydroxylase (DBH) gene with a response to an anti-cocaine vaccine that was tested in a recent clinical trial. This gene is associated with cocaine-induced paranoia, which has a slower onset than the euphoria from cocaine. The vaccine reduced euphoria by slowing the entry of cocaine into the brain, but it may not reduce aversive symptoms like paranoia. A 16-week Phase IIb randomized double-blind placebo-controlled trial of 114 cocaine and opioid dependent subjects who received five vaccinations over the first 12 weeks was examined. We genotyped 71 subjects for the rs1611115 (-1021C>T) variant of the DBH gene and compared vaccine to placebo subjects on cocaine-free urines. Using repeated measures analysis of variance, corrected for population structure, vaccine pharmacotherapy reduced cocaine positive urines significantly based on DBH genotype. Patients with the low D?H level genotype dropped from 77% to 51% on vaccine (p=0.0001), while those with the normal D?H level genotype dropped from 83% to 72%. Placebo showed no effect on cocaine use overall or by genotype. This study indicates that a patient's DBH genotype could be used to identify a subset of individuals for whom vaccine treatment may be an effective pharmacotherapy for cocaine dependence.

SUBMITTER: Kosten TR

PROVIDER: S-EPMC3631430 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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DBH gene as predictor of response in a cocaine vaccine clinical trial.

Kosten Thomas R TR Domingo Coreen B CB Hamon Sara C SC Nielsen David A DA

Neuroscience letters 20130228

We examined a pharmacogenetic association of the dopamine β-hydroxylase (DBH) gene with a response to an anti-cocaine vaccine that was tested in a recent clinical trial. This gene is associated with cocaine-induced paranoia, which has a slower onset than the euphoria from cocaine. The vaccine reduced euphoria by slowing the entry of cocaine into the brain, but it may not reduce aversive symptoms like paranoia. A 16-week Phase IIb randomized double-blind placebo-controlled trial of 114 cocaine an ...[more]

PMID: 23458673

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Project description:BackgroundVaccine clinical studies typically provide time-resolved data on adaptive response read-outs in response to the administration of that particular vaccine to a cohort of individuals. However, modeling such data is challenged by the properties of these time-resolved profiles such as non-linearity, scarcity of measurement points, scheduling of the vaccine at multiple time points. Linear Mixed Models (LMM) are often used for the analysis of longitudinal data but their use in these time-resolved immunological data is not common yet. Apart from the modeling challenges mentioned earlier, selection of the optimal model by using information-criterion-based measures is far from being straight-forward. The aim of this study is to provide guidelines for the application and selection of LMMs that deal with the challenging characteristics of the typical data sets in the field of vaccine clinical studies.MethodsWe used antibody measurements in response to Hepatitis-B vaccine with five different adjuvant formulations for demonstration purposes. We built piecewise-linear, piecewise-quadratic and cubic models with transformations of the axes with pre-selected or optimized knot locations where time is a numerical variable. We also investigated models where time is categorical and random effects are shared intercepts between different measurement points. We compared all models by using Akaike Information Criterion (AIC), Bayesian Information Criterion (BIC), Deviance Information Criterion (DIC), variations of conditional AIC and by visual inspection of the model fit in the light of prior biological information.ResultsThere are various ways of dealing with the challenges of the data which have their own advantages and disadvantages. We explain these in detail here. Traditional information-criteria-based measures work well for the coarse selection of the model structure and complexity, however are not efficient at fine tuning of the complexity level of the random effects.ConclusionsWe show that common statistical measures for optimal model complexity are not sufficient. Rather, explicitly accounting for model purpose and biological interpretation is needed to arrive at relevant models.Trial registrationClinical trial registration number for this study: NCT00805389, date of registration: December 9, 2008 (pro-active registration).

Project description:ContextCocaine dependence, which affects 2.5 million Americans annually, has no US Food and Drug Administration-approved pharmacotherapy.ObjectivesTo evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence.DesignA 24-week, phase 2b, randomized, double-blind, placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24.SettingCocaine- and opioid-dependent persons recruited from October 2003 to April 2005 from greater New Haven, Connecticut.ParticipantsOne hundred fifteen methadone-maintained subjects (67% male, 87% white, aged 18-46 years) were randomized to vaccine or placebo, and 94 subjects (82%) completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and nonprescription opioids (44%).InterventionOver 12 weeks, 109 of 115 subjects received 5 vaccinations of placebo or succinylnorcocaine linked to recombinant cholera toxin B-subunit protein. Main Outcome Measure Semiquantitative urinary cocaine metabolite levels measured thrice weekly with a positive cutoff of 300 ng/mL.ResultsThe 21 vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 microg/mL or higher (ie, high IgG level) had significantly more cocaine-free urine samples than those with levels less than 43 microg/mL (ie, low IgG level) and the placebo-receiving subjects during weeks 9 to 16 (45% vs 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs 23% of subjects, respectively) (P = .048). The most common adverse effects were injection site induration and tenderness. There were no treatment-related serious adverse events, withdrawals, or deaths.ConclusionsAttaining high (>or=43 microg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters. Trial Registration clinicaltrials.gov Identifier: NCT00142857.

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DBH gene as predictor of response in a cocaine vaccine clinical trial.

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DBH gene as predictor of response in a cocaine vaccine clinical trial.

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