The use and reporting of patient-reported outcomes in phase III breast cancer trials.

BACKGROUND: Public and government attention to patient-centered research outcomes has been increasing, evidenced by the recent formation of the Patient Centered Outcomes Research Institute. Drug development clinical trials can be made more patient-centered by collecting patient-reported outcome measures that can inform decision making by patients and their health-care providers. Patient-reported outcomes are important to collect in trials of breast cancer therapeutics, which encompass a wide range of treatment regimens and side effects. PURPOSE: We sought to determine recent trends in the use of patient-reported outcomes in drug trials for the treatment of breast cancer and evaluate the reporting of these data in study publications. METHODS: We searched ClinicalTrials.gov for phase III breast cancer drug trials, recording information on start date, primary completion date, primary outcome measure, primary sponsor, stage of cancer, and patient-reported outcome use. To assess the reporting of patient-reported outcome data, Google.com and PubMed.gov were searched for all publications resulting from included trials. RESULTS: We found 236 eligible trials, starting between May 1989 and December 2011. Of these trials, 83 (35%) stipulated patient-reported outcome use. The rate of patient-reported outcome use in recent years has shown no increase over earlier time periods: 37% (1989-2000) versus 36% (2004-2007) versus 30% (2008-2011) (p = 0.8). Trials with sponsorship led by the pharmaceutical industry and trials including patients with locally advanced or metastatic disease had the highest rates of patient-reported outcome use (40/87 (46%) and 44/102 (43%), respectively). Among the 83 trials that collected patient-reported outcome measures, 36 were completed a minimum of 2 years before our analysis; of these 36 studies, 19 (53%) had published patient-reported outcome data. LIMITATIONS: Data were limited to self-reported descriptions of trials listed on the ClinicalTrial.gov database, which is the best compendium of trial information available, but it is neither a complete nor a fully accurate record of all trials. CONCLUSIONS: Patient-reported outcome use and reporting in breast cancer drug trials has remained relatively low despite calls for more patient-centered research. Increasing the collection and availability of patient-reported outcome data to guide clinical decisions will require aligned support from trial sponsors, researchers, journal editors, regulators and patient advocacy groups, who can all play important roles in implementing change.

The potential benefit of the placebo effect in sham-controlled trials: implications for risk-benefit assessments and informed consent.

There has been considerable debate surrounding the ethics of sham-controlled trials of procedures and interventions. Critics argue that these trials are unethical because participants assigned to the control group have no prospect of benefit from the trial, yet they are exposed to all the risks of the sham intervention. However, the placebo effect associated with sham procedures can often be substantial and has been well documented in the scientific literature. We argue that, in light of the scientific evidence supporting the benefits of sham interventions for pain and Parkinson's disease that stem from the placebo effect, these sham-controlled trials should be considered as offering potential direct benefit to participants. If scientific evidence demonstrates the positive effect of placebo from sham interventions on other conditions, sham-controlled trials of interventions for the treatment of these conditions should be considered to have prospects of benefit as well. This potential benefit should be taken into account by research ethics committees in risk-benefit analyses, and be included in informed consent documents.

Repeated administration of a mutant cocaine esterase: effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys.

Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n = 2) and long-lasting increases in MAP and HR (n = 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans.

The fate of bacterial cocaine esterase (CocE): an in vivo study of CocE-mediated cocaine hydrolysis, CocE pharmacokinetics, and CocE elimination.

Cocaine abuse and toxicity remain widespread problems in the United States. Currently cocaine toxicity is treated only symptomatically, because there is no Food and Drug Administration-approved pharmacotherapy for this indication. To address the unmet need, a stabilized mutant of bacterial cocaine esterase [T172R/G173Q-CocE (DM-CocE)], which hydrolyzes cocaine into inactive metabolites and has low immunogenic potential, has been developed and previously tested in animal models of cocaine toxicity. Here, we document the rapid cocaine hydrolysis by low doses of DM-CocE in vitro and in vivo, as well as the pharmacokinetics and distribution of the DM-CocE protein in rats. DM-CocE at 50.5 µg/kg effectively eliminated 4 mg/kg cocaine within 2 min in both male and female rats as measured by mass spectrometry. We expanded on these findings by using a pharmacologically relevant dose of DM-CocE (0.32 mg/kg) in rats and monkeys to hydrolyze convulsant doses of cocaine. DM-CocE reduced cocaine to below detection limits rapidly after injection; however, elimination of DM-CocE resulted in peripheral cocaine redistribution by 30 to 60 min. Elimination of DM-CocE was quantified by using [³5S] labeling of the enzyme and was found to have a half-life of 2.1 h in rats. Minor urinary output of DM-CocE was also observed. Immunohistochemistry, Western blotting, and radiography all were used to elucidate the mechanism of DM-CocE elimination, rapid proteolysis, and recycling of amino acids into all tissues. This rapid elimination of DM-CocE is a desirable property of a therapeutic for cocaine toxicity and should reduce the likelihood of immunogenic or adverse reactions as DM-CocE moves toward clinical use.

The ability of bacterial cocaine esterase to hydrolyze cocaine metabolites and their simultaneous quantification using high-performance liquid chromatography-tandem mass spectrometry.

Cocaine toxicity is a widespread problem in the United States, responsible for more than 500,000 emergency department visits a year. There is currently no U.S. Food and Drug Administration-approved pharmacotherapy to directly treat cocaine toxicity. To this end, we have developed a mutant bacterial cocaine esterase (DM-CocE), which has been previously shown to rapidly hydrolyze cocaine into inert metabolites, preventing and reversing toxicity with limited immunogenic potential. Herein we describe the ability of DM-CocE to hydrolyze the active cocaine metabolites norcocaine and cocaethylene and its inability to hydrolyze benzoylecgonine. DM-CocE hydrolyzes norcocaine and cocaethylene with 58 and 45% of its catalytic efficiency for cocaine in vitro as measured by a spectrophotometric assay. We have developed a mass spectrometry method to simultaneously detect cocaine, benzoylecgonine, norcocaine, and ecgonine methyl ester to quantify the effect of DM-CocE on normal cocaine metabolism in vivo. DM-CocE administered to rats 10 min after a convulsant dose of cocaine alters the normal metabolism of cocaine, rapidly decreasing circulating levels of cocaine and norcocaine while increasing ecgonine methyl ester formation. Benzoylecgonine was not hydrolyzed in vivo, but circulating concentrations were reduced, suggesting that DM-CocE may bind and sequester this metabolite. These findings suggest that DM-CocE may reduce cocaine toxicity by eliminating active and toxic metabolites along with the parent cocaine molecule.

Evaluation of the hydrolytic activity of a long-acting mutant bacterial cocaine in the presence of commonly co-administered drugs.

BACKGROUND: Cocaine toxicity is a prevalent problem in the Unites States for which there is currently no FDA-approved pharmacotherapy. We have developed a bacterial cocaine esterase (CocE) towards this indication. A thermostabilized mutant of CocE (DM-CocE) retains the hydrolytic activity of the wild-type esterase, rapidly hydrolyzing cocaine into the inactive metabolites ecgonine methyl ester and benzoic acid, and can prevent cocaine toxicities in rodent and non-human primate models. To advance DM-CocE towards clinical use, we examine here how the hydrolytic activity of DM-CocE is altered by some drugs commonly co-administered with cocaine. METHODS: We employed a spectrophotometric cocaine hydrolysis assay to evaluate whether pharmacologically relevant doses of alcohol, nicotine, morphine, phencyclidine, ketamine, methamphetamine, naltrexone, naloxone, or midazolam would alter the Michaelis-Menten kinetics of DM-CocE for cocaine. Mass spectrometry was used to evaluate interaction with diazepam as this drug interferes with the absorbance spectra of cocaine critical for the spectrophotometric assay. RESULTS: Alcohol, nicotine, morphine, phencyclidine, ketamine, methamphetamine, naltrexone, naloxone, and midazolam did not alter cocaine hydrolysis by DM-CocE. However, diazepam significantly slowed DM-CocE cocaine hydrolysis at very high concentrations, most likely through interaction of the phenyl ring of the benzodiazepine with the active site of DM-CocE. CONCLUSIONS: DM-CocE does not display significant drug interactions, with the exception of diazepam, which may warrant further study as DM-CocE progresses towards a clinically used pharmacotherapy for cocaine toxicity. Alternate benzodiazepines, e.g., midazolam could be used to avoid this potential interaction.

A thermally stable form of bacterial cocaine esterase: a potential therapeutic agent for treatment of cocaine abuse.

Rhodococcal cocaine esterase (CocE) is an attractive potential treatment for both cocaine overdose and cocaine addiction. CocE directly degrades cocaine into inactive products, whereas traditional small-molecule approaches require blockade of the inhibitory action of cocaine on a diverse array of monoamine transporters and ion channels. The usefulness of wild-type (wt) cocaine esterase is hampered by its inactivation at 37 degrees C. Herein, we characterize the most thermostable form of this enzyme to date, CocE-L169K/G173Q. In vitro kinetic analyses reveal that CocE-L169K/G173Q displays a half-life of 2.9 days at 37 degrees C, which represents a 340-fold improvement over wt and is 15-fold greater than previously reported mutants. Crystallographic analyses of CocE-L169K/G173Q, determined at 1.6-A resolution, suggest that stabilization involves enhanced domain-domain interactions involving van der Waals interactions and hydrogen bonding. In vivo rodent studies reveal that intravenous pretreatment with CocE-L169K/G173Q in mice provides protection from cocaine-induced lethality for longer time periods before cocaine administration than wt CocE. Furthermore, intravenous administration (pretreatment) of CocE-L169K/G173Q prevents self-administration of cocaine in a time-dependent manner. Termination of the in vivo effects of CoCE seems to be dependent on, but not proportional to, its clearance from plasma as its half-life is approximately 2.3 h and similar to that of wt CocE (2.2 h). Taken together these data suggest that CocE-L169K/G173Q possesses many of the properties of a biological therapeutic for treating cocaine abuse but requires additional development to improve its serum half-life.

Cocaine esterase prevents cocaine-induced toxicity and the ongoing intravenous self-administration of cocaine in rats.

Cocaine esterase (CocE) is a naturally occurring bacterial enzyme, is a very efficient protein catalyst for the hydrolysis of cocaine, and has previously been shown to protect rodents from the lethal effects of cocaine. The current studies were aimed at evaluating the capacity of a longer acting mutant form (CocE T172R/G173Q; DM CocE) of CocE to protect against the lethal effects of cocaine, and alter ongoing intravenous cocaine self-administration in rats. A dose-response analysis revealed a dose-dependent suppression of cocaine-reinforced responding with 1.0 mg of CocE T172R/G173Q producing saline-like rates of responding. The effects of 1.0 mg of CocE T172R/G173Q on cocaine-reinforced responding were then compared with responding when saline was available for injection, whereas the selectivity of CocE T172R/G173Q's effects was assessed by evaluating the effects of 1.0 mg of CocE T172R/G173Q on (-)-2beta-carbomethoxy-3beta-phenyltropane (WIN-35065-2)- and food-reinforced responding. Although 1.0 mg of CocE T172R/G173Q suppressed responding maintained by 0.1 mg/kg/injection cocaine, a significant increase in responding was observed when responding was maintained by 1.0 mg/kg/injection cocaine, resulting in a 10-fold rightward shift in the dose-response curve for cocaine self-administration at a dose that did not significantly alter responding maintained by either WIN-35065-2 or food. These findings demonstrate that a long-acting form of CocE is effective at abruptly reducing the ongoing self-administration of low doses of cocaine, and provides a robust antagonism of cocaine's reinforcing effects. Furthermore, these studies provide strong evidence for the potential usefulness of a suitable, stable, and long-acting form of CocE as a pharmacotherapy for cocaine abuse in humans.