Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation.

Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.

Zonisamide, topiramate, and levetiracetam: efficacy and neuropsychological effects in alcohol use disorders.

The anticonvulsant topiramate not only decreases ethanol consumption in alcohol dependence (AD) but also may produce several adverse events including cognitive impairment. Zonisamide is a structurally related anticonvulsant that is a promising agent for the treatment of AD and may have greater tolerability than topiramate. This study evaluated the effects of zonisamide (400 mg/d) on alcohol consumption and its neurotoxic effects in subjects with AD. A double-blind placebo-controlled clinical trial was conducted using 2 comparator anticonvulsant drugs, topiramate (300 mg/d) and levetiracetam (2000 mg/d), which does not impair cognition. Study medications were administered for 14 weeks, including a 2-week taper period. Medication adherence was facilitated using Brief Behavioral Compliance Enhancement Treatment. The neurotoxicity of the study drugs was assessed using neuropsychological tests and the AB-Neurotoxicity Scale. Compared with placebo, both zonisamide and topiramate produced significant reductions in the drinks consumed per day, percent days drinking, and percent days heavy drinking. Only the percent days heavy drinking was significantly decreased in the levetiracetam group. The topiramate cell was the only group that had a significant increase on the mental slowing subscale of the Neurotoxicity Scale compared with placebo at study weeks 11 and 12. Topiramate and zonisamide both produced modest reductions in verbal fluency and working memory. These findings indicate that zonisamide may have efficacy in the treatment of AD, with effect sizes similar to topiramate. Both of these drugs produced similar patterns of cognitive impairment, although only the topiramate group reported significant increases in mental slowing.

Clearance of drugs for multiple myeloma therapy during in vitro high-cutoff hemodialysis.

Current chemotherapy for multiple myeloma is based on bortezomib (BOR), dexamethasone (DEX), and thalidomide (THA). The purpose of the present study was to examine their clearance during high-cutoff (HCO) hemodialysis and to accordingly apply the results to the dialytic removal of protein-bound substances in general. During in vitro hemodialysis with human blood (blood, dialysate, and ultrafiltration flow rates 250, 500 and 5 mL/min, respectively) comparing a highly permeable HCO dialyzer (Theralite, 2.1 m(2) ) to a high-flux dialyzer (PFX; 2.1 m(2) ), ultrafiltered volume was replaced by saline containing 30 g/L urea. After recirculation for equilibration, BOR was injected, and arterial and venous samples were drawn after 10, 11, and 12 min to measure the plasma clearance (K) of both urea and BOR. The same procedure was performed with THA and DEX. By mathematical simulation, the influence of varying plasma albumin concentrations (CHSA ) on the protein-bound drug fraction (PBF) and K was assessed. Plasma K values of HCO and PFX for THA, BOR, and DEX were about 40% (80 ± 7 vs. 65 ± 6 mL/min; P < 0.05), 70% (40 ± 8 vs. 33 ± 4 mL/min; P < 0.05), and 65% (47 ± 11 vs. 38 ± 7 mL/min; P < 0.05), respectively-lower (P < 0.0001) compared with urea (125 ± 7 vs. 122 ± 5 mL/min). K was highest (P < 0.0001) for THA. K was negatively correlated with CHSA (THA, r(2) = 0.58, P < 0.001; BOR, r(2) = 0.24, P < 0.05; DEX, r(2) = 0.22, P < 0.05). CHSA continually decreased (P < 0.05) over time only with HCO, resulting in lower calculated PBF. Compared with BOR and DEX (minimum 72 and 56%, respectively), the PBF of THA (37%) was significantly lower (P < 0.001). A mathematical simulation based on the K values of urea and the drugs reliably estimated PBF (r(2) = 0.886, P < 0.001). Drugs for multiple myeloma therapy are significantly removed with both HCO and PFX, with important implications for the dosing and timing of administration, particularly in patients with cast nephropathy receiving extended dialysis. If the Kurea of a dialyzer and the PBF of any given drug are known, Kdrug can be reliably estimated by mathematical simulation.

Results of a randomized, double-blind, placebo-controlled trial of lorcaserin in cocaine use disorder.

BACKGROUND: Cocaine use disorder (CUD) is a major public health problem for which there is no approved pharmacotherapy. The primary purpose of this study was to evaluate the ability of lorcaserin, a 5-hydroxytryptamine2 C (5-HT2 C) receptor agonist, to facilitate abstinence in individuals seeking treatment for CUD. METHODS: This was a 12-site, randomized, parallel arm study with a 13-week Treatment Phase that included a 1-week, single-blind run-in period when all participants received twice daily 15mg acetazolamide capsules (a medication adherence marker), followed by randomization to either twice daily 10mg lorcaserin or placebo capsules for the remaining 12 weeks. Pre-randomization data were utilized in an enrichment strategy aimed at achieving high levels of medication adherence and low placebo response rates in a subgroup of participants that qualified for the "efficacy population." For lorcaserin vs. placebo, the primary efficacy endpoint was the proportion of participants in the efficacy population achieving abstinence during the last three weeks of treatment, as evidenced by self-report of no cocaine use, confirmed by urine testing. RESULTS: Within the efficacy population, 1.1% of 91 participants receiving lorcaserin and 4.3% of 92 receiving placebo achieved abstinence during the last 3 weeks of treatment. Among all randomized participants, 2.5% of 118 receiving lorcaserin and 5.6% of 124 receiving placebo achieved similar abstinence. Study participants receiving lorcaserin exhibited significantly greater reductions in body weight and BMI, indicating that medication adherence was sufficient to produce a pharmacological effect. CONCLUSIONS: Twice daily 10mg lorcaserin failed to demonstrate efficacy in the treatment of CUD.

Concealment and fabrication by experienced research subjects.

BACKGROUND: Subjects who enroll in multiple studies have been found to use deception at times to overcome restrictive screening criteria. Deception undermines subject safety as well as study integrity. Little is known about the extent to which experienced research subjects use deception and what type of information is concealed, withheld, or distorted. PURPOSE: This study examined the prevalence of deception and types of deception used by subjects enrolling in multiple studies. METHODS: Self-report of deceptive behavior used to gain entry into clinical trials was measured among a sample of 100 subjects who had participated in at least two studies in the past year. RESULTS: Three quarters of subjects reported concealing some health information from researchers in their lifetime to avoid exclusion from enrollment in a study. Health problems were concealed by 32% of the sample, use of prescribed medications by 28%, and recreational drug use by 20% of the sample. One quarter of subjects reported exaggerating symptoms in order to qualify for a study and 14% reported pretending to have a health condition in order to qualify. LIMITATIONS: Although this study finds high rates of lifetime deceptive behavior, the frequency and context of this behavior is unknown. Understanding the context and frequency of deception will inform the extent to which it jeopardizes study integrity and safety. CONCLUSION: The use of deception threatens both participant safety and the integrity of research findings. Deception may be fueled in part by undue inducements, overly restrictive criteria for entry, and increased demand for healthy controls. Screening measures designed to detect deception among study subjects would aid in both protecting subjects and ensuring the quality of research findings.

A double-blind, placebo-controlled trial assessing the efficacy of levetiracetam extended-release in very heavy drinking alcohol-dependent patients.

BACKGROUND: Despite advances in the development of medications to treat alcohol dependence, few medications have been approved by the U.S. Food and Drug Administration. The use of certain anticonvulsant medications has demonstrated potential efficacy in treating alcohol dependence. Previous research suggests that the anticonvulsant levetiracetam may be beneficial in an alcohol-dependent population of very heavy drinkers. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, 130 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either levetiracetam extended-release (XR) or placebo and a Brief Behavioral Compliance Enhancement Treatment intervention. Levetiracetam XR was titrated during the first 4 weeks to 2,000 mg/d. This target dose was maintained during weeks 5 through 14 and was tapered during weeks 15 and 16. RESULTS: No significant differences were detected between the levetiracetam XR and placebo groups in either the primary outcomes (percent heavy drinking days and percent subjects with no heavy drinking days) or in other secondary drinking outcomes. Treatment groups did not differ on a number of nondrinking outcomes, including depression, anxiety, mood, and quality of life. The only difference observed was in alcohol-related consequences. The levetiracetam XR treatment group showed significantly fewer consequences than did the placebo group during the maintenance period (p = 0.02). Levetiracetam XR was well tolerated, with fatigue being the only significantly elevated adverse event, compared with placebo (53% vs. 24%, respectively; p = 0.001). CONCLUSIONS: This multisite clinical trial showed no efficacy for levetiracetam XR compared with placebo in reducing alcohol consumption in heavy drinking alcohol-dependent patients.

The efficacy of mirtazapine in the treatment of cocaine dependence with comorbid depression.

BACKGROUND: Prior findings concerning the use of mirtazapine in the treatment of a variety of substance use disorders and its antagonistic actions at the serotonin 5-HT(2A) receptor suggest that this drug may have efficacy in the treatment of cocaine dependence in the presence of a depressive disorder. METHODS: Depressed cocaine-dependent subjects received either mirtazapine (target dose 45 mg daily) or placebo for 12 weeks. Urine concentrations of benzoylecgonine and self-report were used to assess cocaine consumption. Depression and sleep quality were evaluated using the Hamilton Depression Rating Scale (HAM-D) and the Pittsburgh Sleep Quality Index, respectively. RESULTS: Cocaine consumption during the treatment period did not differ significantly between the mirtazapine (n = 11) and placebo (n = 13) groups in this study. In week 4 sleep latency was significantly lower in the active medication than in the placebo group. Positive effects of mirtazapine treatment on early insomnia were suggested by an item analysis of the HAM-D. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results of this study suggest that mirtazapine is superior to placebo in improving sleep in patients with comorbid depression and cocaine dependence, but is not more effective than placebo in reducing cocaine use.

Human and Insect Cell-Produced Recombinant Adeno-Associated Viruses Show Differences in Genome Heterogeneity.

In the past two decades, adeno-associated virus (AAV) vector manufacturing has made remarkable advancements to meet large-scale production demands for preclinical and clinical trials. In addition, AAV vectors have been extensively studied for their safety and efficacy. In particular, the presence of empty AAV capsids and particles containing "inaccurate" vector genomes in preparations has been a subject of concern. Several methods exist to separate empty capsids from full particles; but thus far, no single technique can produce vectors that are free of empty or partial (non-unit length) capsids. Unfortunately, the exact genome compositions of full, intermediate, and empty capsids remain largely unknown. In this work, we used AAV-genome population sequencing to explore the compositions of DNase-resistant, encapsidated vector genomes produced by two common production pipelines: plasmid transfection in human embryonic kidney cells (pTx/HEK293) and baculovirus expression vectors in Spodoptera frugiperda insect cells (rBV/Sf9). Intriguingly, our results show that vectors originating from the same construct design that were manufactured by the rBV/Sf9 system produced a higher degree of truncated and unresolved species than those generated by pTx/HEK293 production. We also demonstrate that empty particles purified by cesium chloride gradient ultracentrifugation are not truly empty but are instead packaged with genomes composed of a single truncated and/or unresolved inverted terminal repeat (ITR). Our data suggest that the frequency of these "mutated" ITRs correlates with the abundance of inaccurate genomes in all fractions. These surprising findings shed new light on vector efficacy, safety, and how clinical vectors should be quantified and evaluated.

Frequency of concealment, fabrication and falsification of study data by deceptive subjects.

PURPOSE: Many studies have found evidence that research subjects engage in deceptive practices while participating in health-related studies. Little is known, however, about how often subjects use deception and the percentage of studies a typical subject will contaminate with false data. This study examined the frequency of use of different types of deception among a sample of subjects who admit to using deception. METHODS: A sample of 59 subjects who had participated in at least two health-related studies in the past 12 months and admitted to using deception in at least one were interviewed. Subjects were asked a series of questions about concealing information and fabricating information to gain entry into studies. Subjects were also asked about falsifying data after being enrolled in a health-related study. All study data reported pertains to only subjects who reported using deception in health-related studies and is based on subjects' study participation only within the last 12 months from the date of the interview. RESULTS: Subjects who conceal information in order to enroll in trials reported using concealment in about two thirds (67%) of the trials they participated in over the past 12 months. On average, these subjects' use of concealment was highest for mental health information (58% of studies) and physical health information (57% of studies). The average frequency of fabricating information in order to enroll in trials was 53% with exaggerating health symptoms (45% of studies) and pretending to have a health condition (39% of studies) as the two most widely used strategies. Subjects who falsify study data after enrollment reported doing so 40% of the time. These subjects falsely reported improvement in the health condition being studied in 38% of the trials they took part in. Subjects who admitted to throwing away study medication to create the appearance of compliance reported doing so 32% of the time. LIMITATIONS: Although this study provides evidence that subjects who admit to using deception contaminate a high percentage of studies, larger and more geographically diverse samples are needed to understand the full extent of the problem of deceptive subjects in research. Regional economic, cultural, or organizational factors may be related to the rate of subjects using deception. It is also possible that this sample underrepresents the use of deception as there are likely subjects who use deception that would be unwilling to admit the extent of this behavior. CONCLUSION: Deceptive subject's behavior poses a threat to the integrity of research findings. Given that deceptive subjects contaminate a high percentage of studies they take part in by concealing information, fabricating information, and falsifying study data after enrollment, efforts to identify and exclude these subjects is important to the integrity of research findings. Strategies to exclude deceptive subjects from health research should be used to inform study designs. Widespread adoption of research subject identity registries could greatly reduce the scope of studies that a single deceptive subject could contaminate. Technological solutions that provide an objective measure of medication compliance may be valuable tools for limiting fraudulent reports of compliance.

Open label trial of the tolerability and efficacy of zonisamide in the treatment of alcohol dependence.

OBJECTIVES: The objectives of this study are to assess the tolerability and efficacy of the anticonvulsant zonisamide in an open label trial of the treatment of alcohol dependence. METHODS: In this trial, zonisamide (400-mg daily) was administered to alcohol-dependent subjects (ADS) (n = 16) over 13 weeks. The mean daily consumption of standard alcoholic drinks and performance on a verbal fluency task, the COWAT, and on a measure of attention and visuomotor speed, the DSMT were assessed, and the occurrence of adverse events was monitored weekly. RESULTS: The mean number of drinks consumed daily was significantly reduced from baseline levels during the treatment period. Performances on the COWAT and on the DSMT were not significantly reduced by zonisamide treatment. Overall, zonisamide was well tolerated by the study subjects. CONCLUSION: These results indicate that zonisamide administration may not impair verbal fluency in ADS, and are consistent with other studies that found zonisamide administration may reduce alcohol intake.

Improving Study Conduct and Data Quality in Clinical Trials of Chronic Pain Treatments: IMMPACT Recommendations.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

The anticonvulsant zonisamide reduces ethanol self-administration by risky drinkers.

OBJECTIVE: The purpose of this study is to examine the effects of zonisamide on ethanol self-administration and subjective effects in risky drinkers using a human laboratory paradigm. METHOD: We conducted a double-blind, placebo-controlled study of the effects of zonisamide 100 mg on ethanol self-administration and urge to drink in risky drinkers (N = 10) ( [1] ). RESULT: During the second hour of a 2-hour self-administration session ethanol consumption was 50% lower in the zonisamide group as compared to the placebo group. Urge to drink was also significantly lower under the zonisamide condition. CONCLUSION: These results indicate that a single dose of zonisamide reduces urge to drink and the quantity of ethanol self-administered by risky drinkers during their second hour of access to alcohol. SCIENTIFIC SIGNIFICANCE: Zonisamide may help individuals drinking at risky levels reduce their intake of alcohol.

The effects of levetiracetam on alcohol consumption in alcohol-dependent subjects: an open label study.

The aim of this open-label pilot study was to assess the efficacy and safety of the novel anticonvulsant agent, levetiracetam, for the treatment of alcohol dependence. A maximal dose of 2000 mg was administered daily for 10 weeks to alcohol dependent subjects (n = 20). Mean reported ethanol intake declined significantly from 5.3 to 1.7 standard drinks per day. Levetiracetam was well tolerated by most subjects.

Strategies to exclude subjects who conceal and fabricate information when enrolling in clinical trials.

Clinical trials within the US face an increasing challenge with the recruitment of quality candidates. One readily available group of subjects that have high rates of participation in clinical research are subjects who enroll in multiple trials for the purpose of generating income through study payments. Aside from issues of safety and generalizability, evidence suggests that these subjects employ methods of deception to qualify for the strict entrance criteria of some studies, including concealing information and fabricating information. Including these subjects in research poses a significant risk to the integrity of data quality and study designs. Strategies to limit enrollment of subjects whose motivation is generating income have not been systematically addressed in the literature. The present paper is intended to provide investigators with a range of strategies for developing and implementing a study protocol with protections to minimize the enrollment of subjects whose primary motivation for enrolling is to generate income. This multifaceted approach includes recommendations for advertising strategies, payment strategies, telephone screening strategies, and baseline screening strategies. The approach also includes recommendations for attending to inconsistent study data and subject motivation. Implementing these strategies may be more or less important depending upon the vulnerability of the study design to subject deception. Although these strategies may help researchers exclude subjects with a higher rate of deceptive practices, widespread adoption of subject registries would go a long way to decrease the chances of subjects enrolling in multiple studies or more than once in the same study.

An exploratory evaluation of Take Control: A novel computer-delivered behavioral platform for placebo-controlled pharmacotherapy trials for alcohol use disorder.

Placebo-controlled pharmacotherapy trials for alcohol use disorder (AUD) require an active behavioral platform to avoid putting participants at risk for untreated AUD and to better assess the effectiveness of the medication. Therapist-delivered platforms (TDP) can be costly and present a risk to study design because of the variability in therapist fidelity. Take Control is a novel computer-delivered behavioral platform developed for use in pharmacotherapy trials sponsored by the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG). This behavioral platform was developed with the goal of reducing trial implementation costs and limiting potential bias introduced by therapists providing TDP. This exploratory study is the first to compare Take Control with TDP on measures related to placebo response rate, medication adherence, and participant retention. Data were drawn from the placebo arms of four multisite, double-blind, randomized controlled trials (RCT) for AUD conducted by NCIG from 2007 to 2015. Data were compared from subjects receiving TDP (n=156) in two RCTs and Take Control (n=155) in another two RCTs. Placebo response rate, as represented by weekly percentage of heavy drinking days, was similar between groups. Subjects who received Take Control had a higher rate of medication adherence than those who received TDP. Subject retention was not significantly different between groups. The findings suggest that Take Control is comparable to TDP on measures of retention, medication adherence, and placebo response. Additional research is needed to evaluate Take Control directly against TDPs in a randomized trial.

Coordinating and monitoring multisite clinical trials that combine pharmacological and behavioral treatments.

OBJECTIVE: Coordination of a large, multicenter Phase 3 clinical trial is critical to the success of the trial. The focus of this article is to describe the special challenges involved in the coordination of the 11 clinical centers conducting the COMBINE clinical trial and to discuss the challenges of monitoring the information collected on the 1,383 participants enrolled in this trial. METHOD: The role of the coordinating center in working with the clinical sites is to ensure both high data quality and that the intervention protocol is conducted with appropriate attention paid to patient safety and consistency across sites. To satisfy those goals, a research committee of investigators and coordinating center staff was formed. The committee monitored adverse event reporting, participant safety, recruitment, delivery of the interventions, collection of assessments and completeness and timeliness of transfer of data to the coordinating center. Objective measures of performance were determined for each criterion to provide the principal investigators, study sponsor and Data and Safety Monitoring Board with feedback on conduct of the trial. Site performance as defined by these criteria was evaluated periodically, with both detailed written and verbal feedback provided to each investigator and study coordinator. RESULTS: The system was successful in detecting sites with performance issues, providing feedback to site personnel and measuring improvement. Study leadership, clinical center staff and coordinating center staff felt that the procedures for identifying and solving performance issues worked well and improved overall performance. CONCLUSIONS: Establishing an organizational structure that provided (1) leadership, (2) a venue for communication, (3) performance criteria and (4) a process for monitoring performance goals and providing feedback has enabled COMBINE to achieve success in reaching these markers of clinical trial practice.

Payment expectations for research participation among subjects who tell the truth, subjects who conceal information, and subjects who fabricate information.

Multiple models guide researchers' payment practices but few studies have assessed subjects' expectations for payment. Payments in excess of subjects' expectations may result in undue inducement, while payments below these expectations may be associated with exploitation. Data on subjects' payment expectations will help inform practices to avoid undue inducement and exploitation. This study examined subjects' expectations for payment for common research procedures and explored the relationship between subjects' honesty and payment expectations. One-hundred subjects who participated in two or more studies in the last year reported the minimum payment they expect for completing study procedures. They were also asked about their use of deception while screening for studies. Subjects expected $20 on average to complete the least risky and least burdensome procedure. Subjects' expectations for payment consistently increased with greater procedure risks. Subjects who denied using deception to enroll in studies refused more procedures than subjects who reported using deception. Among subjects who used deception, the rate of procedure refusal increased with procedure risks, suggesting that these subjects have some risk aversion and may act to protect themselves from undue inducement. Although subjects expect greater payments for more risky procedures, ethical considerations for limiting undue inducement may prevent researchers from meeting subjects' expectations. Subjects who use deceptive practices appear to be more risk-tolerant than subjects who deny using deception; nonetheless, these deceptive subjects also exercise some risk aversion when they refuse higher-risk procedures. These subjects may be able to protect themselves from undue inducement by refusing procedures that exceed their risk tolerance.

Binding affinity and capacity for the uremic toxin indoxyl sulfate.

Protein binding prevents uremic toxins from removal by conventional extracorporeal therapies leading to accumulation in maintenance dialysis patients. Weakening of the protein binding may enhance the dialytic elimination of these toxins. In ultrafiltration and equilibrium dialysis experiments, different measures to modify the plasma binding affinity and capacity were tested: (i), increasing the sodium chloride (NaCl) concentration to achieve a higher ionic strength; (ii), increasing the temperature; and (iii), dilution. The effects on the dissociation constant K(D) and the protein bound fraction of the prototypical uremic toxin indoxyl sulfate (IS) in plasma of healthy and uremic individuals were studied. Binding of IS corresponded to one site binding in normal plasma. K(D) increased linearly with the NaCl concentration between 0.15 (K(D) = 13.2 ± 3.7 µM) and 0.75 M (K(D) = 56.2 ± 2.0 µM). Plasma dilution further reduced the protein bound toxin fraction by lowering the protein binding capacity of the plasma. Higher temperatures also decreased the protein bound fraction of IS in human plasma. Increasing the NaCl concentration was effective to weaken the binding of IS also in uremic plasma: the protein bound fraction decreased from 89% ± 3% to 81% ± 3% at 0.15 and 0.75 M NaCl, respectively. Dilution and increasing the ionic strength and temperature enhance the free fraction of IS allowing better removal of the substance during dialysis. Applied during clinical dialysis, this may have beneficial effects on the long-term outcome of maintenance dialysis patients.

Predictors of pretreatment commitment to abstinence: results from the COMBINE study.

OBJECTIVE: Patients entering treatment for alcohol problems do not have uniform treatment goals, and a pretreatment drinking goal has a significant impact on treatment outcome. The objective of this study was to understand better how an array of individual characteristics, including factors that affect treatment, are related to treatment goals before beginning alcohol treatment in the COMBINE (Combining Medications and Behavioral Interventions) Study. METHOD: Participants were alcohol-dependent individuals (N = 1,156; 357 women) recruited at 11 outpatient academic alcoholism-treatment clinics across the United States to participate in a randomized, double-blind, placebo-controlled trial that combined behavioral intervention with acamprosate and/or naltrexone. Treatment goal was coded as controlled drinking, conditional abstinence, or total abstinence. Multinomial logistic regressions assessed whether there were significant relationships between predictor variables and pretreatment goal selection. RESULTS: Lower levels of alcohol-related consequences, lower readiness to change, higher family income, more daily drinkers in social network, and lack of prior treatment or Alcoholics Anonymous engagement predicted choice of a controlled drinking goal over a total abstinence goal. Fewer alcohol-related consequences, lower readiness to change, and more daily drinkers in-network predicted choice of a conditional abstinence goal over a total abstinence goal. CONCLUSIONS: Higher levels of functioning, lower levels of consequences, no prior involvement in treatment and Alcoholics Anonymous, and a more drinking-saturated social environment are associated with the choice of a non-abstinence goal.