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Background and Objective An assessment of clinically important change is useful in interpreting clinical trial outcomes. The 4-point Ashworth Scale (AS) is a widely accepted measure of muscle tone, and the 9-point Physician Global Assessment Score (PGAS) is a global measure of post-treatment change as evaluated by the physician. The quantitative relationship between AS and PGAS has not previously been described in spasticity. Methods Data from three clinical trials of botulinum toxin type A (BOTOX; Allergan, Irvine, CA) in poststroke spasticity were analyzed ( n = 442). Mean change from baseline in AS score was plotted as a function of PGAS and correlations were calculated. Receiver–operator curve (ROC) analyses with the wrist flexor AS change from baseline as the independent variable and PGAS as the dependent variable were performed using the following criteria: PGAS of ≥1 (mild improvement or better) and PGAS of ≥2 (moderate improvement or better). Results In pooled data, the Pearson's correlation coefficient r between the change in wrist Ashworth Score and the PGAS was −0.44 ( p = 0, t = −26.5). Pearson correlations by individual study were also statistically significant. By ROC analysis, a PGAS of ≥1 was associated with 33% reduction of wrist AS and a PGAS of ≥2 was associated with approximately 50% reduction. In a well-powered phase 3 study, the Pearson's correlation coefficient was even higher ( r = −0.76, p = 0, t = −28.5). Conclusions Changes in disease-specific scales that correlate significantly with changes in physician global assessments are considered clinically meaningful. In clinical trials of chronic spasticity, we found that 33% and 50% changes in the Ashworth Scale scores correlate with 1-point or 2-point changes in PGAS. This is similar to findings from pooled chronic pain studies, in which 30% and 50% changes on the pain numeric rating scale were considered clinically important (Farrar et al., Pain 2001;94:149–158). Study supported by Allergan, Irvine, CA.

Background and Objective Nebicapone (BIA 3-202) is a new catechol- O -methyltransferase (COMT) inhibitor. Warfarin is a racemic mixture of the R - and S -enantiomers, with most of the anticoagulant activity attributable to S -warfarin. In vitro , nebicapone showed an inhibitory effect upon CYP2C9, which is known to be responsible for the metabolism of S -warfarin. The objective of this study was to investigate the effect of nebicapone on warfarin pharmacokinetics and pharmacodynamics. Methods In a single-center, open-label, randomized, two-way crossover study in 16 healthy volunteers, two treatment periods were separated by a washout period of 14 days. In one period, subjects received nebicapone 200 mg thrice daily for 9 days, and a warfarin 25 mg single dose concomitantly with the nebicapone morning dose on day 4 (Test). In the other period, a warfarin 25 mg single dose was administered alone (Reference). Results Regarding S -warfarin, mean C max and AUC 0- t were respectively 1644 ng/mL and 66,627 ng.h/mL after Test, and 1739 ng/mL and 70,178 ng.h/mL after Reference. The S -warfarin Test/Reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) was 0.932 (0.845;1.028) for C max and 0.914 (0.875;0.954) for AUC 0- t . Regarding R -warfarin, mean C max and AUC 0- t were respectively 1619 ng/mL and 92,796 ng.h/mL after Test, and 1649 ng/mL and 73,597 ng.h/mL after Reference. The R -warfarin Test/Reference GMR and 90%CI was 0.973 (0.878;1.077) for C max and 1.247 (1.170;1.327) for AUC 0- t . No differences were found regarding the pharmacodynamic parameter INR. Conclusions Nebicapone showed no significant effect on the S -warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R -warfarin metabolism was found, but although the anticoagulant effect of R -warfarin is five times less potent than that of S -warfarin, the reported effect on R -warfarin metabolism is unlikely to be of clinical relevance. Supported by BIAL-Portela & C a SA.

Background and Objective Some adverse events commonly reported by participants in phase I studies are common complaints in individuals from normal populations. The objective of this study was to investigate the relation between the trait anxiety and the adverse non-drug-related complaints in a group of 117 normal subjects who matched the sociodemographic characteristics of our historical database of phase I participants. Methods Trait anxiety was assessed by the trait scale of the State-Trait Anxiety Inventory (STAI-T). Complaints were assessed by a questionnaire derived from the Spitzer's Patient Health Questionnaire (PHQ). Spearman's rho correlations between the STAI-T score and the complaints were performed. Results Significant positive linear correlations were found between the STAI-T score and the following adverse symptoms: stomach pain ( R = 0.189; p R = 0.221; p R = 0.207; p R = 0.397; p R = 0.222; p R = 0.269; p R = 0.365; p R = 0.259; p R = 0.205; p R = 0.213; p R = 0.353; p R = 0.477; p R = 0.400; p R = 0.413; p R = 0.439; p R = 0.493; p R = 0.481; p R = 0.465; p Conclusions A positive correlation was found between trait anxiety and the occurrence of several adverse non-drug-related symptoms in a group of normal healthy subjects. Those complaints are commonly reported as adverse events during participation in phase I studies. It may be then hypothesized that subjects higher in trait anxiety may be more likely to report such symptoms as adverse events during participation in phase I studies.

Background and Objective Some adverse non-drug-related symptoms are highly prevalent among normal populations. Therefore, such symptoms are likely to be reported as adverse events during the course of phase I studies. This study evaluated the adverse non-drug-related symptoms in a group of 192 healthy volunteers for phase I studies and a group of 117 healthy subjects who matched the volunteers group in terms of sociodemographic characteristics. Methods Both groups completed a questionnaire on the occurrence of complaints during the previous 4 weeks. In volunteers to phase I studies, the questionnaire was applied immediately before their admission to participation. Results The mostly commonly reported complaints (volunteers vs. control) were headache (44.8% vs. 55.6%) and back pain (41.4% vs. 52.1%). Compared with the control, subjects who volunteered for phase I studies presented significantly lower prevalence on the following symptoms: stomach pain ( p = 0.002); back pain ( p = 0.008); limb or joint pain ( p = 0.003); headaches ( p = 0.044); fainting spells ( p = 0.005); palpitations ( p = 0.018); shortness of breath ( p = 0.005); constipation, loose stools, or diarrhea ( p = 0.033); nausea, gas, or indigestion ( p = 0.019); feeling nervous or anxious ( p = 0.001); feeling restless ( p = 0.011); getting tired very easily ( p p = 0.007); and concentration difficulties ( p = 0.003). Conclusions Participants in phase I studies are a self-selected sample with a lower tendency to report non-drug-related adverse events than their peers from the normal population. The impact of this self-selection bias on the assessment of tolerability during phase I studies results deserves further evaluation.

Background and Objective Nebicapone (formerly known as BIA 3-202) is a new catechol-O-methyltransferase (COMT) inhibitor in development as a levodopa-sparing agent to be used in levodopa-treated Parkinson disease patients. The objective of this study was to investigate the effect of single oral doses of nebicapone (50 mg, 100 mg and 200 mg) on the levodopa and 3-O-methyldopa (3-OMD) systemic exposure and erythrocyte soluble COMT (S-COMT) activity when coadministered with a single-dose of controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Methods Double-blind, randomized, placebo-controlled, four-way crossover study in 16 healthy subjects, with a washout of 5 or more days between periods. Results Taking placebo as reference, levodopa AUC0-t geometric mean ratios (GMR) and 90% confidence intervals (90%CI) were 1.14 (0.83;1.65), 1.37 (0.91;1.80), and 1.42 (0.97;1.92) for nebicapone 50 mg, 100 mg and 200 mg, respectively. Regarding 3-OMD, AUC0-t GMR and 90%CI were 0.67 (0.53;0.80), 0.63 (0.51;0.77), and 0.55 (0.49;0.75), respectively. Maximum S-COMT inhibition occurred at 1.5 h after the dose and ranged from 57% with nebicapone 50 mg to 74% with nebicapone 200 mg. There was an inverse correlation between plasma concentrations of nebicapone and S-COMT activity, and nebicapone tmax correlated well with tEmax of S-COMT inhibition. Treatments were well tolerated. Conclusions Single doses of 50 mg, 100 mg, and 200 mg of the novel COMT inhibitor nebicapone dose-dependently and significantly inhibited S-COMT activity, increased the bioavailability of levodopa, and reduced the formation of 3-OMD, when administered concomitantly with controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Supported by BIAL-Portela & Ca SA.