Positive impact of omalizumab on angioedema and quality of life in patients with refractory chronic idiopathic/spontaneous urticaria: analyses according to the presence or absence of angioedema.

BACKGROUND: Approximately 50% of patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) report hives and angioedema; some experience hives/angioedema only. OBJECTIVE: Assess omalizumab's effect on angioedema and quality of life (QoL) in subgroups with refractory CIU/CSU: those with and without angioedema. METHODS: Patients received omalizumab (75, 150 or 300 mg) or placebo every 4 weeks for 12/24 weeks. Angioedema and QoL were assessed [Urticaria Patient Daily Diary and Dermatology Quality of Life Index (DLQI)]. Subgroups were based on the presence/absence of baseline angioedema 7 days prior to randomization. RESULTS: Patients with baseline angioedema randomized to omalizumab 300 mg had a greater reduction in mean weekly incidence of angioedema and mean number of days/week with angioedema vs. placebo at 12 and 24 weeks. A 3.3- to 4.5-point greater mean reduction in DLQI score was achieved with omalizumab 300 mg treatment vs. placebo, above the minimal clinically important difference threshold. Results with lower doses vs. placebo were variable. CONCLUSION: Compared with placebo, omalizumab 300 mg treatment over 12-24 weeks resulted in marked reduction in incidence and number of days/week with angioedema accompanied by clinically relevant improvement in QoL.

Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid.

UNLABELLED: A randomized, double-blind, placebo-controlled study assessed the efficacy of acetaminophen or fluvastatin in preventing post-dose symptoms (increases in body temperature or use of rescue medication) following a single infusion of the intravenous (IV) bisphosphonate zoledronic acid (ZOL). Acetaminophen, but not fluvastatin, significantly reduced the incidence and severity of post-dose symptoms. INTRODUCTION: Transient symptoms including myalgia and pyrexia have been reported post-infusion of IV bisphosphonates, typically starting the day after infusion and resolving within several days. The cause is unknown but may be related to transient cytokine elevations. Statins' potential to block release of these cytokines has been hypothesized. This study was aimed to evaluate efficacy of acetaminophen and fluvastatin in preventing/reducing post-dose symptoms following ZOL 5 mg infusion. METHODS: Randomized, double-blind, placebo-controlled study of efficacy of acetaminophen or fluvastatin in preventing increases in body temperature or use of rescue medication (ibuprofen) following a single ZOL infusion. Bisphosphonate-naive postmenopausal women with low bone mass (N = 793) were randomized into three treatment groups and given 650 mg acetaminophen or 80 mg fluvastatin or placebo 45 min before ZOL infusion. The acetaminophen group continued taking 650 mg acetaminophen every 6 h over the next 3 days, and the other two groups took matching placebo according to the same schedule. Subjects recorded body temperature, symptoms in a diary. Inflammatory cytokines and C-reactive protein (CRP) were measured at baseline, 24, and 72 h in a study subset. RESULTS: Acetaminophen four times/day significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion. Single-dose fluvastatin 80 mg prior to ZOL infusion did not prevent/reduce post-dose symptoms. Cytokine levels increased by 24 h and returned towards baseline by 72 h, similar to the pattern for post-infusion symptoms. CRP levels increased from baseline to 72 h. CONCLUSIONS: Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion.

Effect of omalizumab on peripheral blood eosinophilia in allergic asthma.

Eosinophilia is an established marker of asthma-related inflammation. We assessed the effect of omalizumab on peripheral blood eosinophil counts using a pooled analysis of data from five randomized, double-blind, placebo-controlled studies in patients with moderate-to-severe persistent allergic asthma receiving moderate-to-high-dose inhaled corticosteroids (omalizumab, n=1136; placebo, n=1100). Relationships between omalizumab, peripheral blood eosinophils, serum free IgE concentrations and clinical outcomes were explored. Baseline mean eosinophil counts were similar in each treatment group. Post-treatment eosinophil counts were significantly reduced from baseline in the omalizumab group (p<0.0001) but were not significantly different in the placebo group. Greater reductions in eosinophil counts were observed in patients who had post-treatment free IgE levels <50ng/mL. Three studies included steroid-stable and steroid-reduction phases. At the end of each phase in these studies, a significantly greater reduction in eosinophil counts was achieved in the omalizumab group compared with the placebo group (p<0.0001). A consistent pattern of improved clinical outcomes/decreased eosinophils and worsened clinical outcomes/increased eosinophils was observed for both omalizumab and placebo treatment groups. The findings from our analysis of a large patient population are consistent with earlier reports of the inhibitory effect of omalizumab on eosinophils.

A comparison of the efficacy of darifenacin alone vs. darifenacin plus a Behavioural Modification Programme upon the symptoms of overactive bladder.

PURPOSE: This study assessed the benefit of adding behavioural modification to darifenacin treatment for overactive bladder (OAB). MATERIALS AND METHODS: The ABLE trial was a randomised, open-label, parallel-group, multicentre study of 12 weeks of darifenacin treatment [with voluntary up-titration from 7.5 mg once daily (qd) to 15 mg qd at week 2] alone or in combination with a Behavioural Modification Programme (BMP) for men and women with dry or wet OAB. Efficacy was assessed as the change in the number (per day) of micturitions (primary variable), urge urinary incontinence (UUI) episodes, urgency episodes, pads used and nocturnal voids. Health-related quality of life (HRQoL) was also evaluated. Tolerability and safety assessments included adverse events and the number of discontinuations. RESULTS: Of 592 patients screened, 395 were randomised, 190 to darifenacin alone and 205 to darifenacin + BMP. At baseline, the majority of subjects were dry (mean 2.8 and three UUI episodes per day in the darifenacin and darifenacin + BMP groups respectively). At study end, darifenacin alone and darifenacin + BMP both produced significant reductions from baseline in median numbers of micturitions, UUI episodes, urgency episodes and nocturnal voids (all p < 0.05), but not in the number of pads used. HRQoL also improved. There were no significant differences between treatment groups in efficacy or HRQoL variables. CONCLUSIONS: Darifenacin treatment provides a degree of normalisation of micturition variables and improvement in HRQoL that cannot be further enhanced by behavioural therapy of the type used in this study. Whether behavioural modification would add benefit over darifenacin treatment in patients with more pronounced incontinence problems remains to be determined.

A nonparametric procedure associated with a clinically meaningful efficacy measure.

Parametric methods such as analysis of (co)variance are commonly used for the analysis of data from clinical trials. They have the advantage of providing an easily interpretable measure of treatment efficacy such as a confidence interval for treatment difference. If there are doubts about the underlying distribution of the response variable, however, a nonparametric approach may be called for. The nonparametric approaches in such settings concentrate on hypothesis testing and are not typically used for providing easily interpretable measures of treatment efficacy. For comparing two treatments, we propose using a nonparametric measure based on the likelihood of observing a better response on one treatment than the other. The bootstrap method is used to construct a confidence interval for the treatment difference.

Extending Goodman-Kruskal's gamma to the comparison of ordered treatments in multicenter clinical trials.

In a randomized, multicenter clinical trial setting, the treatments may consist of increasing doses of a drug and placebo and the response variable may be ordinal (e.g., physician's global evaluation of treatment effectiveness). Within each center (e.g., hospital), patients are randomly assigned to treatments (rows) such that the row totals are fixed and the rows form a product-multinomial sample of the ordinal response variable. Gamma, a measure of ordinal association in two-way contingency tables, and its asymptotic standard error can be estimated from the data in each center. We use these independent estimates of gamma for testing the hypothesis of homogeneity of gammas, controlling for center effect. If this hypothesis is not rejected, the within-center estimates of gamma can be combined to form a common gamma across the centers.

A multiple comparison procedure to control the strong stagewise family error rate in comparing test treatments and a control.

Multiple comparisons are commonly seen in clinical trials and many other fields. An example, which is the focus of this paper, is the comparison of several test treatments (possibly different doses of a compound) with placebo (control). It is well known that steps must be taken to control the type I error rate when multiple testing is performed. We introduce the concept of the strong stagewise family error rate and propose a multiple comparison procedure to control this error rate. The proposed procedure is compared to Dunnett's step-down procedure when there are two test treatment groups and a placebo group.

Intra- and inter-subject variabilities of CGP 33101 after replicate single oral doses of two 200-mg tablets and 400-mg suspension.

PURPOSE: The purpose of this study was to use a replicate designed trial to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters of CGP 33101 after oral administration of tablets relative to that of powder suspended in water, and to determine the relative proportion of the intra-subject variance to the overall variability. METHODS: Sixteen healthy subjects were randomly assigned to four groups to receive tablets and suspension twice in four different treatment sequences. The plasma concentration-time profile of CGP 33101 was characterized in terms of Cmax, Tmax, and AUC. Bioavailability of tablets relative to suspension and intra- and inter-subject variability were assessed by statistical analysis. RESULTS AND CONCLUSIONS: The overall variabilities in absorption kinetics of CGP 33101 in healthy subjects were small with CV's of the population mean values for AUC and Cmax less than 26% for both tablets and suspension. Contribution of intra-subject variability to the overall variability was also small (approximately 20%). Both the overall and intra-subject variabilities of AUC and Cmax after suspension were larger than after the tablets. However, the differences in variability between tablets and suspension were not statistically significant (p > 0.05). The tablet formulation was bioequivalent to suspension in terms of rate and extent of absorption based on 90% conventional confidence intervals (for AUC and Cmax) and Wilcoxon rank-sum test (for Tmax).

Poisson regression analysis in clinical research.

Generalized linear models (GLM) are now widely used in analyzing data from clinical trials and in epidemiological studies. In Poisson regression, which fits in the framework of a GLM, the response variable is a count that follows the Poisson distribution. This article describes the basic methodology of Poisson regression analysis and its application to clinical research. Overdispersion, model diagnostics, and sample size issues are discussed. The methodology is illustrated on a data set from a clinical trial for the treatment of bladder cancer, using a new procedure (PROC GENMOD) in the statistical package SAS.