Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE's STAT-Net.

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.

Graphical approaches to the analysis of safety data from clinical trials.

Patient safety has always been a primary focus in the development of new pharmaceutical products. The predominant method for statistical evaluation and interpretation of safety data collected in a clinical trial is the tabular display of descriptive statistics. There is a great opportunity to enhance evaluation of drug safety through the use of graphical displays, which can convey multiple pieces of information concisely and more effectively than can tables. Graphs can be used in an exploratory setting to help identify emerging safety signals, or in a confirmatory setting as a tool to elucidate known safety issues. We developed several graphical displays for routine safety data collected during a clinical trial, covering a broad range of graphical techniques, and illustrate here 10 specific graphical designs, many of which display the data along with statistics derived from them. Two are simple plots, comparing distributions in the form of boxplots or cumulative plots, and four more display data and summaries over time, comparing information from two groups in terms of distribution (with boxplots), cumulative incidence, hazard, or simply means with error bars. The other four are multi-panel displays: one-dimensional and two-dimensional arrays of scatterplots, a trellis of individual profiles, and a paired dotplot displaying risk together with relative risk. The displays focus on key safety endpoints in clinical trials including the QT interval from electrocardiograms, laboratory measurements for detecting hepatotoxicity, and adverse events of special interest. We discuss in detail the statistical and graphical principles underlying the production and interpretation of the displays.

Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4.

BACKGROUND: COPD is a relentless, progressive disease. This study evaluated the efficacy of cilomilast, a selective phosphodiesterase (PDE) 4 inhibitor, in the treatment of COPD. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in subjects with COPD. After a 4-week, single-blind, placebo run-in period, eligible subjects were randomized in a 2:1 ratio to receive oral cilomilast, 15 mg bid, or placebo for 24 weeks. Subjects between 40 and 80 years of age who had received a diagnosis of COPD were eligible for the study. The primary efficacy variables were changes from baseline in trough (ie, predose) FEV1 and in total score of the St. George's Respiratory Questionnaire (SGRQ). A key secondary end point was the incidence rate of COPD exacerbations. RESULTS: The average change from baseline in FEV1 over 24 weeks in the cilomilast group was an increase of 10 mL compared with a decrease of 30 mL in the placebo group (difference, 40 mL; p = 0.002). When averaged over 24 weeks, there was a clinically significant reduction in the mean total SGRQ score in subjects receiving cilomilast therapy, with a difference of 4.1 U compared with subjects who received placebo (p = 0.001). A greater percentage of subjects in the cilomilast group were exacerbation-free at 24 weeks (74%; p = 0.008) compared with placebo (62%). Adverse events were generally mild or moderate and were not unexpected for this class of medications. GI adverse events that interfered with daily activities (cilomilast, 17%; placebo, 8%) predominantly occurred within the first 3 weeks of initiating cilomilast therapy. CONCLUSION: Cilomilast is an orally active, potent, and selective inhibitor of PDE-4. Cilomilast maintained pulmonary function and improved health status, and reduced the rate of COPD exacerbations during 24 weeks of treatment. This study supports the use of cilomilast, a novel, selective PDE-4 inhibitor, in subjects with COPD.

Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease.

Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.