Hassan Lakkis

Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I)

Abstract Background: This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD. Methods: In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 μg, aclidinium 400 μg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12, respectively. Health status (St. Georges Respiratory Questionnaire [SGRQ]), COPD symptoms (Transitional Dyspnea Index [TDI], night and early morning symptoms), and safety were also assessed. Results: A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV1 of 1.36 ± 0.54 L (47.2% of predicted value) were randomized. At Week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95% CI) trough FEV1 compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV1 by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p < 0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%–1.6%; constipation: 0%-1.1%). Conclusions: Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo. Trial Registration: This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as “Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)”.

Cardiovascular Safety in Patients Receiving Roflumilast for the Treatment of COPD

BACKGROUND Evaluation of cardiovascular safety for new therapies for COPD is important because of a high prevalence of cardiac comorbidities in the COPD population. Hence, we evaluated the effects of roflumilast, a novel oral phosphodiesterase 4 inhibitor developed for the treatment and prevention of COPD exacerbations, on major adverse cardiovascular events (MACEs). METHODS Intermediate- and long-term placebo-controlled clinical trials of roflumilast in COPD were pooled and assessed for potential cardiovascular events. Studies comprised 14 12- to 52-week placebo-controlled trials in patients with moderate to very severe COPD. All deaths and serious nonfatal cardiovascular events were evaluated by an independent adjudication committee blinded to study and treatment. The MACE composite of cardiovascular death, nonfatal myocardial infarction, and stroke was analyzed according to treatment group. RESULTS Of 6,563 patients receiving roflumilast, 52 experienced MACEs (14.3 per 1,000 patient-years), and of 5,491 patients receiving placebo, 76 experienced MACEs (22.3 per 1,000 patient-years). The MACE composite rate was significantly lower for roflumilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P = .019). CONCLUSIONS A lower rate of cardiovascular events was observed with roflumilast than with placebo in patients with COPD, indicating the lack of a cardiovascular safety signal when treating patients with COPD. Potential cardiovascular benefits of roflumilast should be evaluated in future controlled clinical trials.

Sample size calculation for comparing two negative binomial rates

Negative binomial model has been increasingly used to model the count data in recent clinical trials. It is frequently chosen over Poisson model in cases of overdispersed count data that are commonly seen in clinical trials. One of the challenges of applying negative binomial model in clinical trial design is the sample size estimation. In practice, simulation methods have been frequently used for sample size estimation. In this paper, an explicit formula is developed to calculate sample size based on the negative binomial model. Depending on different approaches to estimate the variance under null hypothesis, three variations of the sample size formula are proposed and discussed. Important characteristics of the formula include its accuracy and its ability to explicitly incorporate dispersion parameter and exposure time. The performance of the formula with each variation is assessed using simulations.