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Background: Hospitalizations for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with increased mortality and decreased quality of life. Replicate hospital discharge studies were initiated to examine efficacy and safety of once-daily tiotropium HandiHaler® versus placebo, in addition to usual care, in patients discharged from the hospital after an AECOPD. Methods: Both studies were randomized, placebo-controlled, double-blind, parallel-group, multicenter, with inclusion/exclusion criteria providing a diverse COPD patient cohort hospitalized for ≤14 days with AECOPD. Patients received tiotropium or placebo, initiated within 10 days post-discharge. Target recruitment was 604 patients/study and planned duration was event-driven, ending after 631 clinical outcome events across both studies. Inability to reach targeted site numbers and patient recruitment/retention difficulties led to early study termination. Recruitment/retention challenges and protocol amendment impacts were assessed qualitatively to understand the major issues. Results: Over 18 months, 219 patients were enrolled; 158 were randomized and 61 failed screening. Premature treatment discontinuation occurred in 49(31%) patients, of whom 20(41%) completed health status follow-up. All-cause, 30-day hospital readmission was low (8[5%] patients). A total of 154(98%) patients had a concomitant diagnosis and most took pulmonary medication pre-randomization (143[91%]) and during study treatment (144[92%]). Inclusion/exclusion criteria changes failed to improve recruitment. Recruitment/retention barriers were identified, relating to patient and clinician factors, health care infrastructure, and clinical practices. Conclusions: Although AECOPD hospitalization is clinically important and incurs high costs, significant challenges exist in studying this population in clinical trials after hospitalization. Studies are needed to evaluate effective management of AECOPD patients at high risk of adverse clinical outcomes.
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OBJECTIVE: To evaluate the bioequivalence (BE), safety, tolerability, and adhesion of Oppanol® polyisobutylene (PIB)-containing transdermal therapeutic system (TTS) formulation (test treatment, T) with VistanexTM PIB-containing TTS formulation (reference treatment, R) of clonidine. METHODS: This randomized, double-blind, 2-way crossover study comprised a 7-day treatment with 0.3 mg clonidine/24 h (T1/R1), a 7-day washout, and another 7-day treatment (R1/T1) period. After a 3-day washout period, subjects used T2 and R2 (each 0.1 mg clonidine/24 h) simultaneously in the 7-day adhesion phase. Primary endpoints were AUC0-168 and Cavg. Secondary endpoints were AUC0-∞ and Cmax. Additional endpoints included adhesion properties for all phases. For the primary endpoint, the geometric mean (gMean) ratios for test/reference treatment were calculated with BE defined as 90% confidence interval (CI) between 80 and 125%. RESULTS: 58 subjects (mean age, 41.3 years) received treatment (T1/R1, n = 29; R1/T1, n = 29); 55 completed the adhesion phase. BE criteria were met for the primary and secondary endpoints. Adjusted gMean ratios for T1/R1 were 102.3% (90% CI: 95.7%, 109.4%) for AUC0-168; 104.3% (90% CI: 98.4%, 110.5%) for Cavg; 102.8% (90% CI: 97.3%, 108.6%) for AUC0-∞; and 104.0% (90% CI: 98.2%, 110.3%) for Cmax. Mean adhesion was greater than 90% for all four patch types when data from all assessment times were included. Most frequently reported adverse events were general disorders and local irritation. CONCLUSIONS: Clonidine Oppanol® PIB-containing TTS formulation was bioequivalent to VistanexTM PIB-containing TTS formulation and had similar adhesive properties. Both doses and formulations of clonidine-TTS were well tolerated.