Long-term Safety of Combivent Respimat Inhalation Spray in COPD Patients

Abstract

BACKGROUND: Chronic obstructive pulmonary disease (COPD) medications are preferentially delivered via oral inhalers. Combivent (CVT; ipratropium+albuterol) is currently only available as a metered-dose inhaler (CVT-MDI) that uses a chlorofluorocarbon (CFC) propellant. The Respimat inhaler is a novel, soft-mist inhaler that is CFC propellant-free. In association with the phase-out of CFCs worldwide, the Combivent Respimat Inhalation Spray (CVT-R) has recently been approved for patients with COPD in the USA, and will replace the phasing out MDI device. This study evaluated patient satisfaction+long-term safety of CVTR vs CVT-MDI vs the free combination of ipratropium (Atrovent) HFA and albuterol HFA metered dose inhalers (I+A). METHOD(S): The study was a Phase III, 1-year, 3-treatment, open-label, randomized, active-controlled, parallel-group study. After initial screening, patients received CVT-MDI during a 3-4 week baseline period, followed by randomization to 1 of 3 treatments: CVT-R, CVT-MDI, or I+A for 48 weeks. Patients were provided with albuterol MDI rescue medication as needed. Study participants were males and females with COPD, aged >=40 years, who were current or ex-smokers (smoking history, >=10 pack-years). Treatment compliance was assessed using a patient Daily Diary Card. The primary endpoint was the Performance Domain Score (PDS) evaluated using a modified Patient Satisfaction and Preference Questionnaire (PASAPQ) at Visit 2 (Day 0 before randomization) and at treatment Visits 3-7 (Weeks 3- 48). Adverse events (AEs) were recorded at each visit. RESULT(S): 688 patients were enrolled at 55 US sites and 470 were randomized to open-label treatment following baseline treatment with CVTMDI. Baseline demographics were similar for all treatment groups. Overall, 58.7% were male, 93.5% were white, 52.0% were current smokers, and 63.0% used pulmonary medication at the time of informed consent. After 48 weeks of treatment, a statistically significantly higher PASAPQ PDS was observed for the CVT-R group vs the CVT-MDI and I+A groups (P<0.0001). Patients also indicated that they liked the actuation indicator component of the Respimat device. Improvements in lung function were similar for all groups from Day 1 through Week 48. Time to first COPD exacerbation (TTFE) hazard was slightly longer in the CVT-R group compared to other treatment groups, and the cumulative risk of COPD exacerbation was comparable. There was no significant difference among groups for TTFE leading to hospitalization and exposure-adjusted event rates. Overall, rescue medication use between the groups was not significantly different. Patients in the CVT-R group withdrew from the study in fewer numbers than patients in the I+A group (P=0.0059). All patients who received at least 1 dose of study medication were included in the safety analysis. Overall, 78.1% of patients completed the study and 72.0% reported an AE; the percentage of patients with serious AEs was similar in the 3 groups. CONCLUSION(S): The environmentally friendly CVT-R was statistically superior vs CVT-MDI and I+A with regard to patient satisfaction, and fewer patients dropped out while receiving CVT-R. All 3 treatments showed a similar safety profile. A relative improvement in TTFE with CVT-R suggests that effective drug delivery and/or patient acceptance of the Respimat inhaler may benefit adherence and, therefore, clinical outcomes in patients with COPD.