Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: A placebo-controlled trial

Abstract

Adding a long-acting beta(2)-agonist (LABA) by dry powder inhaler (DPI) to tiotropium provides significantly increased and sustained bronchodilation in chronic obstructive pulmonary disease (COPD) patients over either product alone. To demonstrate similar benefits with a nebulized LABA, a placebo-controlled trial was conducted to evaluate the efficacy and safety of formoterol fumarate inhalation solution in subjects receiving tiotropium as a maintenance treatment for COPD. After a 7-14-day screening period using tiotropium 18 microg once daily, subjects with diagnosed COPD (> or = 25% to <65% predicted FEV(1)) were randomized to receive 20 microg formoterol fumarate inhalation solution twice daily for nebulization plus tiotropium (FFIS/TIO) or nebulized placebo twice daily plus tiotropium (PLA/TIO) for 6 weeks. Efficacy was assessed with spirometry at each visit (Day 1, Week 1, 3, 6), the transition dyspnea index (TDI), and St. George's Respiratory Questionnaire (SGRQ). Baseline characteristics were comparable, including mean FEV(1)% predicted. At Week 6, FEV(1) AUC(0-3) was 1.52 L for FFIS/TIO-treated subjects vs. 1.34 L for PLA/TIO-treated subjects (p<0.0001). The mean TDI scores in the FFIS/TIO and PLA/TIO groups were 2.30 and 0.16, respectively (p=0.0002). SGRQ did not change significantly with 6 weeks treatment, with the exception of FFIS/TIO improvements in symptom score vs. PLA/TIO (p=0.04). More PLA/TIO- than FFIS/TIO-treated subjects experienced AEs (39.7% vs. 22.9%), COPD exacerbations (7.9% vs. 4.5%), and serious AEs (3.2% vs. 1.5%). Nebulized formoterol fumarate in combination with tiotropium provided statistically and clinically significant improvements in bronchodilation and symptom control over tiotropium alone and demonstrated good tolerability.

Effect of tiotropium on quality of life in COPD: a systematic review

“…71 Further benefits were seen when other drugs were added to tiotropium therapy -for example, with the addition of salmeterol 66 but not with formoterol. 67,69 Comparisons of tiotropium monotherapy with triple therapy (tiotropium plus two other therapies) showed the potential clinical advantages of this latter approach to treatment. 66,68,72 It should be noted that, while the UPLIFT ® trial compared tiotropium monotherapy to placebo (control), its study design means that the comparison was made in the context of a background of "any other respiratory medication".…”

“…66 The addition of formoterol fumarate (a LABA) to tiotropium resulted in little benefit over tiotropium monotherapy in terms of SGRQ in two 6-week studies. 67,69 The only (clinically and statistically) significant change was observed in the symptom score for dual therapy versus monotherapy in one study. 69 In terms of TDI scores, there was a significantly greater improvement with dual therapy in one trial 69 but not the other; 67 more patients had improvements in dyspnoea in the dual therapy versus monotherapy group in both studies.…”

“…[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] Of the 24 publications that met the inclusion criteria for this systematic review (see Table 1), 16 compared tiotropium with placebo, [50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] seven compared tiotropium with an active comparator, [66][67][68][69][70][71][72] and one compared tiotropium with both placebo and an active comparator. 73 The QoL outcomes reported in the 24 included publications were mostly SGRQ and/or TDI (Tables 2 and 3).…”

Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes

“…The proportion of patients achieving the MCID in TDI total score was 31.1-57.1% for tiotropium monotherapy, 48.0-66.7% for LABA monotherapy, and 57.7-77.9% for LABA/LAMA combination therapy. 17,19,20,22 Overall, LABA/LAMA combination therapy demonstrated clinically relevant improvements in dyspnoea, greater than those seen with LABA or tiotropium alone. …”

“…All studies of tiotropium and formoterol/arformoterol combination therapy improved dyspnoea (assessed by the Transitional Dyspnoea Index (TDI)) to a greater extent than either monotherapy. 6,[15][16][17]19,20 Two further studies of tiotropium plus salmeterol (once or twice a day) also showed a marked improvement in dyspnoea with combination therapy over either monotherapy. 21,22 In a study by Aaron et al, 7 no significant difference in mean TDI total score was demonstrated between tiotropium plus salmeterol, tiotropium plus salmeterol/ fluticasone and tiotropium alone; however, it should be noted that a large number of patients discontinued during this study (61.0% completed), making it difficult to draw firm conclusions on efficacy between treatment groups.…”