Efficacy of once-daily indacaterol relative to alternative bronchodilators in COPD: a patient-level mixed treatment comparison.

OBJECTIVE: Indacaterol was evaluated versus placebo, formoterol, and salmeterol in randomized controlled trials. No direct comparisons, however, are available for indacaterol 150 µg with formoterol or indacaterol 300 µg with salmeterol. Indacaterol trial evidence was synthesized to provide coherent estimates of indacaterol 150 µg and indacaterol 300 µg relative to formoterol, salmeterol, and tiotropium. METHODS: Four randomized controlled trials were combined with Bayesian mixed treatment comparisons by using individual patient-level data. End points of interest were trough forced expiratory volume in 1 second (FEV(1)), St. George's Respiratory Questionnaire (SGRQ) total score and response (≥ 4 points), and Transition Dyspnea Index total score and response (≥ 1 point). RESULTS: Indacaterol 150 µg demonstrated a higher FEV(1) than did formoterol at 12 weeks and 6 months (0.10 L difference; 95% credible interval [CrI] = 0.06-0.14), as did indacaterol 300 µg versus salmeterol (0.06 L difference at 12 weeks; CrI = 0.02-0.10; 0.06 L at 6 months; CrI = 0.02-0.11). Regarding SGRQ, indacaterol 150 µg demonstrated a comparable proportion of responders versus formoterol, as did indacaterol 300 µg versus salmeterol. In comparison to tiotropium, indacaterol 150 µg demonstrated a greater proportion of responders (odds ratio = 1.52 at 12 weeks; CrI 1.15-2.00). For Transition Dyspnea Index, indacaterol 150 µg and formoterol showed a similar response. Indacaterol 300 µg was more efficacious than salmeterol (odds ratio = 1.65 at 12 weeks; CrI 1.16-2.34). Overall, indacaterol 150 µg showed the greatest efficacy for SGRQ and indacaterol 300 µg for FEV(1) and Transition Dyspnea Index. CONCLUSION: Indacaterol is expected to be comparable to formoterol, salmeterol, and tiotropium, providing higher FEV(1) than formoterol and salmeterol and greater improvement in the SGRQ total score than tiotropium. Indacaterol 150 µg provided comparable improvement in dyspnea, while indacaterol 300 µg demonstrated the greatest response overall.

Application of latent growth and growth mixture modeling to identify and characterize differential responders to treatment for COPD.

OBJECTIVE: To explore the utility of applying growth mixture models (GMMs) in secondary analyses of clinical trials to identify sources of variability in data reported by patients with COPD. METHODS: Analyses were performed on data from two 6-month clinical trials comparing indacaterol and open-label tiotropium or blinded salmeterol and the first six months of a 12-month trial comparing indacaterol and blinded formoterol. Latent growth model (LGM) analyses were conducted to explore the response of the SGRQ Symptoms score from baseline to six months and GMM analyses were evaluated as a method to identify latent classes of differential responders. RESULTS: Variability in SGRQ Symptom scores was found suggesting subsets of patients with differential response to treatment. GMM analyses found subsets of non-responders in all trials. When the responders were analyzed separately from non-responders, there were increased treatment effects (e.g., symptoms score improvement over six months for whole groups: indacaterol=8-12 units, tiotropium=7 units, salmeterol=9 units, formoterol=11 units. Responder subgroup improvement: indacaterol=9-21 units, tiotropium=7 units, salmeterol=10 units, formoterol=20 units). Responders had significantly different baseline SGRQ Symptom scores, smoking history, age, and mMRC dyspnea scores than non-responders. CONCLUSIONS: Patients with COPD represent a heterogeneous population in terms of their reporting of symptoms and response to treatment. GMM analyses are able to identify sub-groups of responders and non-responders. Application of this methodology could be of value on other endpoints in COPD and in other disease areas.

Cost-utility analysis of indacaterol in Germany: a once-daily maintenance bronchodilator for patients with COPD.

INTRODUCTION: Indacaterol is a novel inhaled once-daily long-acting beta(2)-agonist (LABA) for the maintenance treatment of COPD that has been compared to existing inhaled monotherapies on a number of symptomatic endpoints in clinical studies. With constrained healthcare budgets, the objective of this analysis was to evaluate the cost-effectiveness of indacaterol 150 µg, the approved starting dose for maintenance therapy, from a German heath service perspective against the most widely used bronchodilator tiotropium, and the twice-daily LABA, salmeterol. METHODS: A Markov model was developed with the following main health states: Mild, Moderate, Severe, and Very Severe COPD, based on pre-bronchodilator FEV(1) measures reported in the indacaterol clinical trials, and death. Each disease severity health state had two associated health states for severe or non-severe exacerbation. The model considered patients with moderate to severe COPD, with a mean age of 64 years. The base case time horizon was three years, with discounting set at 3% for costs and benefits. Selected clinical inputs and health state utilities were derived from indacaterol clinical trials, while costs were based on publicly available drug prices and tariffs or published sources. Inputs describing disease progression were based on published data on the rate of FEV(1) decline. RESULTS: Point-estimates show that indacaterol 150 µg is dominant (lower total costs and better outcomes) against tiotropium and salmeterol. An alternative analysis comparing indacaterol 300 µg (maximum dose) against tiotropium, showed an incremental cost-effectiveness ratio (ICER) of approximately €28,300 per QALY. CONCLUSION: Indacaterol is cost-effective compared to tiotropium and salmeterol.

Comparative efficacy of indacaterol 150 µg and 300 µg versus fixed-dose combinations of formoterol + budesonide or salmeterol + fluticasone for the treatment of chronic obstructive pulmonary disease--a network meta-analysis.

OBJECTIVE: To compare efficacy of indacaterol to that of fixed-dose combination (FDC) formoterol and budesonide (FOR/BUD) and FDC salmeterol and fluticasone (SAL/FP) for the treatment of chronic obstructive pulmonary disease (COPD) based on the available randomized clinical trials (RCTs). METHODS: Fifteen placebo-controlled RCTs were included that evaluated: indacaterol 150 µg (n = 5 studies), indacaterol 300 µg (n = 4), FOR/BUD 9/160 µg (n = 2), FOR/BUD 9/320 µg (n = 3), SAL/FP 50/500 µg (n = 5), and SAL/FP 50/250 µg (n = 1). Outcomes of interest were trough forced expiratory volume in 1 second (FEV(1)), total scores for St. George's Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI). All trials were analyzed simultaneously using a Bayesian network meta-analysis and relative treatment effects between all regimens were obtained. Treatment-by-covariate interactions were included where possible to improve the similarity of the trials. RESULTS: Indacaterol 150 µg resulted in a higher change from baseline (CFB) in FEV(1) at 12 weeks compared to FOR/BUD 9/160 µg (difference in CFB 0.11 L [95% credible intervals: 0.08, 0.13]) and FOR/BUD 9/320 µg (0.09 L [0.06, 0.11]) and was comparable to SAL/FP 50/250 µg (0.02 L [-0.04, 0.08]) and SAL/FP 50/500 µg (0.03 L [0.00, 0.06]). Similar results were observed for indacaterol 300 µg at 12 weeks and indacaterol 150/300 µg at 6 months. Indacaterol 150 µg demonstrated comparable improvement in SGRQ total score at 6 months versus FOR/BUD (both doses), and SAL/FP 50/500 µg (-2.16 point improvement [-4.96, 0.95]). Indacaterol 150 and 300 µg demonstrated comparable TDI scores versus SAL/FP 50/250 µg (0.21 points (-0.57, 0.99); 0.39 [-0.39, 1.17], respectively) and SAL/FP 50/500 µg at 6 months. CONCLUSION: Indacaterol monotherapy is expected to be at least as good as FOR/BUD (9/320 and 9/160 µg) and comparable to SAL/FP (50/250 and 50/500 µg) in terms of lung function. Indacaterol is also expected to be comparable to FOR/BUD (9/320 and 9/160 µg) and SAL/FP 50/500 µg in terms of health status and to SAL/FP (50/250 and 50/500 µg) in terms of breathlessness.

Profiling the effects of indacaterol on dyspnoea and health status in patients with COPD.

BACKGROUND: Indacaterol is a novel, inhaled, ultra-long-acting ß(2)-agonist bronchodilator for maintenance use in patients with COPD. The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status, using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators. METHODS: Individual patient data were pooled from three randomized, placebo-controlled studies (NCT00393458; NCT00567996; NCT00463567), conducted in patients with moderate-to-severe COPD. Treatments were double-blind indacaterol 150 µg (n = 746) or 300 µg (n = 853) once-daily, formoterol 12 µg twice-daily (n = 556), salmeterol 50 µg twice-daily (n = 333) and placebo (n = 1185); and open-label tiotropium 18 µg once-daily (n = 415). Evaluation after 6 months' treatment was by transition dyspnoea index (TDI; minimum clinically important difference [MCID] ≥1 point), and St George's Respiratory Questionnaire (SGRQ; MCID ≥4 units). RESULTS: Differences from placebo in TDI total score were 1.01 (indacaterol 150 µg) 1.28 (indacaterol 300 µg), 0.74 (formoterol), 0.92 (salmeterol) and 0.88 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91, 2.69, 2.02, 1.79 and 1.49 (all p < 0.05). Differences versus placebo in SGRQ total score were -4.4 (indacaterol 150 µg), -3.4 (indacaterol 300 µg), -2.8 (formoterol), -4.0 (salmeterol) and -1.7 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID of 1.95, 1.63, 1.54, 1.82 and 1.29 (all p < 0.05 apart from tiotropium). CONCLUSIONS: Indacaterol provided clinically important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD.

Three-year dispensing patterns with long-acting inhaled drugs in COPD: a database analysis.

BACKGROUND: Long-acting muscarinic antagonists (LAMA), long-acting ß2-agonists (LABA) and fixed dose combinations (FDC) of inhaled corticosteroids (ICS) and LABA are used as inhaled maintenance therapies for COPD. OBJECTIVE: To estimate persistence rates from dispensing patterns of long-acting inhaled drugs for COPD. METHODS: From the PHARMO-database, COPD patients starting LAMA, LABA or LABA-ICS FDC between 2002 and 2006 were selected. Persistence with the initial as well as with any long-acting inhaled drug was determined, defined as time between start and stop of initial/any therapy, allowing ≤ 60-days gaps between refills. For patients who did not continue to receive dispensings of the initial therapy for at least one year, the first change in therapy was determined. RESULTS: The study included 2201 LAMA, 1201 LABA and 4146 LABA-ICS FDC users. Persistence rates with initial therapy alone at 1, 2, and 3 years were 25%, 14%, 8% for LAMA, 21%, 10%, 6% for LABA and 27%, 14%, 8% for LABA-ICS FDC. Of patients who did not persist with LAMA alone for one year, 15% added and 13% switched therapy (both mostly LABA-ICS FDC). Of patients not persisting with LABA alone, 9% added therapy (mostly LAMA) and 31% switched therapy (mostly to LABA-ICS FDC). In patients not persisting with LABA-ICS FDC, add-on and switch occurred equally frequent (11%, mostly LAMA). Persistence rates with any long-acting drug at 1, 2 and 3 years were 36%, 23% and 17% respectively. CONCLUSION: Persistence with the initial as well as with any long-acting inhaled drug in COPD is low, with a substantial proportion of patients changing therapy.

Costs of chemotherapy for indolent follicular non-Hodgkin's lymphoma in the UK: an observational study.

Non-Hodgkin's lymphoma (NHL) is the sixth most common cancer in the United Kingdom (UK). This analysis assessed the health service costs of patients receiving chemotherapy for indolent follicular NHL based on a retrospective analysis of patient records in the UK. Each patient was followed up for a period of 3 years or until death. The analysis included 181 patients, who received a total of 187 treatment periods. Costs were estimated from the perspective of the UK National Health Service. The study found the cost of providing treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or fludarabine to patients with indolent follicular NHL to be lower than previously reported.