Comparative efficacy of long-acting bronchodilators for COPD: a network meta-analysis.

BACKGROUND: Clinicians are faced with an increasingly difficult choice regarding the optimal bronchodilator for patients with chronic obstructive pulmonary disease (COPD) given the number of new treatments. The objective of this study is to evaluate the comparative efficacy of indacaterol 75/150/300 µg once daily (OD), glycopyrronium bromide 50 µg OD, tiotropium bromide 18 µg/5 µg OD, salmeterol 50 µg twice daily (BID), formoterol 12 µg BID, and placebo for moderate to severe COPD. METHODS: Forty randomized controlled trials were combined in a Bayesian network meta-analysis. Outcomes of interest were trough and post-dose forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ) score and responders (≥4 points), and Transition Dyspnea Index (TDI) score and responders (≥1 point) at 6 months. RESULTS: Indacaterol was associated with a higher trough FEV1 than other active treatments (difference for indacaterol 150 µg and 300 µg versus placebo: 152 mL (95% credible interval (CrI): 126, 179); 160 mL (95% CrI: 133, 187)) and the greatest improvement in SGRQ score (difference for indacaterol 150 µg and 300 µg versus placebo: -3.9 (95% CrI -5.2, -2.6); -3.6 (95% CrI -4.8, -2.3)). Glycopyrronium and tiotropium 18 µg resulted in the next best estimates for both outcomes with minor differences (difference for glycopyrronium versus tiotropium for trough FEV1 and SGRQ: 18 mL (95% CrI: -16, 51); -0.55 (95% CrI: -2.04, 0.92). CONCLUSION: In terms of trough FEV1 and SGRQ score indacaterol, glycopyrronium, and tiotropium are expected to be the most effective bronchodilators.

The economic burden of fragile x syndrome: healthcare resource utilization in the United States.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability with cognitive and behavioral impairments, and is associated with a lifetime of care-taking challenges. There is a paucity of data on the economic burden of FXS. OBJECTIVE: To analyze the direct costs associated with healthcare and medication utilization for patients with FXS by using commercial and Medicare/Medicaid administrative claims data. METHODS: All-cause direct healthcare and prescription drug utilization were analyzed from the Thomson Reuters Healthcare MarketScan Commercial, the Medicare Supplemental, and the MarketScan Medicaid databases between 2004 and 2009. Inclusion criteria were ≥1 diagnosis of FXS (International Classification of Diseases, Ninth Revision, 759.83) and ≥12 months of continuous enrollment in the current health plan. Emergency department, hospitalization, outpatient visit, nonspecified procedures, and prescription drug data were analyzed for a 12-month follow-up period. Because the number of Medicare patients was <50, commercial and Medicare databases were combined into a single cohort. Descriptive statistics were used to summarize the results. RESULTS: A total of 1505 patients were included in the study; of these, 784 patients had commercial/Medicare insurance and 721 patients had Medicaid. The mean age was 18 years. In all age-groups, the median all-cause healthcare cost per patient was significantly lower in the commercial/Medicare cohort (range, $2222-$2955) than in the Medicaid cohort (range, $4548-$9702). The annual median costs per patient for those who had any medical procedures were $1614 and $3064 for commercial or Medicare and for Medicaid, respectively. The annual median costs per patient for those with at least 1 hospitalization was $7740 in the commercial/Medicare cohort (9.4% of patients) and $4468 in the Medicaid cohort (12.5% of patients). CONCLUSION: This first descriptive US claims analysis supports the overall results from surveys on the economic burden related to FXS. The cost drivers in this population included medical procedures, hospitalizations in a subset of patients, and medications to a lesser extent. This information may be relevant to payers for benefit design and allocation of resources. A more targeted assessment of resource utilization is needed to estimate the value of interventions that reduce costs and improve the outcomes of patients with FXS.

Efficacy of indacaterol 75 µg versus fixed-dose combinations of formoterol-budesonide or salmeterol-fluticasone for COPD: a network meta-analysis.

BACKGROUND: The purpose of this study was to update our network meta-analysis in order to compare the efficacy of indacaterol 75 µg with that of a fixed-dose combination of formoterol and budesonide (FOR/BUD) and a fixed-dose combination salmeterol and fluticasone (SAL/FP) for the treatment of chronic obstructive pulmonary disease (COPD) based on evidence identified previously in addition to two new randomized clinical trials. METHODS: Fifteen randomized, placebo-controlled clinical trials including COPD patients were evaluated: indacaterol 75 µg once daily (n = 2 studies), indacaterol 150 µg once daily (n = 5), indacaterol 300 µg once daily (n = 4), FOR/BUD 9/160 µg twice daily (n = 2), FOR/BUD 9/320 µg twice daily (n = 2), SAL/FP 50/500 µg twice daily (n = 4), and SAL/FP 50/250 µg twice daily (n = 1). 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. Outcomes of interest were trough forced expiratory volume in 1 second (FEV(1)) and transitional dyspnea index at 12 weeks. RESULTS: Based on the results without adjustment for covariates, indacaterol 75 µg resulted in a greater improvement in FEV(1) at 12 weeks compared with FOR/BUD 9/160 µg (difference in change from baseline 0.09 L [95% credible interval 0.04-0.13]) and FOR/BUD 9/320 µg (0.07 L [0.03-0.11]) and was comparable with SAL/FP 50/250 µg (0.00 L [-0.07-0.07]) and SAL/FP 50/500 µg (0.01 L [-0.04-0.05]). For transitional dyspnea index, data was available only for indacaterol 75 µg versus SAL/FP 50/500 µg (-0.49 points [-1.87-0.89]). CONCLUSION: Based on results of a network meta-analysis with and without covariates, indacaterol 75 µg is expected to be at least as efficacious as FOR/BUD (9/320 µg and 9/160 µg) and comparable with SAL/FP (50/250 µg and 50/500 µg) in terms of lung function. In terms of breathlessness (transitional dyspnea index) at 12 weeks, the results are inconclusive given the limited data.

A network meta-analysis of the efficacy of inhaled antibiotics for chronic Pseudomonas infections in cystic fibrosis.

BACKGROUND: Various inhaled antibiotics are currently used for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients, however their relative efficacies are unclear. We compared the efficacy of the inhaled antibiotics tobramycin (TIP, TIS-T, TIS-B), colistimethate sodium (colistin) and aztreonam lysine for inhalation (AZLI) based on data from randomised controlled trials. METHODS: In the base case, efficacies of antibiotics were compared using a network meta-analysis of seven trials including change from baseline in forced expiratory volume in 1 second (FEV(1)) % predicted, P. aeruginosa sputum density and acute exacerbations. RESULTS: The tobramycin preparations, AZLI and colistin, showed comparable improvements in efficacy in terms of FEV1% predicted at 4 weeks; the difference in % change from baseline (95%CrI) for TIP was compared to TIS-T (-0.55, -3.5;2.4), TIS-B (-0.64, -7.1;5.7), AZLI (3.64, -1.0;8.3) and colistin (5.77, -1.2;12.8). CONCLUSION: We conclude that all studied antibiotics have comparable efficacies for the treatment of chronic P. aeruginosa lung infection in CF.

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.

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.

Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review.

BACKGROUND: Interactions between spirometry and patient-reported outcomes in COPD are not well understood. This systematic review and study-level analysis investigated the relationship between changes in FEV1 and changes in health status with bronchodilator therapy. METHODS: Six databases (to October 2009) were searched to identify studies with long-acting bronchodilator therapy reporting FEV1 and health status, dyspnoea or exacerbations. Mean and standard deviations of treatment effects were extracted for each arm of each study. Relationships between changes in trough FEV1 and outcomes were assessed using correlations and random-effects regression modelling. The primary outcome was St George's Respiratory Questionnaire (SGRQ) total score. RESULTS: Thirty-six studies (≥ 3 months) were included. Twenty-two studies (23,654 patients) with 49 treatment arms each contributing one data point provided SGRQ data. Change in trough FEV1 and change in SGRQ total score were negatively correlated (r = -0.46, p < 0.001); greater increases in FEV1 were associated with greater reductions (improvements) in SGRQ. The correlation strengthened with increasing study duration from 3 to 12 months. Regression modelling indicated that 100 mL increase in FEV1 (change at which patients are more likely to report improvement) was associated with a statistically significant reduction in SGRQ of 2.5 (95% CI 1.9, 3.1), while a clinically relevant SGRQ change (4.0) was associated with 160.6 (95% CI 129.0, 211.6) mL increase in FEV1. The association between change in FEV1 and other patient-reported outcomes was generally weak. CONCLUSIONS: Our analyses indicate, at a study level, that improvement in mean trough FEV1 is associated with proportional improvements in health status.

Summarizing historical information on controls in clinical trials.

BACKGROUND: Historical information is always relevant when designing clinical trials, but it might also be incorporated in the analysis. It seems appropriate to exploit past information on comparable control groups. PURPOSE: Phase IV and proof-of-concept trials are used to discuss aspects of summarizing historical control data as prior information in a new trial. The importance of a fair assessment of the similarity of control parameters is emphasized. METHODS: The methodology is meta-analytic-predictive. Heterogeneity of control parameters is expressed via the between-trial variation, which is the key parameter determining the prior effective sample size and its upper bound (prior maximum sample size). RESULTS: For a Phase IV trial (930 control patients in 11 historical trials) between-trial heterogeneity was fairly small, resulting in a prior effective sample size of approximately 90 patients. For a proof-of-concept trial (363 patients in four historical trials) heterogeneity was moderate to substantial, resulting in a prior effective sample size of approximately 20. For another proof-of-concept trial (14 patients in one historical trial), assuming substantial heterogeneity implied a prior effective sample size of 7. The prior effective sample size can only be large if the amount of historical data is large and between-trial heterogeneity is small. The prior effective sample size is bounded by the prior maximum sample size (ratio of within- to between-trial variance), irrespective of the amount of historical data. LIMITATIONS: The meta-analytic-predictive approach assumes exchangeability of control parameters across trials. Due to the difficulty to quantify between-trial variability, sensitivity of conclusions regarding assumptions and type of inference should be assessed. CONCLUSIONS: The use of historical control information is a valuable option and may lead to more efficient clinical trials. The proposed approach is attractive for nonconfirmatory trials, but under certain circumstances extensions to the confirmatory setting could be envisaged as well.