Pulmonary Function Assessment in Mild to Moderate Persistent Asthma Patients Receiving Montelukast,Doxofylline, and Tiotropium With Budesonide: A Randomized Controlled Study

Background

There is no comparative study among asthma patients receiving first-line versus various second-line treatment regimens for mild to moderate persistent asthma.

Objective

We assessed the pulmonary function in asthma patients receiving montelukast, doxofylline, and tiotropium with budesonide in a pilot group.

Methods

Patients were recruited as per the study criteria and randomly allocated to 4 groups to receive budesonide (400 µg) with formoterol (12 µg), doxofylline (400 mg), montelukast (10 mg), or tiotropium (18 µg) for a period of 3 months. Outcomes included forced expiratory volume in 1 second (FEV₁) and rescue medication use.

Results

A total of 167 patients were recruited; among them, 123 patients completed the study. At baseline, no significant difference (P > 0.05) was observed in any of the outcome measures. Significant within-group improvement in FEV₁ was observed in all the groups. At day 90, between-group difference revealed that improvement in FEV₁ was significantly (P < 0.05) high for budesonide plus formoterol followed by budesonide plus doxofylline, budesonide plus montelukast, and, lastly, budesonide plus tiotropium. Similarly, within-group comparison revealed a significant (P < 0.05) reduction in rescue medication use in all the groups. The intensity in decrease was more in budesonide plus formoterol group followed by budesonide plus doxofylline, budesonide plus montelukast, and budesonide plus tiotropium groups.

Conclusion

On the basis of our findings, among the second-line treatment regimens, budesonide plus doxofylline and budesonide plus montelukast was found to be better than budesonide plus tiotropium in patients with mild to moderate persistent asthma. Further studies with a larger sample size are likely to be useful.     

Onset of Bronchodilation with Fluticasone/Formoterol Combination Versus Fluticasone/Salmeterol in an Open-Label, Randomized Study

Introduction

The inhaled corticosteroid, fluticasone propionate (fluticasone), and the long-acting beta₂-agonist, formoterol fumarate (formoterol), have been combined in a single aerosol inhaler (fluticasone/formoterol). In a randomized, open-label study, fluticasone/formoterol showed similar efficacy to fluticasone/salmeterol after 12 weeks of treatment. This post-hoc analysis compared the onset of bronchodilation with the two treatments.

Methods

Adults with mild-to-moderate-severe persistent asthma were randomized to fluticasone/formoterol (100/10 or 250/10 ??g twice daily [b.i.d.]) or fluticasone/salmeterol (100/50 or 250/50 ??g b.i.d.) for 12 weeks. The onset of bronchodilation (the first post-dose time point at which the forced expiratory volume in 1 second [FEV₁] was ??12% greater than the pre-dose value), responder rates (the proportion of patients achieving bronchodilation), and changes in FEV₁ were assessed at days 0 (baseline) and 84.

Results

Fluticasone/formoterol (n = 101) provided more rapid onset of bronchodilation than fluticasone/salmeterol (n = 101) over the first 120 min post-dose on days 0 (hazard ratio [HR] = 1.47 [95% CI 1.05?C2.05]) and 84 (HR = 1.77 [95% CI 1.14?C2.73]). The odds of a patient achieving bronchodilation within 5 min of dosing were almost four-times higher with fluticasone/formoterol than with fluticasone/salmeterol on day 0 (odds ratio [OR] = 3.97 [95% CI 1.96?C8.03]) and almost 10-times higher on day 84 (OR = 9.58 [95% CI 2.14?C42.90]); the odds of achieving bronchodilation within 120 min post-dose were approximately twofold higher with fluticasone/formoterol on both days. The overall percentage increase in least-squares (LS) mean FEV1 during the 120-min post-dose period was significantly greater with fluticasone/formoterol than fluticasone/salmeterol on days 0 (LS mean treatment difference: 4.70% [95% CI 1.57?C7.83]; P = 0.003) and 84 (2.79% [95% CI 0.65?C4.93]; P = 0.011).

Conclusion

These analyses showed that fluticasone/formoterol provided a faster onset of bronchodilation than fluticasone/salmeterol, which was maintained over 12 weeks of treatment. This benefit may facilitate treatment adherence among patients with asthma.     

Efficacy and Tolerability of Tratinterol Hydrochloride Tablets in Bronchial Asthma: A Multicenter,Randomized, Double-blind,Dose-finding Clinical Trial

Purpose

The aims of this study were to determine the efficacy and tolerability of different dosages of, and to identify the best dosage of, tratinterol hydrochloride tablets in the treatment of bronchial asthma.

Methods

This multicenter, randomized, double-blind, dose-finding clinical research study was completed at 3 centers in the People’s Republic of China from March 2008 to February 2009. Each center selected patients with bronchial asthma whose forced expiratory volume in 1 second (FEV₁) values were <80% of predicted normal (pretreatment). Patients were assigned to 1 of 3 groups, based on daily dosage: low, 50 μg/d; intermediate, 100 μg/d; and high, 150 μg/d. Doses were administered orally twice daily for 10 days. The primary end points were the changes from baseline (0 minutes) in peak expiratory flow (PEF) and FEV₁ at 30 minutes and 1, 2, 4, 6, and 12 hours after administration. Secondary end points were changes from baseline in forced vital capacity and asthma scores. Tolerability was monitored throughout the study period using physical examinations, laboratory testing, and spontaneous reporting.

Findings

A total of 72 patients were selected in this study (24 per group; 40 men; 32 women; mean age, 43.48 years). The efficacy analysis (per-protocol set) included 20, 20, and 22 patients in the low-, intermediate-, and high-dosage groups, respectively. In terms of the primary and secondary end points, the intermediate dosage was most efficacious, followed by the high and low dosages, respectively. All 3 dosages were well-tolerated.

Implications

In these patients with bronchial asthma, 100 μg/d was the dosage of tratinterol hydrochloride tablets most efficacious in terms of improvement in lung function. All 3 dosages were well-tolerated.     

Inhaled corticosteroids or long-acting β-agonists alone or in fixed-dose combinations in asthma treatment: A systematic review of fluticasone/budesonide and formoterol/salmeterol

Background: Inhaled corticosteroids (ICSs) and longacting inhaled β₂-agonists (LABAs) are recommended treatment options for asthma.Objective: This review compares the clinical effectiveness and tolerability of the ICSs fluticasone propionate and budesonide and the LABAs formoterol fumarate and salmeterol xinafoate administered alone or in combination.Methods: A systematic review of the clinical studies available on MEDLINE (database period, 1950-September 2009) was conducted to assess English-language randomized controlled trials in children and adults with asthma. Treatment outcomes included lung function, symptom-free days (SFDs), use of rescue/reliever medications, asthma exacerbations, and tolerability profile.Results: Use of fluticasone was associated with significantly greater improvement in lung function and better asthma symptom control than budesonide. Similarly, formoterol was associated with significantly greater improvement in lung function and better asthma symptom control (as measured by less rescue medication use and more SFDs) compared with salmeterol. Single inhaler combination regimens (budesonide/ formoterol and fluticasone/salmeterol) were frequently more effective in improving all treatment outcomes than either monotherapy alone. Across all comparisons, a review of studies in adults and children did not find statistically significant differences in outcomes between the ICS and LABA therapies considered in this research. In general, no differences in tolerability profiles were reported between the ICS and LABA options, although the risk for growth retardation was lower with fluticasone than budesonide and with budesonide/formoterol than with budesonide monotherapy.Conclusions: In this systematic review, fluticasone and formoterol appear to provide improved therapeutic benefits versus budesonide and salmeterol, respectively. Both fluticasone/salmeterol and budesonide/ formoterol combination therapies appeared to be associated with greater improvements in outcomes measures than the corresponding ICS and LABA monotherapies.     

Formoterol 12 microg BID administered via single-dose dry powder inhaler in adults with asthma suboptimally controlled with salmeterol or on-demand salbutamol: a multicenter,randomized, open-label,parallel-group study

BACKGROUND: Although salmeterol and formoterol are both long-acting beta(2) adrenergic receptor agonist bronchodilators, there are distinct differences between them that could translate into differences in clinical response in some patients. OBJECTIVE: The goal of this study was to examine the efficacy of formoterol in patients with moderate to severe persistent asthma that was suboptimally controlled with an inhaled corticosteroid (ICS) combined with on-demand salbutamol (albuterol in the United States) with or without salmeterol. METHODS: This multicenter, 4-week, randomized, open-label, parallel-group study included adult patients (age >/=18 years) with suboptimally controlled asthma (mean salbutamol use, >/=2 puffs/d via pressurized metered-dose inhaler [100 microg/puff]). Patients were randomized in a 2:1 ratio to receive formoterol 12 microg BID via single-dose dry powder inhaler plus on-demand salbutamol or to continue their existing treatment with either on-demand salbutamol alone or salmeterol 50 microg BID via multidose dry powder inhaler plus on-demand salbutamol. ICS regimens were unchanged during the trial. The primary efficacy variable was evening predose peak expiratory flow (PEF). Secondary variables included further measures of asthma symptom control.RESULTS: A total of 6239 adult patients entered the study; data from 6155 patients were available for analysis. Patients who were switched from salmeterol to formoterol reported a significant increase in mean (SD) evening predose PEF compared with patients who continued their existing treatment (402.9 [112.1] vs 385.5 [107.5] Umin, respectively; P < 0.001). Similarly, patients who were switched from on-demand salbutamol alone to formoterol plus on-demand salbutamol reported a significant increase in mean evening predose PEF compared with those who continued treatment with on-demand salbutamol alone (409.3 [105.6] vs 385.0 [105.3] L/min, respectively; P < 0.001). The results for the secondary efficacy measures mirrored the significant improvements seen in patients switched to formoterol compared with those who continued to receive on-demand salbutamol alone or salmeterol plus on-demand salbutamol. CONCLUSION: In this study, formoterol significantly improved lung function and control of asthma symptoms and decreased use of rescue medication in patients whose asthma had been suboptimally controlled with an ICS in combination with on-demand salbutamol with or without salmeterol.     

Effects of Moderate Hepatic Impairment on the Pharmacokinetic Properties and Tolerability of Umeclidinium and Vilanterol in Inhalational Umeclidinium Monotherapy and Umeclidinium/Vilanterol Combination Therapy: An Open-Label,Nonrandomized Study

Background

The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a monotherapy, and in combination with the long-acting β₂-agonist vilanterol (VI), as a once-daily inhaled maintenance bronchodilator therapy for chronic obstructive pulmonary disease in the US and EU; they are not indicated for the treatment of asthma. Preclinical and clinical data suggest that UMEC and VI are predominantly eliminated by the liver.

Objectives

The objectives of the study were to evaluate the effects of moderate hepatic impairment on the plasma and urinary pharmacokinetic properties of each drug, and on the tolerability of inhalational UMEC/VI 125/25 µg and UMEC 125 µg.

Methods

This open-label, nonrandomized study was conducted in patients with moderate hepatic impairment (Child-Pugh score, 7–9) and in healthy volunteers (control). Patients and volunteers were administered a single dose of UMEC/VI 125/25 µg, and, after a 7- to 14-day washout period, repeat-dose UMEC 125 µg once daily for 7 days. Primary end points were the plasma pharmacokinetic properties of single- and repeat-dose UMEC and VI. Secondary end points were the urinary pharmacokinetic properties of UMEC, and the tolerability of each treatment.

Results

All 18 enrolled patients and volunteers (12 men, 6 women; mean age, 53.6 years) completed the study. Mean systemic exposures of UMEC and VI were similar or numerically lower in patients with moderate hepatic impairment compared with those in healthy volunteers, but the differences were not clinically significant. UMEC accumulations with 7-day dosing of UMEC were similar between patients with moderate hepatic impairment and healthy volunteers. UMEC/VI 125/25 µg and UMEC 125 µg were well-tolerated, with no safety concerns identified.

Conclusions

The administration of UMEC/VI 125/25 µg or UMEC 125 µg in patients with moderate hepatic impairment did not result in clinically relevant increases in UMEC or VI exposures compared with those in healthy volunteers. Based on these findings, no dose adjustment for UMEC/VI or UMEC is warranted in patients with moderate hepatic impairment.     

Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma

BACKGROUND: The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma. Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler (pMDI) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma, but it has not been assessed in patients with mild to moderate persistent asthma. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI (budesonide/formoterol pMDI), budesonide pMDI, formoterol dry powder inhaler (DPI), and placebo. METHODS: This 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted at 56 centers across the United States. Patients aged > or =12 years with mild to moderate persistent asthma treated with inhaled corticosteroids (ICSs) for > or =4 weeks before screening and who had a forced expiratory volume in 1 second (FEV(1)) of > or =60% to < or =90% of predicted normal at screening were eligible. After 2 weeks (current asthma therapy discontinued), patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), budesonide pMDI 80 microg x 2 inhalations (160 microg), formoterol DPI 4.5 microg x 2 inhalations (9 microg), or placebo. The coprimary efficacy variables were changes from baseline in morning predose FEV(1) and 12-hour mean FEV(1) (from serial spirometry) after administration of the morning dose of study medication. Tolerability was assessed based on adverse events (AEs); routine laboratory assessments; electrocardiography; 24-hour Holter monitor assessments; and physical examinations, including vital signs (eg, systolic and diastolic blood pressure and heart rate). AEs were recorded manually by the patient in paper notebooks and reviewed at each clinic visit by the investigator and during a final follow-up phone call. RESULTS: A total of 480 patients were randomized (299 females, 181 males; mean age, 36 years; mean FEV(1), 2.4 L; budesonide/formoterol pMDI, 123 patients; budesonide pMDI, 121; formoterol DPI, 114; placebo, 122). At end of treatment, the mean increases from baseline in predose FEV(1) were greater with budesonide/formoterol pMDI versus budesonide pMDI, formoterol DPI, and placebo (0.37 vs 0.23, 0.17, and 0.03 L, respectively; all, P<0.005). 0.005). After administration of the first dose and at weeks 2 and 12, mean increases in 12-hour mean FEV(1) were significantly greater with budesonide/formoterol pMDI (0.41, 0.47, and 0.50 L, respectively) versus budesonide pMDI (0.17, 0.30, and 0.32 L) and placebo (0.15, 0.12, and 0.12 L) (all, P < 0.001). Fewer patients receiving budesonide/formoterol pMDI met criteria for (18.7%; P < 0.001) or withdrew because of (7.3%; P < or = 0.010) worsening asthma versus formoterol DPI (42.1% and 18.4%, respectively) and placebo (56.6% and 32.8%); results were similar between budesonide pMDI (21.5% and 6.6%, respectively) and budesonide/formoterol pMDI. Three patients experienced serious AEs; none was considered related to study medication. The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups. CONCLUSIONS: In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs, twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents. All study drugs were generally well tolerated.     

Comparison of the Pharmacokinetics,Safety, and Tolerability of Vitamin D3 in DP-R206 (150-mg Ibandronate/24,000-IU Vitamin D3 Tablet) and as Monotherapy (24,000 IU) in Healthy Male Korean Adults

Background

Combined treatment with a bisphosphonate and vitamin D has been proposed for postmenopausal osteoporosis. A new, fixed-dose combination tablet of ibandronate plus vitamin D₃ has been developed for monthly administration to treat postmenopausal osteoporosis.

Objectives

The main objective of the present study was to compare the pharmacokinetics of vitamin D₃ administered in 2 forms: a newly developed ibandronate 150-mg/vitamin D₃ 24,000-IU tablet (DP-R206, test drug) and a stand-alone vitamin D₃ 24,000-IU tablet (reference drug). A secondary objective was to evaluate the safety and tolerability of DP-R206 in healthy adult male Korean volunteers.

Methods

This study was a single-dose, open-label, randomized-sequence, 2-treatment, 2-way crossover trial. Blood samples were collected from 24 hours’ predose to 120 hours’ postdose. The plasma concentrations of vitamin D₃ were analyzed by using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated, and the 90% CIs of the ratios of the geometric means of the parameters were determined from the logarithmically transformed data by using ANOVA.

Results

Thirty-sex healthy adult male Korean volunteers with a mean (SD) age of 25.8 (2.7) years, a mean height of 174.0 (5.9) cm, and a mean weight of 69.1 (6.2) kg were enrolled; 29 participants completed the study. The 90% CIs of the ratios of the geometric means (test drug/reference drug) of the baseline-corrected C_max, AUC_0–last, and AUC_0–∞ values were 0.93 to 1.24, 0.89 to 1.19, and 0.87 to 1.18, respectively. The 90% CIs of the ratios of the geometric means (test drug/reference drug) of the baseline-uncorrected C_max, AUC_0–last, and AUC_0–∞ values were 0.93 to 1.24, 0.88 to 1.19, and 0.87 to 1.18, respectively. Eighty-four adverse events (AEs) were reported in 24 of 32 subjects receiving DP-R206, and 14 AEs were reported in 8 of 29 subjects receiving the vitamin D₃ 24,000-IU tablet. All of the subjects who experienced AEs recovered without sequelae, and no serious AEs were observed.

Conclusions

The vitamin D₃ pharmacokinetics were similar for DP-R206 and the 24,000-IU vitamin D₃ tablet. DP-R206 was well tolerated. ClinicalTrials.gov identifier: NCT01577849.     

Tolerability of Fluticasone Furoate/Vilanterol Combination Therapy in Children Aged 5 to 11 Years With Persistent Asthma

Background

Asthma is a chronic disease afflicting millions of children worldwide. Short-acting β₂-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting β₂-agonist and ICS treatment, in which case guidelines recommend adding a long-acting β₂-agonist.

Objective

We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting β₂-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma.

Methods

In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC_0–4, C_max) and PD (serum potassium [0–4 hours], serum cortisol [0–12 hours], and glucose [0–4 hours]) parameters on day 14.

Results

Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC_0–4 (1.02 [0.86–1.22]) and FF C_max (0.98 [0.65–1.48]) were similar. For serum glucose (0–4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19–0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study.

Conclusions

Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.     

A Randomized,Multicenter, Double-blind,Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis

Purpose

The aim of this study was to evaluate the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma compared with the efficacy and safety of montelukast alone.

Tolerability and Pharmacokinetics of Delayed-Release Dimethyl Fumarate Administered With and Without Aspirin in Healthy Volunteers

Background

Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.

Objective

The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.

Methods

Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.

Results

DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC_0–10h, or C_max. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF–treated individuals, plasma concentrations of a prostaglandin D₂ (PGD₂) metabolite were increased.

Conclusions

In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD₂ in some DR-DMF–treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.     

Efficacy and Safety of Aclidinium/Formoterol versus Tiotropium in COPD: Results of an Indirect Treatment Comparison

Introduction

The objective of this study was to estimate the relative efficacy and safety of fixed-dose combination aclidinium/formoterol 400/12 μg twice daily compared to tiotropium 18 μg once daily in adult patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).

Methods

A systematic literature review performed in March 2014, using a predefined search strategy in MEDLINE, EMBASE and Cochrane Library, identified 17 randomized placebo-controlled trials, (tiotropium n = 15; aclidinium/formoterol n = 2). Outcomes of interest were: bronchodilation (peak and trough forced expiratory volume in 1 s (FEV₁)), COPD symptoms [Transition Dyspnea Index (TDI) focal score and % of responders (>1 unit improvement)] and Health Related Quality of Life (HRQoL) [St. George’s Respiratory Questionnaire (SGRQ) total score and % responders (>4 unit improvement)], % of patients with ≥1 exacerbations, adverse events (AE), serious adverse events (SAE), hospitalization and mortality, all at 24 weeks. In the absence of head-to-head trials between aclidinium/formoterol and tiotropium, a Bayesian indirect treatment comparison (ITC) was used with placebo as common control.

Results

Regarding bronchodilation, aclidinium/formoterol was found to be more efficacious than tiotropium at peak FEV₁, with mean difference in change from baseline (DCFB) 143 mL [95% credible interval (CrI): 112, 174] and at trough FEV₁ [DCFB 26 mL (95% CrI ?2, 55)]. Aclidinium/formoterol is expected to be more efficacious than tiotropium in improving dyspnea symptoms measured by TDI [DCFB 0.54 points (95% CrI 0.09, 0.99); odds ratio (OR) of responders 1.51 (95% CrI 1.11, 2.06)]. SGRQ results are comparable for aclidinium/formoterol versus tiotropium [DCFB ?0.52 (95% CrI ?2.21, 1.17); OR of responders 1.16 (95% CrI 0.47, 2.87)]. The ITC results suggest similar safety profiles regarding AEs, SAEs and hospitalization.

Conclusion

Based on the ITC, aclidinium/formoterol is expected to be more efficacious than tiotropium in terms of lung function and symptom control while providing comparable HRQoL results and safety profile.

Funding

AstraZeneca.

     

Budget Impact Analysis of a Fixed-Dose Combination of Fluticasone Propionate and Formoterol Fumarate (FP/FORM) in a Pressurized Metered-Dose Inhaler (pMDI) for Asthma

Introduction

The economic burden of asthma on the UK National Health Service (NHS) is the largest among allergic diseases. Current asthma guidelines recommend adding a long acting β₂-agonist (LABA) to a low-dose inhaled corticosteroid (ICS) in patients who are on ICS monotherapy and have uncontrolled asthma. The fixed-dose combination of fluticasone propionate and salmeterol xinafoate (FP/SAL), available in a pressurized metered-dose inhaler (pMDI) device, is the most commonly prescribed ICS/LABA combination. An additional fixed-dose combination of fluticasone propionate and formoterol fumarate (FP/FORM) in pMDI is now available. In a 12-week non-inferiority study, FP/FORM demonstrated comparable efficacy to FP/SAL. The present analysis estimates the annual budget impact for the UK NHS using FP/FORM as an alternative to FP/SAL.

Methods

Current pMDI prescribing data were from a real-world UK patient database (Cegedim Strategic Data). Annual costs to the NHS for drug acquisition, administration, and monitoring were estimated for FP/FORM and FP/SAL and used to assess the potential budget impact for the NHS for the use of FP/FORM instead of FP/SAL. Varying rates of uptake, adherence, adverse event-related costs, and resource use associated with switching treatment were assessed in scenario analyses.

Results

Assuming similar levels of ICS use with both regimens, annual drug acquisition costs per person were lower with FP/FORM (£412) than with FP/SAL (£509). The difference in acquisition costs and otherwise comparable input costs between the treatments, results in potential annual savings of £15,110,279 to the NHS, assuming uptake of FP/FORM over FP/SAL in 50% of existing patients. The introduction of FP/FORM results in cost savings for the NHS in all of the assessed scenario analyses.

Conclusions

The comparable efficacy and lower acquisition costs of FP/FORM compared with FP/SAL make it a cost-saving option for the UK NHS for the treatment of asthma patients requiring combination maintenance therapy using a pMDI.     

Effectiveness of the antibiotic lock therapy for the treatment of port-related enterococci,Gram-negative,or Gram-positive bacilli bloodstream infections

Objective

The purpose of this study is to evaluate the efficacy of antibiotic lock therapy to treat port-related enterococci, Gram-negative, or Gram-positive bacilli bloodstream infections.

Patients and Methods

We conducted a prospective observational study including all patients with port-related bacteremia diagnosed at the Clinica Universitaria de Navarra, Pamplona, Spain. During a 36-month period, 110 patients were diagnosed with port-related bacteremia. Of these patients, 18 met criteria to be enrolled in the study. They were treated with a combination of systemic and antibiotic lock therapy (12–24 h/day during 7–14 days). Treatment effectiveness was assessed by clinical and microbiologic criteria.

Results

Treatment was associated with clinical and microbiologic success in 88.8% of our patients (2/2 of the Propionibacterium acnes, 5/5 of the Corynebacterium spp., 6/7 of the Gram-negative bacillus, and 3/4 of the Enterococcus faecium port-related bloodstream infections). Mean increase of port life span for all patients after bacteremia was 288 days (range, 0–1403 days).

Conclusion

Antibiotic lock therapy combined with systemic antibiotics appears to be a safe and effective treatment of port-related bacteremia caused by enterococci, Gram-negative, or Gram-positive bacilli if the patient is stable and no septic syndrome is associated.     

A Randomized,Double-Blind Study of Fenofibric Acid Plus Rosuvastatin Compared With Rosuvastatin Alone in Stage 3 Chronic Kidney Disease

Background

Patients with chronic kidney disease (CKD) often have mixed dyslipidemia and high cardiovascular disease risk. Although statins reduce LDL-C, adding a fibrate may further improve lipid parameters.

Objective

This multicenter, randomized study evaluated the short-term efficacy and safety profile of fenofibric acid (FA) + rosuvastatin (R) combination therapy for improving lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. The study also assessed estimated glomerular filtration rate after study drug washout.

Methods

Patients received FA 45 mg + R (5 mg for 8 weeks, then 10 mg for 8 additional weeks) or R monotherapy (5 mg for 8 weeks, then 10 mg for 8 additional weeks), followed by an 8-week washout period. Primary and secondary end points were percent changes in triglycerides and HDL-C, respectively, from baseline to week 8.

Results

FA 45 mg + R 5 mg, compared with R 5 mg, resulted in significant improvements in triglycerides (median % changes: week 8, −38.0% vs −22.4%, P < 0.001; week 16, −42.6% vs −29.7%, P < 0.001) and HDL-C (mean % changes: week 8, 16.9% vs 7.8%, P < 0.001; week 16, 17.3% vs 8.9%, P < 0.001). Adverse event rates were similar between groups (70.7% with FA + R vs 68.6% with R). Mean serum creatinine level at baseline was 1.36 mg/dL in the FA + R group and 1.38 mg/dL in the R group. The final treatment serum creatinine value, defined as the last nonmissing postbaseline value collected within 30 days after the last dose of study drug, was 1.52 mg/dL with FA + R (vs 1.41 mg/dL with R; P < 0.001), which then decreased to 1.39 mg/dL after the 8-week washout (vs 1.42 mg/dL with R).

Conclusions

The data suggest that, after 16 weeks of therapy, FA + R has an acceptable safety profile and improved TG and HDL-C efficacy versus R. FA + R combination therapy may thus further improve lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. ClinicalTrials.gov identifier: NCT00680017.     

Budesonide/formoterol maintenance and reliever therapy. A new treatment approach for adult patients with asthma]

BACKGROUND: An inhaled corticosteroid (ICS) or an ICS/long-acting beta(2)-agonist (LABA) combination plus short-acting beta(2)-agonist (SABA) as needed for symptom relief is recommended for persistent asthma. Additionally, budesonide/formoterol maintenance and reliever therapy (Symbicort) SMART, AstraZeneca, Sweden) has been approved for adults in the European Union. This option is well tolerated and offers greater reductions in asthma exacerbations together with similar improvements in daily symptom control, at a lower overall steroid load, compared with fixed-dose ICS/LABA plus SABA. METHODS: Two large clinical trials investigated the use of budesonide/formoterol as maintenance and reliever compared with medium or high doses of an ICS/LABA combination as controller plus SABA as reliever in adults (aged >or= 18 years). COMPASS was a 6-month, double-blind, randomized trial, while COSMOS was a 1-year, dose titration study which reflected routine clinical practice. RESULTS: Among adults, the studies confirmed a 21-39% reduction in severe exacerbations in patients treated with budesonide/formoterol maintenance and reliever therapy compared with titrated salmeterol/fluticasone plus SABA (COSMOS) or fixed higher budesonide/formoterol or salmeterol/fluticasone plus SABA (COMPASS), respectively. Similar levels of daily asthma control were achieved with budesonide/formoterol maintenance and reliever therapy at a significantly lower overall steroid load compared with salmeterol/fluticasone or budesonide/formoterol plus SABA. Budesonide/formoterol maintenance and reliever therapy was as well tolerated as combination therapies. CONCLUSION: In adult patients, budesonide/formoterol maintenance and reliever therapy is a safe and simplified approach to asthma management, using a single inhaler, which reduces severe exacerbations and maintains similar daily asthma control at a lower drug load compared with the traditional strategy of ICS/LABA plus SABA.     

Systematic Review of Tofacitinib: A New Drug for the Management of Rheumatoid Arthritis

Purpose

The goal of this study was to review and summarize the efficacy and safety of use of tofacitinib for treating rheumatoid arthritis (RA).

Methods

A systematic literature review was conducted to identify English-language articles published through May 2013 within PubMed, ClinicalTrials.gov, and Cochrane Library reporting results from Phase II and Phase III tofacitinib randomized clinical trials. Tofacitinib must have been used as monotherapy or in combination therapy with disease-modifying antirheumatic drugs (DMARDs) in the treatment of RA. Study outcomes had to include at least 1 of the following: American College of Rheumatology (ACR) 20%, 50%, or 70% response rates; tender/swollen joint count; health assessment questionnaire of disability; radiographic outcomes; and drug persistence.

Findings

Eight studies (4 Phase II and 4 Phase III trials) were included in the review. Patients with active RA and who were nonresponders to a biologic agent or the nonbiologic DMARD methotrexate were included in these studies. The results of the Phase II trials show that tofacitinib at doses ≥3 mg BID was efficacious among the nonresponders. The results of the Phase III trials, comparing tofacitinib 5 and 10 mg with placebo, show that tofacitinib led to a significant improvement in ACR20 response (P < 0.0001), Health Assessment Questionnaire–Disability Index (P < 0.0001) scores, and ACR50 response (P < 0.0001) after 3 months. The efficacy of tofacitinib was numerically similar to adalimumab. The most common adverse events were infections, infestations, increases in LDL-C and HDL-C levels, and a decrease in neutrophil counts.

Implications

Tofacitinib is an efficacious drug for the management of moderate to severe RA among patients with an inadequate response to methotrexate and tumor necrosis factor inhibitors. Long-term studies can help in understanding the risk/benefit profile of tofacitinib.     

Evaluation of hemostatic biomarker abnormalities that precede platelet count decline in critically ill patients with sepsis

Purpose

The hemostatic biomarkers for early diagnosis of sepsis-associated coagulopathy have not been identified. The purpose of this study was to evaluate hemostatic biomarker abnormalities preceding a decrease in platelet count, which is a surrogate indicator of overt coagulopathy in sepsis.

Materials and Methods

Seventy-five septic patients with a platelet count more than 80 × 10³/μL were retrospectively analyzed. Hemostatic biomarkers at intensive care unit admission were compared between patients with and patients without a subsequent decrease in platelet count (≥ 30% within 5 days), and the ability of biomarkers to predict a decrease in platelet count was evaluated.

Results

Forty-two patients (56.0%) developed a subsequent decrease in platelet count. Severity of illness, incidence of organ dysfunction, and 28-day mortality rate were higher in patients with a subsequent decrease in platelet count. There were significant differences between patients with and patients without a subsequent decrease in platelet count in prothrombin time–international normalized ratio, fibrinogen, thrombin-antithrombin complex, antithrombin, protein C (PC), plasminogen, and α₂-plasmin inhibitor (α₂-PI). Receiver operating characteristic curve analysis showed that PC (area under the curve, 0.869; 95% confidence interval, 0.699-0.951) and α₂-PI (area under the curve, 0.885; 95% confidence interval, 0.714-0.959) were strong predictors of a subsequent decrease in platelet count.

Conclusions

Decreased PC and α₂-PI activity preceded a decrease in platelet count in intensive care unit patients with sepsis.     

Managing Antithrombotic Therapy in Patients With Both Atrial Fibrillation and Coronary Heart Disease

Purpose

Atrial fibrillation (AF) and coronary heart disease (CHD) commonly occur together. Previous consensus guidelines were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y₁₂ antiplatelet agents. We examine recent evidence to guide management in 3 categories of patients with AF and CHD: patients with stable CHD, nonstented patients with recent acute coronary syndrome, and patients with a coronary stent requiring dual-antiplatelet therapy.

Methods

We conducted a literature search by evaluation of PubMed and other data sources including international meeting reports. We critically reviewed recent clinical trial and relevant registry evidence to update European and US consensus documents.

Findings

Oral anticoagulation with warfarin or NOACs is required to prevent embolic stroke in AF, and antiplatelet therapy is insufficient for this purpose. Antiplatelet therapy using monotherapy with aspirin is the standard of care in stable CHD. Dual-antiplatelet therapy with aspirin and clopidogrel or a new P2Y₁₂ inhibitor (dual-antiplatelet therapy) is needed to reduce coronary events after an acute coronary syndrome or after percutaneous coronary intervention. Combinations of these agents increase the risk of bleeding, and limited clinical trial evidence suggests that withdrawal of aspirin may reduce bleeding without increasing coronary events.

Implications

Available clinical trials and registries provide remarkably little evidence to guide difficult clinical decision making in patients with combined AF and CHD. In patients on triple antithrombotic therapy with vitamin K antagonists, aspirin, and clopidogrel, a single clinical trial indicates that withdrawal of aspirin may reduce bleeding risk without increasing the risk of coronary thrombosis. It is unclear whether this evidence applies to combinations of NOACs and newer P2Y₁₂ inhibitors. Clinical trials of combinations of the newer antithrombotic agents are urgently needed to guide clinical care.     

Maximal Cardiorespiratory Fitness Testing in Individuals With Chronic Stroke With Cognitive Impairment: Practice Test Effects and Test-Retest Reliability

Objectives

To evaluate, for individuals with chronic stroke with cognitive impairment, (1) the effects of a practice test on peak cardiorespiratory fitness test results; (2) cardiorespiratory fitness test-retest reliability; and (3) the relationship between individual practice test effects and cognitive impairment.

Design

Cross-sectional.

Setting

Rehabilitation center.

Participants

A convenience sample of 21 persons (men [n=12] and women [n=9]; age range, 48–81y; 44.9±36.2mo poststroke) with cognitive impairments who had sufficient lower limb function to perform the test.

Interventions

Not applicable.

Main Outcome Measure

Peak oxygen consumption (Vo₂peak, ml·kg⁻¹·min⁻¹).

Results

Test-retest reliability of Vo₂peak was excellent (intraclass correlation coefficient model 2,1 [ICC_2,1]=.94; 95% confidence interval [CI], .86–.98). A paired t test showed that there was no significant difference for the group for Vo₂peak obtained from 2 symptom-limited cardiorespiratory fitness tests performed 1 week apart on a semirecumbent cycle ergometer (test 2–test 1 difference, −.32ml·kg⁻¹·min⁻¹; 95% CI, −.69 to 1.33ml·kg⁻¹·min⁻¹; P=.512). Individual test-retest differences in Vo₂peak were, however, positively related to general cognitive function as measured by the Mini-Mental State Examination (ρ=.485; P<.026).

Conclusions

Vo₂peak can be reliably measured in this group without a practice test. General cognitive function, however, may influence the effect of a practice test in that those with lower general cognitive function appear to respond differently to a practice test than those with higher cognitive function.