The use of plethysmography and oscillometry to compare long-acting bronchodilators in patients with COPD.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Forced expiratory volume in 1 s (FEV(1)) is the standard measurement used to measure drug effects in chronic obstructive pulmonary disease (COPD) clinical trials. Having previously shown that specific airway conductance (sGaw) measured using body plethysmography and impulse oscillometry (IOS) are more sensitive than FEV(1) for assessing short-acting bronchodilator effects in patients with COPD, we conducted the first randomized, placebo-controlled study to compare long-acting bronchodilators in COPD patients using these techniques. WHAT THIS STUDY ADDS: sGaw and IOS sensitively differentiated between the effects of tiotropium and salmeterol when FEV(1) measurements were similar. sGaw and IOS measurements are better than FEV(1) for sensitively assessing bronchodilator pharmacology and differentiating between treatments in COPD clinical trials. AIMS: Assessment of bronchodilator pharmacology in chronic obstructive pulmonary disease (COPD) may be improved by using more sensitive methods than spirometry, such as impulse oscillometry (IOS) and body plethysmography. We sought to compare salmeterol (S) and tiotropium (Tio) using these methods. METHODS: In this double-blind, randomized, four-way crossover study, 32 COPD patients received single doses of Tio (18 microg), S (50 and 100 microg) or placebo. Specific airway conductance (sGaw), forced expiratory volume in 1 s (FEV(1)) and IOS were measured pre- and up to 26 h postdose. Comparisons between treatments were analysed by weighted means (WM) between 0 and 12 (WM 0-12 h) and 12-24 h (WM 12-24 h) postdose. Data are expressed as mean difference (or geometric ratio for nonparametric data) with 95% confidence intervals. RESULTS: Tio and S100 significantly improved FEV(1), sGaw and IOS parameters up to 26 h and S50 up to 16 h. WM analysis showed no difference between Tio and S100 in FEV(1) for 0-12 h or 12-24 h. Maximum mid-expiratory flow (-0.06; -0.11, -0.01) and R35 (0.02; 0.01, 0.03) demonstrated superiority of S100 compared with Tio for WM 0-12 h sGaw (1.12; 1.02, 1.23), R5 (-0.06; -0.09, -0.02), R15 (-0.03; -0.05, -0.01), and resonant frequency (RF) (-2.30; -3.83, -0.77) showed superiority of Tio compared with S100 for WM 12-24 h. At 26 h, sGaw, R5, R15, X5 and RF also showed superiority of Tio compared with S100. CONCLUSIONS: sGaw and IOS parameters sensitively differentiated between the effects of Tio and S when FEV(1) measurements were similar. Clinical trials in patients with COPD should use IOS and sGaw to assess comprehensively bronchodilator pharmacology.

Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study.

BACKGROUND: Wheezing and asthma often begins in early childhood, but it is difficult to predict whether or not a wheezy infant will develop asthma. Some researchers suggest that treatment with inhaled corticosteroids at the first signs of wheezing in childhood could prevent the development of asthma later in life. However, other investigators have reported that although such treatment could help control symptoms, the benefits can disappear within months of stopping treatment. We tested our hypothesis that to prevent loss of lung function and worsening asthma later in childhood, anti-inflammatory treatment needs to be started early in life. METHODS: We did a randomised, double-blind, controlled study of inhaled fluticasone propionate 100 mug twice daily in young children who were followed prospectively and randomised after either one prolonged (>1 month) or two medically confirmed wheezy episodes. The dose of study drug was reduced every 3 months to the minimum needed. If the symptoms were not under control by 3 months, open-label fluticasone propionate 100 mug twice daily was added to the treatment. Children were followed-up to 5 years of age, at which point we gave their parents or guardians questionnaires, and measured the children's lung function (specific airways resistance [sR(aw)], forced expiratory volume in 1s [FEV1]) and airway reactivity (eucapnic voluntary hyperventilation [EVH] challenge). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN86717853. FINDINGS: We followed 1073 children prospectively, of whom 333 were eligible, and 200 of these began treatment (130 male, median age 1.2 years [range 0.5-4.9]; 101 placebo, 99 treatment); 173 (85 treatment, 88 placebo) completed the follow-up at age five years. The groups did not differ significantly in the proportion of children with current wheeze, physician-diagnosed asthma or use of asthma medication, lung function, or airway reactivity (percentage change in FEV1, adjusted mean for placebo 5.5% [95% CI -2.5 to 13.4]) vs for treatment 5.0% [-2.2 to 12.2], p=0.87). There were no differences in the results after adjustment for open-label fluticasone propionate, nor between the two groups in the time before the open-label drug was added (estimated hazard ratio 1.12 [95% CI 0.73-1.73], p=0.60), or the proportion needing the open-label drug (43 [42.57%] placebo, 41 [41.41%] treatment). INTERPRETATION: The early use of inhaled fluticasone propionate for wheezing in preschool children had no effect on the natural history of asthma or wheeze later in childhood, and did not prevent lung function decline or reduce airway reactivity.

Comparison of the effects of salmeterol/fluticasone propionate with fluticasone propionate on airway physiology in adults with mild persistent asthma.

BACKGROUND: This study compared the effect of inhaled fluticasone propionate (FP) with the combination of salmeterol/fluticasone propionate (SFC) on lung function parameters in patients with mild asthma. METHODS: Adult patients with mild persistent asthma (> or = 80% predicted FEV1) receiving 200-500 mug of BDP or equivalent were randomised to receive either FP 100 mug or SFC 50/100 mug twice daily from a Diskus inhaler for four weeks. The primary outcome was the change from baseline in airway resistance (sRaw) at 12 hrs post dose measured by whole body plethysmography. Impulse oscillometry and spirometry were also performed. RESULTS: A comparison of the geometric mean sRaw at 12 hrs post dose in the SFC group to the FP group gave a ratio of 0.76 (0.66 - 0.89, p < 0.001) at week 2 and 0.81 (0.71 - 0.94, p = 0.006) at week 4. Similarly, significant results in favour of SFC for oscillometry measurements of resistance and reactance were observed. FEV1 was also significantly superior at week 2 in the SFC group (mean difference 0.16L, 95% CI; 0.03 - 0.28, p = 0.015), but not at week 4 (mean difference 0.17L, 95% CI -0.01 - 0.34, p = 0.060). CONCLUSION: SFC is superior to FP in reducing airway resistance in mild asthmatics with near normal FEV1 values. This study provides evidence that changes in pulmonary function in patients with mild asthma are detected more sensitively by plethysmography compared to spirometry TRIAL REGISTRATION NUMBER: NCT00370591.

The effect of reducing the fine-particle mass of salmeterol from metered-dose inhalers on bronchodilatation and bronchoprotection against methacholine challenge: a randomized, placebo-controlled, double-blind, crossover study.

OBJECTIVE: This study examined the clinical relevance of fine-particle mass (FPM) delivered from metered dose inhalers (MDIs) to bronchodilatation and bronchoprotection against methacholine challenge by comparing a marketed chlorofluorocarbon (CFC) formulation of salmeterol with an investigational hydrofluoroalkane (HFA)formulation. METHODS: This was a randomized, double-blind, placebo-controlled, 3-way crossover study in patients with mild to moderate asthma who had a forced expiratory volume in 1 second (FEV (1)) of > or =60% predicted and a base-line provocation dose of inhaled methacholine required to produce a 20% decrease in FEV(1) (PD (20) [methacholine]) of < or =3.2 mg. On separate occasions, patients received 2 inhalations of salmeterol 25 microg from either the CFC MDI (FPM 14 microg), the investigational HFA MDI (FPM 7 microg), or placebo via CFC MDI. Serial measurements of FEV(1) were made over 90 minutes after dosing, followed by methacholine challenge. Efficacy end points were PD(20) (methacholine) and FEV(1) AUC (inc) (incremental area under the FEV(1) curve) over 15 to 90 minutes. The study was designed to demonstrate non-inferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness; for PD(20) (methacholine), noninferiority was predefined as 1.0 doubling dose of methacholine. RESULTS: The study enrolled 40 patients (65% men; mean age, 36.9 years). Both active treatments were significantly better than placebo in terms of PD(20) (methacholine) (P < 0.001). In the per-protocol population, the mean (SE) difference in bronchoprotection between the CFC MDI and placebo was 2.7888 (0.3432) doubling doses of methacholine (n = 32), and the difference between the investigational HFA MDI and placebo was 1.8268 (0.3418) doubling doses(n = 33). The adjusted mean (SE) treatment difference between the CFC MDI and HFA MDI was 0.9621 (0.3454) doubling doses. The upperlimit of the 95% CI (0.2714-1.6527) was greater than the predefined limit for noninferiority. There was no significant difference in FEV(1) AUC(inc) between formulations (mean treatment difference, 1.895 L . min; 95% CI, -4.893 to 8.684); however, both active treatments were significantly different from placebo (P < 0.001). CONCLUSIONS: FPM from different MDI formulations may affect the bronchoprotective properties of salmeterol. In this study, the formulation with the smaller FPM was associated with less-effective bronchoprotection, although there was no difference in bronchodilatation. This study did not demonstrate noninferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness.

Fluticasone propionate via the Diskhaler or hydrofluoroalkane-134a metered-dose inhaler on methacholine-induced airway hyperresponsiveness.

STUDY OBJECTIVE: s: To compare the effect of 4 weeks of treatment with fluticasone propionate (FP), 100 micro g bid, delivered either via the Diskhaler (GlaxoSmithKline; Middlesex, UK) or a hydrofluoroalkane (HFA)-134a pressurized metered-dose inhaler (pMDI) on airway responsiveness. DESIGN: A single-center, randomized, double-blind, double-dummy, placebo-controlled crossover study. SETTING: Outpatients. PATIENTS: Patients with mild asthma who had not received corticosteroids for 4 weeks prior to the study. INTERVENTIONS: FP, 100 micro g bid, via the Diskhaler, HFA-134a pMDI, or placebo for periods of 4 weeks. MEASUREMENTS AND RESULTS: The primary efficacy variable was the provocative dose of methacholine causing a 20% fall in FEV(1) (PD(20)) at the end of each 4-week treatment period. The FP formulations were defined as equivalent if the treatment difference was within +/- 1 doubling dose of methacholine. Forty-seven patients were included in the per-protocol population. The baseline PD(20) geometric mean was 0.21 mg, which increased to 0.55 mg with FP via the HFA-134a pMDI and to 0.68 mg with FP via the Diskhaler. The treatment difference between adjusted means was - 0.16 doubling doses (95% confidence interval, - 0.62 to 0.31 doubling doses; p = 0.503). Both significantly decreased airway responsiveness compared to placebo (p < 0.001), and also significantly increased lung function with no difference between the two active groups. FP was well tolerated with few adverse events and no effect on serum cortisol levels. CONCLUSIONS: FP delivered via the HFA-134a pMDI is equivalent to FP via the Diskhaler in reducing airway responsiveness.

A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.

BACKGROUND: Tiotropium, a once-daily anticholinergic, and salmeterol represent two inhaled, long-acting bronchodilators from different pharmacologic classes. A trial was designed to examine the efficacy and safety of both compounds with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD. METHODS: A 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group study of tiotropium, 18 microg once daily via dry-powder inhaler, compared with salmeterol, 50 microg bid via metered-dose inhaler, was conducted in patients with COPD. Efficacy was assessed by 12-h monitoring of spirometry, transition dyspnea index (TDI), and the St. George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 623 patients participated (tiotropium, n= 209; salmeterol, n = 213; and placebo, n = 201). The groups were similar in age (mean, 65 years), gender (75% men), and baseline FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted, 40 +/- 12% [+/- SD]). Compared with placebo treatment, the mean predose morning FEV(1) following 6 months of therapy increased significantly more for the tiotropium group (0.14 L) than the salmeterol group (0.09 L; p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium was statistically superior to salmeterol (difference, 0.08 L; p < 0.001). Tiotropium improved TDI focal score by 1.02 U compared with placebo (p = 0.01), whereas there was no significant change in TDI focal score with salmeterol (0.24 U). Tiotropium was superior to salmeterol in improving TDI focal score (p < 0.05). At 6 months, the mean improvement in SGRQ total score vs baseline was tiotropium, - 5.14 U (p < 0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs placebo); and placebo, - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo. Both active drugs reduced the need for rescue albuterol (p < 0.0001). CONCLUSIONS: Tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD.

Long-term effects of allergen sensitization and exposure in adult asthma: a prospective study.

BACKGROUND: : We investigated the effects of sensitization and exposure to common domestic allergens on longitudinal changes in lung function and bronchial hyperresponsiveness. METHODS: : Subjects attended 2 visits that were 4 years apart. Skin prick testing was performed and household dust samples were collected for quantification of mite, dog, and cat allergens at baseline. Measurements of lung function, exhaled nitric oxide, and bronchial hyperresponsiveness were completed at both visits. RESULTS: : Dust samples were collected in 165 of the 200 subjects completing both visits. Mean length of follow-up was 47 months. Bronchial hyperresponsiveness, measured at both visits in 86 subjects, deteriorated in those exposed to high mite allergen levels compared with those not exposed [mean (95% CI) doubling dose change PD20 = -0.44 (-1.07 to 0.19) vs 0.82 (0.27 to 1.36)], but improved in those exposed to high dog allergen levels compared with those not exposed [1.10 (0.33 to 1.86) vs 0.10 (-0.39 to 0.58)]. The associations were significant in the multivariate models. Cat allergen exposure was not associated with any changes in lung function, exhaled nitric oxide, or bronchial hyperresponsiveness. CONCLUSIONS: : In a 4-year prospective cohort of persons with asthma, exposure to high levels of dust mite allergens at baseline was associated with a subsequent increase in bronchial hyperresponsiveness.

Intranasal air sampling in homes: relationships among reservoir allergen concentrations and asthma severity.

BACKGROUND: The relationship among inhaled allergen exposure, sensitization, and asthma severity is unknown. OBJECTIVES: To investigate the relationship among personal allergen exposure, reservoir dust allergen concentrations, and physiological measures of asthma severity; to examine the numbers of particles inspired that react with autologous IgE and IgG4. METHODS: A total of 117 patients with asthma wore 5 nasal air samplers (NASs) at home: 1 each for exposure to mite, cat and dog allergens, NAS-IgE, and NAS-IgG4. NASs were processed by HALOgen assay for allergen measurement and incubated with autologous serum for detection of NAS-IgE and NAS-IgG4. Reservoir allergen concentrations were measured by ELISA. Subjects' asthma severity was ascertained by measurement of lung function, exhaled nitric oxide, and nonspecific bronchial reactivity to histamine. RESULTS: Nasal air sampler counts correlated with reservoir concentrations for cat (r=0.31; P=.001) and dog (r=0.20; P=.03) but not mite allergen (r=0.001; P=1.0). There was no significant relationship between sensitization with exposure measured by NAS to any allergen and PD20FEV1 (F[3,60]=1.60; P=.20); however, sensitization with exposure in dust reservoirs had significant effects on PD20FEV1 for any allergen (F[3,59]=3.12; P=.03), cat (F[3,59]=3.77; P=.01), and mite (F[3,59]=2.78; P=.05), but not dog (F[3,59]=1.06; P=.37). We repeated the analysis with separate variables for sensitization and exposure, controlling for the confounders; sensitization but not exposure conferred lower PD20FEV1 values. However, increasing cat allergen exposure was associated with improving bronchial reactivity in not cat-sensitized patients. NAS-IgE and NAS-IgG4 counts bore no relationship to any measure of asthma severity. CONCLUSION: Nasal air samplers confer no advantage over reservoir dust analysis for studies of asthma severity. CLINICAL IMPLICATIONS: In common with other measures of exposure, single nasal air samples do not provide a useful measure of home allergen exposure for the individual patient with allergic asthma.

Relationship among pulmonary function, bronchial reactivity, and exhaled nitric oxide in a large group of asthmatic patients.

BACKGROUND: Bronchial reactivity and exhaled nitric oxide (eNO) are not often used to monitor control and severity of asthma in clinical practice. OBJECTIVE: To evaluate the relationship among different physiologic measures (pulmonary function, nonspecific bronchial reactivity, and eNO) in asthmatic patients. METHODS: Cross-sectional, hospital-based study conducted in patients with varied asthma severity. RESULTS: A total of 392 patients participated in the study. There was no difference in eNO levels between patients taking inhaled corticosteroids (ICS group) and patients not receiving inhaled corticosteroids (NICS group). However, the percentage of predicted forced expiratory volume in 1 second (FEV1) and the provocative dose of methacholine causing a 20% decrease in FEV1 were significantly lower in the ICS group compared with the NICS group (mean, 83.2%; 95% confidence interval [CI], 80.4%-86.0%; vs mean, 94.1%; 95% CI, 91.1%-97.1%; P = .001; and geometric mean, 0.32 mg; 95% CI, 0.23-0.45 mg; vs geometric mean, 0.58 mg; 95% CI, 0.42-0.81 mg; P = .01; respectively). Patients with more severe bronchial hyperresponsiveness had a lower percentage of predicted FEV1 values (P < .001) and levels of eNO were significantly increased with increasing bronchial hyperresponsiveness (P < .001). There was no relationship between the percentage of predicted FEV1 and eNO. Atopic patients had significantly higher eNO levels than nonatopic patients (geometric mean, 11.21 ppb; 95% CI, 10.07-12.49 ppb; vs geometric mean, 7.76 ppb; 95% CI, 6.11-9.85 ppb; P = .006; respectively). CONCLUSIONS: eNO values are not related to the degree of airway obstruction but are related to airway reactivity and atopic status independent of inhaled corticosteroid use. Higher values of eNO are seen with increased airway reactivity.

Exposure and sensitization to indoor allergens: association with lung function, bronchial reactivity, and exhaled nitric oxide measures in asthma.

BACKGROUND: Exposure to high levels of allergens in sensitized asthmatic patients causes worsening of pulmonary function in experimental studies. Chronic exposure to lower, naturally occurring levels of allergens might increase the severity of asthma. OBJECTIVE: We sought to study the associations between sensitization and exposure to common indoor allergens (dust mite, cat, and dog) in the home on pulmonary function, exhaled nitric oxide (eNO), and airway reactivity in asthmatic patients. METHODS: Dust samples were collected from the living room carpet and mattress of 311 subject's homes, and Der p 1, Fel d 1, and Can f 1 concentrations were measured by using ELISAs. Spirometry, nonspecific bronchial reactivity, and eNO were measured. RESULTS: Subjects both sensitized and exposed to high levels of sensitizing allergen had significantly lower FEV(1) percent predicted values (mean, 83.7% vs 89.3%; mean difference, 5.6%; 95% CI, 0.6%-10.6%; P =.03), higher eNO values (geometric mean [GM], 12.8 vs 8.7 ppb; GM ratio, 0.7; 95% CI, 0.5-0.8; P =.001), and more severe airways reactivity (PD(20) GM, 0.25 vs 0.73 mg; GM ratio, 2.9; 95% CI, 1.6-5.0; P <.001) compared with subjects not sensitized and exposed. No significant effect of the interaction between sensitization and exposure was found for FEV(1) percent predicted and eNO values. However, there was a significant effect of the interaction between sensitization and exposure to any allergen (P =.05) and between sensitization and exposure to cat allergen (P =.04) for nonspecific bronchial reactivity. CONCLUSION: Asthmatic subjects who are exposed in their homes to allergens to which they are sensitized have a more severe form of the disease.

A comparison of the efficacy and tolerability of single doses of HFA 134a albuterol and CFC albuterol in mild-to-moderate asthmatic patients.

BACKGROUND: After the signing of the Montreal Protocol in 1987, new propellants for use in pressurized metered-dose inhalers that are non-ozone-depleting have been developed. OBJECTIVE: This study was designed to compare the efficacy and tolerability of single doses of albuterol/HFA 134a with albuterol/CFC and to demonstrate a dose-response among the different doses of both formulations. METHODS: A single-center, randomized, double-blind, placebo-controlled, cross-over study. Sixty-three adolescent and adult asthmatic patients were randomized to receive at separate treatment visits single doses via a pressurized metered-dose inhaler of either placebo/hydrofluoroalkane (HFA) 134a; 100 microg, 200 microg, or 400 microg albuterol/HFA 134a; 100 microg or 200 microg albuterol/chlorofluorocarbon (CFC). Triplicate measurements of forced expiratory volume in 1 second (FEV1) were made immediately before dosing and 15 minutes, 30 minutes, 1, 2, 3, 4, 5, and 6 hours postdose. The primary efficacy variables were area under the entire 6-hour FEV1 curve, relative to baseline subtracted from the area above baseline (AUC(0-6)) and peak effect (derived from serial FEV1 measurements). RESULTS: Analysis of AUC(0-6) and peak effect showed that all doses of albuterol had a significantly greater effect than placebo (HFA 134a propellant). Comparisons of the two formulations at 100 microg and 200 microg showed no difference in AUC(0-6) (100 microg, -0.23 Lhr, P = 0.114 and 200 microg -0.08 Lhr, P = 0.590) or in peak effect, percentage of baseline (100 microg, -1.3%, P = 0.354 and 200 microg, 0.17%, P = 0.902). There were no differences seen among formulations in the incidence of adverse events or with any of the other safety parameters, including electrocardiograms, vital signs, clinical laboratory assessments, and asthma exacerbations. CONCLUSIONS: The study demonstrated comparability in terms of efficacy and safety between albuterol/HFA 134a and albuterol/CFC.

Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study.

Antagonizing the effect of interleukin (IL)-5 is a potential new treatment strategy in allergic disorders. We evaluated the safety, biological activity, and pharmacokinetics of SCH55700, a humanized anti-human IL-5 antibody, in subjects with severe persistent asthma treated with oral or high doses of inhaled steroids. In a double-blind, randomized, multicenter trial, a rising single dose of SCH55700 (0.03 mg/kg [n = 2], 0.1 mg/kg [n = 4], 0.3 mg/kg [n = 6], or 1.0 mg/kg [n = 12]) or placebo (n = 8) was administered intravenously. SCH55700 dose dependently reduced circulating eosinophil counts. At a dose of 1.0 mg/kg, the decrease remained significant up to Day 30 [(0.07 +/- 0.01) x 10(9)/L versus (0.23 +/- 0.04) x 10(9)/L at baseline] (mean +/- SEM) (p = 0.05). After administration of SCH55700 at 0.3 and 1.0 mg/kg, a trend toward improvement in baseline FEV1 was observed, which reached significance 24 hours after the 0.3-mg/kg dose (p = 0.019 versus placebo). No significant changes occurred in other clinical indices of disease activity. Adverse events were not different between active treatment and placebo. We conclude that SCH55700 is a biologically active anti-human IL-5 antibody that can be safely used in severe steroid-treated asthma. Its therapeutic potential needs to be addressed in specifically designed efficacy trials.