QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chroni... more QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease (COPD). It combines indacaterol (a longacting β2-agonist) with glycopyrronium (a longacting muscarinic antagonist) as a dual bronchodilator. We aimed to compare the efficacy, safety, and tolerability of QVA149 versus salmeterol-fluticasone (SFC) over 26 weeks in patients with moderate-to-severe COPD. In this multicentre double-blind, double-dummy, parallel-group study, 523 patients (age 40 years or older, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages II-III, without exacerbations in the previous year) were randomly assigned (1:1; via automated, interactive response technology and stratified for smoking status) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks. Efficacy was assessed in the full analysis set (randomised patients who received at least one dose of study drug); safety was assessed in all patients wh...
In patients with severe asthma, tiotropium improves lung function and exacerbation risk when adde... more In patients with severe asthma, tiotropium improves lung function and exacerbation risk when added to high-dose inhaled corticosteroids plus long-acting β2 agonists. We aimed to assess the safety and efficacy of tiotropium in patients with moderate asthma who were symptomatic despite treatment with medium-dose inhaled corticosteroids. We did two 24-week, replicate, randomised, double-blind, placebo-controlled, parallel-group, active-comparator trials at 233 sites in 14 countries. Eligible patients were aged 18-75 years with symptomatic asthma and a pre-bronchodilator forced expiratory volume in 1 s (FEV1) of 60-90% predicted despite use of medium-dose inhaled corticosteroids, and had never smoked or were ex-smokers for 1 year or more with 10 pack-years or less. Patients were randomly assigned (1:1:1:1), with computer-generated pseudorandom numbers, to receive once-daily tiotropium 5 μg or 2·5 μg, twice-daily salmeterol 50 μg, or placebo, while maintaining inhaled corticosteroids. Pa...
Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled cort... more Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting β2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and conve...
International journal of chronic obstructive pulmonary disease, 2010
Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 microg versu... more Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 microg versus placebo, inhaled via the Respimat Soft Mist Inhaler (SMI). The two studies were combined and had 4 co-primary endpoints (trough FEV(1) response, Mahler Transition Dyspnea Index [TDI] and St George's Respiratory Questionnaire scores all at week 48, and COPD exacerbations per patient-year). A total of 1990 patients with COPD participated (mean FEV(1): 1.09 L). The mean trough FEV(1) response of tiotropium 5 or 10 microg relative to placebo was 127 or 150 mL, respectively (both P < 0.0001). The COPD exacerbation rate was significantly lower with tiotropium 5 microg (RR = 0.78; P = 0.002) and tiotropium 10 microg (RR = 0.73; P = 0.0008); the health-related quality of life and Mahler TDI co-primary endpoints were significantly improved with both doses (both P < 0.0001). Adverse events were generally balanced except anticholinergic class effects, which were more frequent with activ...
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010
An antiretroviral treatment (ART) service in Gugulethu township, Cape Town, South Africa. To asse... more An antiretroviral treatment (ART) service in Gugulethu township, Cape Town, South Africa. To assess the inter-observer agreement when using the chest radiographic reading and reporting system (CRRS) to detect radiographic abnormalities in patients with advanced human immunodeficiency virus (HIV) associated immunodeficiency being actively screened for tuberculosis (TB). Second, to assess the associated performance characteristics of radiology as a routine screening test for detection of culture-confirmed pulmonary TB. Radiographs from a study in which patients were actively screened for TB just before starting ART were independently reported by two CRRS-certified readers blinded to clinical status. Good kappa statistic agreements between observers were found when reporting any radiological abnormality consistent with TB among all patients (n = 203, kappa = 0.63, 95%CI 0.52-0.73) and among those with culture-confirmed TB (n = 53, kappa = 0.61, 95%CI 0.40-0.83). However, in comparison ...
To investigate the relative efficacy of ciclesonide and fluticasone propionate (FP) administered ... more To investigate the relative efficacy of ciclesonide and fluticasone propionate (FP) administered at comparable microgram doses in maintaining asthma control in patients with moderate-to-severe persistent asthma. This randomized, open-label, parallel-group study enrolled patients aged 12-75 years with a 6-month history of bronchial asthma. To enter a 2-week run-in period, patients had to have received FP 500-1000 microg/day or equivalent at a stable dose for 4 weeks and have a forced expiratory volume in 1s (FEV 1) 80% of predicted. To enter the treatment period, patients had to have the following during run-in: FEV 1 80% of predicted; reversibility of Delta FEV 1 12% after 200-400 microg salbutamol; and 1 day without asthma symptoms during the last 7 days. Patients were randomized to twice-daily ciclesonide 320 microg (ex-actuator) or twice-daily FP 330 microg (ex-actuator) for 6 months. Efficacy was assessed by lung function, asthma exacerbations, asthma symptoms and rescue medicat...
The Journal of allergy and clinical immunology, 2006
Asthma control is the goal of treatment, but little data exist to support treatment strategies fo... more Asthma control is the goal of treatment, but little data exist to support treatment strategies for stepping down treatment once control has been achieved. We assessed whether either the long-acting beta2-agonist or corticosteroid could be reduced without loss of asthma control once control had been attained with fluticasone propionate/salmeterol (FSC). After 12 weeks of open-label treatment with FSC 250/50 microg twice daily, patients whose asthma was well controlled were randomized to FSC 100/50 microg twice daily or fluticasone propionate (FP) 250 microg twice daily. for 12 weeks. The primary endpoint was mean morning peak expiratory flow over the randomized study period. Secondary endpoints included symptom scores, rescue albuterol use, and asthma control. During open-label treatment, improvements from baseline were seen, and 435 of 641 patients (68%) achieved well controlled status during each of the last 4 weeks of this period. A total of 246 patients received FSC 100/50 microg...
To compare the efficacy and safety of budesonide/formoterol (Symbicort) with formoterol (Oxis) in... more To compare the efficacy and safety of budesonide/formoterol (Symbicort) with formoterol (Oxis) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting beta2-agonist therapy. In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV1 40% of predicted normal) and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 microg), were randomized to receive either budesonide/formoterol (320/9 microg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 microg]) or formoterol (9 microg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 microg]). The primary efficacy variable was the average FEV1 from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV1 at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treat...
Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders, 1999
Immunosuppressives such as azathioprine are occasionally used in sarcoidosis where corticosteroid... more Immunosuppressives such as azathioprine are occasionally used in sarcoidosis where corticosteroids cannot be used because of poor response, contraindications or unacceptable side effects. The aim of this study was to assess the efficacy and safety of azathioprine in the treatment of pulmonary sarcoidosis. A retrospective study was performed on patients in the Respiratory Clinic of the university teaching hospital on all biopsy-proven sarcoid treated with azathioprine between 1969 and 1993 (n = 10). All had previously shown only partial (n = 6) or no (n = 4) response to high dose oral corticosteroids. Azathioprine in a dose of 100-150 mg was administered daily, while continuing a small dose of oral corticosteroid. Patients underwent regular clinical evaluation, pulmonary function testing and chest radiography. In one patient the course was too brief to evaluate (26 days). Two patients had significant and sustained improvement in lung function (vital capacity increasing from 72% to 89...
GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MA... more GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MABA) properties. This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14. MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only. GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.
The 7-item Asthma Control Questionnaire (ACQ) has been validated to measure the goals of asthma m... more The 7-item Asthma Control Questionnaire (ACQ) has been validated to measure the goals of asthma management as defined by international guidelines (minimisation of day- and night-time symptoms, activity limitation, beta(2)-agonist use and bronchoconstriction). Responses are given on a 7-point scale and the overall score is the mean of the responses (0=totally controlled, 6=severely uncontrolled). The aim of this analysis was to determine the cut-point on the ACQ that best differentiates between 'well-controlled' and 'not well-controlled' for (a) clinical practice (low risk of missing 'not well-controlled') and (b) clinical trials (low risk of including 'well-controlled'). All 1323 patients who provided data sets at week 12 in the Gaining Optimal Asthma Control (GOAL) clinical trial were included in the analysis. The gold standard for 'well-controlled' was a composite based on the GINA/NIH guidelines and derived from data collected in the clinic...
Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a... more Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma. We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12-75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (3·0 mg/kg) or placebo every 4 w...
International journal of chronic obstructive pulmonary disease, 2011
Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) ... more Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) patients after administration of some aqueous inhalation solutions. We investigated the incidence of this event during long-term clinical trials of tiotropium delivered via Respimat(®) Soft Mist™ Inhaler (SMI). We retrospectively analyzed pooled data from two identical Phase III clinical trials, in which 1990 patients with COPD received 48 weeks' treatment with once-daily tiotropium (5 or 10 μg) or placebo inhaled via Respimat(®) SMI. We recorded the incidence of bronchospasm and of a range of respiratory events that could suggest bronchoconstriction during the first 30 minutes after inhalation of study treatment on each of the eight test days. No patients reported bronchospasm. Six patients (0.3%) reported a combination of at least two events suggestive of bronchoconstriction, and 21 (1.1%) reported either rescue medication use or a respiratory adverse event. Asymptomatic falls in f...
The frequency and impact of exacerbations identified using healthcare resource utilisation (HCRU)... more The frequency and impact of exacerbations identified using healthcare resource utilisation (HCRU) or the EXAcerbations of Chronic pulmonary disease Tool (EXACT) were compared prospectively in a 24-week, phase III trial (ATTAIN). Patients with moderate-to-severe chronic obstructive pulmonary disease received twice-daily aclidinium 200 μg, aclidinium 400 μg or placebo. All HCRU events were reported to physicians. "EXACT-identified" events were categorised as "EXACT-reported" (detected by EXACT and reported to the physician) and "EXACT-unreported" (detected but not reported). Health status was measured using the St George's Respiratory Questionnaire (SGRQ). Annualised EXACT-identified event rates were higher in all study arms (placebo 1.39, aclidinium 200 μg 1.00 and aclidinium 400 μg 0.98 per patient per year) versus HCRU (placebo 0.60, aclidinium 200 μg 0.43 and aclidinium 400 μg 0.40 per patient per year). Concordance between methods was low (kappa ...
Cryptogenic fibrosing alveolitis (CFA) is a relatively uncommon condition with a variable prognos... more Cryptogenic fibrosing alveolitis (CFA) is a relatively uncommon condition with a variable prognosis and a mean survival of less than 5 years. The prediction of responsiveness to corticosteroid treatment is difficult, but is highly desirable because of the range of beneficial and harmful effects encountered with this treatment. This review of the clinical details of 42 patients with CFA managed at the Respiratory Clinic at Groote Schuur Hospital over the past decade highlights this difficulty, and draws attention to features which may be helpful in predicting response and prognosis. Although 53% of patients experienced symptomatic improvement or had an initial objective response to treatment, only 28% showed sustained improvement on lung function tests. The outcome and pattern of disease of patients in this study are very similar to those reported from other centres.
QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chroni... more QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease (COPD). It combines indacaterol (a longacting β2-agonist) with glycopyrronium (a longacting muscarinic antagonist) as a dual bronchodilator. We aimed to compare the efficacy, safety, and tolerability of QVA149 versus salmeterol-fluticasone (SFC) over 26 weeks in patients with moderate-to-severe COPD. In this multicentre double-blind, double-dummy, parallel-group study, 523 patients (age 40 years or older, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages II-III, without exacerbations in the previous year) were randomly assigned (1:1; via automated, interactive response technology and stratified for smoking status) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks. Efficacy was assessed in the full analysis set (randomised patients who received at least one dose of study drug); safety was assessed in all patients wh...
In patients with severe asthma, tiotropium improves lung function and exacerbation risk when adde... more In patients with severe asthma, tiotropium improves lung function and exacerbation risk when added to high-dose inhaled corticosteroids plus long-acting β2 agonists. We aimed to assess the safety and efficacy of tiotropium in patients with moderate asthma who were symptomatic despite treatment with medium-dose inhaled corticosteroids. We did two 24-week, replicate, randomised, double-blind, placebo-controlled, parallel-group, active-comparator trials at 233 sites in 14 countries. Eligible patients were aged 18-75 years with symptomatic asthma and a pre-bronchodilator forced expiratory volume in 1 s (FEV1) of 60-90% predicted despite use of medium-dose inhaled corticosteroids, and had never smoked or were ex-smokers for 1 year or more with 10 pack-years or less. Patients were randomly assigned (1:1:1:1), with computer-generated pseudorandom numbers, to receive once-daily tiotropium 5 μg or 2·5 μg, twice-daily salmeterol 50 μg, or placebo, while maintaining inhaled corticosteroids. Pa...
Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled cort... more Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting β2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and conve...
International journal of chronic obstructive pulmonary disease, 2010
Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 microg versu... more Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 microg versus placebo, inhaled via the Respimat Soft Mist Inhaler (SMI). The two studies were combined and had 4 co-primary endpoints (trough FEV(1) response, Mahler Transition Dyspnea Index [TDI] and St George's Respiratory Questionnaire scores all at week 48, and COPD exacerbations per patient-year). A total of 1990 patients with COPD participated (mean FEV(1): 1.09 L). The mean trough FEV(1) response of tiotropium 5 or 10 microg relative to placebo was 127 or 150 mL, respectively (both P < 0.0001). The COPD exacerbation rate was significantly lower with tiotropium 5 microg (RR = 0.78; P = 0.002) and tiotropium 10 microg (RR = 0.73; P = 0.0008); the health-related quality of life and Mahler TDI co-primary endpoints were significantly improved with both doses (both P < 0.0001). Adverse events were generally balanced except anticholinergic class effects, which were more frequent with activ...
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010
An antiretroviral treatment (ART) service in Gugulethu township, Cape Town, South Africa. To asse... more An antiretroviral treatment (ART) service in Gugulethu township, Cape Town, South Africa. To assess the inter-observer agreement when using the chest radiographic reading and reporting system (CRRS) to detect radiographic abnormalities in patients with advanced human immunodeficiency virus (HIV) associated immunodeficiency being actively screened for tuberculosis (TB). Second, to assess the associated performance characteristics of radiology as a routine screening test for detection of culture-confirmed pulmonary TB. Radiographs from a study in which patients were actively screened for TB just before starting ART were independently reported by two CRRS-certified readers blinded to clinical status. Good kappa statistic agreements between observers were found when reporting any radiological abnormality consistent with TB among all patients (n = 203, kappa = 0.63, 95%CI 0.52-0.73) and among those with culture-confirmed TB (n = 53, kappa = 0.61, 95%CI 0.40-0.83). However, in comparison ...
To investigate the relative efficacy of ciclesonide and fluticasone propionate (FP) administered ... more To investigate the relative efficacy of ciclesonide and fluticasone propionate (FP) administered at comparable microgram doses in maintaining asthma control in patients with moderate-to-severe persistent asthma. This randomized, open-label, parallel-group study enrolled patients aged 12-75 years with a 6-month history of bronchial asthma. To enter a 2-week run-in period, patients had to have received FP 500-1000 microg/day or equivalent at a stable dose for 4 weeks and have a forced expiratory volume in 1s (FEV 1) 80% of predicted. To enter the treatment period, patients had to have the following during run-in: FEV 1 80% of predicted; reversibility of Delta FEV 1 12% after 200-400 microg salbutamol; and 1 day without asthma symptoms during the last 7 days. Patients were randomized to twice-daily ciclesonide 320 microg (ex-actuator) or twice-daily FP 330 microg (ex-actuator) for 6 months. Efficacy was assessed by lung function, asthma exacerbations, asthma symptoms and rescue medicat...
The Journal of allergy and clinical immunology, 2006
Asthma control is the goal of treatment, but little data exist to support treatment strategies fo... more Asthma control is the goal of treatment, but little data exist to support treatment strategies for stepping down treatment once control has been achieved. We assessed whether either the long-acting beta2-agonist or corticosteroid could be reduced without loss of asthma control once control had been attained with fluticasone propionate/salmeterol (FSC). After 12 weeks of open-label treatment with FSC 250/50 microg twice daily, patients whose asthma was well controlled were randomized to FSC 100/50 microg twice daily or fluticasone propionate (FP) 250 microg twice daily. for 12 weeks. The primary endpoint was mean morning peak expiratory flow over the randomized study period. Secondary endpoints included symptom scores, rescue albuterol use, and asthma control. During open-label treatment, improvements from baseline were seen, and 435 of 641 patients (68%) achieved well controlled status during each of the last 4 weeks of this period. A total of 246 patients received FSC 100/50 microg...
To compare the efficacy and safety of budesonide/formoterol (Symbicort) with formoterol (Oxis) in... more To compare the efficacy and safety of budesonide/formoterol (Symbicort) with formoterol (Oxis) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting beta2-agonist therapy. In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV1 40% of predicted normal) and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 microg), were randomized to receive either budesonide/formoterol (320/9 microg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 microg]) or formoterol (9 microg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 microg]). The primary efficacy variable was the average FEV1 from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV1 at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treat...
Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders, 1999
Immunosuppressives such as azathioprine are occasionally used in sarcoidosis where corticosteroid... more Immunosuppressives such as azathioprine are occasionally used in sarcoidosis where corticosteroids cannot be used because of poor response, contraindications or unacceptable side effects. The aim of this study was to assess the efficacy and safety of azathioprine in the treatment of pulmonary sarcoidosis. A retrospective study was performed on patients in the Respiratory Clinic of the university teaching hospital on all biopsy-proven sarcoid treated with azathioprine between 1969 and 1993 (n = 10). All had previously shown only partial (n = 6) or no (n = 4) response to high dose oral corticosteroids. Azathioprine in a dose of 100-150 mg was administered daily, while continuing a small dose of oral corticosteroid. Patients underwent regular clinical evaluation, pulmonary function testing and chest radiography. In one patient the course was too brief to evaluate (26 days). Two patients had significant and sustained improvement in lung function (vital capacity increasing from 72% to 89...
GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MA... more GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MABA) properties. This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14. MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only. GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.
The 7-item Asthma Control Questionnaire (ACQ) has been validated to measure the goals of asthma m... more The 7-item Asthma Control Questionnaire (ACQ) has been validated to measure the goals of asthma management as defined by international guidelines (minimisation of day- and night-time symptoms, activity limitation, beta(2)-agonist use and bronchoconstriction). Responses are given on a 7-point scale and the overall score is the mean of the responses (0=totally controlled, 6=severely uncontrolled). The aim of this analysis was to determine the cut-point on the ACQ that best differentiates between 'well-controlled' and 'not well-controlled' for (a) clinical practice (low risk of missing 'not well-controlled') and (b) clinical trials (low risk of including 'well-controlled'). All 1323 patients who provided data sets at week 12 in the Gaining Optimal Asthma Control (GOAL) clinical trial were included in the analysis. The gold standard for 'well-controlled' was a composite based on the GINA/NIH guidelines and derived from data collected in the clinic...
Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a... more Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma. We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12-75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (3·0 mg/kg) or placebo every 4 w...
International journal of chronic obstructive pulmonary disease, 2011
Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) ... more Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) patients after administration of some aqueous inhalation solutions. We investigated the incidence of this event during long-term clinical trials of tiotropium delivered via Respimat(®) Soft Mist™ Inhaler (SMI). We retrospectively analyzed pooled data from two identical Phase III clinical trials, in which 1990 patients with COPD received 48 weeks' treatment with once-daily tiotropium (5 or 10 μg) or placebo inhaled via Respimat(®) SMI. We recorded the incidence of bronchospasm and of a range of respiratory events that could suggest bronchoconstriction during the first 30 minutes after inhalation of study treatment on each of the eight test days. No patients reported bronchospasm. Six patients (0.3%) reported a combination of at least two events suggestive of bronchoconstriction, and 21 (1.1%) reported either rescue medication use or a respiratory adverse event. Asymptomatic falls in f...
The frequency and impact of exacerbations identified using healthcare resource utilisation (HCRU)... more The frequency and impact of exacerbations identified using healthcare resource utilisation (HCRU) or the EXAcerbations of Chronic pulmonary disease Tool (EXACT) were compared prospectively in a 24-week, phase III trial (ATTAIN). Patients with moderate-to-severe chronic obstructive pulmonary disease received twice-daily aclidinium 200 μg, aclidinium 400 μg or placebo. All HCRU events were reported to physicians. "EXACT-identified" events were categorised as "EXACT-reported" (detected by EXACT and reported to the physician) and "EXACT-unreported" (detected but not reported). Health status was measured using the St George's Respiratory Questionnaire (SGRQ). Annualised EXACT-identified event rates were higher in all study arms (placebo 1.39, aclidinium 200 μg 1.00 and aclidinium 400 μg 0.98 per patient per year) versus HCRU (placebo 0.60, aclidinium 200 μg 0.43 and aclidinium 400 μg 0.40 per patient per year). Concordance between methods was low (kappa ...
Cryptogenic fibrosing alveolitis (CFA) is a relatively uncommon condition with a variable prognos... more Cryptogenic fibrosing alveolitis (CFA) is a relatively uncommon condition with a variable prognosis and a mean survival of less than 5 years. The prediction of responsiveness to corticosteroid treatment is difficult, but is highly desirable because of the range of beneficial and harmful effects encountered with this treatment. This review of the clinical details of 42 patients with CFA managed at the Respiratory Clinic at Groote Schuur Hospital over the past decade highlights this difficulty, and draws attention to features which may be helpful in predicting response and prognosis. Although 53% of patients experienced symptomatic improvement or had an initial objective response to treatment, only 28% showed sustained improvement on lung function tests. The outcome and pattern of disease of patients in this study are very similar to those reported from other centres.
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