European Respiratory Society (ERS): Annual Congress

LONDON – In chronic obstructive pulmonary disease (COPD), the advantage of a long-acting beta agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) over a LABA plus an inhaled corticosteroid (ICS) was observed in every subgroup in the FLAME trial evaluated, according to post hoc analyses presented at the annual congress of the European Respiratory Society.

“We thought that we might not see the difference in the COPD patients with more severe disease, but the advantage was consistent even among those who entered the trial on triple therapy,” reported Jadwiga A. Wedzicha, MD, professor of respiratory medicine at the National Heart and Lung Institute, Imperial College, London.

FLAME, the recently published study that compared LABA/LAMA to LABA/ICS, was planned as a noninferiority study with the underlying hypothesis that LABA/LAMA would perform as well as LABA/ICS for the primary outcome of annual rate of COPD exacerbations (N Engl J Med. 2016;374:2222-34). Instead, the 11% lower rate of exacerbations for LABA/LAMA proved statistically significant (P = .003).

Six post hoc FLAME analyses were presented at the 2016 ERS Congress to further explore this result. All supported the main result. In addition to evaluating those who entered the trial on a LABA/LAMA/ICS triple-therapy combination, the analyses covered a broad array of subgroups defined by age, smoking history, and COPD severity as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifications.

In FLAME, 3,362 COPD patients who had at least one exacerbation in the preceding year were randomized to the LABA indacaterol (110 mcg) plus the LAMA glycopyrronium (50 mcg) once daily or the combination of the LABA salmeterol (50 mcg) and the ICS fluticasone (500 mcg) twice daily. In addition to the relative advantage on the primary outcome of any exacerbation, the LABA/LAMA combination also significantly reduced the rate of moderate to severe exacerbations (P less than .001), and it extended the times to the first moderate to severe exacerbation (P less than .001) and the first severe exacerbation (P = .046), according to the published data.

In the post hoc analyses, the advantage of LABA/LAMA relative to LAMA/ICS was remarkably consistent. For example, in stratifications made for age (less than 55 years, 55 to less than 65 years, 65-75 years, and greater than or equal to 75 years) at least a numerical advantage of LABA/LAMA was seen in all age groups for prevention of any exacerbation, and the difference reached statistical significance for those in the age group 55 to greater than 65 years. For prevention of moderate to severe exacerbations, the treatments were found to be equivalent for individuals younger than 55 years, but LABA/LAMA was statistically superior for the other three age categories.

For ex-smokers, unlike current smokers, the numerical advantage of LABA/LAMA over LABA/ICS for reduction in the rate ratio of all exacerbations did not reach statistical significance, but the LABA/LAMA combination did provide a statistically significant advantage for both ex-smokers and current smokers for moderate to severe exacerbations.

For patients with two or more exacerbations in the year prior to enrollment in FLAME, the relative degree of protection was of magnitude similar to that of patients with only one exacerbation even though the relative advantage in those with multiple prior exacerbations did not reach statistical significance. However, the lack of significance was likely due to the relatively small number of patients in this subpopulation, according to Dr. Wedzicha.

Similarly, the LABA/LAMA combination was at least numerically superior to LABA/ICS for all exacerbations and for moderate to severe exacerbations across GOLD classifications with one exception. When compared for relative protection against moderate to severe exacerbations, there was a slight and nonsignificant disadvantage for LABA/LAMA, but, again, Dr. Wedzicha reported, “the number of patients in this subgroup was quite small.”

In another FLAME post hoc analysis, the odds ratio (OR) for exacerbations among the 1,893 patients (56.3%) who were on ICS at study entry was found to be almost identical to the OR among those who were not. Specifically, the ORs for all exacerbations and moderate to severe exacerbations were 0.88 (P = .008) and 0.86 (P = .018), respectively, for those previously treated with ICS and 0.88 (P = .021) and 0.78 (P = .002), respectively, for those who had not been treated with ICS.

The LABA/LAMA combination was also superior to LABA/ICS for improvements in quality of life, which was measured via the St. George’s Respiratory Questionnaire. With an improvement of at least four units on the St. George’s Respiratory Questionnaire defined as clinically meaningful, 49.5% of LABA/LAMA patients versus 43.8% of LABA/ICS patients (P less than .024) benefited on this measure.

Overall, the results from the FLAME post hoc analyses have demonstrated “remarkable consistency,” Dr. Wedzicha reported. Taken together, she said the data “imply that LABA/LAMA is the first choice of treatment for COPD patients at risk of exacerbation.”

LONDON – In chronic obstructive pulmonary disease (COPD), the advantage of a long-acting beta agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) over a LABA plus an inhaled corticosteroid (ICS) was observed in every subgroup in the FLAME trial evaluated, according to post hoc analyses presented at the annual congress of the European Respiratory Society.

“We thought that we might not see the difference in the COPD patients with more severe disease, but the advantage was consistent even among those who entered the trial on triple therapy,” reported Jadwiga A. Wedzicha, MD, professor of respiratory medicine at the National Heart and Lung Institute, Imperial College, London.

FLAME, the recently published study that compared LABA/LAMA to LABA/ICS, was planned as a noninferiority study with the underlying hypothesis that LABA/LAMA would perform as well as LABA/ICS for the primary outcome of annual rate of COPD exacerbations (N Engl J Med. 2016;374:2222-34). Instead, the 11% lower rate of exacerbations for LABA/LAMA proved statistically significant (P = .003).

Six post hoc FLAME analyses were presented at the 2016 ERS Congress to further explore this result. All supported the main result. In addition to evaluating those who entered the trial on a LABA/LAMA/ICS triple-therapy combination, the analyses covered a broad array of subgroups defined by age, smoking history, and COPD severity as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifications.

In FLAME, 3,362 COPD patients who had at least one exacerbation in the preceding year were randomized to the LABA indacaterol (110 mcg) plus the LAMA glycopyrronium (50 mcg) once daily or the combination of the LABA salmeterol (50 mcg) and the ICS fluticasone (500 mcg) twice daily. In addition to the relative advantage on the primary outcome of any exacerbation, the LABA/LAMA combination also significantly reduced the rate of moderate to severe exacerbations (P less than .001), and it extended the times to the first moderate to severe exacerbation (P less than .001) and the first severe exacerbation (P = .046), according to the published data.

In the post hoc analyses, the advantage of LABA/LAMA relative to LAMA/ICS was remarkably consistent. For example, in stratifications made for age (less than 55 years, 55 to less than 65 years, 65-75 years, and greater than or equal to 75 years) at least a numerical advantage of LABA/LAMA was seen in all age groups for prevention of any exacerbation, and the difference reached statistical significance for those in the age group 55 to greater than 65 years. For prevention of moderate to severe exacerbations, the treatments were found to be equivalent for individuals younger than 55 years, but LABA/LAMA was statistically superior for the other three age categories.

For ex-smokers, unlike current smokers, the numerical advantage of LABA/LAMA over LABA/ICS for reduction in the rate ratio of all exacerbations did not reach statistical significance, but the LABA/LAMA combination did provide a statistically significant advantage for both ex-smokers and current smokers for moderate to severe exacerbations.

For patients with two or more exacerbations in the year prior to enrollment in FLAME, the relative degree of protection was of magnitude similar to that of patients with only one exacerbation even though the relative advantage in those with multiple prior exacerbations did not reach statistical significance. However, the lack of significance was likely due to the relatively small number of patients in this subpopulation, according to Dr. Wedzicha.

Similarly, the LABA/LAMA combination was at least numerically superior to LABA/ICS for all exacerbations and for moderate to severe exacerbations across GOLD classifications with one exception. When compared for relative protection against moderate to severe exacerbations, there was a slight and nonsignificant disadvantage for LABA/LAMA, but, again, Dr. Wedzicha reported, “the number of patients in this subgroup was quite small.”

In another FLAME post hoc analysis, the odds ratio (OR) for exacerbations among the 1,893 patients (56.3%) who were on ICS at study entry was found to be almost identical to the OR among those who were not. Specifically, the ORs for all exacerbations and moderate to severe exacerbations were 0.88 (P = .008) and 0.86 (P = .018), respectively, for those previously treated with ICS and 0.88 (P = .021) and 0.78 (P = .002), respectively, for those who had not been treated with ICS.

The LABA/LAMA combination was also superior to LABA/ICS for improvements in quality of life, which was measured via the St. George’s Respiratory Questionnaire. With an improvement of at least four units on the St. George’s Respiratory Questionnaire defined as clinically meaningful, 49.5% of LABA/LAMA patients versus 43.8% of LABA/ICS patients (P less than .024) benefited on this measure.

Overall, the results from the FLAME post hoc analyses have demonstrated “remarkable consistency,” Dr. Wedzicha reported. Taken together, she said the data “imply that LABA/LAMA is the first choice of treatment for COPD patients at risk of exacerbation.”

LONDON – In chronic obstructive pulmonary disease (COPD), the advantage of a long-acting beta agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) over a LABA plus an inhaled corticosteroid (ICS) was observed in every subgroup in the FLAME trial evaluated, according to post hoc analyses presented at the annual congress of the European Respiratory Society.

“We thought that we might not see the difference in the COPD patients with more severe disease, but the advantage was consistent even among those who entered the trial on triple therapy,” reported Jadwiga A. Wedzicha, MD, professor of respiratory medicine at the National Heart and Lung Institute, Imperial College, London.

FLAME, the recently published study that compared LABA/LAMA to LABA/ICS, was planned as a noninferiority study with the underlying hypothesis that LABA/LAMA would perform as well as LABA/ICS for the primary outcome of annual rate of COPD exacerbations (N Engl J Med. 2016;374:2222-34). Instead, the 11% lower rate of exacerbations for LABA/LAMA proved statistically significant (P = .003).

Six post hoc FLAME analyses were presented at the 2016 ERS Congress to further explore this result. All supported the main result. In addition to evaluating those who entered the trial on a LABA/LAMA/ICS triple-therapy combination, the analyses covered a broad array of subgroups defined by age, smoking history, and COPD severity as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifications.

In FLAME, 3,362 COPD patients who had at least one exacerbation in the preceding year were randomized to the LABA indacaterol (110 mcg) plus the LAMA glycopyrronium (50 mcg) once daily or the combination of the LABA salmeterol (50 mcg) and the ICS fluticasone (500 mcg) twice daily. In addition to the relative advantage on the primary outcome of any exacerbation, the LABA/LAMA combination also significantly reduced the rate of moderate to severe exacerbations (P less than .001), and it extended the times to the first moderate to severe exacerbation (P less than .001) and the first severe exacerbation (P = .046), according to the published data.

In the post hoc analyses, the advantage of LABA/LAMA relative to LAMA/ICS was remarkably consistent. For example, in stratifications made for age (less than 55 years, 55 to less than 65 years, 65-75 years, and greater than or equal to 75 years) at least a numerical advantage of LABA/LAMA was seen in all age groups for prevention of any exacerbation, and the difference reached statistical significance for those in the age group 55 to greater than 65 years. For prevention of moderate to severe exacerbations, the treatments were found to be equivalent for individuals younger than 55 years, but LABA/LAMA was statistically superior for the other three age categories.

For ex-smokers, unlike current smokers, the numerical advantage of LABA/LAMA over LABA/ICS for reduction in the rate ratio of all exacerbations did not reach statistical significance, but the LABA/LAMA combination did provide a statistically significant advantage for both ex-smokers and current smokers for moderate to severe exacerbations.

For patients with two or more exacerbations in the year prior to enrollment in FLAME, the relative degree of protection was of magnitude similar to that of patients with only one exacerbation even though the relative advantage in those with multiple prior exacerbations did not reach statistical significance. However, the lack of significance was likely due to the relatively small number of patients in this subpopulation, according to Dr. Wedzicha.

Similarly, the LABA/LAMA combination was at least numerically superior to LABA/ICS for all exacerbations and for moderate to severe exacerbations across GOLD classifications with one exception. When compared for relative protection against moderate to severe exacerbations, there was a slight and nonsignificant disadvantage for LABA/LAMA, but, again, Dr. Wedzicha reported, “the number of patients in this subgroup was quite small.”

In another FLAME post hoc analysis, the odds ratio (OR) for exacerbations among the 1,893 patients (56.3%) who were on ICS at study entry was found to be almost identical to the OR among those who were not. Specifically, the ORs for all exacerbations and moderate to severe exacerbations were 0.88 (P = .008) and 0.86 (P = .018), respectively, for those previously treated with ICS and 0.88 (P = .021) and 0.78 (P = .002), respectively, for those who had not been treated with ICS.

The LABA/LAMA combination was also superior to LABA/ICS for improvements in quality of life, which was measured via the St. George’s Respiratory Questionnaire. With an improvement of at least four units on the St. George’s Respiratory Questionnaire defined as clinically meaningful, 49.5% of LABA/LAMA patients versus 43.8% of LABA/ICS patients (P less than .024) benefited on this measure.

Overall, the results from the FLAME post hoc analyses have demonstrated “remarkable consistency,” Dr. Wedzicha reported. Taken together, she said the data “imply that LABA/LAMA is the first choice of treatment for COPD patients at risk of exacerbation.”

LONDON – Despite very promising activity in animal models of idiopathic pulmonary fibrosis (IPF), a monoclonal antibody targeted at an enzyme considered to be important to collagen cross-linking did not produce any improvement in progression-free survival (PFS), according to results of a multicenter study presented at the annual congress of the European Respiratory Society.

“This was such a negative study, there is no point in doing another,” reported Ganesh Raghu, MD, director of the Pulmonary Fibrosis Program at the University of Washington Medical Center, Seattle.

The focus of this study was simtuzumab, a monoclonal antibody targeted at lysyl oxidase like 2 (LOXL2), an enzyme which catalyzes a step in the formation of collagen crosslinks, which are thought to be important in fibrosis formation. Simtuzumab has been entered into clinical trials for treatment of several forms of fibrosis, including fibrosis in the liver.

“In animal models, simtuzumab has demonstrated efficacy in reducing fibrosis when administered prior to fibrosis formation or after the process has already begun,” Dr. Raghu explained. He said a large trial was initiated in IPF because the agent seemed so promising and because a large study was thought to be the best strategy to arrive at a definitive answer regarding safety and efficacy.

The drug was found safe but not effective. The independent data monitoring and safety committee terminated the trial early for futility.

In the study, 544 IPF patients were randomized to 125 mg simtuzumab or placebo administered subcutaneously once weekly. The primary endpoint was PFS, but there were a large number of secondary endpoints including hospitalization for progressive disease, change in 6-minute walk distance (6MWD), and overall survival.

For the endpoint of PFS, “there was absolutely no difference” between the groups receiving simtuzumab or placebo. When the patients were stratified for demonstrating above or below median expression of LOXL2, which was a prespecified analysis for the trial, there was still no difference between groups. Even when those in the top quarter percentile of LOXL2 expression were compared with those with less [expression of the enzyme], there was still “absolutely no difference.”

There was also no significant evidence of benefit for simtuzumab observed on key secondary endpoints, such as overall survival. When patients were stratified by baseline lung function as expressed by percentage of predicted forced expiratory volume in 1 second (FEV₁), there was no signal of benefit for those with severe, moderate, or mild impairment.

One criticism of this study raised after the presentation was that patients with 26% or greater of predicted FEV₁ were permitted into the study. It was suggested that such patients would be expected to already have a high degree of fibrosis and therefore would be less likely to benefit from an antifibrosis therapy. Dr. Raghu acknowledged this criticism, but he said it was important to include patients with advanced disease in order to generate an adequate event rate. Even with inclusion of patients with severe lung impairment, the mortality rate was less than 10%.

He concluded that there was no signal of benefit even among those with the greatest expression of the target.

“We absolutely need better markers for IPF,” Dr. Raghu maintained. While other members of the LOXL family of enzymes may still prove to be valuable markers of IPF risk and targets of therapy, these data appear to rule out a therapeutic role for blocking LOXL2.

Dr. Raghu is a consultant for Boehringer Ingelheim, Biogen, FibroGen, Gilead, Janssen, MedImmune, Promedior, Sanofi-Aventis, and Veracyte.

LONDON – Despite very promising activity in animal models of idiopathic pulmonary fibrosis (IPF), a monoclonal antibody targeted at an enzyme considered to be important to collagen cross-linking did not produce any improvement in progression-free survival (PFS), according to results of a multicenter study presented at the annual congress of the European Respiratory Society.

“This was such a negative study, there is no point in doing another,” reported Ganesh Raghu, MD, director of the Pulmonary Fibrosis Program at the University of Washington Medical Center, Seattle.

The focus of this study was simtuzumab, a monoclonal antibody targeted at lysyl oxidase like 2 (LOXL2), an enzyme which catalyzes a step in the formation of collagen crosslinks, which are thought to be important in fibrosis formation. Simtuzumab has been entered into clinical trials for treatment of several forms of fibrosis, including fibrosis in the liver.

“In animal models, simtuzumab has demonstrated efficacy in reducing fibrosis when administered prior to fibrosis formation or after the process has already begun,” Dr. Raghu explained. He said a large trial was initiated in IPF because the agent seemed so promising and because a large study was thought to be the best strategy to arrive at a definitive answer regarding safety and efficacy.

The drug was found safe but not effective. The independent data monitoring and safety committee terminated the trial early for futility.

In the study, 544 IPF patients were randomized to 125 mg simtuzumab or placebo administered subcutaneously once weekly. The primary endpoint was PFS, but there were a large number of secondary endpoints including hospitalization for progressive disease, change in 6-minute walk distance (6MWD), and overall survival.

For the endpoint of PFS, “there was absolutely no difference” between the groups receiving simtuzumab or placebo. When the patients were stratified for demonstrating above or below median expression of LOXL2, which was a prespecified analysis for the trial, there was still no difference between groups. Even when those in the top quarter percentile of LOXL2 expression were compared with those with less [expression of the enzyme], there was still “absolutely no difference.”

There was also no significant evidence of benefit for simtuzumab observed on key secondary endpoints, such as overall survival. When patients were stratified by baseline lung function as expressed by percentage of predicted forced expiratory volume in 1 second (FEV₁), there was no signal of benefit for those with severe, moderate, or mild impairment.

One criticism of this study raised after the presentation was that patients with 26% or greater of predicted FEV₁ were permitted into the study. It was suggested that such patients would be expected to already have a high degree of fibrosis and therefore would be less likely to benefit from an antifibrosis therapy. Dr. Raghu acknowledged this criticism, but he said it was important to include patients with advanced disease in order to generate an adequate event rate. Even with inclusion of patients with severe lung impairment, the mortality rate was less than 10%.

He concluded that there was no signal of benefit even among those with the greatest expression of the target.

“We absolutely need better markers for IPF,” Dr. Raghu maintained. While other members of the LOXL family of enzymes may still prove to be valuable markers of IPF risk and targets of therapy, these data appear to rule out a therapeutic role for blocking LOXL2.

Dr. Raghu is a consultant for Boehringer Ingelheim, Biogen, FibroGen, Gilead, Janssen, MedImmune, Promedior, Sanofi-Aventis, and Veracyte.

LONDON – Despite very promising activity in animal models of idiopathic pulmonary fibrosis (IPF), a monoclonal antibody targeted at an enzyme considered to be important to collagen cross-linking did not produce any improvement in progression-free survival (PFS), according to results of a multicenter study presented at the annual congress of the European Respiratory Society.

“This was such a negative study, there is no point in doing another,” reported Ganesh Raghu, MD, director of the Pulmonary Fibrosis Program at the University of Washington Medical Center, Seattle.

The focus of this study was simtuzumab, a monoclonal antibody targeted at lysyl oxidase like 2 (LOXL2), an enzyme which catalyzes a step in the formation of collagen crosslinks, which are thought to be important in fibrosis formation. Simtuzumab has been entered into clinical trials for treatment of several forms of fibrosis, including fibrosis in the liver.

“In animal models, simtuzumab has demonstrated efficacy in reducing fibrosis when administered prior to fibrosis formation or after the process has already begun,” Dr. Raghu explained. He said a large trial was initiated in IPF because the agent seemed so promising and because a large study was thought to be the best strategy to arrive at a definitive answer regarding safety and efficacy.

The drug was found safe but not effective. The independent data monitoring and safety committee terminated the trial early for futility.

In the study, 544 IPF patients were randomized to 125 mg simtuzumab or placebo administered subcutaneously once weekly. The primary endpoint was PFS, but there were a large number of secondary endpoints including hospitalization for progressive disease, change in 6-minute walk distance (6MWD), and overall survival.

For the endpoint of PFS, “there was absolutely no difference” between the groups receiving simtuzumab or placebo. When the patients were stratified for demonstrating above or below median expression of LOXL2, which was a prespecified analysis for the trial, there was still no difference between groups. Even when those in the top quarter percentile of LOXL2 expression were compared with those with less [expression of the enzyme], there was still “absolutely no difference.”

There was also no significant evidence of benefit for simtuzumab observed on key secondary endpoints, such as overall survival. When patients were stratified by baseline lung function as expressed by percentage of predicted forced expiratory volume in 1 second (FEV₁), there was no signal of benefit for those with severe, moderate, or mild impairment.

One criticism of this study raised after the presentation was that patients with 26% or greater of predicted FEV₁ were permitted into the study. It was suggested that such patients would be expected to already have a high degree of fibrosis and therefore would be less likely to benefit from an antifibrosis therapy. Dr. Raghu acknowledged this criticism, but he said it was important to include patients with advanced disease in order to generate an adequate event rate. Even with inclusion of patients with severe lung impairment, the mortality rate was less than 10%.

He concluded that there was no signal of benefit even among those with the greatest expression of the target.

“We absolutely need better markers for IPF,” Dr. Raghu maintained. While other members of the LOXL family of enzymes may still prove to be valuable markers of IPF risk and targets of therapy, these data appear to rule out a therapeutic role for blocking LOXL2.

Dr. Raghu is a consultant for Boehringer Ingelheim, Biogen, FibroGen, Gilead, Janssen, MedImmune, Promedior, Sanofi-Aventis, and Veracyte.

LONDON – Maintenance azithromycin may be best reserved for patients with mild to moderate chronic obstructive pulmonary disease (COPD) who also have few symptoms, according to an analysis from the COLUMBUS randomized controlled trial.

Significantly fewer exacerbations (1.06 vs. 2.62; P = .02) occurred at 1 year in patients treated with the macrolide antibiotic azithromycin rather than placebo if they were classified as having GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage 1 or 2 versus stage 4.

©decade3d/Thinkstock

Study participants who were classified as being part of GOLD group C (which includes patients with a high risk of COPD exacerbation but a low level of COPD symptoms) who were treated with maintenance azithromycin were also more likely to have fewer exacerbations at 1 year, compared with patients classified as being part of GOLD group D (which includes patients with a high risk of COPD exacerbation and a high level of COPD symptoms), who took the same antibiotic (0.45 vs. 2.18; P less than .01).

Having a high serum eosinophil level (2% or higher) was a third factor found in COPD patients that was predictive of fewer exacerbations following azithromycin use (1.26 vs. 2.5; P = .02).

“Azithromycin maintenance therapy should not be given to every COPD patient,” Remco Djamin, MD, of Amphia Hospital Breda in the Netherlands said in an interview at the annual congress of the European Respiratory Society. There is, of course, the concern over antibiotic resistance developing and macrolide antibiotic use has been linked with heart problems such as arrhythmia.

These data show, however, that there are certain predictors that might help clinicians decide if long-term antibiotic therapy might be beneficial for their patients who are experiencing frequent acute exacerbations of COPD.

Further research should look at the dosing and duration of azithromycin, Dr. Djamin suggested. Perhaps reducing the dose by half to 250 mg three times per week would be just as good; maybe 6 months’ rather than 12 months’ treatment would be sufficient, or perhaps it could be given intermittently. The aim is to ensure that patients are not being exposed unnecessarily, as there is concern over antibiotic resistance.

The use of azithromycin is not currently recommended in guidelines for COPD management to prevent exacerbations, but it is something that is likely to be added to the guidelines, as the evidence for its benefit mounts, Dr. Djamin said.

In addition to COLUMBUS, there have been at least two other studies looking at long-term antibiotic use to prevent exacerbations in patients with COPD. One (Am J Respir Crit Care Med. 2008;178:1139-47) showed erythromycin could decrease the exacerbation rate at 1 year by 36%, compared with placebo, while the other (N Engl J Med. 2011;365:689-8) again showed a benefit for azithromycin, with a 27% decrease in the 1-year exacerbation rate.

In COLUMBUS, 92 patients who had experienced at least three or more acute COPD exacerbations in the previous year were randomized to treatment with azithromycin 500 mg or placebo, taken three times per week for 12 months. This was a single-center, double-blind trial conducted in the Netherlands that showed a 42% reduction in the 1-year exacerbation rate could be achieved with the antibiotic treatment (Lancet Respir Med. 2014;2:361-8).

An additional benefit to using the antibiotic was seen in patients with GOLD stage 1-2 over patients with GOLD stage 4 and in patients with a higher percentage of serum eosinophils. The GOLD stage 1-2 patients experienced fewer exacerbations leading to hospitalization, compared with patients with GOLD stage 4 (0.31 vs. 1.00; P = .04), while the patients with higher levels of eosinophils experienced fewer exacerbations requiring hospitalization than those patients with lower percentages of eosinophils (0.26 vs. 1.07; P = 0.01).

“What you should consider is that this is a group of patients who have frequent exacerbations, and most of these exacerbations are caused by infections,” Dr. Djamin said, during a poster presentation at the conference. “Their exacerbations are often already being treated with antibiotics and so maintaining treatment has become one possible way of perhaps preventing exacerbations in the future.”

The study received no industry funding. Dr. Djamin had no competing interests to disclose.

LONDON – Maintenance azithromycin may be best reserved for patients with mild to moderate chronic obstructive pulmonary disease (COPD) who also have few symptoms, according to an analysis from the COLUMBUS randomized controlled trial.

Significantly fewer exacerbations (1.06 vs. 2.62; P = .02) occurred at 1 year in patients treated with the macrolide antibiotic azithromycin rather than placebo if they were classified as having GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage 1 or 2 versus stage 4.

©decade3d/Thinkstock

Study participants who were classified as being part of GOLD group C (which includes patients with a high risk of COPD exacerbation but a low level of COPD symptoms) who were treated with maintenance azithromycin were also more likely to have fewer exacerbations at 1 year, compared with patients classified as being part of GOLD group D (which includes patients with a high risk of COPD exacerbation and a high level of COPD symptoms), who took the same antibiotic (0.45 vs. 2.18; P less than .01).

Having a high serum eosinophil level (2% or higher) was a third factor found in COPD patients that was predictive of fewer exacerbations following azithromycin use (1.26 vs. 2.5; P = .02).

“Azithromycin maintenance therapy should not be given to every COPD patient,” Remco Djamin, MD, of Amphia Hospital Breda in the Netherlands said in an interview at the annual congress of the European Respiratory Society. There is, of course, the concern over antibiotic resistance developing and macrolide antibiotic use has been linked with heart problems such as arrhythmia.

These data show, however, that there are certain predictors that might help clinicians decide if long-term antibiotic therapy might be beneficial for their patients who are experiencing frequent acute exacerbations of COPD.

Further research should look at the dosing and duration of azithromycin, Dr. Djamin suggested. Perhaps reducing the dose by half to 250 mg three times per week would be just as good; maybe 6 months’ rather than 12 months’ treatment would be sufficient, or perhaps it could be given intermittently. The aim is to ensure that patients are not being exposed unnecessarily, as there is concern over antibiotic resistance.

The use of azithromycin is not currently recommended in guidelines for COPD management to prevent exacerbations, but it is something that is likely to be added to the guidelines, as the evidence for its benefit mounts, Dr. Djamin said.

In addition to COLUMBUS, there have been at least two other studies looking at long-term antibiotic use to prevent exacerbations in patients with COPD. One (Am J Respir Crit Care Med. 2008;178:1139-47) showed erythromycin could decrease the exacerbation rate at 1 year by 36%, compared with placebo, while the other (N Engl J Med. 2011;365:689-8) again showed a benefit for azithromycin, with a 27% decrease in the 1-year exacerbation rate.

In COLUMBUS, 92 patients who had experienced at least three or more acute COPD exacerbations in the previous year were randomized to treatment with azithromycin 500 mg or placebo, taken three times per week for 12 months. This was a single-center, double-blind trial conducted in the Netherlands that showed a 42% reduction in the 1-year exacerbation rate could be achieved with the antibiotic treatment (Lancet Respir Med. 2014;2:361-8).

An additional benefit to using the antibiotic was seen in patients with GOLD stage 1-2 over patients with GOLD stage 4 and in patients with a higher percentage of serum eosinophils. The GOLD stage 1-2 patients experienced fewer exacerbations leading to hospitalization, compared with patients with GOLD stage 4 (0.31 vs. 1.00; P = .04), while the patients with higher levels of eosinophils experienced fewer exacerbations requiring hospitalization than those patients with lower percentages of eosinophils (0.26 vs. 1.07; P = 0.01).

“What you should consider is that this is a group of patients who have frequent exacerbations, and most of these exacerbations are caused by infections,” Dr. Djamin said, during a poster presentation at the conference. “Their exacerbations are often already being treated with antibiotics and so maintaining treatment has become one possible way of perhaps preventing exacerbations in the future.”

The study received no industry funding. Dr. Djamin had no competing interests to disclose.

LONDON – Maintenance azithromycin may be best reserved for patients with mild to moderate chronic obstructive pulmonary disease (COPD) who also have few symptoms, according to an analysis from the COLUMBUS randomized controlled trial.

Significantly fewer exacerbations (1.06 vs. 2.62; P = .02) occurred at 1 year in patients treated with the macrolide antibiotic azithromycin rather than placebo if they were classified as having GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage 1 or 2 versus stage 4.

©decade3d/Thinkstock

Study participants who were classified as being part of GOLD group C (which includes patients with a high risk of COPD exacerbation but a low level of COPD symptoms) who were treated with maintenance azithromycin were also more likely to have fewer exacerbations at 1 year, compared with patients classified as being part of GOLD group D (which includes patients with a high risk of COPD exacerbation and a high level of COPD symptoms), who took the same antibiotic (0.45 vs. 2.18; P less than .01).

Having a high serum eosinophil level (2% or higher) was a third factor found in COPD patients that was predictive of fewer exacerbations following azithromycin use (1.26 vs. 2.5; P = .02).

“Azithromycin maintenance therapy should not be given to every COPD patient,” Remco Djamin, MD, of Amphia Hospital Breda in the Netherlands said in an interview at the annual congress of the European Respiratory Society. There is, of course, the concern over antibiotic resistance developing and macrolide antibiotic use has been linked with heart problems such as arrhythmia.

These data show, however, that there are certain predictors that might help clinicians decide if long-term antibiotic therapy might be beneficial for their patients who are experiencing frequent acute exacerbations of COPD.

Further research should look at the dosing and duration of azithromycin, Dr. Djamin suggested. Perhaps reducing the dose by half to 250 mg three times per week would be just as good; maybe 6 months’ rather than 12 months’ treatment would be sufficient, or perhaps it could be given intermittently. The aim is to ensure that patients are not being exposed unnecessarily, as there is concern over antibiotic resistance.

The use of azithromycin is not currently recommended in guidelines for COPD management to prevent exacerbations, but it is something that is likely to be added to the guidelines, as the evidence for its benefit mounts, Dr. Djamin said.

In addition to COLUMBUS, there have been at least two other studies looking at long-term antibiotic use to prevent exacerbations in patients with COPD. One (Am J Respir Crit Care Med. 2008;178:1139-47) showed erythromycin could decrease the exacerbation rate at 1 year by 36%, compared with placebo, while the other (N Engl J Med. 2011;365:689-8) again showed a benefit for azithromycin, with a 27% decrease in the 1-year exacerbation rate.

In COLUMBUS, 92 patients who had experienced at least three or more acute COPD exacerbations in the previous year were randomized to treatment with azithromycin 500 mg or placebo, taken three times per week for 12 months. This was a single-center, double-blind trial conducted in the Netherlands that showed a 42% reduction in the 1-year exacerbation rate could be achieved with the antibiotic treatment (Lancet Respir Med. 2014;2:361-8).

An additional benefit to using the antibiotic was seen in patients with GOLD stage 1-2 over patients with GOLD stage 4 and in patients with a higher percentage of serum eosinophils. The GOLD stage 1-2 patients experienced fewer exacerbations leading to hospitalization, compared with patients with GOLD stage 4 (0.31 vs. 1.00; P = .04), while the patients with higher levels of eosinophils experienced fewer exacerbations requiring hospitalization than those patients with lower percentages of eosinophils (0.26 vs. 1.07; P = 0.01).

“What you should consider is that this is a group of patients who have frequent exacerbations, and most of these exacerbations are caused by infections,” Dr. Djamin said, during a poster presentation at the conference. “Their exacerbations are often already being treated with antibiotics and so maintaining treatment has become one possible way of perhaps preventing exacerbations in the future.”

The study received no industry funding. Dr. Djamin had no competing interests to disclose.

LONDON – Four questions from the eight-question COPD Assessment Test (CAT) provide about the same prognostic accuracy in patients with chronic obstructive pulmonary disease (COPD) as does the full CAT, according to an analysis presented at the annual congress of the European Respiratory Society.

When the four- and eight-question versions were compared for exacerbation and other clinical outcomes over a 1-year period of follow-up, “both strategies demonstrated similar discrimination,” reported Carlos H. Martinez, MD, division of pulmonary and critical care medicine, University of Michigan Health System, Ann Arbor.

The CAT is an eight-item tool for evaluating the health status of patients with COPD as well as for predicting risk of COPD-related events, particularly exacerbations. The test is designed for self-administration by patients. For each of the questions, which address symptoms and activity limitations, patients are asked to answer on a scale ranging from one (indicating no clinical burden) to five (indicating severe burden). Based on the maximum score of 40, a score below 10 signifies a low impact from COPD, a score of 10-20 signifies a medium impact, and a score above 20 signifies a high impact.

©designer491/Thinkstock

In this study, a simplified version of the CAT that employed just four of the questions was evaluated in 880 participants in the observational SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study), which was funded by the National Heart, Lung, and Blood Institute and has prospectively enrolled COPD patients at seven participating centers. Ever-smokers from SPIROMICS were eligible for this analysis if they had a forced expiratory volume in one second (FEV₁₎/forced vital capacity (FVC) ratio of greater than or equal to 0.70 and an FVC above the lower limit of normal.

The four questions that were retained were about cough, phlegm, chest tightness, and breathlessness. The four questions that were eliminated were about activity limitation, sleep, energy, and the effect of lung symptoms on willingness to leave the house.

With the traditional test, using a cut point of greater than or equal to 10, 51.8% were classified as having a significant COPD burden. In this group, 15.3% experienced one or more exacerbations during 1 year of follow-up. With the simplified version focused on respiratory-related symptoms alone and using a cut point of greater than or equal to 7, 45.8% were classified as having a significant COPD burden, and 15.6% had one or more exacerbations during the same period of follow-up.

“The two strategies largely identified the same individuals,” according to Dr. Martinez, who reported the agreement as 88.5% (Kappa 0.77; P less than .001). He further noted that there was no difference in the area under the curve (AUC) to predict exacerbations at 1 year.

In further analysis, “subjects identified by either method also had more depression and anxiety symptoms, poorer sleep quality, and greater fatigue [than did the lower risk group],” Dr. Martinez added.

An AUC ROC (receiver operating characteristic) statistical analysis to compare the traditional and abbreviated CATs for cross-sectional associations showed close agreement. The values were nearly identical for such variables as dyspnea, impairment as measured with the 6-minute walking distance (6MWD) test, and quality of life as measured by the St. George’s Respiratory Questionnaire (SGRQ). Similarly, the AUC ROC values diverged little or not at all for longitudinal comparisons of any exacerbation or exacerbations requiring steroids or antibiotics.

The data from this study provide “a proof of concept that simpler strategies could be used for identifying these patients [at risk of exacerbations] in primary care,” Dr. Martinez maintained. Although further validation of this four-question assessment tool is needed, Dr. Martinez implied that there is value in a relatively rapid self-assessment tool that could be interpreted quickly by clinicians.

LONDON – Four questions from the eight-question COPD Assessment Test (CAT) provide about the same prognostic accuracy in patients with chronic obstructive pulmonary disease (COPD) as does the full CAT, according to an analysis presented at the annual congress of the European Respiratory Society.

When the four- and eight-question versions were compared for exacerbation and other clinical outcomes over a 1-year period of follow-up, “both strategies demonstrated similar discrimination,” reported Carlos H. Martinez, MD, division of pulmonary and critical care medicine, University of Michigan Health System, Ann Arbor.

The CAT is an eight-item tool for evaluating the health status of patients with COPD as well as for predicting risk of COPD-related events, particularly exacerbations. The test is designed for self-administration by patients. For each of the questions, which address symptoms and activity limitations, patients are asked to answer on a scale ranging from one (indicating no clinical burden) to five (indicating severe burden). Based on the maximum score of 40, a score below 10 signifies a low impact from COPD, a score of 10-20 signifies a medium impact, and a score above 20 signifies a high impact.

©designer491/Thinkstock

In this study, a simplified version of the CAT that employed just four of the questions was evaluated in 880 participants in the observational SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study), which was funded by the National Heart, Lung, and Blood Institute and has prospectively enrolled COPD patients at seven participating centers. Ever-smokers from SPIROMICS were eligible for this analysis if they had a forced expiratory volume in one second (FEV₁₎/forced vital capacity (FVC) ratio of greater than or equal to 0.70 and an FVC above the lower limit of normal.

The four questions that were retained were about cough, phlegm, chest tightness, and breathlessness. The four questions that were eliminated were about activity limitation, sleep, energy, and the effect of lung symptoms on willingness to leave the house.

With the traditional test, using a cut point of greater than or equal to 10, 51.8% were classified as having a significant COPD burden. In this group, 15.3% experienced one or more exacerbations during 1 year of follow-up. With the simplified version focused on respiratory-related symptoms alone and using a cut point of greater than or equal to 7, 45.8% were classified as having a significant COPD burden, and 15.6% had one or more exacerbations during the same period of follow-up.

“The two strategies largely identified the same individuals,” according to Dr. Martinez, who reported the agreement as 88.5% (Kappa 0.77; P less than .001). He further noted that there was no difference in the area under the curve (AUC) to predict exacerbations at 1 year.

In further analysis, “subjects identified by either method also had more depression and anxiety symptoms, poorer sleep quality, and greater fatigue [than did the lower risk group],” Dr. Martinez added.

An AUC ROC (receiver operating characteristic) statistical analysis to compare the traditional and abbreviated CATs for cross-sectional associations showed close agreement. The values were nearly identical for such variables as dyspnea, impairment as measured with the 6-minute walking distance (6MWD) test, and quality of life as measured by the St. George’s Respiratory Questionnaire (SGRQ). Similarly, the AUC ROC values diverged little or not at all for longitudinal comparisons of any exacerbation or exacerbations requiring steroids or antibiotics.

The data from this study provide “a proof of concept that simpler strategies could be used for identifying these patients [at risk of exacerbations] in primary care,” Dr. Martinez maintained. Although further validation of this four-question assessment tool is needed, Dr. Martinez implied that there is value in a relatively rapid self-assessment tool that could be interpreted quickly by clinicians.

LONDON – Four questions from the eight-question COPD Assessment Test (CAT) provide about the same prognostic accuracy in patients with chronic obstructive pulmonary disease (COPD) as does the full CAT, according to an analysis presented at the annual congress of the European Respiratory Society.

When the four- and eight-question versions were compared for exacerbation and other clinical outcomes over a 1-year period of follow-up, “both strategies demonstrated similar discrimination,” reported Carlos H. Martinez, MD, division of pulmonary and critical care medicine, University of Michigan Health System, Ann Arbor.

The CAT is an eight-item tool for evaluating the health status of patients with COPD as well as for predicting risk of COPD-related events, particularly exacerbations. The test is designed for self-administration by patients. For each of the questions, which address symptoms and activity limitations, patients are asked to answer on a scale ranging from one (indicating no clinical burden) to five (indicating severe burden). Based on the maximum score of 40, a score below 10 signifies a low impact from COPD, a score of 10-20 signifies a medium impact, and a score above 20 signifies a high impact.

©designer491/Thinkstock

In this study, a simplified version of the CAT that employed just four of the questions was evaluated in 880 participants in the observational SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study), which was funded by the National Heart, Lung, and Blood Institute and has prospectively enrolled COPD patients at seven participating centers. Ever-smokers from SPIROMICS were eligible for this analysis if they had a forced expiratory volume in one second (FEV₁₎/forced vital capacity (FVC) ratio of greater than or equal to 0.70 and an FVC above the lower limit of normal.

The four questions that were retained were about cough, phlegm, chest tightness, and breathlessness. The four questions that were eliminated were about activity limitation, sleep, energy, and the effect of lung symptoms on willingness to leave the house.

With the traditional test, using a cut point of greater than or equal to 10, 51.8% were classified as having a significant COPD burden. In this group, 15.3% experienced one or more exacerbations during 1 year of follow-up. With the simplified version focused on respiratory-related symptoms alone and using a cut point of greater than or equal to 7, 45.8% were classified as having a significant COPD burden, and 15.6% had one or more exacerbations during the same period of follow-up.

“The two strategies largely identified the same individuals,” according to Dr. Martinez, who reported the agreement as 88.5% (Kappa 0.77; P less than .001). He further noted that there was no difference in the area under the curve (AUC) to predict exacerbations at 1 year.

In further analysis, “subjects identified by either method also had more depression and anxiety symptoms, poorer sleep quality, and greater fatigue [than did the lower risk group],” Dr. Martinez added.

An AUC ROC (receiver operating characteristic) statistical analysis to compare the traditional and abbreviated CATs for cross-sectional associations showed close agreement. The values were nearly identical for such variables as dyspnea, impairment as measured with the 6-minute walking distance (6MWD) test, and quality of life as measured by the St. George’s Respiratory Questionnaire (SGRQ). Similarly, the AUC ROC values diverged little or not at all for longitudinal comparisons of any exacerbation or exacerbations requiring steroids or antibiotics.

The data from this study provide “a proof of concept that simpler strategies could be used for identifying these patients [at risk of exacerbations] in primary care,” Dr. Martinez maintained. Although further validation of this four-question assessment tool is needed, Dr. Martinez implied that there is value in a relatively rapid self-assessment tool that could be interpreted quickly by clinicians.

LONDON – Having an elevated level of high-density lipoprotein cholesterol (HDL-C) is associated with an increased rate of lung function decline over time, according to results from a cohort analysis of more than 30,000 adults presented at the annual congress of the European Respiratory Society.

For forced expiratory volume in 1 second (FEV₁), “there was a highly statistically significant inverse association for HDL-C for both cross-sectional and longitudinal measures of lung function,” reported Elizabeth C. Oelsner, MD, Columbia University Medical Center, New York. Those in the top quartile for HDL-C, on average, had a 9-mL greater decline in FEV¹, compared with patients in the lowest quartile (P less than .001). To put this in perspective, Dr. Oelsner said this decline is comparable “to a 10-year increment in pack-years of smoking.”

The study, which pooled six population-based cohorts in the United States, included 31,843 adults for whom there were baseline HDL-C levels and at least two longitudinally collected spirometry readings. According to Dr. Oelsner, quality control criteria were rigorously applied. For example, spirometry measures were obtained according to contemporary standards issued by the American Thoracic Society (ATS).

The average age of the study patients was 57 years, and 45% were classified as never smokers. The mean FEV₁ decline over a median follow-up of 5 years was 37 mL per year (range of 22-49 mL/year across the six cohorts). Approximately 15% of individuals had airflow limitation at baseline. There were more than 300,000 total person-years of observation in the pooled data.

In a fully adjusted cross-sectional analysis, each 1 mmol/L increase (38.67 mg/dL) in HDL-C was associated with a 9-mL lower FEV₁, according to Dr. Oelsner. He said the list of adjusted variables included age, gender, pack-years of smoking, weight, and height.

Results were consistent across age groups, presence or absence of smoking history, body mass index, and the presence or absence of airflow limitations at baseline, according to Dr. Oelsner.

HDL-C’s inverse correlation with lung function has been shown in other studies, such as the MESA Lung Study, another population-based analysis, according to Dr. Oelsner. In that study, a 0.4% increase in emphysema on CT lung scans was observed for every 10 mg/dL increase in HDL-C (Am J Respir Crit Care Med. 2010;181:A2878).

In this study, “being in the highest quartile for HDL at baseline was associated with an odds ratio of 1.2 for incident airflow limitation relative to being in the lowest [quartile],” Dr. Oelsner said.

The risk of a decline in airway function from an elevated HDL-C, if confirmed, should be considered in the context of the well-known protective effect exerted by HDL against cardiovascular events, according to Dr. Oelsner. However, she added, these data suggest that “having an excessively high HDL-C may incur risk just as an excessively low HDL may incur risk.” She noted, “there may be a limitation to the good of the good cholesterol.”

When asked after these data were presented whether she would prefer to have a low or high HDL-C, Dr. Oelsner responded, “Everything in moderation.” She also suggested that studies of treatments designed to raise HDL-C to reduce cardiovascular risk should take lung function into consideration. She warned that adverse effects on lung function are a potential “off-target risk” from such therapies.

LONDON – Having an elevated level of high-density lipoprotein cholesterol (HDL-C) is associated with an increased rate of lung function decline over time, according to results from a cohort analysis of more than 30,000 adults presented at the annual congress of the European Respiratory Society.

For forced expiratory volume in 1 second (FEV₁), “there was a highly statistically significant inverse association for HDL-C for both cross-sectional and longitudinal measures of lung function,” reported Elizabeth C. Oelsner, MD, Columbia University Medical Center, New York. Those in the top quartile for HDL-C, on average, had a 9-mL greater decline in FEV¹, compared with patients in the lowest quartile (P less than .001). To put this in perspective, Dr. Oelsner said this decline is comparable “to a 10-year increment in pack-years of smoking.”

The study, which pooled six population-based cohorts in the United States, included 31,843 adults for whom there were baseline HDL-C levels and at least two longitudinally collected spirometry readings. According to Dr. Oelsner, quality control criteria were rigorously applied. For example, spirometry measures were obtained according to contemporary standards issued by the American Thoracic Society (ATS).

The average age of the study patients was 57 years, and 45% were classified as never smokers. The mean FEV₁ decline over a median follow-up of 5 years was 37 mL per year (range of 22-49 mL/year across the six cohorts). Approximately 15% of individuals had airflow limitation at baseline. There were more than 300,000 total person-years of observation in the pooled data.

In a fully adjusted cross-sectional analysis, each 1 mmol/L increase (38.67 mg/dL) in HDL-C was associated with a 9-mL lower FEV₁, according to Dr. Oelsner. He said the list of adjusted variables included age, gender, pack-years of smoking, weight, and height.

Results were consistent across age groups, presence or absence of smoking history, body mass index, and the presence or absence of airflow limitations at baseline, according to Dr. Oelsner.

HDL-C’s inverse correlation with lung function has been shown in other studies, such as the MESA Lung Study, another population-based analysis, according to Dr. Oelsner. In that study, a 0.4% increase in emphysema on CT lung scans was observed for every 10 mg/dL increase in HDL-C (Am J Respir Crit Care Med. 2010;181:A2878).

In this study, “being in the highest quartile for HDL at baseline was associated with an odds ratio of 1.2 for incident airflow limitation relative to being in the lowest [quartile],” Dr. Oelsner said.

The risk of a decline in airway function from an elevated HDL-C, if confirmed, should be considered in the context of the well-known protective effect exerted by HDL against cardiovascular events, according to Dr. Oelsner. However, she added, these data suggest that “having an excessively high HDL-C may incur risk just as an excessively low HDL may incur risk.” She noted, “there may be a limitation to the good of the good cholesterol.”

When asked after these data were presented whether she would prefer to have a low or high HDL-C, Dr. Oelsner responded, “Everything in moderation.” She also suggested that studies of treatments designed to raise HDL-C to reduce cardiovascular risk should take lung function into consideration. She warned that adverse effects on lung function are a potential “off-target risk” from such therapies.

LONDON – Having an elevated level of high-density lipoprotein cholesterol (HDL-C) is associated with an increased rate of lung function decline over time, according to results from a cohort analysis of more than 30,000 adults presented at the annual congress of the European Respiratory Society.

For forced expiratory volume in 1 second (FEV₁), “there was a highly statistically significant inverse association for HDL-C for both cross-sectional and longitudinal measures of lung function,” reported Elizabeth C. Oelsner, MD, Columbia University Medical Center, New York. Those in the top quartile for HDL-C, on average, had a 9-mL greater decline in FEV¹, compared with patients in the lowest quartile (P less than .001). To put this in perspective, Dr. Oelsner said this decline is comparable “to a 10-year increment in pack-years of smoking.”

The study, which pooled six population-based cohorts in the United States, included 31,843 adults for whom there were baseline HDL-C levels and at least two longitudinally collected spirometry readings. According to Dr. Oelsner, quality control criteria were rigorously applied. For example, spirometry measures were obtained according to contemporary standards issued by the American Thoracic Society (ATS).

The average age of the study patients was 57 years, and 45% were classified as never smokers. The mean FEV₁ decline over a median follow-up of 5 years was 37 mL per year (range of 22-49 mL/year across the six cohorts). Approximately 15% of individuals had airflow limitation at baseline. There were more than 300,000 total person-years of observation in the pooled data.

In a fully adjusted cross-sectional analysis, each 1 mmol/L increase (38.67 mg/dL) in HDL-C was associated with a 9-mL lower FEV₁, according to Dr. Oelsner. He said the list of adjusted variables included age, gender, pack-years of smoking, weight, and height.

Results were consistent across age groups, presence or absence of smoking history, body mass index, and the presence or absence of airflow limitations at baseline, according to Dr. Oelsner.

HDL-C’s inverse correlation with lung function has been shown in other studies, such as the MESA Lung Study, another population-based analysis, according to Dr. Oelsner. In that study, a 0.4% increase in emphysema on CT lung scans was observed for every 10 mg/dL increase in HDL-C (Am J Respir Crit Care Med. 2010;181:A2878).

In this study, “being in the highest quartile for HDL at baseline was associated with an odds ratio of 1.2 for incident airflow limitation relative to being in the lowest [quartile],” Dr. Oelsner said.

The risk of a decline in airway function from an elevated HDL-C, if confirmed, should be considered in the context of the well-known protective effect exerted by HDL against cardiovascular events, according to Dr. Oelsner. However, she added, these data suggest that “having an excessively high HDL-C may incur risk just as an excessively low HDL may incur risk.” She noted, “there may be a limitation to the good of the good cholesterol.”

When asked after these data were presented whether she would prefer to have a low or high HDL-C, Dr. Oelsner responded, “Everything in moderation.” She also suggested that studies of treatments designed to raise HDL-C to reduce cardiovascular risk should take lung function into consideration. She warned that adverse effects on lung function are a potential “off-target risk” from such therapies.

LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

imnews@frontlinemedcom.com

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

imnews@frontlinemedcom.com

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

imnews@frontlinemedcom.com

LONDON – Patients with chronic obstructive pulmonary disease (COPD) and persistent hypercapnia were half as likely to be readmitted to hospital 1 year after an acute hypercapnic exacerbation if they had received home mechanical ventilation (HMV) in addition to home oxygen therapy (HOT) than if they had not.

The median admission-free survival time in the HOT-HMV U.K. trial was 4.3 months when HMV was used in addition to HOT, versus 1.4 months for HOT alone (unadjusted hazard ratio = 0.54, P = .007).

©designer491/Thinkstock

“I think what’s really important is that we now have a treatment that we know that if we direct toward [patients with persistent hypercapnia after acute hypercapnic exacerbation] that we effect a significant change in their outcomes,” said study investigator Patrick Murphy, MBBS, PhD, a consultant physician and honorary senior lecturer at the Lane Fox Respiratory Unit at Guy’s and St Thomas’ NHS Foundation Trust (London).

Speaking at the annual congress of the European Respiratory Society, he added: “We need to titrate the home ventilation to control nocturnal hypoventilation, and although I’ve not presented the data as time is short, there is no deleterious effect on quality of life.”

Nicholas Hart, MBBS, PhD, co–study investigator and clinical and academic director of Lane Fox Respiratory Unit, said in a statement issued by Philips Respironics that the results “have the ability to change the way that COPD patients are treated worldwide.”

“We’re looking forward to continuing the trial over the next 5 years to monitor survival rates, which we hope will rise, and readmission rates, which will hopefully fall,” he added.

The HOT-HMV UK Trial was conducted in 15 centers and involved patients with severe COPD who had persistent hypercapnia 2-4 weeks after experiencing an acute, life-threatening hypercapnic exacerbation requiring hospitalization. Persistent hypercapnia was defined as a pH of 7.3 or more and a PaCO2 of 7 kPa or higher. Patients had to have a 20-year or more pack year history of smoking, a forced expiratory volume in 1 second (FEV₁) of 50% or less, and FEV₁ to forced vital capacity (FVC) ratio of below 60%.

Dr. Murphy observed that the trial design assumed that the rate of hospital readmission at 1 year could be reduced from 55% to 25% with the use of noninvasive ventilation (NIV). The hypothesis was that HMV plus long-term HOT would increase admission-free survival compared with HOT alone.

More than 2,000 patients were initially screened for inclusion in the trial, with 116 randomized. Of the excluded patients, 1,609 did not meet inclusion criteria, 296 declined to participate, and 8 patients were not included for other reasons.

The average age of patients participating in the study was 67 years. The patients had a median body mass index of 21.6 kg/m² and most (61%) were female. Prior long-term oxygen therapy had been used by most (80%), and 61% had three or more COPD-related hospital admissions in the last year.

Putting the primary endpoint data into perspective, Dr. Murphy said that six patients with persistent hypercapnia after treatment for an acute exacerbation needed to be treated with HMV to prevent one readmission in the following 12-month period.

Improved nocturnal hypercapnia and sleep-disordered breathing led to improved daytime hypercapnia, he observed. The change in daytime hypercapnia after 6 weeks and 3 months showed a clear statistical benefit for the combined HMV/HOT approach over HOT alone, although this lost statistical significance after 6 and 12 months’ follow-up. “That’s in part explained by the fact that the patient numbers were reduced, but also by the fact that, as part of the trial protocol, once [HOT only] patients had reached the primary outcome we allowed them to move onto HMV.”

The study was supported by Guy’s and St. Thomas’ Charity, Philips Respironics, ResMed, and the ResMed Foundation. Dr. Murphy has received hospitality for conferences and lecturing from Philips Respironics, lecturing from Fisher & Paykel Healthcare, and hospitality for conferences from ResMed.

LONDON – Patients with chronic obstructive pulmonary disease (COPD) and persistent hypercapnia were half as likely to be readmitted to hospital 1 year after an acute hypercapnic exacerbation if they had received home mechanical ventilation (HMV) in addition to home oxygen therapy (HOT) than if they had not.

The median admission-free survival time in the HOT-HMV U.K. trial was 4.3 months when HMV was used in addition to HOT, versus 1.4 months for HOT alone (unadjusted hazard ratio = 0.54, P = .007).

©designer491/Thinkstock

“I think what’s really important is that we now have a treatment that we know that if we direct toward [patients with persistent hypercapnia after acute hypercapnic exacerbation] that we effect a significant change in their outcomes,” said study investigator Patrick Murphy, MBBS, PhD, a consultant physician and honorary senior lecturer at the Lane Fox Respiratory Unit at Guy’s and St Thomas’ NHS Foundation Trust (London).

Speaking at the annual congress of the European Respiratory Society, he added: “We need to titrate the home ventilation to control nocturnal hypoventilation, and although I’ve not presented the data as time is short, there is no deleterious effect on quality of life.”

Nicholas Hart, MBBS, PhD, co–study investigator and clinical and academic director of Lane Fox Respiratory Unit, said in a statement issued by Philips Respironics that the results “have the ability to change the way that COPD patients are treated worldwide.”

“We’re looking forward to continuing the trial over the next 5 years to monitor survival rates, which we hope will rise, and readmission rates, which will hopefully fall,” he added.

The HOT-HMV UK Trial was conducted in 15 centers and involved patients with severe COPD who had persistent hypercapnia 2-4 weeks after experiencing an acute, life-threatening hypercapnic exacerbation requiring hospitalization. Persistent hypercapnia was defined as a pH of 7.3 or more and a PaCO2 of 7 kPa or higher. Patients had to have a 20-year or more pack year history of smoking, a forced expiratory volume in 1 second (FEV₁) of 50% or less, and FEV₁ to forced vital capacity (FVC) ratio of below 60%.

Dr. Murphy observed that the trial design assumed that the rate of hospital readmission at 1 year could be reduced from 55% to 25% with the use of noninvasive ventilation (NIV). The hypothesis was that HMV plus long-term HOT would increase admission-free survival compared with HOT alone.

More than 2,000 patients were initially screened for inclusion in the trial, with 116 randomized. Of the excluded patients, 1,609 did not meet inclusion criteria, 296 declined to participate, and 8 patients were not included for other reasons.

The average age of patients participating in the study was 67 years. The patients had a median body mass index of 21.6 kg/m² and most (61%) were female. Prior long-term oxygen therapy had been used by most (80%), and 61% had three or more COPD-related hospital admissions in the last year.

Putting the primary endpoint data into perspective, Dr. Murphy said that six patients with persistent hypercapnia after treatment for an acute exacerbation needed to be treated with HMV to prevent one readmission in the following 12-month period.

Improved nocturnal hypercapnia and sleep-disordered breathing led to improved daytime hypercapnia, he observed. The change in daytime hypercapnia after 6 weeks and 3 months showed a clear statistical benefit for the combined HMV/HOT approach over HOT alone, although this lost statistical significance after 6 and 12 months’ follow-up. “That’s in part explained by the fact that the patient numbers were reduced, but also by the fact that, as part of the trial protocol, once [HOT only] patients had reached the primary outcome we allowed them to move onto HMV.”

The study was supported by Guy’s and St. Thomas’ Charity, Philips Respironics, ResMed, and the ResMed Foundation. Dr. Murphy has received hospitality for conferences and lecturing from Philips Respironics, lecturing from Fisher & Paykel Healthcare, and hospitality for conferences from ResMed.

LONDON – Patients with chronic obstructive pulmonary disease (COPD) and persistent hypercapnia were half as likely to be readmitted to hospital 1 year after an acute hypercapnic exacerbation if they had received home mechanical ventilation (HMV) in addition to home oxygen therapy (HOT) than if they had not.

The median admission-free survival time in the HOT-HMV U.K. trial was 4.3 months when HMV was used in addition to HOT, versus 1.4 months for HOT alone (unadjusted hazard ratio = 0.54, P = .007).

©designer491/Thinkstock

“I think what’s really important is that we now have a treatment that we know that if we direct toward [patients with persistent hypercapnia after acute hypercapnic exacerbation] that we effect a significant change in their outcomes,” said study investigator Patrick Murphy, MBBS, PhD, a consultant physician and honorary senior lecturer at the Lane Fox Respiratory Unit at Guy’s and St Thomas’ NHS Foundation Trust (London).

Speaking at the annual congress of the European Respiratory Society, he added: “We need to titrate the home ventilation to control nocturnal hypoventilation, and although I’ve not presented the data as time is short, there is no deleterious effect on quality of life.”

Nicholas Hart, MBBS, PhD, co–study investigator and clinical and academic director of Lane Fox Respiratory Unit, said in a statement issued by Philips Respironics that the results “have the ability to change the way that COPD patients are treated worldwide.”

“We’re looking forward to continuing the trial over the next 5 years to monitor survival rates, which we hope will rise, and readmission rates, which will hopefully fall,” he added.

The HOT-HMV UK Trial was conducted in 15 centers and involved patients with severe COPD who had persistent hypercapnia 2-4 weeks after experiencing an acute, life-threatening hypercapnic exacerbation requiring hospitalization. Persistent hypercapnia was defined as a pH of 7.3 or more and a PaCO2 of 7 kPa or higher. Patients had to have a 20-year or more pack year history of smoking, a forced expiratory volume in 1 second (FEV₁) of 50% or less, and FEV₁ to forced vital capacity (FVC) ratio of below 60%.

Dr. Murphy observed that the trial design assumed that the rate of hospital readmission at 1 year could be reduced from 55% to 25% with the use of noninvasive ventilation (NIV). The hypothesis was that HMV plus long-term HOT would increase admission-free survival compared with HOT alone.

More than 2,000 patients were initially screened for inclusion in the trial, with 116 randomized. Of the excluded patients, 1,609 did not meet inclusion criteria, 296 declined to participate, and 8 patients were not included for other reasons.

The average age of patients participating in the study was 67 years. The patients had a median body mass index of 21.6 kg/m² and most (61%) were female. Prior long-term oxygen therapy had been used by most (80%), and 61% had three or more COPD-related hospital admissions in the last year.

Putting the primary endpoint data into perspective, Dr. Murphy said that six patients with persistent hypercapnia after treatment for an acute exacerbation needed to be treated with HMV to prevent one readmission in the following 12-month period.

Improved nocturnal hypercapnia and sleep-disordered breathing led to improved daytime hypercapnia, he observed. The change in daytime hypercapnia after 6 weeks and 3 months showed a clear statistical benefit for the combined HMV/HOT approach over HOT alone, although this lost statistical significance after 6 and 12 months’ follow-up. “That’s in part explained by the fact that the patient numbers were reduced, but also by the fact that, as part of the trial protocol, once [HOT only] patients had reached the primary outcome we allowed them to move onto HMV.”

The study was supported by Guy’s and St. Thomas’ Charity, Philips Respironics, ResMed, and the ResMed Foundation. Dr. Murphy has received hospitality for conferences and lecturing from Philips Respironics, lecturing from Fisher & Paykel Healthcare, and hospitality for conferences from ResMed.

LONDON – Phase III evidence confirms the multiple benefits of using a triple, fixed-dose combination (FDC) therapy over standard options in patients with severe chronic obstructive pulmonary disease (COPD), according to a presentation on two trials at the annual congress of the European Respiratory Society.

In the TRINITY trial, the combination of the inhaled corticosteroid (ICS) beclometasone diproprionate (BDP), the long-acting beta-agonist (LABA) formoterol fumarate (FF), and the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) delivered via a single pressurized metered-dose inhaler (pMDI), was more effective at reducing exacerbations than was tiotropium bromide (Spiriva, Boehringer Ingelheim) monotherapy.

Results of the TRILOGY trial, which were simultaneously published in The Lancet (doi: 10.1016/S0140-6736(16)31354-X) at the time of their presentation at the ERS meeting, showed that the novel single-inhaler, triple fixed-dose combination could induce greater improvements in lung function when compared to a double fixed-dose combination of BDP and FF (Foster, Chiesi Farmaceutici SpA).

Sara Freeman/Frontline Medical News

“LAMA monotherapy or ICS/LABA are standard options for treating patients with advanced COPD,” Jørgen Vestbo, MD, president of ERS and professor of respiratory medicine at the University of Manchester (England), said in an interview.

Dr. Vestbo, who was an investigator in both the TRINITY and TRILOGY trials, added that the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines also mention that these drugs can be combined in patients who continue to experience COPD exacerbations. “But the evidence behind that is fairly weak,” he observed.

Although many patients are already being treated with triple therapy, this is via two inhalers, and “there have not been that many really good, long-term outcome studies” that have proven this approach to be the best way to manage those at risk for continued exacerbations of COPD, he said.

Drug companies are now starting to combine these three drugs into one inhaler, however, and this means that registration studies need to be done to get the products licensed, and so “there is an interest in coming up with the evidence,” Dr. Vestbo said.

“What is good about these two studies is that they are both 1-year studies and they are of sufficient size to give quite good estimates … These are studies that we should have done 5 years ago,” he said. Although the ideal is to have patients on as little therapy as possible, the results of TRINITY and TRILOGY now provide much needed evidence that it will work better than either LAMA or ICS/LABA.

The piece of evidence that is still missing is what the benefit, if any, is over a LAMA/LABA combination, a fact noted during discussion following the presentations of these data at the ERS meeting and in an editorial by Peter Calverley, MD, of the University of Liverpool (England) that accompanied the published TRILOGY findings (Lancet. 2016;388:937-8). There also is a question over whether twice daily is really better than once daily dosing, or vice versa.

“Until these next studies become available, we can be comforted by the knowledge that three therapies can be combined in a single inhaler which offers more effective therapy than at least one of the recommended treatment regimens for patients with severe COPD,” Dr. Calverley observed in reference to TRILOGY only.

Dr. Vestbo noted that at the time the TRILOGY and TRINITY studies were designed, there wasn’t the evidence from other studies such as the FLAME study (N Engl J Med. 2016. doi: 10.1056/NEJMoa1516385), showing the benefit of the LABA/LAMA combination over ICS/LABA. The TRILOGY and TRINITY studies “give that degree of evidence that was needed,” he said.

“I am not sure that the guidelines [for treating severe COPD] will change much, but at least they can say with better certainty that you can use the triple,” he added.

TRINITY – can triple better LAMA monotherapy?

The TRINITY study looked at whether patients with GOLD 3-4 COPD would be better off treated with LAMA monotherapy (tiotropium 18 mcg, one puff per day), the triple fixed-dose combination of BDP (100 mcg), FF (6 mcg), and GB (12.5 mcg) given via the novel pressurized metered-dose inhaler (two puffs twice daily), or a “free” triple combination of BDP (100 mcg) and FF (6 mcg) given via one pressurized metered-dose inhaler (two puffs daily) plus the same dose of the once-daily LAMA.

In all, 2,690 patients were randomized to these three treatments arms. The mean age of patients was 63 years and the majority (74%-77%) were men, with an average FEV₁ predicted of 36% and one COPD exacerbation in the past year. Just under half of the study population were current smokers. Most (75%) had received prior treatment with an ICS/LABA combination, with about 11% receiving LAMA, and the rest either ICS/LAMA (3%), or LABA/LAMA (12%)

The annualized exacerbation rate (the primary endpoint) was 0.457 in the 1,077 patients who were treated with the triple fixed-dose combination versus 0.571 in the 1,074 patients who received tiotropium alone. The rate ratio was 0.8 indicating a 20% reduction in exacerbations was achieved (P = .003).

The annualized exacerbation rate in the 532 patients given the “free” triple combination (BDP/FF plus tiotropium) was 0.452, with a rate ratio of 0.790 (P =.010) versus those who received the LAMA as monotherapy.

There was no significant difference between the two triple combination strategies.

Presenting these data, Dr. Vestbo noted that the benefit was seen in preventing both severe and moderate COPD exacerbations. Significantly improved lung function, as measured by the change in FEV₁ from baseline to week 52, was also observed to a greater degree with the triple therapy approaches than with the LAMA monotherapy.

“All three treatments were well tolerated and there were no particular safety concerns in this study,” he said.

TRILOGY – are three drugs better than two?

In contrast to the TRINITY study, the TRILOGY study looked at whether patients with severe COPD would be better off taking an ICS/LABA or the new triple fixed-dose combination pressurized metered-dose inhaler.

Just over 1,200 patients were recruited into the study, which had two co–primary endpoints: change from baseline to week 26 in predose morning FEV₁ and 2-hour postdose FEV₁, and the change in transition dyspnea index focal score at week 26.

Results showed that the triple fixed-dose combination improved predose FEV₁ by 0.081 L and 2-hour postdose FEV₁ by 0.117 L compared with the ICS/LABA combination (P less than .001 for both comparisons). Mean transition dyspnea index scores were 1.71 and 1.50, with a nonsignificant difference of 0.21.

“To be honest, I don’t think we had expected that [the triple combination] would mean much for patients, but we were hoping there would be a significant increase in lung function and a reduction of symptoms,” Dr. Vestbo said about the TRILOGY study. “What we saw was there was [symptomatic improvement] but it was not quite as impressive as we thought, but we reduced exacerbations.”

There was a significant, 23% reduction in the annualized exacerbation rate via the triple combination versus the ICS/LABA combination (0.41 vs 0.53, adjusted rate ratio 0.77, P = .005).

The triple approach was well tolerated, with no increase in adverse events versus the dual combination. The results support the idea that instead of giving patients an ICS/LABA at the start, better disease control can be achieved with a triple fixed-dose combination, Dr. Vestbo suggested.

Writing in The Lancet, Dr. Calverley noted: “The inability to meet one part of a co–primary endpoint clouds the interpretation of the other findings in the study, a familiar problem in COPD trials.” He added that there was a significant difference in the overall St George’s Respiratory Questionnaire scores favoring the triple over double therapy.

Chiesi Farmaceutici SpA funded the studies. Dr. Vestbo was an investigator for both TRINITY and TRILOGY and has received honoraria for advising and presenting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis. Dr. Calverley has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca.

LONDON – Phase III evidence confirms the multiple benefits of using a triple, fixed-dose combination (FDC) therapy over standard options in patients with severe chronic obstructive pulmonary disease (COPD), according to a presentation on two trials at the annual congress of the European Respiratory Society.

In the TRINITY trial, the combination of the inhaled corticosteroid (ICS) beclometasone diproprionate (BDP), the long-acting beta-agonist (LABA) formoterol fumarate (FF), and the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) delivered via a single pressurized metered-dose inhaler (pMDI), was more effective at reducing exacerbations than was tiotropium bromide (Spiriva, Boehringer Ingelheim) monotherapy.

Results of the TRILOGY trial, which were simultaneously published in The Lancet (doi: 10.1016/S0140-6736(16)31354-X) at the time of their presentation at the ERS meeting, showed that the novel single-inhaler, triple fixed-dose combination could induce greater improvements in lung function when compared to a double fixed-dose combination of BDP and FF (Foster, Chiesi Farmaceutici SpA).

Sara Freeman/Frontline Medical News

“LAMA monotherapy or ICS/LABA are standard options for treating patients with advanced COPD,” Jørgen Vestbo, MD, president of ERS and professor of respiratory medicine at the University of Manchester (England), said in an interview.

Dr. Vestbo, who was an investigator in both the TRINITY and TRILOGY trials, added that the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines also mention that these drugs can be combined in patients who continue to experience COPD exacerbations. “But the evidence behind that is fairly weak,” he observed.

Although many patients are already being treated with triple therapy, this is via two inhalers, and “there have not been that many really good, long-term outcome studies” that have proven this approach to be the best way to manage those at risk for continued exacerbations of COPD, he said.

Drug companies are now starting to combine these three drugs into one inhaler, however, and this means that registration studies need to be done to get the products licensed, and so “there is an interest in coming up with the evidence,” Dr. Vestbo said.

“What is good about these two studies is that they are both 1-year studies and they are of sufficient size to give quite good estimates … These are studies that we should have done 5 years ago,” he said. Although the ideal is to have patients on as little therapy as possible, the results of TRINITY and TRILOGY now provide much needed evidence that it will work better than either LAMA or ICS/LABA.

The piece of evidence that is still missing is what the benefit, if any, is over a LAMA/LABA combination, a fact noted during discussion following the presentations of these data at the ERS meeting and in an editorial by Peter Calverley, MD, of the University of Liverpool (England) that accompanied the published TRILOGY findings (Lancet. 2016;388:937-8). There also is a question over whether twice daily is really better than once daily dosing, or vice versa.

“Until these next studies become available, we can be comforted by the knowledge that three therapies can be combined in a single inhaler which offers more effective therapy than at least one of the recommended treatment regimens for patients with severe COPD,” Dr. Calverley observed in reference to TRILOGY only.

Dr. Vestbo noted that at the time the TRILOGY and TRINITY studies were designed, there wasn’t the evidence from other studies such as the FLAME study (N Engl J Med. 2016. doi: 10.1056/NEJMoa1516385), showing the benefit of the LABA/LAMA combination over ICS/LABA. The TRILOGY and TRINITY studies “give that degree of evidence that was needed,” he said.

“I am not sure that the guidelines [for treating severe COPD] will change much, but at least they can say with better certainty that you can use the triple,” he added.

TRINITY – can triple better LAMA monotherapy?

The TRINITY study looked at whether patients with GOLD 3-4 COPD would be better off treated with LAMA monotherapy (tiotropium 18 mcg, one puff per day), the triple fixed-dose combination of BDP (100 mcg), FF (6 mcg), and GB (12.5 mcg) given via the novel pressurized metered-dose inhaler (two puffs twice daily), or a “free” triple combination of BDP (100 mcg) and FF (6 mcg) given via one pressurized metered-dose inhaler (two puffs daily) plus the same dose of the once-daily LAMA.

In all, 2,690 patients were randomized to these three treatments arms. The mean age of patients was 63 years and the majority (74%-77%) were men, with an average FEV₁ predicted of 36% and one COPD exacerbation in the past year. Just under half of the study population were current smokers. Most (75%) had received prior treatment with an ICS/LABA combination, with about 11% receiving LAMA, and the rest either ICS/LAMA (3%), or LABA/LAMA (12%)

The annualized exacerbation rate (the primary endpoint) was 0.457 in the 1,077 patients who were treated with the triple fixed-dose combination versus 0.571 in the 1,074 patients who received tiotropium alone. The rate ratio was 0.8 indicating a 20% reduction in exacerbations was achieved (P = .003).

The annualized exacerbation rate in the 532 patients given the “free” triple combination (BDP/FF plus tiotropium) was 0.452, with a rate ratio of 0.790 (P =.010) versus those who received the LAMA as monotherapy.

There was no significant difference between the two triple combination strategies.

Presenting these data, Dr. Vestbo noted that the benefit was seen in preventing both severe and moderate COPD exacerbations. Significantly improved lung function, as measured by the change in FEV₁ from baseline to week 52, was also observed to a greater degree with the triple therapy approaches than with the LAMA monotherapy.

“All three treatments were well tolerated and there were no particular safety concerns in this study,” he said.

TRILOGY – are three drugs better than two?

In contrast to the TRINITY study, the TRILOGY study looked at whether patients with severe COPD would be better off taking an ICS/LABA or the new triple fixed-dose combination pressurized metered-dose inhaler.

Just over 1,200 patients were recruited into the study, which had two co–primary endpoints: change from baseline to week 26 in predose morning FEV₁ and 2-hour postdose FEV₁, and the change in transition dyspnea index focal score at week 26.

Results showed that the triple fixed-dose combination improved predose FEV₁ by 0.081 L and 2-hour postdose FEV₁ by 0.117 L compared with the ICS/LABA combination (P less than .001 for both comparisons). Mean transition dyspnea index scores were 1.71 and 1.50, with a nonsignificant difference of 0.21.

“To be honest, I don’t think we had expected that [the triple combination] would mean much for patients, but we were hoping there would be a significant increase in lung function and a reduction of symptoms,” Dr. Vestbo said about the TRILOGY study. “What we saw was there was [symptomatic improvement] but it was not quite as impressive as we thought, but we reduced exacerbations.”

There was a significant, 23% reduction in the annualized exacerbation rate via the triple combination versus the ICS/LABA combination (0.41 vs 0.53, adjusted rate ratio 0.77, P = .005).

The triple approach was well tolerated, with no increase in adverse events versus the dual combination. The results support the idea that instead of giving patients an ICS/LABA at the start, better disease control can be achieved with a triple fixed-dose combination, Dr. Vestbo suggested.

Writing in The Lancet, Dr. Calverley noted: “The inability to meet one part of a co–primary endpoint clouds the interpretation of the other findings in the study, a familiar problem in COPD trials.” He added that there was a significant difference in the overall St George’s Respiratory Questionnaire scores favoring the triple over double therapy.

Chiesi Farmaceutici SpA funded the studies. Dr. Vestbo was an investigator for both TRINITY and TRILOGY and has received honoraria for advising and presenting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis. Dr. Calverley has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca.

LONDON – Phase III evidence confirms the multiple benefits of using a triple, fixed-dose combination (FDC) therapy over standard options in patients with severe chronic obstructive pulmonary disease (COPD), according to a presentation on two trials at the annual congress of the European Respiratory Society.

In the TRINITY trial, the combination of the inhaled corticosteroid (ICS) beclometasone diproprionate (BDP), the long-acting beta-agonist (LABA) formoterol fumarate (FF), and the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) delivered via a single pressurized metered-dose inhaler (pMDI), was more effective at reducing exacerbations than was tiotropium bromide (Spiriva, Boehringer Ingelheim) monotherapy.

Results of the TRILOGY trial, which were simultaneously published in The Lancet (doi: 10.1016/S0140-6736(16)31354-X) at the time of their presentation at the ERS meeting, showed that the novel single-inhaler, triple fixed-dose combination could induce greater improvements in lung function when compared to a double fixed-dose combination of BDP and FF (Foster, Chiesi Farmaceutici SpA).

Sara Freeman/Frontline Medical News

“LAMA monotherapy or ICS/LABA are standard options for treating patients with advanced COPD,” Jørgen Vestbo, MD, president of ERS and professor of respiratory medicine at the University of Manchester (England), said in an interview.

Dr. Vestbo, who was an investigator in both the TRINITY and TRILOGY trials, added that the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines also mention that these drugs can be combined in patients who continue to experience COPD exacerbations. “But the evidence behind that is fairly weak,” he observed.

Although many patients are already being treated with triple therapy, this is via two inhalers, and “there have not been that many really good, long-term outcome studies” that have proven this approach to be the best way to manage those at risk for continued exacerbations of COPD, he said.

Drug companies are now starting to combine these three drugs into one inhaler, however, and this means that registration studies need to be done to get the products licensed, and so “there is an interest in coming up with the evidence,” Dr. Vestbo said.

“What is good about these two studies is that they are both 1-year studies and they are of sufficient size to give quite good estimates … These are studies that we should have done 5 years ago,” he said. Although the ideal is to have patients on as little therapy as possible, the results of TRINITY and TRILOGY now provide much needed evidence that it will work better than either LAMA or ICS/LABA.

The piece of evidence that is still missing is what the benefit, if any, is over a LAMA/LABA combination, a fact noted during discussion following the presentations of these data at the ERS meeting and in an editorial by Peter Calverley, MD, of the University of Liverpool (England) that accompanied the published TRILOGY findings (Lancet. 2016;388:937-8). There also is a question over whether twice daily is really better than once daily dosing, or vice versa.

“Until these next studies become available, we can be comforted by the knowledge that three therapies can be combined in a single inhaler which offers more effective therapy than at least one of the recommended treatment regimens for patients with severe COPD,” Dr. Calverley observed in reference to TRILOGY only.

Dr. Vestbo noted that at the time the TRILOGY and TRINITY studies were designed, there wasn’t the evidence from other studies such as the FLAME study (N Engl J Med. 2016. doi: 10.1056/NEJMoa1516385), showing the benefit of the LABA/LAMA combination over ICS/LABA. The TRILOGY and TRINITY studies “give that degree of evidence that was needed,” he said.

“I am not sure that the guidelines [for treating severe COPD] will change much, but at least they can say with better certainty that you can use the triple,” he added.

TRINITY – can triple better LAMA monotherapy?

The TRINITY study looked at whether patients with GOLD 3-4 COPD would be better off treated with LAMA monotherapy (tiotropium 18 mcg, one puff per day), the triple fixed-dose combination of BDP (100 mcg), FF (6 mcg), and GB (12.5 mcg) given via the novel pressurized metered-dose inhaler (two puffs twice daily), or a “free” triple combination of BDP (100 mcg) and FF (6 mcg) given via one pressurized metered-dose inhaler (two puffs daily) plus the same dose of the once-daily LAMA.

In all, 2,690 patients were randomized to these three treatments arms. The mean age of patients was 63 years and the majority (74%-77%) were men, with an average FEV₁ predicted of 36% and one COPD exacerbation in the past year. Just under half of the study population were current smokers. Most (75%) had received prior treatment with an ICS/LABA combination, with about 11% receiving LAMA, and the rest either ICS/LAMA (3%), or LABA/LAMA (12%)

The annualized exacerbation rate (the primary endpoint) was 0.457 in the 1,077 patients who were treated with the triple fixed-dose combination versus 0.571 in the 1,074 patients who received tiotropium alone. The rate ratio was 0.8 indicating a 20% reduction in exacerbations was achieved (P = .003).

The annualized exacerbation rate in the 532 patients given the “free” triple combination (BDP/FF plus tiotropium) was 0.452, with a rate ratio of 0.790 (P =.010) versus those who received the LAMA as monotherapy.

There was no significant difference between the two triple combination strategies.

Presenting these data, Dr. Vestbo noted that the benefit was seen in preventing both severe and moderate COPD exacerbations. Significantly improved lung function, as measured by the change in FEV₁ from baseline to week 52, was also observed to a greater degree with the triple therapy approaches than with the LAMA monotherapy.

“All three treatments were well tolerated and there were no particular safety concerns in this study,” he said.

TRILOGY – are three drugs better than two?

In contrast to the TRINITY study, the TRILOGY study looked at whether patients with severe COPD would be better off taking an ICS/LABA or the new triple fixed-dose combination pressurized metered-dose inhaler.

Just over 1,200 patients were recruited into the study, which had two co–primary endpoints: change from baseline to week 26 in predose morning FEV₁ and 2-hour postdose FEV₁, and the change in transition dyspnea index focal score at week 26.

Results showed that the triple fixed-dose combination improved predose FEV₁ by 0.081 L and 2-hour postdose FEV₁ by 0.117 L compared with the ICS/LABA combination (P less than .001 for both comparisons). Mean transition dyspnea index scores were 1.71 and 1.50, with a nonsignificant difference of 0.21.

“To be honest, I don’t think we had expected that [the triple combination] would mean much for patients, but we were hoping there would be a significant increase in lung function and a reduction of symptoms,” Dr. Vestbo said about the TRILOGY study. “What we saw was there was [symptomatic improvement] but it was not quite as impressive as we thought, but we reduced exacerbations.”

There was a significant, 23% reduction in the annualized exacerbation rate via the triple combination versus the ICS/LABA combination (0.41 vs 0.53, adjusted rate ratio 0.77, P = .005).

The triple approach was well tolerated, with no increase in adverse events versus the dual combination. The results support the idea that instead of giving patients an ICS/LABA at the start, better disease control can be achieved with a triple fixed-dose combination, Dr. Vestbo suggested.

Writing in The Lancet, Dr. Calverley noted: “The inability to meet one part of a co–primary endpoint clouds the interpretation of the other findings in the study, a familiar problem in COPD trials.” He added that there was a significant difference in the overall St George’s Respiratory Questionnaire scores favoring the triple over double therapy.

Chiesi Farmaceutici SpA funded the studies. Dr. Vestbo was an investigator for both TRINITY and TRILOGY and has received honoraria for advising and presenting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis. Dr. Calverley has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca.

LONDON – AF-219, a promising targeted therapy for chronic cough derailed by taste disturbances, has been revived by new studies suggesting that there is a therapeutic window that preserves benefits but reduces the risk of the adverse effect, according to new data presented at the annual congress of the European Respiratory Society.

The median duration of chronic cough of the patients on which the new data is based was 13 years. For patients with this type of durable cough history, there is a major unmet need for effective agents, reported Dr. Jacky Smith, MB, ChB, PhD, and professor of respiratory medicine at the University of Manchester (England).

The P2X3 antagonist AF-219 “is showing real promise as an antitussive agent when used at low doses,” Dr. Smith said.

P2X3 receptors are expressed by afferent neurons on the vagus nerves and appear to be a strong trigger of cough when stimulated, according to previous work by Dr. Smith and others. AF-219 is an oral antagonist of P2X3 and produced a 75% reduction in cough frequency when administered in a dose of 600 mg twice daily in a previously reported double-blind, placebo-controlled pilot study (Abdulqawi R et al. Lancet. 2015;385:1198-205). “However, there was a small wrinkle. All of the patients had taste disturbances. At this dose, it was primarily loss of taste,” Dr. Smith explained. As P2X3 is also found on neurons mediating taste, the adverse event was consistent with the mechanism of AF-219.

A series of studies have since been conducted to show that much lower doses than the twice-daily 600 mg dose employed in the original trial provide an antitussive effect but impose a much reduced risk of affecting taste.

In the latest dose-ranging study, 30 patients, who on average were aged 60 years, were randomized in a crossover design to receive placebo or active therapy in sequential doses over 4 days each of 7.5 mg, 15 mg, 30 mg, or 50 mg twice daily. At the end of the initial 16-day study period and a washout of 14 to 21 days, the patients who were initially randomized to placebo were evaluated on the sequential doses of active therapy, and those previously treated with active therapy took placebo.

On placebo, there was no change in cough frequency. On active therapy, there were incremental reductions in cough at 7.5 and 15 mg, but the differences relative to placebo did not reach statistical significance. Significant reductions in cough frequency relative to placebo were reached on both the 30 mg (P = 0.001) and the 50 mg dose (P = 0.002). The reductions on these two doses, however, were not significantly different from each other, suggesting that 30 mg may be an adequate dose to achieve clinically relevant antitussive benefits.

Taste disturbances, which were reported in 6.7% of patients taking both the 7.5 mg and 15 mg dose, increased to 46.7% in those taking the 30 mg dose and then to 53.3% of those taking the 50 mg dose. Lack of taste was only reported by 6.7% of those taking the 50 mg dose and none of those taking lower doses. Other adverse events, such as nasal dryness and rhinitis, were infrequent (less than 10%) and not dose related.

“Significantly lower doses than we originally tested appear to provide near maximum antitussive effects but with a much reduced risk of changes in taste,” Dr. Smith reported.

She added that in this dose-ranging study, there was a correlation between increasing dose and increasing cough-specific measures of quality of life.

“These data support a separation of the dose response relationships for antitussive effects and taste disturbance,” Dr. Smith reported. “Studies of longer duration are needed to test sustained efficacy and tolerability.”

LONDON – AF-219, a promising targeted therapy for chronic cough derailed by taste disturbances, has been revived by new studies suggesting that there is a therapeutic window that preserves benefits but reduces the risk of the adverse effect, according to new data presented at the annual congress of the European Respiratory Society.

The median duration of chronic cough of the patients on which the new data is based was 13 years. For patients with this type of durable cough history, there is a major unmet need for effective agents, reported Dr. Jacky Smith, MB, ChB, PhD, and professor of respiratory medicine at the University of Manchester (England).

The P2X3 antagonist AF-219 “is showing real promise as an antitussive agent when used at low doses,” Dr. Smith said.

P2X3 receptors are expressed by afferent neurons on the vagus nerves and appear to be a strong trigger of cough when stimulated, according to previous work by Dr. Smith and others. AF-219 is an oral antagonist of P2X3 and produced a 75% reduction in cough frequency when administered in a dose of 600 mg twice daily in a previously reported double-blind, placebo-controlled pilot study (Abdulqawi R et al. Lancet. 2015;385:1198-205). “However, there was a small wrinkle. All of the patients had taste disturbances. At this dose, it was primarily loss of taste,” Dr. Smith explained. As P2X3 is also found on neurons mediating taste, the adverse event was consistent with the mechanism of AF-219.

A series of studies have since been conducted to show that much lower doses than the twice-daily 600 mg dose employed in the original trial provide an antitussive effect but impose a much reduced risk of affecting taste.

In the latest dose-ranging study, 30 patients, who on average were aged 60 years, were randomized in a crossover design to receive placebo or active therapy in sequential doses over 4 days each of 7.5 mg, 15 mg, 30 mg, or 50 mg twice daily. At the end of the initial 16-day study period and a washout of 14 to 21 days, the patients who were initially randomized to placebo were evaluated on the sequential doses of active therapy, and those previously treated with active therapy took placebo.

On placebo, there was no change in cough frequency. On active therapy, there were incremental reductions in cough at 7.5 and 15 mg, but the differences relative to placebo did not reach statistical significance. Significant reductions in cough frequency relative to placebo were reached on both the 30 mg (P = 0.001) and the 50 mg dose (P = 0.002). The reductions on these two doses, however, were not significantly different from each other, suggesting that 30 mg may be an adequate dose to achieve clinically relevant antitussive benefits.

Taste disturbances, which were reported in 6.7% of patients taking both the 7.5 mg and 15 mg dose, increased to 46.7% in those taking the 30 mg dose and then to 53.3% of those taking the 50 mg dose. Lack of taste was only reported by 6.7% of those taking the 50 mg dose and none of those taking lower doses. Other adverse events, such as nasal dryness and rhinitis, were infrequent (less than 10%) and not dose related.

“Significantly lower doses than we originally tested appear to provide near maximum antitussive effects but with a much reduced risk of changes in taste,” Dr. Smith reported.

She added that in this dose-ranging study, there was a correlation between increasing dose and increasing cough-specific measures of quality of life.

“These data support a separation of the dose response relationships for antitussive effects and taste disturbance,” Dr. Smith reported. “Studies of longer duration are needed to test sustained efficacy and tolerability.”

LONDON – AF-219, a promising targeted therapy for chronic cough derailed by taste disturbances, has been revived by new studies suggesting that there is a therapeutic window that preserves benefits but reduces the risk of the adverse effect, according to new data presented at the annual congress of the European Respiratory Society.

The median duration of chronic cough of the patients on which the new data is based was 13 years. For patients with this type of durable cough history, there is a major unmet need for effective agents, reported Dr. Jacky Smith, MB, ChB, PhD, and professor of respiratory medicine at the University of Manchester (England).

The P2X3 antagonist AF-219 “is showing real promise as an antitussive agent when used at low doses,” Dr. Smith said.

P2X3 receptors are expressed by afferent neurons on the vagus nerves and appear to be a strong trigger of cough when stimulated, according to previous work by Dr. Smith and others. AF-219 is an oral antagonist of P2X3 and produced a 75% reduction in cough frequency when administered in a dose of 600 mg twice daily in a previously reported double-blind, placebo-controlled pilot study (Abdulqawi R et al. Lancet. 2015;385:1198-205). “However, there was a small wrinkle. All of the patients had taste disturbances. At this dose, it was primarily loss of taste,” Dr. Smith explained. As P2X3 is also found on neurons mediating taste, the adverse event was consistent with the mechanism of AF-219.

A series of studies have since been conducted to show that much lower doses than the twice-daily 600 mg dose employed in the original trial provide an antitussive effect but impose a much reduced risk of affecting taste.

In the latest dose-ranging study, 30 patients, who on average were aged 60 years, were randomized in a crossover design to receive placebo or active therapy in sequential doses over 4 days each of 7.5 mg, 15 mg, 30 mg, or 50 mg twice daily. At the end of the initial 16-day study period and a washout of 14 to 21 days, the patients who were initially randomized to placebo were evaluated on the sequential doses of active therapy, and those previously treated with active therapy took placebo.

On placebo, there was no change in cough frequency. On active therapy, there were incremental reductions in cough at 7.5 and 15 mg, but the differences relative to placebo did not reach statistical significance. Significant reductions in cough frequency relative to placebo were reached on both the 30 mg (P = 0.001) and the 50 mg dose (P = 0.002). The reductions on these two doses, however, were not significantly different from each other, suggesting that 30 mg may be an adequate dose to achieve clinically relevant antitussive benefits.

Taste disturbances, which were reported in 6.7% of patients taking both the 7.5 mg and 15 mg dose, increased to 46.7% in those taking the 30 mg dose and then to 53.3% of those taking the 50 mg dose. Lack of taste was only reported by 6.7% of those taking the 50 mg dose and none of those taking lower doses. Other adverse events, such as nasal dryness and rhinitis, were infrequent (less than 10%) and not dose related.

“Significantly lower doses than we originally tested appear to provide near maximum antitussive effects but with a much reduced risk of changes in taste,” Dr. Smith reported.

She added that in this dose-ranging study, there was a correlation between increasing dose and increasing cough-specific measures of quality of life.

“These data support a separation of the dose response relationships for antitussive effects and taste disturbance,” Dr. Smith reported. “Studies of longer duration are needed to test sustained efficacy and tolerability.”