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61 Tiotropium Respimat in cystic fibrosis: Efficacy and safety results of phase III randomized placebo-controlled trial
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4. New therapies
61 Tiotropium Respimat in cystic fibrosis: Efficacy and safety results of phase III randomized placebo-controlled trial F. Ratjen1 , P. Koker2 , D. Geller3 , B. Langellier-Cocteaux4 , F. Le Maulf4 , S. Kattenbeck5 , P. Moroni-Zentgraf6 , J.S. Elborn7 . 1 The Hospital of Sick Children, Toronto, Canada; 2 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, United States; 3 Florida State University College of Medicine, Orlando, United States; 4 Boehringer Ingelheim France SAS, Reims, France; 5 Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 6 Boehringer Ingelheim GmbH, Ingelheim, Germany; 7 Queen’s University Belfast, Centre for Infection and Immunity, Belfast, N Ireland, United Kingdom Background: Tiotropium, a once-daily (qd), long-acting, anticholinergic bronchodilator delivered via Respimat® Soft Mist™ Inhaler, significantly improved lung function in a phase II trial investigating two doses (2.5 and 5 mg qd) in people with cystic fibrosis (CF). Lung function improved dose-dependently and safety was balanced overall, supporting further investigation of the 5 mg dose in a phase III trial. Methods: This phase III, 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of tiotropium 5 mg via Respimat® followed by an open-label, active-treatment phase (>12 weeks) included people with CF and prebronchodilator FEV1 25%pred normal (no upper limit). All usual CF maintenance therapies were allowed throughout the trial. Results: During the double-blind period, 463 patients (tiotropium 308, placebo 155; mean age 19.8 y) were treated. Differences between tiotropium vs placebo in change from baseline at Week 12 in both coprimary efficacy endpoints were not statistically significant: %pred FEV1 AUC0−4h , 1.64%, 95%CI −0.27, 3.55, P = 0.092; %pred trough FEV1, 1.40%; 95%CI −0.50, 3.30; P = 0.15. The proportion of patients with 1 pulmonary exacerbation (per RSSQ method: tiotropium 8.9%, placebo 7.8%) and changes in CFQ-R mean domain scores were similar in both treatment groups over 12 weeks. Adverse events (AEs) were similar in both groups with relevant AEs mainly related to pulmonary exacerbations. Conclusion: Lung function improvement in patients on tiotropium vs placebo as add-on to CF standard of care was not statistically significant. Tiotropium was well tolerated in people with CF, consistent with the known safety profile of tiotropium in COPD.
Posters
63 The use of high resolution computerized tomography of the chest in evaluating the effect of ataluren in nonsense mutation cystic fibrosis (nmCF) lung disease T. Ajayi1 , M. Konstan2 , F.J. Accurso3 , K. De Boeck4 , E. Kerem5 , S. Rowe6 , I. Sermet-Gaudelus7 , M. Wilschanski5 , A. Brody8 , N. Miller1 , G. Elfring1 , R. Spiegel1 , S. Peltz1 , J. Barth1 , Ataluren CF Study Group. 1 PTC Therapeutics, Inc, South Plainfield, United States; 2 Rainbow Babies and Children’s Hospital, Pediatric Pulmonology Division, Cleveland, United States; 3 Children’s Hospital Colorado, Aurora, United States; 4 University Hospital Leuven, Leuven, Belgium; 5 Hadassah University Hospital, Jerusalem, Israel; 6 University of AlabamaBirmingham, Birmingham, United States; 7 Hˆopital Necker, Paris, France; 8 Cincinnati Children’s Hospital Medical Center, Cincinnati, United States Background: Ataluren, which enables readthrough of premature termination codons and production of full-length protein in individuals with nonsense mutations (nm), is being developed as a potential therapy in CF. CT scan scores were used to measure the effects of ataluren on lung disease in nmCF. Methods: This Phase 3, double-blind study enrolled patients 6 yrs of age with nmCF to receive daily TID ataluren 10, 10, 20 mg/kg or placebo (PBO) for 48 wks. A CT scan of the chest was obtained at baseline and at end of treatment (EOT). Each lobe was scored using the Brody scoring system. The average of 2 blinded reviewers was used to determine total lung score (TLS) and specific subscores (lower scores indicating improvement). Results: Baseline and EOT CT scans were obtained for 203 patients who completed 48 wks of blinded treatment. The difference in mean TLS between the ataluren and PBO groups at EOT (−0.28) was not significant. The mean change from baseline in TLS at EOT was small for the ataluren group (0.28±1.34; n = 99) and the PBO group (0.56±1.56; n = 104) and was not significant. Importantly, this lack of change in the PBO group is contrasted to the mean relative change in %-pred FEV1 of −5.5% seen during the same time period. Conclusion: This double-blind study represents the largest study using CT scans to measure the effects of a therapeutic intervention. The lack of change in TLS in the PBO arm, despite a significant reduction in FEV1 over 48 wks, suggests that morphologic change on CT does not parallel functional change in FEV1. That the lack of disease progression as observed on CT may limit its use in study designs dependent on progressive disease in the PBO arm.
62 Oral reduced L-glutathione improves weight and calprotectin in pediatric cystic fibrosis patients
64 Tiotropium in cystic fibrosis: Pooled analysis of phase II and III randomized, controlled trials
A. Visca1 , S.C. Hilton2 , V.M. Hudson3 , C.T. Bishop4 . 1 Azienda Sanitaria Locale TO3, Pediatria, Collegno, Italy; 2 Brigham Young University, Provo, United States; 3 Texas A&M University, Dallas, United States; 4 Intermountain Health Care, Orem, United States
D. Geller1 , P. Koker2 , J.S. Elborn3 , F. Le Maulf4 , S. Kattenbeck5 , P. MoroniZentgraf6 , F. Ratjen7 . 1 Florida State University College of Medicine, Orlando, United States; 2 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, United States; 3 Queen’s University Belfast, Centre for Infection and Immunity, Belfast, N Ireland, United Kingdom; 4 Boehringer Ingelheim France SAS, Reims, France; 5 Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 6 Boehringer Ingelheim GmbH, Ingelheim, Germany; 7 The Hospital of Sick Children, Toronto, Canada
Objectives: The need for effective, non-invasive treatment for Cystic Fibrosis (CF) growth failure is imperative, as lung function scores closely track weight percentile in CF. Methods: We perform an age-stratified, placebo-controlled, double-blinded, repeated measures clinical trial of oral GSH in 44 pediatric CF patients over six months (dose 65 mg/kg, divided into three doses per day). Conclusion: The GSH treatment group gained an average of 16.9 weight percentile points over the course of six months, with no adverse side effects (versus placebo +2.9, p < 0.001), representing almost a doubling of their mean weight percentile at baseline. Other measures, including fecal calprotectin, height percentile, BMI, FEV1% and FVC%, also improved significantly in the GSH treatment group. Glutahione is a ubiquitous tripeptide, found in all mammalian tissue. Glutathione is present in nearly all foods, and a normal diet would provide approximately 100– 250 mg per day. Oral GSH has no known toxicity. There is a pressing need for safe, effective, and non-invasive techniques to augment weight gain in children with cystic fibrosis. Cochrane Database reviews of current weight augmentation treatments in pediatric cystic fibrosis patients found that high calorie oral supplements were non-effective; enteral tube feeding was minimally effective and invasive with negative side effects; and appetite stimulants were marginally effective with significant negative side effects. Given the favorable safety profile of oral GSH, we recommend that clinicians consider whether their patients might benefit from the addition of oral GSH to their daily regimen.
Background: Tiotropium is a once-daily, long-acting, anticholinergic bronchodilator. Tiotropium Respimat® Soft Mist™ Inhaler improved lung function compared with placebo as add-on treatment to standard of care in phase II (Elborn et al. J Cystic Fibrosis. 2011;10;Suppl 1;S21/A080) and III trials in people with cystic fibrosis (CF), but statistical significance was only reached in the phase II trial. A prespecified pooled analysis was conducted to increase the precision of the estimates on the efficacy and safety of tiotropium 5 mg in CF. Methods: The randomized, double-blind, 12-week clinical, phase II and III trials followed the same design to enable pooling. People with CF with a prebronchodilator FEV1 25%pred normal (no upper limit) were included. All usual CF maintenance therapies were allowed throughout the trial. Results: A total of 807 patients (323 placebo; 484 tiotropium) were treated (mean age 20.1 y). A treatment difference in favour of tiotropium was observed in the change from baseline %pred FEV1 AUC0−4h (2.62%; 95% CI 1.34, 3.90) and %pred trough FEV1 (1.85%; 95% CI 0.53, 3.18). The proportion of patients with 1 pulmonary exacerbation (per RSSQ method tiotropium 7.5%; placebo: 8.6%) and changes in mean domain scores of the CFQ-R were similar between treatment groups. Adverse events (AEs) were similar in both groups with relevant AEs mainly related to pulmonary exacerbations. Conclusion: In people with CF, the bronchodilatory effects of tiotropium were not accompanied by improvements in symptomatic and health outcome parameters. Tiotropium was well tolerated in people with CF, consistent with the known safety profile of tiotropium in COPD.
4. New therapies
61 Tiotropium Respimat in cystic fibrosis: Efficacy and safety results of phase III randomized placebo-controlled trial F. Ratjen1 , P. Koker2 , D. Geller3 , B. Langellier-Cocteaux4 , F. Le Maulf4 , S. Kattenbeck5 , P. Moroni-Zentgraf6 , J.S. Elborn7 . 1 The Hospital of Sick Children, Toronto, Canada; 2 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, United States; 3 Florida State University College of Medicine, Orlando, United States; 4 Boehringer Ingelheim France SAS, Reims, France; 5 Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 6 Boehringer Ingelheim GmbH, Ingelheim, Germany; 7 Queen’s University Belfast, Centre for Infection and Immunity, Belfast, N Ireland, United Kingdom Background: Tiotropium, a once-daily (qd), long-acting, anticholinergic bronchodilator delivered via Respimat® Soft Mist™ Inhaler, significantly improved lung function in a phase II trial investigating two doses (2.5 and 5 mg qd) in people with cystic fibrosis (CF). Lung function improved dose-dependently and safety was balanced overall, supporting further investigation of the 5 mg dose in a phase III trial. Methods: This phase III, 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of tiotropium 5 mg via Respimat® followed by an open-label, active-treatment phase (>12 weeks) included people with CF and prebronchodilator FEV1 25%pred normal (no upper limit). All usual CF maintenance therapies were allowed throughout the trial. Results: During the double-blind period, 463 patients (tiotropium 308, placebo 155; mean age 19.8 y) were treated. Differences between tiotropium vs placebo in change from baseline at Week 12 in both coprimary efficacy endpoints were not statistically significant: %pred FEV1 AUC0−4h , 1.64%, 95%CI −0.27, 3.55, P = 0.092; %pred trough FEV1, 1.40%; 95%CI −0.50, 3.30; P = 0.15. The proportion of patients with 1 pulmonary exacerbation (per RSSQ method: tiotropium 8.9%, placebo 7.8%) and changes in CFQ-R mean domain scores were similar in both treatment groups over 12 weeks. Adverse events (AEs) were similar in both groups with relevant AEs mainly related to pulmonary exacerbations. Conclusion: Lung function improvement in patients on tiotropium vs placebo as add-on to CF standard of care was not statistically significant. Tiotropium was well tolerated in people with CF, consistent with the known safety profile of tiotropium in COPD.
Posters
63 The use of high resolution computerized tomography of the chest in evaluating the effect of ataluren in nonsense mutation cystic fibrosis (nmCF) lung disease T. Ajayi1 , M. Konstan2 , F.J. Accurso3 , K. De Boeck4 , E. Kerem5 , S. Rowe6 , I. Sermet-Gaudelus7 , M. Wilschanski5 , A. Brody8 , N. Miller1 , G. Elfring1 , R. Spiegel1 , S. Peltz1 , J. Barth1 , Ataluren CF Study Group. 1 PTC Therapeutics, Inc, South Plainfield, United States; 2 Rainbow Babies and Children’s Hospital, Pediatric Pulmonology Division, Cleveland, United States; 3 Children’s Hospital Colorado, Aurora, United States; 4 University Hospital Leuven, Leuven, Belgium; 5 Hadassah University Hospital, Jerusalem, Israel; 6 University of AlabamaBirmingham, Birmingham, United States; 7 Hˆopital Necker, Paris, France; 8 Cincinnati Children’s Hospital Medical Center, Cincinnati, United States Background: Ataluren, which enables readthrough of premature termination codons and production of full-length protein in individuals with nonsense mutations (nm), is being developed as a potential therapy in CF. CT scan scores were used to measure the effects of ataluren on lung disease in nmCF. Methods: This Phase 3, double-blind study enrolled patients 6 yrs of age with nmCF to receive daily TID ataluren 10, 10, 20 mg/kg or placebo (PBO) for 48 wks. A CT scan of the chest was obtained at baseline and at end of treatment (EOT). Each lobe was scored using the Brody scoring system. The average of 2 blinded reviewers was used to determine total lung score (TLS) and specific subscores (lower scores indicating improvement). Results: Baseline and EOT CT scans were obtained for 203 patients who completed 48 wks of blinded treatment. The difference in mean TLS between the ataluren and PBO groups at EOT (−0.28) was not significant. The mean change from baseline in TLS at EOT was small for the ataluren group (0.28±1.34; n = 99) and the PBO group (0.56±1.56; n = 104) and was not significant. Importantly, this lack of change in the PBO group is contrasted to the mean relative change in %-pred FEV1 of −5.5% seen during the same time period. Conclusion: This double-blind study represents the largest study using CT scans to measure the effects of a therapeutic intervention. The lack of change in TLS in the PBO arm, despite a significant reduction in FEV1 over 48 wks, suggests that morphologic change on CT does not parallel functional change in FEV1. That the lack of disease progression as observed on CT may limit its use in study designs dependent on progressive disease in the PBO arm.
62 Oral reduced L-glutathione improves weight and calprotectin in pediatric cystic fibrosis patients
64 Tiotropium in cystic fibrosis: Pooled analysis of phase II and III randomized, controlled trials
A. Visca1 , S.C. Hilton2 , V.M. Hudson3 , C.T. Bishop4 . 1 Azienda Sanitaria Locale TO3, Pediatria, Collegno, Italy; 2 Brigham Young University, Provo, United States; 3 Texas A&M University, Dallas, United States; 4 Intermountain Health Care, Orem, United States
D. Geller1 , P. Koker2 , J.S. Elborn3 , F. Le Maulf4 , S. Kattenbeck5 , P. MoroniZentgraf6 , F. Ratjen7 . 1 Florida State University College of Medicine, Orlando, United States; 2 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, United States; 3 Queen’s University Belfast, Centre for Infection and Immunity, Belfast, N Ireland, United Kingdom; 4 Boehringer Ingelheim France SAS, Reims, France; 5 Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 6 Boehringer Ingelheim GmbH, Ingelheim, Germany; 7 The Hospital of Sick Children, Toronto, Canada
Objectives: The need for effective, non-invasive treatment for Cystic Fibrosis (CF) growth failure is imperative, as lung function scores closely track weight percentile in CF. Methods: We perform an age-stratified, placebo-controlled, double-blinded, repeated measures clinical trial of oral GSH in 44 pediatric CF patients over six months (dose 65 mg/kg, divided into three doses per day). Conclusion: The GSH treatment group gained an average of 16.9 weight percentile points over the course of six months, with no adverse side effects (versus placebo +2.9, p < 0.001), representing almost a doubling of their mean weight percentile at baseline. Other measures, including fecal calprotectin, height percentile, BMI, FEV1% and FVC%, also improved significantly in the GSH treatment group. Glutahione is a ubiquitous tripeptide, found in all mammalian tissue. Glutathione is present in nearly all foods, and a normal diet would provide approximately 100– 250 mg per day. Oral GSH has no known toxicity. There is a pressing need for safe, effective, and non-invasive techniques to augment weight gain in children with cystic fibrosis. Cochrane Database reviews of current weight augmentation treatments in pediatric cystic fibrosis patients found that high calorie oral supplements were non-effective; enteral tube feeding was minimally effective and invasive with negative side effects; and appetite stimulants were marginally effective with significant negative side effects. Given the favorable safety profile of oral GSH, we recommend that clinicians consider whether their patients might benefit from the addition of oral GSH to their daily regimen.
Background: Tiotropium is a once-daily, long-acting, anticholinergic bronchodilator. Tiotropium Respimat® Soft Mist™ Inhaler improved lung function compared with placebo as add-on treatment to standard of care in phase II (Elborn et al. J Cystic Fibrosis. 2011;10;Suppl 1;S21/A080) and III trials in people with cystic fibrosis (CF), but statistical significance was only reached in the phase II trial. A prespecified pooled analysis was conducted to increase the precision of the estimates on the efficacy and safety of tiotropium 5 mg in CF. Methods: The randomized, double-blind, 12-week clinical, phase II and III trials followed the same design to enable pooling. People with CF with a prebronchodilator FEV1 25%pred normal (no upper limit) were included. All usual CF maintenance therapies were allowed throughout the trial. Results: A total of 807 patients (323 placebo; 484 tiotropium) were treated (mean age 20.1 y). A treatment difference in favour of tiotropium was observed in the change from baseline %pred FEV1 AUC0−4h (2.62%; 95% CI 1.34, 3.90) and %pred trough FEV1 (1.85%; 95% CI 0.53, 3.18). The proportion of patients with 1 pulmonary exacerbation (per RSSQ method tiotropium 7.5%; placebo: 8.6%) and changes in mean domain scores of the CFQ-R were similar between treatment groups. Adverse events (AEs) were similar in both groups with relevant AEs mainly related to pulmonary exacerbations. Conclusion: In people with CF, the bronchodilatory effects of tiotropium were not accompanied by improvements in symptomatic and health outcome parameters. Tiotropium was well tolerated in people with CF, consistent with the known safety profile of tiotropium in COPD.