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WS5.4 Aztreonam for inhalation solution (AZLI) in cystic fibrosis (CF) patients with chronic Burkholderia species (BURK) infection: final results from a randomized, placebo-controlled trial
Oral Presentations
Workshop 5. Clearing Infection from Airways
S11
WS5.1 Inhaled glutathione in cystic fibrosis M. Griese1 , A. Hector2 , M. Kappler2 , M. Ballmann3 , S. Junge3 , E. Rietschel4 , D. Staab5 , S. van Koningsbruggen4 , C. Rolinck-Werninghaus5 , U. Mellis6 , T. K¨ohnlein3 , T. Wagner7 , C. C¨orner-Rettberg8 , H. Teschler6 , E. Heuer9 , M. Kopp10 , S. Heyder11 , J. Hammermann12 , P. K¨uster13 , A. Reimann14 , M. Honer14 , U. Mansmann2 , C. Eismann2 , German IGOR-Study Group. 1 University of Munich, Children’s Hospital, Munich, Germany; 2 University of Munich, Munich, Germany; 3 Medical School Hannover, Hannover, Germany; 4 University of Cologne, Cologne, Germany; 5 Charite, Berlin, Germany; 6 University of Essen, Essen, Germany; 7 University of Frankfurt, Frankfurt, Germany; 8 University of Bochum, Bochum, Germany; 9 Praxis, Hamburg, Germany; 10 University of Freiburg, Freiburg, Germany; 11 University of Leipzig, Leipzig, Germany; 12 University of Dresden, Dresden, Germany; 13 Clemenshospital, M¨unster, Germany; 14 Mukoviszidose-Institut, Bonn, Germany
C.S. Dalboege1 , X.C. Nielsen2 , K. Dalhoff3 , M. Duno4 , A. Buchard5 , A.G. Jensen6 , T. Pressler7 , H. Wang1 , N. Høiby1,8 , H.K. Johansen1 . 1 Rigshospitalet, Dept. of Clinical Microbiology, Copenhagen Ø, Denmark; 2 Slagelse Hospital, Dept. of Clinical Microbiology, Slagelse, Denmark; 3 Bispebjerg Hospital, Dept. of Clinical Pharmacology, Copenhagen NV, Denmark; 4 Rigshospitalet, Dept. of Clinical Genetics, Copenhagen Ø, Denmark; 5 Copenhagen University, Dept. of Forensic Medicine, Copenhagen N, Denmark; 6 Rigshospitalet, Department of Infectious Diseases, Copenhagen Ø, Denmark; 7 Rigshospitalet, Cystic Fibrosis Centre, Copenhagen Ø, Denmark; 8 University of Copenhagen, Dept. of International Health, Immunology, and Microbiology, Copenhagen N, Denmark
Decreased level of reduced glutathione (GSH) were found in CF epithelial lining fluid and anecdotal evidence suggested improved lung function after GSH-inhalation. In a double-blind, placebo-controlled, randomized clinical trial we investigated the safety and efficacy of inhaled glutathione. Of 153 subjects (age 8 years, FEV1 40%, 90%) 73 inhaled glutathione (646 mg GSH-Na) over 24 wks via a specialized e-flow device twice daily and 80 used placebo (0.9% saline). A 5% increase in lung function compared to placebo was predefined as clinically relevant. The primary outcome variable, the absolute change in FEV1 was not significantly affected by treatment over the study period. Exploratory analysis showed only a small effect on FEV1 at 3 months of treatment. Body weight, rate and time to pulmonary exacerbations, quality of life (QOL) total and respiratory score were not different. Safety was good, with no differences of adverse events, rate of premature withdrawals and change in laboratory parameters between treatment groups. In the GSH-group, both free and total GSH in sputum samples were increased after 3 and 6 months of treatment, however, cellular, inflammatory, redox-state and proteolytic markers remained unchanged. This study did not demonstrate a statistically significant effect of inhaled GSH on the primary endpoint FEV1. Other important secondary endpoints also did not change significantly with treatment. Inhaled glutathione was save at dose and duration applied. Supported by Cystic Fibrosis Foundation (CFF), Mukoviszidose eV, Else-Kr¨onerFresenius Stiftung, Pari-research. Sponsor: Mukoviszidose Institut gGmbH, Bonn, Germany.
Objectives: Ciprofloxacin (CIP) is used to treat CF patients and is partly metabolised in the liver by the CYP3A4 enzyme. We investigated the correlation between the enzyme activity and the metabolism of CIP. A Monte Carlo simulation was performed to predict eventual treatment failure. Methods: We included 22 CF patients (21−53 yr) with chronic P. aeruginosa lung infections. The CYP3A activity was measured using the ERMBT. 500 mg CIP was given orally and blood samples were collected every half hour the first 3 h and at 6 and 12 h. The concentrations of CIP were calculated by using a biological assay. AUC, Tmax and Cmax were calculated. The Monte Carlo simulation was based on the MIC of 119 P. aeruginosa strains. Results: A 14-fold variation, median (range), in AUC (mg·min/liter); 473.5 (138– 1880) for CIP, a 30-fold variation in Cmax (mg/liter); 2 (0.25−7.6) and a 3 foldvariation in Tmax (min); 91 (46–153) was found. We found an 8-fold variation in the CYP3A4 activity, with a median (range) of 0.8 (0.3−2.0), but no correlation with CIP metabolism was found. The Monte Carlo simulation showed that some of the patients did not reach concentrations high enough to eradicate the bacteria. Conclusion: We found a large variation in the metabolism of CIP and some patients may not have reached a high enough MIC/AUC ratio. We therefore recommend that plasma concentrations and MIC of the bacteria are measured regularly to avoid treatment failure.
WS5.2 Inhaled dry powder mannitol in cystic fibrosis (CF): impact on pulmonary exacerbations (PEs) in the Phase III studies (CF-301 & CF-302)
WS5.4 Aztreonam for inhalation solution (AZLI) in cystic fibrosis (CF) patients with chronic Burkholderia species (BURK ) infection: final results from a randomized, placebo-controlled trial
D. Bilton1 , M. Aitken2 , K. De Boeck3 , H. Fox4 , B. Charlton4 , CF-301 & CF-302 Study Investigators. 1 Royal Brompton Hospital & Harefield NHS Foundation Trust, Department of Respiratory Medicine, London, United Kingdom; 2 Universiity of Washington, Department of Medicine, Seattle, United States; 3 University Hospital Gasthuisberg, Department of Pediatrics, Leuven, Belgium; 4 Pharmaxis Ltd, Frenchs Forest, Australia
E. Tullis1 , J. Burns2 , G. Retsch-Bogart3 , M. Bresnik4 , N. Henig4 , S. Lewis5 , J.J. LiPuma6 . 1 University of Toronto, Toronto, Canada; 2 University of Washington, Seattle, United States; 3 University of North Carolina, Chapel Hill, United States; 4 Gilead Sciences Inc, Foster City, United States; 5 Gilead Sciences Inc, Seattle, United States; 6 University of Michigan, Ann Arbor, United States
Introduction: PEs in CF are linked to accelerated declines in lung function and mortality [1]. Two large phase III trials of inhaled dry powder mannitol (IDPM) have demonstrated sustained, clinically meaningful improvements in lung function from baseline over 26 weeks. The large population from these studies provides the opportunity to explore the impact of IDPM on PEs in CF. Methods: Data were pooled from two similar, randomized (3:2), controlled, parallel group phase III studies in which a total of 600 pts received either IDPM (400 mg) or control (mannitol 50 mg) b.i.d. for 26 weeks. Protocol defined pulmonary exacerbations (PDPE) were assessed using Fuchs’ criteria [2]. Results: The incidence of pts with 1 PDPE was 29% lower (p = 0.039) in the IDPM group than in the control group. Associated rescue antibiotic use incidence was reduced by 30% (p = 0.033), in the IDPM group vs. the control. The supportive positive trend of a 22% reduction in PDPE-related hospitalization incidence did not reach statistical significance (p = 0.219). The annualized PDPE rate was significantly lower in those patients treated with IDPM who had any improvement from baseline over 26 weeks in %-predicted FEV1 (0.56 PDPE/year) compared to those who did not show FEV1 improvement (1.36/year) (p = 0.03). Conclusions: PEs are a key driver of worsening lung function in CF, which is not restored to pre-exacerbation levels in up to 25% of cases. IDPM has an important impact on the rate of PEs, with a reduced risk seen predominantly in those patients who had also shown an improvement in pulmonary function. Reference(s) [1] de Boer K, et al. Thorax 2011; Aug;66(8):680−5. [2] Fuchs HJ, et al. N Engl J Med. 1994; 331: 637−42.
WS5.3 Wide pharmacokinetic variability of ciprofloxacin in patients with cystic fibrosis (CF) − a reason of treatment failure?
Objectives: A randomized placebo (PBO)-controlled blinded 2-part trial of AZLI was conducted at 35 sites in the US and Canada. In the 24 wk randomized phase, there was no difference between patients (pts) treated with AZLI or PBO in % change in FEV1 % predicted, measured by the time-adjusted area under the curve (AUCave ). Results of the 24 wk single-arm open label (OL) AZLI phase are presented. Methods: CF pts 6 yrs with chronic Burk infection and stable pulmonary disease were randomized to receive 24 wks of AZLI 75 mg or PBO TID daily via the Pari Investigational eFlow® Nebuliser, followed by 24 wks of OL AZLI. Results: Of 100 pts randomized, 84 pts (39 AZLI; 45, PBO) continued in the OL phase [mean age 26.6 yrs; mean FEV1 56% predicted (range 16%-105%)]. Lung function results are shown in Table 1. The number of respiratory events requiring antibiotics decreased in PBO pts when switched to AZLI (73 to 64). Total adverse event rates were similar in both groups. Mean Relative Change in FEV1% Predicted Treatment (Rand/OL)
Mean Change from Day 0 (Rand) Mean Change from Week 24 (OL) Day 28 Wk 24 AUCave at Wk 28 Wk 48 AUCave at Wk 24 Wk 48
AZLI/AZLI PBO/AZLI
4.35 −0.28
1.69 −2.92
0.16 −0.75
−2.43 6.15
−2.92 0.34
−1.52 2.29
Conclusions: Continuous AZLI treatment was safe in Burk-infected CF pts and maintained FEV1 above baseline for the first 24 wks of AZLI treatment in both AZLI-randomized pts and PBO pts crossing over to AZLI. Supported by Gilead Sciences
Workshop 5. Clearing Infection from Airways
S11
WS5.1 Inhaled glutathione in cystic fibrosis M. Griese1 , A. Hector2 , M. Kappler2 , M. Ballmann3 , S. Junge3 , E. Rietschel4 , D. Staab5 , S. van Koningsbruggen4 , C. Rolinck-Werninghaus5 , U. Mellis6 , T. K¨ohnlein3 , T. Wagner7 , C. C¨orner-Rettberg8 , H. Teschler6 , E. Heuer9 , M. Kopp10 , S. Heyder11 , J. Hammermann12 , P. K¨uster13 , A. Reimann14 , M. Honer14 , U. Mansmann2 , C. Eismann2 , German IGOR-Study Group. 1 University of Munich, Children’s Hospital, Munich, Germany; 2 University of Munich, Munich, Germany; 3 Medical School Hannover, Hannover, Germany; 4 University of Cologne, Cologne, Germany; 5 Charite, Berlin, Germany; 6 University of Essen, Essen, Germany; 7 University of Frankfurt, Frankfurt, Germany; 8 University of Bochum, Bochum, Germany; 9 Praxis, Hamburg, Germany; 10 University of Freiburg, Freiburg, Germany; 11 University of Leipzig, Leipzig, Germany; 12 University of Dresden, Dresden, Germany; 13 Clemenshospital, M¨unster, Germany; 14 Mukoviszidose-Institut, Bonn, Germany
C.S. Dalboege1 , X.C. Nielsen2 , K. Dalhoff3 , M. Duno4 , A. Buchard5 , A.G. Jensen6 , T. Pressler7 , H. Wang1 , N. Høiby1,8 , H.K. Johansen1 . 1 Rigshospitalet, Dept. of Clinical Microbiology, Copenhagen Ø, Denmark; 2 Slagelse Hospital, Dept. of Clinical Microbiology, Slagelse, Denmark; 3 Bispebjerg Hospital, Dept. of Clinical Pharmacology, Copenhagen NV, Denmark; 4 Rigshospitalet, Dept. of Clinical Genetics, Copenhagen Ø, Denmark; 5 Copenhagen University, Dept. of Forensic Medicine, Copenhagen N, Denmark; 6 Rigshospitalet, Department of Infectious Diseases, Copenhagen Ø, Denmark; 7 Rigshospitalet, Cystic Fibrosis Centre, Copenhagen Ø, Denmark; 8 University of Copenhagen, Dept. of International Health, Immunology, and Microbiology, Copenhagen N, Denmark
Decreased level of reduced glutathione (GSH) were found in CF epithelial lining fluid and anecdotal evidence suggested improved lung function after GSH-inhalation. In a double-blind, placebo-controlled, randomized clinical trial we investigated the safety and efficacy of inhaled glutathione. Of 153 subjects (age 8 years, FEV1 40%, 90%) 73 inhaled glutathione (646 mg GSH-Na) over 24 wks via a specialized e-flow device twice daily and 80 used placebo (0.9% saline). A 5% increase in lung function compared to placebo was predefined as clinically relevant. The primary outcome variable, the absolute change in FEV1 was not significantly affected by treatment over the study period. Exploratory analysis showed only a small effect on FEV1 at 3 months of treatment. Body weight, rate and time to pulmonary exacerbations, quality of life (QOL) total and respiratory score were not different. Safety was good, with no differences of adverse events, rate of premature withdrawals and change in laboratory parameters between treatment groups. In the GSH-group, both free and total GSH in sputum samples were increased after 3 and 6 months of treatment, however, cellular, inflammatory, redox-state and proteolytic markers remained unchanged. This study did not demonstrate a statistically significant effect of inhaled GSH on the primary endpoint FEV1. Other important secondary endpoints also did not change significantly with treatment. Inhaled glutathione was save at dose and duration applied. Supported by Cystic Fibrosis Foundation (CFF), Mukoviszidose eV, Else-Kr¨onerFresenius Stiftung, Pari-research. Sponsor: Mukoviszidose Institut gGmbH, Bonn, Germany.
Objectives: Ciprofloxacin (CIP) is used to treat CF patients and is partly metabolised in the liver by the CYP3A4 enzyme. We investigated the correlation between the enzyme activity and the metabolism of CIP. A Monte Carlo simulation was performed to predict eventual treatment failure. Methods: We included 22 CF patients (21−53 yr) with chronic P. aeruginosa lung infections. The CYP3A activity was measured using the ERMBT. 500 mg CIP was given orally and blood samples were collected every half hour the first 3 h and at 6 and 12 h. The concentrations of CIP were calculated by using a biological assay. AUC, Tmax and Cmax were calculated. The Monte Carlo simulation was based on the MIC of 119 P. aeruginosa strains. Results: A 14-fold variation, median (range), in AUC (mg·min/liter); 473.5 (138– 1880) for CIP, a 30-fold variation in Cmax (mg/liter); 2 (0.25−7.6) and a 3 foldvariation in Tmax (min); 91 (46–153) was found. We found an 8-fold variation in the CYP3A4 activity, with a median (range) of 0.8 (0.3−2.0), but no correlation with CIP metabolism was found. The Monte Carlo simulation showed that some of the patients did not reach concentrations high enough to eradicate the bacteria. Conclusion: We found a large variation in the metabolism of CIP and some patients may not have reached a high enough MIC/AUC ratio. We therefore recommend that plasma concentrations and MIC of the bacteria are measured regularly to avoid treatment failure.
WS5.2 Inhaled dry powder mannitol in cystic fibrosis (CF): impact on pulmonary exacerbations (PEs) in the Phase III studies (CF-301 & CF-302)
WS5.4 Aztreonam for inhalation solution (AZLI) in cystic fibrosis (CF) patients with chronic Burkholderia species (BURK ) infection: final results from a randomized, placebo-controlled trial
D. Bilton1 , M. Aitken2 , K. De Boeck3 , H. Fox4 , B. Charlton4 , CF-301 & CF-302 Study Investigators. 1 Royal Brompton Hospital & Harefield NHS Foundation Trust, Department of Respiratory Medicine, London, United Kingdom; 2 Universiity of Washington, Department of Medicine, Seattle, United States; 3 University Hospital Gasthuisberg, Department of Pediatrics, Leuven, Belgium; 4 Pharmaxis Ltd, Frenchs Forest, Australia
E. Tullis1 , J. Burns2 , G. Retsch-Bogart3 , M. Bresnik4 , N. Henig4 , S. Lewis5 , J.J. LiPuma6 . 1 University of Toronto, Toronto, Canada; 2 University of Washington, Seattle, United States; 3 University of North Carolina, Chapel Hill, United States; 4 Gilead Sciences Inc, Foster City, United States; 5 Gilead Sciences Inc, Seattle, United States; 6 University of Michigan, Ann Arbor, United States
Introduction: PEs in CF are linked to accelerated declines in lung function and mortality [1]. Two large phase III trials of inhaled dry powder mannitol (IDPM) have demonstrated sustained, clinically meaningful improvements in lung function from baseline over 26 weeks. The large population from these studies provides the opportunity to explore the impact of IDPM on PEs in CF. Methods: Data were pooled from two similar, randomized (3:2), controlled, parallel group phase III studies in which a total of 600 pts received either IDPM (400 mg) or control (mannitol 50 mg) b.i.d. for 26 weeks. Protocol defined pulmonary exacerbations (PDPE) were assessed using Fuchs’ criteria [2]. Results: The incidence of pts with 1 PDPE was 29% lower (p = 0.039) in the IDPM group than in the control group. Associated rescue antibiotic use incidence was reduced by 30% (p = 0.033), in the IDPM group vs. the control. The supportive positive trend of a 22% reduction in PDPE-related hospitalization incidence did not reach statistical significance (p = 0.219). The annualized PDPE rate was significantly lower in those patients treated with IDPM who had any improvement from baseline over 26 weeks in %-predicted FEV1 (0.56 PDPE/year) compared to those who did not show FEV1 improvement (1.36/year) (p = 0.03). Conclusions: PEs are a key driver of worsening lung function in CF, which is not restored to pre-exacerbation levels in up to 25% of cases. IDPM has an important impact on the rate of PEs, with a reduced risk seen predominantly in those patients who had also shown an improvement in pulmonary function. Reference(s) [1] de Boer K, et al. Thorax 2011; Aug;66(8):680−5. [2] Fuchs HJ, et al. N Engl J Med. 1994; 331: 637−42.
WS5.3 Wide pharmacokinetic variability of ciprofloxacin in patients with cystic fibrosis (CF) − a reason of treatment failure?
Objectives: A randomized placebo (PBO)-controlled blinded 2-part trial of AZLI was conducted at 35 sites in the US and Canada. In the 24 wk randomized phase, there was no difference between patients (pts) treated with AZLI or PBO in % change in FEV1 % predicted, measured by the time-adjusted area under the curve (AUCave ). Results of the 24 wk single-arm open label (OL) AZLI phase are presented. Methods: CF pts 6 yrs with chronic Burk infection and stable pulmonary disease were randomized to receive 24 wks of AZLI 75 mg or PBO TID daily via the Pari Investigational eFlow® Nebuliser, followed by 24 wks of OL AZLI. Results: Of 100 pts randomized, 84 pts (39 AZLI; 45, PBO) continued in the OL phase [mean age 26.6 yrs; mean FEV1 56% predicted (range 16%-105%)]. Lung function results are shown in Table 1. The number of respiratory events requiring antibiotics decreased in PBO pts when switched to AZLI (73 to 64). Total adverse event rates were similar in both groups. Mean Relative Change in FEV1% Predicted Treatment (Rand/OL)
Mean Change from Day 0 (Rand) Mean Change from Week 24 (OL) Day 28 Wk 24 AUCave at Wk 28 Wk 48 AUCave at Wk 24 Wk 48
AZLI/AZLI PBO/AZLI
4.35 −0.28
1.69 −2.92
0.16 −0.75
−2.43 6.15
−2.92 0.34
−1.52 2.29
Conclusions: Continuous AZLI treatment was safe in Burk-infected CF pts and maintained FEV1 above baseline for the first 24 wks of AZLI treatment in both AZLI-randomized pts and PBO pts crossing over to AZLI. Supported by Gilead Sciences