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We assessed safety and tolerability of treatment with pirfenidone (1602-2403 mg·day -1 ) and nintedanib (200-300 mg·day -1 ) in patients with idiopathic pulmonary fibrosis (IPF).This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day -1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602-2403 mg·day -1 ) and nintedanib (200-300 mg·day -1 ). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF., Competing Interests: Conflict of interest: K.R. Flaherty has received consultant and research support fees from F. Hoffmann-La Roche/Genentech and Boehringer Ingelheim, consultant fees from FibroGen, Veracyte, Aeolus, PharmaKea, Sanofi-Genzyme and Celgene, and research support fees from Afferent Pharmaceuticals. C.D. Fell has received consultant and research support fees from F. Hoffmann-La Roche Canada and consultant fees from Boehringer Ingelheim. J.T. Huggins has received consultant and research support fees from F. Hoffmann-La Roche/Genentech and Boehringer Ingelheim, and consultant fees from Gilead and iBIOS. H. Nunes has received consultant and research support fees from F. Hoffmann-La Roche/Genentech and Boehringer Ingelheim, and has been an investigator of clinical trials for Sanofi and Gilead. R. Sussman has received research support and speaker and consultation fees from F. Hoffmann-La Roche/Genentech and Boehringer Ingelheim, and research support from Gilead. C. Valenzuela has received speaker and consultation fees from F. Hoffmann-La Roche and Boehringer Ingelheim. J.L. Stauffer is an employee of Genentech and a former employee of FibroGen, and holds shares from both. F. Gilberg is an employee of F. Hoffmann-La Roche. M. Bengus is an employee of F. Hoffmann-La Roche. M. Wijsenbeek has received speaker and consultation fees and unrestricted research grants from F. Hoffmann-La Roche and Boehringer Ingelheim, and consultancy fees from Galapagos; all fees and grants were paid to her institution., (Copyright ©ERS 2018.)

Introduction: Temporary dose modifications, such as reductions or interruptions, may allow patients to better manage adverse events (AEs) associated with pirfenidone use and continue treatment for idiopathic pulmonary fibrosis (IPF). However, the impact of such dosing adjustments on efficacy and safety is uncertain., Methods: Patients randomised to receive treatment with pirfenidone 2403 mg/day or placebo in the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY (Study 004 (NCT00287716)) and Study 006 (NCT00287729))) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND (Study 016 (NCT01366209)) trials were included in the analysis (n=1247). Descriptive statistics and a linear mixed-effects model (slope analysis) for annual rate of decline in forced vital capacity (FVC) by dose intensity were performed. Treatment-emergent AEs (TEAEs) were summarised and grouped by dose intensity or body size., Results: Dose reductions and interruptions occurred in 76.9% (95% CI 73.4% to 80.1%) and 46.5% (95% CI 42.6% to 50.6%) of patients receiving pirfenidone vs 72.0% (95% CI 68.3% to 75.4%) and 31.1% (95% CI 27.5% to 34.9%) of patients receiving placebo, respectively. Dose interruptions tended to occur during the first 6 months of treatment, whereas dose reductions exhibited more variability. Less FVC decline from baseline was observed in patients receiving pirfenidone versus placebo at >90% dose intensity (p<0.001) or ≤90% dose intensity (p=0.0191), showing treatment benefit in both subgroups of dose intensity. No meaningful relationship between weight and TEAEs was observed., Conclusion: Dose interruptions, which may be required to manage TEAEs, mostly occurred during the first 6 months of treatment. Despite dose reductions and interruptions, most patients with IPF maintained relatively high dose intensity on pirfenidone, without compromising its treatment effect compared with placebo., Trial Registration Numbers: NCT00287729, NCT00287716, NCT01366209., Competing Interests: Competing interests: SDN was a member of the ASCEND study steering committee. He has been a consultant for Genentech/Roche, served on speakers’ bureaus for Genentech/Roche and Boehringer Ingelheim and has received research funding from Genentech/Roche and Boehringer Ingelheim. LHL was a member of the ASCEND study steering committee; she has served as a consultant and on scientific advisory boards for Boehringer Ingelheim, InterMune, Genentech and Veracyte. LHL has participated as a clinical trial investigator for Boehringer Ingelheim, Genentech, Stromedix, Gilead, Afferent, FibroGen, Bayer, Celgene and Veracyte. CA was a member of the CAPACITY study steering committee; he has served on a scientific advisory board for InterMune. CA has served as a consultant, steering committee member and speaker for Roche, FibroGen and Boehringer Ingelheim. MKG was a member of the ASCEND study steering committee. JJS was a member of the ASCEND study steering committee; he has served on a scientific advisory board and received research funding from InterMune. JJS served as a consultant to Boehringer Ingelheim and Roche, and has received honoraria from Genentech. UP is an employee of Clinipace Worldwide. PWN was a member of the ASCEND study steering committee and the CAPACITY study steering committee; he has served as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, InterMune, Moerae Matrix, Roche and Takeda. FG and K-UK are employees of F. Hoffmann-La Roche, Ltd., and K-UK is a shareholder. SLL is an employee of Genentech.

Aim: SWING was a prospective, observational study conducted in nine European countries primarily to assess direct treatment costs when switching from short-acting human insulins to rapid-acting insulin analogues (H-A) or vice versa (A-H) in patients with type 2 diabetes., Methods: Data were collected at a baseline visit (time of switch) and at approximately 3, 6 and 12 months post-switch., Results: In total, 2389 patients switched from H-A (n=2203) or A-H (n=186); another 603 were enrolled but ineligible. Mean (SD) direct diabetes-related costs (pro-rated to account for variable visit schedules) were €548.7 (865.8) 6 months prior to switch, €625.6 (1474.9) at 0-6 months and €568.6 (590.7) 6-12 months following switch for H-A, and €544.5 (421.0), €481.0 (301.5) and €461.6 (335.0) for A-H, respectively. Mean (SD) HbA(1c) decreased over 12 months by 1.08 (1.53)% units H-A and 1.17 (1.45)% units A-H. A small decline in hypoglycaemia occurred over time, but there were no clinically meaningful changes in mean PROs., Conclusions: There were small changes in mean direct diabetes-related costs (following adjustment for time interval) in patients switching in either direction. Improvements in mean HbA(1c) and incidence of hypoglycaemia cannot necessarily be attributed to therapeutic switch., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)