OFEV®

Footnotes:

•  
  * The TOMORROW trial was a phase 2 randomized, placebo-controlled, 52-week, dose-finding trial of nintedanib in 428 patients with IPF. Patients were randomized to 1 of 4 
  doses of nintedanib or placebo using a stepwise increasing dose approach. The primary endpoint was the annual rate of decline in FVC.³
• ^† Dose reduction to 100 mg twice daily and dose interruption were allowed to manage adverse events.²
•  
  ^‡ The annual rate of decline in FVC (mL/year) was calculated based on a linear regression model without imputation of missing values. All available FVC values from baseline to 
  week 52 were used, including FVC measurements from the follow-up visit for patients who prematurely discontinued trial medication and did not complete study visits until 
  week 52.²
• ^§ Diagnostic criteria for acute exacerbation of IPF were prespecified in the trial protocol features within 1 month, including all of the following:²
• - Dyspnea - unexplained worsening or development within 30 days
•  
  - Chest X-ray and/or HRCT - new diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion (new 
  ground-glass opacities) since last visit
• - Exclusion of infection - as per routine clinical practice and microbiological studies
• - Exclusion of alternative causes - as per routine clinical practice and including the following: left heart failure, pulmonary embolism, and identifiable cause of acute lung 
  injury
•  
  ^¶ Acute exacerbation of IPF reported by the site investigators as adverse events were adjudicated by a blinded adjudication committee to rule out non-exacerbation events. The 
  analysis of confirmed and suspected acute exacerbation of IPF as assessed by this committee in the pooled data from the 2 INPULSIS® trials was prespecified as a sensitivity 
  analysis of the key secondary endpoint.²
•  
  ^|| Absolute change from baseline was calculated using values at baseline and at 52 weeks.²
• ** Patients with an FVC response were defined as patients in whom the percentage of predicted FVC did not decline by >5% or by >10% at 52 weeks.²
•  
  ^†† Per protocol, the off-treatment period between INPULSIS® and INPULSIS®-ON could be between 4 and 12 weeks.¹⁴
• ^‡‡ The differences in FVC decline in INPULSIS®-ON between patients who received OFEV® and placebo in the preceding INPULSIS® trials were not considered to be clinically 
  meaningful, particularly when put into perspective with the FVC decline observed in placebo-treated patients in INPULSIS® (-223.5 mL/year) and the minimal clinically 
  important difference in FVC, which is believed to be 2% to 6% predicted (a difference of at least 75-80 mL).¹⁴
•  
  ^§§ Pooled analysis of data from three 52-week trials with OFEV® (nintedanib), INPULSIS®-1, INPULSIS®-2, and TOMORROW, including 1231 patients with IPF. Time to first 
  investigator-reported acute exacerbation of IPF over 52 weeks was a predefined secondary endpoint in the TOMORROW and INPULSIS® trials.^2,3,5
•  
  ^¶¶ The Weibull model was based on the better fitting statistical model.
•  
  ^|||| Based on the exponential distribution, mean survival was estimated as 13.1 years (95% CI 11.6, 14.9) in OFEV®-treated patients and 10.1 years (95% CI 7.8, 13.0) in placebo-
  treated patients.
• ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, twice a day; CI, confidence interval; DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, 
  forced expiratory volume at 1 second; FVC, forced vital capacity; HR, hazard ratio; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; IPF, idiopathic 
  pulmonary fibrosis; SGRQ, St. George’s Respiratory Questionnaire; SSc-ILD, systemic sclerosis-associated interstitial lung disease; UIP, usual interstitial pneumonia; ULN, upper 
  limit of normal.

References

1. OFEV® summary of product characteristics. Boehringer lngelheim International GmbH. July 2020.

2. Richeldi L, et al; for the INPULSIS® Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;380(22):2071-2082.

3. Richeldi L, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-1087.

4. TOMORROW Clinical Trial Report (Revision No. 1). Boehringer Ingelheim. January 2012.

5. Richeldi L, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS® trials. Respir Med. 2016;113:74-79. doi:10.1016/j.rmed.2016.02.001.

6. Kondoh Y, et al. Recent lessons learned in the management of acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir Rev. 2017;26(145):170050. doi:10.1183/16000617.0050-2017.

7. Lancaster L, et al. Safety and survival data in patients with idiopathic pulmonary fibrosis treated with nintedanib: pooled data from six clinical trials. BMJ Open Respir Res. 2019 Mar 25;6(1):e000397.

8. Kolb M, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 2017;72(4):340-346. doi:10.1136/thoraxjnl-2016-208710.

9. Costabel U, et al. Efficacy of nintedanib in idiopathic pulmonary fibrosis across prespecified subgroups in INPULSIS. Am J Respir Crit Care Med. 2016;193:178–185.

10. Raghu G, et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am J Respir Crit Care Med. 2017;195(1):78-85. doi:10.1164/rccm.201602-0402OC.

11. Pfeifer M, et al. Effect of baseline emphysema on reduction in FVC decline with nintedanib in the INPULSIS™ trials. Pneumologie. 2015;69:P254. doi:10.1055/s-0035-1544834.

12. Distler O, et al; the SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated lung disease. N Engl J Med. 2019;380(26):2518-2528. doi:10.1056/NEJMoa1903076.

13. Flaherty KR, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718-1727. doi:10.1056/NEJMoa1908681.

14. Crestani B, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON. Lancet Respir Med. 2019;7(1):60-68.
    Doi:10.1016/S2213-2600(18)30339-4.

15. Raghu G, et al; on behalf of the ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. doi:10.1164/rccm.2009-040GL.

16. Song JW, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011;37(2):356-363. doi:10.1183/09031936.00159709.