Efficacy

INPULSIS® trial design

The INPULSIS® trials are 2 replicate phase 3 trials involving over 1000 patients that investigated the efficacy of OFEV® in idiopathic pulmonary fibrosis (IPF).1,2

Decline in lung function (FVC)

OFEV® consistently slowed disease progression in IPF across 3 clinical trials: INPULSIS®-1, INPULSIS®-2 and  TOMORROW.1–4⋆

Acute exacerbation of idiopathic pulmonary fibrosis

OFEV® significantly reduced the risk of acute exacerbation of IPF by ~50%.5,6

Survival

An analysis of pooled data from 6 OFEV® trials has shown a survival benefit for patients with IPF.7

inpulsis

OFEV® was studied in two replicate phase 3, randomized, double-blind, placebo-controlled trials of 1066 patients with idiopathic pulmonary fibrosis (IPF) (INPULSIS®-1 and INPULSIS®-2)1,2

Patients were randomized 3:2 to receive either OFEV® 150 mg or placebo twice daily for 52 weeks with a 28-day follow-up1,2

The INPULSIS® trials were conducted across 24 countries at 205 sites.2

Primary and secondary endpoints1,2

  • Annual rate of decline in forced vital capacity (FVC)

Secondary endpoints:

  • Time to first acute exacerbation of IPF (investigator-reported)§ over 52 weeks
  • All events were adjudicated as a prespecified sensitivity analysis
  • Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score over 52 weeks
  • Absolute change from baseline in FVC at 52 weeks||
  • Proportion of FVC responders (patients who did not have an absolute decline in FVC % predicted of >5% or >10%) at week 52**
  • All-cause, respiratory-related and on-treatment mortality
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Medications excluded at randomization:2

  • N-acetylcysteine or prednisone >15 mg/day or equivalent within 2 weeks of screening
  • Pirfenidone, azathioprine, cyclophosphamide, cyclosporine A, or any investigational drug within 8 weeks of screening
  • Full-dose therapeutic anticoagulation or high-dose antiplatelet therapy at screening

The INPULSIS® trial population is representative of real-world patients, similar to those seen in clinical practice2,8-11

Various patient populations were represented

Decline in lung function (FVC)

fvc_0

OFEV® consistently slowed disease progression in idiopathic pulmonary fibrosis (IPF) across 3 clinical trials1–3

OFEV® significantly reduced the adjusted mean change from baseline in FVC by ~50%1,2,4

OFEV® significantly reduced the annual rate of decline in forced vital capacity (FVC)* by ~50%1–3

The relative treatment effect on slowing FVC decline seen in IPF was consistent with results in OFEV® trials studying patients with progressive fibrosing interstitial lung diseases (ILDs) and systemic sclerosis-associated interstitial lung disease (SSc-ILD)1–3,12,13

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fvc3_0

A sustained treatment effect in reducing FVC decline was observed beyond 4 years in patients receiving OFEV®14††

INPULSIS®-ON was an open-label extension trial that assessed the long-term efficacy and safety of OFEV® in 734 patients with IPF14

The effect of OFEV® on reducing disease progression in INPULSIS®-1 and -2 was consistent over long-term treatment in the INPULSIS®-ON open-label extension trial (up to 192 weeks)14‡‡

Acute exacerbation of idiopathic pulmonary fibrosis

Acute exacerbation of idiopathic pulmonary fibrosis (IPF) has an estimated annual incidence of 5% to 10%.15 50% of patients hospitalized for an acute exacerbation of IPF die during hospitalization.16

OFEV® significantly reduced the risk of acute exacerbation of IPF* by ~50%5,6

pooled_inpulsis

Survival

An analysis of pooled data from various OFEV® trials has shown a survival benefit for patients with idiopathic pulmonary fibrosis (IPF)7

Median survival based on the Weibull distribution¶¶ was extended by approximately 5 years in patients treated with OFEV® compared with placebo (8.5 vs. 3.3 years, respectively)7

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survival2_0
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.

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