trials. A 432-subject phase 2 trial of nintedanib demonstrated a delay in time to first investigator-reported acute exacerbation with nintedanib therapy (75), a finding supported but not confirmed by the 1066-subject phase 3 program (15). Most significant in the phase 3 program was the reduction in centrally-adjudicated confirmed or suspected acute exacerbation of IPF with nintedanib therapy (5.7% on placebo vs. 1.9% on nintedanib, p=0.01) (15). A 107-subject phase 2 trial of pirfenidone was stopped early because of a statistically significant (but numerically small) reduction in acute exacerbation in those receiving pirfenidone, but a subsequent trial did not replicate these results (47, 76). The definitive phase 3 clinical trials of pirfenidone did not report acute exacerbations as an endpoint (77, 78). Pirfenidone has been suggested to reduce the risk of acute exacerbation but these data are only observational and therefore are at high risk for confounding (79). Additional data are needed to fully understand the impact of IPF therapies on the risk of acute exacerbation, as well as whether IPF therapies should be continued or stopped in patients experiencing acute exacerbation. Other potential IPF therapies tested in clinical trials showed no impact on prevention of (acetylcysteine monotherapy, bosentan, interferon-gamma, sildenafil) or possibly increased risk for (e.g. ambrisentan, imatinib, “triple therapy” [combination prednisone, azathioprine, and acetylcysteine], warfarin) acute exacerbation of IPF (80-89). Proposed Conceptual Framework for Acute Respiratory Deterioration in IPF
trials. A 432-subject phase 2 trial of nintedanib demonstrated a delay in time to first investigator-reported acute exacerbation with nintedanib therapy (75), a finding supported but not confirmed by the 1066-subject phase 3 program (15). Most significant in the phase 3 program was the reduction in centrally-adjudicated confirmed or suspected acute exacerbation of IPF with nintedanib therapy (5.7% on placebo vs. 1.9% on nintedanib, p=0.01) (15). A 107-subject phase 2 trial of pirfenidone was stopped early because of a statistically significant (but numerically small) reduction in acute exacerbation in those receiving pirfenidone, but a subsequent trial did not replicate these results (47, 76). The definitive phase 3 clinical trials of pirfenidone did not report acute exacerbations as an endpoint (77, 78). Pirfenidone has been suggested to reduce the risk of acute exacerbation but these data are only observational and therefore are at high risk for confounding (79). Additional data are needed to fully understand the impact of IPF therapies on the risk of acute exacerbation, as well as whether IPF therapies should be continued or stopped in patients experiencing acute exacerbation. Other potential IPF therapies tested in clinical trials showed no impact on prevention of (acetylcysteine monotherapy, bosentan, interferon-gamma, sildenafil) or possibly increased risk for (e.g. ambrisentan, imatinib, “triple therapy” [combination prednisone, azathioprine, and acetylcysteine], warfarin) acute exacerbation of IPF (80-89). Proposed Conceptual Framework for Acute Respiratory Deterioration in IPF