A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis
Talmadge E King Jr, Williamson Z Bradford, Socorro Castro-Bernardini, Elizabeth A Fagan, Ian Glaspole, Marilyn K Glassberg, Eduard Gorina, Peter M Hopkins, David Kardatzke, Lisa Lancaster, David J Lederer, Steven D Nathan, Carlos A Pereira, Steven A Sahn, Robert Sussman, Jeffrey J Swigris, Paul W Noble, ASCEND Study Group, James N Allen Jr, Rogério Lopes Rufino Alves, Danielle Antin-Ozerkis, Abubakr A Bajwa, Rebecca Bascom, Robert Baughman, Lutz Erwin Lothar Beckert, John Belperio, Issahar Ben-Dov, Raphael Breuer, John A Butler, Carlos Roberto Ribeiro de Carvalho, Andrew L Chan, Jacqueline Chang, Uriel Chavarría Martínez, Dennis P Clifford, Francis Cordova, Tamera Corte, Henry D Covelli, Huw Davies, Gerald S Davis, Joao M De Andrade, Jesús Javier Díaz Castañón, Daniel F Dilling, Stephanie Eaton, Richard Enelow, Neil Ettinger, Timothy Evans, Jeremy P Feldman, Elie Fiss, Kevin R Flaherty, Anthony Floreani, Philip R Foti, Adaani E Frost, Sivagini Ganesh, Stuart Garay, Alicia Gerke, Kevin Gibson, Leo E Ginns, Reda Girgis, Carlos Girod, Jeffrey Golden, Mark H Gotfried, Daniel Grinnan, Alfredo Gilberto Guerreros Benavides, Harold D Haller Jr, Mark J Hamblin, Mark Holmes, Todd K Horiuchi, Maureen Horton, John Terrill Huggins, Carlos Alberto Iberico Barrera, Jonathan S Ilowite, Michael C Kallay, Hyun J Kim, Gary Kinasewitz, Mordechai Reuben Kramer, Peter LaCamera, John Landis, Joseph A Lasky, Augustine S Lee, Randolph Lipchik, Daniel G Lorch Jr, Su Ying Low, Monique Malouf, Alberto Matsuno Fuchigami, Keith C Meyer, Christina Migliore, Lake Daniel Morrison, Lee Morrow, Michael Musk, Anoop Nambiar, Maria Eunice Moraes de Oliveira, Maria Padilla, Ralph Panos, John Pantano, Joseph Parambil, Nina M Patel, Roberto Alfonso Perea Sánchez, Rafael L Perez, Tatjana Peroš-Golubiĉić, Andrés Piñeiro García Calderón, Rodolfo Posadas Valay, Luis Enrique Pun Leon, Navdeep S Rai, Murali Ramaswamy, Charles E Rose, Glenn D Rosen, Adalberto Sperb Rubin, Tonya Russell, Donald W Russell, Jay H Ryu, Danilo Joel Salazar Oré, Juan Sanchez, Thomas Schaumberg, Mary Beth Scholand, Yehuda A Schwarz, Moises Eduardo Selman Lama, David Serisier, Wei Shen, Oksana Shlobin, Paul Simonelli, Deren M Sinkowitz, Mary Strek, Frank Thien, Austin B Thompson, William P Tillis, Gregory Tino, Jose William Torres Sales, Neven Tudoric, Antony Veale, Elizabeth Veitch, Mark L Wencel, Lewis J Wesselius, Margaret Wilsher, Mark Yagan, Mordechai Yigla, Mark A Yoder, Dennis K Zawadski, Talmadge E King Jr, Paul W Noble, Williamson Z Bradford, Elizabeth A Fagan, Ian Glaspole, Marilyn K Glassberg, Lisa Lancaster, David J Lederer, Steven D Nathan, Carlos A Pereira, Steven A Sahn, Jeffrey J Swigris, Charles S Davis, Michael Grippi, Robert Wise, David A Zisman, Sonye K Danoff, Robert J Kaner, Timothy Whelan, J David Godwin, Jeffrey P Kanne, David A Lynch, Wayne Richard Webb, Thomas V Colby, Anna Luise Katzenstein, Kevin O Leslie, Henry D Tazelaar, Talmadge E King Jr, Williamson Z Bradford, Socorro Castro-Bernardini, Elizabeth A Fagan, Ian Glaspole, Marilyn K Glassberg, Eduard Gorina, Peter M Hopkins, David Kardatzke, Lisa Lancaster, David J Lederer, Steven D Nathan, Carlos A Pereira, Steven A Sahn, Robert Sussman, Jeffrey J Swigris, Paul W Noble, ASCEND Study Group, James N Allen Jr, Rogério Lopes Rufino Alves, Danielle Antin-Ozerkis, Abubakr A Bajwa, Rebecca Bascom, Robert Baughman, Lutz Erwin Lothar Beckert, John Belperio, Issahar Ben-Dov, Raphael Breuer, John A Butler, Carlos Roberto Ribeiro de Carvalho, Andrew L Chan, Jacqueline Chang, Uriel Chavarría Martínez, Dennis P Clifford, Francis Cordova, Tamera Corte, Henry D Covelli, Huw Davies, Gerald S Davis, Joao M De Andrade, Jesús Javier Díaz Castañón, Daniel F Dilling, Stephanie Eaton, Richard Enelow, Neil Ettinger, Timothy Evans, Jeremy P Feldman, Elie Fiss, Kevin R Flaherty, Anthony Floreani, Philip R Foti, Adaani E Frost, Sivagini Ganesh, Stuart Garay, Alicia Gerke, Kevin Gibson, Leo E Ginns, Reda Girgis, Carlos Girod, Jeffrey Golden, Mark H Gotfried, Daniel Grinnan, Alfredo Gilberto Guerreros Benavides, Harold D Haller Jr, Mark J Hamblin, Mark Holmes, Todd K Horiuchi, Maureen Horton, John Terrill Huggins, Carlos Alberto Iberico Barrera, Jonathan S Ilowite, Michael C Kallay, Hyun J Kim, Gary Kinasewitz, Mordechai Reuben Kramer, Peter LaCamera, John Landis, Joseph A Lasky, Augustine S Lee, Randolph Lipchik, Daniel G Lorch Jr, Su Ying Low, Monique Malouf, Alberto Matsuno Fuchigami, Keith C Meyer, Christina Migliore, Lake Daniel Morrison, Lee Morrow, Michael Musk, Anoop Nambiar, Maria Eunice Moraes de Oliveira, Maria Padilla, Ralph Panos, John Pantano, Joseph Parambil, Nina M Patel, Roberto Alfonso Perea Sánchez, Rafael L Perez, Tatjana Peroš-Golubiĉić, Andrés Piñeiro García Calderón, Rodolfo Posadas Valay, Luis Enrique Pun Leon, Navdeep S Rai, Murali Ramaswamy, Charles E Rose, Glenn D Rosen, Adalberto Sperb Rubin, Tonya Russell, Donald W Russell, Jay H Ryu, Danilo Joel Salazar Oré, Juan Sanchez, Thomas Schaumberg, Mary Beth Scholand, Yehuda A Schwarz, Moises Eduardo Selman Lama, David Serisier, Wei Shen, Oksana Shlobin, Paul Simonelli, Deren M Sinkowitz, Mary Strek, Frank Thien, Austin B Thompson, William P Tillis, Gregory Tino, Jose William Torres Sales, Neven Tudoric, Antony Veale, Elizabeth Veitch, Mark L Wencel, Lewis J Wesselius, Margaret Wilsher, Mark Yagan, Mordechai Yigla, Mark A Yoder, Dennis K Zawadski, Talmadge E King Jr, Paul W Noble, Williamson Z Bradford, Elizabeth A Fagan, Ian Glaspole, Marilyn K Glassberg, Lisa Lancaster, David J Lederer, Steven D Nathan, Carlos A Pereira, Steven A Sahn, Jeffrey J Swigris, Charles S Davis, Michael Grippi, Robert Wise, David A Zisman, Sonye K Danoff, Robert J Kaner, Timothy Whelan, J David Godwin, Jeffrey P Kanne, David A Lynch, Wayne Richard Webb, Thomas V Colby, Anna Luise Katzenstein, Kevin O Leslie, Henry D Tazelaar
Abstract
Background: In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients.
Methods: In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis.
Results: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation.
Conclusions: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).
Source: PubMed