A CFTR potentiator in patients with cystic fibrosis and the G551D mutation
Bonnie W Ramsey, Jane Davies, N Gerard McElvaney, Elizabeth Tullis, Scott C Bell, Pavel Dřevínek, Matthias Griese, Edward F McKone, Claire E Wainwright, Michael W Konstan, Richard Moss, Felix Ratjen, Isabelle Sermet-Gaudelus, Steven M Rowe, Qunming Dong, Sally Rodriguez, Karl Yen, Claudia Ordoñez, J Stuart Elborn, VX08-770-102 Study Group, Richard Ahrens, Moira Aitken, Gopal Allada, Raouf Amin, Ran Anbar, Scott Bell, Joanne Billings, Philip Black, Drucy Borowitz, Michael Boyle, Gerry Canny, Barry Clements, Rubin Cohen, Peter Cooper, Jane Davies, Scott Donaldson, Pavel Drevinek, J Stuart Elborn, Isabelle Fajac, Albert Faro, Deborah Froh, Ronald Gibson, Peter Greally, Matthias Griese, Helge Hebestreit, Michael Konstan, Larry Lands, Allen Lapey, Theodore Liou, Jochen Mainz, Susanna McColley, Karen McCoy, Gerry McElvaney, Edward McKone, Roger Michael, Alison Miller, Kathryn Moffett, Richard Moss, Siobhain Mulrennan, Peter Murphy, Samya Nasr, Mark Pian, Joseph Pilewski, Barry Plant, Felix Ratjen, Gilles Rault, Phil Robinson, John Rogers, Steven Rowe, Ronald Rubenstein, Aruna Sannuti, Michael Schechter, David Serisier, Isabelle Sermet-Gaudelus, Gregory Shay, Jennifer Taylor-Cousar, Henry Thompson, Elizabeth Tullis, Ahmet Uluer, Pierre Vauthy, Robert Vender, Claire Wainwright, Robert Zanni, Theodor Zimmerman, Grace Mullins, Lisa Kent, Susan Martin, Laetitia Gueganton, Mogenet Agnes, Catherine Correia, Erin Hogge, Adrienne Horn, Cathy Powers, Margo Moore, Oisin O'Connell, Swati Rogers, Jeannie Peabody, Diane Kitch, Marie-Jo Toro, Kristy Barca, Renee Jensen, Annette Hempfling, Erin Felling, Julie Lee, Ines Yawa, Claudia Eismann, Li Chen Wann, Emily Stevens, Abagail King, Megan Martin, Patricia Grover, Bridget Marra, Natalie Skurat, Nancy Alarie, Claudia Schien, Connie Pickard, Terri Johnson, Aaron Guzik, Rachel Hennessy, Catherine Gangell, Andrea Dale, Sarah Holland, Bobbi Ksenich, Sandra Scott, Lauren McCann, Mary Jackson, Alexandra Robinson, Nadeene Clarke, Alan Genatossio, Dixie Durham, Myra Slutsky, Catherine McEvoy, Zoe Davies, Colleen Dunn, Donna Linder, Karen McKay, Candy Schmoll, Geraldine Leen, Michelle Wood, Michelle Robinette, Kelly Houser, Anette Scharschinger, Tajuanna Lucious, Nadine Caci, Mary Teresi, Dawn Kruse, Debra Heimes, Carol Barlow, Kristyn Packer, Judy Jensen, Patricia Moss, Alycia Wolfstone, Mary Boyle, Tammy Clark, Bonnie W Ramsey, Jane Davies, N Gerard McElvaney, Elizabeth Tullis, Scott C Bell, Pavel Dřevínek, Matthias Griese, Edward F McKone, Claire E Wainwright, Michael W Konstan, Richard Moss, Felix Ratjen, Isabelle Sermet-Gaudelus, Steven M Rowe, Qunming Dong, Sally Rodriguez, Karl Yen, Claudia Ordoñez, J Stuart Elborn, VX08-770-102 Study Group, Richard Ahrens, Moira Aitken, Gopal Allada, Raouf Amin, Ran Anbar, Scott Bell, Joanne Billings, Philip Black, Drucy Borowitz, Michael Boyle, Gerry Canny, Barry Clements, Rubin Cohen, Peter Cooper, Jane Davies, Scott Donaldson, Pavel Drevinek, J Stuart Elborn, Isabelle Fajac, Albert Faro, Deborah Froh, Ronald Gibson, Peter Greally, Matthias Griese, Helge Hebestreit, Michael Konstan, Larry Lands, Allen Lapey, Theodore Liou, Jochen Mainz, Susanna McColley, Karen McCoy, Gerry McElvaney, Edward McKone, Roger Michael, Alison Miller, Kathryn Moffett, Richard Moss, Siobhain Mulrennan, Peter Murphy, Samya Nasr, Mark Pian, Joseph Pilewski, Barry Plant, Felix Ratjen, Gilles Rault, Phil Robinson, John Rogers, Steven Rowe, Ronald Rubenstein, Aruna Sannuti, Michael Schechter, David Serisier, Isabelle Sermet-Gaudelus, Gregory Shay, Jennifer Taylor-Cousar, Henry Thompson, Elizabeth Tullis, Ahmet Uluer, Pierre Vauthy, Robert Vender, Claire Wainwright, Robert Zanni, Theodor Zimmerman, Grace Mullins, Lisa Kent, Susan Martin, Laetitia Gueganton, Mogenet Agnes, Catherine Correia, Erin Hogge, Adrienne Horn, Cathy Powers, Margo Moore, Oisin O'Connell, Swati Rogers, Jeannie Peabody, Diane Kitch, Marie-Jo Toro, Kristy Barca, Renee Jensen, Annette Hempfling, Erin Felling, Julie Lee, Ines Yawa, Claudia Eismann, Li Chen Wann, Emily Stevens, Abagail King, Megan Martin, Patricia Grover, Bridget Marra, Natalie Skurat, Nancy Alarie, Claudia Schien, Connie Pickard, Terri Johnson, Aaron Guzik, Rachel Hennessy, Catherine Gangell, Andrea Dale, Sarah Holland, Bobbi Ksenich, Sandra Scott, Lauren McCann, Mary Jackson, Alexandra Robinson, Nadeene Clarke, Alan Genatossio, Dixie Durham, Myra Slutsky, Catherine McEvoy, Zoe Davies, Colleen Dunn, Donna Linder, Karen McKay, Candy Schmoll, Geraldine Leen, Michelle Wood, Michelle Robinette, Kelly Houser, Anette Scharschinger, Tajuanna Lucious, Nadine Caci, Mary Teresi, Dawn Kruse, Debra Heimes, Carol Barlow, Kristyn Packer, Judy Jensen, Patricia Moss, Alycia Wolfstone, Mary Boyle, Tammy Clark
Abstract
Background: Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.
Methods: We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)).
Results: The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).
Conclusions: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov number, NCT00909532.).
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Source: PubMed