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Title: | Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis The ISABELA 1 and 2 Randomized Clinical Trials | Authors: | Maher, Toby M. Ford, Paul Brown, Kevin K. Costabel, Ulrich Cottin, Vincent Danoff, Sonye K. Groenveld, Irene Helmer, Eric Jenkins, R. Gisli Milner, Julie MOLENBERGHS, Geert Penninckx, Bjorn Randall, Matthew J. Van den Blink, Bernt Fieuw, Ann Vandenrijn, Charlotte Rocak, Sanda Seghers, Ineke Shao, Lixin Taneja, Amit Jentsch, Garrit Watkins, Timothy R. WUYTS, Tim Kreuter, Michael Verbruggen, Nadia Prasad, Niyati Wijsenbeek, Marlies S. |
Issue Date: | 2023 | Publisher: | AMER MEDICAL ASSOC | Source: | JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 329 (18) , p. 1567 -1578 | Abstract: | Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. | Notes: | Maher, TM (corresponding author), Univ Southern Calif, Keck Sch Med, 1510 San Pablo St, Los Angeles, CA 90033 USA. toby.maher@med.usc.edu |
Document URI: | http://hdl.handle.net/1942/40541 | ISSN: | 0098-7484 | e-ISSN: | 1538-3598 | DOI: | 10.1001/jama.2023.5355 | ISI #: | 000993758100018 | Rights: | 2023 American Medical Association. All rights reserved. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis_ The ISABELA 1 and 2 Randomized Clinical Trials.pdf Restricted Access | Published version | 400.67 kB | Adobe PDF | View/Open Request a copy |
ISABELA primary manuscript_06March23.pdf | Peer-reviewed author version | 486.11 kB | Adobe PDF | View/Open |
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