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A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy

2017; Lippincott Williams & Wilkins; Volume: 89; Issue: 17 Linguagem: Inglês

10.1212/wnl.0000000000004570

1526-632X

Ronald G. Victor, H. Lee Sweeney, Richard S. Finkel, Craig M. McDonald, Barry J. Byrne, Michelle Eagle, Nathalie Goemans, Krista Vandenborne, Alberto Dubrovsky, Haluk Topaloğlu, M. Carrie Miceli, Pat Furlong, John Landry, Robert M. Elashoff, David A. Cox, Hoda Abdel‐Hamid, Susan Apkon, Richard J. Barohn, Е. Д. Белоусова, Enrico Bertini, John F. Brandsema, Claudio Bruno, W. Bryan Burnette, Russell J. Butterfield, Barry J. Byrne, Craig Campbell, Jose Carlo, Jong‐Hee Chae, Saleel Chandratre, Giacomo P. Comi, Anne M. Connolly, Imelda J. M. de Groot, Nicolas Deconinck, Joseph Dooley, Alberto Dubrovsky, Julien Durigneux, Erika Finanger, Richard S. Finkel, Loren M. Frank, Nathalie Goemans, Amy Harper, Ayako Hattori, Özlem Hergüner, Susan T. Iannaccone, Joanne Janas, Yuh‐Jyh Jong, Janbernd Kirschner, Hirofumi Komaki, Nancy L. Kuntz, Wang‐Tso Lee, Edward Leung, Jean K. Mah, Katherine D. Mathews, Craig M. McDonald, Eugenio Mercuri, Hugh J. McMillan, Wolfgang Mueller‐Felber, Adolfo López de Munaín, Akinori Nakamura, Erik H. Niks, Katsuhisa Ogata, Samuel Ignacio Pascual Pascual, Elena Pegoraro, Yann Péréon, Ben Renfroe, Ratna Bhavaraju Sanka, Jens Schallner, Ulrike Schara, Kathryn Selby, Isabel Illa Sendra, Laurent Servais, Edward C. Smith, Susan Sparks, Haluk Topaloğlu, R Medina Victor, Juan J. Vílchez, Matthew Wicklund, Ekkehard Wilichoswki, Brenda Wong,

Exercise and Physiological Responses

To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD).Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg-1·d-1, tadalafil 0.6 mg·kg-1·d-1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome.Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state.Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age.NCT01865084.This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy.