Robert J Fox1, Christopher S Coffey2, Merit E Cudkowicz3, Trevis Gleason4, Andrew Goodman5, Eric C Klawiter6, Kazuko Matsuda7, Michelle McGovern3, Robin Conwit8, Robert Naismith9, Akshata Ashokkumar2, Robert Bermel10, Dixie Ecklund2, Maxine Koepp2, Jeffrey Long2, Sneha Natarajan10, Srividya Ramachandran10, Thomai Skaramagas10, Brenda Thornell3, Jon Yankey2, Mark Agius11, Khurram Bashir12, Bruce Cohen13, Patricia Coyle14, Silvia Delgado15, Dana Dewitt16, Angela Flores17, Barbara Giesser18, Myla Goldman19, Burk Jubelt20, Neil Lava21, Sharon Lynch22, Augusto Miravalle23, Harold Moses24, Daniel Ontaneda10, Jai Perumal25, Michael Racke26, Pavle Repovic27, Claire Riley28, Christopher Severson29, Shlomo Shinnar30, Valerie Suski31, Bianca Weinstock-Gutman32, Vijayshree Yadav33, Aram Zabeti34. 1. Cleveland Clinic, Neurological Institute, Cleveland, OH, United States. Electronic address: foxr@ccf.org. 2. Data Coordinating Center, NeuroNEXT, University of Iowa, Iowa City, IA, United States. 3. Clinical Coordinating Center, NeuroNEXT, Harvard Partners, Boston, MA, United States. 4. Patient Advocate, Seattle, WA, United States. 5. University of Rochester Medical Center, Rochester, NY, United States. 6. Massachusetts General Hospital, Boston, MA, United States. 7. Medicinova Inc., La Jolla, CA, United States. 8. National Institutes of Neurological Disease and Stroke, Bethesda, MD, United States. 9. Washington University School of Medicine, St. Louis, MO, United States. 10. Cleveland Clinic, Neurological Institute, Cleveland, OH, United States. 11. University of California at Davis, Sacramento, CA; currently at Barrows Neurological Institute, Phoenix, AZ, United States. 12. University of Alabama at Birmingham, Birmingham, AL, United States. 13. Northwestern University, Chicago, IL, United States. 14. State University of New York, Stony Brook, NY, United States. 15. University of Miami School of Medicine, Miami, FL, United States. 16. University of Utah, Salt Lake City, UT, United States. 17. University of Texas Southwestern Medical Center, Dallas, TX, United States. 18. University of California at Los Angeles, Los Angeles, CA, United States. 19. University of Virginia at Charlottesville, Charlottesville, VA, United States. 20. State University of New York Upstate Medical University, Syracuse, NY, United States. 21. Emory University, Atlanta, GA, United States. 22. University of Kansas Medical Center, Kansas City, KS, United States. 23. University of Colorado at Denver, Aurora, CO, United States. 24. Vanderbilt University, Nashville, TN, United States. 25. Weill Cornell Medical College, New York, NY, United States. 26. The Ohio State University, Columbus, OH, United States. 27. Swedish Medical Center at Seattle, Seattle, WA, United States. 28. Columbia University Medical Center, New York, NY, United States. 29. Brigham and Women's Hospital, Brookline, MA, United States. 30. Montefiore Medical Center, Bronx, NY, United States. 31. University of Pittsburgh Medical Center, Pittsburgh, PA, United States. 32. State University of New York Buffalo, Buffalo, NY, United States. 33. Oregon Health and Science University, Portland, OR, United States. 34. University of Cincinnati, Cincinnati, OH, United States.
Abstract
BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS:A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.
RCT Entities:
BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.
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Authors: Robert J Fox; Christopher S Coffey; Robin Conwit; Merit E Cudkowicz; Trevis Gleason; Andrew Goodman; Eric C Klawiter; Kazuko Matsuda; Michelle McGovern; Robert T Naismith; Akshata Ashokkumar; Janel Barnes; Dixie Ecklund; Elizabeth Klingner; Maxine Koepp; Jeffrey D Long; Sneha Natarajan; Brenda Thornell; Jon Yankey; Robert A Bermel; Josef P Debbins; Xuemei Huang; Patricia Jagodnik; Mark J Lowe; Kunio Nakamura; Sridar Narayanan; Ken E Sakaie; Bhaskar Thoomukuntla; Xiaopeng Zhou; Stephen Krieger; Enrique Alvarez; Michelle Apperson; Khurram Bashir; Bruce A Cohen; Patricia K Coyle; Silvia Delgado; L Dana Dewitt; Angela Flores; Barbara S Giesser; Myla D Goldman; Burk Jubelt; Neil Lava; Sharon G Lynch; Harold Moses; Daniel Ontaneda; Jai S Perumal; Michael Racke; Pavle Repovic; Claire S Riley; Christopher Severson; Shlomo Shinnar; Valerie Suski; Bianca Weinstock-Guttman; Vijayshree Yadav; Aram Zabeti Journal: N Engl J Med Date: 2018-08-30 Impact factor: 91.245
Authors: Merit Cudkowicz; Marianne K Chase; Christopher S Coffey; Dixie J Ecklund; Brenda J Thornell; Codrin Lungu; Katy Mahoney; Laurie Gutmann; Jeremy M Shefner; Kevin J Staley; Michael Bosch; Eric Foster; Jeffrey D Long; Emine O Bayman; James Torner; Jon Yankey; Richard Peters; Trevis Huff; Robin A Conwit; Shlomo Shinnar; Donna Patch; Basil T Darras; Audrey Ellis; Roger J Packer; Karen S Marder; Claudia A Chiriboga; Claire Henchcliffe; Joyce Ann Moran; Blagovest Nikolov; Stewart A Factor; Carole Seeley; Steven M Greenberg; Anthony A Amato; Sara DeGregorio; Tanya Simuni; Tina Ward; John T Kissel; Stephen J Kolb; Amy Bartlett; Joseph F Quinn; Kellie Keith; Steven R Levine; Nadege Gilles; Patricia K Coyle; Jessica Lamb; Gil I Wolfe; Annemarie Crumlish; Luis Mejico; Muhammad Maaz Iqbal; James D Bowen; Caryl Tongco; Louis B Nabors; Khurram Bashir; Melanie Benge; Craig M McDonald; Erik K Henricson; Björn Oskarsson; Bruce H Dobkin; Catherine Canamar; Tracy A Glauser; Daniel Woo; Angela Molloy; Peggy Clark; Timothy L Vollmer; Alexander J Stein; Richard J Barohn; Mazen M Dimachkie; Jean-Baptiste Le Pichon; Michael G Benatar; Julie Steele; Lawrence Wechsler; Paula R Clemens; Christine Amity; Robert G Holloway; Christine Annis; Mark P Goldberg; Mariam Andersen; Susan T Iannaccone; A Gordon Smith; J Robinson Singleton; Mariana Doudova; E Clarke Haley; Mark S Quigg; Stephanie Lowenhaupt; Beth A Malow; Karen Adkins; David B Clifford; Mengesha A Teshome; Noreen Connolly Journal: JAMA Neurol Date: 2020-06-01 Impact factor: 18.302