Phase 2 trial of ibudilast in progressive multiple sclerosis

R. J. Fox, C. S. Coffey, R. Conwit, M. E. Cudkowicz, T. Gleason, A. Goodman, E. C. Klawiter, K. Matsuda, M. McGovern, R. T. Naismith, A. Ashokkumar, J. Barnes, D. Ecklund, E. Klingner, M. Koepp, J. D. Long, S. Natarajan, B. Thornell, J. Yankey, R. A. BermelJ. P. Debbins, X. Huang, P. Jagodnik, M. J. Lowe, K. Nakamura, S. Narayanan, K. E. Sakaie, B. Thoomukuntla, X. Zhou, S. Krieger, E. Alvarez, M. Apperson, K. Bashir, B. A. Cohen, P. K. Coyle, S. Delgado, L. D. Dewitt, A. Flores, B. S. Giesser, M. D. Goldman, B. Jubelt, N. Lava, S. G. Lynch, H. Moses, D. Ontaneda, J. S. Perumal, M. Racke, P. Repovic, C. S. Riley, C. Severson, Shlomo Shinnar, V. Suski, B. Weinstock-Guttman, V. Yadav, A. Zabeti

Research output: Contribution to journalArticle

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Abstract

BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (=100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P = 0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.) right

Original languageEnglish (US)
Pages (from-to)846-855
Number of pages10
JournalNew England Journal of Medicine
Volume379
Issue number9
DOIs
StatePublished - Aug 30 2018

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Multiple Sclerosis
Brain
Placebos
Chronic Progressive Multiple Sclerosis
Atrophy
Headache
National Institute of Neurological Disorders and Stroke
Macrophage Migration-Inhibitory Factors
Pyramidal Tracts
Toll-Like Receptor 4
Diffusion Tensor Imaging
ibudilast
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Random Allocation
Blood-Brain Barrier
Nerve Fibers
Confidence Intervals

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fox, R. J., Coffey, C. S., Conwit, R., Cudkowicz, M. E., Gleason, T., Goodman, A., ... Zabeti, A. (2018). Phase 2 trial of ibudilast in progressive multiple sclerosis. New England Journal of Medicine, 379(9), 846-855. https://doi.org/10.1056/NEJMoa1803583

Phase 2 trial of ibudilast in progressive multiple sclerosis. / Fox, R. J.; Coffey, C. S.; Conwit, R.; Cudkowicz, M. E.; Gleason, T.; Goodman, A.; Klawiter, E. C.; Matsuda, K.; McGovern, M.; Naismith, R. T.; Ashokkumar, A.; Barnes, J.; Ecklund, D.; Klingner, E.; Koepp, M.; Long, J. D.; Natarajan, S.; Thornell, B.; Yankey, J.; Bermel, R. A.; Debbins, J. P.; Huang, X.; Jagodnik, P.; Lowe, M. J.; Nakamura, K.; Narayanan, S.; Sakaie, K. E.; Thoomukuntla, B.; Zhou, X.; Krieger, S.; Alvarez, E.; Apperson, M.; Bashir, K.; Cohen, B. A.; Coyle, P. K.; Delgado, S.; Dewitt, L. D.; Flores, A.; Giesser, B. S.; Goldman, M. D.; Jubelt, B.; Lava, N.; Lynch, S. G.; Moses, H.; Ontaneda, D.; Perumal, J. S.; Racke, M.; Repovic, P.; Riley, C. S.; Severson, C.; Shinnar, Shlomo; Suski, V.; Weinstock-Guttman, B.; Yadav, V.; Zabeti, A.

In: New England Journal of Medicine, Vol. 379, No. 9, 30.08.2018, p. 846-855.

Research output: Contribution to journalArticle

Fox, RJ, Coffey, CS, Conwit, R, Cudkowicz, ME, Gleason, T, Goodman, A, Klawiter, EC, Matsuda, K, McGovern, M, Naismith, RT, Ashokkumar, A, Barnes, J, Ecklund, D, Klingner, E, Koepp, M, Long, JD, Natarajan, S, Thornell, B, Yankey, J, Bermel, RA, Debbins, JP, Huang, X, Jagodnik, P, Lowe, MJ, Nakamura, K, Narayanan, S, Sakaie, KE, Thoomukuntla, B, Zhou, X, Krieger, S, Alvarez, E, Apperson, M, Bashir, K, Cohen, BA, Coyle, PK, Delgado, S, Dewitt, LD, Flores, A, Giesser, BS, Goldman, MD, Jubelt, B, Lava, N, Lynch, SG, Moses, H, Ontaneda, D, Perumal, JS, Racke, M, Repovic, P, Riley, CS, Severson, C, Shinnar, S, Suski, V, Weinstock-Guttman, B, Yadav, V & Zabeti, A 2018, 'Phase 2 trial of ibudilast in progressive multiple sclerosis', New England Journal of Medicine, vol. 379, no. 9, pp. 846-855. https://doi.org/10.1056/NEJMoa1803583
Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. New England Journal of Medicine. 2018 Aug 30;379(9):846-855. https://doi.org/10.1056/NEJMoa1803583
Fox, R. J. ; Coffey, C. S. ; Conwit, R. ; Cudkowicz, M. E. ; Gleason, T. ; Goodman, A. ; Klawiter, E. C. ; Matsuda, K. ; McGovern, M. ; Naismith, R. T. ; Ashokkumar, A. ; Barnes, J. ; Ecklund, D. ; Klingner, E. ; Koepp, M. ; Long, J. D. ; Natarajan, S. ; Thornell, B. ; Yankey, J. ; Bermel, R. A. ; Debbins, J. P. ; Huang, X. ; Jagodnik, P. ; Lowe, M. J. ; Nakamura, K. ; Narayanan, S. ; Sakaie, K. E. ; Thoomukuntla, B. ; Zhou, X. ; Krieger, S. ; Alvarez, E. ; Apperson, M. ; Bashir, K. ; Cohen, B. A. ; Coyle, P. K. ; Delgado, S. ; Dewitt, L. D. ; Flores, A. ; Giesser, B. S. ; Goldman, M. D. ; Jubelt, B. ; Lava, N. ; Lynch, S. G. ; Moses, H. ; Ontaneda, D. ; Perumal, J. S. ; Racke, M. ; Repovic, P. ; Riley, C. S. ; Severson, C. ; Shinnar, Shlomo ; Suski, V. ; Weinstock-Guttman, B. ; Yadav, V. ; Zabeti, A. / Phase 2 trial of ibudilast in progressive multiple sclerosis. In: New England Journal of Medicine. 2018 ; Vol. 379, No. 9. pp. 846-855.
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abstract = "BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (=100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53{\%} of the patients in the ibudilast group and 52{\%} of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95{\%} confidence interval, 0.00004 to 0.0017; P = 0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.) right",
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TY - JOUR

T1 - Phase 2 trial of ibudilast in progressive multiple sclerosis

AU - Fox, R. J.

AU - Coffey, C. S.

AU - Conwit, R.

AU - Cudkowicz, M. E.

AU - Gleason, T.

AU - Goodman, A.

AU - Klawiter, E. C.

AU - Matsuda, K.

AU - McGovern, M.

AU - Naismith, R. T.

AU - Ashokkumar, A.

AU - Barnes, J.

AU - Ecklund, D.

AU - Klingner, E.

AU - Koepp, M.

AU - Long, J. D.

AU - Natarajan, S.

AU - Thornell, B.

AU - Yankey, J.

AU - Bermel, R. A.

AU - Debbins, J. P.

AU - Huang, X.

AU - Jagodnik, P.

AU - Lowe, M. J.

AU - Nakamura, K.

AU - Narayanan, S.

AU - Sakaie, K. E.

AU - Thoomukuntla, B.

AU - Zhou, X.

AU - Krieger, S.

AU - Alvarez, E.

AU - Apperson, M.

AU - Bashir, K.

AU - Cohen, B. A.

AU - Coyle, P. K.

AU - Delgado, S.

AU - Dewitt, L. D.

AU - Flores, A.

AU - Giesser, B. S.

AU - Goldman, M. D.

AU - Jubelt, B.

AU - Lava, N.

AU - Lynch, S. G.

AU - Moses, H.

AU - Ontaneda, D.

AU - Perumal, J. S.

AU - Racke, M.

AU - Repovic, P.

AU - Riley, C. S.

AU - Severson, C.

AU - Shinnar, Shlomo

AU - Suski, V.

AU - Weinstock-Guttman, B.

AU - Yadav, V.

AU - Zabeti, A.

PY - 2018/8/30

Y1 - 2018/8/30

N2 - BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (=100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P = 0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.) right

AB - BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (=100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P = 0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.) right

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