Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

Robert J. Fox; Christopher S. Coffey; Merit E. Cudkowicz; Trevis Gleason; Andrew Goodman; Eric C. Klawiter; Kazuko Matsuda; Michelle McGovern; Robin Conwit; Robert Naismith; Akshata Ashokkumar; Robert Bermel; Dixie Ecklund; Maxine Koepp; Jeffrey Long; Sneha Natarajan; Srividya Ramachandran; Thomai Skaramagas; Brenda Thornell; Jon Yankey; Mark Agius; Khurram Bashir; Bruce Cohen; Patricia Coyle; Silvia Delgado; Dana Dewitt; Angela Flores; Barbara Giesser; Myla Goldman; Burk Jubelt; Neil Lava; Sharon Lynch; Augusto Miravalle; Harold Moses; Daniel Ontaneda; Jai Perumal; Michael Racke; Pavle Repovic; Claire Riley; Christopher Severson; Shlomo Shinnar; Valerie Suski; Bianca Weinstock-Gutman; Vijayshree Yadav; Aram Zabeti

doi:10.1016/j.cct.2016.08.009

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

Robert J. Fox^*, Christopher S. Coffey, Merit E. Cudkowicz, Trevis Gleason, Andrew Goodman, Eric C. Klawiter, Kazuko Matsuda, Michelle McGovern, Robin Conwit, Robert Naismith, Akshata Ashokkumar, Robert Bermel, Dixie Ecklund, Maxine Koepp, Jeffrey Long, Sneha Natarajan, Srividya Ramachandran, Thomai Skaramagas, Brenda Thornell, Jon YankeyMark Agius, Khurram Bashir, Bruce Cohen, Patricia Coyle, Silvia Delgado, Dana Dewitt, Angela Flores, Barbara Giesser, Myla Goldman, Burk Jubelt, Neil Lava, Sharon Lynch, Augusto Miravalle, Harold Moses, Daniel Ontaneda, Jai Perumal, Michael Racke, Pavle Repovic, Claire Riley, Christopher Severson, Shlomo Shinnar, Valerie Suski, Bianca Weinstock-Gutman, Vijayshree Yadav, Aram Zabeti

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

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 (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks 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.

Original language	English (US)
Pages (from-to)	166-177
Number of pages	12
Journal	Contemporary Clinical Trials
Volume	50
DOIs	https://doi.org/10.1016/j.cct.2016.08.009
State	Published - Sep 1 2016

Funding

This study was funded by the NINDS ( U01NS082329 ) and NMSS ( RG 4778-A-6 ). Ibudilast study drug was provided at no cost by MediciNova Inc. The NeuroNEXT Network is supported by the NINDS (Central Coordinating Center: U01NS077179, Data Coordinating Center: U01NS077352). We thank Dr. Elizabeth McNeil, the former program manager at NINDS, for her steady support through the trial development and start-up process. This study was made possible by the dedication and support of people with MS who volunteered to participate as well as their families and friends who support their involvement in this study.

Keywords

Clinical trial
Ibudilast
Magnetic resonance imaging
Progressive multiple sclerosis

ASJC Scopus subject areas

Pharmacology (medical)

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10.1016/j.cct.2016.08.009

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Fox, R. J., Coffey, C. S., Cudkowicz, M. E., Gleason, T., Goodman, A., Klawiter, E. C., Matsuda, K., McGovern, M., Conwit, R., Naismith, R., Ashokkumar, A., Bermel, R., Ecklund, D., Koepp, M., Long, J., Natarajan, S., Ramachandran, S., Skaramagas, T., Thornell, B., ... Zabeti, A. (2016). Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemporary Clinical Trials, 50, 166-177. https://doi.org/10.1016/j.cct.2016.08.009

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title = "Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis",

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 (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks 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.",

keywords = "Clinical trial, Ibudilast, Magnetic resonance imaging, Progressive multiple sclerosis",

author = "Fox, {Robert J.} and Coffey, {Christopher S.} and Cudkowicz, {Merit E.} and Trevis Gleason and Andrew Goodman and Klawiter, {Eric C.} and Kazuko Matsuda and Michelle McGovern and Robin Conwit and Robert Naismith and Akshata Ashokkumar and Robert Bermel and Dixie Ecklund and Maxine Koepp and Jeffrey Long and Sneha Natarajan and Srividya Ramachandran and Thomai Skaramagas and Brenda Thornell and Jon Yankey and Mark Agius and Khurram Bashir and Bruce Cohen and Patricia Coyle and Silvia Delgado and Dana Dewitt and Angela Flores and Barbara Giesser and Myla Goldman and Burk Jubelt and Neil Lava and Sharon Lynch and Augusto Miravalle and Harold Moses and Daniel Ontaneda and Jai Perumal and Michael Racke and Pavle Repovic and Claire Riley and Christopher Severson and Shlomo Shinnar and Valerie Suski and Bianca Weinstock-Gutman and Vijayshree Yadav and Aram Zabeti",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

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day = "1",

doi = "10.1016/j.cct.2016.08.009",

language = "English (US)",

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Fox, RJ, Coffey, CS, Cudkowicz, ME, Gleason, T, Goodman, A, Klawiter, EC, Matsuda, K, McGovern, M, Conwit, R, Naismith, R, Ashokkumar, A, Bermel, R, Ecklund, D, Koepp, M, Long, J, Natarajan, S, Ramachandran, S, Skaramagas, T, Thornell, B, Yankey, J, Agius, M, Bashir, K, Cohen, B, Coyle, P, Delgado, S, Dewitt, D, Flores, A, Giesser, B, Goldman, M, Jubelt, B, Lava, N, Lynch, S, Miravalle, A, Moses, H, Ontaneda, D, Perumal, J, Racke, M, Repovic, P, Riley, C, Severson, C, Shinnar, S, Suski, V, Weinstock-Gutman, B, Yadav, V & Zabeti, A 2016, 'Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis', Contemporary Clinical Trials, vol. 50, pp. 166-177. https://doi.org/10.1016/j.cct.2016.08.009

TY - JOUR

T1 - Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

AU - Fox, Robert J.

AU - Coffey, Christopher S.

AU - Cudkowicz, Merit E.

AU - Gleason, Trevis

AU - Goodman, Andrew

AU - Klawiter, Eric C.

AU - Matsuda, Kazuko

AU - McGovern, Michelle

AU - Conwit, Robin

AU - Naismith, Robert

AU - Ashokkumar, Akshata

AU - Bermel, Robert

AU - Ecklund, Dixie

AU - Koepp, Maxine

AU - Long, Jeffrey

AU - Natarajan, Sneha

AU - Ramachandran, Srividya

AU - Skaramagas, Thomai

AU - Thornell, Brenda

AU - Yankey, Jon

AU - Agius, Mark

AU - Bashir, Khurram

AU - Cohen, Bruce

AU - Coyle, Patricia

AU - Delgado, Silvia

AU - Dewitt, Dana

AU - Flores, Angela

AU - Giesser, Barbara

AU - Goldman, Myla

AU - Jubelt, Burk

AU - Lava, Neil

AU - Lynch, Sharon

AU - Miravalle, Augusto

AU - Moses, Harold

AU - Ontaneda, Daniel

AU - Perumal, Jai

AU - Racke, Michael

AU - Repovic, Pavle

AU - Riley, Claire

AU - Severson, Christopher

AU - Shinnar, Shlomo

AU - Suski, Valerie

AU - Weinstock-Gutman, Bianca

AU - Yadav, Vijayshree

AU - Zabeti, Aram

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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 (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks 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.

AB - 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 (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks 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.

KW - Clinical trial

KW - Ibudilast

KW - Magnetic resonance imaging

KW - Progressive multiple sclerosis

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UR - http://www.scopus.com/inward/citedby.url?scp=84984783725&partnerID=8YFLogxK

U2 - 10.1016/j.cct.2016.08.009

DO - 10.1016/j.cct.2016.08.009

M3 - Article

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AN - SCOPUS:84984783725

SN - 1551-7144

VL - 50

SP - 166

EP - 177

JO - Contemporary Clinical Trials

JF - Contemporary Clinical Trials

ER -

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

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