Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis

NCT ID: NCT01982942

Last Updated: 2020-07-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 255 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2017-12-31

Brief Summary

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the safety, tolerability and activity of ibudilast administered twice daily over a 96 week period in subjects with primary or secondary progressive multiple sclerosis who are currently untreated with long-term MS disease modifying therapy (DMT) or who are receiving either glatiramer acetate (GA) or interferon beta-1, any formulation (IFNβ-1A [Avonex, Rebif] or IFNβ-1B [Betaseron, Extavia]). Study drug or placebo will be administered to a total of 250 male and female subjects from 21 to 65 years old, inclusive, in two treatment groups. Randomization of subjects will be stratified by disease status (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) and immunomodulating therapy status: current use of immunomodulating therapy or no current use of immunomodulating therapy.

The study will consist of a screening phase (up to 30 days) followed by a treatment phase (96 weeks) and a follow-up visit (1 month post Week 96 visit). Following the screening phase, subjects who continue to meet entry criteria will be randomly assigned to 1 of 2 treatment groups: doses up to ibudilast 100 mg/day or matching-placebo in a 1:1 ratio. Study drug will be administered twice daily (BID), e.g., ibudilast 50 mg or placebo taken in the morning and evening).

Conditions

Multiple Sclerosis, Primary Progressive; Multiple Sclerosis, Secondary Progressive

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

ibudilast

Subjects will receive up to 100 mg/d ibudilast for 96 weeks.

Group Type: EXPERIMENTAL

ibudilast

Intervention Type: DRUG

Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.

Placebo Oral Capsule

Subjects will receive placebo for 96 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type: DRUG

Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.

Interventions

ibudilast

Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.

Intervention Type: DRUG

Placebo oral capsule

Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.

Intervention Type: DRUG

Other Intervention Names

MN-166

Eligibility Criteria

Inclusion Criteria

• Written informed consent is obtained and willing and able to comply with the protocol in the opinion of the Investigator.
• Male or female subjects ages 21 to 65, inclusive
• Confirmed diagnosis of SPMS or primary progressive multiple sclerosis (PPMS) according to 2010 International Panel Criteria
• Typical MS lesions on MRI according to Swanton's MRI Criteria (at least one lesion in two or more of the following regions: periventricular, juxtacortical, infratentorial [brainstem/cerebellum], spinal cord)
• EDSS 3.0-6.5, inclusive
• Clinical evidence of disability progression in the preceding two years, as measured by any of the following (excluding progression during clinical relapses):

• worsening overall EDSS of at least 0.5 points (may be assessed retrospectively but cannot be during a clinical relapse) or
• 20% worsening in 25-foot walk (25-FW) or
• 20% worsening in 9-hole peg test (9-HPT) in either hand
• Existing multiple sclerosis pharmacotherapy status may include interferon-beta or glatiramer acetate or none (i.e. untreated).
• Females of child-bearing potential must have a negative serum ß-hCG at screening and must be willing to use appropriate contraception (as defined by the investigator) for the duration of study treatment and 30 days after the last dose of study treatment.
• Males should practice contraception as follows: condom use and contraception by female partner.
• Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening, as defined by the investigator.
• Subject is willing and able to comply with the protocol assessments and visits, in the opinion of the study nurse/coordinator and the Investigator.

Exclusion Criteria

• Progressive neurological disorder other than SPMS or PPMS
• Relapse and/or systemic corticosteroid steroid treatment for multiple sclerosis within 3 months of screening. Inhaled or topical steroids are allowed.
• Current use of intermittent systemic corticosteroids (i.e., monthly or bimonthly intravenous methylprednisolone)
• Use of oral immunosuppressants (e.g. azathioprine, methotrexate, cyclosporine, teriflunomide [Aubagio®]) within 6 months of screening
• Use of mitoxantrone, natalizumab, or IVIg within 6 months of screening
• Use of fingolimod or dimethyl fumarate [Tecfidera®] within 3 months of screening
• Use of rituximab or other B-cell therapy within 12 months of screening
• Current use of other MS disease-modifying therapies (DMTs) besides glatiramer acetate, IFNβ-1 (any formulation), and the above listed medications.
• Current use of cimetidine, cyclosporine, dronedarone, lopinavir, probenecid, quinidine (including Neudexta), ranolazine, rifampin, ritonavir, or tipranavir.
• Clinically significant cardiovascular disease, including myocardial infarct within last 6 months, unstable ischemic heart disease, congestive heart failure or angina
• Resting pulse < 50 bpm, sinoatrial (SA) or atrioventricular (AV) block, uncontrolled hypertension, or QTcF > 450 ms
• Clinically significant pulmonary conditions, including severe chronic obstructive pulmonary disease (COPD), fibrosis, or tuberculosis
• Evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation including ALP > 1.5x ULN; ALT or AST > 2x ULN; GGT > 3x ULN
• Immune system disease (other than multiple sclerosis and autoimmune thyroid disease)
• History of stomach or intestinal surgery or any other condition that could interfere with or is judged by the Investigator to interfere with absorption, distribution, metabolism, or excretion of study drug.
• Any significant laboratory abnormality which, in the opinion of the Investigator, may put the subject at risk and with the following laboratory abnormalities at screening:

• Creatinine: females > 0.95 mg/dL; males > 1.17 mg/dL
• WBCs < 3,000 mm3
• Lymphocytes < 800 mm3
• Platelets < 90,000 mm3
• History of malignancy < 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
• History of HIV (human immunodeficiency virus), clinically significant chronic hepatitis, or other active infection.
• Subject currently has a clinically significant medical condition (other than MS) including the following: neurological, psychiatric, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular (including uncontrolled hypertension), gastrointestinal, urological disorder, or central nervous system (CNS) infection that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study.

Note: Active medical conditions that are minor or well-controlled are not exclusionary if, in the judgment of the Investigator, they do not affect risk to the subject or the study results. In cases in which the impact of the condition upon risk to the subject or study results is unclear, the Medical Safety Monitor should be consulted.

• Subjects with moderate to severe depression as determined by the Beck Depression Inventory-Fast Screen (BDI-FS).
• Subject has a history of alcohol or substance abuse (DSM-IV-TR criteria) within 3 months prior to screening or alcohol or substance dependence (DSM-IV-TR criteria) within 12 months prior to screening. The only exceptions include caffeine or nicotine abuse/dependence.
• Subject has poor peripheral venous access that will limit the ability to draw blood as judged by the Investigator.
• Subject is currently participating, or has participated in, a study with an investigational or marketed compound or device within 3 months prior to signing the informed consent.
• Subject is unable to cooperate with any study procedures, unlikely to adhere to the study procedures and keep appointments, in the opinion of the Investigator, or was planning to relocate during the study.
• Subject is unable to undergo MRI imaging because of having an artificial heart valve, metal plate, pin, or other metallic objects (including gun shots or shrapnel) in their body or is unable to complete all the five MRI scans required for this study.

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

National Multiple Sclerosis Society

OTHER

Sponsor Role: collaborator

MediciNova

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert J Fox, MD, FAAN

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of California Davis

Davis, California, United States

University of California Los Angeles

Los Angeles, California, United States

University of Colorado Denver

Denver, Colorado, United States

University of Miami Miller School of Medicine

Miami, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University

Evanston, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Washington University School of Medicine in St Louis

St Louis, Missouri, United States

University at Buffalo, The State University of New York

Buffalo, New York, United States

Cornell Medical College

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

University of Rochester

Rochester, New York, United States

University at Stony Brook, The State University of New York

Stony Brook, New York, United States

University at Upstate, The State University of New York

Syracuse, New York, United States

Montefiore Medical Center

The Bronx, New York, United States

University of Cincinnati, Department of Neurology

Cincinnati, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

Ohio State University

Columbus, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

University of Utah

Salt Lake City, Utah, United States

University of Virginia Charlottesville

Charlottesville, Virginia, United States

Swedish Medical Center - Seattle

Seattle, Washington, United States

Countries

United States

References

Singh V, Zheng Y, Ontaneda D, Mahajan KR, Holloman J, Fox RJ, Nakamura K, Trapp BD. Disability independent of cerebral white matter demyelination in progressive multiple sclerosis. Acta Neuropathol. 2024 Aug 31;148(1):34. doi: 10.1007/s00401-024-02796-w.

Reference Type: DERIVED

PMID: 39217272 (View on PubMed)

Nakamura K, Zheng Y, Mahajan KR, Cohen JA, Fox RJ, Ontaneda D. Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis. Mult Scler. 2023 Sep;29(10):1257-1265. doi: 10.1177/13524585231187289. Epub 2023 Aug 3.

Reference Type: DERIVED

PMID: 37537928 (View on PubMed)

Bermel RA, Fedler JK, Kaiser P, Novalis C, Schneebaum J, Klingner EA, Williams D, Yankey JW, Ecklund DJ, Chase M, Naismith RT, Klawiter EC, Goodman AD, Coffey CS, Fox RJ. Optical coherence tomography outcomes from SPRINT-MS, a multicenter, randomized, double-blind trial of ibudilast in progressive multiple sclerosis. Mult Scler. 2021 Aug;27(9):1384-1390. doi: 10.1177/1352458520964409. Epub 2020 Oct 15.

Reference Type: DERIVED

PMID: 33054533 (View on PubMed)

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; NN102/SPRINT-MS Trial Investigators. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018 Aug 30;379(9):846-855. doi: 10.1056/NEJMoa1803583.

Reference Type: DERIVED

PMID: 30157388 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Related Links

http://www.neuronext.org

Related Info

Other Identifiers

1U01NS082329-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RG 4778-A-6

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

NN102 SPRINT - MS

Identifier Type: -

Identifier Source: org_study_id