Clinical trial NCT01982942: Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis
Official title: A Phase 2 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability and Activity of Ibudilast (MN-166) in Subjects With Progressive Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis, Primary Progressive
Multiple Sclerosis, Secondary Progressive
Lead sponsor: MediciNova
Sponsor class: INDUSTRY
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: National Multiple Sclerosis Society
First posted: 2013-11-13
Enrollment: 255
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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.

Primary outcomes:
measure: Covariate-adjusted Mean Rate of Change in Brain Atrophy Over 96 Weeks as Measured by Brain Parenchymal Fraction (BPF).
timeFrame: 96 weeks
measure: Percentage of Participants With Adverse Events.
timeFrame: 96 weeks
Secondary outcomes:
measure: Diffusion Tensor Imaging (DTI) in Descending Pyramidal White Matter Tracts
timeFrame: 48 weeks
measure: Magnetization Transfer Ratio (MTR) Imaging in Normal-appearing Brain Tissue
timeFrame: 96 weeks
measure: Retinal Nerve Fiber Layer as Measured by Optical Coherence Tomography (OCT).
timeFrame: 96 weeks
Other outcomes:
measure: New T1 Lesions Since Baseline
timeFrame: 96 weeks
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Davis
country: United States
facility: University of California Davis
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Denver
country: United States
facility: University of Colorado Denver
state: Colorado
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St Louis
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: University at Buffalo, The State University of New York
state: New York
city: New York
country: United States
facility: Cornell Medical College
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Stony Brook
country: United States
facility: University at Stony Brook, The State University of New York
state: New York
city: Syracuse
country: United States
facility: University at Upstate, The State University of New York
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati, Department of Neurology
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Charlottesville
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center - Seattle
state: Washington
Study officials:
affiliation: The Cleveland Clinic
name: Robert J Fox, MD, FAAN
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.