Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis
Condition: Multiple Sclerosis, Primary Progressive; Multiple Sclerosis, Secondary Progressive
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Intervention: ibudilast; Placebo oral capsule
Intervention description: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.; Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
Intervention MeSH terms: Ibudilast
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 255.0
Sex: All
Minimum age: 21 Years
Maximum age: 65 Years
Healthy volunteers: No

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.