Overview

Status:Not yet recruiting
Keywords:Multiple sclerosis , Ibudilast , Progressive multiple sclerosis
IRB Number:00063489
Specialty:Neurology
Sub Specialty:Multiple Sclerosis

Brief Summary

Despite recent improvements in pharmacotherapy for relapsing remitting multiple sclerosis (RRMS), there are no therapies with demonstrated efficacy in progressive multiple sclerosis (MS) in the absence of relapses. The few studies showing efficacy of anti-inflammatory therapies in progressive forms of MS were likely driven by the anti-inflammatory effect of the therapies. There is great need for a safe, effective, and conveniently-administered therapy for progressive MS without overt inflammation. This phase 2 study is to evaluate the safety and activity of Ibudilast.

Primary objectives

1. To evaluate the activity of ibudilast (MN-166)) (100 mg/day) versus placebo at 96 weeks as measured by quantitative non-contrast magnetic resonance imaging (MRI) analysis for whole brain atrophy using brain parenchymal fraction (BPF).

2. To evaluate the safety and tolerability of ibudilast (MN-166) (100 mg/day) versus placebo administered orally in subjects with primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS).

Secondary objectives

To evaluate the activity if ibudilast (MN-166) as measured at 96 weeks versus placebo as measured by the following:

1. Diffusion tensor imaging (DTI) in descending pyramidal white matter tracts

2. Magnetization transfer ratio (MTR) imaging in normal-appearing brain tissue

3. Retinal nerve fiber layer as measured by ocular coherence tomography (OCT)

4. Cortical atrophy as measured by cortical longitudinal atrophy detection algorithm [CLADA]

Additional secondary outcomes to measure activity of ibudilast versus placebo are as follows:

1. Inflammatory disease activity as measured by T1 lesion volume, T2 lesion volume and annualized relapse rate

2. Disability as measured by the expanded Disability Status scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC)

3. Cognitive Impairment using the Symbol Digit Modalities Test and the Selective Reminding Test

4. Quality of Life as measured by Multiple Sclerosis Impact Scale (MSIS-29), EuroQol

5. Dimensions (EQ5D) and Short Form-36 Health Survey (SF-36)

6. Neuropathic pain, as measured by Brief Pain Inventory (BPI)

Exploratory objectives include the evaluation of the pharmacokinetics of ibudilast (MN-166) and correlations of cerebrospinal fluid, serum, and PBMC biomarkers with imaging and clinical measures of progressive disability.

Principle Investigator: Dana DeWitt
Principle Department: Neurology
Co Investigator: Rob Singleton
Co Investigator: Gordon Smith

Contact Information

Name:Tammy Floore
Phone:801-585-5227
Email:tammy.floore@hsc.utah.edu

Inclusion Criteria

Inclusion Criteria:

  1. Subject provides written informed consent and is willing and able to comply with the protocol in the opinion of the Investigator.
  2. Male or female subjects who are ≥ 21 and ≤ 65 years of age, on the day of signing the informed consent.
  3. Confirmed diagnosis of SPMS or PPMS according to 2010 International Panel Criteria
  4. Typical MS lesions on brain MRI according to Swanton‟s MRI Criteria
  5. EDSS 3.0-6.5, inclusive
  6. Clinical evidence of disability progression in the preceding 2 years, as measured by any of the following:  a) worsening overall EDSS of at least 0.5 points (may be assessed retrospectively, but cannot be during a clinical relapse) or  b)  20% worsening in 25-foot walk (25FW) or  c) 20% worsening in 9-hole peg test (9HPT) in either hand
  7. Existing multiple sclerosis pharmacotherapy status may include interferon-beta or glatiramer acetate or none (i.e. untreated)
  8. 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.
  9. Male subjects should practice contraception as follows: condom use and contraception by female partner.
  10. Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening, as defined by the investigator.
  11. 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

Exclusion Criteria:

  1. Progressive neurological disorder other than SPMS or PPMS
  2. Relapse and/or systemic corticosteroid steroid treatment for multiple sclerosis within 3 months of screening. Inhaled or topical steroids are allowed.
  3. Current use of intermittent systemic corticosteroids (i.e., monthly or bimonthly intravenous methylprednisolone).
  4. Use of oral immunosuppressants (e.g., azathioprine, methotrexate, cyclosporine) within 6 months of screening
  5. Use of mitoxantrone or natalizumab within 6 months of screening
  6. Use of fingolimod within 3 months of screening
  7. Use of rituximab or other B-cell therapy within 12 months of screening
  8. Current use of other MS disease-modifying treatments (DMTs) besides glatiramer acetate, IFNβ-1 (any formulation) and the above listed medication.
  9. Subject has clinically significant cardiovascular disease, including myocardial infarct within last 6 months, unstable ischemic heart disease, congestive heart failure or angina.
  10. Subject has a resting pulse < 50 bpm, SA or AV block or QTcF > 450 ms
  11. Clinically significant pulmonary conditions, including severe COPD, fibrosis, or tuberculosis
  12. Subject demonstrates 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 (Note: If any laboratory exclusion criteria are outside the normal range, the site may have the subject retested. If upon retesting the value remains outside the normal range, the significance of this value must be discussed with the Medical Monitor for enrollment consideration.)
  13. Immune system disease (other than multiple sclerosis and autoimmune thyroid disease)
  14. Subject has a 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.
  15. Subject has any abnormal laboratory parameter at screening that indicates a clinically significant medical condition as determined by the Investigator or has any of the following abnormalities at screening:  1) Creatinine > 1.7 mg/dL  2) WBCs < 3,000 mm3  3) Lymphocytes < 800 mm3  4) Platelets < 90,000 mm3
  16. Subject has a 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
  17. History of HIV, clinically significant chronic hepatitis, or other active infection
  18. Subject currently has a clinically significant medical condition (other than MS) including the following: neurological, 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 Monitor should be consulted.  Any subject with a known cardiovascular disease or condition (even if controlled) must be discussed with the Medical Monitor before being screened.
  19. 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.
  20. Subject has poor peripheral venous access that will limit the ability to draw blood as judged by the Investigator.
  21. 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.
  22. 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.