Ibudilast (MN-166) in Subjects With Amyotrophic Lateral Sclerosis (ALS)
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Intervention: Placebo (for MN-166); MN-166; riluzole
Intervention description: Patient is given 50 mg riluzole twice daily.
Intervention MeSH terms: Ibudilast; Riluzole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: amyotrophic lateral sclerosis; pharmacotherapy; intervention; prospective; safety endpoint; preliminary efficacy; ibudilast

Summary:

      This is a single center, randomized, double-blind, placebo-controlled, 6-month study designed
      to evaluate the safety, tolerability and clinical responsiveness of MN-166/ibudilast (60
      mg/day) when administered as an adjunct to riluzole (100 mg/day) in 60 subjects with ALS.

      This study will consist of two treatment arms, MN-166 and matching placebo. Randomization
      will occur in a 2:1 ratio (MN- 166: placebo).

      Duration of Treatment: Screening Phase: up to 3 months; Double-blind Phase: 6 months;
      Open-label Phase 6 months (for placebo subjects only); Follow-up Phase: 2 weeks after last
      dose.

      During treatment phase, subjects return to the clinic at Months 3 and 6 and will be
      telephoned by staff at Months 1,2,4, and 5 to collect information about side effects and new
      or concomitant medications.

      All subjects (subjects who complete the Double-blind Phase and subjects who complete the
      Open-label Phase) or prematurely discontinue will return for a follow-up visit approximately
      2 weeks after the last dose of study drug to assess adverse event status and to document
      concomitant medications.

      Safety will be assessed by monitoring and recording all treatment-emergent adverse events
      (TEAEs) including serious adverse events (SAEs) and discontinuations due to TEAEs. Additional
      assessments will include regular monitoring of hematology, blood chemistry, and urine values,
      regular measurement of vital signs, ECGs, medical history, physical and neurological
      examinations.
    

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 ≥ 18 to 80 years, inclusive

          -  Diagnosis of familial or sporadic ALS as defined by the El Escorial-Revised (2000)
             research diagnostic criteria for ALS [Clinically Definite, Clinically Probable,
             Probable-Laboratory-Supported]

          -  Diagnosis of ALS with onset of less than or equal to 5 years from first clinical
             weakness

          -  Slow vital capacity ≥ 60% of predicted within 1 month prior to Treatment Day 1

          -  Currently on a stable dose of riluzole for at least 30 days prior to initiation of
             study drug. Subjects not currently taking riluzole will be started on 50 mg qd for the
             first 7 days followed by 50 mg bid for the following 21 days prior to screening.
             Patients may be screened during this time period but not started on study drug until
             they are on a stable dose of riluzole.

          -  All females will be considered to be of childbearing potential unless they are
             postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age
             group, and without other known or suspected cause) or have been sterilized surgically
             (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all
             with surgery at least 1 month before dosing). Females of childbearing potential must
             use an effective method of contraception throughout the entire study period and for 30
             days after study drug discontinuation.

          -  Females must not be lactating or pregnant at Screening or Baseline (as documented by a
             negative beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin
             [hCG]). A separate baseline assessment is required if a negative screening pregnancy
             test was obtained more than 72 hours before the first dose of study drug.

          -  Males should practice contraception as follows: condom use and contraception by female
             partner.

          -  Able to swallow study medication capsules.

          -  Subject is willing and able to comply with the protocol assessments and visits, in the
             opinion of the study nurse/coordinator and the Investigator.

          -  Has no known allergies to the study drug or its excipients.

          -  Has received 23-valent pneumococcal vaccine within 4 years prior to starting clinical
             trial.

        Exclusion Criteria:

          -  Use of tracheostomy, tracheostomy invasive mechanical ventilation [TIMV].

          -  Greater than 3% predicted loss in post-diagnosis vital capacity per month or a greater
             than 1 unit loss in post diagnosis ALSFRS-R total score per month [ exclusive of loss
             due to beginning use of assistive devices]

          -  Confirmed hepatic insufficiency or abnormal liver function (AST and/or ALT greater
             than 3 times the upper limit of the normal range)

          -  Renal insufficiency as defined by a serum creatinine greater than 1.5 times the upper
             limit of normal range

          -  Currently has a clinically significant psychiatric disorder or dementia which would
             preclude evaluation of symptoms.

          -  Has a clinically significant medical condition (other than ALS) including the
             following: neurological, metabolic, hepatic, renal, hematological, pulmonary,
             cardiovascular, gastrointestinal, urological disorder, or central nervous system
             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.

          -  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.

          -  ECG finding of QTcB prolongation > 450 ms for males and > 470 ms for females at
             screening

          -  History of HIV (human immunodeficiency virus), clinically significant chronic
             hepatitis, or other active infection

          -  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.

          -  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.

          -  Subject has poor peripheral venous access that will limit the ability to draw blood as
             judged by the Investigator.

          -  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.

          -  Unable to cooperate with any study procedures, unlikely to adhere to the study
             procedures and keep appointments, in the opinion of the Investigator.

        Advanced ALS group will follow the same inclusion/exclusion as the early ALS subjects with
        the exception of the following:

        Inclusion criteria:

          -  Diagnosis of ALS with onset of ≤10 years from first clinical weakness

          -  On Non-invasive ventilator with Non-invasive pressure [P-NIV] or volume [V-NIV] cycled
             ventilation stable use for ≥ 4 hours daily for 1 month prior to Treatment Day.

          -  Slow vital capacity ≥ 20% of predicted (Knudsen 1983) within 1 month prior to
             Treatment Day 1

          -  Able to swallow study medication capsules or have gastrostomy tube access for delivery
             of contents of medication capsule.

        Exclusion criteria:

          -  Use of tracheostomy, tracheostomy invasive mechanical ventilation [TIMV].

          -  No rate of progression exclusion.