Ibudilast (MN-166) in Subjects With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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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.

Official Title
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A Single-center, Randomized, Double-blind, Placebo-controlled, 6-month Trial Followed by an Open-label Extension to Evaluate the Safety, Tolerability and Clinical Endpoint Responsiveness of Ibudilast (MN-166) in Subjects With (ALS)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Placebo (for MN-166)
* Drug: MN-166
* Drug: riluzole


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (for MN-166)<br>Sugar pill manufactured for MN-166 10 mg tablets plus 50 mg riluzole by mouth twice daily for 6 months. | Drug: Placebo (for MN-166)<br> <br> * Other names: Sugar pill manufactured to mimic MN-166 10 mg tablet;Drug: riluzole<br>* Patient is given 50 mg riluzole twice daily.<br>* Other names: Rilutek;|
| Experimental: MN-166<br>MN-166 10 mg tablets (up to 60 mg/day) by mouth 2-3 times a day plus 50 mg riluzole 2 times a day by mouth for 6 months. | Drug: MN-166<br> <br> * Other names: ibudilast;Drug: riluzole<br>* Patient is given 50 mg riluzole twice daily.<br>* Other names: Rilutek;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of MN-166 60 mg/d Versus Placebo When Administered With Riluzole in Subjects With ALS | Safety will be assessed by monitoring and recording all treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs) and discontinuations due to TEAEs and 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Total Score From Baseline to Month 6 | Functional activity as assessed by the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised from baseline visit to Month 6. The best possible score is 48; the worst possible score is 0. Typically, ALS scores decline. In this outcome, the change in score will be a negative value, e.g., -4, -8, etc. The higher negative value indicates greater decline in functional activity (change in score -8 is worse than change in score -4). | 6 months | 
| Respiratory Function | Change in respiratory function (breathing capacity) from baseline to Month 6, as measured by slow vital capacity, in which the patient breathes into a spirometer slowly until the lungs are cleared of air. SVC is measured in liters (L). The greater the mean change from baseline to 6 months, the worse the outcome. For example, -10 is worse than -6. | 6 months | 
| Muscle Strength | Muscle strength measured by manual muscle testing (MMT) and instrumented hand-held dynamometry. Maximum muscle strength is assessed by measuring the best of 2 handgrips represented as kilograms (kg). The greater the change from baseline to month 6, the worse off the subject is. For example, a change of -0.50 is worse than -0.40. | 6 months | 
| Use of Non-invasive Ventilation | Non-invasive ventilation (NIV) utilization measured by clinically indicated prescription for NIV intervention and time to clinically indicated prescription for NIV intervention in each group (for early ALS subjects only). This is intended to count the number of subjects who had to go on non-invasive ventilation, as prescribed by the Principal Investigator, during study participation. | 6 months | 
| The Mean Change in Baseline to Month 6 in Quality of Life as Measured by the Amyotrophic Lateral Sclerosis Assessment Questionnaire - 5 | A patient self-reported questionnaire specifically designed to measure 5 areas of health: physical mobility, activities of daily living and independence, eating and drinking, communication, and emotional functioning. The ALSAQ-5 is brief and easy to complete questionnaire and has undergone rigorous testing for validity, reliability, and sensitivity to change and has been shown to be a robust tool for assessing ALS. The lowest possible score is 0 and the highest possible score is 20. The greater the mean decrease from baseline to Month 6, the group was considered worse off. For example, -2 is worse than -1. The greater the mean increase from baseline to Month 6, the group was considered improved. For example, 2 is better than 1. | 6 months | 
| Clinical Global Impression of Change (CGIC) | A scale used to provide a global rating of illness severity, improvement, and response to treatment. It is a 3-item observer rating scale and uses a 7-point rating scale. The scale was rated relative to the previous standard of care visit prior to randomization for entry, i.e., -3 much much much worse, -2 much much worse, - 1 much worse, 0 no change, +1 much better, +2 much much better, +3 much, much, much better. Ratings were provided by the Investigator. The greater the mean decrease from baseline to Month 6, the group was considered worse off. For example, -2 is worse than -1. The greater the mean increase from baseline to Month 6, the group was considered improved. For example, 2 is better than 1. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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amyotrophic lateral sclerosis, pharmacotherapy, intervention, prospective, safety endpoint, preliminary efficacy, ibudilast