Clinical trial NCT02238626
Conditions: Amyotrophic Lateral Sclerosis
Keywords: amyotrophic lateral sclerosis pharmacotherapy intervention prospective safety endpoint preliminary efficacy ibudilast
Sponsor: MediciNova
Start date: 2014-09-01; Completion date: 2017-12-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Detailed description:

Arms: arm 1: Sugar pill manufactured for MN-166 10 mg tablets plus 50 mg riluzole by mouth twice daily for 6 months. arm 2: 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.
Interventions: intervention 1: Placebo (for MN-166) intervention 2: MN-166 intervention 3: riluzole
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: Patient is given 50 mg riluzole twice daily.

Protocol documents:
Prot_SAP_000.pdf: 
Confidential 
 
PROTOCOL NO. MN-166-ALS-1201 
A SINGLE-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, SIX MONTH CLINICAL TRIAL FOLLOWED BY 
AN OPEN-LABEL EXTENSION TO EVALUATE THE SAFETY, 
TOLERABILITY AND CLINICAL ENDPOINT RESPONSIVENESS 
OF IBUDILAST (MN-166) IN SUBJECTS WITH AMYOTROPHIC 
LATERAL SCLEROSIS (ALS) 
STEP-IBU-ALS-DB-OLE-1 
 
IND Number: 
118318 
Study Phase: 
1b/2a 
Sponsor: 
 
Kazuko Matsuda, MD PhD MPH 
Chief Medical Officer  
MediciNova, Inc. 
4275 Executive Square  
La Jolla, CA 92037 
Investigational Product Name: 
MN-166 (ibudilast) 
Indication: 
Amyotrophic Lateral Sclerosis (ALS) 
Principal Investigator: 
 
Benjamin Rix Brooks, MD 
Director 
Carolinas Neuromuscular/ALS-MDA Center 
Carolinas HealthCare System Neurosciences Institute 
Adjunct Professor of Neurology 
University of North Carolina School of Medicine 
1010 Edgehill Road North 
Charlotte, NC 28207 
 
                                    ORIGINAL VERSION OF PROTOCOL 
     
14 JULY 2014 
AMENDMENT 1 
 
 
 
 
 
 
20 FEBRUARY 2015 
AMENDMENT 2 
 
 
 
 
 
       27 FEBRUARY 2015 
AMENDMENT 3                                                             08 JULY 2015 
 
 
 
 
 
AMENDMENT 4 
 
 
 
 
 
 
 
    31 MAY 2016 
 


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INVESTIGATOR AGREEMENT 
 
PROTOCOL NUMBER:  MN-166-ALS-1201 
 
I have read the foregoing protocol and agree to conduct the study as described herein. 
By signing the protocol, the Investigator agrees to keep all information provided by MediciNova, 
Inc. in strict confidence and to request the same from his/her staff and the Institutional Review 
Board. Study documents provided by MediciNova, Inc. will be stored appropriately to ensure 
their confidentiality.  The Investigator should not disclose such information to others without 
authorization, except to the extent necessary to conduct the study.  
 
 
 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol Number: MN-166-ALS-1201 
 
Carolina Neuromuscular/ALS-MDA Center Carolinas Healthcare System Neuroscience Institute: 
 
 
 
 
 
MediciNova: 
  
 Signature:           
                               Date:      31 May 2016 
Name: 
Kazuko Matsuda, MD PhD MPH 
 
 
 


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1. 
SYNOPSIS 
 
Name of Sponsor: MediciNova, Inc. 
Name of Investigational Product: MN-166 (ibudilast) 
Protocol No: MN-166-ALS-1201 
Title of Study: A Single-Center, Randomized, Double-Blind, Placebo-Controlled, Six Month Clinical 
Trial Followed by an Open-Label Extension to Evaluate the Safety, Tolerability and Clinical EndPoint 
Responsiveness of Ibudilast (MN-166) in Subjects with Amyotrophic Lateral Sclerosis (ALS)    
STEP-IBU-ALS-DB-OLE 1 
Principal Investigator: Benjamin Rix Brooks, MD 
Study Center: Carolina Neuromuscular/ALS-MDA Center, Carolinas Healthcare System 
Neurosciences Institute 
Duration of Study Treatment: MN-166 group: 6 months;  
Placebo group: 12 months (6 months placebo followed by 6 months 
MN-166) 
Phase of Development: 
1b/2a 
Study Objectives 
Primary Objective 
The primary objective is to evaluate the safety and tolerability of MN-166 60 mg/d versus placebo 
when administered for 6 months with riluzole in subjects with amyotrophic lateral sclerosis. 
Secondary Objectives 
The secondary objective is to evaluate the clinical endpoint responsiveness of MN-166 60 mg/d versus 
placebo when administered with riluzole in subjects with amyotrophic lateral sclerosis as measured by 
the following assessments:  
• 
Functional activity as assessed by the Amyotrophic Lateral Sclerosis Functional Rating Scale-
revised (ALSFRS-R) 
• 
Respiratory function as measured by slow vital capacity (SVC), Maximum Inspiratory Pressure 
(MIP) also known as Negative Inspiratory Force (NIF), Forced Expiratory Volume in 1 second 
(FEV1) measured under SVC protocol and Maximal Voluntary Ventilation (MVV) 
• 
Muscle strength measured by manual muscle testing (MMT) and instrumented hand grip 
dynamometry 
• 
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) 
 


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Tertiary Objectives 
• 
To evaluate quality of life as assessed by the Amyotrophic Lateral Sclerosis Assessment 
Questionnaire (ALSAQ-5)  
• 
To evaluate Clinical Global Impression of Change (CGIC) as assessed by ALS subjects, 
caregivers and physician anchored to most recent standard of care visit prior to screening visit 
• 
To evaluate serum creatinine as a biomarker for disease progression 
• 
To evaluate the pharmacokinetics of MN-166 when administered as an adjunct to riluzole 
STUDY DESIGN 
This is a single center, randomized, double-blind, placebo-controlled, 6-month study designed to 
evaluate the safety, tolerability and clinical endpoint responsiveness of MN-166 (60 mg/d) when 
administered as an adjunct to riluzole (50 mg bid) in 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). To be eligible, subjects must have a diagnosis of sporadic or familial ALS with onset of ≤5 
years (“early ALS”) from first clinical weakness prior to screening or with onset of ≤10 years 
(“advanced ALS”) from first clinical weakness prior to screening for ALS patients on non-invasive 
ventilator support. All subjects must be on a stable dose of riluzole for at least 1 month prior to study 
drug treatment. All subjects will receive optimized standard of care at an ALS Multidisciplinary Clinic 
affiliated with an academic medical center in addition to study medication.  A total of approximately 
120 male and female subjects from 18 to 80 years old, inclusive will be enrolled. Eligible subjects will 
be stratified by ALS stage.  Sixty subjects will be enrolled into the “early ALS” group and 60 subjects 
will be enrolled into the “advanced ALS” group. Subjects will be randomized in a 2:1 ratio for active 
drug and placebo (80 subjects in the MN-166 group; 40 subjects in the placebo group).  Upon 
completion of the Double-blind Phase, subjects randomized to the placebo arm will continue for an 
additional 6 months and will receive open-label MN-166. The safety and tolerability of MN-166 will 
be evaluated by an unblinded Independent Safety Monitor during an interim safety monitoring 
assessment after approximately 20-30 subjects have been followed for approximately 3 months. The 
safety data will also be reviewed at Month 6 and if there are no safety or tolerability concerns in the 
MN-166 treated group, a decision will be made to extend participation to the MN-166 treated group 
into the Open-label Extension (OLE) Phase.  Otherwise, only the placebo-treated patients will 
participate in the OLE Phase. Subjects will be informed of the treatment that they have received during 
the double-blind phase after the last subject has completed the open-label extension or at a time defined 
by the principal investigator in consultation with MediciNova.  
         
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Design  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The study will consist of a Screening Phase (up to 3 months prior to baseline) followed by a double-
blind Treatment Phase (6 months) and an Open-label Extension (OLE) Phase for the Placebo treatment 
arm (6 months).  A follow-up visit will take place within 2 weeks after the last dose of study drug.   
 
Screening Phase (up to 3 months prior to Day 1)  
During the Screening Phase, ALS patients who are potential subjects will be advised concerning the 
clinical trial through open announcement and, if interested, will be approached for study participation 
and provided an informed consent form.  On Day -7, subjects will return to the clinic, and if there are 
no additional questions, subjects will sign the informed consent form.  The following screening 
assessments will be performed: review of inclusion/exclusion criteria: medical history including review 
of prior and current medications, physical and neurological examination, height, body weight, and vital 
signs [temperature, pulse rate, respiratory rate, blood pressure, oxygen saturation (room air)] and an 
electrocardiogram [ECG].  Clinical laboratory testing consisting of [1] comprehensive metabolic panel 
(CMP) including GGT, [2] CK, [3] complete blood count, [4] urinalysis (without microscopic analysis) 
and [5] serum pregnancy test will be collected.  An EMG report to support diagnosis together with 
World Federation of Neurology El Escorial Diagnostic Criteria (Airlie House version) Level of 
Diagnosis [Clinically Definite, Clinically Probable, Probable -Laboratory-Supported] will be 
documented and an ALSFRS-Revised questionnaire, ALSAQ-5 questionnaire and CGIC questionnaire 
will be administered. 
 
During the Screening Phase, subjects who are not currently taking riluzole will be started on riluzole 50 
mg qd for the first 7 days and then 50 mg bid for the next 3 weeks prior to entry into the clinical trial. 
Double-Blind Treatment Phase (6 months) 
On Day 1, subjects will return to the clinic, eligibility criteria confirmed, and will be randomized to 
MN-166 versus matching-placebo in a 2:1 ratio, respectively. Subjects randomized to MN-166 will 
   Screening                                        Double-Blind Phase                    OLE                           Follow-up 
Screen 
Early and 
MN-166 
Placebo 
 *R 
Follow-
up visit 
*R = randomize 
MN-166= ibudilast 
MN-166 
MN-166 
Safety results will 
decide continued 
     Month - 3                                         Day 1                                                            Month 6                                                 Month 12      2wks after     


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begin on MN-166 30 mg/d for 14 days followed by MN-166 60 mg/d for the remainder of the Double-
blind Phase. Subjects who cannot tolerate 60 mg/d will have their dose decreased to 30 mg/d.  After 7 
days, if no tolerability issues arise, the dose can be increased to 60 mg/d.  If the 60 mg/d dose is still 
not tolerable, subjects may remain on 30 mg/d for the remainder of the study. If necessary, an 
alternative dosing regimen may be implemented (e.g., 10 mg tid for the 30 mg/d dose and 20 mg tid for 
the 60 mg dose. Subjects who cannot tolerate 30 mg will be discontinued from the study.  For each 
subject who discontinues from the study due to not tolerating the 30mg daily dose, there will be a 
replacement subject entered. 
Subjects who are currently taking riluzole will continue on the same dose (100 mg/d) during the study. 
Subjects who are not currently taking riluzole will be started on riluzole 50 mg qd for the first 7 days 
and then 50 mg bid for the next 3 weeks prior to entry into the study. Subjects will remain on riluzole 
throughout the study. 
 
During the double-blind Treatment Phase, subjects will return to the clinic at Months 3 and 6 and will 
be telephoned by a study staff member at Months 1, 2, 4, and 5 to collect information about adverse 
events and concomitant medications.  
 
At the end of the Double-blind Phase, subjects randomized to the MN-166 group will complete the 
study and return for the Follow-up visit if continued participation is not extended.  Subjects 
randomized to the placebo group will continue to the Open-label extension (OLE) Phase.   
 
Open-Label Extension (OLE) Phase for Placebo-Treated Group (6 months) 
Upon completion of the Double-blind Treatment Phase, subjects who were taking placebo, will 
participate in the open-label extension (OLE) phase for 6 months. Subjects who were randomized to the 
placebo group will be administered MN-166 30 mg/d for the first 14 days and then 60 mg/d for the 
remainder of the OLE Phase. Subjects who cannot tolerate 60 mg/d will have their dose decreased to 30 
mg/d.  After 7 days, if no tolerability issues arise, the dose can be increased to 60 mg/d.  Subjects who 
are not able to tolerate MN-166 30 mg/d as judged by the Investigator will be discontinued from the 
OLE and will not be replaced.  Subjects who are currently taking riluzole will continue on the same 
dose (100 mg/d) during the study. 
 
Follow-up Phase 
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. 
Number of Subjects (Planned):  
The number of subjects planned for the Double-Blind Phase is approximately 120 (60 subjects with 
early ALS, 60 subjects with advanced ALS, 80 subjects will be randomized to the MN-166 group; 40 
subjects will be randomized to the placebo group).  
The number of subjects planned for the Open-label Extension is approximately 40 placebo subjects 
from the Double-blind Phase). If no safety or tolerability issues are identified during the Double-blind 
Phase in the MN-166 treated group, based on the safety review of approximately 30 patients at the 3- 
month time point, this group of approximately 80 subjects will be extended continued participation into 
the Open-label Extension Phase.  


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Study Entry 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 (Knudsen 1983) 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 (e.g., total 
abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm 
with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) 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], or non-invasive 
pressure - [P-NIV] or volume – [V-NIV] cycled ventilation within the last 3 months prior to 
screening; 
• 
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 


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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 ULN; 
• 
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 1;  
• 
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. 


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Investigational Product, Dosage and Mode of Administration: MN-166 10 mg capsules 
administered orally. Daily dose will be administered as either MN-166 30 mg (3 x 10 mg) qd in AM 
during the titration period or bid in AM and PM. Study drug dosing may be varied based on individual 
tolerability (e.g., 10 mg tid instead of 30 mg qd or 20 mg tid instead of 30 mg bid). 
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.  
Reference Therapy, Dosage, and Mode of Administration: Matching placebo  
Criteria for Evaluation  
Safety Assessments 
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.   
 
Clinical Endpoint Responsiveness Assessments 
Clinical Endpoint Responsiveness  will be assessed by change in 1) ALSFRS-R,                          
2)  muscle strength by manual muscle testing, 3) instrumented hand grip, 4) slow vital capacity 
(SVC), 5) maximum inspiratory pressure (MIP)/negative inspiratory force (NIF), 6)Forced 
Expiratory Volume in One Second (FEV1) measured under SVC protocol 7) maximal 
voluntary ventilation (MVV) and 8) non-invasive ventilation (NIV) utilization ( for early ALS 
subjects only).  
The ALSFRS-R is a well-established scale to measure the functional status of patients with ALS. It is 
based on 12 items, each of which is rated on a 0–4 point scale. The rate of total functional disability 
thus ranges from 0 (maximum disability) to 48 (normal) points. The components of the scale group into 
four factors that encompass gross motor tasks, fine motor tasks, bulbar functions and respiratory 
function (Cedarbaum et al 1997, Gordon et al 2007, Kaufmann et al 2007). 
The manual muscle test (MMT) is a scored neurologic examination derived from the Medical Research 
Council scale (Great Lakes ALS Study Group 2003, Miller 1999, Gordon 2013).  The scale is 
numerical, with scores between 0 and 5 per muscle, based on the examination of 42 muscles. The final 
MMT score per subject is the mean of the scores of all 42 muscles at screening/baseline, Month 3 and 
Month 6. 
Instrumented hand grip will be measured with a dynamometer (Brinkmann et al 1997, Sanjak et al 
2001).  The best of two hand grips will be represented as Kg hand grip strength per hand and percent 
predicted at screening/baseline and Months 3 and 6. 
Slow vital capacity (SVC) is an index of respiratory function measured by a spirometry test to indicate 
potential respiratory compromise in ALS patients (Chhabra 1998, Sanjak 2010).  The subject will be 
asked to inspire fully and then slowly expire all the air in their lungs.  SVC will be assessed at 
screening/baseline, Months 3 and Month 6. 
Maximum Inspiratory Pressure (MIP) or Negative Inspiratory Force (NIF) is a measure of diaphragm 
strength (Mendoza 2007, Roth 2010).  MIP/NIF will be assessed at screening/baseline, Month 3 and 
Month 6. 
Forced Expiration Volume in 1 second [FEV1] is usually measured under conditions of slow vital 
capacity (Camargo 2008, Cooper 1993).  FEV1 will be captured under the protocol of slow vital 


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capacity at screening/baseline, Month 3 and Month 6. 
Maximal Voluntary Ventilation (MVV) is a measure of respiratory stamina that will be assessed at 
screening/baseline, Month 3 and Month 6 (Berto 2007) 
Non-invasive Ventilation Utilization will be measured by occurrence of prescription for NIV and time 
to occurrence of prescription for NIV (for early ALS patients only). 
ALSAQ-5 (Amyotrophic Lateral Sclerosis Assessment Questionnaire-5) (Golab-Janowska 2010; 
Jenkinson 2003, 2007) 
CGIC (Clinical Global Impression of Change) (Brooks 1996; Guy 1976) 
| – 3 much worse | – 2 moderately worse |   – 1 minimally worse |   0 no change   
             |   +1 minimally better |   +2 moderately better |   +3 much better 
Pharmacokinetics: Plasma samples for analysis of MN-166 will be collected at specified timepoints 
throughout the study. 
Analysis Sets 
Safety Analysis Set:  The group of randomized subjects who received at least 1 dose of study drug and 
had at least one postdose safety assessment. 
Full Analysis Set (FAS):  The group of randomized subjects who received at least 14 days of study 
drug and had at least one post-dose efficacy measurement. 
Statistical Methods 
Safety will be assessed based on the frequency of treatment-emergent adverse events (TEAEs), clinical 
laboratory parameters, vital signs, and ECG results. Evaluation of safety will be performed on the 
Safety Analysis Set. Assessments that will be evaluated include TEAEs, clinical laboratory results, 
vital signs, and 12-lead ECGs. Treatment-emergent AEs will be summarized by presenting the 
incidence of TEAEs and the overall incidence. The incidence of out-of-normal-range laboratory safety 
tests variables will be summarized along with change from baseline in laboratory safety test variables 
and vital sign measurements. Descriptive summary statistics of the laboratory, vital signs, and ECG 
parameters will also be evaluated.   
The secondary endpoints focused on clinical responsiveness endpoints are: 
• 
Change from baseline in functional status (ALSFRS-R);  
• 
Change from baseline in muscle strength as measured by a manual muscle test; 
• 
Change from baseline in instrumented hand grip strength; 
• 
Change from baseline in respiratory function as measured by Slow Vital Capacity (SVC); 
• 
Change from baseline in respiratory function as measured by Maximum Inspiratory Pressure / 
Negative Inspiratory Force (MIP/NIF); 
• 
Change from baseline in respiratory function as measured by Forced Expiration Volume in 1 
second [FEV1] under conditions of slow vital capacity; 
• 
Change from baseline in respiratory function as measured by Maximal Voluntary Ventilation 
[MVV]; 
• 
 Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire-5 
(ALSAQ-5); 
• 
Change from baseline in Clinical Global Impression of Change (CGIC). 


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All clinical responsiveness endpoints will be analyzed using analysis of covariance (ANCOVA) 
models with treatment group as a factor and the baseline value of the corresponding endpoint as a 
covariate.    All efficacy analyses will be carried out using two-sided tests at the alpha=0.05 level of 
significance. 
 Pharmacokinetics 
PK parameters for MN-166 concentrations and its metabolite will be calculated. 
Sample Size Justification 
No prior data are available on which to base assumptions for sample size/power considerations.  The 
results of this pilot study will be used to design future studies, and the sample size of approximately 
120 subjects is deemed to be appropriate for this purpose. 
Safety Monitoring 
Safety monitoring will be performed after approximately 20-30 subjects have been followed for 3 
months and a safety analysis of the MN-166 treated subjects will be done at 6 months of treatment by 
an unblinded Independent Safety Monitor to assess whether these subjects will continue treatment in 
the OLE. 


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Table 1: 
Schedule of Assessments 
Phase 
Screening 
Double-Blind Treatment 
Open-Label Extension for Placebo Group only 
Follow-up 
ETe 
 
Day -90 
to Day 
 -8 
Day -7 
Day 1 
Baseline 
 
Month 1/ 
Month 2 
(±7days) 
Month 3 
 
(±7days) 
Month 4/ 
Month 5 
(±7days) 
Month 
6d 
(±7days) 
Month 7/ 
Month 8 
(±7days) 
Month 9 
 
(±7days) 
Month 10/ 
Month 11 
(±7days) 
Month 
12 
(±7days) 
End of 
Study 
 
Visit Type 
 
 
 
TEL 
Clinic 
TEL 
Clinic 
TEL 
Clinic 
TEL 
Clinic 
 
 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Informed consent 
Xa 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
review 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical/Neurological 
Examination 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Body height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Vital signs (sitting) 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
12-lead ECG 
 
X 
X* 
 
X 
 
X* 
 
X 
 
X 
 
 
Comprehensive Metabolic 
Panel including GGT 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Serum creatine kinase 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Serum pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test  
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
SVC/MIP/FEV1/MVV 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xf 
Muscle strength 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xf 
ALSFRS-R 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xf 
ALSAQ-5 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Xf 
CGIC 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xf 
Plasma PK MN-166 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant med review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensing 
 
 
X 
 
X 
 
Xc 
 
X 
 
 
 
 
Dispense/Review Patient 
Diary/Collect 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Study Drug Accountability 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
a. A copy of the informed consent form (ICF) will be given to the patient for review.  
b. Signing of the ICF will occur on Day -7. 
c. End of Double-blind Phase and start of open-label study for Placebo-treated subjects only. 
d. Month 6 safety analysis will determine whether subjects who received MN-166 in the Double-blind Phase will continue to receive 6 additional months of treatment in the OLE Phase.  
e. ET early termination: Assessments to be done for Double-blind and OLE early termination. Other assessments/procedures to be done at PI discretion, if necessary. 
f. Assessments do not need to be performed if prior assessments were within one month of this early termination visit. 
g. TEL: Telephone follow up by study staff via telephone, Email or TEXT message 
*  12-lead ECG 3-4 hour after first dose of study drug for only subjects on Nuedexta 


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2. 
TABLE OF CONTENTS 
 
1. 
SYNOPSIS ................................................................................................................... 4 
2. 
TABLE OF CONTENTS ........................................................................................... 14 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 19 
4. 
BACKGROUND AND RATIONALE ...................................................................... 22 
4.1. 
Introduction ................................................................................................................ 22 
4.2. 
Rationale to include advanced ALS patients ............................................................. 24 
4.3. 
Prior Clinical Experience ........................................................................................... 28 
4.3.1. 
Clinical Study Overview ............................................................................................ 28 
5. 
TRIAL OBJECTIVES AND PURPOSE ................................................................... 34 
5.1. 
Primary Objective ...................................................................................................... 34 
5.2. 
Secondary Objectives ................................................................................................. 34 
5.3. 
Tertiary Objectives ..................................................................................................... 34 
6. 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION .................................. 35 
6.1. 
Screening Phase (up to 3 months prior to Day 1) ...................................................... 36 
6.1.1. 
Diagnosis at Screening ............................................................................................... 37 
6.1.2. 
Double-Blind Treatment Phase (6 months) ................................................................ 37 
6.1.3. 
Open-Label Extension Phase for Placebo-Treated Group (6 months) ....................... 37 
6.1.4. 
Follow-up Phase ......................................................................................................... 38 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 39 
7.1. 
Clinical Trial Population ............................................................................................ 39 
7.2. 
Inclusion/Exclusion Criteria....................................................................................... 39 
7.2.1. 
Inclusion Criteria ........................................................................................................ 39 
7.2.2. 
Exclusion Criteria ....................................................................................................... 40 
7.3. 
Subject Withdrawal/Discontinuation Criteria ............................................................ 41 
7.3.1. 
Follow-up Procedures Upon Discontinuation/Withdrawal ........................................ 42 
8. 
TREATMENT OF SUBJECTS ................................................................................. 43 
8.1. 
Description of Study Drug ......................................................................................... 43 
8.2. 
Concomitant Medications .......................................................................................... 43 
8.3. 
Prohibited Medications .............................................................................................. 43 


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8.4. 
Treatment Compliance ............................................................................................... 44 
8.5. 
Randomization and Blinding...................................................................................... 44 
8.5.1. 
Emergency Unblinding Procedures............................................................................ 45 
8.6. 
Dosing Guidelines ...................................................................................................... 45 
8.6.1. 
Treatment Phase ......................................................................................................... 45 
8.6.2. 
Dose Interruptions ...................................................................................................... 46 
8.6.3. 
Subsequent Additional Laboratory Abnormalities ..................................................... 46 
8.7. 
Written Informed Consent.......................................................................................... 47 
8.8. 
Assessments ............................................................................................................... 47 
8.8.1. 
Study Assessments by Visit ....................................................................................... 47 
8.8.1.1. 
Screening .................................................................................................................... 47 
8.8.1.2. 
Double-Blind Treatment Phase .................................................................................. 48 
8.8.1.3. 
Open-Label Extension Phase ..................................................................................... 49 
8.8.1.4. 
Follow-up Visit (2 weeks after last dose of study drug) ............................................ 50 
8.8.1.5. 
Early Termination visit .............................................................................................. 50 
8.8.1.6. 
Laboratory Re-test visit .............................................................................................. 51 
8.8.1.7. 
Telephone Follow-ups ................................................................................................ 51 
8.8.1.8. 
Follow-up by local neurologist .................................................................................. 52 
8.8.2. 
Additional Safety Assessment with patients on Dextromethorphan-20mg 
and Quinidine-10mg (Nuedexta) in MN-166-ALS-1201 Clinical Trial .................... 52 
8.8.2.1. 
Patients already on Nuedexta prior to participating MN-166-ALS-1201 
Trial ............................................................................................................................ 52 
8.8.2.2. 
Patients starting Nuedexta after beginning Study Medication in MN-166-
ALS-1201 Trial .......................................................................................................... 52 
8.8.3. 
Procedures/Assessment Details .................................................................................. 53 
8.8.3.1. 
Informed Consent ....................................................................................................... 53 
8.8.3.2. 
Medical History .......................................................................................................... 53 
8.8.3.3. 
Prior/Concomitant Medication Review...................................................................... 53 
8.8.3.4. 
Physical/Neurological Examination ........................................................................... 53 
8.8.3.5. 
Vital Signs, Height, and Weight ................................................................................ 53 
8.8.3.6. 
Electrocardiogram (12-Lead ECG) ............................................................................ 54 
8.8.3.7. 
Manual Muscle Test ................................................................................................... 54 
8.8.3.8. 
Instrumented Hand Grip Measurement ...................................................................... 54 


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8.8.3.9. 
Slow Vital Capacity ................................................................................................... 54 
8.8.3.10. 
Maximum Inspiratory Pressure / Negative Inspiratory Force .................................... 54 
8.8.3.11. 
Forced Expiratory Volume in 1 Second measured by Slow Vital Capacity 
Protocol ...................................................................................................................... 55 
8.8.3.12. 
Maximal Voluntary Ventilation ................................................................................. 55 
8.8.3.13. 
Non Invasive Ventilation Utilization ......................................................................... 55 
8.8.3.14. 
Amyotrophic Lateral Sclerosis Functional Rating Scale-revised 
(ALSFRS-R) .............................................................................................................. 55 
8.8.3.15. 
Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) ................... 55 
8.8.3.16. 
Clinical Global Impression of Change ....................................................................... 55 
8.8.3.17. 
Adverse Event (AE) Monitoring ................................................................................ 56 
8.8.3.18. 
Laboratory Evaluations .............................................................................................. 56 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ........................................... 57 
9.1. 
Study Drug ................................................................................................................. 57 
9.2. 
Study Drug Packaging and Labeling .......................................................................... 57 
9.3. 
Study Drug Storage .................................................................................................... 57 
9.4. 
Study Drug Administration ........................................................................................ 58 
9.5. 
Study Drug Accountability ........................................................................................ 58 
10. 
ASSESSMENTS OF SAFETY AND CLINICAL ENDPOINT 
RESPONSIVENESS .................................................................................................. 59 
10.1. 
Primary Endpoints ...................................................................................................... 59 
10.2. 
Secondary Endpoints .................................................................................................. 59 
11. 
ADVERSE EVENTS ................................................................................................. 60 
11.1. 
Definition of Adverse Events ..................................................................................... 60 
11.2. 
Assessment of Adverse Events .................................................................................. 60 
11.2.1. 
Severity Assessment................................................................................................... 60 
11.2.2. 
Relationship to Study Drug ........................................................................................ 61 
11.3. 
Recording Adverse Events ......................................................................................... 62 
11.4. 
Treatment and Follow-Up of AEs .............................................................................. 62 
11.5. 
Serious Adverse Events (SAEs) ................................................................................. 63 
11.5.1. 
SAE Reporting Requirements .................................................................................... 63 
11.6. 
Guidance for Overdose .............................................................................................. 64 
11.7. 
Reporting and Follow-up of Pregnancies ................................................................... 64 


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11.8. 
Preplanned Hospitalizations or Procedures ................................................................ 65 
12. 
STATISTICAL CONSIDERATIONS ....................................................................... 66 
12.1. 
Data Analysis ............................................................................................................. 66 
12.1.1. 
Analysis Populations .................................................................................................. 66 
12.1.2. 
Sample Size Justification ........................................................................................... 66 
12.1.3. 
Safety Analysis........................................................................................................... 66 
12.1.4. 
Clinical Endpoint Responsiveness Analysis .............................................................. 66 
12.2. 
Direct Access to Source Data/Documents ................................................................. 67 
12.3. 
Study Monitoring ....................................................................................................... 67 
12.4. 
Audits and Inspections ............................................................................................... 68 
12.5. 
Institutional Review Board (IRB) .............................................................................. 68 
12.6. 
Study Documentation ................................................................................................. 68 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................... 69 
14. 
ETHICS ...................................................................................................................... 70 
14.1. 
Ethics Review ............................................................................................................. 70 
14.2. 
Ethical Conduct of the Study ..................................................................................... 70 
14.3. 
Written Informed Consent.......................................................................................... 70 
14.4. 
Confidentiality............................................................................................................ 70 
14.4.1. 
Confidentiality of Data ............................................................................................... 70 
15. 
DATA HANDLING AND RECORDKEEPING....................................................... 71 
15.1. 
Review of Records ..................................................................................................... 71 
15.2. 
Retention of Records .................................................................................................. 71 
16. 
ADMINISTRATIVE AND REGULATORY DETAILS .......................................... 72 
16.1. 
Protocol Amendments and Study Termination .......................................................... 72 
16.2. 
Discontinuation of the Study ...................................................................................... 72 
16.3. 
Compliance with Financial Disclosure Requirements ............................................... 72 
17. 
REFERENCES ........................................................................................................... 73 
18. 
APPENDICES............................................................................................................ 79 
Appendix 1: Laboratory Safety Tests for MN-166..................................................................... 80 
Appendix 2: ALS Functional Rating Scale-R ............................................................................... 82 
Appendix 3:  ALSAQ-5 ................................................................................................................ 83 
Appendix 4: Model Informed Consent Form ................................................................................ 84 


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List of Figures and Tables 
 
Figure 1 Survival in V-NIV vs. P-NIV ......................................................................................... 24 
Figure 2 Survival post V-NIV Trilogy .......................................................................................... 25 
Figure 3 FVC Before and After BIPAP [From Kleopa et al, 1999] .............................................. 26 
Figure 4 Study Schema.................................................................................................................. 36 
Table 1: 
Schedule of Assessments ........................................................................................... 13 
Table 2      Abbreviations and Terms ............................................................................................ 19 
Table 3  
Summary Table of Completed and Ongoing Clinical Trials ..................................... 28 
Table 4:  
Study Drug Information ............................................................................................. 57 
Table 5:  
Adverse Events Severity Definitions ......................................................................... 60 
Table 6: 
Adverse Event Causality Definitions ......................................................................... 61 
 
 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2      Abbreviations and Terms 
Abbreviation  
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALS 
amyotrophic lateral sclerosis 
ALSAQ-5 
Amyotrophic Lateral Sclerosis Assessment Questionnaire-5 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale-revised 
ALT (SGPT) 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST (SGOT) 
aspartate aminotransferase 
AV 
atrioventricular 
AUC 
Area under the curve 
β-hCG  
beta-subunit of human chorionic gonadotropin 
bid 
twice daily 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CIRB 
Central Institutional Review Board 
CK 
creatine kinase 
Cmax 
maximum plasma concentration 
CMP 
comprehensive metabolic panel 
CNS 
central nervous system 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CYP 
cytochrome 
DDI 
drug-drug interaction 


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Abbreviation  
Term 
DHD 
dihydrodiol 
dL 
deciliter 
DM 
diabetes mellitus 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders- Fourth 
Edition-Text Revision 
ECG 
electrocardiogram 
EMG 
electromyography 
ET 
Early Termination 
EW 
early withdrawal 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HV 
healthy volunteer 
IBU 
ibudilast 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ISM 
Independent Safety Monitor 
L 
liter 
MMT 
Manual Muscle Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MIF 
macrophage migration inhibitory factor 


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Abbreviation  
Term 
MIP 
maximum inspiratory pressure 
MVV 
Maximal Voluntary Ventilation 
NIF 
negative inspiratory force 
NIV 
non-invasive ventilation 
NSAID 
Non-steroidal anti-inflammatory drug 
OLE 
Open-label extension 
PET 
positron emission tomography 
PDE 
phosphodiesterase 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PO 
per oral 
qd 
once-daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SA 
sinoatrial 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
sub investigator 
SVC 
slow vital capacity 
SOD 
superoxide dismutase  
SOP 
standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
tid 
three times daily 
TMF 
trial master file 
TRAE 
treatment-related adverse event 
ULN 
upper limit of normal 
WBC 
white blood cells 
WHO-DD 
World Health Organization Drug Dictionary 


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4. 
BACKGROUND AND RATIONALE 
4.1. 
Introduction 
 
Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neurological disorder. In 
its classic form, ALS affects motor neurons at two or more levels of the motor neuron network 
supplying multiple regions of the body. It affects lower motor neurons (LMN) that reside in 
the anterior horn of the spinal cord and in the brain stem, corticospinal upper motor neurons 
(UMN) that reside in the precentral gyrus, and, frequently, prefrontal motor neurons that are 
involved in planning or orchestrating the work of the upper and lower motor neurons.  The 
most common symptoms of ALS are muscle weakness, atrophy, loss of motor control, 
weakness, fatigue, and dysarthria.  As the disease progresses, symptoms may include 
shortness of breath, difficulty breathing, dysphagia, and paralysis.  Approximately 5600 
people in the United States are diagnosed with ALS each year. The annual incidence is 2-3 per 
100,000 population. It is estimated that as many as 18,000 Americans may have ALS at any 
given time. ALS is a fatal disease. Median survival is 3 years from clinical onset of weakness. 
However, longer survival is not rare. About 15% of patients with ALS live 5 years after 
diagnosis, and about 5% survive for more than 10 years (Carmel 2014).  
Rationale for the use of MN-166 for the treatment of ALS is based on animal model studies 
and ALS patient studies which indicate that activated glia plays a major role in the 
progression of this disease.  Exact pathophysiology of motor neuron degeneration in ALS is 
unknown, however, there is growing evidence that glial activation and inflammatory 
processes may play a key role in the pathogenesis of ALS.  Microglia, macroglia and 
neuroinflammation are implicated in many CNS disorders. Evidence implicating activation of 
microglia in motor neuron disease was seen in studies on mutant SOD1 (mSOD1) transgenic 
mice, the predominant animal model of ALS. These studies showed that microglial activation 
occurred in the earliest stages of motor neuron degeneration, even before symptoms of 
weakness (Alexianu et al 2001; Hall et al 1998).  In human studies, strong microglia 
activation and proliferation have been described in the primary motor cortex, brainstem motor 
nuclei and ventral horns of the spinal cord: all areas with motor neuron loss. (Ince et al 1996; 
Kawamata et al 1992) Furthermore, a positron emission tomographic (PET) scan study 
showed that microglial activation strongly correlated with clinical signs of upper motor 
neuron loss in sporadic ALS (Turner et al 2004) and a recent PET scan study in ALS patients 
showed microglial activation found in primary motor, supplementary motor and temporal 
cortex (Corcia et al 2012). 
MN-166 (ibudilast) is a small molecule macrophage migration inhibitory factor (MIF)- and 
phosphodiesterase (PDE)-4,10-inhibitor drug candidate with demonstrated neuroprotective 
action in vitro and in vivo.  MIF knockout or antibody-neutralization studies have provided 
neuroprotection validation in certain MS and other neurological animal models.  Ibudilast has 
additionally shown attenuation of glial cell activation in multiple in vitro and in vivo model 
systems which may represent a novel pharmacotherapeutic approach in ALS treatment. 
 


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Ibudilast is an anti-inflammatory/neuroprotective agent that has been in use for over 20 years 
in Japan and other Asian countries for the treatment of asthma and cerebrovascular disorders 
(post-stroke dizziness).  Ibudilast is marketed as Ketas® in delayed-release capsule (innovator, 
Kyorin Pharmaceuticals) or Pinatos® (generic by Teva/Taisho Pharmaceuticals).  While 
ibudilast has not yet been approved for any conditions outside of Asia, clinical development 
for neurological conditions, including multiple sclerosis, neuropathic pain, and certain drug 
addictions, has been undertaken by Avigen, Inc. (as AV411) and MediciNova, Inc. (as MN-
166). (Ledeboer et al 2007a, 2007b; Rolan et al 2009; Barkhof et al 2010). These entities 
merged at the end of 2009 such that all ibudilast assets could be integrated with continued 
development as MN-166 with MediciNova, Inc. (La Jolla, CA).   
Ibudilast distributes well to the CNS and it is a selective inhibitor of certain cyclic nucleotide 
phosphodiesterases (Gibson et al 2006) and the pro-inflammatory cytokine, macrophage 
migration inhibitory factor (MIF) (Cho et al 2010).  At clinically-relevant plasma or CNS 
concentrations, ibudilast selectively inhibits macrophage migration inhibitory factor (MIF) 
and, secondarily, PDEs 3, 4 and 10.  MIF inhibition or knockout has been linked to attenuated 
disease progression in animal models of multiple sclerosis (Powell et al 2005; Kithcart et al 
2010) and attenuates neuronal death and promotes recovery in mouse spinal cord injury 
(Nishio et al 2009).  Another MIF knockout study revealed its role in neurodegeneration in an 
experimental stroke model (Inacio et al 2011).  PDE inhibition has likewise shown some 
neuroprotective actions (Chen et al 2007; Nakamizo et al 2003).  
Ibudilast has been recognized to have glial attenuating activity in vitro and in vivo. In 
activated glia cells in vitro, ibudilast suppresses the production of proinflammatory cytokines 
and increases the production of anti-inflammatory cytokine and various neurotrophic factors. 
(Suzumura et al 1999; Kawanokuchi et al 2004; Mizuno et al 2004). Ibudilast also protects 
hippocampal neurons (Tominaga et al 1996) and oligodendrocytes against excitotoxicity 
(Yoshioka et al 1998, 2000) and astrocytes against apoptosis (Takuma et al 2001). In an 
animal model of cerebral ischemia, ibudilast reduces white matter lesions and microglial 
activation (Wakita et al 2003).  MediciNova scientists, in collaboration with Dr. Linda 
Watkins and researchers at the University of Colorado, have determined that MN-166 reduces 
glial activation and attenuates allodynia in several validated animal models of peripheral and 
central neuropathic pain (Ledeboer et al 2007a; Ellis et al 2010).   
In addition, Ibudilast suppresses the expression of matrix metalloproteinase-9 (MMP-9) (Lee 
et al 2012; Yagi et al 2010): MMP-9 potentially plays an important role in the pathogenesis of 
ALS and when knocked down in animal models, leads to slower progression of the disease 
(Kaplan, et al 2014). 
 


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4.2. 
Rationale to include advanced ALS patients  
We are amending the current MN-166-ALS-1201 protocol to include ALS patients with advanced 
disease as being defined by requiring non-invasive ventilation due to respiratory motor neuron 
involvement. 
This decision is based on our initial safety report (Brooks et al 2015) that indicated safety for three 
months of ibudilast in a cohort of ALS patients in the United States and the finding coincident with 
the report, that there was a decreased mean rate of vital capacity decrease over 3 months in all 
patients in this clinical trial compared with previously published studies and our own internal 
observation.  We will evaluate whether MN-166 (ibudilast) may be beneficial for patients in the 
advanced stages of ALS defined by having respiratory involvement requiring non-invasive 
ventilation.    
Recent animal studies have shown that hypoxia-induced spinal inflammation inhibits respiratory 
motor neuron plasticity via p38 MAPK activation suggesting that at this advanced stage of ALS 
there may be a benefit of ibudilast for the reasons outlined above (Huxtable et al 2015; Huxtable et 
al 2013; Vinit et al 2011; Zhan et al 2015). 
Clinical observational studies conducted at the Carolinas Neuromuscular /ALS-MDA Center have 
indicated that 198 patients have received pressure [P-NIV] – and 142 patients received volume-
cycled [V-NIV] –non-invasive ventilation.  
Survival was significantly [ p = 0.0261] improved with a decreased hazard ratio = 0.748 (95%CI = 
0.580 - 0.965) in patients with V-NIV [50% survival = 15 months (95%CI = 11-18)] compared 
with P-NIV [50% survival = 9 months (95%CI = 8-11)]. 
 
Figure 1 Survival in V-NIV vs. P-NIV 
 
 


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Another observational study at the Carolinas Neuromuscular /ALS-MDA Center has shown that 
ALS patients with V-NIV and maximal inspiratory pressure < 60 cm H20 have a better survival if 
they are on riluzole. Survival post V-NIV Trilogy is significantly enhanced in ALS patients taking 
Riluzole when MIP is < 60 cm H2O. 
Figure 2 Survival post V-NIV Trilogy 
 
 Mean survival on Riluzole is 22.3 months (95% CI = 18.5 - 26.1 months) compared with 14.7 
months (95%CI = 9.8 - 19.6 months) [P = 0.019]  
Vital capacity declines prior to introduction to pressure [P-NIV] – and volume-cycled [V-NIV] – 
cycled non-invasive ventilation.  Following introduction of P-NIV in the form of BiPAP the rate of 
vital capacity loss is reduced almost in half depending on the degree of compliance with use of 
assisted ventilation. 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 3 FVC Before and After BIPAP [From Kleopa et al, 1999] 
 
  
In the medical literature we have collated studies that confirm the rate of loss of vital capacity in 
patients before the initiation of NIV and when on NIV.  In the Kleopa clinical study (Kleopa et al 
1999) patients who use BiPAP for greater than four hours daily demonstrate a small decline in rate 
of vital capacity loss [group 1] [ - 3.5 + 5.3 (standard deviation)] which is significantly less than in 
those patients who do not use the BiPAP at all [group 3] [ - 8.3 + 5.0].  Patients who use the 
BiPAP for less than four hours daily are intermediate [ - 5.9 + 4.8].  In this clinical study the 
results are significant only between the patients who use the BiPAP for more than four hours daily 
and those who do not use the BiPAP at all. 
More recent studies show smaller rates of vital capacity decline [ VC % Predicted / month] than in 
the past for those patients monitored prior to use of non-invasive ventilation in the amalgamated 
Pro-Act Database consisting of a set of patients who participated in ALS clinical trials (Atassi et al 
2014),  in clinic-based populations (Baumann et al 2010; Vender et al 2007), small clinical trial 
populations (Tandan et al 1996; de Carvalho et al 2015).   
The comparability of the rates of decline in vital capacity early in the course of ALS across centers 
and across different population groups [ clinic-based participants, clinical trial eligible 
participants] provides support for this as an outcome measure in clinical trials and other 
observational studies.   
At the Carolinas Neuromuscular / ALS-MDA Center, we see a comparable vital capacity decline 
[ VC % Predicted / month] in our patients early [ - 2.8 + 13.2] prior to the need for non-invasive 
ventilation defined on the basis of vital capacity, maximum inspiratory pressure or other indicators.  
We also confirm a decline in rate of loss of vital capacity when are patients are first put on NIV [ - 
1.2 + 20.5].  In addition, for the subgroup of patients who are participating in MN-166-ALS-1201, 
we see a comparable decrease to that achieved with non-invasive ventilation [ - 1.3 + 7.7].   


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We plan to evaluate the feasibility, tolerability, safety and clinical endpoint responsiveness of 
ibudilast treatment in ALS patients requiring non-invasive ventilation in this protocol.  For clinical 
endpoint responsiveness analysis, in addition to the rate of vital capacity as well as MIP decline, 
we will monitor use of NIV daily, Trilogy pressures will be required daily and the rate of increase 
in use of NIV and transition to other treatments such as mouthpiece ventilation during the day and 
tracheostomy invasive mechanical ventilation will be documented. 
 


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4.3. 
Prior Clinical Experience 
4.3.1. 
Clinical Study Overview 
To date, 8 clinical studies have been completed in Central Eastern Europe (CEE), Australia and US and 4 clinical trials are ongoing in 
the US.  A total of 461 subjects have been known to be exposed to ibudilast (MN-166/AV411) in clinical trials. A summary of 
completed and ongoing MediciNova (and Avigen) and collaborative Investigator-initiated trials is as follows: 
 
Table 3  
Summary Table of Completed and Ongoing Clinical Trials 
 
Type of 
Study 
 
Study 
Protocol 
Number 
 
Study 
Objective(s)  
 
 
Study Design and Type of 
Control 
Test Product(s); 
Dosage 
Regimen; 
Route of 
Administration 
Number of Subjects 
Healthy 
Subjects or 
Diagnosis of 
Patients 
Duration of 
Treatment 
 
Study 
Status 
 
1 
AV411-
009 
To assess safety, 
tolerability and PK 
R (3:1), DB, PC 
On Day 1 subjects received a single dose of 
AV411 30 mg, or placebo. On Day 2 subjects 
received no study medication and on Day 3 
subjects 
commenced dosing with AV411 30 mg or 
placebo bid for 14 d; PO 
 
18 (14 active, 4 pbo) 
Healthy Volunteers  
 
2 wk 
 
Completed 
1 
AV411-
016 
To assess safety, 
tolerability and PK 
R (3:1), DB, PC, single 
escalating dose 
30 mg, 50 mg, 70 mg, 80 mg, and 100 mg or 
placebo; PO 
 
 
60 (45 active, 15 pbo) 
Healthy Volunteers  
 
Single dose 
except 80 mg 
group who 
received dose 
in both fed 
and fasted 
state 
Completed 


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Type of 
Study 
 
Study 
Protocol 
Number 
 
Study 
Objective(s)  
 
 
Study Design and Type of 
Control 
Test Product(s); 
Dosage 
Regimen; 
Route of 
Administration 
Number of Subjects 
Healthy 
Subjects or 
Diagnosis of 
Patients 
Duration of 
Treatment 
 
Study 
Status 
 
1b 
AV411-
026 
To assess safety, 
tolerability and PK 
R (3:1), DB, PC, MD 
 
 
On Days 1 through 6, subjects received MN-166 
(or matching placebo) as follows:  
20 mg bid x 2 d, then  
30 mg bid x 2 d, and then 
40 mg bid x 2 d. 
On Days 7 through 14, subjects were 
administered AV411 50 mg bid or matching 
placebo; PO 
 
 
24 (18 active, 6 pbo)- 
12 HV; 12 DM 
Healthy Volunteers & 
Diabetes Mellitus 
(Type 1 and 2) 
Subjects 
 
2 wk 
Completed 
1b/2a 
AV411-
010 
To assess safety, 
tolerability, PK and 
preliminary efficacy 
R, DB, PC; 7-day single-blind 
run-in phase (placebo and 
active dose) followed by 
14day treatment phase in 2 
cohorts 
Treatment Phase:  
Cohort 1: randomized 1:1:1 to 40 mg, 60 mg or 
pbo.   
Cohort 2: randomized 2:1 (active:pbo) to 60 mg/ 
80 mg or pbo. 
34  
(34 active in Run-in 
phase  
24 active/10 pbo in 
Treatment phase) 
Diab. Periph. 
Neuropath. Pain (DPN) 
subjects  
 
Single and 
multiple 
dosing 
2 wk   
 
Completed 
1b/2a 
AV411-
OWA 
(Investigat
or IND 
102,942) 
To assess safety, 
tolerability and 
preliminary efficacy 
to reduce opioid 
withdrawal 
syndrome and 
prolong the 
analgesic effect of 
oxycodone 
R (1:1:1), DB, PC 
20 mg BID x 14 days,  
40 mg BID x 14 days, 
pbo;  
PO 
 
44 (22 active/22 pbo) 
Heroin addicts 
 
Multiple 
dose 
2 wk 
  Completed 
2 
MN166-
CL-001 
To assess safety, 
tolerability and 
efficacy 
R, DB, PC followed by an 
OLE 
10 mg tid,  
20 mg tid,  
297 (194 active/103 
pbo) 
Multiple Sclerosis 
 
Core 12 
months; 
extension 12 
Completed 


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Type of 
Study 
 
Study 
Protocol 
Number 
 
Study 
Objective(s)  
 
 
Study Design and Type of 
Control 
Test Product(s); 
Dosage 
Regimen; 
Route of 
Administration 
Number of Subjects 
Healthy 
Subjects or 
Diagnosis of 
Patients 
Duration of 
Treatment 
 
Study 
Status 
 
Pbo for 12 mo, then MN-166 for 12 mo; PO 
months  
1b  
UCLA 
Meth. 
(Investigat
or IND 
108,996) 
To assess safety, 
tolerability, PK and 
methamphetamine 
interaction 
 
 
R, DB, PC, Within-subject 
CO 
20 mg bid, 
 50 mg bid x 7 d, 
pbo; 
PO 
 
 
11 
Methamphetamine 
addicts 
 
2 wk 
Completed  
2a/2 
IBU-002 
(Investigat
or-
sponsored
) 
To determine the 
effect of ibudilast in 
patients with 
medication over use 
headaches. 
R, DB ,PC 
40 mg bid, 
placebo;  
PO 
34 (15 active/19 pbo) 
Medication Overuse 
Headache 
 
8 wk 
Completed 
2a 
AV411 
SA 
(Columbia
/ 
NYSPI) 
To evaluate the 
ability of AV411 to 
alter the reinforcing, 
analgesic, 
subjective, 
physiological effects 
of oxycodone 
R, PC, CO 
50 mg bid,  
placebo; 
 PO 
 
Planned 24  
 
 
Opioid and heroin 
dependent users 
 
3 wk 
Ongoing 
2 
UCLA-
Meth-Ph2 
To determine 
whether MN-166 
reduces MA use 
more than placebo 
R, DB, PC 
50mg bid, placebo, PO 
Planned: 140 
Methamphetamine 
addicts 
12 wk 
Ongoing 


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Type of 
Study 
 
Study 
Protocol 
Number 
 
Study 
Objective(s)  
 
 
Study Design and Type of 
Control 
Test Product(s); 
Dosage 
Regimen; 
Route of 
Administration 
Number of Subjects 
Healthy 
Subjects or 
Diagnosis of 
Patients 
Duration of 
Treatment 
 
Study 
Status 
 
2 
UCLA 
Alcohol 
Addiction 
To assess safety, 
tolerability and 
preliminary efficacy 
of MN-166 in 
alcohol addiction 
participants 
R, DB, PC, CO 
50mg bid, placebo, PO 
Planned: 24 
 
Alcohol addiction 
7 d session x 
2 
Ongoing 
2 
SPRINT-
MS 
To evaluate safety, 
tolerability and 
activity of MN-166 
R, DB, PC 
Up to 100 mg/d  
Planned: 250 (125 
MN-166; 125 
placebo) 
Enrolled: 66 
Progressive Multiple 
sclerosis 
96 wk 
Ongoing 


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In the completed studies, the safety of ibudilast from 30 to 80 mg/day has been evaluated in 
single and multiple doses for up to 8 weeks in healthy volunteers and diabetes mellitus 
Type 1 & 2 patients, chronic pain patients (diabetic neuropathy and complex regional pain 
syndrome), opioid-addicted subjects and in chronic medication overuse headache (MOH) 
pain.  The dosage of 100 mg/day has been evaluated in single and multiple doses for up to 
8 days in healthy volunteers (HV), diabetes mellitus (DM) Type 1 & 2 patients and in 
methamphetamine-dependents subjects. In the methamphetamine dependents study 
(UCLA-Meth-Ph1b), subjects received MN-166 40 mg/day for 1 week followed by 100 
mg/day for 1 week.  
Safety Results Multiple Sclerosis Study (24 Months)-30 to 60 mg/day 
A Phase 2 clinical trial evaluating the safety and efficacy of MN-166 in multiple sclerosis 
subjects was completed. The study was a 12-month randomized, double-blind, placebo-
controlled study followed by a 12-month open-label extension (OLE) study.  A total of 297 
subjects were randomized to MN-166 30 mg/d, 60 mg/d or matching placebo.  During the 
12-month double-blind core period, the adverse events most frequently reported (>5%) 
occurred in the SOCs of Infections and Infestations (36%), Nervous System Disorders 
(19%), Gastrointestinal Disorders (15%), Psychiatric Disorders (13%), General Disorders 
and Administration Site Conditions (9%), and Musculoskeletal and Connective Tissue 
Disorders (7%). No significant differences in TEAEs by SOC were observed between 
treatment groups. There was a slight dose-related increase in the percent of subjects with 
gastrointestinal AEs; 8%, 12%, and 15% for the placebo, 30 mg/day, and 60 mg/day 
treatment groups, respectively.  
During the core period, more treatment-related TEAEs were experienced by subjects in the 
60 mg/day group (26) compared to the 30 mg/day (18) or placebo group (12). The most 
common treatment-related AEs were headache (n=3) and nausea (n=2) in the 30 mg/d 
group; nausea (n=4), headache (n=3), vomiting (n=2) and dizziness (n=2) in the 60 mg/d 
group; and upper respiratory infection (n=5) and headache (n=2) in the placebo group.  
During the open-label extension period, five additional treatment-related adverse events 
(TRAEs) occurred. These TRAEs were night cramps (1subject in 60 mg/d cohort), 
hepatotoxity (1 subject in 60 mg/d cohort), depression (1 subject in 60 mg/d cohort), and 
pruritus (2 subjects in placebo to 60 mg/d cohort).  
Over the entire 24-month study, the most frequently occurring AEs (≥ 5% of subjects) were 
nasopharyngitis (20%), headache (14%), urinary tract infection (9%), pharyngitis (6%) and 
nausea (5%). Gastrointestinal AEs occurred in a percentage of subjects: 10%, 12%, 17%, 
and 18% for placebo to 30 mg/day, placebo to 60 mg/day, 30 mg/day, and 60 mg/day 
treatment groups, respectively.  There was a slight increase in gastrointestinal AEs in the 
percent of subjects who received MN-166 treatment for 24 months. 
Over the entire 24-month study, a total of 21 SAEs were reported by 20 subjects. SAEs 
were reported by 12 subjects in the core period and 9 SAEs were reported by 7 subjects 
during the extension period. More subjects in the 60 mg/day dose group (10/99=10.1%) 
experienced an SAE compared to other active group. Four subjects in placebo group 
(4/103= 3.8%) experienced SAEs during core period while on placebo, 1 subject in placebo 


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to 60 mg/d cohort (1/48=2.1%) experienced an SAE during the OLE period while on 60 
mg/d dosage and 4 subjects in the 30 mg/d cohort (4/95=4.2%) experienced an SAE. The 
SAEs were as follows: acetabulum fracture, duodenal ulcer perforation, calculus ureteric, 
and menorrhagia in the placebo group; inguinal hernia, epilepsy, peptic ulcer perforation, 
fibula fracture and menorrhagia in the 30 mg/d group; and bladder diverticulum, epilepsy, 
intervertebral disc protrusion, pneumonia haemophilus, uterine cancer, gastrointestinal 
malignant neoplasms, retinal detachment, hip surgery, depression, acute pancreatitis, ankle 
fracture and congenital anomaly resulting in death (partner pregnancy) in the 60 mg/d 
group. All of these SAEs were considered by the Investigator to be unlikely related or not 
related to study drug. Eight of the SAEs were considered by the Investigator to be severe or 
life threatening. Subject SE-001-009, who was diagnosed with gastrointestinal malignant 
neoplasms, died due to this SAE approximately 1 year after he withdrew from the study 
due to this SAE.  
A total of nine subjects discontinued from the study due to a TEAE. Two of these subjects 
experienced a TEAE that were considered to be related to study drug; hepatic steatosis 
(severe) and hepatotoxicity (moderate) treated with 30 mg/d group and 60 mg/d group, 
respectively.  None of the other TEAEs (duodenal ulcer perforation, osteoarthritis, 
tachycardia, epilepsy, uterine cancer, gastrointestinal neoplasm, acute pancreatitis) that 
resulted in study discontinuation were considered to be related to study medication by 
investigator. 
The pharmacokinetics of MN-166 have been closely monitored in most of the studies and 
the PK has generally been shown to be dose-proportional both within and between studies.  
Based on prior trials, steady state plasma Cmax and AUC0-24h levels at the highest dose (50 
mg bid; 100 mg/d) are anticipated to be approximately 116 ng/ml (Cmax) and 1613 
ng*hr/ml (AUC0-24h) (study AV411-026 HV group).  All of the trials listed in the table 
except for the first two have included all concurrent concomitant medications with ibudilast 
dosing at 80 or 100 mg/d. While pharmacokinetic drug-drug interactions have not been 
carefully assessed (or are in progress), there are no clear pharmacologic or safety 
interactions noted to date.   
 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
This is a single center, randomized, double-blind, placebo-controlled study followed by an 
open-label extension phase (for the placebo-treated group only). This study is designed to 
evaluate the safety, tolerability and efficacy of MN-166 (60 mg/d) when administered as an 
adjunct to riluzole (50 mg bid) in subjects with ALS. 
5.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of MN-166 60 
mg/d versus placebo when administered with riluzole in subjects with amyotrophic lateral 
sclerosis. 
5.2. 
Secondary Objectives 
The secondary objective is to evaluate the clinical endpoint responsiveness of MN-166 60 
mg/d versus placebo when administered with riluzole in subjects with amyotrophic lateral 
sclerosis as measured by the following assessments:  
• Functional activity as assessed by the Amyotrophic Lateral Sclerosis Functional 
Rating Scale-revised (ALSFRS-R) 
• Respiratory function as measured by slow vital capacity (SVC), Maximum 
Inspiratory Pressure (MIP also known as Negative Inspiratory Force (NIF), Forced 
Expiratory Volume in 1 second (FEV1) measured under SVC protocol and Maximal 
Voluntary Ventilation (MVV). 
• Muscle strength measured by manual muscle testing (MMT) and instrumented hand 
grip dynamometry 
• 
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)  
5.3. 
Tertiary Objectives 
• To evaluate quality of life as assessed by the Amyotrophic Lateral Sclerosis 
Assessment Questionnaire (ALSAQ-5)  
• To evaluate Clinical Global Impression of Change (CGIC) as assessed by ALS 
subjects, caregivers and physician anchored to most recent standard of care visit 
prior to screening visit 
• To evaluate serum creatinine as a biomarker for disease progression 
• To evaluate the pharmacokinetics of MN-166 when administered as an adjunct to 
riluzole 
 
 


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6. 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION 
This is a single center, randomized, double-blind, placebo-controlled, 6-month study 
designed to evaluate the safety, tolerability and clinical endpoint responsiveness of MN-
166 (60 mg/d) when administered as an adjunct to riluzole (50 mg bid) in 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). To be eligible, subjects must 
have a diagnosis of sporadic or familial ALS with onset of ≤ 5 years (“early ALS”) from 
first clinical weakness prior to screening or with onset of ≤ 10 years (“advanced ALS”) 
from first clinical weakness prior to screening for ALS patients on non-invasive ventilator 
support. All subjects and must be on a stable dose of riluzole for at least 1 month prior to 
study drug treatment. All subjects will receive optimized standard of care at an ALS 
Multidisciplinary Clinic affiliated with an academic medical center in addition to study 
medication.  A total of approximately 120 male and female subjects from 18 to 80 years 
old, inclusive will be enrolled. Eligible subjects will be stratified by ALS stage.  Sixty 
subjects will be enrolled into the “early ALS” group and 60 subjects will be enrolled into 
the “advanced ALS” group. Subjects will be randomized in a 2 : 1 ration for active drug 
and placebo  ( 80 subjects in the MN-166 group; 40 subjects in the placebo group).  Upon 
completion of the Double-blind Phase, subjects randomized to the placebo arm will 
continue for an additional 6 months and will receive open-label MN-166. The safety and 
tolerability of MN-166 will be evaluated by an unblinded Independent Safety Monitor 
during an interim safety monitoring assessment after approximately 20-30 subjects have 
been followed for approximately 3 months. The safety data will also be reviewed at Month 
6 and if there are no safety or tolerability concerns in the MN-166 treated group, a decision 
will be made to extend participation to the MN-166 treated group into the Open-label 
Extension (OLE) Phase.  Otherwise, only the placebo-treated patients will participate in the 
OLE Phase. Subjects will be informed of the treatment that they have received during the 
double-blind phase after the last subject has completed the open-label extension or at the 
time defined by the principal investigator in consultation with MediciNova.  
 
After approximately 20-30 subjects have been enrolled for 3 months, an unblinded 
independent Safety Monitor (ISM) will review the safety data by treatment group to 
determine whether there are any safety concerns.  If any unexpected safety issues arise, the 
sponsor and PI will be notified and a decision to continue the study will be made. If there 
are no safety concerns, subjects will continue on MN-166 (ibudilast) during the open label 
extension study.   The safety data will also be reviewed at Month 6 and if there are no 
safety or tolerability concerns in the MN-166 treated group, a decision will be made to 
extend participation to the MN-166 treated group in to the Open-label Extension (OLE) 
Phase.   
The study phases are described below and displayed in Figure 1 and the Schedule of 
Assessments is displayed in Table 1. 


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Figure 4 Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1. 
Screening Phase (up to 3 months prior to Day 1) 
 
During the Screening Phase, subjects will be approached for study participation and an 
informed consent form will be given to the patient. On Day -7, subjects will return to the 
office, and if there are no additional questions, subjects will sign the informed consent form.  
The following screening assessments will be performed: review of inclusion/exclusion 
criteria: medical history including review of prior and current medications, physical and 
neurologic examination, height, body weight, and vital signs (sitting). An EMG report will 
be documented and an ALSFRS-revised questionnaire will be administered.  Safety labs 
(chemistry, hematology, urinalysis, and serum pregnancy test) and 12- lead ECG. Slow 
vital capacity and a manual muscle strength test will be conducted; an ALSAQ-5 and CGIC 
questionnaire will be administered.  
 
Subjects who are not currently taking riluzole will be started on riluzole 50 mg qd for the 
first 7 days and then 50 mg bid for the next 3 weeks prior to entry into the study. 
 
Detailed information on permitted and excluded concomitant medications is provided in 
Section 8.2 and Section 8.3 of the protocol.  
   Screening                                        Double-Blind Phase                    OLE                           Follow-up 
Screen 
Early and 
advanced ALS 
MN-166 
 Placebo 
 *R 
Follow-
up visit 
     Month - 3                                         Day 1                                                            Month 6                                                 Month 12      2wks after     
*R = randomize 
MN-166 = ibudilast 
MN-166 
MN-166 
Safety results will 
decide continued 


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6.1.1. 
Diagnosis at Screening 
Subjects must have a diagnosis of familial or sporadic ALS as defined by the El Escorial-
Revised research diagnostic criteria for ALS (clinically definite, clinically probable, 
probable-laboratory supported). 
6.1.2. 
Double-Blind Treatment Phase (6 months) 
 
Subjects who complete all of the screening assessments and continue to meet eligibility 
criteria will be randomized. Subjects will return to the clinic on Treatment Day 1 and will 
be randomized to 1 of 2 treatment arms. They will then receive their first dose of study 
medication. Subjects will be administered 30 mg/d (30 mg qd) for the first 14 days. 
Subjects will be instructed to take study medication with food or within an hour of eating 
to improve gastrointestinal tolerability.  On Day 15, subjects will be instructed to begin 
taking 60 mg/d (30 mg bid) for the remainder of the study.  Subjects who cannot tolerate 
60 mg/d will have their dose decreased to 30 mg/d.  After 7 days, if no tolerability issues 
arise, the dose can be increased to 60 mg/d.  A different dosing regimen may be 
implemented (e.g., 10 mg tid for the 30 mg/d dose; 20 mg tid for the 60 mg/d dose) to 
improve tolerability. Subjects who are not able to tolerate 30 mg/d as judged by the 
Investigator will be discontinued from the study. Subjects who discontinue from the study 
because they cannot tolerate 30 mg/day may be replaced. Subject replacement for other 
reasons is not permitted. 
 
Subjects will continue on the same dose (100 mg/d) of riluzole throughout the study.  
 
Subjects will return to the clinic at Month 3 and Month 6 and will be followed by telephone 
at Months 1, 2, 4, and 5.  
 
Subjects who received placebo during the Double-blind Phase and completed the 6-month 
Double-blind Phase will continue to the OLE Phase.  
 
Safety monitoring will be performed after approximately 20-30 subjects have been 
followed for 3 months and a safety analysis of the MN-166 treated subjects will be done at 
6 months of treatment by an unblinded Independent Safety Monitor to assess whether these 
subjects will also continue treatment in the OLE. 
6.1.3. 
Open-Label Extension Phase for Placebo-Treated Group (6 months) 
 
Upon completion of the double-blind treatment phase, subjects who had been randomized 
to the placebo-treated group will participate in the open-label extension phase for 6 months. 
Subjects will be administered MN-166 30 mg/d for the first 14 days and then 60 mg/d for 
the remainder of the OLE phase. Subject who cannot tolerate 60 mg/d will have their dose 
decreased to 30 mg/d.  After 7 days, if no tolerability issues arise, the dose can be increased 
to 60 mg/d.  Subjects who are not able to tolerate MN-166 30 mg/d as judged by the 
Investigator will be discontinued from the study. A different dosing regimen may be 


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implemented (e.g., for the 30 mg/d dose, 10 mg tid; for the 60 mg/d dose, 20 mg tid) to 
improve tolerability. Subjects who are not able to tolerate 30 mg/d as judged by the 
Investigator will be discontinued from the study.  
Subjects will continue on the same dose (100 mg/d) of riluzole throughout the OLE Phase. 
6.1.4. 
Follow-up Phase 
All subjects who complete the study (double-blind and open-label) or prematurely 
discontinue will return for a safety visit 14 days after their last dose to assess the subject’s 
general health status and to document adverse events and concomitant medications. 
 
 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Clinical Trial Population 
The population for this trial will include approximately 120 male and female subjects ≥ 18 
to 80 years old, inclusive with a diagnosis of ALS stratified by early ALS and advanced 
ALS.  
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug. 
7.2. 
Inclusion/Exclusion Criteria 
7.2.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
1. Written informed consent is obtained and willing and able to comply with 
the protocol in the opinion of the Investigator; 
2. Male or female subjects ages ≥ 18 to 80 years, inclusive; 
3. 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]; 
4. Diagnosis of ALS with onset of ≤ 5 years from first clinical weakness; 
5. Slow vital capacity ≥ 60% of predicted (Knudsen 1983) within 1 month 
prior to Treatment Day 1; 
6. 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;  
7. 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 (ie, 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 
(e.g., total abstinence, an intrauterine device, a double-barrier method [such as 
condom plus diaphragm with spermicide], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study period and for 30 days after study drug 
discontinuation; 


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8. 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; 
9. Males should practice contraception as follows: condom use and 
contraception by female partner; 
10. Able to swallow study medication capsules; 
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; 
12. Has no known allergies to the study drug or its excipients; 
13. Has received 23-valent pneumococcal vaccination within 4 years prior to 
starting clinical trial. 
7.2.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Use of tracheostomy, tracheostomy invasive mechanical ventilation 
[TIMV], or non-invasive pressure - [P-NIV] or volume – [V-NIV] cycled 
ventilation within the last 3 months prior to screening; 
2. 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];  
3. Confirmed hepatic insufficiency or abnormal liver function (ALP greater 
than 1.5 times of upper normal limit, AST and/or ALT greater than 3 times 
the upper limit of the normal range); 
4. Renal insufficiency as defined by a serum creatinine greater than 1.5 times 
the ULN; 
5. Currently has a clinically significant psychiatric disorder or dementia which 
would preclude evaluation of symptoms; 
6. 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;   
7. 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; 


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8. ECG finding of QTcB prolongation > 450 ms for males and > 470 ms for 
females at screening; 
9. History of HIV (human immunodeficiency virus), clinically significant 
chronic hepatitis, or other active infection; 
10. 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; 
11. 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;  
12. Subject has poor peripheral venous access that will limit the ability to draw 
blood as judged by the Investigator;  
13. 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; 
14. 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 [PNIV] 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. 
7.3. 
Subject Withdrawal/Discontinuation Criteria 
Subjects may request to be withdrawn from the study at any time for any reason.  
The Investigator may interrupt the treatment of any subject whose health or well-being may 
be compromised by continuation in the study. The following instances require subjects to 
be withdrawn from the study: 


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 Subject fails to adequately comply with the dosing, evaluations, or other 
requirements of the study at the discretion of Investigator; 
 Subjects who have adverse events that require discontinuation of study medication; 
 Subjects who, in the opinion of the Investigator, should be discontinued for their 
well-being;  
 Subjects who are no longer able to understand task instructions or to perform tests 
adequately; 
 Subject becomes pregnant during the study. See section 11.7 for reporting 
requirements and follow-up of the pregnancy. 
If a subject withdraws or is removed from the study for any reason, the reason and date of 
discontinuation of study medication should be recorded in the appropriate section of the 
Case Report Form (CRF).  At the time of study discontinuation, every effort should be 
made to ensure all Early Termination (ET) procedures and evaluations are performed.  
The study sponsors reserve the right to discontinue the study at any time for medical or 
administrative reasons.   
7.3.1. 
Follow-up Procedures Upon Discontinuation/Withdrawal 
An early termination CRF page should be completed for every subject who received study 
medication whether or not the subject completed the study. The reason for discontinuation 
should be indicated on the CRF. Any AEs that are present at the time of discontinuation/ 
withdrawal should be followed in accordance with the safety requirements outlined in 
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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drug 
MN-166 will be provided in 10 mg capsules in polyethylene bottles and will be stored at 
room temperature.  Study drug should be taken with food.  
8.2. 
Concomitant Medications 
Concomitant medications required for the treatment of symptoms and signs of amyotrophic 
lateral sclerosis are permitted except as excluded below. 
Concomitant medications for treatment of adverse events may be allowed. Subjects will be 
instructed to contact a member of the study staff prior to taking any medication. 
8.3. 
Prohibited Medications 
The following medications are prohibited prior to and during study participation: 
• Systemic corticosteroid treatment within 3 months prior to screening (inhaled or 
topical steroids are allowed); 
o  A single course of systemic corticosteroid treatment will be allowed and a 
course of steroids along with antibiotics to treat intercurrent sinobronchitis 
will be allowed 
• Current use of intermittent systemic corticosteroids (i.e., monthly or bimonthly 
intravenous methylprednisolone); 
• Oral immunosuppressants (e.g. azathioprine, methotrexate, cyclosporine (topical 
and ophthalmic cyclosporine are allowed), teriflunomide (Aubagio®) within 6 
months of screening; 
• Mitoxantrone or natalizumab within 6 months of screening; 
• Fingolimod or dimethyl fumarate [Tecfidera®] within 3 months of screening; 
• Rituximab or other B-cell therapy within12 months of screening; 
• Current use of glatiramer acetate and IFNβ-1 (any formulation); 
• Intravenous or Subcutaneous Immunoglobulin (IVIg/SCIg). 
 
The following medications are prohibited during study participation: 
• cimetidine, cyclosporine (topical and ophthalmic cyclosporine are allowed), 
dronedarone, lopinavir, probenecid, quinidine (Nuedexta is allowed), ranolazine, 
rifampin, ritonavir, or tipranavir 
 


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8.4. 
Treatment Compliance 
Compliance will be monitored closely at each visit. Subjects will be instructed to bring all 
unused study medication with them to each visit. Compliance will be assessed by counting 
capsules and dividing the actual number of doses taken (per capsule count) by the number 
of doses the subject should have taken within a visit period and multiplying by 100. All 
subjects will be reminded of the importance of strict compliance with taking study 
medication for the effectiveness of treatment and for the successful outcome of the study. 
Subjects who miss more than 25% of scheduled doses over the course of the study or take 
more than 125% of the scheduled doses will be considered noncompliant and may be 
discontinued from the study per investigator’s judgment.    
8.5. 
Randomization and Blinding 
During the Double-blind Treatment Phase, subjects and all personnel involved with the 
conduct and interpretation of the study, including the investigators, site personnel, and 
sponsor staff will be blinded to the treatment codes. Randomization data will be kept 
strictly confidential, filed securely by an appropriate group with the sponsor and accessible 
only to authorized persons (e.g., unblinded safety monitor) until the time of unblinding. 
Randomization procedures will be addressed in the statistical analysis plan. 
To ensure that treatment allocation remains concealed to both staff and participants, the 
following measures will be taken:  
•  Active drug and placebo will be identical in appearance;  
•  Drug supplies to investigational pharmacy will be coded;  
•  The randomization list will be held by Dickson Advanced Analytics (DA2) to ensure 
that treatment allocation is concealed from the investigator’s team and the participant, 
whilst providing provisions for emergency unblinding.  
Details of the randomization process will be available in the Investigator Site File (ISF). 
The identities of the Dickson Advanced Analytics (DA2) whose randomization roles in the 
trial require them to have access to treatment allocation codes will be recorded in the trial 
master file (TMF).  
The randomization system will be web-based and require a personal log-in and password. 
Only those individuals who have attended the site-initiation visit, are trained and are in the 
delegation-log can carry out this process.  
Once a consented patient meets criteria for clinical trial entry as a subject has been 
randomized they will be given a card to indicate they are on the trial with the emergency 
contact numbers for medical advice. Patients will be instructed to show this card to any 
healthcare professional involved in their care who is not involved in the trial. Any trial 
participant who withdraws from the study will not be replaced.  
 


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Subjects will be informed of the treatment that they have received during the double-blind 
phase after the last subject has completed the open-label extension or at the time defined by 
the principal investigator in consultation with MediciNova. 
8.5.1. 
Emergency Unblinding Procedures 
 
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the sponsor.  In the event that emergency conditions 
require knowledge of the study treatment given, the blind may be broken. If possible, 
before breaking the blind, the investigator should consult with the sponsor to ascertain the 
necessity of breaking the code. 
Unblinding may take place in situations where the safe management of the patient’s 
medical condition necessitates knowledge of the study medication by the person(s) 
responsible for the patient’s care. Where possible, members of the local research team 
should remain unblinded.  
If unblinding is required, the local PI/other medical staff should contact the sponsor at 858-
373-1500 via telephone or safetymonitors@medicinova.com via email.  
The person requesting the unblinding will provide details including the protocol number 
and trial name, name of the requester, reason for unblinding, patient name, participant 
number and timeline to receive the unblinded information. If knowledge of the treatment 
allocation is required in order to treat the patient, the code break number will be given to 
the local PI/other medical staff requesting to unblind the patient. In this way, the treatment 
will be unblinded at the local site but not to sponsor.  
The local PI/medical staff will deal with the medical emergency (upon receipt of the 
treatment allocation revealed by the code break number). Details of the code break will be 
documented on the code break form and filed at the local site.  
Code breaks will also be documented at the end of the study in the statistical report. 
 
8.6. 
Dosing Guidelines 
8.6.1. 
Treatment Phase 
Study drug will be administered as MN-166 30 mg/d (3 capsules) for the first 14 days then 
titrated to 60 mg/d (6 capsules) for the remainder of the study. Study drug should be taken 
with food or within an hour of eating to improve gastrointestinal tolerability. Subject who 
cannot tolerate 60 mg/d will have their dose decreased to 30 mg/d. After 7 days, if no 
tolerability issues arise, the dose can be increased to 60 mg/d. If the 60 mg/d dose is still 
not tolerable, subjects may remain on 30 mg/d for the remainder of the study. If necessary, 
an alternative dosing regimen may be implemented (e.g., 10 mg tid for the 30 mg/d dose 


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and 20 mg tid for the 60 mg dose. Subjects who cannot tolerate 30 mg/d will be 
discontinued from the study.   
On Day 1, subjects will be given a paper diary to record the number of capsules they take 
each day. Subjects will be instructed to bring the diary to each visit. 
If a subject forgets to take their study drug dose, subjects will be encouraged to take their 
medication as soon as possible. If subjects missed to take study drug for more than 12 
hours, subjects will be instructed to skip the dose and take the next dose at their regularly 
scheduled time.   
If a subject is not tolerating the study drug or experiences an adverse event that is severe in 
intensity, the subject will be instructed to contact a member of the study team prior to 
taking their next dose of study drug so that they can be closely monitored.  
8.6.2. 
Dose Interruptions 
Laboratory tests should be repeated within two weeks after any of the following laboratory 
values are met: 
• AST or ALT or ALP or T.bil >3x upper limit of normal (ULN); 
• GGT > 4 x ULN;  
• Cre > 1.5 x ULN; 
• White blood count <2500/mm3; 
• Platelet count <75,000/ mm3. 
If, after repeat testing, the laboratory value is still outside the above limits, then the subject 
should stop study medication. While dosing is withheld, subjects will continue tests and 
assessments according to the schedule defined in the protocol (and may also undergo 
additional assessments to evaluate the laboratory abnormality as per the Investigator’s 
standard practice).  In addition, subjects must have the abnormal laboratory result 
rechecked at least every 2 weeks (rechecks will be run at the local laboratory) until 
resolution or stabilization of the laboratory value. 
After laboratory values return within normal limits, resumption of blinded study treatment 
is to be considered on a case by case basis and must be discussed with the Independent 
Safety Monitor.  
8.6.3. 
Subsequent Additional Laboratory Abnormalities 
Subjects who subsequently develop the same abnormal laboratory value at any other time 
must permanently discontinue dosing with study treatment (i.e., only one dosing 
interruption is allowed for the same lab abnormality). However, subjects who subsequently 
experience a different laboratory abnormality can have study treatment withheld again for a 
different laboratory abnormality. However, only two dosing interruptions are allowed for 
each subject. Any subject who experiences a third abnormal laboratory tests as defined in 
the section above (Section 8.6.2) must permanently discontinue study treatment. 


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8.7. 
Written Informed Consent 
Each subject is required to provide written informed consent prior to undergoing any study 
procedures. A copy of the signed and dated informed consent (in a language in which the 
subject is fluent) is required to be given to the subject. If a subject withdraws consent, data 
collected up to the time of discontinuation will be used to evaluate study results.  
8.8. 
Assessments  
The Schedule of Assessments is presented in Table 1.  
Each visit during the Treatment Phase and Open-label Extension will have a window of ± 5 
days.   
Clinical laboratory evaluations will be performed by Carolinas Laboratory Network 
Diagnostic Services. All clinical and laboratory evaluations, procedures related to 
inclusion/exclusion criteria, or performed during treatment must be reviewed, initialed and 
dated by the Principal Investigator or appropriate designee listed on Form FDA 1572.  
8.8.1. 
Study Assessments by Visit 
The following is a summary of assessments by study visit: 
8.8.1.1. 
Screening 
Study Visit 1 (Day - 90 to Day -8) 
At any point during this time, subject may be approached for participation in the study. An 
informed consent form (ICF) will be given to the subject and the subject will be instructed 
to read the ICF and ask the study staff any questions they may have.  The subject can either 
sign the ICF then or defer signing until they return for Study Visit 2. 
 
Study Visit 2 (Day -7)  
Signing of informed consent (if not signed during Visit 1) the following assessments will 
be performed during Study Visit 2: 
• Inclusion/Exclusion review 
• Medical history 
• Medication history (include all medication taken for ALS and all current 
medication within 1 month prior to screening) 
• Physical/neurological examination 
• Height/body weight 
• Vital signs (sitting) [Temperature, pulse rate, respiratory rate, blood pressure] 


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• 12-lead ECG 
• Laboratory:  Comprehensive Metabolic Panel (CMP) including GGT, Complete 
Blood Count (CBC), Urinalysis without microscopic examination 
• Serum β-hCG (in pre-menopausal females) 
• Serum CK 
• Slow Vital capacity (SVC), Maximum Inspiratory Pressure (MIP/NIF), Forced 
Expiratory Volume in 1 second (FEV1) measured with SVC protocol, Maximal 
Voluntary Ventilation (MVV)  
• Muscle strength by manual muscle testing and instrumented hand grip 
dynamometry 
• ALSFRS-R 
• ALSAQ-5 
• CGIC  
8.8.1.2. 
Double-Blind Treatment Phase  
The following assessments will be performed at Day 1 (Baseline): 
• Inclusion/Exclusion review 
• Vital signs (sitting) [Temperature, pulse rate, respiratory rate, blood pressure] 
• Randomization 
• Study drug dispensing 
• Adverse Event review  
• Concomitant medication review 
• 12-lead ECG* (3-4 hours after first dose) 
• Dispense paper diary to record medication compliance 
Once the assessments have been completed, the subject will be instructed to take 3 
capsules per day with a meal or the subject may take the capsules in the clinic with food. 
*for patients on Nuedexta 
Month 3 and Month 6 
The following evaluations will be conducted at Month 3 and Month 6: 
• Physical/neurological exam 
• Body weight 
• Vital signs (sitting) [Temperature, pulse rate, respiratory rate, blood 
pressure] 


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• 12-lead ECG* 
• Laboratory:  Complete Metabolic Panel (CMP) including GGT, Complete 
Blood Count (CBC), Urinalysis without microscopic examination 
• Urine β-hCG (in pre-menopausal females) 
• Serum CK 
Slow Vital capacity (SVC), Maximum Inspiratory Pressure (MIP/NIF),   Forced 
Expiratory Volume in 1 second (FEV1) measured with SVC protocol, 
Maximal Voluntary Ventilation (MVV)   
• Muscle strength by manual muscle testing and instrumented hand grip 
dynamometry 
• ALSFRS-R 
• ALSAQ-5 (at Month 6 only) 
• CGIC  
• Plasma PK sample 
• Study drug dispensing 
• Review patient diary 
• Study drug accountability 
• Adverse Event review 
• Concomitant medication review 
Month 6 Clinic Visit is the start day (Day 1) of the Open-Label Extension (OLE) phase. 
All subjects will take MN-166 in OLE if there are no safety or tolerability issues. 
Otherwise, only the placebo-treated patients will participate in the OLE Phase. 
*For the patients on Nuedexta, 12-lead ECG at Month 6 visit should be done 3-4 hours 
after first dose of Ibudilast 
8.8.1.3. 
Open-Label Extension Phase  
The following assessments will be conducted at Month 9 and Month 12: 
• Physical/neurological exam 
• Body weight 
• Vital signs (sitting) [Temperature, pulse rate, respiratory rate, blood 
pressure] 
• 12-lead ECG 
• Laboratory: Comprehensive Metabolic Panel (CMP) including GGT, 
Complete Blood Count (CBC), Urinalysis without microscopic examination 


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• Urine β-hCG (in pre-menopausal females) 
• Serum CK 
• Slow Vital capacity (SVC), Maximum Inspiratory Pressure (MIP/NIF), 
Forced Expiratory Volume in 1 second (FEV1) measured with SVC 
protocol, Maximal Voluntary Ventilation (MVV)  
• Muscle strength by manual muscle testing and instrumented hand grip 
dynamometry  
• ALSFRS-R 
• ALSAQ-5 (at Month 12 only) 
• CGIC  
• Plasma PK sample 
• Study drug dispensing (at Month 9 only) 
• Study drug accountability 
• Adverse Event review 
• Concomitant medication review 
 
8.8.1.4. 
Follow-up Visit (2 weeks after last dose of study drug) 
Subjects who complete the study and subjects who discontinue prematurely will complete a 
follow-up visit. 
The following assessments will be conducted: 
• Physical/neurological exam 
• Vital signs (sitting) [Temperature, pulse rate, respiratory rate, blood 
pressure] 
• Adverse Event review 
• Concomitant medication review 
• Study drug accountability 
 
8.8.1.5. 
Early Termination visit 
Subjects who prematurely discontinue from the study will have the following assessments 
performed: 
• Physical/neurological exam 


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• Vital signs (sitting) [Temperature, pulse rate, respiratory rate, blood 
pressure] 
• Slow Vital capacity (SVC), Maximum Inspiratory Pressure (MIP/NIF), 
Forced Expiratory Volume in 1 second (FEV1) measured with SVC 
protocol, Maximal Voluntary Ventilation (MVV)  
• Muscle strength by manual muscle testing and instrumented hand grip 
dynamometry* 
• ALSFRS-R* 
• ALSAQ-5 (at Month 12 only)* 
• CGIC*  
• Plasma PK sample 
• Adverse event review 
• Concomitant medication review 
• Study drug accountability 
 
Additional procedures and assessments may be done at PI's discretion, if necessary.  
*Assessments do not need to be performed if prior assessments were within one month of this early 
termination visit. 
 
8.8.1.6. 
Laboratory Re-test visit 
Subjects who have an abnormal lab finding will return for a laboratory re-test visit and will 
have the following assessments performed, as needed: 
• Laboratory:  Comprehensive Metabolic Panel (CMP) including GGT, CK, 
Complete Blood Count (CBC), Urinalysis without microscopic examination as 
indicated. 
Adverse events and concomitant medication will also be documented. 
   
8.8.1.7. 
Telephone Follow-ups 
Subjects will be contacted by telephone between office visits at Months 1, 2, 4, and 5 for 
double-blind phase and Months 7, 8, 10, and 11 for the open-label-phase by a member of 
the study staff to inquire about adverse events or changes in concomitant medications.  
In the event that subjects have difficulty communicating via telephone, (i.e. due to 
respiratory distress), alternative ways of communication with study staff (i.e., email, text 


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message or patients’ care-giver communications, etc.) will be acceptable with prior consent 
from the MediciNova, Inc. medical monitor. 
 
8.8.1.8. 
Follow-up by local neurologist  
If, during the course of subject participation, remotely-located subjects find it difficult to 
travel to the study site for the clinic visits (e.g., physical deterioration or other physical 
hardship etc.), evaluation by the subject’s local neurologist may be accepted with prior 
consent from the MediciNova, Inc. medical monitor. 
 
8.8.2. 
Additional Safety Assessment with patients on Dextromethorphan-20mg 
and Quinidine-10mg (Nuedexta) in MN-166-ALS-1201 Clinical Trial   
8.8.2.1. 
Patients already on Nuedexta prior to participating MN-166-ALS-1201 Trial  
If patient is already on Nuedexta, then patient should undergo additional electrocardiogram 
(ECG) evaluation at 3-4 hours after receiving Study Medication on Day 1 and Month 6 
visit (first day of Open-Label–Extension phase) Review of the QTc results should occur 
prior to continuing patient on Study Medication and Nuedexta.  If there is an increase in 
QTc to above 450 ms in males and above 470 ms in females, but less than 500 ms for both 
groups, the patient may continue on both medications, receiving ECG evaluations every 
three months per protocol.  If there is an increase in QTc above 500 ms, then investigator 
should repeat ECG within 24 hours before allowing the patient to continue on both 
medications.  If the repeat QTc is above 500 ms, the patient will have to discontinue Study 
Medication in order to be treated with Nuedexta. 
8.8.2.2. 
Patients starting Nuedexta after beginning Study Medication in MN-166-
ALS-1201 Trial 
If patient is already on Study Medication and it is deemed medically necessary to start 
Nuedexta, then patient should undergo additional electrocardiogram (ECG) evaluation 3-4 
hours after receiving Nuedexta the first time and again at Month 6 visit (first day of Open-
Label-Extension phase).  Review of the QTc results should occur prior to continuing 
patient on Nuedexta and the Study Medication.  If there is an increase in QTc to above 450 
ms in males and above 470 ms in females, but less than 500 ms, the patient may continue 
on both medications, receiving ECG evaluations every three months per protocol.  If there 
is an increase in QTc above 500 ms, then investigator should repeat ECG within the next 
24 hours before allowing the patient to continue on both medications.  If the repeat QTc is 
above 500 ms, the patient will have to discontinue Study Medication in order to be treated 
with Nuedexta. 


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8.8.3. 
Procedures/Assessment Details 
8.8.3.1. 
Informed Consent 
The Principal Investigator or a qualified designee (e.g., a licensed, qualified medical 
practitioner such as a physician’s assistant or a nurse practitioner) listed on Form FDA 
1572 will explain the study to the subject, answer all of the subject’s questions, and obtain 
written informed consent before performing any study-related procedure. Informed 
Consent should be conducted in accordance with local requirements. Subjects should be 
able to verbally describe the benefits and risks associated with this study and what other 
treatment alternatives are available (as described in the consent form). Only subjects who 
provide informed consent, as assessed and documented by the Investigator, will be 
enrolled. 
8.8.3.2. 
Medical History  
A medical history obtained by the PI or qualified designee as listed on the Form FDA 
1572.   
8.8.3.3. 
Prior/Concomitant Medication Review 
Site study staff will record all medications taken for ALS and all current medication within 
1 month prior to screening visit in the CRF. Also, the following parameters will be 
recorded for all concomitant medications: drug name, route of administration, total daily 
dose, unit, frequency, start/stop dates, indication, and whether the medication was started 
after last dose of study medication.  The concomitant medications will subsequently be 
coded using the World Health Organization Drug Dictionary (WHO-DD).   
Subjects who are not currently taking riluzole will be started on riluzole 50 mg QD for the 
first 7 days and then 50 mg BID for the next 3 weeks prior to entry into the study. 
8.8.3.4. 
Physical/Neurological Examination 
The physical exams must be performed by the PI or qualified designee (physician, 
physician’s assistant or nurse practitioner) listed on the Form FDA 1572. Clinically 
significant changes from the signing of the informed consent form (ICF) should be 
captured as AEs in the CRF. 
A complete physical examination includes the following assessments: general appearance, 
head, eyes, ears/nose/throat, neck, lymph nodes, skin, lungs, heart, abdomen, and 
musculoskeletal. If the subject is discontinued for any reason, every attempt should be 
made to perform a final physical and neurological examination. 
8.8.3.5. 
Vital Signs, Height, and Weight  
Blood pressure (BP), heart rate (HR) measurements will be taken in a sitting position. 
Respiratory rate and temperature will also be measured and all measurements will be 
recorded in the CRF. Clinically significant changes, as defined by the PI, from the signing 
of the ICF should be captured as AEs in the CRF. 


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Weight will be measured in pounds.  Height will be measured in inches at Visit 1 
(screening) and this height is the canonical height for the duration of the clinical trial.  
8.8.3.6. 
Electrocardiogram (12-Lead ECG) 
All subjects will have standard resting 12-lead ECGs performed and interpreted. Subjects 
are to be supine for at least 5 minutes prior to ECG assessments. The time the ECG is 
performed will be recorded (using a 24-h clock).  
The PI or a qualified designee listed on Form Food and Drug Administration (FDA) 1572 
must review, initial, and date the report, which must be filed in the subject’s study chart.  
Clinically significant findings from the screening report must be captured in the medical 
history.  Any clinically significant changes compared with screening must be captured as 
an AE in the CRF. 
8.8.3.7. 
Manual Muscle Test 
The manual muscle test (MMT) is a scored neurologic examination derived from the 
Medical Research Council scale. The scale is numerical, with scores between 0 and 5 per 
muscle, and is based on the examination of 42 muscles: neck flexors and extensors; 
shoulder abductors and external rotators; elbow flexors and extensors; wrist extensors and 
flexors; finger extensors and flexors, abductor pollicis brevis; first dorsal interosseus, 
abductor digiti minimi; index finger pinch, hip flexors, extensors, and abductors; knee 
extensors and flexors; ankle dorsiflexors; plantar flexors; and extensor hallucis longus.  
Each muscle is scored from 0 to 5, with 0 representing paralysis and 5 representing normal 
strength. If a muscle is rated between two scores, the lower score is entered into the CRF. 
The final MMT score is the mean of the scores of all 42 muscles.  
8.8.3.8. 
Instrumented Hand Grip Measurement 
Instrumented hand grip will be measured by Jamar Dynamometer. The best of two hand 
grips will be represented as Kg hand grip strength per hand and percent predicted. Results 
are represented in liters and percent predicted (Knudsen 1983).   
8.8.3.9. 
Slow Vital Capacity 
Slow vital capacity (SVC) is an index of respiratory function measured by a spirometry test 
to indicate potential respiratory compromise in ALS subjects.  It measures the volume of 
air expired, non-forcefully, in one breath. The subject will be asked to inspire fully and 
then slowly expire all the air in their lungs. 
8.8.3.10. Maximum Inspiratory Pressure / Negative Inspiratory Force 
Maximum Inspiratory Pressure (MIP) / Negative Inspiratory Force (NIF) is a measure of 
diaphragm strength (Mendoza 2007, Roth 2010).  
 


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8.8.3.11. Forced Expiratory Volume in 1 Second measured by Slow Vital Capacity 
Protocol 
Forced Expiratory Volume in 1 Second (FEV1) will be measured by Slow Vital Capacity 
(SVC) protocol (Knudson et al 1983). 
 
8.8.3.12. Maximal Voluntary Ventilation 
Maximal Voluntary Ventilation (MVV) will be measured as the maximum amount of air 
that can be inhaled and exhaled within one minute. For the comfort of the patient this is 
done over a 15 second time period before being extrapolated to a value for one minute 
expressed as liters/minute (Berto et al 2007). 
8.8.3.13. Non Invasive Ventilation Utilization 
Non-invasive Ventilation Utilization will be measured by occurrence of prescription for 
NIV and time to occurrence of prescription for NIV (early ALS patients only). 
8.8.3.14. Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-
R)  
The ALSFRS-R is a well-established and validated questionnaire to measure the 
progression of disability in patients with ALS. It is based on 12 items, each of which is 
rated on a 0 – 4 point scale. The rate of total functional disability thus ranges from 0 
(maximum disability) to 48 (normal) points. The components of the scale group into four 
factors that encompass gross motor tasks, fine motor tasks, bulbar functions and respiratory 
function (Cedarbaum et al 1999). 
8.8.3.15. Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) 
The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) is a patient self-
report questionnaire specifically designed to measure five 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 and has undergone 
rigorous testing for validity, reliability and sensitivity to change and has been shown to be a 
robust tool for assessing ALS (Jenkinson et al 2001). 
8.8.3.16. Clinical Global Impression of Change 
The Clinical Global Impression of Change (CGIC) scale is used to provide a global rating 
of illness severity, improvement, and response to treatment. It is a three-item observer 
rating scale and uses a seven-point rating scale.  The scale is rated relative to the previous 
standard of care visit prior to randomization for entry. [ -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]. Rating will be provided by patient, caregiver or family member 
and physician on separate forms.  


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8.8.3.17. Adverse Event (AE) Monitoring 
The PI or a qualified designee listed on Form FDA 1572 must assess the severity and 
relationship to study medication for all AEs (see Section 11.2). 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be recorded on the AE page(s) of the 
CRF.  
The PI, sub-investigator (SI) and members of the clinical research team are responsible for 
identifying adverse events and reporting them to RN coordinator. 
 
For all AEs, the Investigator must pursue and obtain information adequate to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
(see Section 11.2) requiring immediate notification to the Sponsor or its designated 
representative.  
For all AEs, sufficient information should be obtained by the Investigator to determine the 
causality of the AE. The Investigator is required to assess causality and indicate that 
assessment on the CRF. For AEs with a causal relationship to the investigational product, 
follow-up by the Investigator is required until the event or its sequelae resolve or stabilize 
at a level acceptable to the Investigator, and Sponsor concurs with that assessment.  
Adverse events (serious and non-serious) including all Suspected Unexpected Serious 
Adverse Reactions (SUSARs) should be recorded on the CRF from the date of informed 
consent until the end of their participation in the study (i.e., the subject has discontinued or 
completed the follow-up visit). 
8.8.3.18. Laboratory Evaluations 
Laboratory evaluations will include the tests listed in Appendix 1. Samples will be sent to 
the local laboratory listed on Form FDA 1572. 
Laboratory test results as they are reported will be tabulated per subject by date, time, test 
name, test result and reviewed by PI, SI, RN coordinator daily; if a clinically significant 
laboratory result is identified upon reporting, it will be reviewed with the PI or SI 
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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
The investigational product is MN-166 30 or 60 mg. 
9.1. 
Study Drug 
Table 4:  
Study Drug Information 
Investigational Drug: 
MN-166 
Formulation: 
10 mg capsules or 10 mg placebo capsules 
Frequency: 
30 mg qd or 30 mg bid. Study drug dosing may be varied based on 
individual tolerability (e.g., 10 mg tid instead of 30 mg qd or 20 mg tid 
instead of 30 mg bid). 
Storage Conditions: 
Store at room temperature  
Packaging Description: 
Polyethylene bottles 
9.2. 
Study Drug Packaging and Labeling 
 
At a minimum the following information will be included on each bottle:  
• 
Name of Sponsor  
• 
Study number/Acronym/IND number 
• 
Route of administration 
• 
Quantity of dosage unit 
• 
Directions for use 
• 
Storage conditions 
• 
Space for information to be completed by Investigator/designee: 
o Name and telephone number of Investigator 
o Dispensing date 
o Subject number 
• 
Statement “Caution: New Drug – Limited by federal law to investigational use” 
• 
Statement: “Keep out of reach of children” 
9.3. 
Study Drug Storage 
The study drug MN-166 should be stored at room temperature (preferably 18-230C, but 15-
250C is acceptable). 


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9.4. 
Study Drug Administration 
The study drug will be dispensed by appropriately qualified site study staff as indicated on 
the delegation of authority log. Subjects will self-administer the study drug orally at home 
following the directions given to them in the clinic. The subject will be instructed to return 
all unused study drug to the clinical trial site at each visit. The subject will be given a drug 
administration diary to complete and have available for telephone and clinic visits.  Subject 
drug diary information will be transcribed into eCRF from the subject’s diary at each 
monthly telephone or clinic visit.  If the subject loses a diary he will be advised to keep 
drug administration data on a separate piece of paper until he had a replacement diary. 
 
9.5. 
Study Drug Accountability 
Investigational clinical supplies must be received by the PI or a designated person at the 
study site, handled and stored safely and properly, and kept in a secured location to which 
only the Investigator and/or designated assistants have access. Clinical supplies are to be 
dispensed only in accordance with the protocol.  
The PI or designee is responsible for keeping accurate records of the clinical supplies 
received from the Sponsor or designee, the amount dispensed to and returned by the 
subjects, and the amount remaining at the conclusion of the study. At the end of the study, 
all clinical supplies must be returned to the Sponsor, or designee, after confirmation with 
the CRA (Clinical Research Associate) or destroyed at the clinical site. Study drug will not 
be destroyed until written documentation is received from the study sponsor or designee. 
Proper documentation of the destruction of study drug must be provided by the site. 
The following information is to be included in each subject's CRF: visit medication 
dispensed, dosing start/stop dates, dosage level, number of tablets dispensed and number of 
tablets returned. 


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10. 
ASSESSMENTS OF SAFETY AND CLINICAL ENDPOINT 
RESPONSIVENESS 
10.1. 
Primary Endpoints 
Safety will be assessed by the proportion of subjects with the following events: 
• clinical and laboratory treatment emergent adverse events (TEAEs) 
o stratified by severity 
o stratified by persistence over time 
o stratified by relationship to study drug 
• discontinuations due to TEAEs 
• treatment emergent serious adverse events (TESAEs) 
Safety (relationship and severity) and tolerability will further be assessed by statistical and 
clinical review of AEs, laboratory values, ECGs, physical examinations, vital signs and 
weight.  
10.2. 
Secondary Endpoints 
The secondary endpoints focused on clinical endpoint responsiveness are: 
• Change from baseline in functional status (ALSFRS-R)  
• Change from baseline in muscle strength as measured by a manual muscle test 
• Change from baseline in instrumented hand grip strength 
• Change from baseline in respiratory function as measured by Slow Vital 
Capacity (SVC) 
• Change from baseline in respiratory function as measured by Maximum 
Inspiratory Pressure / Negative Inspiratory Force (MIP/NIF) 
• Change from baseline in respiratory function as measured by Forced Expiration 
Volume in 1 second [FEV1] under conditions of slow vital capacity. 
• Change from baseline in respiratory function as measured by Maximum 
Voluntary Ventilation (MVV) 
• Change from baseline in Amyotrophic Lateral Sclerosis Assessment 
Questionnaire-5 (ALSAQ-5) 
• Change from anchored visit in Clinical Global Impression of Change (CGIC) 
 


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11. 
ADVERSE EVENTS 
 
11.1. 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a study subject administered 
a medicinal (investigational) product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including a clinically significant abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product. Adverse events may include 
the onset of a new illness and the exacerbation of pre-existing conditions. 
Other untoward events occurring in the framework of a clinical study are also to be 
recorded as AEs (e.g., those occurring during treatment-free periods, including screening or 
post-treatment follow-up periods), in association with study-related procedures and 
assessments. 
In this study, symptoms of progression/worsening of ALS, including ‘normal’ progression, 
will be recorded as adverse events. The following measures of disease progression will not 
be recorded as adverse events even if they worsen: vital capacity results, non-invasive 
ventilatory requirements, and ALSFRS-R, and ALSAQ-5. These measures will be recorded 
and analyzed separately. 
 
11.2. 
Assessment of Adverse Events 
The PI or an authorized physician will assess all AEs for severity, relationship with study 
medication, and whether it meets the criteria for classification as a SAE, requiring 
immediate notification to the Sponsor or designee (see Section 11.5). These assessments 
will be made in accordance with the standard ratings detailed in the following sections. 
11.2.1. 
Severity Assessment 
The severity of AEs will be determined as described in Table 4. 
Table 5:  
Adverse Events Severity Definitions 
Mild 
Grade 1 
Ordinarily transient symptoms that do not influence performance of subject’s daily 
activities. Treatment is not ordinarily indicated. 
Moderate 
Grade 2 
Marked symptoms sufficient to make the subject uncomfortable. Moderate influence 
on performance of subject’s daily activities. Treatment may be necessary. 
Severe 
Grade 3 
Symptoms cause considerable discomfort. Substantial influence on subject’s daily 
activities. May be unable to continue in the study and treatment may be necessary. 


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Life-
threatening 
Grade 4 
Extreme limitation in activity, significant assistance required; significant 
medical/therapy intervention required hospitalization probable. 
Death 
Grade 5 
Death. 
 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the event should be noted for that day. Any change in severity of 
signs and symptoms over a number of days will be captured by recording a new AE, with 
the amended severity grade and the date (and time, if known) of the change. 
11.2.2. 
Relationship to Study Drug 
One of the following categories in Table 5 should be selected based on medical judgment, 
considering the definitions below and all contributing factors. 
Table 6: Adverse Event Causality Definitions 
Related 
 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration, and which cannot be explained by 
concurrent disease or other medications or chemicals. The response to 
withdrawal of the treatment (dechallengea) should be clinically plausible. The 
event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallengeb procedure if necessary. 
Probably related 
 
A clinical event, including laboratory test abnormality, occurs within a 
reasonable time sequence to administration of the treatment, unlikely to be 
attributed to concurrent disease or other medications or chemicals, and which 
follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition. 
Possibly related 
 
A clinical event, including laboratory test abnormality, occurs within a 
reasonable time sequence to administration of the treatment, but which could 
also be explained by concurrent disease or other medications or chemicals. 
Information on treatment withdrawal may be lacking or unclear. 
Unlikely to be 
related 
 
A clinical event, including laboratory test abnormality, occurs with a temporal 
relationship to treatment administration that makes a causal relationship 
improbable, and in which other medications, chemicals, or underlying disease 
provide plausible explanations. 
Unrelated 
 
A clinical event, including laboratory test abnormality, occurs with little or no 
temporal relationship with treatment administration. May have negative 
dechallenge and rechallenge information. Typically explained by extraneous 
factors (e.g., concomitant disease, environmental factors, or other medications or 
chemicals). 


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a Dechallenge is when a medication suspected of causing an AE is discontinued. If the symptoms of the AE 
disappear partially or completely, within a reasonable time from medication discontinuation, this is termed 
a positive dechallenge. If the symptoms continue despite withdrawal of the medication, this is termed a 
negative dechallenge. Note that there are exceptions when an AE does not disappear upon discontinuation 
of the medication, yet medication-relatedness clearly exists (e.g., as in bone marrow suppression, fixed 
medication eruptions, or tardive dyskinesia). 
b Rechallenge is when a medication suspected of causing an AE in a specific subject in the past is readministered to that 
subject. If the AE recurs upon exposure, this is termed a positive rechallenge. If the AE does not recur, this is termed a 
negative rechallenge. 
As this is a double-blind study, the causality assessment should be made under the 
assumption that the subject is receiving active study medication. If considering unblinding, 
this assessment should be made prior to unblinding to avoid bias. 
11.3. 
Recording Adverse Events 
Adverse events should be collected and recorded for each subject from the date the 
informed consent form (ICF) was signed until the end of their participation in the study, 
(ie, the subject has discontinued or completed the study) through the follow-up visit with 
the exception of those subjects who discontinue study medication during the study and are 
followed on a semi-annual basis. Subjects who discontinue study medication but continue 
follow-up within the study will not have AEs collected after study drug discontinuation. 
Only those AEs that occurred while on study drug that have not been resolved will be 
followed until resolution or stabilization. 
Following the end of the subject’s participation in the study, the PI or an authorized 
delegate should report SAEs “spontaneously” if considered at least possibly related to 
study medication. 
Adverse events may be volunteered spontaneously by the study subject, or discovered by 
the study staff during physical examinations or by asking an open, non-leading question 
such as, “How have you been feeling since you were last asked?” All AEs and any required 
remedial action will be recorded in the subject’s source documentation and transcribed onto 
the appropriate CRF page for the study period indicated. The nature of AE, date (and time, 
if known) of AE onset, date (and time, if known) of AE outcome to date, severity, and 
action taken of the AE will be documented together with the PIs or an authorized 
physician’s assessment of the seriousness of the AE and causal relationship to study 
medication and/or study procedure (at the time of assessment). 
All AEs should be recorded individually in the study subject’s own words (verbatim) 
unless, in the opinion of the PI or an authorized physician, the AEs constitute components 
of a recognized condition, disease, or syndrome. In the latter case, the condition, disease, or 
syndrome should be named rather than each individual symptom. The AEs will 
subsequently be coded using the MedDRA. 
11.4. 
Treatment and Follow-Up of AEs 
Appropriate measures should be taken to treat AEs as necessary, and the response of the 
study subject should be monitored and recorded. Clinical, laboratory, and diagnostic 


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measures should be obtained as needed, and the results of which should be recorded in the 
subject’s source documentation and transcribed onto the appropriate CRF page. 
All SAEs will be followed until resolution, stabilization of the condition, the event is 
otherwise explained, or the subject is lost to follow-up. 
11.5. 
Serious Adverse Events (SAEs) 
An AE is considered serious if it meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (i.e., a subject is at immediate risk of death at the time of the 
event, not an event where occurrence in a more severe form might have caused 
death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is another important medical event (see below). 
Important medical events that do not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or in a 
physician’s office, blood dyscrasias or seizures that do not result in inpatient 
hospitalization, and the development of drug dependency or drug abuse. A distinction 
should be drawn between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above. For example, a mild degree of 
gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes 
would be considered an SAE, but is not necessarily severe. Similarly, an AE that is severe 
in intensity is not necessarily an SAE. For example, alopecia may be assessed as severe in 
intensity, but would probably not be considered an SAE. 
11.5.1. 
SAE Reporting Requirements 
The PI or an authorized delegate is responsible for faxing the requested SAE information to 
the Sponsor or designee within 24 hours or as soon as possible after learning of the event. 
Following the end of the subject’s participation in the study, the PI or an authorized 
delegate should report SAEs “spontaneously” if considered at least possibly related to 
study medication. 
Notification should be made by fax or email a completed SAE Report Form to the Sponsor. 
Study sites in the US should fax or email a completed SAE Report Form to fax number 
858-404-0048 or safetymonitors@medicinova.com. As a minimum requirement, the initial 
notification should provide the following information: 


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• Study number 
• Subject number 
• Gender 
• Date of birth 
• PI’s name and full study site address 
• Details of SAE 
• Criterion/criteria for classification as “serious” 
• Study medication name, or code if blinded, and treatment start date 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this 
classification). 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g., hospital reports, consultant reports, 
autopsy reports, etc.), with the study subject’s personal identifiers removed. All relevant 
information obtained by the PI or an authorized delegate through review of these 
documents will be recorded on the AE eCRF page and/or a new SAE Report Form and 
faxed to the Sponsor or designee within 24 hours of receipt of the information. If a new 
SAE Report Form is faxed, the PI must sign and date the form. The Sponsor may also 
request additional information on the SAE, which the PI or an authorized delegate must fax 
to the Sponsor or designee within 24 hours of the request using a new SAE Report Form, 
bearing the PI’s signature and date. 
Any AE fulfilling the criteria for expedited reporting will be reported by the Sponsor to 
regulatory authorities and Investigators and IEC(s) in accordance with the Sponsor’s 
standard operating procedures (SOPs) and local regulatory requirements. 
The PI should report all Investigational New Drug Application safety alerts received from 
the Sponsor to the local IRB. 
11.6. 
Guidance for Overdose  
There is no clinical experience with MN-166 overdose in humans and there is no available 
specific antidote to the effects of MN-166. Standard symptomatic support measures should 
be used in the case of excessive pharmacological effects or overdose. 
11.7. 
 Reporting and Follow-up of Pregnancies 
If any study subject or subject’s partner becomes pregnant after receiving the first dose of 
study medication (MN-166 or placebo) and until the follow-up period specified in the 
protocol, the PI or an authorized delegate should submit a Pregnancy Report Form to the 
sponsor within 24 hours of the PI or an authorized delegate first becoming aware of the 
pregnancy.  If a pregnancy is to be terminated, the anticipated date of termination should 


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also be provided in the “Additional Information/Comments” field of the Pregnancy Report 
Form. If a maternal SAE is reported for the study subject during the initial notification of 
pregnancy, a separate SAE Report Form should also be completed and submitted to the 
sponsor within 24 hours of the PI or an authorized delegate first becoming aware of the 
SAE.  
Subjects who become pregnant while in the study should be followed for the duration of 
their pregnancy.  If the pregnancy is discovered between regularly scheduled study visits, 
subjects should return for an unscheduled visit to return their study medication.  A 
quantitative β-hCG should be obtained and subjects should be encouraged to return for 
follow-up visits. If follow-up visits are not possible, then the principal investigator should 
collect information about the pregnancy such as spontaneous or elective termination, 
details of birth, and presence or absence of birth defects, congenital abnormalities, or 
maternal and newborn complications. 
The Sponsor will request that the PI follow the progress of the study subject’s pregnancy 
with the doctor medically responsible for the pregnancy. A new Pregnancy Report Form 
should be submitted within 24 hours of the PI or an authorized delegate first becoming 
aware of any new information. 
If additional information on the outcome of the pregnancy and/or the details of the 
birth/delivery is received “spontaneously” by the study site, the PI or authorized delegate 
should also submit a Pregnancy Report Form within 24 hours of becoming aware of the 
information. If the outcome of the pregnancy is reported as premature birth, or as elective 
termination due to a medical reason or as spontaneous or accidental miscarriage, the details 
of the outcome should be described in the “Additional Information/Comments” field of the 
Pregnancy Report Form. The pregnancy outcome will generally be reported as a follow-up 
report.  
Complete an SAE Report Form if the delivery outcome meets the criteria for a SAE (e.g., 
congenital anomaly/birth defect, stillbirth, some other sickness, etc.). The SAE Report 
Form should be completed with the study subject’s details (e.g., subject number, initials, 
date of birth, investigational product information, etc.) and the details of the fetal SAE and 
maternal complications should be described in the “Narrative” field of the SAE Report 
Form. 
If a pregnancy is reported for the study subject’s partner, the sponsor will provide 
instructions on how to collect pregnancy information in accordance with local 
requirements. 
11.8. 
Preplanned Hospitalizations or Procedures 
During the study, if a subject has a hospitalization or procedure (e.g., elective surgery) that 
was scheduled prior to the subject entering the study (i.e., before the subject signed the 
ICF) for an event/condition that occurred before the study, the hospitalization is considered 
a therapeutic intervention and not the result of an SAE. However, if the event/condition 
worsens during the study, it must be reported as an AE or SAE (if the event/condition 
results in a serious outcome such as prolongation of hospitalization.) 


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12. 
STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan (SAP) will provide comprehensive details on the statistical 
methods planned for this study. 
12.1. 
Data Analysis 
12.1.1. 
Analysis Populations 
Safety Analysis Set:  The group of subjects who received at least one dose of study drug 
and had at least one post dose safety assessment. 
Full Analysis Set (FAS):  The group of randomized subjects who received at least 14 days 
of study drug and had at least one post-dose efficacy measurement. 
12.1.2. 
Sample Size Justification 
No prior data are available on which to base assumptions for sample size/power 
considerations.  The results of this pilot study will be used to design future studies, and the 
sample size of 120 subjects is deemed to be appropriate for this purpose. 
 
12.1.3. 
Safety Analysis 
Safety analyses will be conducted on the Safety Analysis Set. 
The incidence of treatment-emergent AEs (TEAEs, defined as AEs occurring from the time 
of first dose through 7 days after the last dose of study medication), SAEs and AEs leading 
to discontinuations will be summarized by treatment group.  Incidence of TEAEs will also 
be summarized by severity (mild, moderate, or severe), as well as by relationship to 
treatment (not related, possibly related, or probably related) and by seriousness. 
Changes from baseline in laboratory values will be summarized by treatment groups for 
continuous variables.  Lab shift tables showing incidence of new or worsening clinically 
significant findings from baseline to the last visit will be displayed by treatment groups.  
Shift from baseline to the highest lab value, and from baseline to the lowest lab value will 
also be displayed. 
Incidence of out-of-normal-range values and markedly abnormal change from baseline in 
laboratory safety test variables will be tabulated by treatment group.  
Changes in vital signs from baseline to each visit will be summarized by treatment groups. 
12.1.4. 
Clinical Endpoint Responsiveness Analysis 
 
The clinical endpoints for early and advanced ALS subject will be analyzed separately.  All 
clinical endpoints will be analyzed for responsiveness using analysis of covariance 
(ANCOVA) models with treatment group (three levels: placebo intent to treat, 60 mg/d 


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intent to treat and 30 mg/d down-titrated and unable to return to 60mg/d) as a factor and the 
baseline value of the corresponding endpoint as a covariate.  The pairwise comparisons 
between 30 mg/d down titrated and placebo, 60mg/d completers and placebo, and between 
60 mg/d intention to treat and placebo will be tested.  All clinical endpoint analyses will be 
carried out using two-sided tests at the alpha=0.05 level of significance. 
 
12.2. 
Direct Access to Source Data/Documents 
By signing this protocol, the PI agrees to conduct the study in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (GCP); and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical study. 
The PI also agrees to allow monitoring, audits, and regulatory agency inspection of study-
related documents and procedures and provide for direct access to all study-related source 
data and documents. 
The PI shall prepare and maintain complete and accurate study documentation in 
compliance with GCP standards and applicable federal, state, and local laws, rules, and 
regulations; and, for each subject participating in the study, provide all data, and upon 
completion or termination of the clinical study submit any other reports to the Sponsor, or 
its designee, as required by this protocol or as otherwise required pursuant to any 
agreement with the Sponsor. 
Study documentation will be promptly and fully disclosed to the Sponsor, or its designee, 
by the PI upon request and shall also be made available at the PI’s site upon request for 
inspection, copying, review, and audit at reasonable times by representatives of the 
Sponsor or any regulatory agencies. The PI agrees to promptly take any reasonable steps 
that are requested by the Sponsor, or its designee, as a result of an audit to address 
deficiencies in the study documentation and worksheets/CRFs.  
The PI will promptly inform the Sponsor or its designee of any regulatory agency 
inspection conducted for this study. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on this Sponsor’s studies. The PI will 
immediately disclose in writing to the Sponsor or its designee if any person who is 
involved in conducting the study is debarred, or if any proceeding for debarment is pending 
or, to the best of the Investigator’s knowledge, threatened. 
12.3. 
Study Monitoring  
Monitoring will include on-site monitoring to assure that the investigation is conducted 
according to protocol, to protect subject rights and safety, and to confirm data integrity and 
quality.  


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This study will be monitored through all phases of study conduct by the Sponsor or its 
representative. Monitoring will include personal visits and telephone communication to 
assure that the investigation is conducted according to protocol and in order to comply with 
guidelines of GCP. On-site review of CRFs will include a review of forms for 
completeness and clarity, and consistency with source documents available for each 
subject. Investigators will be required to store all source documents.  
12.4. 
Audits and Inspections 
The PI and appropriate personnel may be periodically requested to attend meetings 
organized by the Sponsor or its designee to assure acceptable protocol execution. The study 
may be subject to audit by the Sponsor/designee or by regulatory authorities. If such an 
audit occurs, the PI must agree to allow access to required subject records. By signing this 
protocol, the Investigator grants permission to personnel from the Sponsor, its 
representatives, and appropriate regulatory authorities for on-site monitoring and auditing 
of all appropriate study documentation, as well as on-site review of the procedures 
employed in CRF generation, where clinically appropriate. The PI has to inform the 
Sponsor if he/she is approached for a regulatory audit.  
12.5. 
Institutional Review Board (IRB) 
Before initiation of the study, the PI must obtain approval of the research protocol, 
informed consent form (ICF), and any advertisement for subject recruitment from the IRB 
complying with the provisions specified in the Code of Federal Regulations (CFR) 21 Part 
56 and applicable government regulations. A copy of written IRB approval of the protocol, 
ICF, and advertising (if applicable) must be provided to the Sponsor or their designee prior 
to initiation of the study.  
12.6. 
Study Documentation 
By signing a copy of Form FDA 1572, the Investigator acknowledges that he/she has 
received a copy of the investigational drug brochure on MN-166 and assures the Sponsor 
that he/she will comply with the protocol and the provisions stated in Form FDA 1572.  No 
changes in this protocol can be made without the Sponsor’s written approval.  
The Investigator will supply the Sponsor with the following:  
1. Original, signed Form FDA 1572;  
2. Curricula vitae for all Investigators listed on Form FDA 1572;  
3. Copy of the Investigator’s medical licensure/medical registration number;  
4. Signed protocol signature page; 
5. Signed IB signature page; 
6. Financial disclosure forms for all study staff listed on the FDA 1572.  


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
By signing this protocol, the Sponsor and Clinical Study Site Principal Investigator agree to 
be responsible for implementing and maintaining quality control and quality assurance 
systems with written standard operating procedures (SOPs) reviewed and approved by the 
sponsor to ensure that the study is conducted and data are generated, documented, and 
reported in compliance with the protocol, accepted standards of GCP, and all applicable 
federal, state, and local laws, rules and regulations relating to the conduct of the clinical 
study. 


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14. 
ETHICS 
14.1. 
Ethics Review 
Documented approval from the IRB will be obtained for all participating centers prior to 
clinical trial start, according to ICH (International Conference on Harmonisation) GCP, 
local laws, regulations and organization. When necessary, an extension, amendment or 
renewal of the CIRB approval must be obtained. 
14.2. 
Ethical Conduct of the Study 
The procedures set out in this clinical trial protocol pertaining to the conduct, evaluation, 
and documentation of this clinical trial, are designed to ensure that the Sponsor and 
Principal Investigator abide by Good Clinical Practice Guidelines (GCP in the appropriate 
current version). The clinical trial will also be carried out in accordance with applicable 
local law(s) and regulation(s). This may include an inspection by representatives from 
MediciNova Inc. and/or Regulatory Authority representatives at any time. The PI must 
agree to the inspection of clinical trial-related records by MediciNova, Inc. representatives, 
and must allow representatives direct access to source documents. 
14.3. 
Written Informed Consent 
An information and consent form will be provided to the subject. The process of obtaining 
informed consent must be in accordance with applicable regulatory requirements, and must 
adhere to GCP and ethical principles in the Declaration of Helsinki. Written informed 
consent must be obtained and documented before any clinical trial-specific procedure takes 
place. Participation in the clinical trial and date of informed consent given by the subject 
must be documented in the subject files. 
14.4. 
Confidentiality 
14.4.1. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to the Sponsor that information furnished 
to the Investigator by the Sponsor will be maintained in confidence and such information 
will be divulged to the IRB or similar or expert committee; affiliated institution; and 
employees only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees.  
 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Review of Records 
The results from Screening and data collected during the study will be recorded in the 
subject’s CRF, which will be designed and provided by the sponsor or a designee. The 
Investigator will review all CRFs. The CRFs will be signed by the PI or a sub-Investigator 
who is listed on the Form FDA 1572 if the PI is unavailable. In order to maintain 
confidentiality, the subject will be identified only by his/her subject number and initials. 
15.2. 
Retention of Records 
The PI must arrange for retention of study records at the site for at least two years after the 
New Drug Application (NDA) is approved or Investigational New Drug (IND) is 
withdrawn, as required by the US Food and Drug Administration (FDA) regulations, or in 
accordance with local and/or national requirements, whichever is longer. The PI should 
take measures to prevent accidental or premature destruction of these documents. 
Documents cannot be destroyed without written Sponsor authorization. The Sponsor will 
inform the PI when the destruction of documents is permitted.  


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16. 
ADMINISTRATIVE AND REGULATORY DETAILS 
16.1. 
Protocol Amendments and Study Termination  
All revisions and/or amendments to this protocol must be approved in writing from the 
Sponsor and the IRB, except where necessary to eliminate an apparent immediate hazard to 
a study subject. 
16.2. 
Discontinuation of the Study  
The Sponsor reserves the right to discontinue the study at site(s) for safety or 
administrative reasons at any time.  Should the study be terminated and/or the site closed 
for whatever reason, all documentation and study medication pertaining to the study must 
be returned to the Sponsor or its representative.  
16.3. 
Compliance with Financial Disclosure Requirements 
By signing this protocol, the PI agrees to provide to the Sponsor accurate financial 
information to allow the Sponsor to submit complete and accurate certification and 
disclosure statements as required by the US FDA regulations (21 CFR Part 54). The PI 
further agrees to provide this information on a Financial Disclosure/Certification Form that 
is provided by MediciNova, Inc. The Investigator will update this information if there are 
any relevant changes during the conduct of the study and for one year after completion of 
the study. This requirement also extends to sub-Investigators. The PI also consents to the 
transmission of this information to MediciNova, Inc. for these purposes.  


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17. 
REFERENCES 
 
1. Alexianu ME, Kozovska M, Appel SH. Immune reactivity in a mouse model of 
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4. Barkhof F, Matsuda K, Landin R.  Ibudilast in relapsing-remitting multiple sclerosis.  
A neuroprotectant?  Neurology 2010; 74:1033-1040. 
5. Baumann F, Henderson RD, Morrison SC, Brown M, Hutchinson N, Douglas JA, 
Robinson PJ, McCombe PA. Use of respiratory function tests to predict survival in 
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10. Camargo CA Jr, Tsai CL, Clark S, Kenney PA, Radeos MS.  Spirometric correlates 
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11. Carmel A. (2014, May 2) Amyotrophic Lateral Sclerosis. Retrieved from 
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12. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS 
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15. Cho Y, Johnson K, Lolis  E.  AV411 (Ibudilast) and AV1013 are allosteric 
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22. Gołąb-Janowska M, Honczarenko K, Stankiewicz J.  Usefulness of the ALSAQ-5 
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23. Gordon PH, Cheng B, Montes J, Doorish C, Albert SM, Mitsumoto H.  Outcome 
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24. Gordon PH, Miller RG, Moore DH.  ALSFRS-R.  Amyotroph Lateral Scler Other 
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Elbaz A, Meininger V.  Predicting survival of patients with amyotrophic lateral 
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27. Hall ED, Oostveen JA, Gurney ME. Relationship of microglial and astrocytic 
activation to disease onset and progression in a transgenic model of familial ALS. 
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28. Help for Speech, Swallowing, and Salivation Problems in ALS Series - 26th 
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Speech, Swallowing, and Salivation Problems in ALS Series ALZFORUM 
Networking for a Cure 
29. http://www.alzforum.org/news/conference-coverage/help-speech-swallowing-
and-salivation-problems-als     
30. Huxtable AG, Smith SM, Peterson TJ, Watters JJ, Mitchell GS. Intermittent 
Hypoxia-Induced Spinal Inflammation Impairs Respiratory Motor Plasticity by a 
Spinal p38 MAP Kinase-Dependent Mechanism. J Neurosci. 2015 Apr 
29;35(17):6871-80 
31. Huxtable AG, Smith SM, Vinit S, Watters JJ, Mitchell GS. Systemic LPS induces 
spinal inflammatory gene expression and impairs phrenic long-term facilitation 
following acute intermittent hypoxia. J Appl Physiol (1985). 2013 Apr;114(7):879-
87.  
32. Inacio AR, Ruscher K, Leng L, et al.  Macrophage migration inhibitory factor 
promotes cell death and aggravates neurologic deficits after experimental stroke.  J 
Cerebral Blood Flow & Metab. 2011; 31(4):1093–1106. 
33. Ince PG, Shaw PJ, Slade JY, et al. Familial amyotrophic lateral sclerosis with a 
mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and 
immunocytochemical changes. Acta Neuropathol 1996; 92 (4):395–403. 
34. Jenkinson C, Fitzpatrick R, Swash M, Jones G.  Comparison of the 40-item 
Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) with a 
short-form five-item version (ALSAQ-5) in a longitudinal survey.  Clin Rehabil. 
2007 Mar;21(3):266-72.   
35. Jenkinson C, Fitzpatrick R. A reduced item set for the Amyotrophic Lateral 
Sclerosis Assessment Questionnaire: Development and validation of the ALSAQ-5. 
J Neurol Neurosurg Psychiatry 2001; 70:70–3. 
36. Kaplan A, Spiller KJ, Towne C, et al. Neuronal matrix metalloproteinase-9 is a 
determinant of selective neurodegeneration. Neuron. 2014 Jan 22;81(2):333-48. 
doi: 10.1016/j.neuron.2013.12.009.   
37. Kaufmann P, Levy G, Montes J, et al. QALS study group.  Excellent inter-rater, 
intra-rater, and telephone-administered reliability of the ALSFRS-R in a multicenter 
clinical trial.  Amyotroph Lateral Scler. 2007 Feb;8(1):42-6.   
38. Kawamata T, Akiyama H, Yamada T, et al. Immunologic reactions in amyotrophic 
lateral sclerosis brain and spinal cord tissue. Am J Pathol 1992; 140 (3):691–707. 
39. Kawanokuchi J, Mizuno T, Kato H, et al.  Effects of interferon-beta on microglial 
functions as inflammatory and antigen presenting cells in the central nervous 
system. Neuropharmacology 2004; 46, 734–742. 


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40. Kithcart A, Cox GM, Sielecki T, et al., A small-molecule inhibitor of macrophage 
migration inhibitory factor for the treatment of inflammatory disease.  Faseb J.  
2010; 11:4459-4466.Kleopa KA, Sherman M, Neal B, Romano GJ, Heiman-
Patterson T. BiPAP improves survival and rate of pulmonary function decline in 
patients with ALS. J Neurol Sci. 1999 Mar 15;164(1):82-8. 
41. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal 
maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 
1983; 127:725-34. (article available upon request)  
42. Ledeboer A, Liu T, Shumilla JA, et al.  The Glial Modulatory Drug AV411 
Attenuates Mechanical Allodynia in Rat Models of Neuropathic Pain.  Neuron Glia 
Biology (Pain special issue). 2007a: 2:279-291.  
43. Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. AV411 (ibudilast): a new 
class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes.  
Expert Opinion on Investigational Drugs. 2007b; 16:935-950. 
44. Lee JY1, Cho E, Ko YE, et al. Ibudilast, a phosphodiesterase inhibitor with anti-
inflammatory activity, protects against ischemic brain injury in rats. Brain Res. 
2012 Jan 11; 1431:97-106. 
45. Mendoza M, Gelinas DF, Moore DH, Miller RG.  A comparison of maximal 
inspiratory pressure and forced vital capacity as potential criteria for initiating non-
invasive ventilation in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2007 
Apr;8(2):106-11.  
46. Miller RG, Munsat TL, Swash M, Brooks BR.  Consensus guidelines for the design 
and implementation of clinical trials in ALS. World Federation of Neurology 
committee on Research.  J Neurol Sci. 1999 Oct 31;169(1-2):2-12.  
47. Mizuno T, Kurotani T, Komatsu Y, et al. Neuroprotective role of phosphodiesterase 
inhibitor ibudilast on neuronal cell death induced by activated microglia. 
Neuropharmacology 2004;46(3):404-11. 
48. Nakamizo T, Kawamata J, Yoshida K, et al. Phosphodiesterase inhibitors are 
neuroprotective to cultured spinal motor neurons. J Neurosci Res 2003; 71(4):485-
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49. Nishio Y, Koda M, Hashimoto M, et al. Deletion of MIF attenuates neuronal death 
and promotes functional recovery after spinal cord injury in mice. Acta 
Neuropathol. 2009; 117:321-328. 
50. Powell ND, Papenfuss TL, McClain MA, et al.  Cutting edge: macrophage 
migration inhibitory factor is necessary for progression of experimental 
autoimmune encephalomyelitis. J. Immunol. 2005: 175(9):5611–5614. 
51. Rolan P, Hutchinson M, Johnson K. Ibudilast: a review of its pharmacology, 
efficacy and safety in respiratory and neurological disease. Expert Opin 
Pharmacother 2009; 10:2897-904. 
52. Roth EJ, Stenson KW, Powley S, Oken J, Primack S, Nussbaum SB, Berkowitz M.  
Expiratory muscle training in spinal cord injury: a randomized controlled trial.  
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53. Sanjak M, Brinkmann J, Belden DS, Roelke K, Waclawik A, Neville HE, Ringel 
SP, Murphy JR, Brooks BR.  Quantitative assessment of motor fatigue in 
amyotrophic lateral sclerosis.   J Neurol Sci. 2001 Oct 15;191(1-2):55-9.  
54. Sanjak M, Salachas F, Frija-Orvoen E, Theys P, Hutchinson D, Verheijde J, Pianta 
T, Stewart H, Brooks BR, Meininger V, Douillet P; Xaliproden [SR57746A] ALS 
International Study Group.  Quality control of vital capacity as a primary outcome 
measure during phase III therapeutic clinical trial in amyotrophic lateral sclerosis.  
Amyotroph Lateral Scler. 2010 Aug;11(4):383-8. doi: 
10.3109/17482960903486083.   
55. Smith R, Pioro E, Meekins G, Gelinas D, KatzJ, Sirdofsky M, Goslin K, Pattee G.  
C8: The Experimental Treatment of Bulbar Symptoms with Nuedexta  (2015) 
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16:sup1, 5-6, DOI: 10.3109/21678421.2015.1089039. 
56. http://www.tandfonline.com/doi/pdf/10.3109/21678421.2015.1089039    Suzumura 
A, Ito A, Yoshikawa M, et al. Ibudilast suppresses TNF alpha production by glial 
cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain 
Res 1999; 837:203-12. 
57. Takuma K, Lee E, Enomoto R, Mori K, Baba A, Matsuda T. Ibudilast attenuates 
astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion 
model. British Journal of Pharmacology 2001; 133, 841–848. 
58.  Tandan R, Bromberg MB, Forshew D, Fries TJ, Badger GJ, Carpenter J, Krusinski 
PB, Betts EF, Arciero K, Nau K. A controlled trial of amino acid therapy in 
amyotrophic lateral sclerosis: I. Clinical, functional, and maximum isometric torque 
data. Neurology. 1996 Nov;47(5):1220-6. 
59. Thakore N, Pioro E. Medication Exposure and Survival in ALS: An Observational 
Study Using Inverse Probability of Treatment Weighting (P3.182) American 
Academy of Neurology Scientific Program Vancouver British Columbia Canada 
April 18, 2016 Poster Session III Motor Neuron Disease: Clinical Trials, Treatment, 
and Outcome. 
https://www.neurology.org/content/86/16_Supplement/P3.182.abstract 
60. Tominaga Y, Nakamura Y, Tsuji K. Ibudilast protects against neuronal damage 
induced by glutamate in cultured hippocampal neurons. Clin Exp Pharmacol 
Physiol. 1996 Jun-Jul;23(6-7):519-23. 
61. Turner MR, Cagnin A, Turkheimer FE, et al. Evidence of widespread cerebral 
microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 
positron emission tomography  study. Neurobiol Dis 2004; 15(3):601–9. 
62. Wakita H, Tomimoto H, Akiguchi I, et al. Ibudilast, a phosphodiesterase inhibitor, 
protects against white matter damage under chronic cerebral hypoperfusion in the 
rat. Brain Research 2003; 992(1):53–59. 


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63. Yagi K, Tada Y, Kitazato KT, et al. Ibudilast inhibits cerebral aneurysms by down-
regulating inflammation-related molecules in the vascular wall of rats. 
Neurosurgery. 2010 Mar;66(3):551-9; discussion 559. 
64. Yoshioka A., Shimizu Y., Hirose G., et al. Cyclic AMP-elevating agents prevent 
oligodendroglial excitotoxicity. Journal of Neurochemistry 1998; 70:2416–2423. 
65. Yoshioka A, Yamaya Y, Saiki S., et al. Cyclic GMP/cyclic GMP-dependent protein 
kinase system prevents excitotoxicity in an immortalized oligodendroglial cell line. 
Journal of Neurochemistry 2000; 74:633–640. 
66. Vender RL, Mauger D, Walsh S, Alam S, Simmons Z. Respiratory systems 
abnormalities and clinical milestones for patients with amyotrophic lateral sclerosis 
with emphasis upon survival. Amyotroph Lateral Scler. 2007 Feb;8(1):36-41. 
67. Vinit S, Windelborn JA, Mitchell GS. Lipopolysaccharide attenuates phrenic long-
term facilitation following acute intermittent hypoxia. Respir Physiol Neurobiol. 
2011 May 31;176(3):130-5. 
68. Zhan L, Xie Q, Tibbetts RS. Opposing roles of p38 and JNK in a Drosophila model 
of TDP-43 proteinopathy reveal oxidative stress and innate immunity as pathogenic 
components of neurodegeneration. Hum Mol Genet. 2015 Feb 1;24(3):757-72. 


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18. 
APPENDICES 
 


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Appendix 1: 
Laboratory Safety Tests for MN-166 
 
 
Blood Chemistry Tests 
 
aspartate aminotransferase (AST) 
 
alanine aminotransferase (ALT) 
 
albumin  
 
alkaline phosphatase  
 
bicarbonate  
 
blood urea nitrogen  
 
calcium  
 
chloride  
 
creatinine  
 
gamma-glutamyl transferase  
 
potassium  
 
sodium  
 
total bilirubina 
 
total protein  
 
glucose  
              creatinine kinase 
 
Endocrine Tests 
 
serum beta-human chorionic gonadotropin (for females of childbearing potential) 
 
urine beta-human chorionic gonadotropin  
 
Hematology Tests 
 
white blood cell count 
 
white blood cell differential 
 
eosinophilic leukocyte count 
 
basophilic leukocyte count 
 
neutrophil count 
 
lymphocyte count 
 
monocyte count 
 
platelet count 
 
hemoglobin  
 
blood hematocrit 
 
red blood cell count 
 
red cell distribution width  
 
red blood cell indices: 
 
mean corpuscular volume 
 
mean corpuscular hemoglobin concentration 
 
mean corpuscular hemoglobin 
 
Urinalysis Tests 
 
color  
 
appearance  
 
total ketones  
 
urobilinogen  
 
bilirubin  
 
red blood cells 
 
leukocyte esterase  
 
nitrite  
 
pH  


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protein  
 
specific gravity  
 
glucose  
 
microscopic evaluationb 
a Bilirubin will be fractionated (direct serum bilirubin test/indirect serum bilirubin test) if elevated 2.0 times 
the upper limit of the normal range. 
b Microscopic evaluation will be performed if dipstick analysis indicates the presence of any significant 
abnormality. 
  
 
 
 


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Appendix 2: ALS Functional Rating Scale-R 
 
 
 
 
 
 


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Appendix 3:  ALSAQ-5 
 
Instructions to patient. 
Please complete this questionnaire as soon as possible. If you have any difficulties filling in 
this questionnaire by yourself, please have someone help you. However, it is your 
responses that we are interested in. 
The questionnaire consists of a number of statements about difficulties that you may have 
experienced during the last 2 weeks. There are no right or wrong answers: your first 
response is likely to be the most accurate for you. Please check the box that best describes 
your own experiences or feelings. 
Please answer every question even though some may seem very similar to others, or may 
not seem relevant to you. 
All the information you provide is confidential. 
The following statements all refer to difficulties that you may have had during the last 2 
weeks. Please indicate, by checking the appropriate box, how often the following 
statements have been true for you. 
The following statements all refer to certain difficulties that you may have had during the 
last 2 weeks. Please indicate, by checking the appropriate box, how often the following 
statements have been true for you. 
If you cannot do the activity at all please check Always/cannot do at all. 
 
How often during the last 2 weeks have the following been true? 
Please check one box for each question. 
Never    Rarely    Sometimes   Often   Always or cannot do at all 
1. I have found it difficult to stand up.  
2. I have had difficulty using my arms and hands. 
3. I have had difficulty eating solid food.  
4. I have felt that my speech has not been easy to understand. 
5. I have felt hopeless about the future. 


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Appendix 4: Model Informed Consent Form 
 


 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
A SINGLE-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED SIX- 
MONTH CLINICAL TRIAL FOLLOWED BY AN OPEN LABEL EXTENSION TO EVALUATE 
THE SAFETY, TOLERABILITY AND CLINICAL ENDPOINT RESPONSIVENESS OF 
IBUDILAST (MN-166) IN SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS (ALS) 
Protocol No. MN-166-ALS-1201 (31 May 2016 (Amendment 4)) 
 
Sponsor: 
 
MediciNova, Inc. 
 
 
 
4275 Executive Square, Suite 300 
 
 
 
La Jolla, CA 92037 
 
Prepared by:  
MediciNova, Inc. 
 
 
 
4275 Executive Square, Suite 300 
 
 
 
La Jolla, CA 92037 
 
 
 
 
Contributor:  
Charles S. Davis, Ph.D. 
 
 
 
CSD Biostatistics, Inc. 
1005 W. Soft Wind Place 
Oro Valley, AZ  85737 
Version: 
 
3  
Date:  
 
01 MAY 2019 
 
CONFIDENTIALITY STATEMENT 
The information being provided in this protocol is considered confidential, proprietary trade 
secret information as defined by the Federal Trade Secrets Acts, and is thus protected from 
disclosure to unauthorized parties under the Freedom of Information Act. This protocol shall be 
considered a confidential document that provides information for the sole use of clinical 
Investigators for the referenced study, their teams, and the study site Institutional Review 
Boards/Ethics Committees (IRB/EC). 
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TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................................. 6 
2 
STUDY OBJECTIVES .......................................................................................................... 6 
3 
STUDY DESIGN AND PLAN .............................................................................................. 6 
3.1 
STUDY DESIGN ............................................................................................................... 6 
3.2 
RANDOMIZATION AND BLINDING.................................................................................. 7 
3.3 
SAFETY AND EFFICACY ANALYSIS PLAN ........................................................................ 8 
4 
DETERMINATION OF SAMPLE SIZE ............................................................................ 8 
5 
GENERAL ANALYSIS CONSIDERATIONS ................................................................... 9 
6 
ANALYSIS POPULATIONS ................................................................................................ 9 
7 
STUDY POPULATION......................................................................................................... 9 
7.1 
SUBJECT DISPOSITION .................................................................................................... 9 
7.2 
PROTOCOL DEVIATIONS .............................................................................................. 10 
7.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .................................................... 10 
7.4 
PRIOR AND CONCOMITANT MEDICATIONS ................................................................. 10 
8 
SAFETY ANALYSES .......................................................................................................... 10 
8.1 
EXTENT OF EXPOSURE ................................................................................................ 10 
8.2 
ADVERSE EVENTS ........................................................................................................ 10 
8.3 
CLINICAL LABORATORY EVALUATION ....................................................................... 11 
8.4 
VITAL SIGNS ................................................................................................................ 11 
8.5 
PHYSICAL EXAMINATION ............................................................................................ 11 
8.6 
ELECTROCARDIOGRAM ................................................................................................ 12 
9 
CLINICAL ENDPOINT RESPONSIVENESS VARIABLES ......................................... 12 
9.1 
RESPONSIVENESS VARIABLES ..................................................................................... 12 
9.2 
BASELINE VALUES ....................................................................................................... 13 
9.3 
ADJUSTMENTS FOR COVARIATES ................................................................................ 13 
9.4 
HANDLING OF DROPOUTS OR MISSING DATA ............................................................ 13 
9.5 
SAFETY MONITORING AND INTERIM EFFICACY ANALYSIS ........................................... 13 
9.5.1 
Safety Monitoring ........................................................................................... 13 
9.5.2 
Interim Efficacy Analysis ............................................................................... 14 
9.6 
EXAMINATION OF SUBGROUPS .................................................................................... 14 
9.7 
MULTIPLE COMPARISON/MULTIPLICITY ..................................................................... 15 
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9.8 
MULTICENTER STUDIES ............................................................................................... 15 
10 METHODS OF CLINICAL RESPONSIVENESS ANALYSIS ...................................... 15 
10.1 RESPONSIVENESS ANALYSES ....................................................................................... 15 
10.2 PHARMACOKINETIC ANALYSES ................................................................................... 15 
11 CHANGES TO PROTOCOL-SPECIFIED ANALYSES................................................. 15 
APPENDIX A:  LIST OF TABLES AND DATA LISTINGS ........................................................... 17 
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LIST OF ABBREVIATIONS 
6,7-DHD 
6,7-dihydrodiol 
AE 
adverse event 
ALS 
amyotrophic lateral sclerosis 
ALSFRS-R 
amyotrophic lateral sclerosis functional rating scale-revised 
ALSAQ-5 
Amyotrophic Lateral Sclerosis Assessment Questionnaire-5 
ALT/SGPT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST/SGOT 
aspartate aminotransferase 
b.i.d. 
twice daily 
BLQ 
below limit of quantification 
CGIC 
clinical global impression scale 
CI 
confidence interval 
CRF 
case report form 
CS 
clinically significant 
CSR 
clinical study report 
ECG 
electrocardiogram 
ET 
FAS 
Early Termination 
Full Analysis Set 
FEV1 
forced expiratory volume in one second 
G 
gram(s) 
ISF 
Investigator Site File 
ISM 
independent safety monitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
MIP 
maximum inspiratory pressure 
ms 
millisecond(s) 
MVV 
maximal voluntary ventilation 
NCS 
not clinically significant 
NIF 
negative inspiratory force 
NIV 
non-invasive ventilator 
OLE 
open-label extension 
PK 
pharmacokinetic(s) 
QTc 
corrected QT interval 
QTcB 
QT interval corrected according to Bazett’s method 
QTcF 
QT interval corrected according to Friderecia’s method 
RTF 
rich text format 
SAE 
serious adverse event 
SD 
standard deviation 
SE 
SOC                   
standard error 
system-organ-class 
SVC 
slow vital capacity 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
WHO 
World Health Organization 
 
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DEFINITIONS 
Adverse Event  
An adverse event (AE) is any untoward medical 
occurrence in a subject administered a pharmaceutical 
product, regardless of causality assessment. 
Full Analysis Set 
Population 
Group of randomized subjects who received at least 14 
days of study drug and had at least one post-dose efficacy 
measurement. 
Safety Analysis Set 
Population 
Group of subjects who received at least one dose of study 
drug and had at least one post-dose safety assessment. 
Serious AE 
An AE occurring at any dose that: results in death; is a 
life-threatening experience; requires inpatient 
hospitalization or prolongation of an existing 
hospitalization; results in a persistent or significant 
disability/incapacity; or is a congenital anomaly/birth 
defect in the offspring of a patient who received study 
drug. 
Treatment-emergent AE 
 
AEs occurring from the time of first dose through 7 days 
after the last dose  
Treatment group 
“Placebo”  
Subjects received placebo during the double-blind phase  
Treatment group  
“MN-166”  
Subjects received MN-166 during the double-blind phase  
Treatment group  
Placbeo/MN-166 
Subjects received placebo during double blind phase and 
received MN-166 druing open-label phase  
Treatment group  
MN-166/MN-166 
Subjects received MN-166 for both double-blind phase 
and open-label phase  
 
 
 
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1 INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of MediciNova, Inc. Protocol No. MN-166-ALS-1201 [A 
SINGLE-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED SIX MONTH CLINICAL 
TRIAL FOLLOWED BY AN OPEN-LABEL EXTENSION TO EVALUATE THE SAFETY, TOLERABILITY AND 
CLINICAL ENDPOINT RESPONSIVENESS OF IBUDILAST (MN-166) IN SUBJECTS WITH AMYOTROPHIC 
LATERAL SCLEROSIS (ALS)] (NCT02714036).  The purpose of this plan is to provide specific 
guidelines from which the analysis will proceed. Any deviations from these guidelines will be 
documented in the clinical study report (CSR). 
2 STUDY OBJECTIVES 
The primary objective of this clinical study is to examine the safety and tolerability of MN-166 60 
mg/d versus placebo when administred with riluzole in subjects with amyotrophic lateral sclerosis 
(ALS).  
The secondary objective is to evaluate the clinical endpoint responsiveness of MN-166 60 mg/d 
versus placebo when administered with riluzole in subjects with ALS as measured by the 
following assessments:  
• Functional activity as assessed by the Amyotrophic Lateral Sclerosis Functional Rating 
Scale-revised (ALSFRS-R) test battery.   
• Respiratory function as measured by slow vital capacity (SVC), Maximum Inspiratory 
Pressure (MIP) also known as Negative Inspiratory Force (NIF), and Maximal Voluntary 
Ventilation (MVV).   
3 STUDY DESIGN AND PLAN 
This is a U.S.-based, single-center, randomized, double-blind, placebo-controlled, 6- month study. 
Each subject will receive MN-166 (ibudilast) or placebo administered orally (60 mg/d) as an 
adjunct to riluzole (50 mg bid) for ALS. Upon completion of the Double-blind Phase, subjects 
randomized to the placebo arm will continue for an additional 6 months and will receive 
open-label MN-166. The safety data will also be reviewed at Month 6 and if there are no safety or 
tolerability concerns in the MN-166 treated group, a decision will be made to extend participation 
to the MN-166 treated group into the Open-label Extension (OLE) Phase. Otherwise, only the 
placebo-treated patients will participate in the OLE Phase. 
This study is designed to evaluate the safety, tolerability and clinical endpoint responsiveness of 
MN-166 (60 mg/d) when administered as an adjunct to riluzole (50 mg bid) in subjects with ALS. 
This study will consist of two treatment arms, MN-166 and matching placebo.  
3.1 
STUDY DESIGN  
The study will consist of a Screening Phase (up to 3 months prior to baseline) followed by a 
double-blind Treatment Phase (6 months) and an Open-label Extension (OLE) Phase for the 
Placebo treatment arm (6 months). Safety, tolerability and clinical endpoint responsiveness will be 
monitored throughout the 6-month period with in-person visits at 3 and 6 months and monthly 
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phone calls at months 1, 2, 4, and 5. Plasma samples collected will be analyzed for MN-166. A 
follow-up visit will take place within 2 weeks after the last dose of study drug. 
Patients will be randomized at enrollment to one of the following treatment groups in a 2:1 ratio. 
 
 
Double-Blind Phase Open-Label Extension 
Phase 
ENTIRE STUDY 
 
Treatment   
(Treatment group) 
MN-166 
(MN-166)  
MN-166 
(MN-166/MN-166)  
 
(MN-166/MN-166) 
Placebo 
(Placebo)  
MN-166 
(Placebo/MN-166)  
 
(Placebo/MN-166) 
 
3.2 
RANDOMIZATION AND BLINDING 
During the Double-blind Treatment Phase, subjects and all personnel involved with the conduct 
and interpretation of the study, including the investigators, site personnel, and sponsor staff will be 
blinded to the treatment codes. Randomization data will be kept strictly confidential, filed securely 
by the third-party database vendor (ScienceTRAX) and accessible only to authorized persons (e.g., 
unblinded safety monitor) until the time of unblinding.  
To ensure that treatment allocation remains concealed to both staff and participants, the following 
measures will be taken:  
• Active drug and placebo will be identical in appearance  
• Drug supplies to investigational pharmacy will be coded  
• The randomization list will be held by ScienceTRAX to ensure that treatment allocation is 
concealed from the investigator’s team and the participant, whilst providing provisions for 
emergency unblinding.  
Details of the randomization process will be available in the Investigator Site File (ISF). 
Randomization roles in the trial outlining who has access to treatment allocation codes will be 
recorded in the trial master file (TMF). 
The randomization system will be web-based and require a personal log-in and password. Only 
those individuals who are trained and are on the delegation-log can carry out this process.  
Once a consented patient meets criteria for clinical trial entry and the subject has been randomly 
assigned, they will be given a card to indicate they are enrolled in the trial with the emergency 
contact numbers for medical advice. Patients will be instructed to show this card to any healthcare 
professional involved in their care who is not involved in the trial. Any trial participant who 
withdraws from the study will not be replaced.  
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Subjects will be informed of the treatment that they have received during the double-blind phase 
after the last subject has completed the open-label extension (OLE) or at the time defined by the 
principal investigator in consultation with MediciNova. 
Randomization will occur in a 2:1 ratio (MN-166: placebo). To be eligible, subjects must have a 
diagnosis of sporadic or familial ALS with onset of ≤5 years (“early ALS”) from first clinical 
weakness prior to screening or with onset of ≤10 years (“advanced ALS”) from first clinical 
weakness prior to screening for ALS patients on non-invasive ventilator (NIV) support. All 
subjects must be on a stable dose of riluzole for at least 1 month prior to study drug treatment. All 
subjects will receive optimized standard of care in addition to MN-166 at an ALS 
Multidisciplinary Clinic affiliated with an academic medical center. A total of approximately 120 
male and female subjects from 18 to 80 years old, inclusive, are planned to be enrolled.  
Eligible subjects will be stratified by ALS stage (early, advanced). Approximately 60 subjects will 
be enrolled into the “early ALS” group with identifying subject numbers starting with the digits 
“00” and approximately 60 subjects will be enrolled into the “advanced ALS” group with 
identifying subject numbers starting with the digits “20”. Within each stratum, subjects will be 
randomized in a 2:1 ratio to active drug and placebo (approximately 80 subjects in the MN-166 
group; approximately 40 subjects in the placebo group). Upon completion of the Double-blind 
Phase, subjects randomized to the placebo arm will continue for an additional 6 months and will 
receive open-label MN-166.  
3.3 
SAFETY AND EFFICACY ANALYSIS PLAN 
Periodic safety and efficacy evaluations will be performed by the unblinded Independent Safety 
Monitor (ISM) and independent unblinded biostatistician. 
The safety and tolerability of MN-166 will be evaluated by an unblinded ISM during the interim 
safety monitoring assessment after approximately 20-30 subjects each for the early and advanced 
ALS groups have been followed for approximately 3 months. The safety data will also be reviewed 
at Month 6 and if there are no safety or tolerability concerns in the MN-166 treated group, a 
decision will be made to extend participation to the MN-166 treated group into the OLE Phase.  
Two interim efficacy analyses will be performed by an independent biostatistician. The 
biostatistician will be unblinded to the treatment assignments.  The first analysis will be performed 
after the 30th subject in the early ALS group completes 6 months of evaluation during the 
double-blind phase. The second analysis will be performed after the 30th subject in the advanced 
ALS group completes 6 months of evaluation during the double-blind phase period. This 
mid-study analysis will be summarized in a report. Any data collected after this cutoff, that is, 
from patients continuing to receive extended treatment, will be presented in a separate analysis. 
All data will be analyzed and summarized in a clinical study report when all patients have 
discontinued treatment and their data are collected. 
4 DETERMINATION OF SAMPLE SIZE 
The primary outcomes for the trial are safety and tolerability as measured by treatment-emergent 
adverse events (TEAEs), clinical laboratory parameters, vital signs, ECG results, and 
discontinuations of study drug. No prior data are available on which to base assumptions for 
sample size/power considerations. The results of this pilot study will be used to design future 
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studies, and the sample size of approximately 120 subjects (n=60 early ALS; n=60 advanced ALS) 
is deemed to be appropriate for this purpose. 
5 GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables and data listings.  Unless otherwise 
noted, all statistical testing will be two-sided and will be performed at the 0.05 significance level.  
Tests will be declared statistically significant if the calculated p-value is <0.05. Continuous 
variables will be summarized with means, standard deviations, medians, minimums, and 
maximums. Categorical variables will be summarized by counts and by percentage of subjects in 
corresponding categories. All summary tables will be presented by treatment group. Baseline 
summaries will also include a total summary column.  
Individual subject data obtained from the case report forms (CRFs), clinical laboratory, spirometry 
testing, muscle and strength testing, ECG lab, pharmacokinetic (PK) data, and any derived data 
will be presented by subject in data listings. 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock and prior to breaking the blind. Any analyses performed subsequent to breaking the 
blind will be considered post-hoc and exploratory. Post-hoc analyses will be labeled as such on the 
output and identified in the CSR. 
All analyses and tabulations will be performed using SAS Enterprise Guide Version 6.1 or higher 
on a PC platform. Tables and listings will be presented in RTF format. Upon completion, all SAS 
programs will be validated by an independent programmer. In addition, all program output will 
undergo a senior level statistical review. The validation process will be used to confirm that 
statistically valid methods have been implemented and that all data manipulations and calculations 
are accurate. Checks will be made to ensure accuracy, consistency with this plan, consistency 
within tables, and consistency between tables and corresponding data listings. Upon completion of 
validation and quality review procedures, all documentation will be collected and filed by the 
project statistician or designee. 
6 ANALYSIS POPULATIONS 
The Safety Analysis population will include all randomized subjects who received at least one 
dose of study drug and had at least one post dose safety assessment. 
The Full Analysis Set (FAS) population will include all randomized subjects who received at least 
14 days of study drug and had at least one post-dose efficacy measurement.  
The exclusion of any subject from the FAS analysis population will be determined prior to 
database lock and unblinding. 
7 STUDY POPULATION 
7.1 
SUBJECT DISPOSITION 
Subject disposition information will be summarized for all subjects by treatment group. 
Summaries will include: the number of enrolled (randomized) subjects, the number of subjects in 
each analysis population, the number of subjects completing study visits at Months 1 to 6 during 
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the double-blind treatment, the number of subjects completing study visits at Months 7 to 12 
during the open-label extension, the number completing the 2-week follow up after the end of 
treatment, and the primary reason for early termination. 
7.2 
PROTOCOL DEVIATIONS 
Major protocol deviations that could potentially affect the safety or clinical endpoints of the study 
will be identified prior to database lock and unblinding of individual subject treatment 
information. Major protocol deviations may include: 
• Randomized subjects who did not satisfy certain inclusion and exclusion criteria that 
would clearly impact efficacy interpretations; 
• Subjects who received the wrong treatment or substantially incorrect dose; 
• Subjects who received an excluded concomitant treatment that might markedly impact 
safety or efficacy (see Section 8.3 of the Protocol for Prohibited Medications). 
Major protocol deviations will be summarized by deviation category and treatment group.   
7.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic variables include: age, sex, ethnicity, and race. Other baseline characteristics 
include: medical history, weight, height, months since diagnosis. Demographic and baseline 
characteristics will be summarized for the Safety and Full Analysis Set (FAS) populations.  
7.4 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications will be recorded that were taken from 1 month prior to screening through study 
completion or early termination.  
Concomitant medications will be summarized for each treatment. 
8 SAFETY ANALYSES 
All safety analyses will be based on the Safety population. All analyses will be stratified by early 
or advanced ALS. All summaries of safety variables will be given by treatment group for the 
double-blind phase, for the open-label extension phase and for the entire study (Double-Blind and 
Open Lable Phase). 
8.1 
EXTENT OF EXPOSURE 
Study drug exposure will be summarized for each treatment using the average number of days on 
drug. The total subject number of discontinuations and the reasons for discontinuation will be 
summarized in the Subject Disposition table.  
8.2 
ADVERSE EVENTS 
The incidence of treatment-emergent AEs (TEAEs, defined as AEs occurring from the time of first 
dose through 7 days after the last dose of MN-166), SAEs and AEs leading to discontinuations will 
be summarized by treatment group. Incidence of TEAEs will also be summarized by severity 
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(mild, moderate, or severe), as well as by relationship to treatment (not related, possibly related, or 
probably related) and by seriousness. If it cannot be determined whether the AE is treatment 
emergent due to a partial onset date then it will be counted as such.  
Summaries that are displayed by system organ class (SOC) and preferred terms will be ordered by 
descending order of incidence of SOC and preferred term within each SOC.   
Summaries of the following types will be presented: 
• Subject incidence of TEAEs and total number of unique TEAEs by MedDRA system organ 
class and preferred term.   
• Subject incidence of TEAEs by MedDRA SOC, preferred term, and highest severity.  At 
each level of subject summarization, a subject is classified according to the highest severity 
if the subject reported one or more events.  AEs with missing severity will be considered 
severe for this summary. 
• Subject incidence of TEAEs by MedDRA SOC, preferred term, and closest relationship to 
study drug (Related/Not Related). At each level of subject summarization, a subject is 
classified according to the closest relationship if the subject reported one or more events.  
AEs with a missing relationship will be considered related for this summary. 
• Subject incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA SOC class and preferred term.   
• Subject incidence of TEAEs leading to study discontinuation or death by MedDRA SOC 
and preferred term.   
As this is a double-blind study, the causality assessment should be made under the assumption 
that the subject is receiving active study medication. If considering unblinding, this assessment 
should be made prior to unblinding to avoid bias. 
8.3 
CLINICAL LABORATORY EVALUATION 
Changes from baseline in laboratory values will be summarized by treatment groups for 
continuous variables. Lab shift tables showing incidence of new or worsening clinically significant 
findings from baseline to the last visit will be displayed by treatment groups. Shift from baseline to 
the highest lab value, and from baseline to the lowest lab value will also be displayed. Incidence of 
out-of-normal-range values and markedly abnormal change from baseline in laboratory safety test 
variables will be tabulated by treatment group. Baseline is defined as the last non-missing value 
prior to the start of study drug administration. 
8.4 
VITAL SIGNS 
Changes in vital signs from baseline to each visit will be summarized by treatment groups.  
8.5 
PHYSICAL EXAMINATION 
Physical examination results will be included in data listings only.  
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8.6 
ELECTROCARDIOGRAM 
Investigator assessment (Normal, Abnormal NCS, Abnormal CS) of ECG results will be 
summarized using shift tables.  
Descriptive statistics at baseline and at each post-baseline time point as well as changes from 
baseline will be summarized for each ECG parameter. In addition, a categorical summary of 
abnormal QTc values will be presented. At each time point, the number of subjects with QTcF and 
QTcB values of > 450 ms, > 480 ms, and > 500 ms will be presented. At each post-baseline time 
point, the number of subjects with change from baseline values in QTcF and QTcB of > 30 ms and 
> 60 ms will also be presented. 
9 CLINICAL ENDPOINT RESPONSIVENESS VARIABLES 
The Full Analysis Set (FAS) population will be used for all responsiveness analyses. All analyses 
will be stratified by early or advanced ALS.  
9.1 
RESPONSIVENESS VARIABLES 
Secondary endpoints focused on clinical responsiveness at 6 months are as follows: 
• Change from baseline in function status as measured by the ALSFRS-R 
• Change from baseline in respiratory function as measured by Slow Vital Capacity (SVC) 
• Change from baseline in respiratory function as measured by Maximum Inspiratory 
Pressure/Negative Inspiratory Force (MIP/NIF) 
• Change from baseline in respiratory function as measured by Maximal Voluntary 
Ventilation [MVV] 
• Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire-5 
(ALSAQ-5) 
• Clinical Global Impression of Change 
• Change from baseline in muscle strength as measured by manual muscle test 
• Change from baseline in instrumented hand grip strength 
Additional secondary endpoints are as follows:  
• Latency to onset of ALS progression from baseline measured by ALSFRS-R  
o ALS progression is defined as the first decrease in the ALSFRS-R Total Score. 
Subjects without a decrease are censored on the last assessment date for 
ALSFRS-R. 
• 
Latency to death (due to ALS) from date of randomization  
o Time to death will be calculated death date from randomization date. Subjects who 
did not die during the study are censored on last known living date. 
Analyses based on unmonitored data are as follows:  
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• Latency to occurrence of prescription for NIV (early ALS patients only) 
• Latency to onset of ALS milestone measured by ALS milestone (assessed by investigator) 
9.2 
BASELINE VALUES 
The baseline value for each endpoint is defined as the last non-missing value prior to study drug 
initiation. For spirometry endpoints the baseline value will be the value collected during the 
screening period. 
9.3 
ADJUSTMENTS FOR COVARIATES 
The primary analysis model comparing changes at 6 months in the secondary measures will 
include the baseline value as a covariate. 
9.4 
HANDLING OF DROPOUTS OR MISSING DATA 
The secondary clinical responsiveness endpoints are assessed at the 3- and 6-month visits. The 
amount of missing data will be reported for each measure at both time points by treatment group. If 
a subject has a missing baseline value, the endpoint will be set to missing and will not be included 
in the analysis. Our primary responsiveness analysis focuses on subjects’ 6-month data. For 
subjects missing 6-month data but with 3-month data, the missing value will be imputed using 
multiple imputation assuming the missing data are missing at random. The results of this 
imputation will be compared to an exploratory analysis using a linear mixed model on all post 
randomization data with contrasts for the between drug group comparison at 6 months. This 
method also assumes a missing at random missing data mechanism.  
9.5 
SAFETY MONITORING AND INTERIM EFFICACY ANALYSIS 
9.5.1 
SAFETY MONITORING  
The safety and tolerability of MN-166 will be evaluated by an unblinded Independent Safety 
Monitor during interim safety monitoring assessments after approximately 20-30 subjects in each 
stratum (early ALS group and advanced ALS group) have been followed for approximately 3 
months. The safety data will also be reviewed at Month 6 in each stratum and if there are no safety 
or tolerability concerns in the MN-166 treated group, a decision will be made to extend 
participation to the MN-166 treated group into the Open-label Extension (OLE) Phase. Otherwise, 
only the placebo-treated patients will participate in the OLE Phase. 
Independent oversight of this study will be provided by an Independent Safety Monitor (ISM). The 
ISM will review safety data to assess risk in the context of possible benefit. Efficacy data will be 
made available to the ISM upon request. The ISM is empowered to recommend four courses of 
action with respect to continuing the study: 
• 
The study should continue without modification; 
• 
The study should continue but with modification to the protocol or with additional data 
presentation needs; 
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• 
The study should be temporarily suspended to further enrollment and treatment 
administration, pending further evaluation of data; or 
• 
The study should be terminated because of safety concerns. 
• 
The ISM is not empowered to recommend premature stopping of the study because of 
apparent extreme efficacy. 
If the ISM determines that an unacceptably greater proportion of subjects is experiencing a safety 
problem and that there is no counterbalancing evidence of efficacy, the ISM may request a joint 
decision with MediciNova regarding stopping prematurely or recommending a change in the trial 
for safety reasons. The responsibility for the final decision regarding a ISM-recommended course 
of action will rest with MediciNova. Investigational sites will be advised in writing of the course of 
action recommended by the ISM after each of its review sessions. This information will be 
promptly forwarded to the Investigator at each study site. 
9.5.2 
 INTERIM EFFICACY ANALYSIS 
Two interim efficacy analyses will be performed by an indendent biostatistician who will be 
unblinded to the treatment. The first analysis will be performed after the 30th subject in the early 
ALS group completes 6 months of evaluation during the double-blind phase. The second analysis 
will be performed after the 30th subject in the advanced ALS group completes 6 months of 
evaluation during the double-blind phase period. This mid-study analysis will be summarized in a 
report.  Any data collected after this cutoff, that is, from patients continuing to receive extended 
treatment, will be presented in a separate analysis.   
The investigator, study staff, and sponsor will not be informed of the treatment assignments given 
to the subjects, i.e., they will not know the treatment received by individual subjects.  Each 
analysis will focus on the clinical endpoint responsiveness for the early and advanced ALS patient 
groups separately.  Clinical endpoint responsiveness assessments are as follows: 
• Change from baseline in function status as measured by the ALSFRS-R 
• Change from baseline in respiratory function as measured by Slow Vital Capacity (SVC) 
• Change from baseline in respiratory function as measured by Maximum Inspiratory 
Pressure/Negative Inspiratory Force (MIP/NIF) 
• Change from baseline in respiratory function as measured by Maximal Voluntary 
Ventilation [MVV] 
9.6 
EXAMINATION OF SUBGROUPS 
Efficay analyses will be additionally carried out in the following subgroups: 
• 
Patients with bulbar onset ALS 
• 
Patients with limb onset ALS  
 
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9.7 
MULTIPLE COMPARISON/MULTIPLICITY 
No adjustments for multiplicity will be made in this study. 
9.8 
MULTICENTER STUDIES 
This is a single-center study therefore no adjustments need to be made for multiple centers.  
10 METHODS OF CLINICAL RESPONSIVENESS ANALYSIS 
10.1 RESPONSIVENESS ANALYSES 
The responsiveness comparison will explore the following hypotheses (ALSFRS-R used as an 
example): 
H0: The average change in the ALSFRS-R at 6 months is equal between the Placebo and 
MN-166 treatment groups; 
H1: The average change in the ALSFRS-R at 6 months is different between the Placebo and 
MN-166 treatment groups.   
Treatment groups will be compared using an ANCOVA model that includes terms for treatment 
group, the randomization stratification factor, and baseline ALSFRS-R. Descriptive statistics will 
be presented as well as estimates of least-square (LS) means, LS mean difference, and p-value 
from the ANCOVA model. The same analysis approach will be used for all clinical responsiveness 
endpoints (muscle and respiratory measures) with the exception of the Clinical Global Impression 
of Change (CGIC) and the occurrence of prescription for NIV. The CGIC is an ordinal measure 
which will be categorized into “Better” versus “Worse/No Change” and compared between the 
two groups using the Mantel-Haenszel test stratified by the randomization stratification variable. 
The occurrence of prescription for NIV and the time to occurrence of prescription for NIV (for 
early ALS patients only) will be explored using Fisher’s exact test and Kaplan-Meier curves with a 
log-rank test, respectively. 
10.2 PHARMACOKINETIC ANALYSES 
Specific details regarding the pharmacokinetic (PK) analysis of MN-166 and its metabolite, 
6,7-dihydrodiol (DHD), will be documented elsewhere. As specific in the protocol, all plasma 
concentration-time data sets for MN-166 and 6,7-DHD will be evaluated by a non-compartmental 
model. Actual sampling time will be utilized for computation of PK parameters. All below limit of 
quantification (BLQ) values will be set to zero.  Missing values will be treated as if they were 
never drawn.  Summary statistics will be provided for all PK parameters. These include mean, 
median, standard deviation, percent, coefficient of variation, and maximum and minimum values.   
11 CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
The following modifications have been made to the analyses described in the protocol: 
• Added stratification by early and advanced ALS for all analyses 
• Added missing data analysis plan 
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• Added steps to minimize unblinding due to adverse events 
• Added analysis plan for CGIC  
• Added analysis for latency to onset of ALS progression from baseline measured by 
ALSFRS-R  
• Added latency to death (due to ALS) from date of randomization 
• Added Analyses based on unmonitored data:  
o Latency to occurrence of prescription of NIV (early ALS patients only)  
o Latency to onset of ALS milestone measured by ALS milestone (assessed by 
investigator) 
 
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APPENDIX 
APPENDIX  A:  LIST OF TABLES AND DATA LISTINGS 
List of Tables: All Tables will be stratified by Early and Advanced ALS. Table numbers with an 
asterisk (*) will be provided as“Double-blind Phase”, “Open-label Phase” and “Entire Study” 
separately.  
 
Table 
Number 
 
Table Description 
1* 
Subject Disposition (All Subjects)  
2 
Major Protocol Deviations (Safety Population) 
3.1 
Demographic and Baseline Characteristics (Safety Population) 
3.2 
Demographic and Baseline Characteristics (FAS Population) 
4 
Medical History (Safety Population) 
5 
Prior and Concomitant Medications (Safety Population) 
6* 
Study Drug Exposure (Safety Population) 
7* 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
8* 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Severity (Safety Population) 
9* 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Relationship to Study Drug (Safety Population) 
10 
Treatment-Emergent Serious Adverse Events and Total Number of Unique 
Serious TEAEs by System Organ Class and Preferred Term (Safety Population) 
11* 
Treatment-Emergent Adverse Events Leading to Study Discontinuation or Death 
by System Organ Class and Preferred Term (Safety Population) 
12* 
Hematology (Safety Population) 
13 
Hematology – Shift from Baseline (Safety Population) 
14* 
Serum Chemistry (Safety Population) 
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Table 
Number 
 
Table Description 
1* 
Subject Disposition (All Subjects)  
2 
Major Protocol Deviations (Safety Population) 
3.1 
Demographic and Baseline Characteristics (Safety Population) 
15* 
Serum Chemistry – Shift from Baseline (Safety Population) 
16* 
Vital Signs (Safety Population) 
17* 
Electrocardiogram – Investigator Assessment (Safety Population) 
18* 
Electrocardiogram (Safety Population) 
19* 
Electrocardiogram – Abnormal QTc Results (Safety Population) 
20 
ALSFRS-R – Change from Baseline (FAS Population) 
21 
Manual muscle test – Change from Baseline (FAS Population) 
22 
Instrumented hand grip – Change from Baseline (FAS Population) 
23 
Respiratory function as Measured by SVC, MIP/NIF, FEV1, and MVV – Change 
from Baseline (FAS Population) 
24 
ALSAQ-5 – Change from Baseline (FAS Population) 
25 
CGIC (FAS Population) 
26 
Latency to onset of ALS progression measured by ALSFRS-R 
(FAS Population) 
27 
Latency to onset of death due to ALS (FAS Population) 
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List of Data Listings 
List of Listings: All Listings will be stratified by Early and Advanced ALS. Listings numbers with 
an asterisk (*) will be provided three times (double-blind phase, open label phase, entire study, and 
will be identified as ”Double-Blind Phase”,"Open-Label Phase” and “Entire Study," respectively).  
Listing 
Number 
 
Listing Description 
1* 
Subject Disposition 
2 
Major Protocol Deviations  
3 
Subject Eligibility 
4 
Demographics 
5 
Medical History 
6 
Serum Pregnancy Test (Female subjects)  
7 
Urine Pregnancy Test (Female subjects)  
8 
Prior and Concomitant Medications 
9* 
Study Drug Exposure 
10 
Slow vital capacity – Change from Baseline (FAS Population) 
11 
Maximum inspiratory pressure (MIP)/negative inspiratory force (NIF) – 
Change from Baseline (FAS Population) 
12 
Forced Expiratory Volume in One Second (FEV1) measured under SVC 
protocol (FAS Population) 
13 
Maximal voluntary ventilation (MVV) (FAS Population) 
14 
Muscle Strength (FAS population)  
15 
ALSFRS-R (FAS population)  
16 
ALSAQ-5 (FAS population)  
17 
CGIC (FAS polulation)  
18 
Plasma PK MN-166 
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Listing 
Number 
 
Listing Description 
19* 
Adverse Events 
20* 
Serious Adverse Events 
21* 
Adverse Events Leading to Study Discontinuation or Death 
22* 
Hematology 
23* 
Serum Chemistry 
24* 
Urinalysis 
25* 
Vital Signs 
26 
Physical/Neurological Examination 
27* 
12-Lead Electrocardiogram 
 
 
 
 
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MediciNova Inc.