Clinical trial NCT02714036
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS
Sponsor: MediciNova
Start date: 2016-05-06; Completion date: 2020-06-30
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, open-label study of MN-166 (ibudilast) in subjects with ALS. To be eligible subjects must meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. Safety, tolerability, blood, neuro-imaging biomarkers, and clinical outcomes will be collected on all subjects. Subjects will receive study drug for 36 weeks.

The study will consist of a Screening Phase (up to 6 weeks), an Open-Label Treatment Phase (36 weeks) and an Off-Treatment Follow-up Phase (4 Weeks).

Number of Subjects (Planned):

Approximately 45 subjects are planned to be screened with the goal of enrolling 35 subjects.

Detailed description:
This is a multi-center, open-label study of MN-166 (ibudilast) in subjects with ALS. To be eligible subjects must meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. Safety, tolerability, blood, neuro-imaging biomarkers, and clinical outcomes will be collected on all subjects. Subjects will receive study drug for 36 weeks.

The study will consist of a Screening Phase (up to 6 weeks), an Open-Label Treatment Phase (36 weeks) and a Off-Treatment Follow-up Phase (4 Weeks).

During the Screening Phase, eligible ALS subjects will sign an informed consent form and the following screening assessments will be performed: review of inclusion/exclusion criteria: El Escorial ALS Diagnostic criteria, medical history and demographics, ALS diagnosis history, physical and neurological examination, U. Penn upper motor Neuron Burden (UMNB), pulmonary function tests, vital signs including height and weight, blood for safety labs including TSPO affinity test, ECG and review and documentation of concomitant medications and therapies.

Screening Phase (up to 6 weeks) The Treatment Phase will consist of a Baseline visit and 3 subsequent clinic visits at Weeks 4, 12, 24, and 36. Telephone follow-ups will occur at Weeks 1, 2, 8, 16, 20, 28, and 32.

Open-Label Treatment Phase (36 weeks) At the Baseline visit, subjects will return to the clinic and the following assessments will be performed/administered: review of inclusion and exclusion criteria for continued eligibility, vital signs, blood for safety labs and biomarkers, ECG, ALSFRS-R questionnaire, slow vital capacity (SVC), baseline strength as measured by hand held dynamometry (HHD), and Columbia Suicide Severity Rating Scale (C-SSRS). At this visit, study drug will be dispensed, and adverse events, concomitant medications and therapies will be assessed and documented. At subsequent visits during the Treatment Phase, similar assessments will be performed.

In addition, a \[11C\]PBR28-PET scan will be performed once between the Screening and Baseline visit, and once between the Week 12 and Week 28 phone calls. The ALSFRS-R, SVC and U Penn Upper Motor Neuron Burden will be repeated on the same day as the PET scans.

The follow-up visit will consist of a telephone call to document adverse events and concomitant therapies

Arms: arm 1: Participants will receive up to 100 mg /day MN-166 for 36 weeks. MN-166 dosing may vary based on individual tolerability. arm 2: Participants will receive up to 100 mg /day MN-166 for 36 weeks. MN-166 dosing may vary based on individual tolerability. Participants will have all assessments except PET scans.
Interventions: intervention 1: ibudilast intervention 2: Ibudilast
Intervention descriptions: intervention 1: Ibudilast is a small molecule that crosses the blood-brain barrier after oral administration. Its potential as a neuroprotective agent is based on in vitro and in vivo evidence of its ability to reduce microglial activation, inhibit microglia-monocyte recruitment to the central nervous system (CNS), and trigger the release of neurotrophic factors. intervention 2: Ibudilast is a small molecule that crosses the blood-brain barrier after oral administration. Its potential as a neuroprotective agent is based on in vitro and in vivo evidence of its ability to reduce microglial activation, inhibit microglia-monocyte recruitment to the central nervous system (CNS), and trigger the release of neurotrophic factors.

Protocol documents:
Prot_SAP_000.pdf: 
Confidential 
 
PROTOCOL NO. MN-166-ALS-1202 
Amendment 4 
A MULTI-CENTER, OPEN-LABEL BIOMARKER STUDY TO 
EVALUATE MN-166 (IBUDILAST) IN SUBJECTS WITH 
AMYOTROPHIC LATERAL SCLEROSIS (ALS) 
 
IND Number: 
128011 
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: 
 
Nazem Atassi, MD, MMSc 
Massachusetts General Hospital  
Neurological Clinical Research Institute (NCRI) 
165 Cambridge St, Suite 600 
Boston, MA 02114
 
 
 
 
Confidentiality Statement 
This document is confidential.  It contains proprietary information of MediciNova Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or conducting this study.


MediciNova, Inc.                                                                                                              MN-166 (ibudilast) 
MN-166-ALS-1202 Protocol Amendment 4                                                                    December 12, 2017 
 
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INVESTIGATOR AGREEMENT 
 
PROTOCOL NUMBER:  MN-166-ALS-1202 
 
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.  
 
 
Nazem Atassi MD MMSc 
Associate Director, Neurological Clinical Research Institute (NCRI) 
Massachusetts General Hospital 
 
 
_____________________________________ 
Investigator Name (Print)  
 
______________________________________                   ____________________________ 
Investigator Signature 
Date 
 
 
 


MediciNova, Inc.                                                                                                              MN-166 (ibudilast) 
MN-166-ALS-1202 Protocol Amendment 4                                                                    December 12, 2017 
 
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PROTOCOL SIGNATURE PAGE 
 
Protocol Number: MN-166-ALS-1202 
 
Signature:                                                                                   Date: 
  
Nazem Atassi, MD MMSc 
 
 
 
 
 
 
 
MediciNova: 
  
 Signature:                                                                                     Date: 
 
Kazuko Matsuda, MD PhD MPH 
 
 
 
 


MediciNova, Inc.                                                                                                              MN-166 (ibudilast) 
MN-166-ALS-1202 Protocol Amendment 4                                                                    December 12, 2017 
 
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1. 
SYNOPSIS 
 
Name of Sponsor: MediciNova, Inc. 
Name of Investigational Product: MN-166 (ibudilast) 
Protocol No: MN-166-ALS-1202 
Title of Study: A Multi-Center, Open-Label Biomarker Study to Evaluate MN-166 (ibudilast) in 
Subjects with Amyotrophic Lateral Sclerosis (ALS)   
Principal Investigator: Nazem Atassi, MD, MMSc 
Study Centers: Massachusetts General Hospital (MGH); South Shore Neurologic Associates Long 
Island 
Duration of Study Treatment: Screening up to 6 weeks; 
Treatment for 36 weeks; Follow-up at Week 40 for a total 
duration of 46 weeks.  
Phase of Development: 1b/2a 
Study Rationale 
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease for which there is no cure.  
  
A substantial body of evidence implicates the neuroimmune system and specifically activated microglia 
in ALS pathophysiology. Activated microglia are detected near the motor neurons of SOD1G93A 
transgenic mice at 39 days, well before the onset of weakness, and the inflammatory response in these 
mice correlates with disease progression. Under-expression of mSOD1 in microglia prolonged the post-
symptomatic survival of these transgenic mice. With relevance to human disease, activated microglia 
are increased in postmortem brain and spinal cord tissue from patients with ALS compared to healthy 
controls, and the number of activated microglia positively correlates with the rate of disease 
progression. 
 
Ibudilast is a small molecule macrophage migration inhibitory factor (MIF) and phosphodiesterase 
(PDE) 4,10 inhibitor. Ibudilast has an excellent safety track record and has been marketed for more 
than 2 decades in Japan for the treatment of post-stroke dizziness.  In addition, ibudilast has been 
shown to reduce microglia activation in multiple in vitro and in vivo model systems.  Ibudilast 
inhibited the release of specific inflammatory mediators and upregulated the release of neurotrophic 
factors from cultured microglia in a dose-dependent manner. Further, in neuron and microglia co-
cultures, ibudilast significantly suppressed neuronal cell death induced by the activation of microglia 
with lipopolysaccharide (LPS) and interferon (IFN)-gamma.  Thus, ibudilast-mediated neuroprotection 
is thought to be primarily due to the inhibition of microglia/monocyte recruitment, modulation of the 
inflammatory response, and release of neurotrophic factors. 
 
Numerous PET radioligands have been developed to image activated immune cells by binding to 
translocator protein (18kDa, TSPO), also called the peripheral benzodiazepine receptor (PBR). TSPO is 
highly expressed in both activated monocytes and microglia. Older generation TSPO radioligands, such 
as [11C]PK11195, suffer from poor signal-to-noise ratio in the brain. Our tracer, [11C]-PBR28, binds to 
TSPO with 80times higher specificity, offering a unique opportunity to study in vivo 
neuroinflammation due to activated microglia and monocytes.  
 


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The principal investigators of this study were able to successfully synthesize and administer [11C]-
PBR28 to over 40 subjects at MGH. We found that [11C]-PBR28 uptake is significantly increased in the 
motor cortices of ALS patients compared to healthy controls, and that the anatomical distribution of 
increased [11C]-PBR28 binding corresponds to ALS site of weakness onset (i.e., limb-onset patients 
have more inflammation in the motor cortex and bulbar-onset patients have more inflammation in the 
brain stem), and higher levels of inflammation were correlated with pathological reflexes and worse 
functional status. Thus, [11C]-PBR28 is an ideal biomarker to inform ibudilast target engagement and 
proof-of-mechanism in patients with ALS. 
Study Objectives 
Primary Objective 
The primary objectives are: 
• 
to measure the impact of MN-166 (ibudilast) on [11C]-PBR28 uptake in the motor cortices and 
brain stem measured by positron emission tomography (PET) imaging at 24 weeks 
• 
to measure the impact of MN-166 (ibudilast) on several markers of neuro-inflammation 
measured by blood biomarkers. 
 Secondary Objectives 
The secondary objectives are: 
• 
to evaluate the safety and tolerability of ibudilast over 36 weeks  
• 
to evaluate the effect of ibudilast on ALS clinical outcomes (ALS functional rating scale 
[ALSFRS-R], slow vital capacity [SVC], strength [measured by HHD- Hand-held 
dynamometry]) over 36 weeks.  
STUDY DESIGN 
This is a multi-center, open-label study of MN-166 (ibudilast) in subjects with ALS. To be eligible 
subjects must meet the El Escorial criteria of possible, laboratory-supported probable, probable, or 
definite criteria for a diagnosis of ALS. Safety, tolerability, blood, neuro-imaging biomarkers, and 
clinical outcomes will be collected on all subjects.  Subjects will receive study drug for 36 weeks. 
 
The study will consist of a Screening Phase (up to 6 weeks), an Open-Label Treatment Phase (36 
weeks) and an Off-Treatment Follow-up Phase (4 Weeks).  
Screening Phase (up to 6 weeks prior to Baseline Visit)  
During the Screening Phase, eligible ALS subjects will sign an informed consent form and the 
following screening assessments will be performed: review of inclusion/exclusion criteria: El Escorial 
ALS Diagnostic criteria, medical history and demographics, ALS diagnosis history, physical and 
neurological examination, U. Penn upper motor Neuron Burden (UMNB), pulmonary function tests, 
vital signs including height and weight, blood for safety labs including TSPO affinity test,  ECG and 
review and documentation of concomitant medications and therapies. 
 
Open-Label Treatment Phase (36 weeks) 
The Treatment Phase will consist of a Baseline visit and 4 subsequent clinic visits at Weeks 4, 12, 24, 
and 36. Telephone follow-ups will occur at Weeks 1, 2, 8, 16, 20, 28, and 32.  
At the Baseline visit, subjects will return to the clinic and the following assessments will be 
performed/administered: review of inclusion and exclusion criteria for continued eligibility, vital signs, 
blood for safety labs and biomarkers, ECG, ALSFRS-R questionnaire, slow vital capacity (SVC), 


MediciNova, Inc.                                                                                                              MN-166 (ibudilast) 
MN-166-ALS-1202 Protocol Amendment 4                                                                    December 12, 2017 
 
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baseline strength as measured by hand held dynamometry (HHD), and Columbia Suicide Severity 
Rating Scale (C-SSRS). At this visit, study drug will be dispensed, and adverse events, concomitant 
medications and therapies will be assessed and documented.  
 
At subsequent visits during the Treatment Phase, similar assessments will be performed.  
In addition, a [11C]-PBR28-PET scan will be performed once between the Screening and Baseline visit, 
and once between the Week 12 and Week 24 visits. The ALSFRS-R, SVC and UMNB will be repeated 
on the same day as the PET scans.   
 
Off-Treatment Follow-up Phase (4 Weeks post-Treatment Phase) 
The follow-up visit will consist of a telephone call to document adverse events and concomitant 
therapies. 
Number of Subjects (Planned):  
Approximately 45 subjects are planned to be screened with the goal of enrolling 35 subjects. Subjects 
enrolled and followed at the South Shore Neurologic Associates Long Island site will come to 
Massachusetts General Hospital for two PET scans. Five subjects s will be enrolled by flexible 
inclusion and exclusion criteria and will not have any PET scans.  
 
Study Entry Criteria:  
Inclusion Criteria:  
1. Subjects must be diagnosed as having possible, probable, probable-laboratory supported, or 
definite ALS, either sporadic or familial according to modified El Escorial criteria.  
2. Age 18 or above, able to provide informed consent, and safely comply with study procedures.  
3. Vital capacity (VC) of at least 50% predicted value for gender, height and age at screening visit, 
or in the opinion of the study physician, able to safely tolerate study procedures. (Not applicable 
to flexible arm) 
4. Subject must be able to swallow oral medication at the Baseline Visit and expected to be able to 
swallow the capsules throughout the course of the study.  
5. Subject must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at 
least 30 days, prior to screening (riluzole-naïve participants are permitted in the study). (Not 
applicable to flexible arm) 
6. Women must not be able to become pregnant (e.g. post-menopausal, surgically sterile, or using 
adequate birth control) for the duration of the study and 3 months after study completion.  
7. Males should practice contraception for the duration of the study and 3 months after completion. 
8. Ability to safely lie flat for 90 min for PET procedures in the opinion of the study physician. 
(Not applicable to flexible arm) 
9. High or mixed affinity to bind TSPO protein (Ala/Ala or Ala/Thr) (see Section 7.2.1). (Not 
applicable to flexible arm) 
10. Upper motor Neuron Burden (UMNB) Score ≥25 (out of 45) at screening visit. (Not applicable 
to flexible arm) 
Exclusion Criteria 
1. Abnormal liver function defined as AST and/or ALT > 3 times the upper limit of normal. 
2. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal. 
3. The presence of unstable psychiatric disease, cognitive impairment, or dementia that would 
impair ability of the participant to provide informed consent, according to PI judgment. 


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4. Clinically significant unstable medical condition (other than ALS) that would pose a risk to the 
participant if they were to participate in the study.   
5. History of HIV, clinically significant chronic hepatitis, or other active infection. 
6. Active inflammatory condition of autoimmune disorder (Not applicable to flexible arm) 
7. Females lactating or pregnant. 
8. Active participation in another ALS clinical trial or exposure to an off-label ALS experimental 
treatment within 30 days of the Baseline Visit (Not applicable to flexible arm) 
9. Exposure to immunomodulatory medications within 30 days of the Baseline Visit. (Not 
applicable to flexible arm) 
10. Any contraindication to undergo MRI studies such as  
a. History of a cardiac pacemaker or pacemaker wires 
b. Metallic particles in the body 
c. Vascular clips in the head 
d. Prosthetic heart valves 
e. Claustrophobia 
                 (Not applicable to flexible arm) 
11. Radiation exposure that exceeds the site’s current guidelines (Not applicable to flexible arm) 
12. EKG finding of QTc prolongation > 450 ms for males and > 470 ms for females at screening or 
baseline. 
13. Not on any prohibited medications: Refer to 8.3 Prohibited Medications 
Investigational Product, Dosage and Mode of Administration: MN-166 (ibudilast) 10 mg capsules 
administered orally. 50 mg bid (5 capsules) in the morning and evening will be administered for a total 
daily dose of 100 mg/d. Study drug dosing may vary based on individual tolerability.  
Duration of Treatment:  Open-label treatment for 36 weeks 
Reference Therapy, Dosage, and Mode of Administration: N/A  
Outcome Measures 
1. Neuroimaging biomarkers ([11C]-PBR28-PET) including both regions of interest (ROI) and 
voxel-based analyses; 
2. Safety, as measured by AEs and clinically meaningful changes in vital signs, physical 
examination, and standard clinical laboratory tests; 
3. Tolerability, defined as the ability of subjects to complete the entire 36-week treatment portion 
of study; 
4. Clinical outcomes: Measured by ALSFRS-R, SVC, and strength (measured by HHD).  
5. Blood biomarkers: including analysis of pro-inflammatory cytokines. 
Sample Size Justification 
Sample size calculation was based on the primary outcome of the biomarker. The primary outcome is 
the changes in the ROI in the motor cortex as assessed by [11C]-PBR28-PET. The study PI's previous 
studies comparing mean PBR28 binding in the motor cortices in limb-onset ALS subjects (1.18 units) 
with matching healthy volunteers (1.064 units) revealed 0.116 mean difference between the two 
groups, with 0.08 standard deviation in the ALS group. With 10 people tolerating the drug among 15 
participants in this study, the probability is 90 percent that the study will detect a treatment difference 
at a one-sided 0.1 significance level if the true difference is 0.096 units. The proposed increase in 
sample size will increase the statistical power to detect changes in PBR28 uptake after MN-166 
treatment. This will also provide more safety and tolerability data on MN-166 for up to 50 mg BID in 
people with ALS. 


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Table 1: 
Schedule of Assessments 
 
 
Screening 
Visit1 
 
Baseline 
***   
Visit 
(Day 1) 
Week 1, 
Week 2 
Phone call 
(±3 Days) 
Week 4
Visit 
(±7 Days) 
Week 8
Phone call 
(±3 Days) 
Week 12
Visit 
(±7 Days) 
Monthly 
Phone 
calls  
Week 16, 
Week 20 
(±3 Days)  
Week 24 
Visit 
(±7 Days) 
Monthly 
Phone calls 
Week 28, 
Week 32 
(±3 Days)  
 
Week 36
Visit 
(±7 Days) 
Week 40
Phone call 
(±3 Days) 
Final Safety 
Visit           
(for early 
drug 
discontinuati
on only) 
Informed Consent 
X 
 
 
 
Eligibility Criteria 
X 
X 
 
 
El Escorial Criteria  
X 
 
 
 
Medical History 
X 
 
 
 
Create GUID 
X 
 
 
 
 
 
 
 
 
 
Blood sample for 
TSPO Affinity test5 
X 
 
 
 
 
 
 
 
 
 
Safety Labs2 
X 
X 
X
X
 
X
X
X 
12-lead ECG 
X 
X 
X
X
 
X
X
X 
Vital Signs3 /Height 
and weight4 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Physical & 
Neurological exam 
X 
 
 
X 
 
X 
 
X 
X 
X 
[11C]-PBR28-PET5 
 
X* 
 
 
 
X**
 
 
MRI Safety 
Questionnaire5 
X 
 
 
 
 
 
 
X 
 
 
ALSFRS-R 
 
X* 
X
X
 
X**
X
X 
U Penn Upper Motor 
Neuron Burden 
X* 
 
 
X 
 
X 
 
X** 
X 
X 
Slow Vital Capacity 
X 
X* 
X
X
 
X**
X
X 
Hand-held    
Dynamometry 
 
X* 
 
X 
 
X 
 
X 
X 
X 
Columbia Suicide 
Severity Rating Scale 
 
X* 
 
 
 
 
 
 
X 
X 
Ibudilast Dispensing 
 
X 
X
X
 
X
 
Ibudilast 
Accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE review 
 
X 
X
X
X
X
X 
X
X
X
X
X 
Concomitant Meds 
X 
X 
X
X
X
X
X 
X
X
X
X
X 
Collection of blood for 
biobanking 
 
X*6 
 
X 
 
X 
 
X6 
X6 
 
1 Screening procedures must be completed within 6 weeks prior to Baseline Visit.  
2 Safety labs include Hematology (CBC with differential), Complete Chemistry Panel, Liver Function Tests, Serum pregnancy test (WOCBP). 


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3 Vital signs include systolic and diastolic pressure in mmHg, respiratory rate/minute, heart rate/minute and temperature.   
4 Height measured at Baseline Visit only. 
5 Assessments not applicable to flexible arm cohort 
6 PBMC Collection to be done. (Serum Biomarkers to be collected at Baseline, Week 4, 12, 24, 36). PBMC collection not applicable for flexible arm. 
*Off treatment Assessments will be performed one time only between the Screening and Baseline visits. ALSFRS-R, SVC and UPenn Upper Motor Neuron Burden will 
be repeated on the same day as the scan for subjects screened and enrolled at South Shore Neurologic Associates (SSNA). For subjects screened and enrolled at 
Massachusetts General Hospital (MGH), the ALSFRS-R, SVC and UMNB do not need to be repeated on the same day as the pre-treatment MRI/PET scan, if the pre-
scan visit differs from the baseline visit. These outcomes can be collected within + 14 days of the scan for MGH subjects. 
**On treatment [11C]-PBR28-PET will be performed one time only between the Week 12 and Week 24 visits. ALSFRS-R, SVC and UPenn Upper Motor Neuron Burden 
will be repeated on the same day as the scan for subjects screened and enrolled at South Shore Neurologic Associates (SSNA). For subjects screened and enrolled at 
Massachusetts General Hospital (MGH), the ALSFRS-R, SVC and UMNB do not need to be repeated on the same day as the post-treatment MRI/PET scan, if the post-
scan visit differs from the week 12 or week 24 visit. These outcomes can be collected within + 14 days of the scan for MGH subjects. 
 
*** The baseline visit or Day 1 is the time when study drug is dispensed and the first dose of drug is administered. Safety labs, Vital signs, ECG, and AE review should happen on 
Day 1.  


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2. 
TABLE OF CONTENTS 
 
1. 
SYNOPSIS ................................................................................................................... 4 
2. 
TABLE OF CONTENTS ........................................................................................... 10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 15 
4. 
BACKGROUND AND RATIONALE ...................................................................... 19 
4.1. 
Clinical Features and Epidemiology of ALS ............................................................. 19 
4.2. 
Role of neuro-inflammation in ALS Pathogenesis .................................................... 19 
4.3. 
Biomarkers of neuro-inflammation in ALS ............................................................... 20 
4.3.1. 
PBR28 PET ................................................................................................................ 20 
4.3.2. 
Imaging glial activation in ALS ................................................................................. 20 
4.4. 
MN-166 (ibudilast) ..................................................................................................... 22 
4.5. 
Prior Clinical Experience ........................................................................................... 24 
4.5.1. 
Clinical Study Overview ............................................................................................ 24 
4.6. 
Study Dose Rationale ................................................................................................. 28 
5. 
TRIAL OBJECTIVES AND PURPOSE ................................................................... 30 
5.1. 
Primary Objectives ..................................................................................................... 30 
5.2. 
Secondary Objectives ................................................................................................. 30 
6. 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION .................................. 31 
6.1. 
Screening Phase (up to 6 weeks prior to Baseline Visit) ........................................... 32 
6.1.1. 
Diagnosis at Screening ............................................................................................... 32 
6.1.2. 
Open-Label Treatment Phase (36 weeks) .................................................................. 32 
6.1.3. 
Off-Treatment Follow-up Phase (4 Weeks post Treatment Phase) ........................... 33 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 34 
7.1. 
Clinical Trial Population ............................................................................................ 34 
7.2. 
Inclusion/Exclusion Criteria ....................................................................................... 34 
7.2.1. 
Inclusion Criteria ........................................................................................................ 34 
7.2.2. 
Exclusion Criteria ....................................................................................................... 35 
7.2.3. 
Subject Withdrawal/Discontinuation Criteria ............................................................ 36 
7.2.4. 
Follow-up Procedures Upon Discontinuation/Withdrawal ........................................ 37 
8. 
TREATMENT OF SUBJECTS ................................................................................. 38 


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8.1. 
Description of Study Drug ......................................................................................... 38 
8.2. 
Concomitant Medications .......................................................................................... 38 
8.3. 
Prohibited Medications .............................................................................................. 38 
8.3.1. 
Prohibited drugs prior to and during the study ........................................................... 38 
8.3.2. 
Prohibited drugs during the study .............................................................................. 38 
8.3.3. 
Prohibited drug for “flexible arm” subjects ............................................................... 39 
8.4. 
Treatment Compliance ............................................................................................... 39 
8.5. 
Randomization and Blinding ...................................................................................... 39 
8.6. 
Dosing Guidelines ...................................................................................................... 39 
8.6.1. 
Treatment Phase ......................................................................................................... 39 
8.6.2. 
Dose Adjustments ...................................................................................................... 40 
8.6.3. 
Dose Interruptions ...................................................................................................... 40 
8.6.4. 
Subsequent Additional Laboratory Abnormalities ..................................................... 40 
8.7. 
Informed Consent ....................................................................................................... 41 
8.8. 
Assessments ............................................................................................................... 41 
8.8.1. 
Study Assessments by Visit ....................................................................................... 41 
8.8.1.1. 
Screening .................................................................................................................... 41 
8.8.1.2. 
Screen Failures ........................................................................................................... 42 
8.8.1.3. 
Baseline Visit (Day 1) ................................................................................................ 42 
8.8.1.4. 
Study Visits (Week 4, Week 12, Week 24, and Week 36) ........................................ 43 
8.8.1.5. 
Study Phone Calls (Week 1, Week 2, Week 8, Week 16, Week 20, Week 
28, Week 32, and Week 40) ....................................................................................... 43 
8.8.1.6. 
Final Safety Visit ........................................................................................................ 44 
8.8.1.7. 
Follow-up ................................................................................................................... 44 
8.8.2. 
Procedures/Assessment Details .................................................................................. 44 
8.8.2.1. 
Informed Consent ....................................................................................................... 44 
8.8.2.2. 
Medical History .......................................................................................................... 45 
8.8.2.3. 
Prior/Concomitant Medication Review ...................................................................... 45 
8.8.2.4. 
Physical/Neurological Examination ........................................................................... 45 
8.8.2.5. 
Vital Signs, Height, and Weight ................................................................................ 45 
8.8.2.6. 
Electrocardiogram (12-Lead ECG) ............................................................................ 45 
8.8.2.7. 
Neuroimaging ............................................................................................................. 46 
8.8.2.8. 
Pulmonary Function Test ........................................................................................... 46 


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8.8.2.9. 
The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised 
(ALSFRS-R) .............................................................................................................. 46 
8.8.2.10. 
Upper Motor Neuron-Burden (UMN-B) .................................................................... 47 
8.8.2.11. 
Blood Biomarkers ...................................................................................................... 47 
8.8.2.12. 
Strength Measurement (HHD) ................................................................................... 47 
8.8.2.13. 
Adverse Event (AE) Monitoring ................................................................................ 48 
8.8.2.14. 
Laboratory Evaluations .............................................................................................. 48 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ........................................... 49 
9.1. 
Study Drug ................................................................................................................. 49 
9.2. 
Study Drug Packaging and Labeling .......................................................................... 49 
9.3. 
Study Drug Storage .................................................................................................... 49 
9.4. 
Study Drug Administration ........................................................................................ 49 
9.5. 
Study Drug Accountability ........................................................................................ 50 
10. 
ASSESSMENTS OF SAFETY AND CLINICAL ENDPOINT 
RESPONSIVENESS .................................................................................................. 51 
10.1. 
Primary Endpoints ...................................................................................................... 51 
10.2. 
Secondary Endpoints .................................................................................................. 51 
Clinical Efficacy Endpoints ........................................................................................................... 51 
11. 
ADVERSE EVENTS ................................................................................................. 52 
11.1. 
Definition of Adverse Events ..................................................................................... 52 
11.2. 
Assessment of Adverse Events .................................................................................. 52 
11.2.1. 
Severity Assessment ................................................................................................... 52 
11.2.2. 
Relationship to Study Drug ........................................................................................ 53 
11.3. 
Recording Adverse Events ......................................................................................... 54 
11.4. 
Treatment and Follow-Up of AEs .............................................................................. 55 
11.5. 
Serious Adverse Events (SAEs) ................................................................................. 55 
11.5.1. 
SAE Reporting Requirements .................................................................................... 55 
11.6. 
Guidance for Overdose .............................................................................................. 56 
11.7. 
Reporting and Follow-up of Pregnancies ................................................................... 57 
11.8. 
Preplanned Hospitalizations or Procedures ................................................................ 58 
12. 
STATISTICAL CONSIDERATIONS ....................................................................... 59 
12.1. 
Sample Size Justification ........................................................................................... 59 
12.2. 
Safety Analysis ........................................................................................................... 59 


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12.3. 
Direct Access To Source Data/Documents ................................................................ 59 
12.4. 
Study Monitoring ....................................................................................................... 60 
12.5. 
Audits and Inspections ............................................................................................... 60 
12.6. 
Institutional Review Board (IRB) .............................................................................. 61 
12.7. 
Study Documentation ................................................................................................. 61 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................... 62 
14. 
ETHICS ...................................................................................................................... 63 
14.1. 
Ethics Review ............................................................................................................. 63 
14.2. 
Ethical Conduct of the Study ..................................................................................... 63 
14.3. 
Written Informed Consent .......................................................................................... 63 
14.4. 
Confidentiality ............................................................................................................ 63 
14.4.1. 
Confidentiality of Data ............................................................................................... 63 
15. 
DATA HANDLING AND RECORDKEEPING ....................................................... 64 
15.1. 
Review of Records ..................................................................................................... 64 
15.2. 
Retention of Records .................................................................................................. 64 
15.3. 
Role of Data Management ......................................................................................... 64 
15.4. 
Data Entry and Checks ............................................................................................... 64 
15.5. 
Data Lock Process ...................................................................................................... 65 
15.6. 
Data handling and record keeping .............................................................................. 65 
15.7. 
Publications ................................................................................................................ 65 
16. 
ADMINISTRATIVE AND REGULATORY DETAILS .......................................... 66 
16.1. 
Protocol Amendments and Study Termination .......................................................... 66 
16.2. 
Discontinuation of the Study ...................................................................................... 66 
16.3. 
Compliance with Financial Disclosure Requirements ............................................... 66 
17. 
REFERENCES ........................................................................................................... 67 
18. 
APPENDICES ............................................................................................................ 70 
Appendix 1: Laboratory Safety Tests for MN-166 ....................................................................... 71 
Appendix 2: El Escorial World Federation of Neurology Criteria for the Diagnosis of 
ALS ............................................................................................................................ 72 
Appendix 3:  ALS Functional Rating Scale-Revised (ALSFRS-R) .............................................. 74 
Appendix 4: Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................ 77 
Baseline (Version 1/14/09) ............................................................................................................ 77 
Since Last Visit (Version 1/14/09) ................................................................................................ 81 


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Appendix 5: The Penn Upper Motor Neuron-Burden (UMN-B) .................................................. 86 
Appendix 6: Modified Ashworth Spasticity Scale ........................................................................ 87 
 
  
 
 
 
 
 
List of Figures 
 
Figure 1: [11C]PBR28 uptake in ALS patients .................................................... 21 
Figure 2: Study Design ........................................................................................... 31 
  
 
List of Tables 
Table 1: Schedule of Assessments ......................................................................... 8 
Table 2: Abbreviations and Terms ..................................................................... 15 
Table 3: Summary Table of Completed and Ongoing Clinical Trials ............ 24 
Table 4: Dose versus Efficacy Results in RRMS study ..................................... 28 
Table 5: Study Drug Information ....................................................................... 49 
Table 6: Adverse Events Severity Definitions .................................................... 52 
Table 7: Adverse Event Causality Definitions ................................................... 53 
  
 
 


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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 
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 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome 
DBP 
Diastolic Blood Pressure 
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 
EAE 
Experimental autoimmune encephalomyelitis 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
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 
GUID 
Global Unique Identifier 
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 


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Abbreviation  
Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MGH 
Massachusetts General Hospital 
MIF 
macrophage migration inhibitory factor 
MIP 
maximum inspiratory pressure 
MRI 
Magnetic Resonance Imaging 
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 
ROI 
Region of Interest 
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 
TSPO 
translocator protein 
ULN 
upper limit of normal 


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Abbreviation  
Term 
WBC 
white blood cells 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of Childbearing Potential 


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4. 
BACKGROUND AND RATIONALE 
4.1. 
Clinical Features and Epidemiology of ALS 
Amyotrophic lateral sclerosis (ALS) is a rare degenerative disorder of large motor neurons of 
the cerebral cortex, brain stem and spinal cord that results in progressive wasting and paralysis 
of voluntary muscles1. The incidence of ALS is currently approximately 2/100,0002. The 
lifetime ALS risk is 1 in 600 to 1 in 10002. Even though the incidence of ALS is similar to 
that of multiple sclerosis, the prevalence is only 4 to 6/100,000 (about 25,000-30,000 subjects 
in the United States), due to the higher mortality rate. Fifty percent of ALS cases die within 
three years of onset of symptoms and 90% die within five years3. The median age of onset is 
55 years3. The cause in most cases is unknown4. Age and male gender are the only risk factors 
repeatedly documented in epidemiological studies. No treatment prevents, halts or reverses 
the disease, although the use of riluzole (FDA-approved therapy for ALS) is associated with a 
slight prolongation of survival5. Another drug that recently received FDA approval for 
treatment of ALS is Edaravone (Radicava®) and its use is not exclusionary for this study. 
4.2. 
Role of neuro-inflammation in ALS Pathogenesis 
Despite decades of focused research, a unifying and well-tested theory of ALS disease 
pathophysiology remains enigmatic4. At the same time, the body of knowledge has expanded 
dramatically as research tools have improved. Research increasingly implicates neuro-
inflammation as one of the major molecular mechanisms leading to neuronal death in ALS.  
 
Preclinical evidence: 
Activated microglia are detected near the motor neurons of SOD1G93A transgenic mice at 39 
days, well before the onset of weakness, and the inflammatory response in these mice 
correlates with disease progression6. Underexpression of mSOD1 in microglia prolonged the 
post-symptomatic survival of these transgenic mice7. In SOD1G93A ALS mice, there is an 
influx of inflammatory blood monocytes (CD14+/CD16-), which are recruited to the CNS and 
mimic the appearance of activated microglia8. In addition, in SOD1G93A mice, peripheral 
blood monocytes (CD14+/CD16-) become activated, demonstrating a pro-inflammatory gene 
profile8. Furthermore, miR-155, a micro-RNA that acts as an upstream regulator of 
inflammation, becomes upregulated in peripheral blood monocytes, and in central nervous 
system tissue in these SOD1G93A mice8. Knocking out this gene ameliorates disease in 
transgenic SOD1 mice, as does reducing its expression with an antisense oligonucleotide8-10. 
 
Human studies: 
With relevance to human disease, activated microglia are increased in postmortem brain and 
spinal cord tissue from patients with ALS compared to healthy controls, and the number of 
activated microglia correlates positively with faster rate of disease progression11. Studies of 
cerebrospinal fluid (CSF) show increased immune cells, including monocytes/macrophages, 
and pro-inflammatory cytokines12-14. 


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4.3. 
Biomarkers of neuro-inflammation in ALS 
 
4.3.1. 
PBR28 PET 
 
[11C]-PBR28 is an investigational PET tracer that binds to the translocator protein (TSPO) 
expressed on activated microglia and astrocytes. The name of the non-radioactive drug is 
PBR. N-Acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine. More than 168 individuals 
received PBR28 (mean dose 2.2mCi/nmol) at MGH and there were no reported tracer-related 
Adverse Events.  
 
4.3.2. 
Imaging glial activation in ALS 
 
It was found that PBR28 uptake is significantly increased in the motor cortices in ALS 
patients compared to healthy controls15 (Figure 1). We also demonstrated that the anatomical 
distribution of increased PBR28 uptake corresponds to ALS clinical presentation; patients 
with limb-onset weakness had higher PBR28 uptake in the motor cortices and patients with 
bulbar-onset weakness had higher PBR28 uptake in the brainstem15 (Figure 1). Furthermore, 
higher PBR28 uptake was strongly correlated with worse functional status measured by 
ALSFRS-R and more pathological upper motor neuron signs measured by upper motor 
neuron burden scale (UMNB) 15.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A. [11C]-PBR28 uptake for 10 individual ALS patients and 10 age- and binding 
affinity- matched healthy controls. B. Mean [11C]-PBR28 binding images for the ALS 
and control groups, including comparisons between limb- and bulbar-onset patients C. 
Brain regions that exhibit significantly higher binding in ALS compared to the control 
group in the voxel-wise whole brain analysis, pFWE<0.05 
 
Figure 1: 
[11C]PBR28 uptake in ALS patients 
 
 


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4.4. 
MN-166 (ibudilast) 
Ibudilast is a small molecule that crosses the blood-brain barrier after oral administration16. Its 
potential as a neuroprotective agent is based on in vitro and in vivo evidence of its ability to 
reduce microglial activation, inhibit microglia-monocyte recruitment to the central nervous 
system (CNS), and trigger the release of neurotrophic factors. Ibudilast has been marketed for 
more than 2 decades in Japan for the treatment of post-stroke dizziness and has an excellent 
safety track record. 
 
Ibudilast reduces active microglia: 
Ibudilast inhibits the pro-inflammatory cytokine, macrophage migration inhibitory factor 
(MIF) and suppresses mononuclear cell migration to the brain in a dose-dependent fashion17. 
MIF is essential for promoting microglial activation and production of the innate soluble 
mediators IL-1β, IL-6, tumor necrosis factor (TNF)-α, and inducible nitric oxide (NO) 
synthase18. The in vivo suppression of MIF effects inhibits CNS inflammation and reduces the 
number of active microglia and infiltrating inflammatory macrophages18. Ibudilast also 
reduces microglial activation and protects against white matter damage induced by chronic 
cerebral ischemia19. These data suggest that by inhibiting MIF, ibudilast is a potent suppressor 
of both microglial recruitment and activation. 
 
Ibudilast modulate neuroinflammation: 
In cultures of active microglia, ibudilast inhibits the production of the pro-inflammatory 
cytokine TNF-α and of NO in a dose-dependent manner20,21. Ibudilast also inhibits the 
production of TNF-α by microglia that are activated in response to viral proteins22. In 
addition, ibudilast reduces microglial TNF-α expression, demyelination on histology, and the 
development of clinical symptoms in a rodent genetic model of Krabbe’s neurodegeneraton23. 
Oral administration of ibudilast reduces the severity of clinical signs of the autoimmune 
encephalitis (EAE) rodent model of multiple sclerosis in a dose-dependent manner24. In a 
multicenter, double-blind, phase II trial in patients with relapsing multiple sclerosis, ibudilast 
reduced inflammation measured by two independent MRI outcomes, and showed beneficial 
clinical effect on disease disability25. Based on these promising results, ibudilast is currently 
under investigation as a disease-modifying agent for multiple sclerosis (NCT01982942). 
 
Ibudilast is neuroprotective: 
The anti-inflammatory effects of Ibudilast are neuroprotective in several in vitro models. In 
murine neuron and microglia co-culture experiments, ibudilast suppresses neuronal cell death 
that is induced by the activation of microglia with lipopolysaccharide (LPS) and interferon 
(IFN)-γ21. These activities were medicated by selective inhibition of certain 
phosphodiesterases (PDEs)20,26. At the same time, ibudilast increases the production of the 
anti-inflammatory cytokine IL-10, and of neurotrophic factors (nerve growth factor (NGF), 
glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-421. Further, ibudilast 
protects against glutamate excitotoxicity in cultured hippocampal neurons27. Ibudilast exerts 
beneficial effects on glial cell survival as it protects astrocytes against apoptosis28 and 
prevents kainate-induced excitotoxicity in cultured oligodendrocytes29.  


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In summary, ibudilast reduces active microglia, inhibits neuroinflammation, and has strong 
neuroprotective properties in several disease models.    
 
 
 
 
 


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4.5. 
Prior Clinical Experience 
4.5.1. 
Clinical Study Overview 
To date, 5 clinical studies have been completed and 2 clinical trials are ongoing in the US.  As of May 29, 2015, approximately 537 
subjects have received MN-166 and 290 subjects have received placebo.   
 
Table 3: 
Summary Table of Completed and Ongoing Clinical Trials 
Type 
of 
Study 
Study 
Identifier 
Study Objectives  
 
Study Design and 
Type of Control 
Test Product(s); 
Dosage 
Regimen; 
Route of 
Administration 
Healthy 
Subjects or 
Diagnosis of
Patients 
Number 
of 
Enrolled 
Subjects 
Number of 
MN-166 Subjects
Number 
of 
Placebo 
Subjects 
Duration 
of Treat-
ment 
Study 
Status; 
Type of 
Report 
Multiple Sclerosis Study 
2 
MN-166-CL-
001 
To assess safety, 
tolerability and 
efficacy 
R (1:1:1), DB, PC AV411 30 mg/d, 60 
mg/d or placebo; oral 
Multiple 
Sclerosis 
(18 to 55 
years old) 
297 
 (291 during entire 
study)  
103 
(core 
period) 
Core 12 
months; 
extension 
12 mos 
Completed; 
Full 
2 
NN102-
SPRINT-MS 
To assess safety and 
efficacy 
Multi-center, R, DB, 
PC 
MN-166 100 mg/d 
orally or placebo 
Progressive 
multiple 
sclerosis 
255 
129 
126 
96 weeks 
Completed;  
In Progress 
Phase 1 Studies 
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 
pbo; no study drug on 
Day 2 and on Day 3 
subjects received 
AV411 60 mg/d or 
pbo for 14 days; oral 
Healthy 
Volunteers 
(18 to 70 
years old) 
18 (14 
active, 4 
pbo) 
14 
4 
2 wk 
Completed; 
Full 


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Type 
of 
Study 
Study 
Identifier 
Study Objectives  
 
Study Design and 
Type of Control 
Test Product(s); 
Dosage 
Regimen; 
Route of 
Administration 
Healthy 
Subjects or 
Diagnosis of
Patients 
Number 
of 
Enrolled 
Subjects 
Number of 
MN-166 Subjects
Number 
of 
Placebo 
Subjects 
Duration 
of Treat-
ment 
Study 
Status; 
Type of 
Report 
1 
AV411-016 
To assess safety, 
tolerability and PK 
R (3:1), DB, PC, 
single escalating 
dose 
AV411 30 mg, 50 mg, 
70 mg, 80 mg, and 
100 mg or placebo; 
oral 
Healthy 
Volunteers 
(18 to 55 
years old) 
60 (45 
active, 15 
pbo) 
45 
15 
Single 
dose 
Completed; 
Full 
1b 
AV411-026 
To assess safety, 
tolerability and PK 
R (3:1), DB, PC, MD
 
 
On Days 1 thr 6, subjs 
received AV411 or 
pbo as follows: 40mg 
x 2d then 60 mg x 2 d, 
and 80 mg x 2 d. On D 
7 -14, subjects 
received AV411 100 
mg/d or pbo; oral 
Healthy 
Volunteers & 
Diabetes 
Mellitus 
(Type 1 and 2) 
Subjects 
(18 to 75 
years old) 
24 (18 
active, 6 
pbo); 
12 HV; 12 
DM 
18 
6 
2 wk 
Completed; 
Full 
Neuropathic Pain Study 
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 14 day treatment 
phase in 2 cohorts 
Treatment Phase: 
Cohort 1: randomized 
1:1:1 to AV411 40 
mg, 60 mg or pbo.  
Cohort 2: randomized 
2:1 (AV411:pbo) to 60 
mg/80 mg/d or pbo; 
oral 
Diab. Periph. 
Neuropath. 
Pain (DPN) 
subjects 
(18 to 75 
years old) 
34 (24 
active/10 
pbo) 
 
34 
Run-in 
24 
Treatment 
34 
Run-in 
10 
Treatment 
Single and 
multiple 
dosing 
2 wk  
(subset 
>3mos) 
Completed; 
Full 
Ongoing Studies 
2 
MN-166-ALS-
1201 
To assess safety and 
efficacy 
Single-center, R 2:1, 
DB,PC with an OLE
MN-166 60 mg/d or 
placebo 
Amyotrophic 
lateral 
sclerosis 
(ALS) 
21 
 
~14 
~7 
52 weeks 
Ongoing; 
unblinded interim 
safety report 
 CO=crossover, OLE=open label extension, MD=multiple dose,  PC=placebo-controlled, PK=pharmacokinetic, PBO=placebo, R=randomized


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Safety and Tolerability Summary of MN-166 (ibudilast) 
As of 29 May 2015, approximately 537 subjects have received MN-166 and 290 subjects 
have received placebo in five completed Phase 1 and Phase 2 clinical trials and two 
ongoing trials.   
A total of 124 subjects with multiple sclerosis have received MN-166 30 mg/day and 60 
mg/day for up to 12 months and 167 have received MN-166 30 mg/day and 60 mg/day for 
up to 24 months.   
The safety of MN-166 from 30 to 80 mg/day in single and multiple doses up to 14 days has 
been evaluated in 77 subjects (68 healthy volunteers, 9 diabetes mellitus subjects).  Of 
these 77 subjects, MN-166 100 mg/day has been evaluated as a single dose in 9 healthy 
volunteers and multiple doses for up to 8 days in 9 healthy volunteers and 9 diabetes 
mellitus patients. Additionally, MN-166 has been evaluated in 34 subjects with neuropathic 
pain.  
The results of the completed Phase 2 randomized double-blind relapsing-remitting multiple 
sclerosis (RRMS) study suggest that MN-166 at daily doses up to and including 60 mg/day 
appear to be generally safe and well-tolerated.  A smaller number of subjects have received 
MN-166 at 80 mg/day and 100mg/day; the adverse event profile appears to be similar to 
that of the lower doses. The adverse events that appear to be drug-related based on the 
available data are headache, nausea, vomiting, dyspepsia and hyperhidrosis.  In the 
multiple sclerosis study, there was a slight dose related increase in the percent of subjects 
with headaches and gastrointestinal AEs.  The incidence of nausea demonstrated a dose-
related increase with the greatest incidence in the 60 mg/day group compared to the 30 
mg/day, and placebo groups although the number of subjects experiencing nausea was 
small. Similarly, the incidence of vomiting followed the same pattern. MN-166 also 
appeared to cause transient changes in laboratory values particularly AST, ALT and GGT 
which, in most cases, seemed to resolve over time. These adverse events appear to be 
consistent with the more commonly reported adverse drug reactions reported in the Ketas® 
package insert. MN-166 does not appear to cause significant changes in blood pressure, 
heart rate or ECGs. No new adverse events appear to occur with long-term exposure. 
Ongoing Studies 
There are currently two ongoing Phase 2 studies to evaluate MN-166 for the treatment of 
amyotrophic lateral sclerosis (ALS) and the treatment of multiple sclerosis (MS).  
Amyotrophic Lateral Sclerosis (ALS) Study 
The ALS study is currently being conducted under IND 118318 and has enrolled 
approximately 21 patients.  An unblinded interim analysis was conducted by an 


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independent Safety Monitor and as of 01 April 2015, a total of 61 adverse events have been 
reported in 21 subjects (64% of these were considered mild and 36% were considered 
moderate). Of the 61 AEs, only 2 were determined to be "possibly related". All others AEs 
were deemed to be either "unrelated" or "unlikely related".  Adverse events were evenly 
distributed among the two treatment groups. No clinically significant abnormalities were 
noted on ECG and there were no clinically significant laboratory abnormalities. The 
recommendation was to continue the trial as planned. 
As per the recommendation of the Division of Neurology Products, this proposed IND is 
being filed to conduct future ALS studies.  
Multiple Sclerosis (MS) Study 
As of an interim analysis cutoff date of 05/04/2015, a total of 645 adverse events (AEs) 
have been reported (307 in treatment group A, 338 in treatment group B) in 178 subjects. 
No significant trend appears for the overall distribution of AEs across the treatment groups. 
When examined by system organ class (SOC), there is a trend towards significantly more 
AEs in the “Infections” SOC with treatment A. However, this trend does not appear to be 
due to any particular difference for any MedDRA preferred term within this SOC.  
 
Of the 645 AEs, a total of 196 (30%) have been determined to be at least possibly related 
to treatment (59 in treatment group A, 137 in treatment group B). When restricted only to 
the subset of AEs determined to be at least possibly related to treatment, there is a trend 
towards significantly more related AEs with treatment B (31% of subjects on treatment A 
with at least one related AE vs. 50% of subjects on treatment B; RR = 0.62 w/ 95% CI: 
0.44, 0.87). The data suggests that this is primarily due to a trend towards significantly 
more related AEs in the “Gastrointestinal” & “Nervous System” SOCs with treatment B – 
with the overall observed differences primarily due a significant increase in study-related 
“Nausea” (8% of subjects on treatment A vs. 21% of subjects on treatment B; RR = 0.37 
w/ 95% CI: 0.18, 0.76) and a marginally significant increase in study-related “Headache” 
(3% of subjects on treatment A vs. 10% of subjects on treatment B; RR = 0.34 w/ 95% 
CI: 0.11, 1.02) on treatment B. 
Other Clinical Studies 
There have been 6 additional studies conducted with MN-166 under Investigator-Initiated 
INDs for drug and alcohol addiction, and medication overuse headache. 
 
 
 
 


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4.6. 
Study Dose Rationale 
The findings from the efficacy endpoints from the previous Phase 2 RRMS trial (MN-166-
CL-001) indicated that patients receiving 60 mg/d MN-166 exhibited significantly reduced 
brain volume loss, reduced progression to persistent black hole (PBH) formation from 
gadolinium-enhancing lesions and extended time to first relapse vs. patients treated with 
placebo25 (see table below). A dose-response effect was evident between the 30 and 60 
mg/d regimens, with 60 mg/d showing statistical significance for all efficacy measures. 
These study results suggest that MN-166 is best positioned for primary neuroprotection in 
MS patients30 and the dose-response data reported here and combined with animal PK-PD 
and preliminary clinical efficacy outcomes in other trials suggest that doses of 60 mg/d up 
to 100 mg/d be suitable to demonstrate neuroprotective efficacy of MN-166. 
A summary of daily dose vs. efficacy results across some of the sponsor’s patient trials are 
presented in the table below. 
Table 4: 
Dose versus Efficacy Results in RRMS study 
Study 
Indication 
Endpoint 
Dose (mg/d) 
Significance (p <0.05) 
Pilot study Ibudilast 
for MS  
RRMS 
Mean relapse rate  
60 
+ 
MN-166-CL-001 
RRMS 
(small subset of 
SPMS) 
Reduced Brain 
atrophy 
30 
60 
- 
+ 
Reduced PBH 
formation 
30 
60 
- 
+ 
Time to first relapse 
 
30 
60 
_ 
 
+ 
AV411-OWA 
Opioid Analgesia 
Addiction  
McGill pain survey, 
Subjective Opioid 
Withdrawal Scale 
40 
80 
Not available 
+ 
Note:  A 60 mg/d MN-166 regimen yields steady-state plasma conc. ~75 ng/mL and estimated brain conc. 
~225 ng/mL. Correlates for 80 and 100 mg/d regimens are proportionally higher.   
 
 
For the first clinical trial with ALS subjects (MN-166-ALS-1201), 60 mg/d MN-166 was 
selected for the following reasons: 1)  60 mg/d was administered to patients in the RRMS 
trial and found to be generally safe and well-tolerated; 2) the safety and tolerability of MN-
166 given as an adjuvant to riluzole had not been previously evaluated and, 3) MN-166 and 
riluzole each have shown  hepatotoxicity on their own and it was uncertain whether co-
administration of the drugs would result in an additive hepatotoxic effect.  For these 
reasons, it was decided that a more conservative dose regimen was to be implemented.  
Recently, however, the safety and tolerability of MN-166 were evaluated in the ongoing 
progressive MS and ALS trials with recommendations from the independent safety 
monitors to continue the dosing regimens and the trials, overall. In April 2015, an interim 


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safety analysis was conducted by an Independent Safety Monitor to evaluate the safety 
results of the first 21 subjects (n =14 ibudilast; n =7 placebo) who had completed 3 months 
of study drug treatment in the MN-166-ALS-1201 study.  It was reported that there was no 
trends or signs of increased hepatotoxicity in these subjects who were administered MN-
166 with riluzole. Moreover, no trends or signs of increased incidence of adverse events or 
laboratory value changes were reported from the interim safety analysis of the ongoing 
Phase 2 progressive MS trial utilizing up to 100 mg/day.  
 
Collectively, the safety and efficacy findings from the completed and ongoing trials make a 
compelling case for administering up to 100 mg/d MN-166 to ALS patients in this study. 
 
 
 
 
 
 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
 
5.1. 
Primary Objectives 
 
The primary objectives are: 
• to measure the impact of MN-166 (ibudilast) on [11C]-PBR28 uptake in the motor 
cortices and brain stem measured by positron emission tomography (PET) imaging 
at 24 weeks 
• to measure the impact of MN-166 (ibudilast) on several markers of neuro-
inflammation measured by blood biomarkers. 
 
5.2. 
Secondary Objectives 
 
 
The secondary objectives are: 
 
• to evaluate the safety and tolerability of ibudilast over 36 weeks  
• to evaluate the effect of ibudilast on ALS clinical outcomes [ALS functional rating 
scale (ALSFRS-R), slow vital capacity (SVC), strength (measured by HHD- Hand-
held dynamometry)] over 36 weeks. 


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6. 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION 
This is a multi-center, open-label study with a 6-week Screening Phase, 36-week Treatment 
Phase, and a Follow-up Phase 4 week after the last dose. Approximately 45 subjects are 
expected to be screened and 35 subjects are planned to be enrolled. Subjects enrolled and 
followed in South Shore Neurologic Associates Long Island will come to Massachusetts 
General Hospital for two PET scans. Five subjectss will be enrolled by flexible inclusion 
and exclusion criteria and will not have any PET scans. MN-166 (ibudilast) 50 mg will be 
administered orally twice a day.  
 
All study visit windows (±7 days) after baseline are consecutive calendar days and are 
calculated from the day the subject starts study treatment (the day of the Baseline Visit). 
The study phases are described below and displayed in Figure 2 and the Schedule of 
Assessments is displayed in Table 1. 
 
 
Figure 2: 
Study Design 
 
 


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6.1. 
Screening Phase (up to 6 weeks prior to Baseline Visit) 
 
During the Screening Phase, a total of up to 6 weeks will be allowed to complete the 
screening assessments.   
Subjects will be approached for study participation and upon signing an informed consent 
form, the following 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, and serum pregnancy test), 12-lead ECG, slow vital capacity and a 
manual muscle strength test will be conducted; an ALSAQ-5 will be administered.  
 
Detailed information on permitted and excluded concomitant medications is provided in 
Section 8.2 and Section 8.3 of the protocol.  
6.1.1. 
Diagnosis at Screening 
Subjects must have a diagnosis of ALS as defined by the El Escorial-Revised research 
diagnostic criteria for ALS (clinically definite, clinically probable, probable-laboratory 
supported). 
6.1.2. 
Open-Label Treatment Phase (36 weeks) 
 
During the Open-label Treatment Phase, subjects will return to the clinic at Baseline, and at 
Week 4, Week 12, Week 24, and Week 36 (end of study drug dosing).  Telephone follow-
ups will occur at Weeks 1, 2, 8, 16, 20, 28, and 32 (see Table 1 Schedule of Assessments).   
At the Baseline Visit, subjects who have completed all of the screening assessments and 
continue to meet eligibility criteria will have their baseline assessments performed.  
Subjects will take their first dose of study medication (30 mg MN-166) on the evening of 
the Baseline Visit (Day 1).  On the morning of Day 2, all subjects will begin a 3 capsule 
BID dosing regimen and will remain on 60 mg/d through Day 14. Beginning on Day 15, all 
subjects will increase dosing to 5 capsules BID regimen. After Day 15, subjects who 
experience intolerable side-effects (e.g., nausea, diarrhea, vomiting) may reduce their dose 
to either 4 capsules twice a day (80 mg/d) or 3 capsules twice a day (60 mg/d) in discussion 
with the site investigator. The daily dose of ibudilast may be divided and taken three times 
per day if needed to improve tolerability. At the end of the first 8 weeks of treatment, the 
subject must maintain their then-current daily dose of study medication (6 capsules per day, 
8 capsules per day, or 10 capsules per day).  
Subject with intolerable side-effects (e.g., nausea, diarrhea, vomiting) may discontinue the 
study drug at any time at the investigator’s discretion.  


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6.1.3. 
Off-Treatment Follow-up Phase (4 Weeks post Treatment 
Phase) 
All subjects who complete the study will receive a follow-up phone call at Week 40 to 
collect adverse events and concomitant therapies. Subjects who stop study medication for 
any reason prior to the end of treatment period (week 36) will also have a Final Safety Visit 
4 weeks after the last MN-166 dose. 
 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Clinical Trial Population 
The population for this trial will include approximately 35 male and female subjects at least 
18 years old with a diagnosis of 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. Subjects must be diagnosed as having possible, probable, probable-laboratory 
supported, or definite ALS, either sporadic or familial according to modified El 
Escorial criteria.  
2. Age 18 or above, able to provide informed consent, and safely comply with study 
procedures.  
3. Vital capacity (VC) of at least 50% predicted value for gender, height and age at 
screening visit, or in the opinion of the study physician, able to safely tolerate study 
procedures. (Not applicable to flexible arm) 
4. Subject must be able to swallow oral medication at the Baseline Visit and expected to 
be able to swallow the capsules throughout the course of the study.  
5. Subject must not have taken riluzole for at least 30 days, or be on a stable dose of 
riluzole for at least 30 days, prior to screening (riluzole-naïve participants are 
permitted in the study). (Not applicable to flexible arm) 
6. Women must not be able to become pregnant (e.g. postmenopausal, surgically sterile, 
or using adequate birth control) for the duration of the study and 3 months after study 
completion.  
7. Males should practice contraception for the duration of the study and 3 months after 
completion. 
8. Ability to safely lie flat for 90 min for PET procedures in the opinion of the study 
physician. (Not applicable to flexible arm) 
9. High or mixed affinity to bind TSPO protein (Ala/Ala or Ala/Thr) (Details below). 
(Not applicable to flexible arm) 
10. Upper motor Neuron Burden (UMNB) Score ≥ 25 at screening visit. (Not applicable 
to flexible arm). 
TSPO affinity test: venous blood will be drawn from all participants at Screening in order 
to have them genotyped for the Ala147Thr TSPO polymorphism in the TSPO gene 
(rs6971). About 10% of humans show low binding affinity to PBR2831. A recent study has 
demonstrated that the rs6971 polymorphism predicts PBR28 binding affinity in human 
platelets31. Since the low-affinity binder phenotype is consistent across all tissues within 
the same person, testing for the Ala147Thr polymorphism can be performed to predict low 
affinity for PBR28 in all organs, including the brain32. High or Mixed affinity binders 


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(Ala/Ala or Ala/Thr) will be considered eligible, whereas the low affinity binders 
(Thr/Thr) will be considered ineligible for the study. 
7.2.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Abnormal liver function defined as AST and/or ALT > 3 times the upper limit of 
normal. 
2. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of 
normal. 
3. The presence of unstable psychiatric disease, cognitive impairment, or dementia 
that would impair ability of the participant to provide informed consent, according 
to PI judgment.  
4. Clinically significant unstable medical condition (other than ALS) that would pose 
a risk to the participant if they were to participate in the study.   
5. History of HIV, clinically significant chronic hepatitis, or other active infection. 
6. Active inflammatory condition or autoimmune disorder (Not applicable to flexible 
arm) 
7. Females must not be lactating or pregnant. 
8. Active participation in another ALS clinical trial or exposure to an off-label ALS 
experimental treatment within 30 days of the Baseline Visit (Not applicable to 
flexible arm) 
9. Exposure to immunomodulatory medications within 30 days of the Baseline Visit. 
(Not applicable to flexible arm) 
10. Any contraindication to undergo MRI studies such as  
a. History of a cardiac pacemaker or pacemaker wires 
b. Metallic particles in the body 
c. Vascular clips in the head 
d. Prosthetic heart valves 
e. Claustrophobia 
                  (Not applicable to flexible arm)  
11. Radiation exposure that exceeds the site’s current guidelines (Not applicable to 
flexible arm) 
12. EKG finding of QTc prolongation > 450 ms for males and > 470 ms for females at 
screening or baseline. 
13. Not on any prohibitive medications.: Refer to Section 8.3 Prohibited Medications 
 
Contraception requirements/pregnancy testing 
For the purposes of this study, women of child bearing potential are defined as all women 
who are capable of becoming pregnant, unless they meet one of the following criteria: 
• 12 months postmenopausal  


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• Post-hysterectomy 
• Surgically sterile 
 
If a female subject does not meet these criteria and is considered of child bearing potential 
they will have a stat serum pregnancy test performed during any visit at which a PET/MR 
scan or lumbar puncture is done, immediately prior to the PET/MR scan, before 
administration of the radiopharmaceutical. Subjects with a positive test will be excluded. 
 
7.2.3. 
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: 
 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, the subject should return 
any unused study drug and will be asked to return to the study site for a final safety visit.  
 
This study may be prematurely terminated if, in the opinion of the PI, there is sufficient 
reasonable cause.   
 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects. 
• Enrollment is unsatisfactory. 
• Insufficient adherence to protocol requirements. 
• Data are not sufficiently complete and/or evaluable.  
The study sponsors reserve the right to discontinue the study at any time for medical or 
administrative reasons.   
Subjects who wish to discontinue from study may be replaced.  


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7.2.4. 
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 
Section 11. 


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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 
8.3.1. 
Prohibited drugs prior to and during the study 
The following medications are prohibited prior to and during study participation: 
• Systemic corticosteroid treatment within 30 days prior to Baseline (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, 
teriflunomide [Aubagio®]) within 30 days of Baseline 
 
8.3.2. 
Prohibited drugs during the study 
The following medications are prohibited as newly prescribed drugs during study 
participation (i.e., after Screening visit): 
• cimetidine, cyclosporine, dronedarone, lopinavir, probenecid, quinidine (with the 
exception of Nuedexta, which will be allowed with more frequent ECG 
monitoring), ranolazine, rifampin, ritonavir, or tipranavir. 
 
Additionally, subjects should washout from benzodiazepines and non-steroidal anti-
inflammatory medications one week prior to PET scan as these compounds would affect 
the results of the scan. 
 


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8.3.3. 
Prohibited drug for “flexible arm” subjects 
The following medications are prohibited prior to and during study participation for the 
flexible arm subjects:  
• cimetidine, cyclosporine, dronedarone, lopinavir, probenecid, quinidine (with the 
exception of Nuedexta, which will be allowed with more frequent ECG 
monitoring), ranolazine, rifampin, ritonavir, tipranavir, retigabine, and mexiletine.  
 
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 
Subjects will not be randomized in this study. All subjects will receive MN-166 (ibudilast). 
 
8.6. 
Dosing Guidelines 
8.6.1. 
Treatment Phase 
Capsules containing MN-166 (10 mg) will be used. At the Baseline Visit (Day 1), subjects 
will be instructed to take 3 capsules of study medication in the evening.  Although the 
study drug can be taken in a fasted or fed state, subjects will be instructed to take study 
medication with food or within an hour of eating to improve gastrointestinal tolerability. 
Starting from Day 2, subjects will be instructed to take 3 capsules of study medication 
twice daily during the first 14 days and 5 capsules twice a day thereafter (or as directed by 
Investigator) once in the morning (e.g., between approximately 6-9 AM) and once in the 
evening (e.g., approximately 12 h later, which would be approximately 6-9 PM), by mouth. 
The investigator may also choose to administer the total daily dose of study medication on 
a three-times a day regimen to help reduce side effects.  
If a subject forgets to take their AM or PM study drug dose at the assigned time (between 
6-9 AM and PM), subjects will be allowed to take their medication up to 12 PM or 12 AM, 
respectively.  Beyond this time, subjects will be instructed to skip the dose and take the 
next dose at their regularly scheduled time.  


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8.6.2. 
Dose Adjustments 
Any dosage adjustment, including the reason for and dates of adjustment, will be 
documented in the CRF for each subject requiring this manipulation. The PIs or licensed 
physician Sub-Investigator may reduce the dosage of study drug or discontinue the study 
drug in its entirety for AEs thought to be related to the study drug or for other reason 
during the trial (the reason for, and dates of suspension or dose reduction must be 
documented).  If the AE is mild or moderate, the dosage may be reduced until the event 
improves.  The PIs may then choose to resume the higher dosage or maintain the subject at 
a reduced dosage. If the event is serious or life threatening, and deemed to be definitely 
drug related, the study drug will be discontinued immediately.  Study subjects must remain 
off the study drug permanently. Subjects may not resume study drug.  All AEs will be 
followed to resolution. 
8.6.3. 
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 study treatment is to be 
considered on a case by case basis and must be discussed with the Independent Safety 
Monitor.  
8.6.4. 
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. 
Informed Consent 
Only patients capable of providing informed consent will be enrolled. Each subject is 
required to provide written informed consent prior to undergoing any study procedures. 
However, some patients may be incapable of physically signing the Consent Form due to 
their disease. If the person retains the ability to understand the concepts of the study and to 
evaluate the risk and benefit of being in the study when it is explained verbally and the 
individual is able to indicate approval or disapproval to study enrollment, they may be 
enrolled. The consent form will document the method used to communicate with the 
prospective subject and the specific means by which the prospective subject communicated 
agreement to participate in the study. An impartial third party will witness the entire 
consent process and sign the consent document. 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 will have a window of ±3 days.   
Clinical and laboratory evaluations will be performed by qualified study staff at 
Massachusetts general Hospital and South Shore Neurologic Associates Long Island. 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 (up to 6 weeks) 
The following procedures will be performed to determine the subject’s eligibility for the 
study: 
 
• Obtain written informed consent from subject 
• Assess inclusion and exclusion criteria 
• Assess El Escorial ALS Diagnostic criteria  
• Obtain medical history and demographics 
• Obtain ALS diagnosis history 
• Perform physical and neurological examination 
• Perform U. Penn upper motor Neuron Burden (UMNB)  
• Measure vital signs including height and weight 


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• Perform Pulmonary Function Tests 
• Collect blood for labs including TSPO affinity test 
• Perform ECG 
• Review and document concomitant medications and therapies 
• MRI Safety Questionnaire 
 
8.8.1.2. 
Screen Failures 
 
Any subject who signs consent will be considered enrolled in the study.  If a subject fails 
screening, at a minimum, the following information should be captured and entered in the 
Electronic Data Capture (EDC) System: 
• Demographics 
• Inclusion and Exclusion criteria 
• Reason for screen failure 
• Screening labs results 
 
8.8.1.3. 
Baseline Visit (Day 1) 
 
This visit will take place within 6 weeks of the Screening Visit.  The following procedures 
will be performed: 
 
• Review inclusion and exclusion criteria  
• Measure vital signs  
• Collect blood for safety labs  
• Perform ECG 
• Collect blood samples for biobanking  
• Administer ALSFRS-R questionnaire Perform Pulmonary Function Tests  
• Measure baseline strength (HHD) 
• Columbia Suicide Severity Rating Scale (C-SSRS) – Baseline 
• Dispense study medication for the following 4 weeks 
• Review and document concomitant medications and therapies 
• Assess and document AEs 
• Create GUID 
 
Pre- treatment neuroimaging study (MRI/PET) will take place after TSPO affinity test 
results are available. This may occur on any day between release of TSPO test results and 
Baseline, or on the same day as the Baseline Visit. This first neuroimaging study will be 
performed before any treatment is administered. ALSFRS-R, U Penn Motor Neuron 
Burden (UMN-B) and SVC will be repeated on the same day as the scan for subjects 
screened and enrolled at South Shore Neurologic Associates (SSNA). For subjects screened 
and enrolled at Massachusetts General Hospital (MGH), the ALSFRS-R, SVC and UMNB 
do not need to be repeated on the same day as the pre-treatment MRI/PET scan, if the pre-


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scan visit differs from the baseline visit. These outcomes can be collected within + 14 days 
of the scan for MGH subjects. 
 
8.8.1.4. 
Study Visits (Week 4, Week 12, Week 24, and Week 36) 
 
The following procedures will be performed at these visits: 
 
• Perform neurological examination 
• Measure vital signs  
• Perform ECG 
• Collect blood for safety labs  
• Collect blood samples for biobanking 
• Administer ALSFRS-R questionnaire  
• Perform U. Penn upper motor Neuron Burden (UMN-B) 
• Perform Pulmonary Function Tests  
• Measure baseline strength (HHD) 
• Columbia Suicide Severity Rating Scale (C-SSRS) – Baseline 
• Dispense study medication 
• Review and document concomitant medications and therapies 
• Assess and document AEs 
• Check study drug compliance  
 
Post-treatment neuroimaging study (MRI/PET) will be performed one time only 
between the Week 12 and Week 24 visits. It can be done on the same day of the Week 24 
visit. ALSFRS-R, SVC and UMN-B will be repeated on the same day as the scan for 
subjects screened and enrolled at South Shore Neurologic Associates (SSNA). For subjects 
screened and enrolled at Massachusetts General Hospital, the ALSFRS-R, SVC and 
UMNB do not need to be repeated on the same day as the post-treatment MRI/PET scan, if 
the post-scan visit differs from either the week 12 and week 24 visit. These outcomes can 
be collected within + 14 days of the scan for MGH subjects. 
 
 
8.8.1.5. 
Study Phone Calls (Week 1, Week 2, Week 8, Week 16, Week 20, Week 28, 
Week 32, and Week 40) 
 
The following assessments will be performed at the study phone calls: 
 
• Check study drug compliance  
• Review and document concomitant medications and therapies 
• Assess and document AEs 
 


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8.8.1.6. 
Final Safety Visit 
Subjects who withdraw consent will be asked to come in for a Final Safety Visit and will 
be asked to have a final Follow-Up Telephone Call (+7 days, but no earlier than 28 days, 
after subject’s last dose of study drug). 
 
The following will be performed at the Final Safety Visit: 
 
• Vital signs  
• ECG 
• Neurological exam 
• Blood samples for safety labs  
• ALSFRS-R questionnaire  
• U. Penn upper motor Neuron Burden (UMNB) 
• Pulmonary Function Tests  
• HHD 
• Columbia Suicide Severity Rating Scale (C-SSRS) – Since last visit 
• Review and document concomitant medications and therapies 
• Assess and document AEs 
• Check study drug compliance  
• Perform study drug accountability and collect all unused study drug and empty 
containers 
 
The following procedures will be performed via telephone 28 (+7) days after the Final 
Safety Visit: 
• Administer ALSFRS-R questionnaire 
• Review and document concomitant medications and therapies 
• Document AEs 
8.8.1.7. 
Follow-up 
After the Week 40 Follow-up Telephone Interview, subjects may be contacted every three 
months for up to two years, or until consent is withdrawn, in order to obtain vital status and 
clinical information including the ALSFRS-R.  Additionally, two years of post-study 
access to subjects’ medical records will be requested to allow for review in combination 
with study data in order to investigate any correlation between imaging data collected 
during this study and subjects’ clinical outcomes.   
 
8.8.2. 
Procedures/Assessment Details 
8.8.2.1. 
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 


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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. 
8.8.2.2. 
Medical History  
A medical history obtained by the PI or qualified designee as listed on the Form FDA 
1572.   
8.8.2.3. 
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).   
8.8.2.4. 
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. 
8.8.2.5. 
Vital Signs, Height, and Weight  
 
Vital signs, including systolic and diastolic blood pressure, pulse rate (radial 
artery)/minute, respiratory rate/minute, temperature and weight will be assessed at 
specified visits and will be recorded in the CRFs.  Height will be measured and recorded at 
the Screening Visit only.   
Clinically significant changes, as defined by the PI, from the signing of the ICF should be 
captured as AEs in the CRF. 
 
8.8.2.6. 
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).  


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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. 
8.8.2.7. 
Neuroimaging 
Subjects will undergo Magnetic Resonance Imaging (MRI) / PBR28 Positron Emission 
Tomography (PET) twice during the course of the study. The goal of these scans is to 
measure activated microglia in study participants before treatment and after several weeks 
of treatment. The first scan will occur between the Screening and the Baseline visits (off 
treatment), after subject eligibility has been confirmed by TSPO affinity binding assay. The 
second scan will occur between the Week 12 and Week 24 visits (on treatment). 
Neuroimaging will be performed at the MGH Martinos Center for Biomedical Imaging.  
Subjects will be asked to lie still in a supine position for the duration of the study, which 
will take approximately 90 min.  
 
Each PET scan will include one administration of [11C]-PBR28 (up to 15mCi, which is 
equivalent to ~3.7 mSv), injected intravenously with a slow bolus over a 30s period. The 
catheter will be flashed post-injection of with 0.9% saline solution. Dynamic data will be 
collected over approximately 90 minutes in list mode, and framed post-collection.  
 
8.8.2.8. 
Pulmonary Function Test 
Pulmonary Function Testing includes Slow Vital Capacity (SVC).  
Slow Vital Capacity (SVC): The vital capacity (VC) (percent of predicted normal) will be 
determined, using the upright slow VC method. The SVC can be measured using 
conventional spirometers that have had a calibration check prior to subject testing.  A 
printout from the spirometer of all VC trials will be retained.  Three SVC trials are required 
for each testing session, however up to 5 trials may be performed if the variability between 
the highest and second highest SVC is 10% or greater for the first 3 trials. Only the 3 best 
trials are recorded on the CRF.  
 
8.8.2.9. 
The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised  
ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0 to 4) used 
to determine subjects' assessment of their capability and independence in 12 functional 
activities.  All 12 activities are relevant in ALS. Initial validity was established by 
documenting that in ALS patients, change in ALSFRS-R scores correlated with change in 
strength over time, was closely associated with quality of life measures, and predicted 
survival. The test-retest reliability is greater than 0.88 for all test items. The advantages of 
the ALSFRS-R are that the categories are relevant to ALS, it is a sensitive and reliable tool 
for assessing activities of daily living function in those with ALS, and it is quickly 
administered.  With appropriate training, the ALSFRS-R can be administered with high 


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inter-rater reliability and test-retest reliability.  The ALSFRS-R can be administered by 
phone with good inter-rater and test-retest reliability.  The equivalency of phone versus in-
person testing, and the equivalency of study subject versus caregiver responses have also 
recently been established.  Therefore, if necessary, the ALSFRS-R may be given to the 
study subject over the phone.  All ALSFRS-R evaluators must be NEALS certified. 
 
8.8.2.10. Upper Motor Neuron-Burden (UMN-B) 
 
The Penn Upper Motor Neuron-Burden (UMN-B) is the total number of pathological UMN 
signs on examination including pathologically brisk biceps, supinator, triceps, finger, knee 
and ankle reflexes, and extensor plantar responses assessed bilaterally and brisk facial and 
jaw jerks (9).  The scale is a combination of Ashworth, Reflexes, and Pseudobulbar Affect 
scale (Range score: 0 to 32).  
The UMN also includes scoring of the Center for Neurologic Study-Lability Scale (CNS-
LS), a 7-item self-report scale that assesses pseudobulbar affect (PBA) by measuring the 
perceived frequency of PBA episodes (laughing or crying) and the Ashworth Spasticity 
Scale, a standard measure for spasticity that has been used in numerous ALS clinical trials 
to assess spasticity due to upper motor neuron dysfunction in ALS.  Data is generated from 
the clinical exam and scored from 1 to 5, the lowest score indicating normal tone and the 
highest extreme spasticity. 
8.8.2.11. Blood Biomarkers 
Subjects will also be asked to provide blood samples for biomarker analysis per Schedule 
of Assessments. These blood samples will be stored in a sample repository.  These samples 
will be used for biomarker research.  All samples will be labeled with a code.  The code 
will not include any identifiable information.  Any analysis performed on these samples is 
for research purposes only.  Using a bar coding and scanner system, each sample aliquot 
will be catalogued for future reference.  In the electronic data capture system, sample 
number and location will be cross-referenced to the clinical information. All samples will 
be linked to GUID and may be stored using the Global Unique Identifier (GUID) to 
identify the sample. 
Unused samples will remain in the biorepository for future research. There is no scheduled 
date on which the samples will be destroyed.  Samples may be stored for research until 
they are used, damaged, decayed or otherwise unfit for analysis. Subjects have the option 
of declining participation in this portion of the study at any time by withdrawing their 
consent to have their sample used.  However, it will not be possible to destroy samples that 
may have already been used.   
8.8.2.12. Strength Measurement (HHD) 
Changes in strength will be measured using HHD (hand-held dynamometry), a non-
invasive device that allows measurements of isometric strength in muscle groups of the 
arms and legs. It has been directly validated against maximum voluntary isometric 
contraction (MVIC) in ALS patients, and shown to change at a similar rate with variability 


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that is only slightly greater than MVIC. The MVIC has proven useful as an outcome 
measure in natural history studies and clinical trials in ALS and is a valid and reliable 
measure of disease progression. For both upper and lower extremity muscles, correlations 
between MVIC and HHD measurements ranged between 0.84 and 0.92, with test–retest 
variability that was extremely similar as well. The only time at which correlation between 
HHD and MVIC broke down was at extremely high strength levels, an area not likely to be 
a problem in an ALS clinical trial. HHD equipment is inexpensive and it takes less than 5 
min to complete a test of both upper and lower extremities. 
8.8.2.13. 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). 
8.8.2.14. 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 
immediately.  
 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
The investigational product is MN-166 (ibudilast) Study drug information is provided in 
Table 5. 
Table 5: 
Study Drug Information 
Investigational Drug: 
MN-166 
Formulation: 
10 mg capsules  
Frequency: 
50 mg bid (total daily dose of 100 mg). Study drug dosing may be 
varied based on individual tolerability. 
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). 
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 


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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 
• Neuroimaging biomarkers ([11C]-PBR28-PET) including both regions of interest 
(ROI) and voxel-based analyses. 
• Blood biomarkers: including analysis of pro-inflammatory cytokines. 
 
10.2. 
Secondary Endpoints 
 
Safety 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.  
Clinical Efficacy Endpoints 
Clinical outcomes will be measured by ALSFRS-R, SVC, and strength (measured by 
HHD).  
 


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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: ALSFRS-R. 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 6. 
Table 6: 
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 7 should be selected based on medical judgment, 
considering the definitions below and all contributing factors. 
Table 7: 
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 (eg, concomitant disease, environmental factors, or other medications 
or chemicals). 
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 


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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. 
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. 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. 
Throughout the study, safety will be monitored closely for unexpected or significant 
adverse effects by the Principal Investigator. Any unanticipated problems involving risks to 
subjects or others including adverse events will be reported to the PHRC in accordance 
with PHRC unanticipated problems reporting guidelines. The Principal Investigator will 
confirm that study staff is appropriately trained in study procedures. The Principal 
Investigator will delegate tasks based on appropriate staff qualifications. The Principal 
Investigator will carefully monitor each subject throughout the study for possible AEs. 
AEs, SAEs and all safety-related events will be reported in accordance with IRB 
guidelines.  
 


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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 
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” to the Sponsor if considered at least possibly 
related to study medication (MN-166). 


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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 safetyreports@medicinova.com. As a minimum requirement, the initial 
notification should provide the following information: 
• 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. 


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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 
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. 


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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 details on the statistical methods planned 
for this study. 
12.1. 
Sample Size Justification 
 
Sample size calculation was based on the primary outcome of the biomarker. The primary 
outcome is the changes in the ROI in the motor cortex as assessed by [11C]-PBR29-PET. 
Our previous studies comparing mean PBR28 binding in the motor cortices in limb-onset 
ALS subjects (1.18 units) with matching healthy volunteers (1.064 units) revealed 0.116 
mean difference between the two groups, with 0.08 standard deviation in the ALS group. 
With 10 people tolerated the drug among 15 participants in this study, the probability is 90 
percent that the study will detect a treatment difference at a one-sided 0.1 significance level 
if the true difference is 0.096 units. The proposed increase in sample size will increase the 
statistical power to detect changes in PBR28 uptake after MN-166 treatment. This will also 
provide more safety and tolerability data on MN-166 for up to 50 mg BID in people with 
ALS. 
 
 
12.2. 
Safety Analysis 
 
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. Incidence of out-of-
normal-range values and markedly abnormal change from baseline in laboratory safety test 
variables will be tabulated.  
 
Changes in vital signs from baseline will be summarized. 
 
 
12.3. 
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. 


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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. 
12.4. 
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.  
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.  
12.5. 
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 


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employed in CRF generation, where clinically appropriate. The PI has to inform the 
Sponsor if he/she is approached for a regulatory audit.  
12.6. 
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.  
12.7. 
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.  
All data collected as part of this study will be entered into an EDC maintained by the 
Massachusetts General Hospital (MGH) Neurological Clinical Research Institute (NCRI).  
This platform facilitates: 
1. Capture of clinical and research data from neurologic patients for individual 
projects in a structured and secure system; 
2. Aggregating and sharing uniform, deidentified and/or anonymized datasets for 
secondary analyses. 
15.3. 
Role of Data Management 
Data Management (DM) is responsible for the development, execution and supervision of 
plans, policies, programs, and practices that control, protect, deliver, and enhance the value 
of data and information assets. 
 
All data will be managed in compliance with applicable Sponsor and regulatory 
requirements. Site personnel will collect, transcribe, correct, and transmit the data onto 
source documents, Case Report Forms (CRFs), and/or other forms used to report, track and 
record clinical research data.  DM is responsible for developing, testing, and managing 
clinical data management activities. 
15.4. 
Data Entry and Checks 
The site personnel are instructed to enter information into the EDC. Data capture is the 
responsibility of the staff at the site under the supervision of the PIs.  During the study, the 
PIs must maintain complete and accurate documentation for the study. The EDC provide 
password protection.  An edit checking and data clarification process will be put in place to 


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ensure accuracy of the data.  Logic and range checks as well as more sophisticated rules 
may be built into the eCRFs to provide immediate error checking of the data entered.  The 
system has the capability to automatically create electronic queries for forms that contain 
data that are out of range, out of window, missing or not calculated correctly.   
15.5. 
Data Lock Process 
The platform will have the ability to lock the project-specific visits to prevent any 
modification of data once the project is closed.  Once this option is activated, every user 
will have Read-Only access to the data. 
15.6. 
Data handling and record keeping 
 
The PIs are responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported.  Data reported in the eCRF derived from source documents should be 
consistent with the source documents and discrepancies should be explained. 
 
15.7. 
Publications 
 
The PIs will be responsible for publications of results from this trial. Responsibilities will 
include the following: 
• Analyze and interpret data gathered in this study, and write publications from these 
data. 
• Submit manuscripts to selected journals and address peer reviewers’ comments. 
• Submit abstracts to selected meetings and present data at the meetings. 
• Determine authorship on the basis of the Uniform Requirements for Manuscripts. 
 


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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 
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3. Chio A, Logroscino G, Hardiman O, et al. Prognostic factors in ALS: A critical 
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4. Turner MR, Hardiman O, Benatar M, et al. Controversies and priorities in 
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5. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis 
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6. Henkel JS, Beers DR, Siklos L, Appel SH. The chemokine MCP-1 and the dendritic 
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7. Boillee S, Yamanaka K, Lobsiger CS, et al. Onset and progression in inherited ALS 
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8. Butovsky O, Siddiqui S, Gabriely G, et al. Modulating inflammatory monocytes 
with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 
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9. Koval ED, Shaner C, Zhang P, et al. Method for widespread microRNA-155 
inhibition prolongs survival in ALS-model mice. Hum Mol Genet 2013;22:4127-
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15. Zurcher NR, Loggia ML, Lawson R, et al. Increased in vivo glial activation in 
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29. Yoshioka A, Shimizu Y, Hirose G, et al. Cyclic AMP-elevating agents prevent 
oligodendroglial excitotoxicity. J Neurochem 1998;70:2416-2423. 
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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 
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. 
 
 
 


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Appendix 2: El Escorial World Federation of Neurology Criteria for the Diagnosis of ALS 
 
Information obtained from the web site: www.wfnals.org. 
 
The diagnosis of Amyotrophic Lateral Sclerosis [ALS] requires:  
A - The presence of: 
 
(A:1) evidence of lower motor neuron (LMN) degeneration by clinical, 
 
electrophysiological or neuropathologic examination,  
 
(A:2) evidence of upper motor neuron (UMN) degeneration by clinical examination, 
 
and  
 
(A:3) progressive spread of symptoms or signs within a region or to other regions, as 
 
determined by history or examination, together with 
B - The absence of: 
 
(B:1) electrophysiological and pathological evidence of other disease processes that 
 
might explain the signs of LMN and/or UMN degeneration, and  
 
(B:2) neuroimaging evidence of other disease processes that might explain the observed 
 
clinical and electrophysiological signs.  
 
CLINICAL STUDIES IN THE DIAGNOSIS OF ALS 
A careful history, physical and neurological examination must search for clinical evidence 
of UMN and LMN signs in four regions [brainstem, cervical, thoracic, or lumbosacral 
spinal cord] (see Table 1) of the central nervous system [CNS]. Ancillary tests should be 
reasonably applied, as clinically indicated, to exclude other disease processes. These should 
include electrodiagnostic, neurophysiological, neuroimaging and clinical laboratory 
studies.  Clinical evidence of LMN and UMN degeneration is required for the diagnosis of 
ALS.  The clinical diagnosis of ALS, without pathological confirmation, may be 
categorized into various levels of certainty by clinical assessment alone depending on the 
presence of UMN and LMN signs together in the same topographical anatomic region in 
either the brainstem [bulbar cranial motor neurons], cervical, thoracic, or lumbosacral 
spinal cord [anterior horn motor neurons]. The terms Clinical Definite ALS and Clinically 
Probable ALS are used to describe these categories of clinical diagnostic certainty on 
clinical criteria alone: 
 
A. Clinically Definite ALS is defined on clinical evidence alone by the presence of UMN, 
as well as LMN signs, in three regions.  
 
B. Clinically Probable ALS is defined on clinical evidence alone by UMN and LMN signs 
in at least two regions with some UMN signs necessarily rostral to (above) the LMN signs. 
 
C. Clinically Probable ALS - Laboratory-supported is defined when clinical signs of UMN 
and LMN dysfunction are in only one region, or when UMN signs alone are present in one 
region, and LMN signs defined by EMG criteria are present in at least two limbs, with 
proper application of neuroimaging and clinical laboratory protocols to exclude other 
causes. 
 


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D. Clinically Possible ALS is defined when clinical signs of UMN and LMN dysfunction 
are found together in only one region or UMN signs are found alone in two or more 
regions; or LMN signs are found rostral to UMN signs and the diagnosis of Clinically 
Probable - Laboratory-supported ALS cannot be proven by evidence on clinical grounds in 
conjunction with electrodiagnostic, neurophysiologic, neuroimaging or clinical laboratory 
studies. Other diagnoses must have been excluded to accept a diagnosis of Clinically 
Possible ALS. 
 
Table 1 
 
Brainstem  
Cervical  
Thoracic  
Lumbosacral  
Lower motor 
neuron signs 
weakness, 
atrophy, 
fasciculations  
jaw, face, 
palate, 
tongue, larynx 
neck, arm, 
hand, 
diaphragm  
back, 
abdomen  
back, abdomen, 
leg, foot  
Upper motor 
neuron signs 
pathologic spread 
of reflexes, 
clonus, etc.  
clonic jaw 
gag reflex 
exaggerated 
snout reflex 
pseudobulbar 
features 
forced 
yawning 
pathologic 
DTRs 
spastic tone  
clonic DTRs  
Hoffman reflex
pathologic 
DTRs 
spastic tone 
 
preserved 
reflex in weak 
wasted limb  
loss of 
superficial 
abdominal 
reflexes 
pathologic 
DTRs 
spastic tone  
clonic DTRs - 
extensor plantar 
response 
pathologic DTRs 
spastic tone 
 
preserved reflex in 
weak wasted limb 
 
 
 
 
 
 


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Appendix 3: ALS Functional Rating Scale-Revised (ALSFRS-R) 
 
 
 
QUESTIONS: 
 
 
 
 
 
 
 
                                    SCORE:     
1. Speech 
4 = Normal speech processes 
3 = Detectable speech disturbances 
2 = Intelligible with repeating 
1 = Speech combined with nonvocal communication 
0 = Loss of useful speech 
 
2. Salivation 
4 = Normal 
3 = Slight but definite excess of saliva in mouth; may have nighttime drooling 
2 = Moderately excessive saliva; may have minimal drooling 
1 = Marked excess of saliva with some drooling 
0 = Marked drooling; requires constant tissue or handkerchief 
 
3. Swallowing 
4 = Normal eating habits 
3 = Early eating problems – occasional choking 
2 = Dietary consistency changes 
1 = Needs supplemental tube feeding 
0 = NPO (exclusively parenteral or enteral feeding) 
 
4. Handwriting 
4 = Normal 
3 = Slow or sloppy; all words are legible 
2 = Not all words are legible 
1 = No words are legible but can still grip a pen  
0 = Unable to grip pen 
 
5a. Cutting Food and Handling Utensils (patients without gastrostomy) 
 
 
4 = Normal 
3 = Somewhat slow and clumsy, but no help needed 
2 = Can cut most foods, although clumsy and slow; some help needed 
1 = Food must be cut by someone, but can still feed slowly 
0 = Needs to be fed 
 
5b. Cutting Food and Handling Utensils (alternate scale for patients with gastrostomy) 
4 = Normal 
3 = Clumsy, but able to perform all manipulations independently 
2 = Some help needed with closures and fasteners 


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1 = Provides minimal assistance to caregivers 
0 = Unable to perform any aspect of task 
 
6. Dressing and Hygiene 
4 = Normal function 
3 = Independent, can complete self-care with effort or decreased efficiency 
2 = Intermittent assistance or substitute methods 
1 = Needs attendant for self-care 
0 = Total dependence 
 
7. Turning in Bed and Adjusting Bed Clothes 
4 = Normal function 
3 = Somewhat slow and clumsy, but no help needed 
2 = Can turn alone, or adjust sheets, but with great difficulty 
1 = Can initiate, but not turn or adjust sheets alone 
0 = Helpless 
 
8. Walking 
4 = Normal 
3 = Early ambulation difficulties 
2 = Walks with assistance 
1 = Nonambulatory functional movement only 
0 = No purposeful leg movement 
 
9. Climbing Stairs 
4 = Normal 
3 = Slow 
2 = Mild unsteadiness or fatigue 
1 = Needs assistance 
0 = Cannot do 
 


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R-1. Dyspnea  
 
 
 
4 = None 
3 = Occurs when walking 
2 = Occurs with one or more of the following: eating, bathing, dressing 
1 = Occurs at rest, difficulty breathing when either sitting or lying 
0 = Significant difficulty, considering using mechanical respiratory support 
 
R-2 Orthopnea 
 
 
 
4 = None 
3 = Some difficulty sleeping at night due to shortness of breath, does not routinely use 
more than two pillows 
2 = Needs extra pillow in order to sleep (more than two) 
1 = Can only sleep sitting up 
0 = Unable to sleep without mechanical assistance 
 
R-3 Respiratory Insufficiency 
 
4 = None 
3 = Intermittent use of BiPAP 
2 = Continuous use of BiPAP during the night 
1 = Continuous use of BiPAP during the night and day 
0 = Invasive mechanical ventilation by intubation or tracheostomy 
  
Evaluator’s Initials: _____ _____ ______ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4: Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Baseline (Version 1/14/09) 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors 
for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 
Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu  
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 
 
 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Lifetime:  
Time He/She 
Felt Most 
Suicidal 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
 
 
Yes       No 
□    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 
Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with 
time, place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about 
taking an overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
 
Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?                                                          
If yes, describe: 
 
 
Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least 
severe and 5 being the most severe). Ask about time he/she was feeling the most suicidal.  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting 
on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 


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Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the 
way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get 
attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                        living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal 
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get sympathy, 
or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes    No 
□   □
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck 
but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did 
anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
            C-SSRS—Baseline (Version 1/14/09)    
 
 
  


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© 2008 Research Foundation for Mental Hygiene, Inc. 
 
                  C-SSRS—Baseline (Version 1/14/09)     
 
                                                
 
 
 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □
Answer for Actual Attempts Only 
Most Recent  
Attempt 
Date: 
Most Lethal         
Attempt 
Date: 
Initial/First  
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, 
had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 


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Since Last Visit (Version 1/14/09) 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, 
P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors 
for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 
Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu 
 
 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?                                                              
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 


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Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)   


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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, 
a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of 
a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling 
trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down 
from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of interrupted 
 
______ 
 
Aborted or Self-Interrupted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before 
you actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted or self-interrupted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
Yes      No 
□   □ 
 
Total # of preparatory acts 
 
______ 
Suicide: 
Death by suicide occurred since last assessment. 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of 
major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-
degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% 
of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 


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Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for 
very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming 
train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit - Clinical (Version 1/14/09)     
 
                        Page 2 of 2 


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Appendix 5: The Penn Upper Motor Neuron-Burden (UMN-B) 
 
 
Center for Neurologic Study – Lability Scale (CNS-LS) 
 
INSTRUCTIONS   
 
 
 
 
 
 
 
 
 
The purpose of this questionnaire is to help us better understand your neurologic problems.  Please 
read each statement, and using the scale below, determine the degree to which it has applied to you 
DURING THE PAST WEEK.  Circle the appropriate answer, or if you need help in marking your 
responses, tell the interviewer the number of the best response.   Please choose only one response 
for each item. 
 
 
Total: __________________ 
 
 
 
 
 
 
 
Please select the number that describes the degree to which each item has applied to you DURING 
THE PAST WEEK. 
 
Does not 
Apply 
1 
Rarely 
Applies 
2 
Occasionally   
Applies 
3 
Frequently 
Applies 
4 
Applies 
Most 
of the 
Time 
5 
1. There are times when I feel fine 1 
minute, and then I’ll become tearful the 
next over something small or for no 
reason at all. 
 
 
 
 
 
2. Others have told me that I seem to 
become amused very easily or that I 
seem to become amused about things 
that aren’t funny. 
 
 
 
 
 
3. I find myself crying very easily. 
 
 
 
 
 
4. I find that even when I try to control 
my laughter, I am often unable to do so. 
 
 
 
 
 
5. There are times when I won’t be 
thinking of anything happy or funny at 
all, but then I’ll suddenly be overcome 
by funny or happy thoughts.  
 
 
 
 
 
6. I find that even when I try to control 
my crying, I am often unable to do so. 
 
 
 
 
 
7. I find that I am easily overcome by 
laughter. 
 
 
 
 
 


MediciNova, Inc.  
                                                                      MN-166 (ibudilast) 
MN-166-ALS-1202 Protocol Amendment 4                                                          December 12, 2017 
 
Confidential 
Page 87 of 87 
 
Appendix 6: Modified Ashworth Spasticity Scale 
 
ASHWORTH SPASTICITY SCALE 
 
 
Key: 
1. No increase in muscle tone 
2. Slight increase in tone giving a “catch” when affected part is moved in 
flexion or extension 
3. More marked increase in tone but affected part is easily flexed. 
4. Considerable increase in tone; passive movement difficult. 
5. Affected part is rigid in flexion or extension 
 
 
 
 
  
Limb 
Score 
Right Arm 
 
Left Arm 
 
Right Leg 
 
Left Leg 
 


Babu (PI) lbudilast Trial: Statistical Analysis Plan 
Version 1.0, 21 Jun 2019 
STATISTICAL ANALYSIS PLAN (SAP) 
Title 
A multi-Center, open-label biomarker study to evaluate MN-
166 (Ibudilast) in Subjects with Amyotrophic Lateral Sclerosis 
(ALS) 
Regulatory Sponsor 
Current Protocol Version 
Current Protocol Date 
Statistical Analysis Plan 
Version 
Statistical Analysis Plan 
Date 
Suma Babu, MD 
4.0 
12 December 2017 
1.0 
21 Jun 2019 
SAP APPROVAL SIGNATURES 
Suma Babu, MD 
Principal Investigator and Sponsor 
7 
James Chan, MA 
MGH Biostatistician 
Study Biostatistician 
Date 
Date 
Page 1 of 11 


Babu (PI) Ibudilast Trial: Statistical Analysis Plan 
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SAP REVISION HISTORY 
Version 
Date 
Description of Changes 
1.0 
21Jun2019 
Initial version 
 


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Page 3 of 11 
 
Table of Contents 
 
1. 
Introduction ........................................................................................................................... 4 
2. 
Study Design .......................................................................................................................... 4 
2.1 
Overview ......................................................................................................................... 4 
2.2 
Study Objectives ............................................................................................................. 4 
2.3 
Study Populations ........................................................................................................... 4 
2.4 
Schedule of Assessments ................................................................................................ 5 
3. 
General Statistical Considerations ...................................................................................... 5 
3.1 
Statistical Software ......................................................................................................... 5 
3.2 
Summary Statistics.......................................................................................................... 5 
3.3 
Precision .......................................................................................................................... 5 
4. 
Analysis Samples ................................................................................................................... 6 
5. 
Study Endpoints .................................................................................................................... 6 
5.1 
PET Endpoint .................................................................................................................. 6 
5.2 
Biofluid Biomarker Endpoints ........................................................................................ 6 
5.3 
Safety Endpoints ............................................................................................................. 6 
5.4 
Tolerability Endpoints .................................................................................................... 7 
5.5 
Efficacy Endpoints .......................................................................................................... 7 
6. 
Measurement Definitions ..................................................................................................... 7 
6.1 
PET Measures ................................................................................................................. 7 
6.2 
Blood biomarkers ............................................................................................................ 7 
6.3 
Clinical Progression Measures ........................................................................................ 8 
6.3.1 ALSFRS-R ...................................................................................................................... 8 
6.3.2 SVC ................................................................................................................................. 8 
6.3.3 Handheld dynamometry .................................................................................................. 8 
6.4 
Safety and Tolerability Endpoints .................................................................................. 9 
6.4.1 Safety .............................................................................................................................. 9 
6.4.2 Tolerability ...................................................................................................................... 9 
7 
Power Calculations ............................................................................................................... 9 
8 
Participant Characterization ............................................................................................. 10 
9 
Statistical Analyses .............................................................................................................. 10 
9.1 PET Analysis ...................................................................................................................... 10 
9.2 Biofluid Biomarkers Analysis ............................................................................................ 10 
9.3 Clinical Outcomes ............................................................................................................... 11 
9.4 Safety Outcomes ................................................................................................................. 11 
9.5 Notes on Analyses .............................................................................................................. 11 
10 References ............................................................................................................................ 11 
 
 
 
 
 
 


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1. 
Introduction 
This statistical analysis plan (SAP) defines the outcome measure and analysis samples and 
specifies the planned analyses of data from the phase Ib/IIa open label trial of MN-166 (Ibudilast) 
in Amyotrophic Lateral Sclerosis (ALS). The SAP supplements the clinical protocol. Please refer 
to the clinical protocol for details on the rationale for the intervention, eligibility criteria, conduct 
of the trial, clinical assessments and the timing of their use in the trial, definitions and reporting of 
adverse events, data management conventions, and regulatory oversight and compliance 
procedures. In case of discrepancies between the SAP and the clinical protocol concerning matters 
of data analysis, the SAP is authoritative. On all other matters, the clinical protocol is authoritative. 
 
2. 
Study Design 
2.1 
Overview 
This is a multi-center, open label Ib/IIa phase study to evaluate Ibudilast in subjects with ALS. 
Participants go through 6 weeks of screening and 36 weeks of treatment followed by 4 weeks of 
off-treatment follow-up.  
2.2 
Study Objectives 
The primary objectives of the study are to measure Ibudilast uptake in motor cortices and brain 
stem as measured by positron emission tomography (PET) imaging at 12-24 weeks and impact of 
Ibudilast on biofluid biomarkers of neuro-inflammation over 36 weeks.  
The secondary objectives of the study are to evaluate safety and tolerability and the effect of 
Ibudilast on ALS clinical outcomes such as the revised ALS function rating scale (ALSFRS-R), 
slow vital capacity (SVC), and strength measured by hand held dynamometry (HHD) over 36 
weeks 
2.3 
Study Populations 
Individuals eligible for trial participation are men or women aged 18 or above who are diagnosed 
as having possible, probable, probable-laboratory supported, or definite ALS, either sporadic or 


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familial according to the El Escorial Criteria and have a vital capacity of more than 50% of 
predicted normal. Detailed inclusion and exclusion criteria are specified in the clinical protocol.  
Participants will be enrolled at MGH and the South Shore Neurologic Associates Long Island Site. 
Up to five participants are expected to be enrolled in the study by flexible inclusion and exclusion 
criteria and not have PET imaging done. This is referred to as the flexible arm.   
2.4 
Schedule of Assessments 
Off-treatment PET imaging will be performed at baseline and on-treatment PET imaging will be 
performed once between weeks 12 and 24. Blood samples for biomarkers will be collected at 
baseline and weeks 4, 12, 24, and 36. ALSFRS-R, SVC, and HHD will be collected at baseline 
and weeks 4, 12, 24, and 36 (SVC will have an additional collection at screening to assess inclusion 
criteria). Full schedule of assessments is specified in the clinical protocol. 
3. 
General Statistical Considerations 
3.1 
Statistical Software 
Statistical analyses will be performed using SAS (SAS Institute, NC, USA) or R (R Foundation 
for Statistical Computing, Vienna, Austria). PET analyses will be done using Freesurfer v6.0 
(https://surfer.nmr.mgh.harvard.edu) and FSL Stats. 
3.2 
Summary Statistics 
Data will be summarized with respect to disposition, demographics, pre-treatment characteristics, 
safety outcomes, tolerability, and efficacy outcomes. Summary statistics for continuous variables 
will include the number of subjects, the mean, median, standard deviation, and range. For 
categorical data, summaries will include counts and percentages. 
Biomarkers and clinical outcomes will be summarized longitudinally from baseline to week 36 
with means and standard deviations at each timepoint.  
3.3 
Precision 
Results will be reported to 3 significant figures. Percentages will be reported to 0.1 percentage 
points. P-values will be reported to two digits when greater than or equal to 0.095, to three digits 
when greater than or equal to 0.00095 and less than 0.095, and as <0.001 for all smaller values.  


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4. 
Analysis Samples 
The following analysis samples will be used for testing endpoints: 
• 
Per-protocol (PP) sample: Participants who are eligible, randomized, initiate at least the 
first Ibudilast dose and successfully titrated up to and maintained the full Ibudilast dose of 50mg 
BID. Flexible arm participants will not be included. This sample will be used to analyze PET, 
blood biomarker, safety and tolerability endpoints.  
• 
Modified Intent-to-treat (mITT) sample: Participants who are eligible, randomized, 
initiate at least the first Ibudilast dose, and complete both pre and post-treatment PET scans. 
Observations made after premature permanent discontinuation or permanent dose reduction of 
Ibudilast are included in this sample, should such participants remain on study. Flexible arm 
participants will not be included. This sample will be used to analyze PET, blood biomarker, 
safety and tolerability endpoints.  
• 
Intent-to-treat (ITT) sample: Participants who are eligible, randomized, and initiate at 
least the first Ibudilast dose. Observations made after premature permanent discontinuation of 
Ibudilast are included in this sample, should such participants remain on study. Flexible arm 
participants will not be included. This sample will be used to analyze blood biomarker, safety 
and tolerability endpoints.  
• 
Safety (ST) sample: Participants who are eligible, randomized, and initiate at least the 
first Ibudilast dose. Observations made after premature permanent discontinuation of Ibudilast 
are included in this sample, should such participants remain on study. Flexible arm participants 
will be included. This sample will be used to analyze safety and tolerability endpoints.  
5. 
Study Endpoints 
5.1 
PET Endpoint 
The ratio of standardized uptake value (SUVR) will be the only imaging endpoint.   
5.2 
Biofluid Biomarker Endpoints 
MIF (Macrophage migration inhibitory factor), TNF-alpha, Neurofilament light will be used as 
blood biomarkers for inflammation. All blood biomarkers will be presented as picograms/milliliter 
(pg/mL). 
5.3 
Safety Endpoints 
To describe safety, clinical and laboratory treatment emergent adverse events (TEAEs) will be 
summarized overall and stratified by severity, persistence over time and relationship to study drug. 
Kaplan Meier plots of survival will be presented.  


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5.4 
Tolerability Endpoints 
Tolerability will be summarized as the proportion of participants who are tolerant of study drug. 
Reported proportions will use as their denominator all participants in the ST sample.  
5.5 
Efficacy Endpoints 
• 
ALSFRS-R Total Score 
• 
SVC as a percent of predicted normal volume 
• 
HHD of the following standardized megascores: (a) upper limbs: proximal (bilateral 
shoulder and elbow flexion), distal (bilateral wrist extension and first dorsal interossei), (b) lower 
limbs: proximal (bilateral hip flexion and knee extension) and distal (bilateral ankle dorsiflexion) 
6. 
Measurement Definitions 
6.1 
PET Measures  
Glial activation will be estimated in eligible participants in the regular arm by combined magnetic 
resonance positron emission tomography (MR-PET) using the [11C]-PBR28 radioligand. Per 
protocol, individuals who are homozygous for the T/T allele of the Ala147Thr TSPO 
polymorphism (rs6971) are excluded from the regular arm, since this genotype is associated with 
low affinity binding for [11C]-PBR28. Glial activation will be quantified as a mean standardized 
uptake value (SUV) using PET images acquired from 60 to 90 minutes post-injection of 
approximately 430 MBq [11C]-PBR28. FreeSurfer v6.0 (https://surfer.nmr.mgh.harvard.edu) will 
be employed to circumscribe a region of interest (ROI) defined anatomically as bilateral grey and 
white matter of primary motor cortices. SUV of the ROI will be normalized to the SUV of the 
whole brain tissue and occipital lobes (pseudoreference region)(Albrecht DS et al, J Nucl Med, 
2018) and expressed as a SUV ratio (SUVR) separately to control for variability in the global 
[11C]-PBR28 PET signal. An independent neuroimaging rater, who is blinded to the clinical data 
will assess for quality control of the PBR28-PET images and SUVR values. 
6.2 
Blood biomarkers  
Blood biomarkers of inflammation and neurodegeneration, including TNF-alpha, MIF 
(Macrophage migration inhibitory factor) and Neurofilament light will be measured pre- and post- 
treatment. Prior studies have suggested that by inhibiting MIF, Ibudilast is a potent suppressor of 
both microglial recruitment and activation in a dose dependent fashion (Cho Y et al, 2010; Cox 
GM et al 2013). Further, in neuron and microglia co-cultures, Ibudilast significantly suppressed 
neuronal cell death induced by the activation of microglia and hence exerting a neuroprotective 
action (Mizuno T et al, 2004). Neuofilament light is a marker of neuronal cell death and axon loss, 


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shown to be a promising biomarker in ALS, which correlates with disease activity. Measuring NFl 
is an indirect measure of Ibudilast’s effect on neuroprotection in ALS and is hypothesized to be 
inversely correlated with disease progression markers such as ALSFRS-R and SVC, as well as 
markers of glial activation on imaging and blood biofluids. TNF-alpha is a marker of 
neuroinflammation, shown to be elevated in ALS in in vitro and in vivo models and Ibudilast has 
shown inhibitory action of production of TNF-alpha in a dose-dependent manner (Suzumura A et 
al, 1999). All these biomarkers will be measures in pg/ml. 
6.3 
Clinical Progression Measures 
6.3.1 
ALSFRS-R 
The ALSFRS-R (Cedarbaum et al. 1999) is a 12-item clinician-completed interview scale for 
assessing participants’ function in four domains: bulbar, fine motor, gross motor, and respiratory. 
Each item is scored from 0 to 4 with higher scores indicating greater function. The ALSFRS-R 
total score is the sum of all items (range 0 to 48).  
6.3.2 
SVC 
Slow vital capacity (SVC) is the maximum volume of air that can be slowly exhaled after slow, 
maximal inhalation. Trained technicians coach participants through 3 to 5 maneuvers using an 
EasyOne Plus spirometer (ndd Medical Technologies, Inc., Andover, MA). Assessments will be 
analyzed if at least two acceptable maneuvers are recorded. The maximum volume expired is 
converted to percent of predicted normal. Normal values are calculated based on sex, age, and 
height using equations published by Knudsen et al. (1983). Higher values indicate better 
pulmonary function.  
6.3.3 
Handheld dynamometry  
Handheld dynamometry (HHD) will be used by trained technicians to estimate isometric strength 
using a MicroFET2 HHD (Hoggan Scientific, Salt Lake City, UT). Nine upper and lower extremity 
muscles or muscle groups will be examined: shoulder flexion, elbow flexion,  wrist extension, first 
dorsal interosseous contraction, hip flexion, knee extension, and ankle dorsiflexion. Each muscle 
or muscle group will be measured twice or three times bilaterally. The average of the two highest 
measurements will be analyzed. To calculate megascores, the mean and standard deviation of each 
muscle or muscle group, without regard to laterality, will be calculated from the baseline 
assessment of all participants in the ITT sample. Maneuvers that cannot be completed by a 


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participant due to weakness will be scored as zero kg. Strength estimates of each bilateral muscle 
or muscle group will be converted to Z scores by subtracting the relevant mean and dividing by 
the relevant standard deviation. Z scores for will be averaged into the standardized megascores:(a) 
upper limbs: proximal (bilateral shoulder and elbow flexion), distal (bilateral wrist extension and 
first dorsal interossei), (b) lower limbs: proximal (bilateral hip flexion and knee extension) and 
distal (bilateral ankle dorsiflexion) 
 
6.4 
 Safety and Tolerability Endpoints 
6.4.1 
Safety 
TEAEs will be reported for AEs that are possibly or definitely related to study drug and occur in 
more than 5% of subjects or lead to early drug discontinuation. Discontinuations due to TEAEs, 
treatment emergent serious adverse events, all SAEs and study deaths, treatment emergent 
laboratory abnormalities judged to be clinically significant by assay, and mean change from 
baseline and percent change from baseline in weight, systolic blood pressure, and diastolic blood 
pressure will also be summarized to describe safety. Reported proportions will use as their 
denominator all participants in the ST sample and AEs will be classified by MedDRA system 
organ and preferred term. 
6.4.2 
Tolerability 
Participants will be judged tolerant of Ibudilast if they complete all 36-weeks of treatment and 
remain on study drug and free from any possibly or definitely drug related AEs leading to 
permanent study drug discontinuation to the week 36. 
7 
Power Calculations 
Sample size calculation was based on the primary outcome of the biomarker. The primary outcome 
is the changes in the ROI in the motor cortex as assessed by [11C]-PBR28-PET. The study PI’s 
previous studies comparing mean PBR28 binding in the motor cortices in limb-onset ALS subjects 
(1.18 units) with matching healthy volunteers (1.064 units) revealed 0.116 mean difference 
between the two groups, with 0.08 standard deviation in the ALS group. With 10 people tolerating 
the drug among 15 participants in this study, the probability is 90 percent that the study will detect 
a treatment difference at a one-sided 0.1 significance level if the true difference is 0.096 units. The 
proposed increase in sample size will increase the statistical power to detect changes in PBR28 


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uptake after Ibudilast treatment. This will also provide smore safety and tolerability data on 
Ibudilast for up to 50mg BID in people with ALS.  
8 
Participant Characterization 
Each analysis sample will be summarized overall for the following characteristics: age, sex, race, 
ethnicity, El Escorial diagnosis, years since ALS symptom onset, delay between symptom onset 
and ALS diagnosis, site of ALS symptom onset, use of Riluzole at baseline, and baseline levels of 
[PET score(s)], [biomarker(s)], ALSFRS-R, SVC, and HHD standardized megascores.  
9 
Statistical Analyses  
9.1 PET Analysis 
Primary analysis will be on changes from baseline for [11C]PBR-28 ROI SUVR at 12-24 weeks 
using the mITT sample. ROI SUVR in the pre- and post- treatment groups will be reported as 
Median (range) values. Change SUVR scores post-treatment will be tested using Wilcoxon signed 
rank test to assess if there was a significant change from baseline.  
Subjects scan quality will be assessed by an independent imaging expert rater, who is blinded to 
the clinical data. All poor-quality scans, defined by incomplete scans (less than 20 minutes of PET 
data collected or incomplete anatomical FOV affecting reliable PET attenuation correction) and 
excessive motion degradation, will be excluded from the study.   
9.2 Biofluid Biomarkers Analysis 
Primary analyses will be on changes from baseline for biofluid biomarkers (TNF-alpha, MIF, and 
NF-l) at week 36 using the ITT sample. Biofluid biomarker concentrations for pre- and post- 
treatment groups will be reported as median (range) values. Change scores post-treatment will be 
tested using a Wilcoxon signed rank test to assess if there was a significant change from baseline. 
Only subjects with complete baseline and week 36 biomarker data will be included. Secondary 
analysis will repeat the primary analysis using the PP sample. 
Exploratory analysis will look at the 36-week trajectory using mixed effects models with a fixed 
effect for time (weeks since baseline), and a random slope and intercept for each subject with an 
unstructured covariance will be used for this analysis using the ITT sample. Further exploratory 


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analyses will use baseline SUVR as a covariate to the mixed effects models of change over 36 
weeks to assess the predictive value of SUVR in biofluid biomarker trajectory. 
9.3 Clinical Outcomes 
Change in clinical outcomes measures (ALSFRS-R, SVC and HHD-megascores) will be assessed 
over the 36 weeks of the study using mixed effects models with a fixed effect for time (weeks 
since baseline), and a random slope and intercept for each subject with an unstructured covariance 
will be used for this analysis on the ITT sample.  
Exploratory analyses will use Pearson correlation coefficient to correlate the a) 12-24 week change 
in PBR28- SUVR in the primary motor cortices and b) 36-week change in biofluid biomarkers 
(TNF-alpha, MIF, and NF-l) with changes in clinical outcome measures over 36 weeks.  
9.4 Safety Outcomes 
Safety and tolerability endpoints will be reported for the Ibudilast ST sample and described as 
counts and proportions. 
9.5 Notes on Analyses 
Alpha of 0.05 will be split between PET and biomarker outcomes with 0.025 used for SUVR and 
0.025 split evenly between the 3 biomarkers. Non-primary analyses will not be corrected for 
multiple testing.  
10 
References  
1. Albrecht DS, Normandin MD, Shcherbinin S, et al. Pseudoreference regions for glial imaging with 
(11)C-PBR28: Investigation in 2 clinical cohorts. J Nucl Med 2018;59:107-114 
2. Cho Y, Crichlow GV, Vermeire JJ, et al. Allosteric inhibition of macrophage migration 
inhibitory factor revealed by ibudilast. Proc Natl Acad Sci U S A 2010;107:11313-11318. 
3. Cox GM, Kithcart AP, Pitt D, et al. Macrophage migration inhibitory factor potentiates 
autoimmune-mediated neuroinflammation. J Immunol 2013;191:1043-1054. 
4. Mizuno T, Kurotani T, Komatsu Y, et al. Neuroprotective role of phosphodiesterase 
inhibitor ibudilast on neuronal cell death induced by activated microglia. 
Neuropharmacology 2004;46:404-411. 
5. Suzumura A, Ito A, Yoshikawa M, et al. Ibudilast suppresses TNFalpha production by glial 
cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res 
1999;837:203-212.