A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy, Safety, Tolerability, Biomarkers and Pharmacokinetics of Ibudilast (MN-166) in COVID-19 Subjects at Risk for Developing Acute Respiratory Distress Syndrome
Phase: PHASE2
Conditions: Pneumonia, Viral
Sponsor: MediciNova

CONFIDENTIALITY STATEMENT 
The information being provided in this protocol is considered confidential, proprietary trade secret information as 
defined by the Federal Trade Secrets Acts and is thus protected from disclosure to unauthorized parties under the 
Freedom of Information Act. This protocol shall be considered a confidential document that provides information 
for the sole use of clinical Investigators for the referenced study, their teams, and the study site Institutional Review 
Board (IRB). 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Study to Evaluate the Efficacy, Safety, 
Tolerability, Biomarkers and PK of ibudilast (MN-166) 
in COVID-19 Subjects at Risk for Developing Acute 
Respiratory Distress Syndrome (ARDS) 
Protocol Number 
MN-166-COVID-19-201 
Investigational Product MN-166 (ibudilast) 
Indication 
Prevention of Acute Respiratory Distress Syndrome 
(ARDS) 
Sponsor
MediciNova, Inc.
4275 Executive Square 
La Jolla, CA 92037 
Sponsor Signatory 
Kazuko Matsuda, MD PhD MPH 
Chief Medical Officer 
MediciNova, Inc. 
Date 
Original protocol dated 24 April 2020 
Amendment 1 protocol dated 18 June 2020 
Amendment 2 protocol dated 03 November 2020 
Amendment 3 protocol dated 18 February 2021 
Amendment 4 protocol dated 31 March 2021 

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1.0 STATEMENT OF COMPLIANCE 
This study will be conducted in accordance with International Conference on Harmonization 
Good Clinical Practice (ICH GCP), applicable United States (U.S.) Code of Federal Regulations 
(CFR), applicable country and local regulations and in accordance with the ethical principles 
outlined in the Declaration of Helsinki. The Principal Investigator will assure that no changes to 
the protocol will take place without prior agreement from the Investigational New Drug (IND) 
sponsor and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participant.  
The protocol and informed consent form will be submitted to the IRB for review and approval. 
Approval of both the protocol and the consent form must be obtained before any participant is 
enrolled. 

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2.0 INVESTIGATOR AGREEMENT 
 
PROTOCOL:  MN-166-COVID-19-201 Amendment 4 
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.  
 
 
_____________________________________________      ______________________________ 
Investigator (Print Name)        
 
 
 
 
       Date 
 
 
_____________________________________________ 
Investigator’s Signature  
 
 
 
 
 
 
 
 

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3.0 PROTOCOL SIGNATURE PAGE 
 
 Protocol: MN-166-COVID-19-201 Amendment 4 
 
MediciNova, Inc.          
    
                                       March 31, 2021 
_____________________________________________      _______________________ 
Kazuko Matsuda, M.D., Ph.D., M.P.H.   
 
 
 
 
Date 
Chief Medical Officer 
 
 
 

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4.0 TABLE OF CONTENTS 
1.0 STATEMENT OF COMPLIANCE ...........................................................................................2 
2.0 INVESTIGATOR AGREEMENT.............................................................................................3 
3.0 PROTOCOL SIGNATURE PAGE ...........................................................................................4 
4.0 TABLE OF CONTENTS ...........................................................................................................5 
5.0 LIST OF ABBREVIATIONS ....................................................................................................9 
6.0 SYNOPSIS ...............................................................................................................................12 
7.0 SCHEDULE OF ASSESSMENTS ..........................................................................................17 
8.0 BACKGROUND .....................................................................................................................19 
8.1 Acute Respiratory Distress Syndrome (ARDS) .......................................................................19 
8.2 MN-166 (ibudilast) ..................................................................................................................19 
8.3 Clinical Pharmacology .............................................................................................................20 
8.4 Rationale for Use of Ibudilast for prevention of ARDS ..........................................................20 
8.5 MIF Inhibition and ARDS .......................................................................................................20 
8.6 PDE4 Inhibition and ARDS .....................................................................................................21 
8.7 ARDS animal model study with Ibudilast ...............................................................................21 
8.8 Previous Human Experience ....................................................................................................21 
9.0 CLINICAL OVERVIEW.........................................................................................................22 
9.1 MediciNova-Sponsored Studies...............................................................................................22 
9.2 Study Dose Justification ..........................................................................................................23 
9.3 Treatment Duration Justification .............................................................................................23 
10.0 TRIAL OBJECTIVES ...........................................................................................................24 
10.1 Primary Objectives .................................................................................................................24 
10.2 Secondary Objectives.............................................................................................................24 
11.0 OVERALL STUDY DESIGN ...............................................................................................24 
11.1 Screening................................................................................................................................24 
11.2 Treatment Phase .....................................................................................................................25 
11.3 Follow-up ...............................................................................................................................25 
11.4 Early Termination/Discharge from Hospital .........................................................................25 
12.0 SELECTION OF SUBJECTS................................................................................................25 
12.1 Study Population ....................................................................................................................25 

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12.2 Inclusion Criteria ...................................................................................................................26 
12.3 Exclusion Criteria ..................................................................................................................26 
12.4 Child-Pugh Scoring Table ......................................................................................................27 
12.5 Screen Failures .......................................................................................................................27 
12.6 Subject Withdrawal/Discontinuation Criteria ........................................................................27 
12.7 Subject Stopping Criteria .......................................................................................................28 
12.8 Study Stopping Criteria..........................................................................................................28 
13.0 TREATMENTS .....................................................................................................................29 
13.1 Study Drug Supply .................................................................................................................29 
13.2 Study Drug Packaging and Labeling .....................................................................................29 
13.3 Study Drug Storage ................................................................................................................30 
13.4 Study Drug Administration ....................................................................................................30 
13.5 Dose Interruptions ..................................................................................................................30 
13.6 Method of Assigning Subjects to Treatment Groups .............................................................30 
13.7 Blinding..................................................................................................................................31 
13.8 Prohibited Medication ............................................................................................................31 
13.9 Treatment Compliance ...........................................................................................................31 
14.0 STUDY PROCEDURES .......................................................................................................31 
14.1 Informed Consent ...................................................................................................................31 
14.2 Clinical Lab Testing ...............................................................................................................31 
14.3 Biomarker Samples ................................................................................................................32 
14.4 Pharmacokinetic (PK) Samples .............................................................................................32 
14.5 Clinical Assessment Scale .....................................................................................................32 
15.0 STUDY ASSESSMENTS .....................................................................................................33 
15.1 Screening................................................................................................................................33 
15.2 Randomization .......................................................................................................................33 
15.3 
Treatment Phase ..........................................................................................................33 
15.3.1 Day 1 (Baseline), Day 3, Day 5 and Day 7 .........................................................................33 
15.3.2 Day 2, Day 4, and Day 6 .....................................................................................................34 
15.3.3 
Follow-up Phase (Day 14 Day 28 and Day 60) ..........................................................34 
15.3.4 
Early Termination/Discharged from Hospital ............................................................35 
16.0 SAFETY ASSESSMENTS ....................................................................................................35 

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16.1 Definition of Adverse Event ..................................................................................................36 
16.2 Assessment of Adverse Events ..............................................................................................36 
16.3 Severity Assessment ..............................................................................................................36 
16.4 Relationship to Study Drug ....................................................................................................37 
16.5 Recording Adverse Events .....................................................................................................37 
16.6 Treatment and Follow-Up of Adverse events (AEs) .............................................................38 
16.7 Serious Adverse Events (SAEs).............................................................................................38 
16.8 SAE Reporting Requirements ................................................................................................38 
17.0 GUIDANCE FOR OVERDOSE ............................................................................................39 
18.0 REPORTING AND FOLLOW-UP OF PREGNANCIES .....................................................39 
19.0 STATISTICAL CONSIDERATIONS...................................................................................40 
19.1 Analysis Population ...............................................................................................................40 
19.2 Primary Endpoints .................................................................................................................41 
19.3 Secondary Endpoints .............................................................................................................41 
19.4 Safety Analysis ......................................................................................................................41 
19.5 Pharmacokinetic Analysis ......................................................................................................42 
20.0 ETHICS..................................................................................................................................42 
20.1 Ethics Review ........................................................................................................................42 
20.2 Ethical Conduct of the Study .................................................................................................42 
20.3 Written Informed Consent .....................................................................................................42 
20.4 Confidentiality .......................................................................................................................42 
21.0 REFERENCES ......................................................................................................................43 
  
 
 
 
 
 
 
 

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List of Tables 
Table 1 Schedule of Assessments ..................................................................................................17 
Table 2 Child-Pugh Scoring Table ................................................................................................27 
Table 3 Study Drug Information ....................................................................................................29 
Table 4 CMP, CBC, and Coagulation Tests ..................................................................................31 
Table 5 Adverse Events Severity Definitions ................................................................................36 
Table 6 Adverse Events Causality Definitions ..............................................................................37 
 

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5.0 LIST OF ABBREVIATIONS 
Abbreviation  
Term 
AE 
adverse event 
ALI 
acute lung injury 
ALP 
alkaline phosphatase 
ALS 
amyotrophic lateral sclerosis 
ALT (SGPT) 
alanine aminotransferase 
ARDS 
acute respiratory distress syndrome 
AST (SGOT) 
aspartate aminotransferase 
AUC 
Area under the curve 
β-hCG  
beta-subunit of human chorionic gonadotropin 
bid 
twice daily 
BiPAP 
Bilevel positive airway pressure 
BPD 
bronchopulmonary dysplasia 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CIRB 
Central Institutional Review Board 
Cmax 
Maximum plasma concentration 
CMP 
Comprehensive Metabolic Panel 
CNS 
central nervous system 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CPAP 
Continuous positive airway pressure 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CYP 
cytochrome 
DDI 
drug-drug interaction 
dL 
deciliter 

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Abbreviation  
Term 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FiO2 
fraction of oxygen in inspired air 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GOLD 
Global initiative for chronic obstructive lung disease 
HIPAA 
Health Insurance Portability and Accountability Act 
HV 
healthy volunteer 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL-1β 
Interleukin-1 beta 
IL-6 
Interleukin-6 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
L 
liter 
LPS 
lipopolysaccharide 
MCP 
monocyte chemoattractant protein  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MIF 
migration inhibitory factor 
MMP 
matrix metalloproteinase 
MS 
Multiple sclerosis 
ms 
milliseconds 
NIAID 
National Institute of Allergy and Infectious Diseases 
PaO2 
partial pressure of oxygen in arterial blood 
PCR 
polymerase chain reaction 
PDE 
phosphodiesterase 
PEEP 
Positive end-expiratory pressure 

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Abbreviation  
Term 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PT 
prothrombin time 
PTT 
Partial thromboplastin time 
qd 
Once daily 
RA 
room air 
RR 
respiratory rate 
RRMS 
Relapsing-remitting MS  
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2  
severe acute respiratory syndrome coronavirus 2 
SOPs 
standard operating procedures 
SpO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TNFα 
tumor necrosis factor alpha  
TRAE 
treatment-related adverse event 
ULN 
Upper limit of normal 
WBC 
White blood cells 
WHO 
World Health Organization  

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6.0 SYNOPSIS 
 
Name of Investigational Product: MN-166 (ibudilast) 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy, Safety, Tolerability, Biomarkers and PK of ibudilast (MN-166) in COVID-19 
Subjects at Risk for Developing Acute Respiratory Distress Syndrome (ARDS) 
Study Number: MN-166-COVID-19-201 
Study Phase: Phase 2 
Study Center: Multicenter 
Number of Subjects (Planned): Approximately 40 patients 
FPI Date: Anticipated 4Q2020 
Screening Phase: up to 3 days, Treatment Phase: 7 days, Follow-up Phase: Study Day 14, 28, 
and Day 60  
Duration of Study Drug Treatment: 7 days 
Study Treatments 
Test Drug: Ibudilast (MN-166) oral 50 mg bid 
Comparator Drug: Matching placebo oral 50 mg bid 
Study drug administration: Study drug will be administrated orally. If subject becomes dependent 
on a gastric tube, study drug can be given via gastric tube by opening the capsules in an enteral 
syringe, then suspend in 30 mL distilled water. 
If study drug is started on Day 1 in the PM, the last dose of study drug will be taken on Day 8 in the 
AM. 
Duration of Subject Participation: Approximately 60 days  
Study Design: This is a randomized (1:1) double-blind, placebo-controlled, parallel-group study of 
ibudilast in hospitalized COVID-19 subjects at risk for developing ARDS receiving standard of care 
including anticoagulation. The study will consist of a Screening Phase followed by a Treatment and 
Follow-up Phase. Following the Screening Phase, if the subject meets eligibility criteria, subject will 
be administered treatment with MN-166 (ibudilast) or placebo. Subjects will receive ibudilast 100 
mg/d (50 mg b.i.d) or placebo every day for 7 days.  Upon completion of the 7-day Treatment Phase, 
subject will be followed-up at Day 14, Day 28 and Day 60 post baseline.  
Screening Phase (up to 3 days)  
The following screening assessments will be performed upon signing the ICF: inclusion/exclusion 
criteria review, physical examination, assess vital signs and O2 use and SpO2, clinical status using 
the NIAID scale, ECG, draw blood for plasma cytokines that include migration inhibitory factor 
(MIF), (interleukin 1-beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor (TNFα), C-reactive 
protein (CRP) and other exploratory biomarkers. Pharmacokinetic (PK) samples, complete blood 
count (CBC), comprehensive metabolic panel (CMP), D-dimer, and coagulation tests will also be 

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drawn. A serum pregnancy test will be done in non-menopausal females. The use of prior 
medications taken will be recorded for 7 days prior to Day 1. 
Treatment Phase (7 days)  
On Day 1 (Baseline) of the Treatment Phase, hospitalized subjects will be treated with MN-166 or 
placebo for a 7-day period. Subjects will undergo study-related procedures including physical 
examination, vital signs, clinical status assessment using the NIAID scale, O2 use and SpO2, ECG, 
blood collection of biomarkers, PK (except Day 7), CBC, CMP, D-dimer and coagulation and 
information on adverse events and concomitant medications will be recorded. (see Table 1 Schedule 
of Events).  
Individual patient stopping criteria based on the known safety profile of ibudilast and study stopping 
criteria will be implemented (see protocol sections 12.7 and 12.8). 
 
An independent medical safety monitor will evaluate safety on an ongoing basis during the study. 
After each of the first three subjects are dosed, the medical safety monitor will review the data with 
the PI and sponsor and will make a recommendation to proceed/stop. After the first three subjects 
are evaluated, the medical safety monitor will continue to review safety data throughout the study.  
 
Follow-up Phase 
The Follow-up Phase consists of three visits, Day 14 (± 3 d), Day 28 (± 3 d) and Day 60 (± 7d).    
Day 14  
On Day 14, site staff will conduct physical examination, clinical status scale, vital signs and O2 use, 
ECG, CBC, CMP, D-dimer, and coagulation tests, biomarkers, AE and conmed review, and record 
survival status. If subject is no longer hospitalized, a telephone follow-up to record O2 usage and 
SpO2, survival, AEs and conmeds taken will be conducted.  
 
Day 28 (telephone follow-up if patient is no longer hospitalized)  
On Day 28, the following assessments will be performed in all subjects: clinical status, O2 therapy 
status use, AE and conmed review, and survival status. 
. 
Day 60  
On Day 60, the following assessments will be performed in all subjects: clinical status, O2 therapy 
status, survival status, and AE and conmed review. In addition, vital signs, 12-lead ECG, and 
clinical safety labs (CBC, CMP, CRP, D-Dimer, PT and INR) will be performed in intubated 
subjects only. 
Discharged prior to Study Day 7 
Subjects who are discharged prior to Day 7 will be given the remainder of their study medication to 
be taken at home twice daily and will be given a pulse oximeter to measure their oxygen levels once 
daily until Study Day 14.  
 
 
 
 
 
 

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Primary Efficacy Objectives 
Primary Efficacy Endpoints 
To evaluate the efficacy of ibudilast vs. placebo 
in COVID-19 subjects measured by the 
proportion of subjects free of respiratory failure 
(i.e., decreased need for O2 therapy)  
• 
Proportion of subjects free from 
respiratory failure as defined by the 
need for decreased oxygen 
requirements (invasive mechanical 
ventilation, non-invasive ventilation, 
high-flow oxygen, or ECMO, CPAP, 
BiPAP, nasal cannula) at Day 28  
• 
Incidence of mechanical ventilation 
/intubation at Day 28 
To evaluate the efficacy of ibudilast vs. placebo 
in COVID-19 subjects measured by clinical 
status (i.e., improvement on NIAID scale)  
• 
Mean change from baseline in clinical 
status on NIAID 8-point ordinal scale 
at Day 28 
• 
Percentage of patients with at least a 
one-point improvement in clinical 
status using the NIAID 8-point ordinal 
scale at Day 28.  
• 
All-cause mortality at Day 28 
Secondary Efficacy Objectives 
Secondary Efficacy Endpoints 
To evaluate the efficacy of ibudilast vs. placebo 
in COVID-19 subjects measured by the 
proportion of subjects free of respiratory failure 
(i.e., decreased need for O2 therapy)  
• 
Proportion of subjects free from 
respiratory failure as defined by the 
need for decreased oxygen 
requirements (invasive mechanical 
ventilation, non-invasive ventilation, 
high-flow oxygen, or ECMO, CPAP, 
BiPAP, nasal cannula) at Days 7, 14, 
and Day 60  
• 
Incidence of mechanical ventilation 
/intubation at Day 7, Day 14, and Day 
60  
• 
Incidence of ICU admission 
To evaluate the efficacy of ibudilast vs. placebo 
in COVID-19 subjects measured by clinical 
status (i.e., improvement on NIAID scale)  
• 
Mean change from baseline in clinical 
status on NIAID 8-point ordinal scale 
at Day 7, Day 14, and Day 60  
• 
Percentage of patients with at least a 
one-point improvement in clinical 
status using the NIAID 8-point ordinal 
scale at Day 7, Day 14, and Day 60  
All-cause mortality at Day 7, Day 14, 
and Day 60  
To evaluate the anti-inflammatory effects of 
ibudilast vs. placebo on cytokine levels  
• 
Mean change from baseline in 
migration inhibitory factor (MIF), 
(interleukin 1-beta (IL-1β), interleukin 
6 (IL-6), tumor necrosis factor alpha 

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(TNFα), and C-reactive protein (CRP) 
at Day 7  
Secondary Safety Objectives 
Secondary Safety Endpoints 
To evaluate the safety and tolerability of 
ibudilast versus placebo  
• 
Incidence, frequency and severity of 
treatment-emergent adverse events at 
Days 7, 14, 28, and 60  
• 
Mean change from baseline of the 
following parameters throughout the 
study at Days 7, 14, and 60 (in 
intubated subjects only): 
o ALT 
o AST 
o serum creatinine 
o BUN 
o complete blood count 
o total bilirubin 
o D-dimer 
To evaluate pharmacokinetics (PK) of ibudilast  
• 
PK plasma concentrations of ibudilast  
 
Study Entry Criteria 
Inclusion Criteria: 
1. Written or verbal informed consent by subject or subject representative is obtained  
2. Male or female subjects age 18 to 80 years, inclusive 
3. SARS-CoV-2 infection confirmed with WHO criteria (including a positive PCR of any 
specimen, (e.g., blood, respiratory, stool, urine, or any other body fluid) 
4. Chest imaging (radiograph, CT scan or lung ultrasound) with abnormalities consistent with 
COVID-19 pneumonia 
5. SpO2 ≤ 92% on room air (RA), RR ≥24 breaths per min on RA, and/or requirement for 
supplemental oxygen  
6. At least 1 risk factor which may put patient at higher risk for more severe illness from 
COVID-19: Age > 65, underlying serious heart disease, chronic lung disease, moderate to 
severe asthma, body mass index of ≥ 40 or diabetes 
7. C-reactive protein >35 mg/L 
8. No known allergies to the study drug or its excipients 
Exclusion Criteria: 
1. Suspected active bacterial, fungal, viral or other cause of respiratory failure other than 
COVID-19 
2. Known or suspected immunosuppression with immunosuppressant medications or 
chemotherapeutic agents 
3. Active primary lung cancer or another metastatic malignancy to the lungs 
4. Moderate to severe liver failure (see section 12.4) defined by Child-Pugh score of ≥ 7 
measured by: 
• 
Total bilirubin 
• 
Serum albumin 
• 
INR 

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• 
Ascites 
• 
Hepatic encephalopathy 
5. The following abnormal laboratory tests if any of the criteria are met: 
• 
Platelet Count < 75,000 /mm3 
• 
White Blood Count < 2500 /mm3 
• 
ALT or AST or Total Bilirubin >3 x ULN 
• 
Bilirubin > 3 mg/dL 
• 
Serum albumin less than 28 g/L 
6. Subject is on dialysis 
7. On home ventilator support or continuous domiciliary O2 therapy for baseline lung disease  
8. Active tuberculosis (TB) infection 
9. Lactating or pregnant at Screening  
10. History of stomach or intestinal surgery or any other condition that could interfere with or is 
judged by the Investigator to interfere with absorption, distribution, metabolism, or 
excretion of study drug 
11. Treatment with an investigational drug or off-label medication within 5 half-lives or 30 days 
whichever is longer prior to study drug treatment 
12. Participating in another COVID-19 clinical trial   
13. Any other serious medical condition or abnormality that, in the Investigator’s opinion, 
would preclude participation in the study. 
Analysis Populations 
Full Analysis Set: All subjects who sign informed consent, are randomized, receive treatment and 
have at least one post dose efficacy assessment. 
Per Protocol Analysis: all randomized subjects who sufficiently complied with the protocol. Details 
of the evaluability criteria will be outlined in the statistical analysis plan. 
Statistical Methods 
Full details of the statistical methods including handling of missing data and deaths will be outlined 
in the statistical analysis plan. Since this is an early proof of concept study, no formal sample size 
calculations have been performed.  

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7.0 SCHEDULE OF ASSESSMENTS 
Table 1 Schedule of Assessments 
 
Phase 
Screening 
Double-Blind Treatment Phase e,g  
Follow-up 
Study Day 
 
Day -3 
Day 1  
BL 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
 
Day 14e 
(± 3) 
 
Day 28 
(+/-3) 
Day 60 
(+/- 7d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 Brief physical exam  
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Clinical status using 
NIAID scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, RR,  
HR, Temp) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xi 
O2 therapy status and 
SpO2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
 
Xi 
Biomarker plasma 
samples: MIF, IL-1β, 
IL-6, TNF-α 
Xb 
X 
 
 
X 
 
X 
 
X 
X 
 
 
PK blood samplec 
 
X 
 
X 
 
X 
 
 
 
 
 
CBC, CMP, CRP,  
D-dimer, PT, INR  
Xd 
X 
 
X 
 
X 
 
X 
X 
 
Xi 
Randomize f 
X 
 
 
 
 
 
 
 
 
 
 
Administer study drug 
 
X h 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse event review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Prior/Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record survival 
statusj 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
a 12-lead ECG to be done between 2-4 hours after AM dose.   
b Biomarker blood sample collection at screening is optional if Screening and Day 1 assessments occur on the same day. 
c Collect PK samples on Day 1 in the AM prior to study drug dosing and at 2, 4, 8, and 12 hours (Predose of PM dose); Day 3  
  and Day 5 prior to AM study drug dosing. PK samples to be collected for 8 subjects only.      
d Serum β-hCG for pre-menopausal women. 
e  Telephone follow-up if subject is not in hospital. If subject is no longer hospitalized or cannot return due to COVID restrictions,  
a telephone follow-up to record O2 usage/levels, AEs and conmeds may be conducted. All other assessments are optional. 
f Subjects may be randomized during the Screening Phase after all of the screening assessments are completed and subject is  
   considered eligible for the study or on Day 1.  
g If subject prematurely discontinues from the study or is discharged from the hospital on Days 2, 4, or 6 collect biomarker  
   samples in addition to other scheduled assessments. If subject prematurely discontinues from the study or is discharged on Days 1, 3, 5, or 7,  
conduct the study assessments scheduled on those days.  
h The first dose of study drug may be started in the AM or the PM. 
i  Vital signs, ECG and safety labs will be done in intubated subjects only.   
J  Survival status is captured on the NIAID questionnaire. 

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8.0 BACKGROUND 
8.1 Acute Respiratory Distress Syndrome (ARDS) 
ARDS is recognized as the most severe form of acute lung injury (ALI), a form of diffuse 
alveolar injury, which is an acute inflammatory lung process, associated with increased 
pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue. The 
acute, intense inflammatory response of the lungs occurs as a result of direct (e.g., toxins, 
infection) or indirect (sepsis, trauma) insult to the alveolar capillary membrane leading to 
increased permeability and subsequent edema from vascular leakage resulting in the loss of 
aerated lung tissue (Ranieri VM et al 2012, Eworuke et al 2018).  ARDS is defined by timing 
(within 1 week of clinical insult or onset of respiratory symptoms); radiographic changes 
(bilateral opacities not fully explained by effusions, consolidation, or atelectasis); origin of 
edema (not fully explained by cardiac failure or fluid overload); and severity based on the 
PaO2/FiO2 ratio on 5 cm of continuous positive airway pressure (CPAP). The 3 categories are 
mild (PaO2/FiO2 200-300), moderate (PaO2/FiO2 100-200), and severe (PaO2/FiO2 ≤100)  
(Ranieri VM, et al 2012).  
8.2 MN-166 (ibudilast) 
MN-166 (ibudilast) is a small molecule macrophage migration inhibitory factor (MIF) and 
phosphodiesterase (PDE) 4,10-inhibitor drug candidate with demonstrated neuroprotective action 
in vitro and in vivo. MIF knockout or antibody-neutralization studies have provided 
neuroprotection validation in certain multiple sclerosis (MS) and other neurological animal 
models. MN-166 (ibudilast) has additionally shown attenuation of glial cell activation in multiple 
in vitro and in vivo model systems which may represent a novel pharmacotherapeutic approach 
in ALS treatment. 
MN-166 (ibudilast) distributes well to the CNS and is a selective inhibitor of the pro-
inflammatory cytokine, macrophage migration inhibitory factor (MIF (Cho et al 2010) and 
certain cyclic nucleotide phosphodiesterases (Gibson et al 2006) at clinically relevant plasma or 
CNS concentrations. MIF inhibition or knockout has been linked to attenuated disease 
progression in animal models of multiple sclerosis (Powell et al 2005; Kithcart et al 2010) and 
attenuates neuronal death and promotes recovery in mouse spinal cord injury (Nishio et al 2009). 
Another MIF knockout study revealed its role in neurodegeneration in an experimental stroke 
model (Inacio et al 2011). PDE inhibition has likewise shown some neuroprotective actions (
Chen et al 2007; Nakamizo et al 2003).  
MN-166 (ibudilast) has been recognized to have glial attenuating activity in vitro and in vivo. In 
activated glia cells in vitro, MN-166 (ibudilast) suppresses the production of proinflammatory 
cytokines and increases the production of anti-inflammatory cytokine and various neurotrophic 
factors. (Suzumura et al 1999; Kawanokuchi et al 2004; Mizuno et al 2004). MN-166 (ibudilast) 
also protects hippocampal neurons (Tominaga et al 1996) and oligodendrocytes against 
excitotoxicity (Yoshioka et al 1998, 2000) and astrocytes against apoptosis (Takuma et al 2001). 
In an animal model of cerebral ischemia, ibudilast reduces white matter lesions and microglial 

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activation (Wakita et al 2003). MN-166 (Ibudilast) was also reported to reduce glial activation 
and attenuate allodynia in several validated animal models of peripheral and central neuropathic 
pain (Ledeboer et al 2007; Ellis et al 2014).   
In addition, MN-166 (ibudilast) suppresses the expression of matrix metalloproteinase-9 (MMP-
9) (Lee et al 2012; Yagi et al 2010). MMP-9 potentially plays an important role in the 
pathogenesis of ALS and when knocked down in animal models, leads to slower progression of 
the disease (Kaplan et al 2014). 
8.3 Clinical Pharmacology 
The pharmacokinetics of MN-166 has generally been shown to be dose-proportional both within 
and between studies. Based on prior trials, steady state plasma Cmax and AUC0-24h levels at the 
highest dose (50 mg bid; 100 mg/day) are anticipated to be approximately 116 ng/ml (Cmax) and 
1613 ng*hr/ml (AUC0-24h) (study AV411-026 HV group). All of the trials except for Protocol 
Nos. AV411-009 and AV411-016 have included all concurrent concomitant medications with 
ibudilast dosing at 80 or 100 mg/day. While pharmacokinetic drug-drug interactions have not 
been carefully assessed (or are in progress), there are no clear pharmacologic or safety 
interactions noted to date. Please refer to the Investigator’s Brochure (IB) for tabulated 
summaries and details of the findings.   
8.4 Rationale for Use of Ibudilast for prevention of ARDS 
The rationale for the use of MN-166for prevention of ARDS is based upon its cellular and 
molecular target actions and recent research in ARDS animal model (D Yang, Y Yang, Y Zhao,  
2020). At the molecular level, ibudilast inhibits macrophage migration inhibitory factor (MIF) 
and certain cyclic nucleotide phosphodiesterases (PDEs to reduce pro-inflammatory cytokines 
such as IL-1-beta, IL-6, and TNF-alpha (Cho et al 2010; Gibson et al 2006). 
8.5 MIF Inhibition and ARDS 
Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine that not only acts on 
macrophages but is also produced by these cells in response to endotoxins, exotoxins, and other 
cytokines such as TNFα and interferon-gamma (IFN-γ) (Bach et al 2009).  The critical role of 
MIF in mediating inflammatory lung injury in ARDS has been discussed. The study identified 
enhanced MIF protein expression in alveolar capillary endothelium and infiltrating macrophages 
in lung tissues from ARDS patients. The possibility that MIF up‐regulates its synthesis in an 
autocrine fashion in ARDS was tested using cultured endothelial cells stimulated with MIF and a 
murine model of lipopolysaccharide (LPS)‐induced acute lung injury. MIF induced significant 
TNFα synthesis in cultured endothelial cells and the effect was blocked by neutralizing anti‐MIF 
antibody. A similar blocking effect was observed when MIF‐stimulated endothelial cells were 
pretreated with neutralizing anti‐TNFα antibody, supporting the notion that MIF induced TNFα 
production via an amplifying pro‐inflammatory loop (Lai et al 2003). 

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8.6 PDE4 Inhibition and ARDS 
There are multiple studies suggest that potential PDE4 inhibitors for ARDS treatment. In the 
animal model of ALI, roflumilast, PDE4 inhibitor treatment reduced leak of cells (P<0.01), 
particularly of neutrophils (P<0.001), into the lung, decreased lung edema formation (P<0.01), 
and improved respiratory parameters. The results indicate a future potential of PDE4 inhibitors 
also in the therapy of ALI (Kosutova et al 2017). 
The anti-inflammatory effect of two PDE4 inhibitors was investigated in a pre-term rat model of 
hyperoxia-induced lung injury. Pre-term rat pups were exposed to room air, hyperoxia, or 
hyperoxia and one of two PDE4 inhibitors: rolipram and piclamilast. The anti-inflammatory 
effects of prolonged PDE4 inhibitor therapy were investigated by studying survival, 
histopathology, fibrin deposition, alveolar vascular leakage, and differential mRNA expression 
(reverse transcription, or RT-PCR) of key genes involved in inflammation, alveolar enlargement, 
coagulation and fibrinolysis. PDE4 inhibitor therapy prolonged median survival by up to 7 days 
and reduced alveolar fibrin deposition, lung inflammation and vascular leakage by decreasing the 
influx of monocytes and macrophages and protein efflux in bronchoalveolar lavage fluid.   
Analysis of mRNA expression of key genes involved in experimental bronchopulmonary 
dysplasia (BPD) revealed a significant PDE4 inhibitor-induced improvement of genes involved 
in inflammation, fibrin deposition and alveolarisation. In conclusion, phosphodiesterase-4 
inhibition prolongs survival by inhibiting inflammation and reducing alveolar fibrin deposition in 
pre-term rat pups with neonatal hyperoxic lung injury, whereby piclamilast outperformed 
rolipram (de Visser et al 2008). 
8.7 ARDS animal model study with Ibudilast  
In this study, ibudilast was tested in a LPS-induced neonatal ARDS animal model to evaluate its 
anti-inflammatory effect. Ibudilast ameliorated LPS-induced pathological manifestations and 
pulmonary edema in lung tissue. In addition, ibudilast attenuated the secretion of inflammatory 
cytokines TNF-alpha, IL-1 beta, IL-6 and MCP-1 by inactivating the chemokine axis and 
significantly reduced LPS-induced cell apoptosis in lung tissue (Yang et al 2020). 
8.8 Previous Human Experience 
Ibudilast is approved in Japan and South Korea for treatment of asthma (20 mg/day) and post-
stroke dizziness in cerebrovascular disorders (30 mg/day) and has been prescribed for these 
indications for almost 30 years. The largest accumulation of clinical safety experience with 
ibudilast (MN-166) is from the approval of Ketas® for asthma and post-stroke dizziness. Dosing 
was 20 to 30 mg/day (included uses up to 40 mg/day) and based on chronic administration.  In 
the Ketas package insert, the most common adverse events were anorexia (0.6%), nausea (0.6%), 
increased liver enzymes (ALT 0.4%, AST 0.3%, and GTP 0.4%).  Following regulatory 
approval, adverse event data continued to be collected and, to date, approximately 14,968 
subjects were evaluated. Safety data was taken from the 2009 Ketas package insert and Interview 
Forms collected from 1989 to 1996. Seven hundred sixty- nine (769) adverse drug reactions 
occurred in 507 (3.39%) patients. The most common (≥5%) adverse drug reactions were: itching 
(8; 0.05%), rash (8;  0.05%), abdominal pain (7; 0.05%), heavy head feeling (7; 0.05%), stomach 

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pain (7; 0.05%), epigastric discomfort (8; 0.5%), BUN increased (7; 0.05%), heart rate/heart 
rhythm disorders (8; 0.05%),vertigo (10; 0.7%), serum cholesterol increased (10; 0.07%), 
general malaise (10; 0.07%), lack of appetite (13; 0.09%), headache (13; 0.09%), heartburn (16; 
0.11%), vomiting (19; 0.13%), nausea (22; 0.15%), stomach discomfort (24; 0.16%), ALP 
increased (36; 0.24%), AST increased (45; 0.30%), ALT increased (53; 0.35%), sickness (54; 
0.36%), gamma-GTP increased (54; 0.36%), and anorexia (71; 0.47%). 
9.0 CLINICAL OVERVIEW 
To date, ibudilast has been evaluated in a total of 21 ongoing and completed clinical trials; 11 
clinical trials by the sponsor and 10 trials by investigator and more than 750 subjects have been 
exposed.  Eight investigator-initiated studies are conducted or ongoing in US cross-referenced to 
sponsor’s IND. Two trials were conducted in Australia, one study targeted medication overuse 
headache (Australian CTN File No. 2011/012799) and the other targeted chemotherapy-induced-
peripheral neuropathy (Australian CTN File No. 2018/010601).  An overview of the safety 
profile in each of the Phase 2 clinical trials will be reported below.  
9.1 MediciNova-Sponsored Studies 
Among 10 completed Phase 1 and 2 studies, more than 620 received ibudilast up 100 mg/d in 
single and multiple doses up to 2 years. 
Ibudilast was tested at dosages of 30 or 60 mg/d up to 2 years in the Phase 2 clinical trial (MN-
166-CL-001) with relapsing-remitting multiple sclerosis (RRMS) patients.  A total of 297 
subjects were randomized; of those, 103 subjects were randomized to placebo, 95 subjects were 
randomized to 30 mg/d, and 99 subjects were randomized to 60 mg/d. A total of 291 subjects 
received ibudilast 30 mg/d or 60 mg/d for up to 2 years in the open-label-extension phase. The 
most common treatment related AEs were nausea, headache, and upper respiratory tract 
infection. There were 20 SAEs reported during entire 2-year duration of the study. All SAEs were 
considered not related to ibudilast in this study. 
In the Phase 2 SPRINT-MS/NN102 trial, a total of 255 progressive MS subjects were enrolled, 129 
subjects received doses of ibudilast up to 100 mg/d and 126 subjects received placebo for up to 96 
weeks. Safety results of study SPRINT-MS/NN102 suggests that the adverse event profile of 
ibudilast appears to be similar to the pattern of events seen in the MN-166-CL-001 study at daily 
doses up to 100 mg/day. Most of the adverse events that appear to be related to ibudilast fall 
under the Gastrointestinal SOC, nausea, vomiting diarrhea, abdominal pain, and dyspepsia. Other 
treatment-related adverse events included fatigue, hepatic enzymes increased, WBC decreased, 
alanine aminotransferase, headache, decreased appetite, and insomnia. Although there was a 
higher incidence of depression in the ibudilast group, most of the events were considered to be 
unrelated by the principal investigator There were 58 SAEs reported in 44 subjects across both 
treatment groups during the 96 weeks trial. One SAE of ataxia was considered related to 
ibudilast, which was a single event and resolved the next day.  
In the Phase 1b/2a MN-166-ALS-1201 study, 45 subjects with ALS received ibudilast 60 mg/d 
for up to 52 weeks. Safety results of the MN-166-ALS-1201 study also show a similar profile to 
the MS studies. The most commonly reported adverse events fall under the Gastrointestinal and 

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Nervous System SOCs. The most commonly reported TEAEs in the ibudilast group were 
dysphagia, nausea, fatigue, pain, upper respiratory infection, fall, weight loss, anorexia, headache, 
depression, insomnia, cough, and dyspnea. Treatment-related events that were attributed to 
ibudilast were decreased/loss of appetite, anorexia/weight loss, nausea, and ECG changes 
(atrioventricular junctional rhythm), and increased QTcB to upper normal of 470 (Brooks et al 
2017).  
In the Phase 2 open-label study (MN-166-ALS-1202) a total of 35 subjects with ALS received 
100 mg/day up to 9 months. The most commonly reported treatment-related adverse event was 
nausea. 
These studies suggest that ibudilast at daily doses of up to 100 mg/d appear to be generally safe 
and well-tolerated. The most commonly reported AEs have been nausea, abdominal pain, 
diarrhea, and headaches. There was a slight dose-related increase in the percent of subjects with 
headaches and gastrointestinal AEs. The incidence of nausea suggested a dose-related increase. 
Ibudilast also appeared to cause transient changes in laboratory values, particularly AST, ALT 
and GGT which, in most cases, appeared to resolve over time. 
9.2 Study Dose Justification 
In a preclinical model of ARDS in mice, ibudilast 7.5 mg/kg i.p. treatment significantly reduced 
LPS-induced pathological changes and pulmonary edema in lung tissues. In addition, ibudilast 
treatment attenuated the secretion of inflammatory cytokines IL-1β beta, IL-6, TNF, and MCP-1, 
and significantly reduced LPS-induced cell apoptosis in lung tissues.  
Based on internal data, a 7.5 mg/kg dose of ibudilast administered i.p. resulted in an AUC of 
approximately 862 h*ng/mL, an exposure that is achieved in healthy volunteers at doses of 30-50 
mg administered twice daily. 
In ALS patients receiving ibudilast 100 mg per day orally, a significant reduction in MIF was 
observed after treatment. This effect was maintained throughout the 36-week duration of the 
study. 
The safety of a single dose of 100 mg has been established in healthy volunteers. In addition, 
long term safety of up to 96 weeks of 100 mg/day doses has been established in MS and ALS 
patients without any significant safety sequelae. The 100 mg/day is the dose that is shown to 
exert significant reductions in MIF levels, and therefore considered the targeted clinical dose. 
9.3 Treatment Duration Justification  
According to CDC, among the COVID-19 patients who developed severe disease, the medium 
time to dyspnea ranged from 5 to 8 days, the median time to acute respiratory distress syndrome 
(ARDS) ranged from 8 to 12 days, and the median time to ICU admission ranged from 10 to 12 
days. According to the published paper discussing a total of 191 COVID-19 patients treated in 
Wuhan, China, (Zhou et al 2020 Lancet), the median time from illness to dyspnea was 7.0 days, 
median time from illness to onset of ARDS was 12 days, and median time from illness to ICU 
admission was 12 days in total patients. The median time from dyspnea to intubation was 10.0 
days (IQR 5.0–12.5) for patients who received invasive mechanical ventilation.  

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The steady-state plasma ibudilast concentrations are reached within 3 days of initiating b.i.d. and 
we want to treat at least 5 days with steady state drug level, thus, we determined duration of 
treatment to be 7 days. 
10.0 TRIAL OBJECTIVES 
10.1 Primary Objectives 
The primary objectives of the study are to evaluate the: 
• Efficacy of ibudilast vs. placebo in COVID-19 subjects measured by the proportion of 
subjects free of respiratory failure (i.e., decreased need for O2 therapy) at Day 28; 
• Efficacy of ibudilast vs. placebo in COVID-19 subjects measured by clinical status (i.e., 
improvement on NIAID scale) at Day28;  
10.2 Secondary Objectives 
The secondary objectives of the study are to evaluate the: 
• Safety and tolerability of ibudilast vs. placebo in COVID-19 subjects;  
• Efficacy of ibudilast vs. placebo in COVID-19 subjects measured by the proportion of 
subjects free of respiratory failure (i.e., decreased need for O2 therapy) at Days 7, 14, and 
60; 
• Efficacy of ibudilast vs, placebo in COVID-19 subjects by clinical response of ibudilast 
vs. placebo in COVID-19 subjects at Days 7, 14, and Day 60;  
• Anti-inflammatory effects of ibudilast vs. placebo on cytokine levels; 
• Pharmacokinetics of ibudilast vs. placebo in COVID-19 subjects. 
11.0 OVERALL STUDY DESIGN 
This is a randomized (1:1), double-blind, placebo-controlled, parallel-group study of ibudilast in 
hospitalized COVID-19 subjects at risk for developing ARDS receiving standard of care.  The 
study will consist of a Screening Phase followed by a Treatment and Follow-up Phase. 
Following the Screening Phase, if the subject meets eligibility criteria, subject will be randomly 
assigned treatment with MN-166 (ibudilast) or placebo. Upon completion of the 7-day Treatment 
Phase, subject will be followed-up at Day 14, Day 28, and Day 60. Subjects will receive ibudilast 
100 mg/d (50 mg b.i.d) or matching placebo (50 mg b.i.d.) every day for 7 days.  (See Table 1 
for study assessments). 
11.1 Screening 
The following screening assessments will be performed upon signing the ICF: 
inclusion/exclusion criteria review, physical exam, assess vital signs and O2 use and SpO2, 
clinical status using the NIAID scale, 12-lead ECG, draw blood for plasma biomarkers that 
include migration inhibitory factor (MIF), (interleukin 1-beta (IL-1β), interleukin 6 (IL-6), tumor 
necrosis factor (TNF-α), C-reactive protein (CRP) and other exploratory biomarkers. A complete 
blood count (CBC), comprehensive metabolic panel (CMP), D-dimer and coagulation tests will 

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also be drawn. A serum pregnancy test will be done in pre-menopausal females. Prior 
concomitant medications taken within the last 7 days prior to study drug administration will be 
recorded.  
11.2 Treatment Phase 
During the Treatment Phase, hospitalized subjects will be treated with MN-166 or placebo for a 
7-day period. During the Treatment Phase, subjects will undergo study-related procedures 
including physical exam, ECG, O2 use assessment and SpO2, biomarkers and PK samples (except 
Day 7) draw, CBC, CMP, D-dimer blood collection, clinical assessment using the NIAID scale, 
and information on adverse events and concomitant medications will be recorded (see Table 1 
Schedule of Assessments). 
11.3 Follow-up 
On Study Day 14, if subject is still hospitalized, the site will conduct physical examination, 
clinical status (NIAID scale), vital signs, O2 use and SpO2, CBC, CMP, D-dimer, coagulation 
tests, biomarkers, and AE and concomitant medications review.  
On Study Day 28, subject’s clinical status (NIAID scale) and survival status will be recorded,  O2 
therapy status use, AE and conmed review.  A telephone follow-up is permitted if subject is no 
longer hospitalized.  
On Study Day 60, subjects will undergo the following assessments: clinical status using the 
NIAID scale, O2 therapy status, survival status, AE and conmed review. In addition, vital signs, 
12-lead ECG, and clinical safety labs (CBC, CMP, CRP, D-Dimer, PT and INR) will be 
performed in intubated subjects only. 
11.4 Early Termination/Discharge from Hospital 
If subject early terminates from the study or is discharged from the hospital on Days 2, 4, or 6, 
the site will conduct clinical assessment, take vital signs, O2 use and SpO2, draw biomarker 
sample, and review AEs and concomitant medications.  If subject early terminates from the study 
or is discharged on Days 1, 3, 5, or 7, the site will conduct the study assessments scheduled on 
those days.  
Subjects who are discharged prior to Day 7 will be given the remainder of their study medication 
to be taken at home and a pulse oximeter supplied by the sponsor to measure their O2 levels once 
daily until Study Day 14. 
12.0 SELECTION OF SUBJECTS 
12.1 Study Population 
This study will enroll approximately 40 subjects diagnosed with COVID-19 who are at risk for 
developing acute respiratory distress syndrome (ARDS) receiving standard of care including 
anticoagulation. Randomization of subjects will be stratified by use of IL-6 antibody therapy.  
 

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Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion criteria 
are not eligible to participate in the study. 
12.2 Inclusion Criteria 
1. Written or verbal informed consent by subject or subject representative is obtained  
2. Male or female subjects age 18 to 80 years, inclusive 
3. SARS-CoV-2 infection confirmed with WHO criteria (including a positive PCR of any 
specimen, e.g., blood, respiratory, stool, urine, or any other body fluid) 
4. Chest imaging (radiograph, CT scan or lung ultrasound) with abnormalities consistent 
with COVID-19 pneumonia 
5. SpO2 ≤ 92% on room air (RA), RR ≥24 breaths per min on RA, and/or requirement for 
supplemental oxygen  
6. At least 1 risk factor which may put patient at higher risk for more severe illness from 
COVID-19: Age > 65, underlying serious heart disease, chronic lung disease, moderate to 
severe asthma, body mass index of ≥ 40 or diabetes 
7. C-reactive protein >35 mg/L 
8. No known allergies to the study drug or its excipients 
12.3 Exclusion Criteria 
1. Suspected active bacterial, fungal, viral, or other cause of respiratory failure other than 
COVID-19 
2. Known or suspected immunosuppression with immunosuppressant medications or 
chemotherapeutic agents 
3. Active primary lung cancer or another metastatic malignancy to the lungs 
4. Moderate to severe liver failure (see section 12.4) defined by Child-Pugh score of ≥ 7 
measured by: 
• 
Total bilirubin 
• 
Serum albumin 
• 
INR 
• 
Ascites 
• 
Hepatic encephalopathy 
5. The following abnormal laboratory tests if any of the criteria are met: 
a. Platelet Count < 75,000 /mm3 
b. White Blood Count < 2500 /mm3 
c. ALT or AST or Total Bilirubin >3 x ULN 
d. Bilirubin > 3 mg/dL 
e. Serum albumin less than 28 g/L 
6. Subject is on dialysis 
7. On home ventilator support or continuous domiciliary O2 therapy for baseline lung 
disease  
8. Active tuberculosis (TB) infection 
9. Lactating or pregnant at Screening  

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10. History of stomach or intestinal surgery or any other condition that could interfere with or 
is judged by the Investigator to interfere with absorption, distribution, metabolism, or 
excretion of study drug 
11. Treatment with an investigational drug or off-label medication within 5 half-lives or 30 
days whichever is longer prior to study drug treatment 
12.  Participating in another COVID-19 clinical trial   
13. Any other serious medical condition or abnormality that, in the Investigator’s opinion, 
would preclude participation in the study. 
12.4 Child-Pugh Scoring Table 
Subjects will be excluded from study if Child-Pugh score at screening is ≥7. 
Table 2 Child-Pugh Scoring Table 
Measure  
1 point  
2 points  
3 points  
Bilirubin (total) mg/dL 
<2  
2-3  
>3  
Serum albumin g/L 
>35  
28-35  
<28  
INR  
<1.7  
1.71-2.20  
>2.20  
Ascites  
None  
Mild  
Severe  
Hepatic encephalopathy  None  
Grade I-II (or 
suppressed with 
medication)  
Grade III-IV (or 
refractory)  
12.5 Screen Failures 
A Screen failure is defined as a potential subject who did not meet one or more criteria required 
for participation who consent to participate in the clinical trial but is not subsequently randomly 
assigned to the study intervention or entered in the study.  
Individuals who do not meet the criteria for participation in this trial (screen failure) due to 
abnormal clinical laboratory results may be rescreened. Study staff should notify sponsor prior to 
rescreening. 
12.6 Subject Withdrawal/Discontinuation Criteria 
A subject 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 continuing participation 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  

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• Subjects who are no longer able to understand task instructions or to perform tests 
adequately 
• Subject becomes pregnant during the study. See Section 18 for reporting requirements 
and follow-up of the pregnancy 
If a subject withdraws or is removed from the study for any reason, the reason and date of 
discontinuation of study medication should be recorded in the appropriate section of the Case 
Report Form (CRF). At the time of study discontinuation, every effort should be made to ensure 
that the scheduled study procedures and evaluations for that day are performed. Subjects who are 
discontinued from study drug for reasons other than loss to follow-up or withdrawal of consent 
will remain in the study and continue regularly scheduled efficacy and safety assessments.  
The study sponsor reserves the right to discontinue the study at any time for medical or 
administrative reasons.   
12.7 Subject Stopping Criteria 
A subject should be withdrawn from the study if any of the following abnormal lab values occur, 
after repeat testing: 
• AST or ALT or total bilirubin >3 x upper limit of normal (ULN) 
• Bilirubin >3 mg/dL 
• Serum albumin less than 28 g/L 
• White blood count <2500/mm3 
• Platelet count <75,000/ mm3 
A subject should also be withdrawn from the study if any of the following adverse events occur: 
• Nausea considered moderate or severe and related to study drug by investigator for 
greater than 3 consecutive days despite maximal supportive therapy 
• Vomiting considered moderate or severe and related to study drug by investigator for 
greater than 3 consecutive days despite maximal supportive therapy 
• Diarrhea considered moderate or severe and related to study drug by investigator for 
greater than 3 consecutive days despite maximal supportive therapy 
• Occurrence of an SAE or grade 3 adverse event related to study drug 
Subjects who are withdrawn/discontinued from study drug to an abnormal lab result or adverse 
event will remain in the study and continue regularly scheduled efficacy and safety assessments. 
 
12.8 Study Stopping Criteria  
An independent medical safety monitor will evaluate safety on an ongoing basis during the 
study. After each of the first three subjects are dosed, the medical safety monitor will review the 
data with the PI and sponsor and will make a recommendation to proceed/stop. After the first 
three subjects are evaluated, the medical safety monitor will continue to review safety data 
throughout the study.  

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If two or more subjects experience similar adverse events of moderate or severe intensity or 
similar serious adverse events related to study drug or if two or more subjects discontinue study 
treatment due to safety concerns, study dosing will be temporarily halted until the safety data has 
been reviewed. Once reviewed by an independent safety monitor, sponsor and PI, a 
determination will be made to continue or stop the study.  
13.0 TREATMENTS 
MN-166 (ibudilast) will be administered as MN-166 50 mg (5 capsules) b.i.d for 7 days. Study 
drug may be taken with food or within an hour of eating to improve gastrointestinal tolerability. 
Subjects who cannot tolerate a b.i.d. dosing regimen may be administered a t.i.d. dosing regimen 
(40 mg at breakfast, 30 mg at lunch, 30 mg dinner). Subjects who cannot tolerate this regimen 
will be discontinued from the study.   
Day 1 study drug may be administered starting with the PM dose. If the first dose of study drug is 
administered in the PM then the last dose should be administered on Study Day 8 in the AM. 
Matching placebo will also be provided and will be administered as 50 mg (5 capsules) b.i.d. for 
7 days. 
13.1 Study Drug Supply 
MN-166 and matching placebo will be provided in 10 mg non-vegetarian capsules in 
polyethylene bottles and will be stored at room temperature.  
MN-166 is an extended release pharmaceutical preparation comprised of white extended release 
granules contained in a No.4 white capsule (Table 3).  
 Table 3 Study Drug Information 
Investigational Drug 
MN-166 or matching placebo 
Formulation 
10 mg capsules 
Frequency 
MN-166: 50 mg b.i.d. for 7 days  
Storage Conditions 
Store at room temperature  
13.2 Study Drug Packaging and Labeling 
At a minimum, the following information will be included on each package:  
• 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 

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o Dispensing date 
o Subject number 
• 
Statement “Caution: New Drug – Limited by federal law to investigational use” 
13.3 Study Drug Storage 
The study drug should be stored at room temperature. Do not freeze.    
13.4 Study Drug Administration 
 The study drug will be dispensed by appropriately qualified site study staff.  
Investigational clinical supplies will 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.  
Study drug will be administrated orally. If subjects become dependent on a gastric tube, study 
drug can be given via gastric tube by opening the capsules in an enteral syringe, then suspend in 
30 ml distilled water. It is recommended that the gastric tube is rinsed before and after each 
study drug delivery via gastric tube. Study drug is extended-release granule in gelatin capsule 
and gelatin capsule has no functionality in the release of drug.  
Also, open capsule MN-166 administration has been used in 2 clinical trials in ALS patients 
who became gastric tube dependent due to bulbar symptoms, with no safety concerns. 
13.5 Dose Interruptions 
The following abnormal laboratory tests should be repeated within 24 hours if any of the criteria 
are met: 
• AST or ALT or Total Bilirubin >3 x upper limit of normal (ULN) 
• Bilirubin >3 mg/dL 
• Serum albumin less than 28 g/L 
• White blood count <2500/mm3 
• Platelet count <75,000/ mm3 
If, after repeat testing, the laboratory value is still outside the above-stated 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).   
13.6 Method of Assigning Subjects to Treatment Groups 
Subjects will be assigned to treatments based on a randomization scheme generated by a 
computer program. The randomization scheme will be reviewed and approved by an independent 
statistician from the Sponsor and locked after approval. 

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13.7 Blinding 
The subject and all study staff members including the Sponsor will be blinded to the treatment 
codes. Randomization information will be kept strictly confidential, filed securely by an 
appropriate group at the sponsor company and accessible only to authorized personnel until the 
time of unblinding. 
13.8 Prohibited Medication 
The use of any unauthorized investigational therapy is prohibited during the study.  
13.9 Treatment Compliance 
Records of treatment compliance for each subject will be kept throughout the study. The clinical 
research monitor will review treatment compliance during site visits and at the completion of the 
study. 
14.0 STUDY PROCEDURES 
14.1 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 FDA Form 1572 will explain the 
study to the subject or subject’s representative, answer all of the subject’s questions, and obtain 
written or verbal informed consent before performing any study-related procedure. Informed 
Consent should be conducted in accordance with local requirements. Subject 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 Informed Consent form).  
Only subject or subject’s representative who provide informed consent, as assessed and 
documented by the Investigator, will be enrolled. The subject is required to provide written 
informed consent prior to undergoing any study procedures. If subject is unable to sign their full 
name, an “X” can be acceptable. 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. 
14.2 Clinical Lab Testing 
Clinical laboratory testing (CMP, CBC, and coagulation) will be performed at Screening, Day 
1, Day 3, Day 5, Day 7, Day 14 and Day 60 (in intubated subjects only) at the site’s local 
laboratory.  
 Table 4 CMP, CBC, and Coagulation Tests 
Comprehensive Metabolic Panel (CMP) 
Complete Blood Count (CBC) with Diff  
Serum albumin 
white blood cell count (WBC) 
blood urea nitrogen (BUN) 
white blood cell differential 
calcium 
eosinophilic leukocyte count 
carbon dioxide (bicarbonate) 
basophilic leukocyte count 

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chloride 
neutrophil count 
Serum creatinine 
lymphocyte count 
glucose 
monocyte count 
potassium 
platelet count 
sodium 
red blood cell count (RBC) 
total bilirubin 
hemoglobin 
total protein 
hematocrit 
alanine aminotransferase (ALT) 
D-dimer 
alkaline phosphatase (ALP) 
       PT 
aspartate aminotransferase (AST) 
       INR 
GFR (estimated- will be autocalc by 
database) 
 
 
14.3 Biomarker Samples 
The biomarker samples, migration inhibitory factor (MIF), (interleukin 1-beta (IL-1β), 
interleukin 6 (IL-6), tumor necrosis factor (TNFα), C-reactive protein (CRP), and other 
exploratory markers will be sent to a central laboratory. Biomarker samples will be collected at 
Screening, Day 1, Day 3, Day 5, Day 7, and Day 14. See Laboratory Manual for biomarker 
sample collection, processing, and shipping. 
14.4 Pharmacokinetic (PK) Samples 
Pharmacokinetic samples will be collected on Day 1: AM Predose, and at 2, 4, 8 and  
12 hours (Predose of PM dose), and on Day 3 and Day 5 at AM Predose.  
 
PK samples will be collected for 8 subjects only.  
See Laboratory Manual for PK collection, processing, and shipping. 
14.5 Clinical Assessment Scale 
At Screening and on Study Days 1 through 7, and on Days 14 28, and Day 60 of the Follow-up 
visits, subjects will be assessed using the NIAID 8-point ordinal scale: 
1) Death;  
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO);  
3) Hospitalized, on non-invasive ventilation or high flow oxygen devices;  
4) Hospitalized, requiring supplemental oxygen;  
5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise);  
6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care;  
7) Not hospitalized, limitation on activities and/or requiring home oxygen;  

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8) Not hospitalized, no limitations on activities 
 
15.0 STUDY ASSESSMENTS 
15.1 Screening 
After signing of informed consent form the following assessments will be performed: 
• Inclusion/Exclusion criteria review 
• Conduct brief physical exam 
• Assess clinical status using NIAID scale 
• Assess vital signs (BP, RR, HR, Temp) 
• Conduct ECG 
• Assess O2 use including CPAP, BiPAP, and nasal cannula and SpO2 
• Collect blood sample for biomarkers *(MIF, IL-1β, IL-6, TNF-α) 
• Complete blood count (CBC), comprehensive metabolic panel (CMP), CRP, D-dimer, 
and coagulation test (PT and INR) 
• Collect serum β-hCG in pre-menopausal women 
• Record prior medication use within the past 7 days prior to study drug administration 
 
*Biomarker blood sample collection is optional at Screening if the Screening and Day 1 
assessments occur on the same day but the sample must be collected pre-study drug dosing. 
15.2 Randomization 
Once all of the screening assessments have been conducted, subject will be randomized. 
Randomization will be stratified according to subject’s use of IL-6 antibody therapy and may 
occur on either the last day of screening or the morning of Day 1. 
15.3Treatment Phase  
       15.3.1 Day 1 (Baseline), Day 3, Day 5 and Day 7 
• Brief physical exam 
• Assess clinical status using NIAID scale 
• Assess vital signs (BP, RR, HR, Temp),  
• Assess O2 use including invasive mechanical ventilation, non-invasive ventilation 
(CPAP, BiPAP, nasal cannula high-flow oxygen), or ECMO and SpO2  
• 12-lead ECG (check between 2-4 hours after AM dose of study drug)  
• Collect blood sample for biomarkers (MIF, IL-1β, IL-6, TNFα) 
• Collect PK samples (except Day 7)  
• Comprehensive Metabolic Panel (CMP), Complete Blood Count (CBC), CRP, D-dimer, 
PT, INR 
• Adverse events review 
• Concomitant medication review  

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• Administer study drug (Study drug is administered every day on Days 1 through 7) 
 
15.3.2 Day 2, Day 4, and Day 6 
• Assess clinical status using the NIAID scale 
• Assess vital signs (BP, RR, HR, Temp) 
• Assess O2 use including invasive mechanical ventilation, non-invasive ventilation 
(CPAP, BiPAP, nasal cannula high-flow oxygen), or ECMO and SpO2 
• Administer study drug  
• Adverse events review 
• Concomitant medication review  
 
15.3.3 Follow-up Phase (Day 14 Day 28 and Day 60) 
The Follow-up Phase consists of a Day 14, Day 28, and Day 60 visit. 
 
Day 14  
• Brief physical exam 
• Assess clinical status using NIAID scale 
• Assess vital signs (BP, RR, HR, Temp) 
• Assess O2 use including invasive mechanical ventilation, non-invasive ventilation 
(CPAP, BiPAP, nasal cannula high-flow oxygen), or ECMO and SpO2 
• Collect blood sample for biomarkers (MIF, IL-1β, IL-6, TNFα)  
• Comprehensive Metabolic Panel (CMP), Complete Blood Count (CBC), CRP, D-dimer, 
PT, INR 
• Adverse events review 
• Concomitant medication review  
 
If subject is no longer hospitalized or cannot return due to COVID restrictions,  
a telephone follow-up to record O2 usage/levels, AEs and conmeds may be conducted. All other 
assessments are optional. 
 
Day 28  
 
• Assess clinical status using NIAID scale 
•  Assess O2 use including invasive mechanical ventilation, non-invasive ventilation 
(CPAP, BiPAP, nasal cannula high-flow oxygen), or ECMO and SpO2 
• Survival status 
• Adverse events review 
• Concomitant medication review  
 
If subject is not in the hospital, a telephone follow-up may be conducted. 
 
 

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Day 60  
 
The following assessments will be performed in all subjects: 
• Assess clinical status using NIAID scale 
• Assess O2 use including invasive mechanical ventilation, non-invasive ventilation (CPAP, 
BiPAP, nasal cannula high-flow oxygen), or ECMO and SpO2 
• Survival status 
• Adverse events review 
• Concomitant medication review  
 
In addition, for subjects who are intubated (at screening or during the study) perform the 
following: 
• Vital signs (BP, RR, HR, Temp)  
• 12-lead ECG  
• Comprehensive Metabolic Panel (CMP), Complete Blood Count (CBC), CRP, D-dimer, 
PT, INR  
 
 
 
15.3.4 Early Termination/Discharged from Hospital 
If subject is no longer hospitalized or cannot return due to COVID restrictions, a telephone 
follow-up to record O2 usage, AEs and conmeds taken will be conducted. All other assessments 
are optional. 
 
If subject terminates early from the study or is discharged from the hospital prior to completion 
of the Treatment Phase, complete assessments scheduled for that Study Day. If subject 
discontinues or are discharged on Days 2, 4, or 6, collect a biomarker sample in addition to their 
regularly scheduled assessments.   
 
Subjects who are discharged prior to Day 7, will be given their study medication to be taken at 
home and a pulse oximeter (ClinicalGuard CMS-50DL Fingertip Pulse Oximeter) supplied by 
the sponsor to record their O2 saturation once daily until Day 14.  
 
 
16.0 SAFETY ASSESSMENTS  
Adverse events (serious and non-serious) including all Suspected Unexpected Serious Adverse 
Reactions (SUSARs) should be collected from time of first dose of study drug until the end of 
their participation in the study (i.e., the subject has discontinued or completed the follow-up 
visit). 

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The PI or a qualified designee listed on Form FDA 1572 must assess the severity and 
relationship to study medication for all AEs.  
The PI, sub-investigator (Sub-I) and members of the clinical research team are responsible for 
identifying adverse events and reporting them to the RN/study 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 
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 treatment-emergent 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.  
16.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a study subject administered an 
investigational medicinal 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 the investigational medicinal product, whether or not considered related to the 
investigational medicinal product. Adverse events may include the onset of a new illness and the 
exacerbation of pre-existing conditions. 
16.2 Assessment of Adverse Events 
The PI or 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. These assessments will be made in accordance with the standard ratings detailed in the 
following sections. 
16.3 Severity Assessment 
The severity of AEs will be determined as described in Table 5. 
Table 5 Adverse Events Severity Definitions 
Mild 
Grade 1 
Ordinarily transient symptoms that do not influence performance of subject’s 
daily activities.  
Moderate 
Grade 2 
Marked symptoms sufficient to make the subject uncomfortable. Moderate 
influence on performance of subject’s daily activities.  
Severe 
Grade 3 
Symptoms cause considerable discomfort. Substantial influence on subject’s daily 
activities.  
Life-threatening 
Grade 4 
Extreme limitation in activity, significant assistance required; significant 
medical/therapy intervention required hospitalization probable. 

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When changes in the severity of an AE occur more frequently than once a day, the maximum 
severity 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. 
16.4 Relationship to Study Drug 
One of the following categories in Table 6 should be selected based on medical judgment, 
considering the definitions below and all contributing factors. 
Table 6 Adverse Events 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.  
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.  
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 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. Typically explained by 
extraneous factors (e.g., concomitant disease, environmental factors, or other 
medications or chemicals). 
16.5 Recording Adverse Events 
Adverse events should be collected and recorded for each subject from the date the patient 
receives study drug until the end of their participation in the study, (i.e., the subject has 
discontinued or completed the study) through the follow-up visit.  
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 PI’s or an authorized physician’s assessment of the 

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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 most 
current version of MedDRA. 
16.6 Treatment and Follow-Up of Adverse events (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. 
16.7 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. 
16.8 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 

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the end of the subject’s participation in the study, the PI or an authorized delegate should report 
SAEs “spontaneously” if considered at least possibly related to study medication. 
Notification of the SAE must be sent by fax (+01 858-404-0048) or email 
(safetyreports@medicinova.com) in the form of a completed SAE Report to the Sponsor. 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  
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 (+01 858-404-0048) 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 IRB/IEC(s) in accordance with the Sponsor’s 
standard operating procedures (SOP) and local regulatory requirements. 
The PI should report all Investigational New Drug Application safety alerts received from the 
Sponsor to the local or central IRB. 
  17.0 GUIDANCE FOR OVERDOSE  
There is no clinical experience with MN-166 overdose in humans and there is no available 
specific antidote (i.e., rescue protocol) to the effects of MN-166. Standard symptomatic support 
measures should be used in the case of excessive pharmacological effects or overdose. 
18.0 REPORTING AND FOLLOW-UP OF PREGNANCIES 
If any study subject or subject’s partner becomes pregnant after receiving the first dose of study 
medication 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, 

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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, the PI 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.  
An SAE Report Form should be completed 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. 
19.0 STATISTICAL CONSIDERATIONS 
Full details of the statistical methods including handling of missing data and deaths will be 
outlined in the statistical analysis plan. Since this is an early proof of concept study, no formal 
sample size calculations have been performed.  
19.1 Analysis Population 
Full Analysis Set: All subjects who sign informed consent, are randomized, receive treatment 
and have at least one post dose efficacy assessment. 
Per Protocol Analysis: all randomized subjects who sufficiently complied with the protocol. 
Details of the evaluability criteria will be outlined in the statistical analysis plan. 

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19.2 Primary Endpoints 
• 
Proportion of subjects free from respiratory failure as defined by the need for decreased 
oxygen requirements (invasive mechanical ventilation, non-invasive ventilation, high-
flow oxygen, or ECMO, CPAP, BiPAP, nasal cannula) at Day 28 
• 
Incidence of mechanical ventilation /intubation at Day 28 
• Mean change from baseline in clinical status using the NIAID 8-point ordinal scale at 
Day 28 
• Percentage of patients with at least a one-point improvement in clinical status using the 
NIAID 8-point ordinal scale at Day 28 
• All cause mortality at Day 28  
19.3 Secondary Endpoints 
• Incidence, frequency, and severity of adverse events at Day 7, 14, 28, and Day 60 Mean 
change from baseline of the following parameters at Day 7, 14, and Day 60 (in intubated 
subjects only): 
o Mean change from baseline in ALT 
o Mean change from baseline in AST 
o Mean change from baseline in serum creatinine 
o Mean change from baseline in BUN 
o Mean change from baseline in complete blood count 
o Mean change from baseline total bilirubin 
o Mean change from baseline in D-dimer 
• Proportion of subjects free from respiratory failure as defined by the need for decreased 
oxygen requirement (invasive mechanical ventilation, non-invasive ventilation, high-flow 
oxygen, or ECMO, CPAP, BiPAP, nasal cannula) at Days 7, 14, and Day 60 
• Incidence of mechanical ventilation /intubation at Day 7, Day 14, and Day 60 
• Incidence of ICU admission 
• Mean change from baseline in clinical status using the NIAID 8-point ordinal scale at 
Days 7, 14, and Day 60   
• Percentage of patients with at least a one-point improvement in clinical status using the 
NIAID 8-point ordinal scale at Day 7, Day 14, and Day 60  
• All-cause mortality at Days 7, 14, and Day 60  
• Mean change from baseline in migration inhibitory factor (MIF), interleukin 1-beta (IL-
1β), interleukin 6 (IL-6), tumor necrosis factor (TNFα), and C-reactive protein (CRP) at 
Day 7 
• PK plasma concentrations  
19.4 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 

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summarized by severity (mild, moderate, or severe), as well as by relationship to treatment (not 
related, possibly related, or probably related) and by seriousness. 
19.5 Pharmacokinetic Analysis 
Plasma concentrations of MN-166 will be summarized.  
20.0 ETHICS 
20.1 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 Harmonization) GCP, local laws, 
regulations, and organization. When necessary, an extension, amendment or renewal of the IRB 
approval must be obtained. 
20.2 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). The clinical trial will also be 
carried out in accordance with applicable local law(s) and regulation(s).  
20.3 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. 
20.4 Confidentiality 
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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21.0 REFERENCES 
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inhibitory factor in tumorigenesis and central nervous system tumors. Cancer 2009;115(10):2031–
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Chen RW, Williams AJ, Liao Z, Yao C, Tortella FC, Dave JR. Broad spectrum neuroprotection profile of 
phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 
activation. Neurosci Lett 2007(418):165-9. 
Cho, Y, Crichlow GV, Vermeire JJ, et al. Allosteric inhibition of macrophage migration inhibitory factor 
revealed by ibudilast. PNAS – USA, 2010 Jun 22;107(25):11313-8. 
De Visser YP, Walther FJ, Laghmani EH, van Winjngaarden S, Nieuwland K, Wagenaar GT. 
Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury. Eur 
Respir J 2008 Mar;31(3):633-44. Epub 2007 Dec 19. 
Ellis A, Wieseler J, Favret J, Johnson KW, Rice KC, Maier SF, Falci S, Watkins LR. Systemic 
administration of propentofylline, ibudilast, and (+)-naltrexone each reverses mechanical allodynia 
in a novel rat model of central neuropathic pain. J Pain. 2014 Apr;15(4):407-21. doi: 
10.1016/j.jpain.2013.12.007. Epub 2014 Jan 9. PMID: 24412802; PMCID: PMC3972272. 
Eworuke E, Major JM, Gilbert McClain LI. National incidence rates for Acute Respiratory Distress 
Syndrome (ARDS) and ARDS cause-specific factors in the United States (2006-2014). J Crit Care. 
2018 October; 47:192-197. doi: 10.1016/j.jcrc.2018.07.002 Epub 2018 Jul 10. 
Gibson L, Hastings S, McPhee I, Clayton R, Darroch C, Mackenzie A, Mackenzie F, Nagasawa M, 
Stevens P, Mackenzie S. The inhibitory profile of ibudilast against the human phosphodiesterase 
enzyme family. Eur J Pharmacol 2006 24;538(1-3):39-42. 
Inacio AR, Ruscher K, Leng L, et al. Macrophage migration inhibitory factor promotes cell death and 
aggravates neurologic deficits after experimental stroke. J Cereb Blood Flow Metab 2011 
Apr;31(4):1096-106. Epub 2010 Nov 10. 
Kaplan A, Spiller KJ, Towne C, et al. Neuronal matrix metalloproteinase-9 is a determinant of selective 
neurodegeneration. Neuron. 2014;81(2):333-48. doi:10.1016/j.neuron.2013.12.009 
Kawanokuchi J, Mizuno T, Kato H, Mitsuma N, Suzumura A.  Effects of interferon-beta on microglial 
functions as inflammatory and antigen presenting cells in the central nervous system. 
Neuropharmacol 2004;46(5):734-42. 
Kithcart A, Cox GM, Sielecki T et al. A small-molecule inhibitor of macrophage migration inhibitory 
factor for the treatment of inflammatory disease.  Faseb J 2010;11:4459-66. 
Kosutova P, Mikolka P, Kolomaznik M, Rezakova S, Calkovska A, Mokra D. Effects of roflumilast, a 
phosphodiesterase-4 inhibitor, on the lung functions in a saline lavage-induced model of acute lung 
injury. Physiol Res 2017 Sep 22;66(Suppl.2):S237-S245. 
Lai KN, Leung JC, Metz CN, Lai FM, Bucala R, Lan HY. Role for macrophage migration inhibitory 
factor in acute respiratory distress syndrome. J Pathol 2003;199(4):496–508. doi:10.1002/path.1291 
Ledeboer A, Liu T, Shumilla JA, Mahoney JH, Vijay S, Gross MI, et al. The Glial Modulatory Drug 
AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biology 
(Pain special issue) 2007;2:279-91. 
 

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Lee JY, Cho E, Ko YE, et al. Ibudilast, a phosphodiesterase inhibitor with anti-inflammatory activity, 
protects agains ischemic brain injury in rats. Brain Res Brain Res. 2012;1431:97–106. 
doi:10.1016/j.brainres.2011.11.007 
Mizuno T, Kurotani T, Komatsu Y et al. Neuroprotective role of phosphodiesterase inhibitor ibudilast on 
neuronal cell death induced by activated microglia. Neuropharmacology 2004;46(3):404-11. 
Nakamizo T, Kawamata J, Yoshida et al. Phosphodiesterase inhibitors are neuroprotective to cultured 
spinal motor neurons. J Neurosci Res 2003; 71:485-95. 
Nishio Y, Koda M, Hashimoto M et al. Deletion of macrophage migration inhibitory factor attenuates 
neuronal death and promotes functional recovery after compression-induced spinal cord injury in 
mice. Acta Neuropathol 2009;117(3):321-8. 
Powell ND, Papenfuss TL, McClain MA et al. Cutting edge: macrophage migration inhibitory factor is 
necessary for progression of experimental autoimmune encephalomyelitis. J Immunol 2005 Nov 
1;175(9):5611–4. 
Ranieri VM, Rubenfeld GD, Thompson BT, et al; ARDS Definition Task Force. Acute respiratory 
distress syndrome: the Berlin Definition. JAMA 2012; 307(23):2526-2533. 
Suzumura A, Ito A, Yoshikawa M, Sawada M.  Ibudilast suppresses TNF-alpha production by glial cells 
functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res 1999;837(1-2):203-
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Takuma K., Lee E., Enomoto R., Mori K., Baba A. and Matsuda T. (2001) Ibudilast attenuates astrocyte 
apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model. British J Pharmacol 
2001;133:841–8. 
Tominaga Y., Nakamura Y., Tsuji K., Shibata T. and Kataoka K. Ibudilast protects against neuronal 
damage induced by glutamate in cultured hippocampal neurons.  Clin Exper Pharmacol Physiol 
1996;23:519–523. 
Wakita H, Tomimoto H, Akiguchi I, Lin JX, et al. Ibudilast, a phosphodiesterase inhibitor, protects 
against white matter damage under chronic cerebral hypoperfusion in the rat. Brain Res 2003; 
992:53-59. 
Yagi K, Tada Y, Kitazato KT, Tamura T, Satomi J, Nagahiro S. Ibudilast inhibits cerebral aneurysms by 
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Mar;66(3):551-9. 
Yang D, Yang Y, Zhao Y. Ibudilast, a Phosphodiesterase-4 inhibitor, ameliorates Acute Respiratory 
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2020; 26:e922281 
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Yoshioka A, Yamaya Y, Saiki S, Kanemoto M, Hirose G, Pleasure D.  Cyclic GMP/cyclic GMP-
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“Model” Informed Consent 
This is a “Model” informed consent provided by MediciNova, Inc., only as a guide for 
the convenience of the Principal Investigator and the affiliated institution. It is the 
responsibility of each Investigator and institution to draft and obtain IRB/EC/REB 
approval of an Informed Consent that complies with Regulatory guidelines and 
ethical standards for their particular site. Any use, in whole or in part, of this 
“Model” Informed Consent shall be at the sole discretion of said Investigator and 
institution, and MediciNova, Inc., shall have no liability for the form or content of the 
Informed Consent adopted for actual use by said Investigator and institution. 
 
Subject Information Sheet 
and Consent Form  
Protocol Number 
MN-166-COVID-19-201 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group Study to Evaluate the Safety, Tolerability, Biomarkers 
and PK of ibudilast (MN-166) in COVID-19 Subjects at Risk for 
Developing Acute Respiratory Distress Syndrome (ARDS) 
Principal Investigator 
(Study Doctor) 
 
Sponsor 
MediciNova, Inc. 
4275 Executive Square 
Suite 300 
La Jolla, CA 92037 
Sponsor Contact 
Kazuko Matsuda, MD, PhD, MPH 
Chief Medical Officer, MediciNova, Inc.  
(858) 373-1500 
Date 
31 March 2021 
 
 
 
 
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Invitation to Participate in a Research Study 
You are being asked to participate in a research study because you are at risk for developing Acute 
Respiratory Distress Syndrome, or ARDS. In order to decide whether or not to take part in this 
research study, you should know enough about its risks and benefits to make a decision. This 
process is called informed consent. 
The following information is provided in order to help you make an informed decision whether 
or not to participate in this study.  Please read this consent form carefully and take your time 
making your decision.  Please ask the study doctor or the study staff to explain any words or 
information that you do not clearly understand.  You will receive a copy of this signed and dated 
consent form to keep. For the purposes of this research, you will be referred to as a 
“participant.” 
It is expected that about 40 people will take part in this research study.  
MediciNova, Inc, a pharmaceutical company, is the sponsor of the study and is providing 
funding for the research study, including the study drug. 
XXX Hospital will be paid by the sponsor to conduct this research study.  
Purpose of this Research Study 
You are being asked to take part in this Phase 2 research study to evaluate the safety and 
tolerability of ibudilast (also called MN-166) compared to placebo (pills that looks like MN-166 
capsules but contain no active medicine).  Ibudilast is the investigational drug (study medication) 
being studied. ‘Investigational’ means that the drug has not been approved for treatment of any 
indication by the U.S. Food and Drug Administration (FDA).  
This is the first study to test ibudilast in subjects who have been diagnosed with COVID-19 and 
are at risk for developing ARDS.  
The study will be conducted at two study sites and approximately 40 subjects will be involved in 
this research study which will last for approximately 30 days in non-intubated patients and 60 
days in patients who are intubated days.  
The purpose of this study is to see if ibudilast can help prevent acute respiratory distress 
syndrome (ARDS), a serious lung injury in patients who are diagnosed with COVID-19 and have 
an increased risk of developing ARDS such as: 
• Age greater than 65 years old 
• Serious heart disease 
• Chronic lung disease 
• Moderate to severe asthma 
• Diabetes, and/or  
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• Have a BMI (body mass index) at or greater than 40.  
 
Ibudilast has been approved in Japan for over 30 years for treatment of post-stroke dizziness and 
asthma. However, ibudilast has not been approved by the US Food and Drug Administration 
(FDA) for use in the US, Canada and Europe. This means that ibudilast can only be used in 
research studies. So far, this drug has been given to more than 750 people who have participated 
in clinical trials including healthy volunteers, people with diabetes who have nerve pain, and 
people with multiple sclerosis and amyotrophic lateral sclerosis (ALS). 
 
What should you know before you give consent? 
You are at risk for developing ARDS (acute respiratory distress syndrome) and are now 
considering the use of ibudilast because your doctor believes that ibudilast may help prevent it 
from occurring.  
Before you consent to receiving treatment with ibudilast, you must be informed of the following: 
• In this study, you will receive standard of care and will have all the standard medications 
and procedures given for your condition. 
• Ibudilast is not proven to prevent ARDS, therefore, there is no promise that your 
condition will not get worse; 
• You do not have to take this experimental drug and your decision about what to do must 
be made voluntarily. 
The experimental drug, Ibudilast, has not received approval for use in humans from the U.S. 
Food and Drug Administration (FDA). Research studies to see how safe and how effective this 
drug treats diseases have been conducted and future clinical trials are possible. Your study doctor 
has agreed to be the Principal Investigator, that is, they accept the responsibilities that come 
along with treating a patient with an experimental drug. These responsibilities include, but are 
not limited to, the following:  
• Carrying out the research study as described;  
• Monitoring you for safety, tolerability, and changes in your condition, if any, throughout 
the course of treatment and post-treatment;  
• Submitting the necessary documents to the FDA, Institutional Review Board (IRB), and 
the sponsor throughout the course of treatment and follow-up.  
 
What will happen to you during the study? 
In order to enroll in the study, you will have to review and sign this Information and Informed 
Consent Form before having any study-specific procedures to determine if you are eligible to 
participate.  
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The study consists of a Screening Phase, a 7-day double-blind Treatment Phase and a Follow up 
Phase consisting of Day 14, Day 28 and Day 30 visits. Screening procedures may be done over a 
3-day period. Study drug will be given to you twice a day (at around breakfast and dinner time) 
for 7 days. Two days after you finish taking study drug, you will be assessed for clinical status 
and side effects. At 30 days after taking study drug, you will have a follow-up call to see how 
you are doing. 
If you are eligible to participate, you will be randomized to one of two study drug treatments. 
“Study drug” used in this consent form refers to both MN-166 and placebo. Being randomized 
means that you are put in a group by a chance process, like flipping a coin. You won't know what 
group you are in and neither will your study doctor, study team or sponsor. You will have a 1 out 
of 2 (or 50%) chance of being assigned to the MN-166 group and 1 out of 2 (or 50%) chance of 
being assigned to the placebo group. The placebo looks like ibudilast but does not contain the 
active drug.  Although you and your doctor will not know which study drug you are receiving, 
this information can be determined in the event of an emergency.  
During the study, and after signing the Information and Consent form, the following procedures 
and assessments will be done. 
Screening Procedures: 
• Confirm that you are eligible to participate in the study 
• A physical exam will be done 
• Your clinical status will be assessed using a brief questionnaire 
• Your vital signs (blood pressure, heart rate, pulse, and temperature) will be taken 
• A 12-lead ECG will be performed 
• Your oxygen use including CPAP, BiPAP, and nasal cannula will be assessed 
• A blood sample to collect biomarkers and routine clinical labs (complete blood 
count and comprehensive metabolic panel) will be taken from a needle in your arm 
for routine laboratory tests and biomarkers (to measure inflammation in your body). 
The total amount of blood that will be taken will be about 2 tablespoons; 
• If you are a female of child-bearing potential, you will be given a pregnancy test; 
• You will be asked to report any prior medications taken within 7 days of starting the 
investigational drug; 
Upon review of all labs, tests and clinical status, Dr. XXX or a designated study associate, will 
speak with you about beginning participation in this research study. 
Treatment Phase: 
Once you have been randomly assigned to receive either ibudilast (MN-166) or placebo, the 
following assessments will be completed on Study Days 1 through 7: 
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• Ibudilast (MN-166) or placebo capsules will be given to you twice a day, once in 
the AM and once in the PM; 
• A physical exam will be done 
• Your oxygen use including CPAP, BiPAP, and nasal cannula will be measured; 
• Your clinical status will be assessed; 
• You will be asked questions about your general health; 
• You will be asked if there was a change in your medication(s). 
In addition, on Study Days 1, 3, 5 and 7, a 12-lead ECG will be done and a blood sample will be 
taken from a needle in your arm for routine, laboratory tests, biomarkers and pharmacokinetic 
samples to measure the amount of ibudilast in your blood. The total amount of blood that will be 
taken is estimated to be about 2 tablespoons (30 CC). 
Study Day 14 
The following assessments will be completed on Study Day 14: 
• A physical exam will be done 
• Your clinical status will be assessed using a brief questionnaire 
• Your vital signs (blood pressure, heart rate, pulse, and temperature) will be taken 
• Your oxygen use including CPAP, BiPAP, and nasal cannula will be measured; 
• A blood sample to collect biomarkers and routine clinical labs (complete blood 
count and comprehensive metabolic panel) will be taken from a needle in your arm 
for routine laboratory tests and biomarkers (to measure inflammation in your body). 
The total amount of blood that will be taken will be about 2 tablespoons; 
• You will be asked questions about your general health and any medications you may 
have taken 
 
Study Day 28 
The following assessments will be completed on Study Day 28: 
• Your clinical status will be assessed using a brief questionnaire 
• Your oxygen use including CPAP, BiPAP, and nasal cannula will be measured; 
• You will be asked questions about your general health and any medications you may 
have taken 
 
Study Day 60 
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The following assessments will be completed on Study Day 60: 
• Your clinical status will be assessed using a brief questionnaire 
• Your oxygen use including CPAP, BiPAP, and nasal cannula will be measured; 
• You will be asked questions about your general health and any medications you may 
have taken 
In addition, for subjects who are intubated (at screening or during the study the following will 
be done at Study Day 60: 
• Vital signs (blood pressure, heart rate, pulse, and temperature) 
• 12-lead ECG  
• A blood sample will be taken for routine labs  
If you are discharged from the hospital early, you will be given your study medication with 
instructions to take at home. You will also be given a pulse oximeter, a device to measure your 
oxygen levels, once a day up to Day 14. You do not need to return the device.  
 
As a participant in this study, you have certain responsibilities to help ensure your safety. 
These responsibilities are listed below: 
• Report all side effects and medical problems to the study personnel; 
• Inform the study doctor or staff if you decide to discontinue your participation 
at which time you will be requested to complete the assessments that were 
scheduled on the last day of study treatment. 
What are the risks associated with this study? 
While participating in this research study, you are at risk for side effects. Your study doctor will 
discuss these with you. The treatment used in this study may cause all, some, or none of the side 
effects listed. There also may be other side effects that have not been reported. Other drugs may 
be given to manage side effects and make you more comfortable (such as for nausea or 
headache). Many side effects go away shortly after the treatment is stopped, but in some cases 
side effects can be serious, or long-lasting.  
The known side effects are: 
Likely  (occurring in more than 20% of people taking the drug) 
 
 
• none 
 
Less Likely (occurring in less than 5% of people taking the drug)  
• appetite loss 
• nausea  
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• diarrhea  
• headache  
• rash 
• itching 
Rare but serious (uncommon, between 1-10 out of 1000 people who have taken MN-166) 
elevated liver enzymes which can be an indication of liver damage.  
Because this treatment is considered investigational and has not received FDA approval, there 
may be other risks that we do not know about at this time.  
 
Risk of Allergic Reaction  
As with any drug, an allergic reaction can occur. Allergic reactions can be mild or serious, which 
can even result in death in some cases. Common symptoms of an allergic reaction are rash, 
itching, skin problems, swelling of the face and throat, or trouble breathing. If you think you are 
having an allergic reaction or you are having trouble breathing, seek help from medical 
personnel right away.  
 
Number of Subjects who took Ibudilast in Prior Clinical Trials 
Approximately 750 people, including nearly 300 with multiple sclerosis (another serious 
neurological disease), 130 with progressive MS and nearly 50 with early ALS (ALS history 
within 5 years) have been treated with MN-166 in research studies. Generally, good safety and 
tolerability have been seen. The side effects that were seen in a 2-year study were gastrointestinal 
(meaning related to the stomach and intestines), and included nausea and diarrhea, and an 
increase in liver enzymes.   
MN-166 has been given to nearly 300 patients with relapsing remitting multiple sclerosis. There 
were 20 serious adverse events (side effects) reported. Most of the serious adverse events were 
gastrointestinal in nature or having to do with bone fractures. All of these serious adverse events 
were considered by the study doctors to be unlikely or not related to MN-166. Six of the serious 
adverse events were considered severe and two were considered life-threatening. Nine subjects 
stopped the study due to a side effect.  Two side effects (liver disorders) were possibly related to 
taking MN-166. 
MN-166 was given to approximately 130 patients with progressive multiple sclerosis. There 
were 58 serious adverse events (31 in placebo group, 27 in MN-166 group) reported.  Two 
serious adverse events were considered possibly related to study treatment: thrombocytopenia in 
the placebo group and ataxia in the MN-166 group. 
MN-166 were given to nearly 50 subjects with early ALS patients (ALS history within 5 years). 
A total of 7 serious adverse events were reported in ALS patients. All of the serious adverse 
events were considered to be unlikely or unrelated to study drug by study doctor. Four of these 
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serious events were considered severe (dysphagia, ureteral stone, pneumonia and ankle fracture) 
and bowel obstruction was considered life-threatening.  
As noted from the above-mentioned studies, gastrointestinal (GI) distress, which includes nausea 
and diarrhea, appears to be the most common side effect. The GI symptoms associated with MN-
166 tend to occur early (within 1-2 weeks) and usually last for only a few days or weeks and then 
improve. These symptoms may be relieved with anti-diarrheal or anti-nausea drugs, if necessary. 
Usually, a majority of those receiving MN-166 recover from these symptoms within several days 
(with or without anti-diarrheal drugs). Talk to your study doctor if you experience these 
symptoms, particularly if they last for more than 2-3 weeks.  
Other rare side effects associated with MN-166 are cold symptoms, itching sensation, rash, 
dizziness, tremors, insomnia (trouble sleeping), drowsiness, sudden blushing, anorexia 
(decreased appetite), abdominal pain, abdominal bloating, palpitations, flushed appearance, 
anemia (low red blood cell counts), low white blood cells, tiredness, facial edema (swelling), 
abnormal sound sensitivity (changes in your hearing) and metallic taste in your mouth.     
Risks associated with blood drawing may include pain, bruising, and infection. Rarely, a person 
will faint. 
Reproductive Risks 
The effect of MN-166 on an embryo or fetus (developing baby still in the womb), or on a 
breastfeeding infant, is unknown and may be potentially harmful. Because of these unknown 
risks, if you are capable of giving birth to or fathering a child, you and your sexual partner 
should use adequate birth control measures while you are in this study. If you are a female who 
is sexually active and able to become pregnant, or a man with a sexual partner who is able to 
become pregnant, you must agree to use one or more of the birth control methods listed below. 
You must use birth control for the entire study and at least 30 days after your last dose of study 
drug. Acceptable birth control methods for this study are:  
• Abstinence (no sex) 
• Oral contraceptives (birth control pills) 
• IUD (a small T-shaped device containing either copper or a hormone inserted into the 
womb for birth control) 
• Diaphragm with spermicide (a foam, cream or gel that kills sperm)  
• Norplant (birth control capsules that are inserted in the skin of the upper arm of a female) 
• Approved hormone injections 
• Condoms with spermicide 
•  
Women cannot take part in this study if they are: 
• Pregnant 
• Trying to become pregnant  
• Breastfeeding 
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If you are a menopausal woman and have not had a period for the past 12 months or more, you 
will not need to have a pregnancy test. Also, you will not need to have a pregnancy test if you 
have had a well-documented method of surgical sterilization (meaning hysterectomy or had your 
tubes tied/tubal ligation).  All other female subjects must have a negative pregnancy test before 
starting the study drug. 
If during the study you think you are pregnant, you must tell your study doctor and stop taking 
the study drug immediately. Your study doctor may ask you about the outcome of your 
pregnancy.  
Men cannot take part in this study if they are actively trying to get their sexual partner pregnant. 
During this study if you think your partner is pregnant you must tell the study doctor 
immediately. Your study doctor may ask you about the outcome of your partner’s pregnancy. 
What if there are new findings about the study drug? 
You will be told about any new information that might change your decision to take this 
experimental drug. 
 
What are the possible benefits of taking part in this study? 
There may be no direct clinical benefit from participating in this study. However, the information 
obtained from this study will be used by the Sponsor to determine the safety and tolerability of 
the study drug and may help in the future development of a new therapy for patients who are at 
risk for developing ARDS. 
 
What will it cost me to take part in this study? 
The cost of the study drug will be paid for by the sponsor, MediciNova. The cost for some of 
your tests may be billed to your insurance. 
 
Can you choose to not participate or withdraw from the study without penalty or loss of 
benefits? 
Your participation in this study is completely voluntary. You may refuse to participate or withdraw 
from the study at any time. If you refuse to participate or withdraw from the study, you will not be 
penalized or lose any benefits and your decision will not affect your relationship with your doctor 
or hospital. 
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However, if you decide to stop study participation, you are encouraged to talk with your doctor 
regarding safe removal from the study as described below. If you must be discontinued from the 
study prior to its completion, you will be asked to have a final assessment to evaluate your general 
health. 
 
What alternatives are there if I do not want to take the experimental drug? 
You do not have to participate in this study to receive treatment for your condition. The study 
doctor will discuss other treatment options with you, including any potential side effects or risks. 
If you decide not to take part in this study it will not affect your ability to receive medical care. 
You will be treated as per standard of care.  
Does my doctor need my authorization to use and disclose my health information?  
Federal regulations give you certain rights related to your health information. These include the 
right to know who will be able to get the information and why they may be able to get it. Your 
doctor must get your authorization (permission) to use or give out any health information that 
might identify you. 
What about your confidentiality?   
Research records will be kept confidential to the extent allowed by law. The records of this study 
will be kept private.  In any kind of report published, we will not include any information that 
will make it possible to identify a patient. Under the terms specified in the Health Insurance 
Portability and Accountability Act of 1996 you have the right to privacy, and all information 
obtained in this clinical research study that can identify you will remain confidential to the 
greatest extent possible within state and federal laws.  Your name will not be revealed in any 
reports or publications resulting from this study.  The United States Food and Drug 
Administration (FDA), the Institutional Review Board (IRB), Sponsor and/or its designee (the 
study monitor), may inspect and copy your records pertaining to this study. The results of the 
study will be reported to the FDA and possibly other governmental agencies.  
When FDA requires subject names, FDA will treat such information as confidential; however 
disclosure to third parties may be required on rare occasions.  Therefore, absolute protection of 
confidentiality by FDA cannot be promised or implied. Every effort will be made to keep your 
personal information confidential. 
 
What will happen to the results of this clinical study? 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify you. At most, the web- 
site will include a summary of the results. You can search this website at any time. 
The results of this study will be used to make informed clinical decisions for developing this new 
study drug. If you want the results to be made available to you, please talk to the study doctor. 
Results from clinical studies are often published in scientific journals, however, your personal 
information will remain confidential. 
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Will you be compensated for participating in this study? 
You will not be paid to participate in this research study. However, you will be reimbursed for 
travel expenses, if applicable, when accompanied by receipts. Your study coordinator will discuss 
this with you.  
Who may use and give out information about me? 
Information about your health may be used and given to others by your doctor and staff. This 
may include information obtained both during and after the experimental treatment. 
Who might get this information? 
Anyone working for or with your doctor may have access to your medical and experimental drug 
treatment information. 
Information about you and your health that might identify you may be given to: 
• The U.S. Food and Drug Administration (FDA) 
• Department of Health and Human Services (DHHS) agencies 
• Governmental agencies in other countries 
• The [Name of Institutional Review Board] 
• MediciNova, Inc. (sponsor) 
What if I decide not to give permission to use and give out my health information? 
By signing this consent form, you are giving permission to use and give out the health 
information listed above for the purposes described above. If you refuse to give permission, you 
will not be able to be treated with the experimental drug. 
 
May I review or copy the information obtained from me or created about me? 
You have the right to review and copy your health information.  
May I withdraw or revoke (cancel) my permission? 
Yes, but this permission will not stop automatically. You may withdraw or take away your 
permission to use and disclose your health information at any time. You do this by giving written 
notice to your doctor. If you withdraw your permission, you will not be able to continue taking 
the experimental drug. 
When you withdraw your permission, no new health information that might identify you will be 
gathered after that date. Information that has already been gathered may still be used and given 
to others.  
What happens if I am hurt while taking Ibudilast? 
If it is determined by Dr. Geoffrey Chupp that an injury occurred as a direct result of taking 
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CONFIDENTIAL
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MN-166 oral capsule
______________________________________________________________________________________________
IND 149627 / Sequence No. 0006
Protocol No. MN-166-COVID-19-201 (Amendment 4) - Model Informed Consent and Information Sheet
MediciNova Inc.

Page 12 of 13 
 
Ibudilast, then you and/or your insurance will not have to pay for the cost of immediate medical 
care to treat the injury. 
There are no plans to pay for any injury caused by the usual care you would normally receive for 
treating your illness or the costs of any additional care. 
By signing this consent form, you will not give up any legal rights. 
Who do I call if I have questions or concerns? 
Contact Dr. XXX at XXX-XXX-XXXX, or Dr. Kazuko Matsuda, Chief Medical Officer at 
MediciNova (858-373-1500) for any of the following reasons: 
• If you have any questions concerning your participation in this study;   
• If at any time, you feel you have experienced a study-related injury or a reaction to the 
experimental drug and for information about how to receive treatment; or 
• If you have questions, concerns or complaints about the study 
If you have questions about your rights as a patient in this study or if you have questions, 
concerns or complaints about the study, you may contact: 
[Name, address and contact information of Institutional Review Board) 
Telephone:   
E-mail:   
[Name of IRB] is a group of people who independently review research, including single patient 
treatment plans. 
[Name of IRB] will not be able to answer some study-specific questions, such as questions about 
appointment times. However, you may contact [Name of IRB] if your doctor or your doctor’s 
staff cannot be reached or if you wish to talk to someone other than your doctor or doctor’s staff. 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
If you agree to participate in this study, you will receive a signed and dated copy of this consent 
form for your records. 
 
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CONFIDENTIAL
______________________________________________________________________________________________
MN-166 oral capsule
______________________________________________________________________________________________
IND 149627 / Sequence No. 0006
Protocol No. MN-166-COVID-19-201 (Amendment 4) - Model Informed Consent and Information Sheet
MediciNova Inc.

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CONSENT 
I have read the information in this consent (or it has been read to me). All my questions about 
this research study and my participation in it have been answered. I freely consent to participate 
in this research study. 
 
I authorize the use and disclosure of my health information to the parties listed in the 
authorization section of this consent for the purposes described above.  
 
By signing this consent form, I have not given up any of my legal rights. 
 
 
________________________________________ 
Print [Name of Patient] 
 
CONSENT SIGNATURES: 
 
 
________________________________________ 
__________________ 
Signature of Patient 
Date 
 
 
________________________________________ 
__________________ 
Signature of person obtaining consent 
Date 
 
 
 
_______________________________________________________________________ 
 
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MN-166 oral capsule
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Protocol No. MN-166-COVID-19-201 (Amendment 4) - Model Informed Consent and Information Sheet
MediciNova Inc.

MediciNova Inc. 
Protocol No: MN- 166-COVID- 19-20 I 
Statistical Analysis Plan Y2.0 
18 August 2022 
ST A TISTICAL ANALYSIS PLAN 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the 
Efficacy, Safety, Tolerability, Biomarkers and Pharmacokinetics oflbudilast (MN-166) in 
COVID-19 Subjects at Risk for Developing Acute Respiratory Distress Syndrome 
Authored 
bv: 
Reviewed 
bv: 
Contributor: 
Approved 
by: 
Date: 
MN-166-COVID-19-201 
Protocol Version: Amendment 2 (03 November 2020) 
Protocol Version: Amendment 4 (31 March 2021) 
Name 
Sie:nature 
Malath Makhay, PhD 
Director, Research & 
Development 
MediciNova, Inc. 
Trina Wells 
,J1-j-
Data Scientist I 
MediciNova, Inc. 
Charles S Davis, PhD 
Date 
18-AUG-2022 
18-Aug-2022 
ddlr/J(fa/, 
Biostatistician 
Jf" /J IAj v 21/?2__ 
CSD Biostatistics, Inc 
Kazuko Matsuda, MD, 
PhD, MPH 
Chief Medical Officer 
18-AUG-2022 
MediciNova, Inc. 
August 18, 2022 
Version: 2.0 (replaces SAP vl.0) 
Confidential 
Page. 1 of 23 

MediciNova Inc. 
 
Statistical Analysis Plan V2.0  
Protocol No: MN-166-COVID-19-201 
 
18 August 2022 
 
Confidential 
  
 
Page: 2 of 23 
 
HISTORY OF CHANGES 
All versions of the document must be documented in the table of history of changes. The 
owner of this document must act in accordance with the latest version of the document.  
Version 
 
Effective Date 
 
Change description 
2.0 
August 18, 2022 
. Section 1 Introduction 
• Age range was corrected to reflect protocol. 
• Discrepancies between protocol and SAP was 
addressed 
. Section 2.2.3 Secondary Outcome Variables 
• Exploratory Analysis was described. 
. Section 6 Analysis Population 
• Full Analysis Set was corrected 
. Section 10.1. Primary Efficacy Variable Analysis 
• Nonresponders in the study were defined 
• A supportive analysis for each of the two co-
primary endpoints will be conducted. 
. Section 10.2 Secondary Efficacy Variable Analysis 
• Secondary endpoints that are defined as the change 
from baseline will be analyzed using analysis of 
covariance (ANCOVA) models 
1.0 
May 18, 2022 
None: Initial Document 
 
 

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TABLE OF CONTENTS    
 
1 
INTRODUCTION ........................................................................................................ 6 
2 
STUDY OBJECTIVE AND ENDPOIINTS .............................................................. 6 
2.1 
Study Objectives .......................................................................................................... 6 
2.1.1 Primary objectives ................................................................................................... 6 
2.1.2 Secondary Objectives .............................................................................................. 6 
2.2 
Study Endpoints (Outcome Variables) ........................................................................ 7 
2.2.1 Co-Primary Outcome Variable(s) ........................................................................... 7 
2.2.2 Secondary Outcome Variable(s) ............................................................................. 7 
2.2.3 Exploratory Endpoints ............................................................................................. 8 
3 
STUDY METHODS AND ENDPOINTS ................................................................... 8 
3.1 
Overall Study Design and Plan .................................................................................... 8 
3.2 
Selection of Study Population ...................................................................................... 8 
3.3 
Method of Treatment Assignment and Randomization ............................................... 9 
3.4 
Treatment Masking (Blinding)..................................................................................... 9 
4 
SEQUENCE OF PLANNED ANALYSIS .................................................................. 9 
4.1 
Interim Analysis ........................................................................................................... 9 
4.2 
Data Monitoring Committee Meetings ........................................................................ 9 
5 
SAMPLE SIZE DETERMINATION ......................................................................... 9 
6 
ANALYSIS POPULATIONS ...................................................................................... 9 
6.1 
Use of analysis populations in different analyses ...................................................... 10 
7 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ......................................... 10 
7.1 
Definition of Treatment Arms .................................................................................... 10 
7.2 
Definition of Baseline ................................................................................................ 10 
7.3 
Definition of Visit Windows ...................................................................................... 10 
7.4 
Multicenter Study ....................................................................................................... 10 
7.5 
Multiple Comparisons and Multiplicity ..................................................................... 11 
7.6 
Planned Subgroup Analyses....................................................................................... 11 
7.7 
Analysis Software ...................................................................................................... 11 
7.8 
Clinical Status Scale................................................................................................... 11 
8 
STUDY PARTICIPANTS ......................................................................................... 11 
8.1 
Disposition of Participants and Withdrawals ............................................................. 11 

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8.2 
Protocol Deviations .................................................................................................... 12 
8.3 
Inclusion and Exclusion Criteria ................................................................................ 12 
9 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .............. 12 
9.1 
Demographics ............................................................................................................ 12 
9.2 
Prior and Concomitant Medications .......................................................................... 12 
9.3 
Baseline and Screening Conditions............................................................................ 13 
9.3.1 Baseline Medical History ...................................................................................... 13 
10 EFFICACY ANALYSIS ............................................................................................ 13 
10.1 Primary Efficacy Variable Analysis .......................................................................... 13 
10.2 Secondary Efficacy Variable Analysis ...................................................................... 14 
10.3 Exploratory Analysis.................................................................................................. 14 
10.4 Pharmacokinetics Analysis ........................................................................................ 14 
10.4.1 Pharmacokinetic Samples ...................................................................................... 14 
10.4.2 Pharmacokinetic Parameters ................................................................................. 14 
11 SAFETY AND TOLERABILITY ANALYSIS ....................................................... 15 
11.1 Adverse Events .......................................................................................................... 15 
11.1.1 All Adverse Events ................................................................................................ 16 
11.1.2 Adverse Events Leading to Withdrawal ................................................................ 16 
11.1.3 Serious Adverse Events ......................................................................................... 16 
11.1.4 Deaths .................................................................................................................... 16 
11.2 Pregnancies ................................................................................................................ 17 
11.3 Clinical Laboratory Evaluations ................................................................................ 17 
11.4 Electrocardiogram (ECG) .......................................................................................... 17 
11.5 Vital Signs .................................................................................................................. 17 
11.6 Physical examination ................................................................................................. 17 
12 REFERENCES ........................................................................................................... 18 
13 APPENDICES ............................................................................................................ 19 
13.1 Schedule of Assessments (Amendment 2) ................................................................. 19 
13.2 Schedule of Assessments (Amendment 4) ................................................................. 20 
13.3 List of Tables ............................................................................................................. 21 
13.4 List of Listings ........................................................................................................... 23 
 
 
 

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ABBREVIATIONS 
 
Acronyms, 
Abbreviations, Initials 
Description / Explanation 
AE 
Adverse Event 
ANOVA 
analysis of variance 
BS 
Biostatistics 
Cfb 
Change from baseline 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
FAS 
Full Analysis Set 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
The International Concil for Harmonisation of Technical  
Requirements for Pharmaceuticals for Human Use 
IPF 
Idiopathic Pulmonary Fibrosis 
NA 
Not Applicable 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
PM 
Project Manager 
PPS 
Per Protocl Set  
RA 
Regulatory Authority 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SOP 
Standard Operating Procedure 
TESAE 
Treatment Emergent Serious Adverse Event 
TEAE 
Treatment Emergent Adverse Event 
 

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1 
INTRODUCTION  
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting 
MediciNova Inc. protocol MN-166-COVID-19-201, A Randomized, Double-Blind, 
Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy, Safety, Tolerability, 
Biomarkers and PK of ibudilast (MN-166) in COVID-19 Participants at Risk for Developing 
Acute Respiratory Distress Syndrome.  
This phase 2 study is being completed to assess the safety, tolerability, and efficacy of 
MN-166 in male and female subjects 18 to 80 years of age, inclusive, who are hospitalized 
for complications from COVID-19 infection, are at risk for developing ARDS, and receive 
standard of care including anticoagulation. The following documents were reviewed in 
preparation of this SAP: 
• Clinical Study Protocol MN-166-COVID-19-201, amendment 2 issued 01 November 
2021 and amendment 4 issued 31 March 2021* 
• Case report forms (CRFs) for Protocol MN-166-COVID-19-201. 
• ICH E9: Guidance on Statistical Principles for Clinical Trials. 
• ICH E3: Guideline for the format and content of the clinical and statistical sections of 
an application 
• ICH E14: Clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs 
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. 
*No subjects were consented under Protocol v.1.0, Amendment 1, and Amendment 3 because they were not 
submitted to the institutions’ IRB.  
2 
STUDY OBJECTIVE AND ENDPOIINTS  
2.1 
Study Objectives  
2.1.1 Primary objectives 
The primary objectives of the study are to evaluate: 
• Efficacy of ibudilast vs. placebo in COVID-19 subjects measured by the proportion 
of subjects free of respiratory failure at Day 7  
• Efficacy of ibudilast vs. placebo in COVID-19 subjects measured by clinical status 
at Day 7 
2.1.2 Secondary Objectives 
The secondary objectives of the study are to evaluate: 

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• Efficacy of ibudilast vs. placebo in COVID-19 subjects measured by the proportion 
of subjects free of respiratory failure at Days 14, 28 and 60 (in intubated subjects 
only)  
• Efficacy of ibudilast vs, placebo in COVID-19 subjects measured by clinical status     
at Days 14, 28 and Day 60 (in intubated subjects only) 
• Anti-inflammatory effects of ibudilast vs. placebo on cytokine levels 
• Safety and tolerability of ibudilast vs. placebo in COVID-19 subjects  
• Pharmacokinetics of ibudilast vs. placebo in COVID-19 subjects 
2.2 
Study Endpoints (Outcome Variables) 
2.2.1 Co-Primary Outcome Variable(s) 
The co-primary objectives of the study will be evaluated based on the following clinical 
measures:  
• Proportion of subjects free from respiratory failure defined by free from 
supplemental oxygen requirements (invasive mechanical ventilation, non-invasive 
ventilation, high-flow oxygen, or ECMO, CPAP, BiPAP, nasal cannula) at Day 7 
• Proportion of subjects with at least a one-point improvement in clinical status using 
the NIAID 8-point ordinal scale and discharge record at Day 7 
2.2.2 Secondary Outcome Variable(s) 
• Proportion of subjects free from respiratory failure as defined by free from 
supplemental oxygen requirement (invasive mechanical ventilation, non-invasive 
ventilation, high-flow oxygen, or ECMO, CPAP, BiPAP, nasal cannula) at Days 14, 
28 and Day 60* 
• Proportion of subjects with mechanical ventilation /intubation at Days 7, 14, 28 and 
Day 60* 
• Changes from baseline in clinical status using the NAID 8-point ordinal scale and 
discharged record at Days 7, 14, 28 and 60*  
• Proportion of subjects with at least a one-point improvement in clinical status using 
the NIAID 8-point ordinal scale and discharge record at Days 14, 28 and 60* 
• All-cause mortality at Days 28and Day 60*  
• Proportion of the subjects discharged from hospital at Days 7, 14, 28 and 60*  
• Change from baseline in migration inhibitory factor (MIF), (interleukin 1-beta (IL-
1β), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and C-reactive protein 
(CRP) at Day 3,5,7 and 14 
• Incidence, frequency, and severity of adverse events at Day 7, 14, 28 and Day 60* 
• Change from baseline of the following parameters at Days 7, 14 and Day 60*: 
o ALT 
o AST 

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o Serum creatinine 
o BUN 
o Complete blood count 
o    Total bilirubin 
o D-dimer 
• PK plasma concentrations and parameter (PK population) 
 
*Intubated subjects only on Study Day 60 
2.2.3 Exploratory Endpoints 
Exploratory analysis not necessarily identified in this SAP may be performed to support the 
clinical development program. Any post-hoc or unplanned analysis not identified in this SAP 
performed will be clearly identified in the respective CSR. 
3 
STUDY METHODS AND ENDPOINTS 
3.1 
Overall Study Design and Plan 
This is a randomized (1:1), placebo-controlled, double-blind, parallel-group study of MN-166 
(ibudilast) in hospitalized COVID-19 subjects at risk for developing ARDS receiving 
standard of care including anticoagulation. Approximately 40 participants are planned to be 
enrolled. The study will consist of a Screening Phase followed by a 7-days Double-blind 
Treatment (DBT) and Follow-up Phase. Following the Screening Phase, if the subject meets 
eligibility criteria, subject will be administered treatment with MN-166 (ibudilast) or placebo. 
Subjects will receive ibudilast 100 mg/d (50 mg b.i.d) or placebo every day for 7 days.  The 
Follow-up phase is consisted of three visits: Day 14, Day 28, and Day 60 (subjects enrolled 
under amendment 4 only) post-baseline visit.   
Subjects who are discharged prior to Day 7 will be given the remainder of their study 
medication to be taken at home and a pulse oximeter supplied by the sponsor to measure their 
O2 levels once daily until Study Day 14. 
Eligible participants will consist of males and females ranging in age from 21 to 80 years old, 
inclusive, who have SARS-CoV-2 infection confirmed by WHO criteria, chest abnormalities 
consistent with COVID-19 pneumonia, SpO2 ≤92% on room air, ≥24 BPM, and/or 
requirement of supplemental O2.   
Overall study design and plan is described in detail in Protocol Section 11.  
3.2 
Selection of Study Population 
Inclusion and exclusion criteria are described in detail in Final Protocol Sections 12.2 and 
12.3. 

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3.3 
Method of Treatment Assignment and Randomization 
During the Double-blind Treatment Phase, randomization occurred in a 1:1 ratio (MN-166: 
Placebo). The randomization scheme was generated by an independent statistician and sent to 
each site’s unblinded pharmacist in a password protected file.  
3.4 
Treatment Masking (Blinding) 
Participants and all personnel involved with the conduct and interpretation of the study, 
including the investigators, site personnel, and sponsor staff will be blinded to the treatment 
codes. Randomization data will be kept strictly confidential, filed securely by an appropriate 
group with the sponsor and accessible only to authorized persons (e.g., unblinded pharmacist) 
until the database is locked 
To ensure that treatment allocation remains concealed to both staff and participants, the 
following measures will be taken: 
• Active drug and placebo will be identical in appearance 
• Drug supplies to investigational pharmacy will be coded 
4 
 SEQUENCE OF PLANNED ANALYSIS 
4.1 
Interim Analysis 
There are no planned interim analyses for this study. 
4.2 
Data Monitoring Committee Meetings 
 Not applicable. 
5 
SAMPLE SIZE DETERMINATION 
No prior data are available on which to base assumptions for sample size/power 
considerations. The results of this pilot study will be used to design future studies, and the 
sample size of approximately 40 participants is deemed to be appropriate for this purpose. 
6 
ANALYSIS POPULATIONS  
The following analysis populations are planned for the studies: 
• Full Analysis Set (FAS) will include all randomized subjects. 
• Safety Analysis Set (SAS) will include all randomized subjects who received at least 
one dose of study drug and had at least one post-dose safety assessment. 
• Per Protocol Analysis (PP): will consist of the FAS subjects excluding those with 
major protocol violations.  

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• Pharmacokinetic Population (PK): will consist of the subjects for which PK 
collection was performed. Eight subjects are anticipated to participate in PK sample 
collection.  
6.1 
Use of analysis populations in different analyses 
Safety analyses will be conducted on the Safety Analysis Set, and participants will be 
analyzed based on the treatment they received. Efficacy analysis will be conducted on the 
Full Analysis Set, and participants will be analyzed based on the treatment to which they 
were randomly assigned. 
7 
GENERAL ISSUES FOR STATISTICAL ANALYSIS 
Data from all clinical assessments will be listed and, where appropriate, summarized by 
treatment arms using descriptive statistics. Summary (descriptive) statistics of continuous 
variables include n, mean, standard deviation (SD), median, first quartile (Q1), third quartile 
(Q3), minimum and maximum values at each time-point. For categorical variables, the 
number and percent of counts will be presented.  
7.1 
Definition of Treatment Arms 
Treatment arms will be denoted as follows in the TLFs: 
• “MN-166” - 50 mg of MN-166 administered orally twice daily 
• “Placebo” – Matching Placebo administered orally twice daily 
7.2 
Definition of Baseline 
Unless otherwise specified, baseline is defined as the measurement closest to the date of the 
first administration of Investigational Medicinal Product (IMP) and preceding the first dose 
of IMP (MN-166 or Placebo). 
7.3 
Definition of Visit Windows 
The same visit windows will be used as defined in the protocol.  
• Screening visit (up to -3 days) 
• Day 1 (baseline) (0 days) 
• Days 2-7 (0 days) 
• Day 14 (±3 days) 
• Day 28 (±3 days) 
• Day 60 (±7 days) 
7.4 
Multi-center Study 
The study will be conducted at two centers:   

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Denver Health and Hospital Authority 
Yale School of Medicine 
7.5 
Multiple Comparisons and Multiplicity 
There are two co-primary endpoints. Because study success requires success on both, each 
will be tested using a one-sided alpha level value of 0.025 (equivalent to a two-sided alpha of 
0.05). All other analyses will be conducted using one-sided tests at the alpha=0.025 level of 
significance, with no adjustment for multiplicity.  
7.6 
Planned Subgroup Analyses 
No subgroup analyses are planned in this study. 
7.7 
Analysis Software 
All analysis will be performed using SAS® Software version 9.4 or above.  
7.8 
Clinical Status Scale 
In this trial, the National Institute of Allergy and Infectious Diseases (NIAID) 8-point ordinal 
scale is utilized to assess clinical status at Screening, Days 1-7, and on Days 14, 28, and 60 
(for intubated subjects only). In Section 14.5 of the protocol, the numbers (1-8) are in reverse, 
where a higher number represents improvement, which is inconsistent with the official 
NIAID 8-point ordinal scale. The SAS programmer will correct the NIAID 8-point ordinal 
scale to reflect the official scale shown below. 
1. Not hospitalized, no limitations on activities 
2. Not hospitalized, limitation on activities and/or requiring home oxygen 
3. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing 
medical care 
4. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical 
care (COVID-19 related or otherwise) 
5. Hospitalized, requiring supplemental oxygen 
6. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
7. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO) 
8. Death 
8 
STUDY PARTICIPANTS 
8.1 
Disposition of Participants and Withdrawals 
All participants who provide informed consent will be accounted for in this study. The 
number of screen failures will be presented. The number and proportion of participants in 
each analysis set will be presented by treatment arm (in percentage of the number of 

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participants randomly assigned) and overall. The number and proportion of completers will 
be presented by treatment arm and overall. The number and proportion of early withdrawals 
will be presented by the coded term for main reason of withdrawal and overall, by treatment 
arm and overall.  
Participants who are in the Safety Analysis Set but not in the Full Analysis Set will be listed. 
Randomization errors will be listed. 
8.2 
Protocol Deviations 
The number and proportion of participants with protocol deviations will be presented by 
treatment arm, for each coded term. 
All protocol deviations will be listed. 
8.3 
Inclusion and Exclusion Criteria 
Participants who meet all the inclusion criteria and none of the exclusion criteria are eligible 
to participate in the clinical trial. 
Deviations from inclusion/exclusion criteria will be listed. 
9 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
9.1 
Demographics 
For variables assumed to be continuous, like age at screening, body weight and height 
descriptive statistics will be prepared by treatment arm, for each analysis set separately.  
For categorical variables like gender, race, ethnicity, frequency tables (n and percentage) will 
be prepared by treatment arm, for each analysis set separately. 
All demography data will be listed. 
9.2 
Prior and Concomitant Medications 
Prior medications/therapies are defined as those for which the end date is prior to the date of 
first IMP administration. Concomitant medications/therapies are defined as those with start 
date on or after the date of first IMP administration and those with start date prior to the first 
IMP use but with end date on or after the date of first IMP administration. 
Concomitant medications in the database will be coded using the most recent version of the 
World Health Organization Drug Dictionary which employs the Anatomical Therapeutic 
Chemical (ATC) classification system. The number and percentage of participants who took 
prior and concomitant medications will be summarized separately by ATC classification first 
level (alphabetically), ATC classification second level (in decreasing order of frequency) and 
treatment arm. 

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These therapeutics will be listed by subject along with their classification, indication of the 
treatment, total daily dose and start and stop date of the treatment. 
The number and percentage of participants who took prior and concomitant treatments will 
be presented separately. 
All prior and concomitant medication data will be listed. 
9.3 
Baseline and Screening Conditions 
Baseline and Screening condition data will be assessed by treatment arm using descriptive 
statistics. No inferential test statistics are planned for baseline comparison of the treatment 
arms. 
9.3.1 Baseline Medical History 
All medical history records will be coded according to the latest version od MedDRA and 
summarized by system organ class and preferred term. The number and percentage of 
participants in different medical history categories will be presented by treatment arm. 
10 
EFFICACY ANALYSIS 
Efficacy analysis will be performed on the Full Analysis Set. All efficacy measurements will 
be listed. 
10.1 Primary Efficacy Variable Analysis  
The co-primary efficacy endpoints are listed below.   The primary analysis for each of these 
two endpoints will be conducted  using Pearson’s chi-square tests. Because study success is 
defined as success on both, each of the two co-primary endpoints will be tested using a one-
sided significance level of 0.025.  
• Proportion of subjects free from respiratory failure  
o Calculate the proportion of the subjects free from supplemental oxygen 
(invasive mechanical ventilation, non-invasive ventilation, high-flow 
oxygen, ECMO, CPAP, BiPAP, nasal cannula) at Day 7 
• Proportion of subjects with improvement in clinical status using the NIAID 8-point 
ordinal scale and discharge record at Day 7 
o Calculate the proportion of the subjects who improved at least one-point 
from baseline  
For each of the two co-primary endpoints, subjects whose response status is unknown will 
be assumed to be nonresponders. 
A supportive analysis for each of the two co-primary endpoints will be conducted using 
the Mantel-Haenszel test stratified by the randomization stratification variable (use of IL-6 
antibody therapy). 

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10.2 Secondary Efficacy Variable Analysis 
The secondary efficacy endpoints are the following: 
• Proportion of subjects free from respiratory failure as defined by free from 
supplemental oxygen requirement (invasive mechanical ventilation, non-invasive 
ventilation, high-flow oxygen, or ECMO, CPAP, BiPAP, nasal cannula) at Days14, 
28 and Day 60* Proportion of subjects with mechanical ventilation /intubation at 
Days 7, 14, 28 and Day 60*  
• Change from baseline in clinical status using NIAID 8-point scale and discharge 
record at Days 7, 14, 28 and 60* Proportion of subjects with at least a one-point 
improvement in clinical status using the NIAID 8-point ordinal scale and discharge 
record at Day 14,28 and 60*  
• All-cause mortality at Days 28 and Day 60* Proportion of the subjects discharged 
from hospital at Day 7,14, 28 and 60*  
• Change from baseline in migration inhibitory factor (MIF), (interleukin 1-beta (IL-
1β), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and C-reactive protein 
(CRP) at Day 3, 5, 7 and 14  
*Intubated subjects only on Study Day 60 
All secondary endpoints that are defined as proportion variables will be analyzed using 
Pearson’s chi-square tests.   Secondary endpoints that are defined as the change from baseline 
will be analyzed using analysis of covariance (ANCOVA) models with treatment group as a 
factor and the baseline value of the corresponding endpoint as a covariate. All secondary 
analyses will be conducted using one-sided tests at the alpha=0.025 level of significance, 
with no adjustments for multiplicity.  
10.3 Exploratory Analysis  
Time to discharge  
10.4 Pharmacokinetics Analysis  
Pharmacokinetic analyses will be performed on plasma samples from eight subjects. Blood 
samples (approximately 2 mL per sample) will be collected at each time point for the 
bioanalytical assay of MN-166 and stored frozen at approximately -80°C until shipment is 
sent to the PK vendor. Blood samples will be assayed for MN-166 using a validated liquid 
chromatography/tandem mass spectroscopy (LC/MS/MS) method. 
10.4.1 Pharmacokinetic Samples 
Pharmacokinetic samples will be collected on Day 1: AM Predose, and at 2, 4, 8 and  
12 hours (Predose of PM dose), and on Day 3 and Day 5 at AM Predose.  
10.4.2 Pharmacokinetic Parameters 
The following PK parameters will be calculated using model-independent approaches (NCA) 
from MN-166 individual plasma concentrations, whenever practical. 

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Parameter 
Description of Parameter 
tmax 
Time from the start of dosing at which the maximum concentration was observed 
Cmax 
Maximum observed concentration 
AUC0-t 
Area under the concentration versus time curve from the start of dose administration to the 
last quantifiable point within the dosing interval 
λz 
Terminal rate constant calculated from the terminal slope of the log-linear regression of 
concentration with time 
t1/2 
Terminal half-life, calculated as ln(2)/ λz 
AUC0-∞ 
Area under the concentration versus time curve from time 0 to infinity calculated as AUC0-t 
+ Clast/ƛz, where Clast is the last quantifiable concentration 
CL or CL/F 
Total body clearance, calculated as Dose/ AUC0-( 
Vz or Vz/F 
Terminal volume of distribution, calculated as CL/λz 
11 
SAFETY AND TOLERABILITY ANALYSIS 
All safety analyses will be performed for participants in the safety analysis set. 
The analysis of safety assessments in this study will include summaries of the following 
categories of safety and tolerability data collected for each subject: 
• Treatment Emergent Adverse Events: 
o Clinical laboratory Treatment Emergent Adverse Events 
o Discontinuation due to TEAEs 
o Treatment Emergent Serious Adverse Events 
• Pregnancies (if any reported) 
• Clinical Laboratory Investigations 
• Vital Signs  
• Physical examinations 
11.1 Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) central coding dictionary, version 25.0. 
The incidence of treatment-emergent AEs (TEAEs, defined as AEs occurring from the time 
of first dose through 7 days after the last dose of MN-166), SAEs and AEs leading to 
discontinuations will be summarized by treatment group. Incidence of TEAEs will also be 
summarized by severity (mild, moderate, or severe), as well as by relationship to treatment 
(not related, possibly related, or probably related) and by seriousness. If it cannot be 
determined whether the AE is treatment emergent due to a partial onset date then it will be 
counted as such.  
Summaries that are displayed by system organ class and preferred terms will be ordered by 
descending order of incidence of system organ class and preferred term within each system 
organ class.  Summaries of the following types will be presented: 

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• Subject incidence of TEAEs and total number of unique TEAEs by MedDRA system 
organ class and preferred term.   
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
highest severity.  At each level of subject summarization, a subject is classified 
according to the highest severity if the subject reported one or more events.  AEs with 
missing severity will be considered severe for this summary. 
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
closest relationship to study drug (Related/Not Related).  At each level of subject 
summarization, a subject is classified according to the closest relationship if the 
subject reported one or more events.  AEs with a missing relationship will be 
considered related for this summary. 
• Subject incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA system organ class and preferred term.   
• Subject incidence of TEAEs leading to study discontinuation or death by MedDRA 
system organ class and preferred term.   
As this is a double-blind study, the causality assessment should be made under the 
assumption that the subject is receiving active study medication. If considering unblinding, 
this assessment should be made prior to unblinding to avoid bias. 
11.1.1 All Adverse Events 
An overview of number of participants (%) with treatment-emergent AEs will be presented 
for the main AE categories (All AEs, AEs leading to discontinuation, SAEs, SAEs leading to 
discontinuation, AEs with at least Grade 3 severity (Severe AEs, Life-threatening AEs, 
Deaths), AEs and SAEs with relationship to IMP as possibly related, probably related, or 
related) by treatment arm and phase. 
11.1.2 Adverse Events Leading to Withdrawal 
A data listing of AEs leading to withdrawal will be provided, displaying details of the 
event(s) captured on the CRF. 
11.1.3 Serious Adverse Events 
A data listing of SAEs will be provided, displaying details of the event(s) captured on the 
CRF. Serious adverse event narratives will be provided for the CSR by MediciNova.  
11.1.4 Deaths 
If any subject dies during the study, relevant information will be supplied in a data listing, 
and appropriate SAE narratives. 

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11.2 Pregnancies 
Pregnancy data will be shown in a data listing. No special analysis will be performed on the 
pregnancy data. Participants are to be discontinued from the study if they become pregnant. 
11.3 Clinical Laboratory Evaluations 
Changes from baseline in laboratory values will be summarized by treatment groups for 
continuous variables. Lab shift tables showing incidence of new or worsening clinically 
significant findings from baseline to the last visit will be displayed by treatment groups. Shift 
from baseline to the highest lab value, and from baseline to the lowest lab value will also be 
displayed. Incidence of out-of-normal-range values and markedly abnormal change from 
baseline in laboratory safety test variables will be tabulated by treatment group.  Baseline is 
defined as the last non-missing value prior to the start of study drug infusion. 
11.4 Electrocardiogram (ECG)  
Descriptive statistics will be presented for ECG measures of PR interval, QRSD interval, QT 
interval, QTc interval (Fridericia’s method), and HR. These statistics will be presented by 
treatment arm, phase and visit. 
The number and percentage of subjects with normal and abnormal ECG results will be 
summarized by treatment arm, phase, and visit. All ECG measurements will be listed. 
11.5 Vital Signs 
Changes in vital signs from baseline to each visit will be summarized by treatment groups.  
11.6 Physical examination 
Physical examination results will be included in data listings only. 
 
 

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12 
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Statistical Principles for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Structure and Content of Clinical Study Reports (E3), 30 November 
1995. 
3. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY: Marcel Dekker; 1982. 
4. Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L et al. Assessment of 
dose proportionality: Report from the Statisticians in the Pharmaceutical 
Industry/Pharmacokinetics UK joint working party. Drug Information Journal 1995; 
29: 1039-1048. 
5. Emergent Product Development Gaithersburg Inc. Randomized, double-blind, placebo-
controlled, parallel group, single ascending dose study to determine the safety, 
tolerability and pharmacokinetics of UV-4B solution administered orally in healthy 
subjects. Clinical Report for Study ID 13-0001 issued 07 July 2016. 

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13 
APPENDICES 
13.1 Schedule of Assessments (Amendment 2)  
 
 
 
 
 
 
 
 
Phase 
Screening 
Double-Blind Treatment Phase d,f 
    Follow-up  
Study Day 
 
Day -3 
Day 1  
BL 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 14d 
 (± 3) 
Day 28   
(+/-3)  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 Brief physical exam  
X 
X 
 
X 
 
X 
 
X 
X 
 
Clinical status using 
NIAID scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, RR,  
HR, Temp) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
O2 therapy status  
and SpO2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
 
Biomarker plasma 
samples: MIF, IL-1β,  
IL-6, TNF-α 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
PK blood sampleb 
 
X 
 
X 
 
X 
 
 
 
 
CBC, CMP, CRP,  
D-dimer, PT, INR  
Xc 
X 
 
X 
 
X 
 
X 
X 
 
Randomizee 
X 
 
 
 
 
 
 
 
 
 
Administer study 
drug 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event review 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record survival 
status 
 
 
 
 
 
 
 
 
 
X 
 
 
a 12-lead ECG to be done between 2-4 hours after AM dose.   
b Collect PK samples on Day 1 in the AM prior to study drug dosing and at 2, 4, 8, and 12 hours (Predose of PM dose); Day 3 and  
   Day 5 prior to AM study drug dosing. PK samples to be collected for 8 subjects only.      
c Serum β-hCG for pre-menopausal women. 
d Telephone follow-up if subject is not in hospital. If subject is no longer hospitalized or cannot return due to COVID restrictions,  
a telephone follow-up to record O2 usage/levels, AEs and conmeds may be conducted. All other assessments are optional. 
e Subjects may be randomized during the Screening Phase after all of the screening assessments are completed and subject is  
  considered eligible for the study or on Day 1.  
f If subject prematurely discontinues from the study or is discharged from the hospital on Days 2, 4, or 6 collect biomarker samples in  
addition to other scheduled assessments. If subject prematurely discontinues from the study or is discharged on Days 1, 3, 5, or 7,  
conduct the study assessments scheduled on those days.  
gThirty-one (31) subjects were consented under Protocol amendment 2. 

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13.2  Schedule of Assessments (Amendment 4)  
 
 
Phase 
Screening 
Double-Blind Treatment Phase e,g  
Follow-up 
Study Day 
 
Day -3 
Day 1  
BL 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
 
Day 14e 
(± 3) 
 
Day 28 
(±3) 
Day 60 
(±7) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 Brief physical exam  
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Clinical status 
using NIAID scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, 
RR,  
HR, Temp) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xi 
O2 therapy status 
and SpO2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
 
Xi 
Biomarker plasma 
samples: MIF, IL-
1β, IL-6, TNF-α 
Xb 
X 
 
 
X 
 
X 
 
X 
X 
 
 
PK blood samplec 
 
X 
 
X 
 
X 
 
 
 
 
 
CBC, CMP, CRP,  
D-dimer, PT, INR  
Xd 
X 
 
X 
 
X 
 
X 
X 
 
Xi 
Randomize f 
X 
 
 
 
 
 
 
 
 
 
 
Administer study 
drug 
 
X h 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse event 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record survival 
statusj 
 
 
 
 
 
 
 
 
X 
X 
X 
a 12-lead ECG to be done between 2-4 hours after AM dose.   
b Biomarker blood sample collection at screening is optional if Screening and Day 1 assessments occur on the same day. 
c Collect PK samples on Day 1 in the AM prior to study drug dosing and at 2, 4, 8, and 12 hours (Predose of PM dose); Day 3  
 and Day 5 prior to AM study drug dosing. PK samples to be collected for 8 subjects only.      
d Serum β-hCG for pre-menopausal women. 
e Telephone follow-up if subject is not in hospital. If subject is no longer hospitalized or cannot return due to COVID restrictions,  
a telephone follow-up to record O2 usage/levels, AEs and conmeds may be conducted. All other assessments are optional. 
f Subjects may be randomized during the Screening Phase after all of the screening assessments are completed and subject is  
  considered eligible for the study or on Day 1.  
g If subject prematurely discontinues from the study or is discharged from the hospital on Days 2, 4, or 6 collect biomarkers  
  samples in addition to other scheduled assessments. If subject prematurely discontinues from the study or is discharged on Days 1, 3, 5, or 7,  
conduct the study assessments scheduled on those days.  
h The first dose of study drug may be started in the AM or the PM. 
i  Vital signs, ECG and safety labs will be done in intubated subjects only.   
j Survival status is captured on the NIAID questionnaire. 
kFive (5) subjects were consented under Amendment 4.  

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13.3 List of Tables 
 
Table 
Number 
Table Description 
14.1 
Demographic Data 
14.1.1  
Subject Disposition (including discontinued subjects) 
14.1.2 
Summary of Protocol Deviations 
14.1.3 
Demographics and Baseline Characteristics 
 
Summary of Disease Characteristics at Baseline by Treatment 
14.1.4 
Summary of Medical History  
14.1.5 
Prior and Concomitant Medications (Safety Population) 
14.1.6 
Study Drug Exposure 
14.2 
Efficacy 
14.2.1 
Number (%) of subjects free from respiratory failure at Day 7 
14.2.2 
Number (%) of subjects with at least a 1-point improvement in clinical status using the NIAID 8-point 
ordinal scale at Day 7 
14.2.3 
Number (%) of subjects free from respiratory failure at Days 14, 28, and 60  
14.2.4 
Number (%) of subjects with mechanical ventilation/intubation at Days 7, 14, 28, and 60 
14.2.5 
Change from baseline in clinical status using the NIAID 8-point ordinal scale at Days 7, 14, 28, and 60 
14.2.6 
Number (%) of subjects with at least a 1-point improvement in clinical status using the NIAID 8-point 
ordinal scale at Days 14, 28, and 60 
14.2.7 
Number (%) of subjects discharged from hospital at Days 7, 14, 28, and 60 
14.2.8 
All-cause mortality at Days 28 and 60 
14.3 
Safety 
14.3.1 
Summary of Treatment-emergent adverse events by Treatment 
 14.3.1.1 
Incidence of TEAEs MedDRA System Organ Class and Preferred Term by Treatment  
14.3.1.2 
Incidence of TEAEs Occurring in more than 5% of Subjects by Treatment  
14.3.1.3 
Incidence of Post-treatment AEs by Treatment  
14.3.1.4 
Incidence of TEAEs by MedDRA System Organ Class, Preferred Term and Severity 
14.3.1.5 
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred Term and 
Relationship to Study Drug 
14.3.1.6 
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred Term, 
Relationship to Study Drug, and Severity 
14.3.2 
Incidence of Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred 
Term 
14.3.3 
Incidence of Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred 
Term and Severity 
14.3.4 
Incidence of Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class,  Preferred 
Term and Severity 
14.3.4.1   
Incidence of Subjects with Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class, 
Preferred Term and Relationship 
14.3.4.2 
Incidence of Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred 
Term and Relationship 
14.3.4.3 
Incidence of Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred 
Term, Relationship and Severity 
14.3.4.4 
Incidence of TEAEs Leading to Early Termination by Treatment 

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14.3.4.5  
Incidence of Deaths by Treatment  
14.3.4.6 
Incidence of TEAEs by Maximum Severity by Treatment 
14.3.4.7 
Summary of Clinical Laboratory Data: Clinical Chemistry by Treatment 
14.3.4.8 
Summary of Clinical Laboratory Data: Clinical Hematology by Treatment 
14.3.4.9 
Shifts from Baseline of Clinical Laboratory Data: Clinical Chemistry – Shift from Baseline to the Last Visit 
14.3.4.10 
Shifts from Baseline of Clinical Laboratory Data: Clinical Hematology by Treatment 
 
 
 

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13.4 List of Listings 
Listing 
Number 
Listing Description 
16.2 
Subject Data Listings 
16.2.1  
Analysis Populations and Treatment  
16.2.1.1 
Subject Disposition 
16.2.1.2 
Inclusion/Exclusion Criteria 
16.2.2 
Protocol Deviations  
16.2.2.1 
Major and Minor Protocol Deviations 
16.2.2.3 
Randomization Errors  
16.2.3.1 
Demographics and Other Baseline Characteristics 
16.2.4 
Prior, Concomitant, and Post-treatment Medications 
16.2.4.1  
Medical History 
16.2.5 
Study Drug Exposure 
16.2.5.1 
Drug Accountability and Compliance 
16.2.5.2 
Investigator Dose Optimization 
14.2.5.3 
Dose Interruptions 
16.2.6 
Individual Response Efficacy 
16.2.6.1 
NIAID clinical status 8-point ordinal scale 
16.2.6.2 
O2 assessment including invasive mechanical ventilation, non-invasive ventilation (CPAP, 
BiPAP, nasal cannula high-flow oxygen), or ECMO and SpO2 
16.2.6.3 
Day of Hospital Discharge  
16.2.6.4 
Survival Status 
16.2.7 
Individual Safety 
16.2.7.1 
Adverse Events 
16.2.7.2 
Serious Adverse Events 
16.2.7.3 
Adverse Events Leading to Early Termination 
16.2.7.4 
Listing of Deaths 
16.2.8 
Listing of Individual Laboratory Measurements by Subject, when Required by Regulatory 
Authorities 
16.2.8.1 
Clinical Laboratory Data: Chemistry 
16.2.8.2 
Clinical Laboratory Data: Hematology 
16.2.8.3 
Pregnancy Tests 
16.2.8.4 
Vital Signs 
16.2.8.5 
Electrocardiogram, Site Interpretation 
16.2.8.6 
Electrocardiogram, Central Reader Interpretation 
16.2.8.7 
Physical Examination