Conditions: Non-alcoholic Steatohepatitis Hypertriglyceridemia Non-alcoholic Fatty Liver Disease Hypercholesterolemia
Keywords: NASH NAFLD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
This is a multi-center, proof-of-principle, open-label study designed to evaluate the efficacy, safety, and tolerability of MN-001 in non-alcoholic steatohepatitis (NASH) and Non-Alcoholic Fatty Liver Disease (NAFLD) subjects with hypertriglyceridemia.

Detailed description:
The study will consist a Screening Phase (up to 4 months) followed by a Treatment Phase (12 weeks), and a Follow-up visit (within 1 week after the last dose). A total of 40 male and female subjects ≥18 years of age are planned to be enrolled. During the Screening Phase, subjects will be assessed for study eligibility. After signing the informed consent form, the following assessments will be performed: medical history including review of prior and current medications, physical examination including height and body weight, waist circumference, vital signs and an electrocardiogram. Clinical labs, routine chemistries, hematology, coagulation profile, urinalysis and a serum pregnancy test will be collected as well as cytokeratin-18 (CK-18), a biomarker for NASH diagnosis. An alcohol consumption questionnaire will be administered and a MRI scan of the liver will be performed. Serum fibrosis markers, the Fib-4 index (age, AST, ALT, PLT) and NAFLD fibrosis score (age, BMI, AST/ALT ratio, IFG/DM, PLT, Albumin) will be calculated.

Arms:
arm 1: All 40 subjects will receive MN-001 for the first 4 weeks. At Week 4 subjects will increase their dosage frequency for remaining 8 weeks. Subjects will receive MN-001 for a total of 12 weeks.

Interventions: intervention 1: MN-001
Intervention descriptions: intervention 1: MN-001 is a novel, orally bioavailable small molecule compound which demonstrates anti-inflammatory activity

Protocol document:
Prot_SAP_ICF_001.pdf: 
 
 
9 
 
PROTOCOL NO. MN-001-NATG-201 
Title of Study: An Open-Label Study to Evaluate the Efficacy, 
Safety, Tolerability and Pharmacokinetics of MN-001 (tipelukast) 
on HDL (High Density Lipoprotein) Function and Serum 
Triglyceride Levels in Non-Alcoholic Steatohepatitis (NASH) and 
Non-Alcoholic Fatty Liver Disease (NAFLD) Subjects with 
Hypertriglyceridemia 
 
                            ORIGINAL PROTOCOL                                   
28 May 2015 
 AMENDMENT 1  
 
 
 
 
 
      20 November 2015 
AMENDMENT 2                                                    06 June 2016 
   AMENDMENT 3                 
 
 
 
        14 August 2017 
Confidentiality Statement 
This document is confidential. It contains proprietary information of MediciNova, Inc. Any viewing or disclosure of 
such information that is not authorized in writing by the sponsor is strictly prohibited. Such information may be 
used solely for the purpose of reviewing or conducting this study.  
IND Number: 
123659 
Study Phase: 
2a 
Sponsor: 
 
MediciNova, Inc. 
4275 Executive Square 
Suite 650 
La Jolla, CA 92037 
Sponsor Contact: 
Kazuko Matsuda, MD PhD MPH 
Chief Medical Officer 
4275 Executive Square 
Suite 650 
La Jolla, CA 92037 
858-373-1500 


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PROTOCOL SIGNATURE PAGE 
 
Study No: MN-001-NATG-201 
 
 
 
 
MediciNova Approval: 
  
                         
 
Signature:         
 
 
 
 
 
 
 
 
 
 
           Date: 
   August 14, 2017 
Name: 
Kazuko Matsuda, MD PhD MPH 
 
  
 
INVESTIGATOR AGREEMENT 
 
PROTOCOL NUMBER:  MN-001-NATG-201 
 
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 Name (Print)  
 
______________________________________ 
_______________________ 
Investigator Signature 
Date 
 


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1. 
SYNOPSIS 
Name of Sponsor: MediciNova Inc. 
Name of Investigational Product: MN-001 
Protocol Number: MN-001-NATG-201 
Title of Study: An Open–label Study to Evaluate the Efficacy, Safety, Tolerability and 
Pharmacokinetics of MN-001 (tipelukast) on HDL (high density lipoprotein) Function and Serum 
Triglyceride Levels in Non-Alcoholic Steatohepatitis (NASH) and Non-alcoholic Fatty Liver 
Disease (NAFLD) Subjects with Hypertriglyceridemia 
Study Center:  Multiple centers  
Phase of Development: 2a 
STUDY OBJECTIVES 
Primary Objectives:  
• 
To evaluate the effects of MN-001 on Cholesterol Efflux Capacity in NASH and NAFLD 
subjects with hypertriglyceridemia 
• 
To evaluate the effects of MN-001 on triglyceride levels in NASH and NAFLD subjects with 
hypertriglyceridemia 
Secondary Objectives:  
• 
To evaluate the safety and tolerability of MN-001  
• 
To evaluate PK profile of MN-001/MN-002 (metabolite) 
• 
To evaluate the effect of MN-001 on lipid profile  
o HDL-C, LDL-C, total cholesterol level  
• 
To evaluate the effect of MN-001/002 on liver enzymes  
• 
To evaluate the effect of MN-001/002 on percentage of fat in the liver assessed using MRI at 
Week 12  
METHODOLOGY 
This is a multi-center, proof-of-principle, open-label study designed to evaluate the efficacy, safety, 
and tolerability of MN-001 in subjects diagnosed with non-alcoholic steatohepatitis (NASH) or 
NAFLD with hypertriglyceridemia.  Subjects will receive MN-001 250 mg qd for the first 4 weeks and 
will take 250 mg bid for 8 weeks. Subjects will receive MN-001 for a total of 12 weeks.  A total of 
forty (40) subjects will be enrolled.  Eligible subjects will consist of males and females ≥ 18 of age.  To 
be eligible, subjects must have a histologically confirmed diagnosis of NASH within 36 months prior 
to baseline visit or NAFLD confirmed by imaging studies and an elevated serum triglyceride (> 150 
mg/dL) during the Screening Phase. 


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The study will consist of a Screening Phase (up to 4 months) followed by a Treatment Phase (12 
weeks), and a Follow-up visit (within 1 week after the last dose).   
Screening Phase (Day -120 to -7)  
During the Screening Phase, subjects will be assessed for study eligibility. After signing the informed 
consent form, the following assessments will be performed: medical history including review of prior 
medications, physical examination including height and body weight, waist circumference, vital signs 
and an electrocardiogram (ECG).  Clinical labs, chemistry (including CPK, liver enzymes and fasting 
lipid profile), hematology, coagulation profile, urinalysis and a serum pregnancy test will be collected 
as well as cytokeratin-18 (CK-18), a serum biomarker for NASH diagnosis.  An alcohol consumption 
questionnaire will be administered and a MRI scan of the liver will be performed.   
Treatment Phase (12 weeks) 
Subjects who complete all of the screening assessments will return to the clinic on Treatment Day 1 
(Baseline) to repeat laboratory tests and physical assessments. Subjects who continue to be eligible will 
be enrolled to receive MN-001 250 mg qd (250 mg/day) for 4 weeks and will take 250 mg bid (500 
mg/day) for 8 weeks. 
Subjects will receive their first dose of study medication on Day 1 at the clinic.  The first 6 subjects 
will have the option to stay at the study center overnight on Day 1 or return to the clinic the following 
day for the last/final blood draw. Blood samples for MN-001 /MN-002 (major metabolite) 
concentrations will be collected at the following timepoints:  
• Day 1  
o Baseline:  prior to the first dose  
o post dose hour 0.5, 1.5, 3, 6, 9, 12, 24* (*Day 2)   
PK parameters will be calculated and results will be reviewed prior to increasing the dose to 250 mg 
bid after Week 4. 
Subjects will return to the clinic at Weeks 4, 8, and 12. After Week 4, subjects will start taking 250 mg 
bid. During these visits, subjects will undergo safety and efficacy assessments. ECGs will be conducted 
at Tmax at hour 1.5 (± 30 minutes) after drug ingestion at each clinic visits: See Table 1 for visit 
schedule and procedures for all assessments. 
Throughout the Treatment Phase, safety parameters will be assessed and concomitant medications will 
also be documented.  The safety and tolerability of MN-001 will be evaluated by an Independent Safety 
Monitor during this phase. 
Follow-up Visit (Week 13) 
All subjects who complete the study will return for a follow-up visit at Week 13. At the last visit a 
physical examination including body weight, vital signs, and safety labs will be done.  Adverse events 
and concomitant medications will be collected. 
Individual Stopping Criteria 
Subjects who experience an adverse event of Grade 2 nausea and/or diarrhea for greater than 3 
consecutive days or Grade 3 nausea and/or vomiting for greater than 1 day thought to be related to 
study drug will be discontinued from the study.  Additionally, subjects who experience an adverse 
event of Grade 3 abdominal pain lasting for greater than 1 day thought to be related to study drug will 
be discontinued from the study.   
Additionally, study drug will be discontinued or temporarily interrupted under the following 


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conditions: 
•  When the baseline values were <2X ULN, discontinue if ALT or AST increases to >5X baseline 
value (BLM). 
•  When the baseline values were ≥2X ULN but <5X ULN, discontinue if ALT or AST  
increases to >3X BLM 
•  When the baseline values were ≥5X ULN, discontinue if ALT or AST increases to >2X BLM 
•  Discontinue if ALT or AST increase >2X BLM AND the increase is accompanied by a    
concomitant total bilirubin (TBL) increase to >2X BLM OR the INR concomitantly increases by 
>0.2 
Study Stopping Rules 
The study will be stopped if two subjects experience a Grade 4 adverse event thought to be related to 
study drug.   
Number of Subjects (Planned): The number of subjects planned for enrollment is 40.  
STUDY ENTRY CRITERIA:  
Inclusion Criteria: 
• 
Written informed consent is obtained and willing and able to comply with the protocol in the 
opinion of the Investigator. 
• 
Male or female subjects age ≥18 years of age 
• 
Histologically proven NASH (NAFLD activity score of 3 or greater with at least 1 point being 
ballooning) based on liver biopsy performed within the last 36 months or NAFLD confirmed 
by imaging studies. 
• 
Fasting serum triglyceride level > 150 mg/dL (confirmed at screening)  
• 
Serum ALT, AST, ALP and total bilirubin levels at Screening (- 120 days to – 30 days) and 
Lab Visit values (- 1 week ± 5 days) are stable or changes at the Lab visit are < 20% of the 
values from Screening. 
• 
Subjects on the following medications can be enrolled if these medications are necessary, 
cannot be stopped, and the dose has been stable for 3 months or more prior to baseline: 
o 
Stable doses of anti-diabetic medications 
o 
Stable doses of fibrates, statins, niacin, ezetimibe 
o 
Stable doses of Vitamin E for at least 8 weeks 
• 
Less than 21units of alcohol/week for men and 14 units of alcohol/week for women over a 2-
year time frame  
• 
Females of child-bearing potential must have a negative serum ß-hCG at screening and must be 
willing to use appropriate contraception (as defined by the investigator) for the duration of 
study treatment and 30 days after the last dose of study treatment 
• 
Males should practice contraception as follows:  condom use and contraception by female 


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partner 
• 
Subject is in good physical health on the basis of medical history, physical examination, and 
laboratory screening, as defined by the investigator 
• 
Subject is willing and able to comply with the protocol assessments and visits, in the opinion of 
the study nurse/coordinator and the Investigator 
Exclusion Criteria: 
• 
Diagnosis of other known cause of liver disease (autoimmune, viral, genetic, drug- or alcohol-
induced, or storage disease) 
• 
Decompensated or severe liver disease defined by one or more of the following: 
1)  biopsy-proven cirrhosis 
2)  INR >1.5 
3) Total bilirubin (TBL) > 1.5x ULN, or > 2 x ULN for unconjugated bilirubin 
4) serum albumin < 2.8 g/dL 
5) ALT or AST > 10 x ULN 
6) evidence of portal hypertension including splenomegaly, ascites, encephalopathy 
and/or esophageal varices 
• 
Current diagnosis of hepatocellular carcinoma (HCC) or suspicion of HCC clinically or on 
ultrasound 
• 
Uncontrolled diabetes mellitus Type 2  
• 
Recent heart attack, coronary artery intervention, coronary bypass surgery, or stroke. 
• 
Patients with class 3 or 4 heart failure 
• 
History of bariatric surgery 
• 
Greater than 10-pound weight gain or loss in the last 6 months 
• 
Clinically significant cardiovascular/cerebrovascular disease, including myocardial infarction 
within last 6 months, coronary artery intervention, coronary artery bypass, unstable ischemic 
heart disease, heart failure Class III or IV, angina or cerebral vascular accident 
• 
Resting pulse < 50 bpm, SA or AV block, uncontrolled hypertension, or QTcF  > 450 ms 
• 
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  
• 
Any significant laboratory abnormality which, in the opinion of the Investigator, may put the 
subject at risk 
• 
History of malignancy < 5 years prior to signing the informed consent, except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer 
• 
History of HIV (human immunodeficiency virus), HBV, HCV (cured HCV is not excluded), 
EBV CMV or other active infection. 
• 
Currently has a clinically significant medical condition including the following: neurological, 


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psychiatric, metabolic, immunologic, hematological, pulmonary, cardiovascular (including 
uncontrolled hypertension), gastrointestinal, urological disorder, or central nervous system 
(CNS) infection that would pose a risk to the subject if they were to participate in the study or 
that might confound the results of the study   
Note: Active medical conditions that are minor or well-controlled are not exclusionary if, in 
the judgment of the Investigator, they do not affect risk to the subject or the study results. In 
cases in which the impact of the condition upon risk to the subject or study results is 
unclear, the Medical Safety Monitor should be consulted. 
• 
CYP2C8 substrates with a narrow therapeutic index (e.g., paclitaxel) within 15 days prior to 
study, and throughout the study are prohibited 
• 
CYP2C9 substrates with a narrow therapeutic index (e.g., phenytoin, S-warfarin, tolbutamide) 
within 15 days prior to study and throughout the study are prohibited 
• 
Macrolide or quinolone class antibiotics within 15 days of Screening and throughout the study 
are prohibited  
• 
Steroids within 30 days prior to study drug dosing and throughout the study unless 
administered for a short term treatment course during the study are prohibited 
• 
History of alcohol or substance abuse (DSM-IV-TR criteria) within 3 months prior to screening 
or alcohol or substance dependence (DSM-IV-TR criteria) within 12 months prior to screening. 
The only exceptions include caffeine or nicotine abuse/dependence 
• 
Poor peripheral venous access that will limit the ability to draw blood as judged by the 
Investigator  
• 
Currently participating, or has participated in, a study with an investigational or marketed 
compound or device within 3 months prior to signing the informed consent 
• 
Unable to cooperate with any study procedures, unlikely to adhere to the study procedures and 
keep appointments, in the opinion of the Investigator, or was planning to relocate during the 
study 
Investigational Product, Dosage and Mode of Administration: MN-001 tablets (250 mg) to be 
administered orally for a total of 12 weeks (250 mg qd for 4 weeks and 250 mg bid for 8 weeks). 
Duration of Treatment: Total 12 weeks  
Reference Therapy, Dosage, and Mode of Administration: N/A 
Pharmacokinetics: Plasma samples for analysis of MN-001 and its metabolite MN-002 will be 
collected from the first 6 subjects at the following timepoints: 
o 
Baseline:  prior to the first dose  
o 
Post first dose at hours: 0.5, 1.5, 3, 6, 9, 12, 24   
Statistical Methods 
Analysis Populations: 
Safety Analysis Set: The group of subjects who received at least one dose of study drug and had at 
least one post dose safety assessment. 
Per Protocol Set: The group of subjects who received at least one dose of study drug and who did not 


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have any major protocol deviations. 
Safety Analysis 
Safety analyses will be conducted on the Safety Analysis Set. 
The incidence of treatment-emergent AEs (TEAEs, defined as AEs occurring from the time of first 
dose through 7 days after the last dose of study medication), SAEs and AEs leading to discontinuations 
will be summarized by treatment group.  Incidence of TEAEs will also be summarized by severity 
(mild, moderate, or severe), as well as by relationship to treatment (not related, possibly related, or 
probably related) and by seriousness. 
Changes from baseline in laboratory values will be summarized by treatment groups for continuous 
variables.  Lab shift tables showing incidence of new or worsening clinically significant findings from 
baseline to the last visit will be displayed by treatment groups.  Shift from baseline to the highest lab 
value, and from baseline to the lowest lab value will also be displayed. 
Incidence of out-of-normal-range values and markedly abnormal change from baseline in laboratory 
safety test variables will be tabulated by treatment group.  
Changes in vital signs from baseline to each visit will be summarized by treatment groups. 
Plasma MN-001 concentrations and its metabolite will be measured.  
Sample Size Justification:   
The sample size is not based on hypothesis testing. The selected sample size is considered adequate to 
provide a preliminary evaluation of efficacy and safety. 


 
                                                                                                                      
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Table 1: 
Schedule of Assessments 
 
* Baseline visit will be overnight stay for selected 6 subjects from whom PK samples will be obtained  
** ET: Early termination visit  
*** PK sample for MN-001/002 will be also obtained when subjects experience SAE  
**** Liver MRI can be scheduled on different day of each lab/clinic visit 
a Pre-treatment Liver MRI may be performed between Day -120 and Day -1prior to Baseline Day 1 
Phase 
Screening 
Treatment  
Follow-up   
 
Tests and Evaluations 
Day -120 
to Day -7 
 – 1 week 
± 5 days 
 
Baseline 
Day 1-2* 
 
Week 2  
± 3 days 
Week 4 
± 5 days 
 
Week 8 
± 5 days 
Week 12/ET** 
± 5 days 
Week 13  
± 5 days 
Type of Visit 
Clinic 
Lab 
Clinic 
Tel 
Clinic 
Clinic 
Clinic 
Clinic 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
X 
X 
X 
X 
Body height 
X 
 
 
 
 
 
 
 
Body weight/Waist circumference 
X 
 
X 
 
X 
X 
X 
X 
Vital signs 
X 
 
X 
 
X 
X 
X 
X 
Alcohol consumption questionnaire 
X 
 
 
 
 
 
X 
 
Pregnancy test (serum /urine)  
X (serum)  
X (serum)  
 
 
X 
X 
X 
 
12-lead ECG 
X 
 
X 
 
X 
X 
X 
 
Clinical labs (chemistry, incl CPK, 
hematology, lipid panel coagulation 
profile including INR, urinalysis) 
X 
X 
 
 
X 
X 
X 
X 
CK-18 biomarker  
X 
 
 
 
 
 
X 
 
Fib-4 Index calculation 
X 
 
 
 
 
 
 
 
NAFLD fibrosis score 
X 
 
 
 
 
 
 
 
Blood Sample for Cholesterol Efflux  
 
 
X 
 
 
 
X 
 
MN-001 plasma concentration *** 
 
 
X 
 
 
 
 
 
Liver MRIa 
X**** 
 
 
 
 
 
X**** 
 
Adverse event review 
 
 
X 
X 
X 
X 
X 
X 
Concom med review 
X 
 
X 
X 
X 
X 
X 
 
Study Drug Dispensing 
 
 
X 
 
 
 
 
 
Study Drug Accountability 
 
 
 
X 
X 
X 
X 
 


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2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................3 
2. 
TABLE OF CONTENTS ...........................................................................................10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
4. 
BACKGROUND AND RATIONALE .......................................................................17 
4.1. 
Introduction .................................................................................................................17 
4.1.1. 
Rationale of the MN-001 for treatment of NASH and NAFLD Subjects with 
hypertriglyceridemia ...................................................................................................18 
4.2. 
Prior Clinical Experience ............................................................................................19 
4.2.1. 
Clinical Study Overview .............................................................................................19 
4.3. 
Potential Drug-Drug Interactions ...............................................................................24 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................26 
5.1. 
Primary Objectives .....................................................................................................26 
5.2. 
Secondary Objectives .................................................................................................26 
6. 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ..................................27 
6.1. 
Screening Phase (up to - 4 months to – 7 days) ..........................................................27 
6.1.1. 
Diagnosis at Screening ...............................................................................................27 
6.1.2. 
Treatment Phase ..........................................................................................................28 
6.1.3. 
Follow-up Phase .........................................................................................................28 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
7.1. 
Clinical Trial Population .............................................................................................29 
7.2. 
Inclusion/Exclusion Criteria .......................................................................................29 
7.2.1. 
Inclusion Criteria ........................................................................................................29 
7.2.2. 
Exclusion Criteria .......................................................................................................30 
7.3. 
Subject Withdrawal/Discontinuation Criteria .............................................................31 
7.3.1. 
Individual Stopping Criteria .......................................................................................32 
7.3.2. 
Study Stopping Rules .................................................................................................32 
7.3.3. 
Follow-up Procedures Upon Discontinuation/Withdrawal ........................................32 
8. 
TREATMENT OF SUBJECTS ..................................................................................33 
8.1. 
Description of Study Drug ..........................................................................................33 
8.2. 
Concomitant Medications ...........................................................................................33 
8.3. 
Prohibited Medications ...............................................................................................33 


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8.4. 
Treatment Compliance ................................................................................................33 
8.5. 
Randomization and Blinding ......................................................................................33 
8.6. 
Dosing Guidelines ......................................................................................................34 
8.6.1. 
Treatment Phase ..........................................................................................................34 
8.6.2. 
Abnormal Laboratory Values .....................................................................................34 
8.6.3. 
Dosing Interruption for Abnormal Laboratory Values ...............................................34 
8.7. 
Written Informed Consent ..........................................................................................34 
8.8. 
Assessments ................................................................................................................35 
8.8.1. 
Study Assessments by Visit ........................................................................................35 
8.8.1.1. 
Screening Phase (up to – 120 to – 7 days) ..................................................................35 
8.8.1.2. 
Treatment Phase (12 weeks) .......................................................................................36 
8.8.1.3. 
Follow Up Phase .........................................................................................................38 
8.8.2. 
Procedures/Assessment Details ..................................................................................39 
8.8.2.1. 
Informed Consent .......................................................................................................39 
8.8.2.2. 
Medical History ..........................................................................................................39 
8.8.2.3. 
Prior/Concomitant Medication Review ......................................................................39 
8.8.2.4. 
Physical Examination .................................................................................................39 
8.8.2.5. 
Vital Signs, Height, and Weight .................................................................................39 
8.8.2.6. 
Electrocardiogram (12-Lead ECG) .............................................................................40 
8.8.2.7. 
Fib-4 Index ..................................................................................................................40 
8.8.2.8. 
Nonalcoholic fatty liver disease (NAFLD) Fibrosis Score .........................................40 
8.8.2.9. 
Cytokeratin-18 (CK-18) ..............................................................................................40 
8.8.2.10. 
Adverse Event (AE) Monitoring ................................................................................40 
8.8.2.11. 
Laboratory Evaluations ...............................................................................................41 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................42 
9.1. 
Study Drug ..................................................................................................................42 
9.2. 
Study Drug Packaging and Labeling ..........................................................................42 
9.3. 
Study Drug Storage .....................................................................................................42 
9.4. 
Study Drug Administration.........................................................................................42 
9.5. 
Study Drug Accountability .........................................................................................43 
10. 
ASSESSMENT OF EFFICACY ................................................................................44 
10.1. 
Primary Endpoints ......................................................................................................44 
10.2. 
Secondary Endpoints ..................................................................................................44 


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11. 
ASSESSMENT OF SAFETY .....................................................................................45 
12. 
ADVERSE EVENTS..................................................................................................46 
12.1. 
Definition of Adverse Events .....................................................................................46 
12.2. 
Assessment of Adverse Events ...................................................................................46 
12.2.1. 
Severity Assessment ...................................................................................................46 
12.2.2. 
Relationship to Study Drug ........................................................................................47 
12.3. 
Recording Adverse Events .........................................................................................47 
12.4. 
Treatment and Follow-Up of AEs ..............................................................................48 
12.5. 
Serious Adverse Events (SAEs) .................................................................................48 
12.5.1. 
SAE Reporting Requirements .....................................................................................49 
12.6. 
Guidance for Overdose ...............................................................................................50 
12.7. 
Reporting and Follow-up of Pregnancies ...................................................................50 
12.8. 
Preplanned Hospitalizations or Procedures ................................................................51 
13. 
STATISTICS ..............................................................................................................52 
13.1. 
Data Analysis ..............................................................................................................52 
13.1.1  
 Analysis Populations .................................................................................................52 
13.1.2  
 Statistical Analysis Plan ............................................................................................52 
13.1.3  
 Sample Size Justification ...........................................................................................52 
13.1.4  
 Safety Analysis ..........................................................................................................52 
13.2. 
Direct Access to Source Data/Documents ..................................................................53 
13.3. 
Study Monitoring ........................................................................................................53 
13.4. 
Audits and Inspections ................................................................................................54 
13.5. 
Institutional Review Board (IRB) ...............................................................................54 
13.6. 
Study Documentation .................................................................................................54 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................55 
15. 
ETHICS ......................................................................................................................56 
15.1. 
Ethics Review .............................................................................................................56 
15.2. 
Ethical Conduct of the Study ......................................................................................56 
15.3. 
Written Informed Consent ..........................................................................................56 
15.4. 
Confidentiality ............................................................................................................56 
15.4.1. 
Confidentiality of Data ...............................................................................................56 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................57 
16.1. 
Review of Records ......................................................................................................57 


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16.2. 
Retention of Records ..................................................................................................57 
17. 
ADMINISTRATIVE AND REGULATORY DETAILS ...........................................58 
17.1. 
Protocol Amendments and Study Termination...........................................................58 
17.2. 
Discontinuation of the Study ......................................................................................58 
17.3. 
Compliance with Financial Disclosure Requirements ................................................58 
18. 
REFERENCES ...........................................................................................................59 
19. 
APPENDICES ............................................................................................................61 
Appendix 1: Laboratory Safety Tests for MN-001 .....................................................................62 
Appendix 2: Informed Consent Form ............................................................................................64 
Appendix 3: Cholesterol Efflux Study Protocol ............................................................................72 
 
 
List of Figures and Tables 
 
Figure 1: 
Study Design ...............................................................................................................27 
 
 
Table 1: 
Schedule of Assessments ..............................................................................................9 
Table 2:      Abbreviations and Terms ............................................................................................14 
Table 3:  
Clinical Studies ...........................................................................................................23 
Table 4:  
Study Dug Information ...............................................................................................42 
Table 5:  
Adverse Events Severity Definition ...........................................................................46 
Table 6:  
Adverse Event Causality Definition ...........................................................................47 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2:      Abbreviations and Terms 
Abbreviation  
Term 
AE 
adverse event 
Alb 
albumin 
ALP 
alkaline phosphatase 
ALT (SGPT) 
alanine aminotransferase 
aPTT 
activated partial prothrombin time 
AST (SGOT) 
aspartate aminotransferase 
AV 
atrioventricular 
β-hCG  
beta-subunit of human chorionic gonadotropin 
bid 
twice daily 
BLM 
Baseline values 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CIRB 
Central Institutional Review Board 
CK-18 
cytokeratin-18 
Cmax 
Maximum plasma concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CTCAE 
Common terminology criteria for adverse events 
CVD 
cardiovascular disease 


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Abbreviation  
Term 
CYP 
cytochrome 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
dL 
deciliter 
DM 
Diabetes mellitus 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders- Fourth 
Edition-Text Revision 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
Early Termination 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
gastrointestinal 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDL 
high density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HV 
Healthy volunteer 
IC50 
inhibition constant 50% 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMM 
independent medical monitor 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
L 
liter 


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Abbreviation  
Term 
LDL 
low-density lipoprotein 
LO 
lipoxygenase 
LT 
leukotriene 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MRI 
magnetic resonance imaging 
NAFLD 
Non-alcoholic fatty liver disease 
NAS 
Non-alcoholic fatty liver disease activity score 
NASH 
Non-alcoholic steatohepatitis 
NDA 
new drug application 
NSAID 
Non-steroidal anti-inflammatory drug 
PK 
pharmacokinetics 
PI 
Principal Investigator 
PTT 
prothrombin time 
qd 
once-daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SA 
sinoatrial 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SOC 
system-organ-class 
SOP 
standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total bilirubin 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
tid 
three times daily 
Tmax 
time maximum plasma concentration 
TRAE 
Treatment-related adverse event 
ULN 
Upper limit of normal 
WBC 
White blood cells 
WHO-DD 
World Health Organization Drug Dictionary 


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4. 
BACKGROUND AND RATIONALE 
4.1. 
Introduction 
In the United States, non-alcoholic fatty liver disease (NAFLD) has emerged as the most 
common chronic liver disease. Population based studies in the United States estimate that the 
prevalence of NAFLD ranges between 17% and 30% in the general population and as high as 
80% in obese individuals undergoing weight loss surgery.  NAFLD represents a histopathologic 
spectrum ranging from steatosis alone, to necroinflammation - an entity described as 
nonalcoholic steatohepatitis (NASH). Less than 1% - 4% of patients with simple steatosis 
progress to a more advanced fibrosis while NASH has an increased risk for the progression to 
advanced fibrosis and cirrhosis. The prevalence of NASH is between 12%-17%. Despite the high 
prevalence of this disease, the natural history of NAFLD/NASH remains unclear.  
 
There is sufficient clinical and epidemiological evidence supporting the assertion that 
NAFLD/NASH is strongly associated with an increased prevalence and incidence of cardio- 
vascular disease (CVD) (Ballestri et al 2014). Patients with NAFLD/NASH often have 
dyslipidemia along with other features of metabolic syndrome such as obesity, diabetes mellitus, 
and hypertension. The presence of dyslipidemia (hypercholesterolemia, hypertriglyceridemia or 
both) has been reported in 20-80% of cases associates with NAFLD (Souza et al 2012). The 
dyslipidemia is characterized by increased serum triglycerides, increased small, dense low-
density lipoprotein (LDL nontype A) particles, and low high-density lipoprotein (HDL) 
cholesterol. The pathogenesis of dyslipidemia in NAFLD/NASH is not well understood 
(Chatrath et al 2012).  
 
A low level of high-density lipoprotein (HDL) cholesterol has been considered a major 
independent risk factor for atherosclerotic cardiovascular disease. HDL has numerous anti-
atherosclerotic actions that are not readily reflected by HDL cholesterol levels (deGoma et al 
2008).  A key function of HDL is to promote reverse cholesterol transport from the periphery to 
the liver, and the critical initial step in reverse cholesterol transport is cholesterol efflux from 
macrophages to HDL (Rader et al 2009). Macrophage-specific cholesterol efflux capacity has 
been directly and causally linked to the prevention of atherosclerosis in animal models (Rader et 
al 2009).  In a recent population-based cohort study, cholesterol efflux capacity, a key step in 
reverse cholesterol transport, was inversely associated with the incidence of cardiovascular 
events (Rohatgi et al 2014) and is considered to be a new biomarker to assess cardiovascular 
risk.  
 
MN-001 
MN-001 (4-[6-acetyl-3-[3-[(4-acetyl-3-hydroxy-2-propylphenyl)thio]propoxy]-2-
propylphenoxy]butanoic acid), formerly KCA-757 (Kyorin Pharmaceutical Co., Ltd.) is a novel, 
orally bioavailable small molecule compound which demonstrates anti-inflammatory activity in 
preclinical models.  The 5-lipoxygenase (5-LO) pathway, which generates leukotrienes (LT) 
from arachidonic acid, is one of the major inflammatory systems in mammals (Samuelsson et al 


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1987; Funk 2001).  It has been shown that 5-LO expression and LT formation were increased in 
livers in animals with induced cirrhosis (Titos et al 2000), suggesting that 5-LO plays an 
important role in Kupffer cell survival and in the pathogenesis of liver inflammation and fibrosis 
(Titos et al 2004).  Kupffer cells are known as the predominant primary inflammatory effector 
cells to promote tissue remodeling and fibrosis (Titos et al 2004).  MN-001 is thought to exert an 
inhibitory effect on 5-LO and the 5-LO/LT pathway and, therefore, may have potential utility for 
the treatment of fatty liver disease, including non-alcoholic steatohepatitis (NASH). 
4.1.1. 
Rationale of the MN-001 for treatment of NASH and NAFLD Subjects with 
hypertriglyceridemia 
 
Rationale for the use of MN-001 in NASH and NAFLD with hypertriglyceridemia is based on 
preclinical studies and previous clinical studies.  
The safety pharmacology of MN-001 and its major metabolite MN-002 was examined in vitro 
and in vivo. Effects on serum lipids were evaluated in rats with both MN-001 and MN-002 as 
single doses at 0, 30, 100 and 300 mg/kg. With MN-001, a significant decrease was observed in 
the [total cholesterol - free cholesterol]/free cholesterol ratio in some approximate dose-
dependent manner 2-6 hours after dosing.  At 100 mg/kg, MN-002 caused significant decreases 
in triglycerides and 300 mg/kg led to significant decreases in triglycerides and β-lipoprotein. In a 
52- week oral toxicity study in dogs treated with MN-001, a reduction in triglycerides and ß-
lipoprotein was evident in both sexes at dose 180 mg/kg (Study Report #K93CD02). 
The in vivo effects of MN-001 on fatty liver disease were directly evaluated using a mouse 
model for NASH. In this mouse model of NASH, treatment with MN-001 significantly reduced 
fibrosis as compared with vehicle in a dose dependent manner demonstrating the anti-fibrotic 
effect of MN-001.  High dose of MN-001 tended to reduce liver hydroxyproline content 
supporting its anti-fibrotic property.  Treatment with high dose of MN-001 significantly 
decreased the NAS.  The improvement in NAS was attributable to the reduction in lobular 
inflammation and hepatocyte ballooning. Notably, high dose of MN-001 significantly reduced 
ballooning score.  Since hepatocyte ballooning is derived from oxidative stress-induced 
hepatocellular damage and is associated with disease progression of NASH (Fujii et al 2009; 
Rangwala et al 2011), the data strongly suggest that MN-001 improved NASH histopathology by 
inhibiting hepatocyte damage and ballooning.  Treatment with low dose of MN-001 significantly 
reduced the area of inflammation compared with vehicle; demonstrating anti-inflammatory effect 
of MN-001 
In a Phase 2 trial with asthma patients (Protocol #MN-001-CL-001), an interesting observation 
was the change in the fasting lipid profiles from screening to the end of the study. Mean total 
cholesterol decreased 8 mg/dL in the combined MN-001 treatment groups while increasing 3.7 
mg/dL in the placebo group. Mean low density lipoprotein cholesterol (LDL) decreased 6.5 
mg/dL in the combined MN-001 treatment groups while increasing 1.7 mg/dL in the placebo 
group. Mean triglycerides decreased 16.4 mg/dL in the combined MN-001 treatment groups 
while increasing 1.1 mg/dL in the placebo group. Similar trends were also observed in the Phase 
2 trial with Interstitial Cystitis patients and a Phase 1 trial with healthy volunteers. 


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With these preclinical and clinical studies data, we hypothesized that MN-001 is beneficial to 
improve lipid profile and to protect liver damage in patients with NASH and NAFLD with 
elevated serum triglyceride level. 
 
4.2. 
Prior Clinical Experience 
4.2.1. 
Clinical Study Overview 
To date, a total of 11 clinical trials have been conducted with MN-001 and over 600 subjects 
have been dosed. Doses of MN-001 ranging from 80 mg to 2000 mg for up to 12 weeks in 6 
Phase 1 studies, 4 Phase 2 studies and 1 Phase 3 study have been studied in healthy subjects and 
patients with asthma and interstitial cystitis. A summary of completed studies is listed in Table 3. 
Phase 1 Studies 
In the single dose studies of 80 mg to 600 mg, there appeared to be few adverse events. The most 
common treatment emergent adverse events (TEAEs) were mild diarrhea, sensation of 
borborygmus, and heavy headedness. No clinically significant changes in vital signs, ECGs, and 
safety labs were observed.   
In two multiple dose studies (study KCA-757 and study 478-02), MN-001 250 mg to 1000 mg 
bid was administered for approximately 7 days in healthy volunteers and subjects with mild 
bronchial hypersensitivity. No serious adverse events were reported and no subjects discontinued 
the study due to an adverse event. The most common AEs experienced in study 478-02 were 
upper abdominal pain (reported by 1 subject each in the 500 mg and 750 mg groups), loose 
stools (reported by 1 subject each in the 500 mg and 1000 mg groups), and nausea (reported by 1 
subject each in the 750 mg and 1000 mg groups). The Investigator considered the following 
treatment-emergent AEs to be possibly or probably related to study drug (treatment group in 
parentheses): abdominal pain (placebo), upper abdominal pain (500 mg and 750 mg), dyspepsia 
(1000 mg), fatigue (placebo), loose stools (500 mg and 1000 mg), nausea (750 mg and 1000 mg), 
somnolence (750 mg), urine odor abnormal (500 mg). 
In study 478-02, vital signs were within normal limits.  All mean ECG measurements remained 
within normal limits. At Hour 359.67 mean QTc for the 750 mg group increased 27.66 ms from 
baseline for a mean QTc of 395.83 ms and mean heart rate increased 14.50 bpm from baseline 
for a mean heart rate of 70.67 ms. No other marked mean changes from baseline were noted. The 
Investigator did not consider any of the ECG abnormalities in this study to be adverse events. 
All treatment groups, including the placebo group, exhibited notable mean increases in 
CPK (ranging between 22 to 135 U/L) at Hour 360. No other marked mean changes from 
baseline were noted for the remaining serum chemistry parameters. 
High Doses of MN-001 (1500 mg) 
Study MN-001-CL-003 was another multiple dose study in healthy volunteers testing doses of 
1500 mg for 5 days. In this study, no SAEs occurred and no subjects discontinued the study due 


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to a TEAE. Two subjects reported a TEAE during the study. Both subjects experienced dizziness 
(mild, possibly related), one on Day 2 and the other on Day 3 of dosing with MN-001 750 mg 
bid. 
 
Mean serum chemistry and hematology results showed transient fluctuations between screening 
and follow-up on Day 11, 8 hours after the last dose, but no apparent treatment-related trends 
were observed for any of the serum chemistry or hematological parameters evaluated. None of 
the abnormal laboratory values observed during the study was considered a clinically significant 
treatment-related change, and no AEs related to abnormal laboratory values were reported. No 
clinically significant changes in vital sign parameters and ECGs were noted during the study. 
 
The mean triglyceride (mg/dL) changes from baseline at Day 11 are listed below.  
Time point 
MN-001 1500 mg/day  
(N=11)  
Screening 
145.4 
Day 11 
87.5  
(-39.8%)  
 
Phase 2 Studies 
Study KCA-757-T201 
MN-001 100 mg, 200 mg, 400 mg and 600 mg was evaluated in 112 asthma patients over 6 
weeks. No serious adverse events occurred and 11 subjects discontinued due to a TEAE. Seven 
subjects experienced 20 adverse reactions. 
Study MN-001-CL-001  
MN-001 (500 mg tid, 750 mg bid, or 750 mg qd) or placebo was evaluated for 4 weeks in 147 
asthma patients. AEs within the Gastrointestinal Disorders system organ class were the most 
commonly observed, reported by 18.2% of the combined MN-001 subjects and 10.8% of those 
receiving placebo. These AEs appeared to demonstrate a dose relationship, and the most frequent 
AEs among the combined MN-001 treatment groups were diarrhea, nausea, and vomiting. Each 
of these individual events occurred in less than 10% (with only diarrhea exceeding 5%) of all 
MN-001-treated subjects. No severe gastrointestinal AEs were reported, and none led to 
discontinuation from the study. 
 
The mean triglyceride (mg/dL) changes from baseline at Week 4 are listed below. 


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Time point 
Placebo (N=36) 
500mg tid 
(N=36) 
750mg bid 
(N=36) 
750mg qd (N=36) 
Screening 
132.3 
109.5 
125.5 
112.2 
Week 4 
126.9 
(-4.1%)  
91.6 
(-16.3%) 
98.5 
(-21.5%) 
117.2 
(+4.5%) 
 
Study MN-001-CL-002 
MN-001 500 mg bid and 500 mg qd were evaluated in 305 patients with interstitial cystitis. The 
TEAE most frequently reported by all the patients in the MN-001 group was diarrhea, which was 
higher in both MN-001 groups compared with placebo and higher in the MN-001 500 mg bid 
group compared with the MN-001 500 mg qd group. Although the incidence of loose stools was 
lower than the incidence of diarrhea, similar comparisons as seen with diarrhea among the 
treatment groups were also observed for loose stools. 
The mean triglyceride (mg/dL) changes from baseline at Week 4 are listed below. 
Time point 
Placebo  
(N=100) 
500mg qd  
(N=94) 
500mg bid  
(N=106) 
Baseline 
144.3 
136.1 
135.7 
Week 4 
144.5 
(+0.1%) 
109.5 
(-19.5%) 
106.7 
(-21.3%) 
 
Phase 3 Study 
MN-001 (500 mg tid or 750 mg bid) or placebo was evaluated for 12 weeks in patients with 
asthma.  This study was stopped early by sponsor in June 2007 due to strategic reasons unrelated 
to the safety or efficacy of study drug. (MediciNova, Inc.’s business decision to discontinue 
further development of MN-001 in its current immediate-release formulation for asthma 
indication was based on the competitive landscape at that time.) 
 
There were total 154 subjects enrolled, 152 subjects were randomized (108 in MN-001 groups 
and 44 in placebo group). The study was terminated before planned enrollment was achieved. In 
the all MN-001 groups, the system organ class (SOC) categories with the most reported TEAEs 
were gastrointestinal disorders (19% vs. 5% in the placebo group), infections and Infestations 
(11% vs. 18% in the placebo group) and respiratory, thoracic and mediastinal disorders (8% vs.  
7% in the placebo group). In the placebo group, the SOC category with the most reported TEAEs 


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(incidence of ≥ 10%) was infections and infestations (18%). The only AE that was reported in > 
2 subjects in each treatment group was diarrhea, which occurred at a higher frequency in the 750 
mg bid group than the 500 mg tid group (21% vs. 9% respectively). The TEAEs experienced by 
> 2 subjects in the all MN-001 group were nasopharyngitis (4%), urinary tract infection (3%), 
asthma (3%), and joint sprain (3%). 
 
The mean triglyceride (mg/dL) changes from baseline at Week 4 are listed below. 
 
Time point 
Placebo  
(N=44) 
500 mg tid  
(N=54) 
750 mg bid  
(N=53) 
Baseline 
135.4 
159.4 
117.0 
Week 4 
123.1 
(-9.1%) 
112.5 
(-29.4%) 
94.1 
(-19.6%) 
 
 
Additional safety information is reported in the Investigator Brochure. 


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Table 3:  
Clinical Studies 
Phase 
Study 
Number  
Title 
Design 
Dosage 
Treatment 
Duration 
Target 
Population 
# of Subjects 
Enrolled 
1 
2254 
Ascending dose tolerance 
study of KCA-757 (MN-
001) in healthy volunteers 
with preliminary 
pharmacokinetic assessment 
Open-label, single-
dose 
80 mg, 
160 mg 
single-dose 
Healthy 
Volunteers 
5 
1 
151408 
The disposition of 14C-
KCA-757 (MN-001) in man 
Open-label, single 
oral dose to 
investigate the 
rates and routes of 
excretion and the 
plasma kinetics of 
total radioactivity 
following [14C]-
KCA-757 (MN-
001) 
80 mg 
single-dose 
Healthy 
Volunteers 
4 
1 
Kyorin 
Phase 1 Trial of KCA-757 
(MN-001) Single-dose 
study 
Ascending, single-
dose to evaluate 
safety and PK 
100 mg 
to 600 
mg 
single-dose 
Healthy 
Volunteers 
29 
1 
Kyorin 
Phase 1 Trial of KCA-757 
(MN-001) Repeated-dose 
study 
Safety and PK 
300 mg 
bid 
7 days 
Healthy 
Volunteers 
6 
1 
478-02 
A Randomized, Double-
Blind, Placebo-Controlled, 
Ascending Dose Study to 
Assess the Safety and 
Tolerability of MN-001 
When Given in Multiple 
Doses to Healthy 
Volunteers and the 
Pharmacodynamic Effect of 
MN-001 When Given in 
Multiple Doses to 
Volunteers with Mild 
Bronchial Hypersensitivity 
Randomized, 
double-blind safety 
and tolerability 
250, 
500, 
750, 
1000 mg 
bid 
6 days 
Healthy 
Volunteers 
and 
bronchial 
hypersensiti
ve subjects 
32 
1 
MN-
001-CL-
003 
A Phase I, Randomized 
Single-blind study to 
Determine the Relative 
Pharmacokinetics of Two 
Dosing Regimens of MN-
001 Administered Orally to 
Normal, Healthy Male and 
Female Subjects 
Single-Blind, 
Randomized 1:1, 
Crossover 
500mg 
tid and 
750mg 
bid 
5 days of 
dosing for 
each regimen 
Healthy 
Volunteers 
11 subjects 
randomized and 
completed 
2 
KCA-
757-
T201 
Early Phase 2 Study of 
KCA-757 (MN-001) 
 Open-label 
50 mg 
bid, 100 
mg bid, 
200 mg 
bid, 300 
mg bid 
6 weeks 
Bronchial 
asthma 
 108 subjects  
2 
4204 
A standard antigen 
challenge study of KCA-
757 (MN-001) in 10 
 Cross-over 
300 mg 
bid 
single-dose 
Asthma 
3  


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Phase 
Study 
Number  
Title 
Design 
Dosage 
Treatment 
Duration 
Target 
Population 
# of Subjects 
Enrolled 
patients with asthma 
2 
MN-
001-CL-
001 
A Randomized, Double-
Blind, Placebo-Controlled 
Study Evaluating the Effects 
of MN-001 in Subjects with 
Mild to Moderate Asthma 
Double-Blind, 
Randomized  
500mg 
tid, 
750mg 
bid, 
750mg 
qd, or 
placebo 
4 weeks  
Mild to 
Moderate 
Asthma pts 
147 subjects 
randomized 
with 131 
completing, 
placebo N=37, 
500mg tid 
N=37, 750mg 
bid N=37, 
750mg qd 
N=36 
2 
MN-
001-CL-
002 
A Phase II, Randomized, 
Double-blind, Placebo-
Controlled Multi-Center 
Study to Evaluate the 
Efficacy and Safety of Two 
Dosing Regimens of MN-
001 in Patients with 
Interstitial Cystitis 
Double-Blind, 
Randomized 1:1:1 
500mg 
bid          
500mg 
qd, or 
placebo 
8 weeks  
Interstitial 
Cystitis pts 
305 subjects 
randomized 
with 251 
completing, 
placebo N=102, 
500mg qd=95, 
500mg bid 
N=108 
3 
MN-
001-CL-
004 
A Randomized, Double-
Blind, Placebo-Controlled 
Study Evaluating the Effects 
of MN-001 in Subjects with 
Mild to Moderate Asthma 
Double-Blind, 
Randomized 1:1:1 
500mg 
tid         
750mg 
bid, or 
placebo 
12 weeks  
Mild to 
Moderate 
Asthma pts 
152 subjects 
randomized          
108 MN-001        
44 Placebo 
 
 
4.3. 
Potential Drug-Drug Interactions 
From the in vitro CYP enzyme study, both MN-001 and MN-002 were found to be highly bound 
to human serum albumin.  
• MN-001 and MN-002 directly inhibit CYP2C enzymes in a Michaelis-Menten manner, 
and do so with a relatively high degree of potency according to the following rank 
order: CYP2C8 > CYP2C9 > CYP2C19. The IC50 values for MN-001 and MN-002 are 
1.5 and 1.4 μM for CYP2C8; 3.8 and 8.1 μM for CYP2C9; and 25 and 28 μM for 
CYP219, respectively. As an inhibitor of these CYP2C enzymes, MN-001 tended to be 
slightly more potent than MN-002 and neither compounds exhibited evidence of 
metabolism- or time-dependent inhibition of CYP2C8, CYP2C9 or CYP2C19. 
• MN-001 and MN-002 directly inhibited several CYP enzymes (CYP1A2, CYP2A6, 
CYP2B6, CYP2D6, CYP2E1 and CYP3A4/5) in a non-Michaelis-Menten manner 
whereby they caused little or no inhibition up to a certain concentration, after which they 
caused marked inhibition of these CYP enzymes by an unknown mechanism. 
Based on data from single and repeat oral dose PK study, with the proposed dose of MN-
001 250 mg/day (250 mg qd), plasma concentrations may peak at ~ 575 ng/ml (~ 1.1 μM) 
for MN-001 and ~ 5200 ng/mL (~ 9.8 μM). These results suggest that MN-001 and MN-


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002 could potentially inhibit the metabolism of concomitantly administered drugs, 
particularly the concomitant drugs that are substrates of CYP2C8 and CYP2C9. 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
 
This is a multi-center, proof-of-principle, open-label study designed to evaluate the efficacy, 
safety, and tolerability of MN-001 in non-alcoholic steatohepatitis (NASH) and non-alcoholic 
fatty liver disease (NAFLD) subjects with hypertriglyceridemia.  
5.1. 
Primary Objectives 
 
The primary objectives of the study are: 
 
• To evaluate the effects of MN-001 on Cholesterol Efflux Capacity in NASH and NAFLD 
subjects with hypertriglyceridemia 
 
• To evaluate the effects of MN-001 on triglyceride levels in NASH and NAFLD subjects 
with hypertriglyceridemia 
 
5.2. 
Secondary Objectives 
 
The secondary objectives are:  
• To evaluate the safety and tolerability of MN-001  
• To evaluate PK profile of MN-001/MN-002  
• To evaluate the effect of MN-001 on Lipid profile  
o HDL-C, LDL-C, Total cholesterol level  
• To evaluate the effect of MN-001/002 on liver enzymes  
• To evaluate the effect of MN-001/002 on the percentage of fat in the liver assessed using 
MRI at Week 12  


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6. 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION 
The study will consist a Screening Phase (up to 4 months) followed by a Treatment Phase (12 
weeks), and a Follow-up visit (within 1 week after the last dose).   
A total of 40 male and female subjects ≥18 years of age are planned to be enrolled.  
The study phases are described below and displayed in Figure 1 and the Schedule of 
Assessments is displayed in Table 1.           
     Figure 1: Study Design 
 
 
 
 
 
 
 
 
 
6.1. 
Screening Phase (up to - 4 months to – 7 days) 
 
A total of up to 4 months will be allowed to complete the screening assessments.  During the 
Screening Phase, subjects will be assessed for study eligibility. After signing the informed 
consent form, the following assessments will be performed: medical history including review of 
prior and current medications, physical examination including height and body weight, waist 
circumference, vital signs and an electrocardiogram.  Clinical labs, routine chemistries (including 
CPK, liver enzymes and fasting lipid profile), hematology, coagulation profile, urinalysis and a 
serum pregnancy test will be collected as well as cytokeratin-18 (CK-18), a biomarker for NASH 
diagnosis.  An alcohol consumption questionnaire will be administered and a MRI scan of the 
liver will be performed.  Serum fibrosis markers, the Fib-4 index (age, AST, ALT, PLT) and 
NAFLD fibrosis score (age, BMI, AST/ALT ratio, IFG/DM, PLT, Albumin) will be calculated. 
 
Detailed information on permitted and excluded concomitant medications is provided in Section 
8.2 and Section 8.3 of the protocol.  
6.1.1. 
Diagnosis at Screening 
Subjects must have a histologically confirmed diagnosis of NASH (NAS of ≥ 3 with at least 1 
point being ballooning) by liver biopsy within the past 36 months or NAFLD confirmed by 
imaging studies. The diagnosis must be noted in the source documents and a copy of the report 
must be obtained. 
 
Screening 
 
  Follow-up 
Day -120 to -30                    Day 1                                                        Week 4                                                    7 days after last dose     
Screening Phase                                       Treatment Phase (12 Weeks)                                   Follow-up 
MN-001 
250 mg qd  
x 4 weeks  
MN-001 
250 mg bid (500 mg/d) 
x 8 weeks  


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6.1.2. 
Treatment Phase  
Subjects who complete all of the screening assessments will repeat laboratory tests around 1 
week prior to Treatment Day 1 (Baseline) to confirm their eligibility. Subjects who continue to 
be eligible will return to the clinic on Treatment Day 1 (Baseline) and be enrolled to receive 
MN-001 250 mg qd for 4 weeks and will take MN-001 250 mg bid (500 mg) for 8 weeks. 
Subjects will receive MN-001 for a total of 12 weeks. Subjects will receive their first dose of 
study medication on Day 1 in the clinic.  
Thereafter, subjects will return to the clinic at Weeks 4, 8 and 12. During these visits, subjects 
will undergo safety and efficacy assessments. ECGs will be conducted at Tmax at hour 1.5 (± 30 
minutes) at each clinic visit: See Table 1 for visit schedule and procedures for all assessments. 
 
Throughout the Treatment Phase, safety parameters will be assessed and concomitant 
medications will also be documented.  An independent safety monitor will review the data on a 
regular basis during the Treatment Phase.  
 
 
6.1.2.1. 
Pharmacokinetics 
The first 6 subjects who are eligible to be dosed will stay at the clinic overnight or return to the 
clinic the following day for last/final blood draw. Blood samples for MN-001/002 serum 
concentration will be collected at the following timepoints: 
• Day 1 (Baseline):  prior to the first dose  
• Post dose hour 0.5, 1.5, 3, 6, 9, 12, 24* (*Day2)   
PK parameters will be calculated and reviewed prior to increasing the dose to 250 mg bid (500 
mg/d) after Week 4. 
 
6.1.3. 
Follow-up Phase 
All subjects who complete the study will return for their final visit at Week 13 for safety 
assessments and to assess adverse event status and document concomitant medications. 
 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Clinical Trial Population 
The population for this trial will include male and female subjects ≥ 18 years of age with 
elevated serum triglycerides and a diagnosis of NASH by liver biopsy or NAFLD confirmed by 
abdominal ultrasound. 
7.2. 
Inclusion/Exclusion Criteria 
7.2.1. 
Inclusion Criteria 
• Written informed consent is obtained and willing and able to comply with the protocol in 
the opinion of the Investigator. 
• Male or female subjects ≥ 18 years of age 
• Histologically proven NASH (NAFLD activity score of 3 or greater with at least 1 point 
being ballooning) based on liver biopsy performed within the last 36 months or NAFLD 
confirmed by imaging studies.  
• Fasting serum triglyceride level > 150 mg/dL (confirmed at screening)  
• Serum ALT, AST, ALP and total bilirubin levels at Screening (- 120 days to -30 days) 
and Lab Visit values (- 1 week ± 5 days) are stable or changes at the Lab visit are < 20% 
of the values from Screening. 
• Subjects on the following medications can be enrolled if these medications are necessary, 
cannot be stopped, and the dose has been stable for 4 months or more prior to baseline: 
o Stable doses of anti-diabetic medications 
o Stable doses of fibrates, statins, niacin, ezetimibe.  
o Stable doses of Vitamin E for at least 8 weeks  
• Less than 21 units of alcohol/week for men and 14 units of alcohol/week for women over 
a 2-year time frame 
• Females of child-bearing potential must have a negative serum ß-hCG at screening and 
must be willing to use appropriate contraception (as defined by the investigator) for the 
duration of study treatment and 30 days after the last dose of study treatment. 
• Males should practice contraception as follows: condom use and contraception by female 
partner. 
• Subject is in good physical health on the basis of medical history, physical examination, 
and laboratory screening, as defined by the investigator. 
• Subject is willing and able to comply with the protocol assessments and visits, in the 
opinion of the study nurse/coordinator and the Investigator. 
 


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7.2.2. 
Exclusion Criteria 
• Diagnosis of other known cause of liver disease (autoimmune, viral, genetic, drug- or 
alcohol-induced, or storage disease) 
• Decompensated or severe liver disease defined by one or more of the following: 
• biopsy-proven cirrhosis 
• INR >1.5 
• Total bilirubin (TBL) > 1.5 x ULN, or > 2 x ULN for unconjugated bilirubin 
• serum albumin <2.8 g/dL 
• ALT or AST > 10 x ULN 
• evidence of portal hypertension including splenomegaly, ascites, 
encephalopathy and/or esophageal varices 
• Current diagnosis of hepatocellular carcinoma (HCC) or suspicion of HCC clinically or 
on ultrasound 
• Uncontrolled diabetes mellitus Type 2  
• History of bariatric surgery  
• Greater than 10-pound weight gain or loss in the last 6 months 
• Clinically significant cardiovascular/cerebrovascular disease, including myocardial 
infarct within last 6 months, coronary artery intervention, coronary artery bypass, 
unstable ischemic heart disease, heart failure class III or IV, angina or cerebral vascular 
accident. 
• Resting pulse < 50 bpm, SA or AV block, uncontrolled hypertension, or QTcF  > 450 ms 
• 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.  
• Any significant laboratory abnormality which, in the opinion of the Investigator, may put 
the subject at risk 
• History of malignancy < 5 years prior to signing the informed consent, except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. 
• History of HIV (human immunodeficiency virus), HBV, HCV (cured HCV is not 
excluded), EBV CMV or other active infection. 
• Currently has a clinically significant medical condition including the following: 
neurological, psychiatric, metabolic, immunologic, hematological, pulmonary, 
cardiovascular (including uncontrolled hypertension), gastrointestinal, urological 
disorder, or central nervous system (CNS) infection that would pose a risk to the subject 
if they were to participate in the study or that might confound the results of the study.   
Note: Active medical conditions that are minor or well-controlled are not exclusionary 
if, in the judgment of the Investigator, they do not affect risk to the subject or the study 
results. In cases in which the impact of the condition upon risk to the subject or study 
results is unclear, the Medical Safety Monitor should be consulted. 


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• CYP2C8 substrates with a narrow therapeutic index (e.g., paclitaxel) within 15 days prior 
to study and throughout the study are prohibited. 
• CYP2C9 substrate with narrow therapeutic index (e.g., phenytoin, S-warfarin, 
tolbutamide) within 15 days prior to study and throughout the study are prohibited. 
• Macrolide or quinolone class antibiotics within 15 days of Screening Visit and 
throughout the study are prohibited. 
• Steroids within 30 days prior to study drug dosing and throughout the study unless 
administered for a short-term treatment course during the study are prohibited. 
• History of alcohol or substance abuse (DSM-IV-TR criteria) within 3 months prior to 
screening or alcohol or substance dependence (DSM-IV-TR criteria) within 12 months 
prior to screening. The only exceptions include caffeine or nicotine abuse/dependence. 
• Poor peripheral venous access that will limit the ability to draw blood as judged by the 
Investigator.  
• Currently participating, or has participated in, a study with an investigational or marketed 
compound or device within 3 months prior to signing the informed consent. 
• Unable to cooperate with any study procedures, unlikely to adhere to the study 
procedures and keep appointments, in the opinion of the Investigator, or was planning to 
relocate during the study. 
 
7.3. 
Subject Withdrawal/Discontinuation Criteria 
Subjects may request to be withdrawn from the study at any time for any reason.  
The Investigator may interrupt the treatment of any subject whose health or well-being may be 
compromised by continuation in the study.  The following instances require subjects to be 
withdrawn from the study: 
 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 or abnormal laboratory tests that require 
discontinuation of study medication; 
 Subjects who, in the opinion of the Investigator, should be discontinued for their well-
being;  
 Subjects who are no longer able to understand task instructions or to perform tests 
adequately. 
 Subject becomes pregnant during the study. See section 12.7 for reporting requirements 
and follow-up of the pregnancy. 
If a subject withdraws or is removed from the study for any reason, the reason and date of 
discontinuation of study medication should be recorded in the appropriate section of the Case 
Report Form (CRF).  At the time of study discontinuation, every effort should be made to ensure 
all Early Termination (ET) procedures and evaluations are performed.  


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The study sponsors reserve the right to discontinue the study at any time for medical or 
administrative reasons.   
7.3.1. 
Individual Stopping Criteria 
Subjects who experience an adverse event of Grade 2 nausea and/or diarrhea for greater than 3 
consecutive days, or Grade 3 nausea and/or vomiting for greater than 1 day thought to be related 
to study drug will be discontinued from the study.  Additionally, subjects who experience an 
adverse event of Grade 3 abdominal pain lasting for greater than 1 day thought to be related to 
study drug will be discontinued from the study.   
  
Subjects with abnormal laboratory tests should be discontinued or study drug temporarily 
interrupted. Please see section 8.6.2 and 8.6.3 for details. 
7.3.2. 
Study Stopping Rules 
The study will be stopped if two subjects experience any Grade 4 (i.e., life-threatening 
consequences; urgent intervention indicated) adverse event thought to be related to study drug.  
The medical monitor will review the cases with the PI prior to the decision to terminate the study 
is made. 
7.3.3. 
Follow-up Procedures Upon Discontinuation/Withdrawal 
A termination CRF page should be completed for every subject who received study medication 
whether or not the subject completed the study. The reason for discontinuation should be 
indicated on the CRF. Any AEs that are present at the time of discontinuation/ withdrawal 
should be followed in accordance with the safety requirements outlined in Section 11. 


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drug 
MN-001 will be provided in bottles and will be stored at room temperature. 
8.2. 
Concomitant Medications 
Concomitant medications required for the treatment of symptoms and signs of baseline disease 
(e.g., hypercholesterolemia, Type 2 diabetes) are permitted except as excluded below. 
Concomitant medications for treatment of adverse events may be allowed. Subjects will be 
instructed to contact a member of the study staff prior to taking any medication. 
Based on data in vitro CYP enzyme studies, MN-001 and MN-002 could potentially inhibit the 
metabolism of concomitantly administered drugs, particularly the concomitant drugs that are 
substrates of CYP2C8 and CYP2C9.  
8.3. 
Prohibited Medications 
The following medications are prohibited prior to and during study participation: 
• CYP2C8 substrate with narrow therapeutic index (e.g., paclitaxel) within 15 days prior 
to study drug dosing and throughout the study 
• CYP2C9 substrate with narrow therapeutic index (e.g., phenytoin, S-warfarin, 
tolbutamide) within 15 days prior to study drug dosing and throughout the study 
• Macrolides and other antibiotics within 15 days prior to study drug dosing and 
throughout the study unless administered for a short-term treatment course during the 
study. 
• Steroids within 30 days prior to study drug dosing and throughout the study unless 
administered for a short-term treatment course during the study 
 The medical monitor should be consulted prior to administration of a prohibited concomitant 
medication. 
8.4. 
Treatment Compliance 
Compliance will be monitored closely at each visit. Subjects will be instructed to bring all 
unused study medication with them to each visit. Compliance will be assessed by counting 
capsules and dividing the actual number of doses taken (per capsule count) by the number of 
doses the subject should have taken within a visit period and multiplying by 100. All subjects 
will be reminded of the importance of strict compliance with taking study medication for the 
effectiveness of treatment and for the successful outcome of the study. Subjects who miss more 
than 25% of scheduled doses or take more than 125% of the scheduled doses will be considered 
noncompliant and may be discontinued from the study per investigator’s judgment.    
8.5. 
Randomization and Blinding 
This study is an open-label study; randomization and blinding are not applicable. 


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8.6. 
Dosing Guidelines 
8.6.1. 
Treatment Phase 
On Day 1, once baseline assessments are completed, subjects will be administered their first dose 
(one MN-001 250 mg tablet) of study drug in the clinic. Subjects will continue to take study drug 
once daily for 4 weeks and will increase the dose to 250 mg bid (500 mg/d) for 8 weeks.  
8.6.2. 
Abnormal Laboratory Values 
 Laboratory tests should be repeated within 48 hours* after any of the following laboratory 
values are met: 
• Develop elevations of AST or ALT greater than 2 times baseline values (BLM) or total 
bilirubin (TBL) is greater than 1.5 X BLM  
If there are persistent elevations in ALT or AST > 2 X BLM or TBL > than 1.5 X BLM, then 
close observation by a hepatologist, repeat further laboratory tests, and physical examination 2-3 
times per week should be initiated in order to identify the cause of liver function deterioration 
(i.e. potential of drug-induced liver injury (DILI). 
(*If a patient resides in a remote area, they can be tested locally and the results be 
communicated to the investigator site promptly) 
8.6.3. 
Dosing Interruption for Abnormal Laboratory Values 
If the laboratory values are any of the following, then the subjects should stop study 
medication. When baseline values were:  
• 
 < 2X ULN, discontinue if ALT or AST increases to >5X BLM. 
• 
≥ 2X ULN but <5X ULN, discontinue if ALT or AST increases to >3X BLM 
• 
≥ 5X ULN, discontinue if ALT or AST increases to >2X BLM 
• 
Discontinue if ALT or AST increase >2X BLM AND the increase is accompanied 
by a concomitant TBL increase to >2X BLM OR the INR concomitantly increases 
by >0.2. 
While dosing is withheld, subjects will continue tests and assessments according to the schedule 
defined in the protocol (and may also undergo additional assessments to evaluate the laboratory 
abnormality as per the Investigator’s standard practice). In addition, subjects must have the 
abnormal laboratory result rechecked at least every 2 weeks (rechecks will be run at the local 
laboratory if a patient lives remote area) until resolution or stabilization of the laboratory value. 
After laboratory values return within normal limits, resumption of blinded study treatment is to 
be considered on a case by case basis and must be discussed with the Independent Medical 
Monitor. 
8.7. 
Written Informed Consent 
Each subject is required to provide written informed consent prior to undergoing any study 
procedures. A copy of the signed and dated informed consent (in a language in which the subject 
is fluent) is required to be given to the subject. If a subject withdraws consent, data collected up 
to the time of discontinuation will be used to evaluate study results.  


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8.8. 
Assessments  
The Schedule of Assessments is presented in Table 1.  
Clinical laboratory evaluations will be performed by a central laboratory. All clinical and 
laboratory evaluations, procedures related to inclusion/exclusion criteria, or performed during 
treatment must be reviewed, initialed and dated by the Principal Investigator or appropriate 
designee listed on Form FDA 1572.  
8.8.1. 
Study Assessments by Visit 
The following is a summary of assessments by study visit. 
8.8.1.1. 
Screening Phase (up to – 120 to – 7 days) 
Visit 1: Screening 
During the Screening Phase, once the informed consent form is signed, the following 
assessments will be performed/collected: 
• Inclusion/Exclusion review 
• Medical history 
• Body height/weight 
• Waist circumference 
• Vital signs  
• Physical examination 
• Electrocardiogram (12-lead)  
• Fasting safety labs - chemistry (including CPK, liver enzymes, lipid panel) 
hematology, coagulation profile, and urinalysis labs 
• CK-18 biomarker 
• Liver MRI (can be scheduled on separate date)  
• Serum β-hCG (pre-menopausal females) 
• Fib-4 Index 
• NAFLD fibrosis score 
• Prior/concomitant medication review  
• Alcohol consumption questionnaire 
 
      Visit 2: Laboratory visit (-1 week ± 5 days)  
Fasting safety labs and serum β-hCG (for pre-menopausal females) will be repeated around 1 
week prior to Day 1 Baseline visit.  


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8.8.1.2. 
Treatment Phase (12 weeks) 
Subjects who complete all of the screening assessments will return to the clinic on Treatment 
Day1 (Baseline) to repeat laboratory tests and physical assessments. Subjects who continue to be 
eligible will be enrolled to receive MN-001 250 mg qd for 4 weeks and then increase their 
dosage to 250 mg bid (500 mg/d) for the remaining 8 weeks (total dosing of 12 weeks). Subjects 
will receive their first dose of study medication on Day 1 at the clinic.   
Subjects will enter the clinic in the morning prior to breakfast. Once the pre-dose fasting labs 
have been completed, subjects will be given breakfast.   
Visit 3: Baseline Day 1  
• Inclusion/Exclusion review 
• Body weight/waist circumference 
• Vital signs  
• Physical Examination 
• 12-lead ECG at hour 1.5 (± 30 minutes) post dose 
• Blood sample for Cholesterol efflux capacity test 
• MN-001 blood concentration sample will be collected at the following timepoints:  
prior to the first dose and at Hour 0.5, 1.5, 3, 6, 9, 12 and 24 (± 30 minutes) post dose 
for the first 6 subjects only* 
• Concomitant medication review 
• Adverse event review 
• Dispense study drug 
Once the pre-dose assessments have been completed, the subject will be administered a single 
dose of MN-001 with room temperature water. 
* The first 6 subjects enrolled in the study will have the option to remain in the clinic overnight 
until the last PK blood sample is drawn or return the following day for the last/final blood draw. 
 
Visit 4: Telephone Visit Week 2 ± 3 days 
The study nurse/coordinator will telephone the subject to review adverse events and 
concomitant medications.    
 
Visit 5: Week 4 ± 5 days 
The following assessments will be conducted: 
• Body weight /waist circumference 
• Vital signs  
• Abbreviated physical examination 


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• 12-lead ECG at hour 1.5 (± 30 minutes) post dose 
• Fasting safety labs - chemistry (including CPK, liver enzymes, lipid panel) 
hematology, coagulation profile, and urinalysis labs 
• Urine pregnancy test (pre-menopausal female)  
• Adverse event review 
• Concomitant medication review 
• Study drug accountability  
• Subjects will be instructed to increase their dose to 250 mg bid. 
 
Visit 6: Week 8 ± 5 days 
• Body weight/waist circumference 
• Vital signs  
• Abbreviated physical examination 
• 12-lead ECG at hour 1.5 (± 30 minutes) post dose 
• Fasting safety labs - chemistry (including CPK, liver enzymes, lipid panel) 
hematology, coagulation profile, and urinalysis labs 
• Urine β-hCG (in pre-menopausal females) 
• Adverse event review 
• Concomitant medication review 
• Study drug accountability 
 
Visit 7: Week 12 ± 5 days 
• Body weight/waist circumference 
• Vital signs 
• Abbreviated physical examination 
• 12-lead ECG at hour 1.5 ± 30 minutes) post dose 
• Fasting safety labs - chemistry (including CPK, liver enzymes, lipid panel) 
hematology, coagulation profile, and urinalysis labs 
• CK-18 biomarker  
• Blood sample for Cholesterol efflux capacity test 
• Liver MRI  
• Urineβ-hCG (in pre-menopausal females) 


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• Alcohol consumption questionnaire 
• Adverse event review 
• Concomitant medication review 
• Study drug accountability/return of study drug 
 
8.8.1.3. 
Follow Up Phase 
Visit 8: Week 13 ± 3 days 
• Body weight/waist circumference 
• Vital signs  
• Physical examination 
• Adverse event review 
Early Termination visit  
Subjects who discontinued study medication will undergo the following assessments: 
• Body weight/waist circumference 
• Vital signs  
• Abbreviated physical examination 
• 12-lead ECG  
• Fasting safety labs - chemistry (including CPK, liver enzymes, lipid panel) 
hematology, coagulation profile, and urinalysis labs 
• CK-18 biomarker  
• Blood sample for cholesterol efflux 
• Liver MRI 
• Urine β-hCG (in pre-menopausal females) 
• Alcohol consumption questionnaire 
• Adverse event review 
• Concomitant medication review 
• Study drug accountability /return of study drug 
Laboratory Re-test visit 
Subjects who have an abnormal lab finding will return for a laboratory re-test visit and will have 
the following assessments performed: 
• Fasting chemistry, hematology, or urinalysis lab, as indicated 
• Adverse event review 


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• Concomitant medication review 
8.8.2. 
Procedures/Assessment Details 
8.8.2.1. 
Informed Consent 
The Principal Investigator or a qualified designee (e.g., a licensed, qualified medical practitioner 
such as a physician’s assistant or a nurse practitioner) listed on Form FDA 1572 will explain the 
study to the subject, answer all of the subject’s questions, and obtain written informed consent 
before performing any study-related procedure. Informed Consent should be conducted in 
accordance with local requirements. Subjects should be able to verbally describe the benefits and 
risks associated with this study and what other treatment alternatives are available (as described 
in the consent form). Only subjects who provide informed consent, as assessed and documented 
by the Investigator, will be enrolled. 
8.8.2.2. 
Medical History  
A medical history obtained by the PI or qualified designee as listed on the Form FDA 1572.   
8.8.2.3. 
Prior/Concomitant Medication Review 
Site study staff will record all medications taken within 1 month prior to screening visit in the 
CRF. Also, the following parameters will be recorded for all concomitant medications: drug 
name, route of administration, total daily dose, unit, frequency, start/stop dates, indication, and 
whether the medication was started after last dose of study medication.  The concomitant 
medications will subsequently be coded using the World Health Organization Drug Dictionary 
(WHO-DD).  
8.8.2.4. 
Physical Examination 
The physical exams must be performed by the PI or qualified designee (physician, physician’s 
assistant or nurse practitioner) listed on the Form FDA 1572. Clinically significant changes from 
the signing of the informed consent form (ICF) should be captured as AEs in the CRF. 
A complete physical examination includes the following assessments: general appearance, head, 
eyes, ears/nose/throat, neck, lymph nodes, skin, lungs, heart, abdomen, and musculoskeletal. If 
the subject is discontinued for any reason, every attempt should be made to perform a final 
physical examination. 
8.8.2.5. 
Vital Signs, Height, and Weight  
Blood pressure (BP), heart rate (HR) measurements will be taken in a supine position. 
Respiratory rate and temperature will also be measured and all measurements will be recorded in 
the CRF. Clinically significant changes from baseline should be captured as AEs in the CRF. 
Weight will be measured in pounds.  Height will be recorded only at Visit 1 (screening).  Waist 
circumference will also be recorded. 


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8.8.2.6. 
Electrocardiogram (12-Lead ECG) 
All subjects will have standard resting 12-lead ECGs performed and interpreted. Subjects are to 
be supine for at least 5 minutes prior to ECG assessments. The time the ECG is performed will 
be recorded (using a 24-h clock).  
The PI or a qualified designee listed on Form Food and Drug Administration (FDA) 1572 must 
review, initial, and date the report, which must be filed in the subject’s study chart. Clinically 
significant findings at screening must be captured in the medical history.  Any clinically 
significant changes compared post study drug administration must be captured as an adverse 
event in the CRF. 
8.8.2.7. 
Fib-4 Index 
The Fib-4 index is a non-invasive method for identification of patients with advanced fibrosis. 
The Fib-4 is a simple formula based on age, AST, ALT and platelets that corresponds with 
fibrosis stage (Martinez et al 2011). 
8.8.2.8. 
Nonalcoholic fatty liver disease (NAFLD) Fibrosis Score 
The NAFLD Fibrosis Score is a validated method of noninvasively estimating the fibrosis stage 
in a patient with NAFLD. This score calculates a patient’s risk of fibrosis based on age, body 
mass index (BMI), presence of impaired fasting glucose/diabetes, platelets, albumin, ALT and 
AST (Angulo et al 2007). 
8.8.2.9. 
Cytokeratin-18 (CK-18) 
Cytokeratin 18 (CK-18) fragment levels correlate with the magnitude of hepatocyte apoptosis 
and independently predict the presence of NASH. 
8.8.2.10. Adverse Event (AE) Monitoring 
The PI or a qualified designee listed on Form FDA 1572 must assess the severity and 
relationship to study medication for all AEs (see Section 12.2). 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the investigational product(s) will be recorded on the AE page(s) of the CRF.  
Each PI and research team are responsible for identifying adverse events and reporting them. 
For all AEs, the Investigator must pursue and obtain information adequate to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE (see 
Section 12.2) requiring immediate notification to the Sponsor or its designated representative.  
For all AEs, sufficient information should be obtained by the Investigator to determine the 
causality of the AE. The Investigator is required to assess causality and indicate that assessment 
on the CRF. For AEs with a causal relationship to the investigational product, follow-up by the 
Investigator is required until the event or its sequelae resolve or stabilize at a level acceptable to 
the Investigator, and Sponsor concurs with that assessment.  
Adverse events (serious and non-serious) including all suspected unexpected serious adverse 
reactions (SUSARs) should be recorded on the CRF from the date of informed consent until the 


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end of their participation in the study (i.e., the subject has discontinued or completed the follow-
up visit). 
8.8.2.11. Laboratory Evaluations 
Laboratory evaluations will include the tests listed in Appendix 1. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
Table 4:  
Study Dug Information 
Investigational Drug: 
MN-001 
Formulation: 
250 mg tablet  
Frequency: 
250 mg qd or 250 mg bid 
Storage Conditions: 
Store at room temperature  
9.2. 
Study Drug Packaging and Labeling 
 
At a minimum the following information will be included on each bottle:  
• 
Name of Sponsor  
• 
Study number/Acronym/IND number 
• 
Route of administration 
• 
Quantity of dosage unit 
• 
Directions for use 
• 
Storage conditions 
• 
Space for information to be completed by Investigator/designee: 
o Name and telephone number of Investigator 
o Dispensing date 
o Subject number 
• 
Statement “Caution: New Drug – Limited by federal law to investigational use” 
• 
Statement: “Keep out of reach of children” 
9.3. 
Study Drug Storage 
The clinical study drug MN-001 should be stored at room temperature (preferably 18-230C, but 
15-250C is acceptable). 
9.4. 
Study Drug Administration 
The study drug will be dispensed by appropriately qualified site study staff as indicated on the 
delegation of authority log. Subjects will self-administer the study drug at home except on 
scheduled visits to the clinic. On those days, subjects will wait until they come to the clinic to 
take their study medication. The subject will be instructed to return all unused study drug to the 
clinical trial site at each visit. 


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9.5. 
Study Drug Accountability 
Investigational clinical supplies must be received by the PI or a designated person at the study 
site, handled and stored safely and properly, and kept in a secured location to which only the 
Investigator and/or designated assistants have access. Clinical supplies are to be dispensed only 
in accordance with the protocol.  
The PI or designee is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects, and the 
amount remaining at the conclusion of the study. At the end of the study, all clinical supplies 
must be returned to the Sponsor, or designee, after confirmation with the CRA (Clinical 
Research Associate) or destroyed at the clinical site. Study drug will not be destroyed until 
written documentation is received from the study sponsor or designee. Proper documentation of 
the destruction of study drug must be provided by the site. 
The following information is to be included in the CRF: visit medication dispensed, dosing 
start/stop dates, dosage level, number of tablets dispensed and number of tablets returned. 


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10. 
ASSESSMENT OF EFFICACY 
 
10.1. 
Primary Endpoints 
 
The primary endpoint, cholesterol efflux, will be calculated as the percent of cholesterol 
removed from the cells and appearing in the culture medium normalized to a reference serum 
pool. The ability of serum HDL to remove cholesterol from cultured cells will be assessed as an 
in vitro method to evaluate functional changes in HDL mediated by changes due to MN-001 
treatment. 
Cholesterol efflux with HDL will be measured by Cholesterol Efflux Fluorometric Assay Kit 
(BioVision, Inc.). Detailed protocol is attached in Appendix 3.  
 
An additional primary endpoint is will evaluate the effects of MN-001 on triglyceride level in 
subjects with NAFLD or NASH. The primary endpoint will be decreased triglycerides measured 
as the difference after 12 weeks of treatment from baseline levels. The data are expressed as the 
percent change from the baseline value and calculated using he equation: Change = 
[100%*(Endpoint value - Baseline Value)/Baseline Value] 
10.2. 
Secondary Endpoints 
Safety will be assessed by the monitoring and recording of all AEs and serious adverse events 
(SAEs), regular monitoring of hematology, blood chemistry and urine values, regular 
measurement of vital signs, electrocardiograms (ECGs), and the performance of physical 
examinations. 
Other secondary measures, lipid profile including HDL-C, LDL-C, total cholesterol level, liver 
enzymes and percentage of fat in the liver assessed, will be measured by the change from 
baseline to Week 12.  
Pharmacokinetic parameters of MN-001 and its metabolite, MN-002 will be calculated in a 
subset of 6 subjects.  
 
 


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11. 
ASSESSMENT OF SAFETY 
Safety will be assessed by the proportion of subjects with the following events: 
• clinical and laboratory treatment emergent adverse events (TEAEs) 
• discontinuations due to TEAEs 
• treatment emergent serious adverse events (TESAEs) 
Safety (relationship and severity) and tolerability will further be assessed by statistical and 
clinical review of AEs, laboratory values, ECGs, physical examinations, vital signs and weight.  
 
 


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12. 
ADVERSE EVENTS 
12.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a study subject administered a medicinal 
(investigational) product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. Adverse events may include the onset of a new illness and the 
exacerbation of pre-existing conditions. 
Other untoward events occurring in the framework of a clinical study are also to be recorded as 
AEs, (e.g., those occurring during treatment-free periods, including screening or post-treatment 
follow-up periods), in association with study-related procedures and assessments.  
12.2. 
Assessment of Adverse Events 
The PI or an authorized physician will assess all AEs for severity, relationship with study 
medication, and whether it meets the criteria for classification as a SAE, requiring immediate 
notification to the Sponsor or designee (see Section 12.5). These assessments will be made in 
accordance with the standard ratings detailed in the following sections. 
12.2.1. 
Severity Assessment 
The severity of AEs will be determined as described in Table 5. 
Table 5:  
Adverse Events Severity Definition 
Mild 
Grade 1 
Ordinarily transient symptoms that do not influence performance of subject’s daily 
activities. Treatment is not ordinarily indicated. 
Moderate 
Grade 2 
Marked symptoms sufficient to make the subject uncomfortable. Moderate influence on 
performance of subject’s daily activities. Treatment may be necessary. 
Severe 
Grade 3 
Symptoms cause considerable discomfort. Substantial influence on subject’s daily 
activities. May be unable to continue in the study and treatment may be necessary. 
Life-
threatening 
Grade 4 
Extreme limitation in activity, significant assistance required; significant 
medical/therapy intervention required hospitalization probable. 
Death 
Grade 5 
Death. 
 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted for that day. Any change in severity of signs and 
symptoms over a number of days will be captured by recording a new AE, with the amended 
severity grade and the date (and time, if known) of the change. 


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12.2.2. 
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 Event Causality Definition 
Related 
 
A clinical event, including laboratory test abnormality, occurs in a 
plausible time relationship to treatment administration, and which 
cannot be explained by concurrent disease or other medications or 
chemicals. The response to withdrawal of the treatment (dechallengea) 
should be clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory 
rechallengeb procedure if necessary. 
Probably 
related 
 
A clinical event, including laboratory test abnormality, occurs within a 
reasonable time sequence to administration of the treatment, unlikely to 
be attributed to concurrent disease or other medications or chemicals, 
and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this 
definition. 
Possibly related 
 
A clinical event, including laboratory test abnormality, occurs within a 
reasonable time sequence to administration of the treatment, but which 
could also be explained by concurrent disease or other medications or 
chemicals. Information on treatment withdrawal may be lacking or 
unclear. 
Unlikely to be 
related 
 
A clinical event, including laboratory test abnormality, occurs with a 
temporal relationship to treatment administration that makes a causal 
relationship improbable, and in which other medications, chemicals, or 
underlying disease provide plausible explanations. 
Unrelated 
 
A clinical event, including laboratory test abnormality, occurs with 
little or no temporal relationship with treatment administration. May 
have negative dechallenge and rechallenge information. Typically 
explained by extraneous factors (e.g., concomitant disease, 
environmental factors, or other medications or chemicals). 
a Dechallenge is when a medication suspected of causing an AE is discontinued. If the symptoms of 
the AE disappear partially or completely, within a reasonable time from medication discontinuation, 
this is termed a positive dechallenge. If the symptoms continue despite withdrawal of the 
medication, this is termed a negative dechallenge. Note that there are exceptions when an AE does 
not disappear upon discontinuation of the medication, yet medication-relatedness clearly exists 
(e.g., as in bone marrow suppression, fixed medication eruptions, or tardive dyskinesia) 
b Rechallenge is when a medication suspected of causing an AE in a specific subject in the past is 
readministered to that subject. If the AE recurs upon exposure, this is termed a positive rechallenge. 
If the AE does not recur, this is termed a negative rechallenge. 
12.3. 
Recording Adverse Events 
Adverse events should be collected and recorded for each subject from the date that the first 
study dose was taken until the end of their participation in the study (i.e., the subject has 
discontinued or completed the study).  Only those AEs that occurred while on study drug that 
have not been resolved will be followed until resolution or stabilization. 


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Following the end of the subject’s participation in the study, the PI or an authorized delegate 
should report SAEs “spontaneously” if considered at least possibly related to study medication. 
Adverse events may be volunteered spontaneously by the study subject, or discovered by the 
study staff during physical examinations or by asking an open, non-leading question such as, 
“How have you been feeling since you were last asked?” All AEs and any required remedial 
action will be recorded in the subject’s source documentation and transcribed onto the 
appropriate CRF page for the study period indicated. The nature of AE, date (and time, if known) 
of AE onset, date (and time, if known) of AE outcome to date, severity, and action taken of the 
AE will be documented together with the PI or an authorized physician’s assessment of the 
seriousness of the AE and causal relationship to study medication and/or study procedure (at the 
time of assessment). 
All AEs should be recorded individually in the study subject’s own words (verbatim) unless, in 
the opinion of the PI or an authorized physician, the AEs constitute components of a recognized 
condition, disease, or syndrome. In the latter case, the condition, disease, or syndrome should be 
named rather than each individual symptom. The AEs will subsequently be coded using the 
MedDRA. 
12.4. 
Treatment and Follow-Up of AEs 
Appropriate measures should be taken to treat AEs as necessary, and the response of the study 
subject should be monitored and recorded. Clinical, laboratory, and diagnostic measures should 
be obtained as needed, and the results of which should be recorded in the subject’s source 
documentation and transcribed onto the appropriate CRF page. 
All SAEs will be followed until resolution, stabilization of the condition, the event is otherwise 
explained, or the subject is lost to follow-up. 
12.5. 
Serious Adverse Events (SAEs) 
An AE is considered serious if it meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (i.e., a subject is at immediate risk of death at the time of the event, 
not an event where occurrence in a more severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is another important medical event (see below). 
Important medical events that do not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or in a physician’s office, blood dyscrasias 
or seizures that do not result in inpatient hospitalization, and the development of drug 
dependency or drug abuse. A distinction should be drawn between serious and severe AEs. 


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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. 
A blood sample for MN-001 concentration will be obtained when a subject experiences a SAE. 
12.5.1. 
SAE Reporting Requirements 
The PI or an authorized delegate is responsible for faxing the requested information to the 
Sponsor or designee within 24 hours or as soon as possible after learning of the event. Following 
the end of the subject’s participation in the study, the PI or an authorized delegate should report 
SAEs “spontaneously” if considered at least possibly related to study medication. 
Notification should be made by emailing a completed SAE Report Form to the Sponsor. Study 
sites in the US should email a completed SAE Report Form to: 
Safetymonitors@medicinova.com.As a minimum requirement, the initial notification should 
provide the following information: 
• Study number 
• Subject number 
• Gender 
• Date of birth 
• PI’s name and full study site address 
• Details of SAE 
• Criterion/criteria for classification as “serious” 
• Study medication name, or code if blinded, and treatment start date 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this 
classification). 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g., hospital reports, consultant reports, autopsy 
reports, etc.), with the study subject’s personal identifiers removed. All relevant information 
obtained by the PI or an authorized delegate through review of these documents will be recorded 
on the AE eCRF page and/or a new SAE Report Form and faxed to the Sponsor or designee 
within 24 hours of receipt of the information. If a new SAE Report Form is faxed, the PI must 
sign and date the form. The Sponsor may also request additional information on the SAE, which 
the PI or an authorized delegate must fax to the Sponsor or designee within 24 hours of the 
request using a new SAE Report Form, bearing the PI’s signature and date. 
Any AE fulfilling the criteria for expedited reporting will be reported by the Sponsor to 
regulatory authorities and Investigators and IEC(s) in accordance with the Sponsor’s standard 
operating procedures (SOPs) and local regulatory requirements. 


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PIs should report all Investigational New Drug Application safety alerts received from the 
Sponsor to their local IRB/IECs. 
12.6. 
Guidance for Overdose  
There is no clinical experience with MN-001 overdose in humans and there is no available 
specific antidote to the effects of MN-001. Standard symptomatic support measures should be 
used in the case of excessive pharmacological effects or overdose. 
12.7. 
 Reporting and Follow-up of Pregnancies 
If any study subject or subject’s partner becomes pregnant after receiving the first dose of study 
medication (MN-001) and until the follow-up period specified in the protocol, the PI or an 
authorized delegate should submit a Pregnancy Report Form to the sponsor within 24 hours of 
the PI or an authorized delegate first becoming aware of the pregnancy.  If a pregnancy is to be 
terminated, the anticipated date of termination should also be provided in the “Additional 
Information/Comments” field of the Pregnancy Report Form. If a maternal SAE is reported for 
the study subject during the initial notification of pregnancy, a separate SAE Report Form should 
also be completed and submitted to the sponsor within 24 hours of the PI or an authorized 
delegate first becoming aware of the SAE.  
Subjects who become pregnant while in the study should be followed for the duration of their 
pregnancy.  If the pregnancy is discovered between regularly scheduled study visits, subjects 
should return for an unscheduled visit to return their study medication.  A quantitative β-hCG 
should be obtained and subjects should be encouraged to return for follow-up visits.   If follow-
up visits are not possible, then the principal investigator should collect information about the 
pregnancy such as spontaneous or elective termination, details of birth, and presence or absence 
of birth defects, congenital abnormalities, or maternal and newborn complications. 
The Sponsor will request that the PI follow the progress of the study subject’s pregnancy with 
the doctor medically responsible for the pregnancy. A new Pregnancy Report Form should be 
submitted within 24 hours of the PI or an authorized delegate first becoming aware of any new 
information. 
If additional information on the outcome of the pregnancy and/or the details of the birth/delivery 
is received “spontaneously” by the study site, the PI or authorized delegate should also submit a 
Pregnancy Report Form within 24 hours of becoming aware of the information. If the outcome of 
the pregnancy is reported as premature birth, or as elective termination due to a medical reason 
or as spontaneous or accidental miscarriage, the details of the outcome should be described in the 
“Additional Information/Comments” field of the Pregnancy Report Form. The pregnancy 
outcome will generally be reported as a follow-up report.  
Complete an SAE Report Form if the delivery outcome meets the criteria for a SAE (e.g., 
congenital anomaly/birth defect, stillbirth, some other sickness, etc.). The SAE Report Form 
should be completed with the study subject’s details (e.g., subject number, initials, date of birth, 
investigational product information, etc.) and the details of the fetal SAE and maternal 
complications should be described in the “Narrative” field of the SAE Report Form. 
If a pregnancy is reported for the study subject’s partner, the sponsor will provide instructions on 
how to collect pregnancy information in accordance with local requirements. 


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12.8. 
Preplanned Hospitalizations or Procedures 
During the study, if a subject has a hospitalization or procedure (e.g., elective surgery) that was 
scheduled prior to the subject entering the study (i.e., before the subject signed the ICF) for an 
event/condition that occurred before the study, the hospitalization is considered a therapeutic 
intervention and not the result of an SAE. However, if the event/condition worsens during the 
study, it must be reported as an AE or SAE (if the event/condition results in a serious outcome 
such as prolongation of hospitalization.) 


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13. 
STATISTICS 
The Statistical Analysis Plan (SAP) will provide comprehensive details on the statistical methods 
and sensitivity analyses for dealing with dropouts, planned for this study prior to database lock. 
13.1. 
Data Analysis 
 
13.1.1   
Analysis Populations 
Safety Analysis Set (SAS) will include all subjects who received at least one dose of study drug 
and had at least one post dose safety assessment. 
 
Per Protocol Set: The group of subjects who received at least one dose of study drug and who did 
not have any major protocol deviations. 
 
13.1.2   
Statistical Analysis Plan 
A statistical analysis plan will outline the efficacy analysis and safety analysis prior to database 
lock.  
13.1.3   
Sample Size Justification 
No prior data are available on which to base assumptions for sample size/power considerations. 
The results of this pilot study will be used to design future studies, and the sample size of 
approximately 40 subjects is deemed to be appropriate for this purpose. 
 
13.1.4   
Safety Analysis 
Safety analyses will be conducted on the Safety Analysis Set. 
 
The incidence of treatment-emergent AEs (TEAEs, defined as AEs occurring from the time of 
first dose through 7 days after the last dose of study medication), SAEs and AEs leading to 
discontinuations will be summarized by treatment group.  Incidence of TEAEs will also be 
summarized by severity (mild, moderate, or severe), as well as by relationship to treatment (not 
related, possibly related, or probably related) and by seriousness. 
 
Changes from baseline in laboratory values will be summarized for continuous variables.  Lab 
shift tables showing incidence of new or worsening clinically significant findings from baseline 
to the last visit will be displayed.  Shift from baseline to the highest lab value, and from baseline 
to the lowest lab value will also be displayed. 
 


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Incidence of out-of-normal-range values and markedly abnormal change from baseline in 
laboratory safety test variables will be tabulated.  
Changes in vital signs from baseline to each visit will be summarized by treatment groups. 
13.2. 
Direct Access to Source Data/Documents 
By signing this protocol, the PI agrees to conduct the study in an efficient and diligent manner 
and in conformance with this protocol; generally accepted standards of Good Clinical Practice 
(GCP); and all applicable federal, state, and local laws, rules and regulations relating to the 
conduct of the clinical study. 
The PI also agrees to allow monitoring, audits, and regulatory agency inspection of study-related 
documents and procedures and provide for direct access to all study-related source data and 
documents. 
The PI shall prepare and maintain complete and accurate study documentation in compliance 
with GCP standards and applicable federal, state, and local laws, rules, and regulations; and, for 
each subject participating in the study, provide all data, and upon completion or termination of 
the clinical study submit any other reports to the Sponsor, or its designee, as required by this 
protocol or as otherwise required pursuant to any agreement with the Sponsor. 
Study documentation will be promptly and fully disclosed to the Sponsor, or its designee, by the 
PI upon request and shall also be made available at the PI’s site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory agencies. The PI agrees to promptly take any reasonable steps that are requested by 
the Sponsor, or its designee, as a result of an audit to address deficiencies in the study 
documentation and worksheets/CRFs.  
The PI will promptly inform the Sponsor or its designee of any regulatory agency inspection 
conducted for this study. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on this Sponsor’s studies. The PI will 
immediately disclose in writing to the Sponsor or its designee if any person who is involved in 
conducting the study is debarred, or if any proceeding for debarment is pending or, to the best of 
the Investigator’s knowledge, threatened. 
13.3. 
Study Monitoring  
Monitoring will include on-site monitoring to assure that the investigation is conducted 
according to protocol, to protect subject rights and safety, and to confirm data integrity and 
quality.  
This study will be monitored through all phases of study conduct by the Sponsor or its 
representative. Monitoring will include personal visits and telephone communication to assure 
that the investigation is conducted according to protocol and in order to comply with guidelines 
of GCP. On-site review of CRFs will include a review of forms for completeness and clarity, and 
consistency with source documents available for each subject. Investigators will be required to 
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13.4. 
Audits and Inspections 
The PI and appropriate personnel may be periodically requested to attend meetings organized by 
the Sponsor or its designee to assure acceptable protocol execution. The study may be subject to 
audit by the Sponsor/designee or by regulatory authorities. If such an audit occurs, the PI must 
agree to allow access to required subject records. By signing this protocol, the Investigator grants 
permission to personnel from the Sponsor, its representatives, and appropriate regulatory 
authorities for on-site monitoring and auditing of all appropriate study documentation, as well as 
on-site review of the procedures employed in CRF generation, where clinically appropriate. The 
PI has to inform the Sponsor if he/she is approached for a regulatory audit.  
13.5. 
Institutional Review Board (IRB) 
Before initiation of the study, the PI must obtain approval of the research protocol, informed 
consent form (ICF), and any advertisement for subject recruitment from the IRB complying with 
the provisions specified in the Code of Federal Regulations (CFR) 21 Part 56 and applicable 
government regulations. A copy of written IRB approval of the protocol, ICF, and advertising (if 
applicable) must be provided to the Sponsor or their designee prior to initiation of the study.  
13.6. 
Study Documentation 
By signing a copy of Form FDA 1572, the Investigator acknowledges that he/she has received a 
copy of the investigational drug brochure on MN-001 and assures the Sponsor that he/she will 
comply with the protocol and the provisions stated in Form FDA 1572. No changes in this 
protocol can be made without the Sponsor’s written approval.  
The Investigator will supply the Sponsor with the following:  
1. Original, signed Form FDA 1572  
2. Curricula vitae for all Investigators listed on Form FDA 1572  
3. Copy of the Investigator’s medical licensure/medical registration number  
4. Signed protocol signature page  
5. Signed IB signature page 
6. Financial disclosure forms for all study staff listed on the FDA 1572.  


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
By signing this protocol, the Sponsor and Clinical Study Sites Principal Investigator agree to be 
responsible for implementing and maintaining quality control and quality assurance systems with 
written standard operating procedures (SOPs) reviewed and approved by the sponsor to ensure 
that the study is conducted and data are generated, documented, and reported in compliance with 
the protocol, accepted standards of GCP, and all applicable federal, state, and local laws, rules 
and regulations relating to the conduct of the clinical study. 


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15. 
ETHICS 
15.1. 
Ethics Review 
Documented approval from the IRB will be obtained for all participating centers prior to clinical 
trial start, according to ICH (International Conference on Harmonisation) GCP, local laws, 
regulations and organization. When necessary, an extension, amendment or renewal of the CIRB 
approval must be obtained. 
15.2. 
Ethical Conduct of the Study 
The procedures set out in this clinical trial protocol pertaining to the conduct, evaluation, and 
documentation of this clinical trial, are designed to ensure that the Sponsor and Principal 
Investigator abide by Good Clinical Practice Guidelines (GCP in the appropriate current 
version). The clinical trial will also be carried out in accordance with applicable local law(s) and 
regulation(s). This may include an inspection by representatives from MediciNova Inc. and/or 
Regulatory Authority representatives at any time. The PI must agree to the inspection of clinical 
trial-related records by MediciNova, Inc. representatives, and must allow representatives direct 
access to source documents. 
15.3. 
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. 
15.4. 
Confidentiality 
15.4.1. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to the Sponsor that information furnished to the 
Investigator by the Sponsor will be maintained in confidence and such information will be 
divulged to the IRB or similar or expert committee; affiliated institution; and employees only 
under an appropriate understanding of confidentiality with such board or committee, affiliated 
institution and employees.  
 


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Review of Records 
The results from Screening and data collected during the study will be recorded in the subject’s 
CRF, which will be designed and provided by the sponsor or a designee. The Investigator will 
review all CRFs. The CRFs will be signed by the PI or a sub-Investigator who is listed on the 
Form FDA 1572 if the PI is unavailable. In order to maintain confidentiality, the subject will be 
identified only by his/her subject number and initials. 
16.2. 
Retention of Records 
The PI must arrange for retention of study records at the site for at least two years after the New 
Drug Application (NDA) is approved or Investigational New Drug (IND) is withdrawn, as 
required by the US Food and Drug Administration (FDA) regulations, or in accordance with 
local and/or national requirements, whichever is longer. The PI should take measures to prevent 
accidental or premature destruction of these documents. Documents cannot be destroyed without 
written Sponsor authorization. The Sponsor will inform the PI when the destruction of 
documents is permitted.  


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17. 
ADMINISTRATIVE AND REGULATORY DETAILS 
17.1. 
Protocol Amendments and Study Termination  
All revisions and/or amendments to this protocol must be approved in writing from the Sponsor 
and the IRB, except where necessary to eliminate an apparent immediate hazard to a study 
subject. 
17.2. 
Discontinuation of the Study  
The Sponsor reserves the right to discontinue the study at site(s) for safety or administrative 
reasons at any time. For example, a site that does not recruit at an acceptable rate may be 
discontinued. Should the study be terminated and/or the site closed for whatever reason, all 
documentation and study medication pertaining to the study must be returned to the Sponsor or 
its representative.  
17.3. 
Compliance with Financial Disclosure Requirements 
By signing this protocol, the PI agrees to provide to the Sponsor accurate financial information to 
allow the Sponsor to submit complete and accurate certification and disclosure statements as 
required by the US FDA regulations (21 CFR Part 54). The PI further agrees to provide this 
information on a Financial Disclosure/Certification Form that is provided by MediciNova Inc. 
The Investigator will update this information if there are any relevant changes during the conduct 
of the study and for one year after completion of the study. This requirement also extends to sub-
Investigators. The PI also consents to the transmission of this information to MediciNova Inc. for 
these purposes.  


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18. 
REFERENCES 
 
Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system 
that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45:846-54. 
Ballestri S, Lonardo A, Bonapace S, Byrne CD, Loria P, Targher G. Risk of cardiovascular, 
cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. 
World J Gastroenterol 2014 Feb 21; 20(7):1724-45.   
Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic 
Steatohepatitis: A proposal for grading and staging the histological lesions. Am J 
Gastroenterol 1999; 94: 2467-2474. 
Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, for the NASH CRN. 
The NAS and the histopathologic diagnosis in NAFLD: Distinct clinicopathologic meanings. 
Hepatol 2011 March; 53(3):810-20. doi:10.1002/jep.24127.  
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic 
fatty liver disease: practice guideline by the American Association for the Study of Liver 
Diseases, American College of Gastroenterology, and the American Gastroenterological 
Association. Gastroenterol 2012 Jun; 142(7):1592-609. doi:10.1053/j.gastro.2012.04.001.  
Chatrath H, Vuppalanchi R, Chalasani N. Dyslipidemia in patients with nonalcoholic fatty 
liver disease. Semin Liver Dis 2012 Feb; 32(1):22-29. 
deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels: 
evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J 
Am Coll Cardiol 2008 Jun 10; 51(23):2199-2211.   
Fujii H, Ikura Y, Arimoto J, Sugioka K, Iezzoni JC, Park SH, Naruko T, Itabe H, Kawada N, 
Caldwell SH, Ueda M.  2009.  Expression of perilipin and adipophilin in nonalcoholic fatty 
liver disease: relevance to oxidative injury and hepatocyte ballooning. J Atheroscler Thromb 
16(6):893-901. 
Funk, CD. 2001. Prostaglandins and leukotrienes: advance in eicosanoid biology. Science 
294:1871-1875. 
Navab M, Hama SY, Hough GP, Subbanagounder G, Reddy ST, Fogelman AM. A cell-free 
assay for detecting HDL that is dysfunctional in preventing the formation of or inactivating 
oxidized phospholipids. J Lipid Res 2001; 42:1308-17. 
Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH. The role of reverse 
cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res 
2009 Apr; S189-S194. 
Rangwala F, Guy CD, Lu J, Suzuki A, Burchette JL, Abdelmalek MF, Chen W, Diehl AM.  
Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol 2011 
Jul;224(3):401-10. 


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Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol efflux capacity and incident 
cardiovascular events. N Engl J Med 2014; 371:2383-93.  
Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: 
structures, biosynthesis, and biological effects. Science 1987; 237:1171-1176. 
Souza M, Diniz M, Medeiros-Filho J, Araujo M Metabolic syndrome and risk factors for 
non-alcoholic fatty liver disease. Arq Gastroenterol 2012; 49(1):89-96. 
Titos E, Claria J, Bataller R, Bosch-Marce M, Gines P, Jimenez W, Arroyo V, Rivera F, 
Rodes J. Hepatocytes-derived cysteinyl-leukotrienes modulate vascular tone in experimental 
cirrhosis. Gastoenterology 2000; 119:794-805. 
Titos E, Planaguma A, Lopez-Parra M, Villamor N, Miquel R, Jimenez W, Arroyo V, Rivera 
F, Rodes J, Claria J. 5-Lipoxygenase (5-LO) is involved in Kupffer cell survival: Possible 
role of 5-LO products in the pathogenesis of liver fibrosis. Comparative Hepatology 2004; 
3(Suppl 1): S19. 
 


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19. 
APPENDICES 


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Appendix 1: 
Laboratory Safety Tests for MN-001 
 
 
Blood Chemistry Tests 
 
aspartate aminotransferase (AST) 
 
alanine aminotransferase (ALT) 
 
albumin  
 
alkaline phosphatase  
 
bicarbonate  
 
blood urea nitrogen  
 
calcium  
 
chloride  
 
creatinine  
              creatine phosphokinase (CPK) 
 
gamma-glutamyl transferase  
 
phosphorous  
 
potassium  
 
sodium  
 
total bilirubina 
 
total protein  
 
lactate dehydrogenase  
 
triglyceride  
 
serum cholesterol  
 
serum high-density lipoprotein cholesterol  
 
serum low-density lipoprotein cholesterol  
 
glucose  
 
Endocrine Tests 
 
serum beta-human chorionic gonadotropin (for females of childbearing potential) 
 
urine beta-human chorionic gonadotropin  
 
Hematology Tests 
 
white blood cell count 
 
white blood cell differential 
 
eosinophilic leukocyte count 
 
basophilic leukocyte count 
 
neutrophil count 
 
lymphocyte count 
 
monocyte count 
 
platelet count 
 
hemoglobin  
 
blood hematocrit 
 
red blood cell count 
 
red cell distribution width  
 
red blood cell indices: 
 
mean corpuscular volume 
 
mean corpuscular hemoglobin concentration 
 
mean corpuscular hemoglobin 
 Coagulation Tests 
              INR 
              PT 
             APTT 


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Urinalysis Tests 
 
color  
 
appearance  
 
total ketones  
 
urobilinogen  
 
bilirubin  
 
red blood cells 
 
leukocyte esterase  
 
nitrite  
 
pH  
 
protein  
 
specific gravity  
 
glucose  
 
microscopic evaluationb 
a Bilirubin will be fractionated (direct serum bilirubin test/indirect serum bilirubin test) if elevated 2.0 times the 
upper limit of the normal range. 
b Microscopic evaluation will be performed if dipstick analysis indicates the presence of any significant 
abnormality. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Informed Consent Form  
“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 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. 
Informed Consent 
 
Protocol Number: 
MN-001-NATG-201 
 
  Protocol Title: 
An Open-Label Study to Evaluate the Efficacy, Safety and    
Pharmacokinetics of MN-001 (tipelukast) in Non-alcoholic 
Steatohepatitis (NASH) and Non-Alcoholic Fatty Liver Disease 
(NAFLD) Subjects with Hypertriglyceridemia 
 
Protocol Date: 
June 6, 2016 
 
Investigator: 
{Investigator Name/Address} 
 
1.  General Information 
You are being asked to participate in a research project to study MN-001 (tipelukast) because you 
are diagnosed with Non-alcoholic steatohepatitis (NASH) or Non-Alcoholic Fatty Liver Disease 
(NAFLD) and your blood triglyceride level is high. Before agreeing to participate in this research 
study sponsored by MediciNova, Inc, it is important that you read and understand this document. It 
describes the purpose, procedures, benefits, risks, discomforts and precautions of the study. It also 
describes the alternative procedures that are available to you and your right to withdraw from the 
study at any time. If you are not completely truthful with your doctor regarding your health history, 
you may harm yourself by participating in this study. If this form contains any words that you do not 
understand, please ask your study doctor or member of the study staff to explain them to you. 
2.  About the Study 
The purpose of this research study is to evaluate the effectiveness and safety of MN-001 on subjects 
with NASH or Non-Alcoholic Fatty Liver Disease (NAFLD) and high triglyceride level. This will 
be assessed by looking at how the drug affects your blood cholesterol function and triglyceride level. 
The name of the investigational drug that you may take in this study is MN-001. “Investigational” 
means that the drug has not been approved by the Food and Drug Administration (FDA). Animal 


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and human studies have shown that MN-001 may be useful for treating the NASH and blood lipid 
profile.  
Approximately 40 subjects will participate in this research study. Your participation in this study 
will last for approximately 13 weeks. You can expect a total of 7 study visits (including 1 telephone 
visit) during this time, although more visits may be required if your Study Doctor decides they are 
needed for medical reasons. 
3.  Study Eligibility 
To participate in this study,  
• Male or female and must be at least 18 years of age  
• Diagnosis of NASH by liver biopsy or NAFLD confirmed by imaging studies with elevated 
blood triglyceride level 
• All females must not be pregnant or nursing, and must be practicing an acceptable method of 
birth control  
• All males should practice contraception for the duration of study treatment and 30 days after 
the last dose of study treatment as follows:  condom use and contraception by female 
partner  
• You must currently not be participating in another clinical study and not have participated 
in another clinical study in the previous 3 months to signing this informed consent  
• No other significant diseases, such as heart attack within 6 months, unstable ischemic heart 
disease, etc. 
During your study participation there are certain medications that you will not be allowed to 
use. These medications are listed under Prohibited Medications in Section 10 of this form. 
Please discuss any new medication that you would like to take during study participation 
with your study doctor prior to starting this study and discuss the medication you are 
currently taking. 
4.  Description of the Procedures 
This is an open-label study. This means that you will receive the active drug (MN-001 tablets). 
You will be instructed to take MN-001 250 mg tablet once a day for first 4 weeks. After 4 weeks, 
you will start taking a MN-001 250 mg tablet twice a day for the next 8 weeks. 
If you qualify to participate, you will receive study medication at Baseline Visit and continue for 
total of 12 weeks. Study medication will be taken once a day for first 4 weeks. After the Week 4 visit, 
you will start to take study drug 2 times per day, morning, and evening (for example, 7 AM and 9 
PM). 
On Baseline visit (Day 1 of study), you may be asked to stay overnight at the study center and 
blood samples will be collected before and after taking medication. Blood samples will be used to 
evaluate the study drug concentration. 
After baseline visit, this study requires 4 more visits (Week 4, Week 8, Week 12, and Week 
13/Follow-up) to the clinic over a period of approximately 13 weeks. The clinic visits will require 
you to be in the clinic for approximately 2-3 hours for a physical exam, ECG test, and blood test.  


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You must fast (no food or liquid intake) after midnight before each clinic visit. You must not drink 
alcoholic beverages for at least 6 hours prior to each visit.  No caffeinated food, beverages, or 
medications will be allowed for at least 6 hours before each visit.  
5.  Study Visits and Procedures 
During your regular follow-up clinical visit, your doctor will ask you if you are interested in 
participating in the study. If you are interested in the study, your doctor will give you “Informed 
consent” (this form) to review. After reading the form carefully and if you are interested in the 
study, your doctor can determine whether you are eligible to participate in the study when you 
return for your next clinic visit.  You will receive no study drug at pre-treatment visits. 
Screening Phase  
Screening Visit (This Visit will last approximately 2-3 hours) 
If you read the informed consent form and are still interested in participating study, the tests listed 
below will be conducted to evaluate your eligibility 
• Vital signs, physical exam, body weight, height and waist circumference. 
• Review your medical history and medication you are taking 
• 12 lead- ECG test 
• Blood test and Urine test  
• Liver MRI ( MRI may be scheduled on different day) 
 
Treatment Phase  
Baseline visit: This Visit will last approximately 1 hour 
If you are eligible for the study, you will be asked to return to the clinic later. During this visit, the 
Study Doctor will 
• Check vital signs  
• Perform a blood pregnancy test (if you are pre-menopausal female)  
• Review your other medications 
• Provide you with study medication. The first dose will be taken at the clinic. (Selected 
patients will stay at the research center overnight and blood samples will be collected 
multiple times before and after taking study drug)  
• Perform a 12-lead ECG after about 1.5 hour after first dose 
• Schedule next visit for 4 weeks later 
Telephone visit 
At Week 2, you will be called by a study team member (for example, a study coordinator or nurse) 
to collect information regarding your health status. Your medications and any adverse events will 
be documented. 
Clinic Visits (Week 4, 8 and 12): These Visits will last approximately 2-3 hours 


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• Vital signs, physical exam, body weight / waist circumference 
• Review your medication  
• 12 lead- ECG test  
• Blood draw 
• Urine pregnancy test (if you are pre-menopausal female) 
If you decide to discontinue from the study early, you need to come back to the clinic to complete 
evaluations for an “Early termination” visit.  
Follow-up visit 
You will be asked to come back to the clinic about 1 week after your last dose.  
This visit will last approximately 1 hour and the following assessments will be performed:  
• 
Physical examination 
• 
Vital signs  
• 
Adverse event review 
• 
Concomitant medication review 
6.  Subject Responsibilities 
As a subject in this study, you have certain responsibilities to help ensure your safety. These 
responsibilities are listed below: 
Complete all required visits. 
• 
Take the study medication as prescribed. You will be asked to withhold your morning 
dose of study medication on the day of each clinic visit. On the day of your 
appointment, the morning dose of study medication will be administered at the clinic. 
• Report all side effects and medical problems to your doctor or the study coordinator. 
• 
Inform the study doctor or staff if you decide to discontinue your participation 
at which time you will be required to complete a close-out visit. 
7.  Potential Benefits 
There is no guarantee that you will benefit from study participation. The study treatment may 
result in an improvement in your blood lipid profile or you may have no improvement at all.  
8.  Potential Risks and/or Discomforts 
Tipelukast is an investigational drug that has been evaluated in clinical trials in the U.S. and other 
countries. More than 600 individuals have been exposed to tipelukast to date. 
Based on past experience, common side effects of MN-001 are the following: 
• 
diarrhea /loose stools 
• 
headache   
• 
nausea 
Other side effects associated with tipelukast are vomiting and dizziness. The majority of side 
effects was mild and reversible. 


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Additionally, in a MN-001 study of subjects with interstitial cystitis, there was one event that was 
serious and considered possibly related to MN-001 by the treating physician: an infant, whose 
mother became pregnant during her study participation, was born with a birth defect in the right 
eye. 
9.  Cautions and Warnings 
Serious allergic reactions that can be life-threatening may occur. 
All study medication must be taken only by the person for whom it has been prescribed. The 
study medication is not in a package that is resistant to opening by children. 
10. Pregnancy/Birth Control  
Female subjects 
The risks of taking MN-001 to pregnant women on an unborn baby are unknown. For this 
reason, females must have a negative pregnancy test before the study starts and again at 
Visit 3. You must not become pregnant during this study. If you are a female of childbearing 
potential, you must use an effective form of birth control during this study. Acceptable 
methods of birth control include 
• consistent use of an approved oral contraceptive (birth control pill) 
• an implantable contraceptive (such as Norplant®) 
• an injectable contraceptive (Depo-Provera®) 
Note: If your primary birth control method is one of these first three methods (that is, hormonal) you 
are encouraged to add the use of a barrier method and spermicide since the effect MN-001 may have 
on hormonal methods has not yet been determined. 
• a double-barrier method (diaphragm with spermicide, condom with spermicide) 
• abstinence  
Oral, implantable, or injectable contraceptives are only considered effective if used properly 
and started at least 30 days prior to the screening visit. Some drugs (e.g., antibiotics) may 
interact with hormonal contraceptives, making them not work properly. Please inform your 
Study Doctor of all other medications you are taking. If you suspect that you may have 
become pregnant during the study, you must contact the study doctor immediately. Your study 
doctor may want to follow you and the progress of your pregnancy until the baby is born. The 
effect of MN-001on a nursing infant is also unknown; if you are breastfeeding, you cannot 
participate in the study. 
Male subjects 
Male subjects should be advised that the effects of the study drug on the male reproductive 
system are not known at this time, and contraceptive methods should be used throughout the 
study and for 30 days after completion of the study. It is recommended that both partners use 
contraception. If you suspect your partner may be pregnant you must contact the study 
doctor immediately. Your study doctor may want to follow the progress of your partner’s 
pregnancy until the baby is born. 
Prohibited Medications 


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During your study participation there are certain medications that you will not be allowed 
to use. Please discuss any new medication that you would like to take during study 
participation with your Study Doctor prior to starting this study and discuss the medication 
you are currently taking. 
• CYP2C8 substrate with narrow therapeutic index (for example, paclitaxel) within 15 days 
prior to starting study drug and throughout the study 
• CYP2C9 substrate with narrow therapeutic index (for example, phenytoin, S-warfarin, 
tolbutamide) within 15 days prior to starting study drug dosing and throughout the study 
• Macrolides and other antibiotics within 15 days prior to starting study drug dosing and 
throughout the study unless administered for a short-term treatment course during the study 
• Steroids within 30 days prior to starting study drug dosing and throughout the study 
unless administered for a short term treatment course during the study. 
11.   Compensation for Research-Related Injury 
You can obtain medical treatment for an injury related to treatment with MN-001 at the 
[Insert Institution’s Name Here]. Please ask your Study Doctor for more details. If you believe 
you have been injured as a result participating in this study, please contact your study doctor 
immediately. 
 
If you have any injury that is related to treatment with study drug, MediciNova will pay for the 
reasonable cost of necessary medical care to the extent the cost is not paid by your commercial 
medical insurance, or another party. You may not be compensated for uninsured medical care if 
you do not follow instructions regarding proper use of the study drug.  If you have an injury 
related to treatment with the study drug, your doctor will decide what medical care you need. 
MediciNova will not pay for the normal progress of your disease, or any injury or complication 
due to the medical condition you already have.  MediciNova will not provide any other kind of 
compensation such as compensation for lost wages, disability or discomfort.  You do not give up 
any of your legal rights by signing this consent form. 
Neither the sponsor nor the study doctor has a program in place to provide other compensation in 
the event of an injury. 
12.    Alternative Treatments 
If you do not wish to participate in this study, you will continue to be treated by your doctor 
and your care will not be jeopardized in any way. Your doctor may continue with your 
current treatment regimen with modifications that you and your doctor agree are appropriate.  
13.    Publication of Information and Confidentiality of Subject’s 
Name 
All reasonable measures to protect the confidentiality of your study records and your identity 
will be taken to the extent permitted by the applicable laws and/or regulations, and will not 
be made publicly available. U.S. Federal Privacy Regulations require that you authorize 
the release of any health information that may reveal your identity. The persons and 
entities that you are authorizing to use or disclose your individually identifiable health 
information may include the study doctor, the study staff, the Institution, and the Sponsor. 
In order to analyze the data collected during this research study, all of the health 


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information generated or collected about you during the study may be inspected by 
MediciNova, Inc. or the authorized agents of MediciNova, the FDA, the Department of 
Health and Human Services (DHHS) other government regulatory agencies from other 
countries, the study center ethics committee (Internal Review Board). 
The results of this study may be presented at meetings or in publications; however, your 
identity will not be disclosed in these presentations. By signing this informed consent form, 
you are authorizing such access to your medical records. This authorization will not have an 
expiration date. 
14.   Voluntary Participation and Termination of Participation 
Your participation in this research study is voluntary. You can choose not to participate in 
this study either at the beginning or at any time during the study. Your choice will not have 
an adverse impact on your present or future health care. There will be no penalty or loss of 
benefits to which you are otherwise entitled. To ensure your safety, you will be asked to 
undergo a final evaluation visit. If you wish to withdraw from the study, you should contact: 
 
(Insert name of study doctor) or study personnel at (insert phone no.). 
 
You may also revoke the authorization to use or disclose personal information about your health. If 
you choose to withdraw your authorization, you must notify the study doctor in writing and you 
will be withdrawn from the study. The study doctor’s mailing address is: 
 
(Insert Principal Investigator’s name and mailing address) 
 
The study doctor will still be able to use the information collected about you prior to your 
withdrawal from the study. Information that has already been sent to the study sponsor cannot be 
withdrawn. 
 
Your participation in this study may be discontinued without your consent by the investigator 
or the sponsoring company if you fail to follow the investigator’s instructions. You may also 
be withdrawn from the study if, in the investigator’s opinion, the study drug is ineffective, 
harmful, or has medically unacceptable side effects, or for other reasons at the discretion of 
the sponsor or investigator. If you are withdrawn from the study, you will be asked to have 
the appropriate medical tests and follow-up to evaluate your health and safety. 
15.   Who to Contact to Ask Questions about Your Rights as a 
Research Subject 
This research project has been reviewed by the (insert name of board) or institutional review 
board (IRB)/ independent ethic committee (IEC). This committee or board is a group of 
individuals from the community responsible for the review and approval of research 
proposals to be conducted. If you have questions about your rights as a research subject, you 
may contact: 
The (insert name of IRB/IEC), at (insert phone number). 


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16.   Subject’s Consent to Participate 
I have read the above information, have been given the opportunity to ask questions, 
and my questions have been answered to my satisfaction. By signing this form, I 
voluntarily consent to participate in the research study. I am also authorizing the 
use and disclosure of my personal health information. I cannot participate in this 
research study without this authorization. If I refuse to give my authorization, my 
medical care will not be affected. I will be given a copy of this signed consent form. 
I hereby elect to participate in this research study. 
Signature Page 
 
 
Subject Name (Print) 
 
 
 
Subject Name (Signature) 
Date 
 
 
 
Legally Authorized Representative (Print) (If Applicable) 
Relationship to Subject 
 
 
 
Legally Authorized Representative (Signature) (If Applicable) 
Date 
 
 
 
Name of Person Conducting Consent Discussion (Print) 
 
 
 
Person Conducting Consent Discussion (Signature) 
Date 
 
 
Investigator Name (Print) 
 
 
  Investigator Name (Signature)  
 
 
 
 
 
 
 
 
 
     Date 


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Appendix 3: Cholesterol Efflux Study Protocol 
 
Cholesterol Efflux Assay Protocol 
The procedure described below is for macrophage cell line J774.1. This procedure can also 
be used with macrophage cells derived from THP-1 monocytes, by addition of 100 nM 
phorbol 12-myristate 13-acetate (PMA) for 48 h. 
 
1. Label Cells:  
Grow J774.1 cells in RPMI 1640 media containing 10% FBS in cell culture flask till ~90% 
confluency (37°C incubator containing 5% CO2). Split cells under sterile conditions using 
basic cell culture techniques & plate approximately 1 x 105 J774.1 cells/well in a 96-well 
plate (white plate with clear bottom) using 100 2l media/well. Grow for 2 h in a 37°C 
incubator containing 5% CO2. After 2 hours, when the cells are attached to the plates, wash 
the cell monolayer with RPMI 1640 media (no serum added). Premix 50 2l of Labeling 
Reagent and 50 2l of Equilibration Buffer containing Reagent A and B/well just before use. 
Add 100 2l mix/well. Incubate the plate overnight (16 hrs.) in a 37°C incubator containing 
5% CO2. 
 
Notes: 
a. To test the background fluorescence, add 100 2l of Equilibration Buffer containing 
Reagent A and B to the cell monolayer. Don’t add labelling reagent to the background 
control well(s). 
b. For accurate assay, we recommend each treatment and control to be performed in 
triplicates. 
 
2. Treat Cells:  
After 16 h, remove the Labeling Reagent. Wash the cells gently by adding 200 2l of RPMI 
media (no serum) to all the wells. Remove the media. Treat cells with desired cholesterol 
acceptors in RPMI media. If using human serum as cholesterol acceptor, pre-treat the 
serum with Serum Treatment Reagent. Add 2 parts of Serum Treatment Reagent to 5 parts 
of human serum (Ratio 2:5). 
Incubate for 20 min. on ice. Centrifuge the mixture at 9,000 x g, for 10 min. at 4°C. Use the 
supernatant to treat the cells as desired and make up the volume to 100 2l by RPMI media. 
For Positive Control, add 20 2l of Positive Control & make up the volume to 100 2l by 
RPMI media. For no treatment control, add 100 2l RPMI media (no serum) to no treatment 
control well(s). Incubate cells for 4-6 h. in a 37°C incubator containing 5% CO2. 


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3. Measurement:  
At the end of incubation, transfer supernatant to a 96-well plate (white plate). Measure the 
fluorescence (Ex/Em = 482/515 nm). Solubilize the cell monolayer by adding 100 2l of 
Cell Lysis Buffer and shaking on a plate shaker for 30 min at room temperature. Pipette up 
and down to dissolve any cell debris. Measure the fluorescence (Ex/Em = 482/515 nm). 
 
4. Calculations:  
Cholesterol efflux of the treatments is calculated by dividing the fluorescence intensity of 
the media by total fluorescence intensity of the cell lysate of the same treatment & media. 
This value is multiplied by 100 to obtain % Cholesterol Efflux. Subtract % 
Cholesterol Efflux obtained from no treatment control from the treatment groups to 
determine the final % Cholesterol Efflux. 
 
% Cholesterol Efflux =               Fluorescence intensity of the media             X 100  
                                        Fluorescence intensity of the cell lysate + media  
                                  
 
 
Figure: Percentage (%) Cholesterol Efflux: J774.1 cells were labeled with the Labeling 
Media and treated with various cholesterol acceptors like Human Serum, HDL (50 2g) or 
Positive control known to cause cholesterol efflux. Cholesterol efflux is expressed as % 
efflux elicited by cells in 4h. 
 
 


1 
 
1 STATISTICAL ANALYSIS PLAN 
CONFIDENTIALITY STATEMENT 
The information being provided in this protocol is considered confidential, proprietary trade 
secret information as defined by the Federal Trade Secrets Acts and is thus protected from 
disclosure to unauthorized parties under the Freedom of Information Act. This protocol shall be 
considered a confidential document that provides information for the sole use of clinical 
Investigators for the referenced study, their teams, and the study site Institutional Review 
Boards/Ethics Committees (IRB/EC). 
 
 
STUDY TITLE 
An Open-Label Study to Evaluate the Efficacy, Safety, 
Tolerability and Pharmacokinetics of MN-001 (tipelukast) on 
HDL (High Density Lipoprotein) Function and Serum 
Triglyceride Levels in Non-Alcoholic Steatohepatitis (NASH) 
and Non-Alcoholic Fatty Liver Disease (NAFLD) Subjects with 
Hypertriglyceridemia  
SPONSOR 
MediciNova, Inc. 
4275 Executive Square, Suite 300 
La Jolla, California 92037  
PREPARED BY  
Kazuko Matsuda, M.D., Ph.D., M.P.H. 
Chief Medical Officer 
MediciNova, Inc. 
Malath Makhay, Ph.D., MWC  
Director, Medical Writing, 
MediciNova, Inc. 
SAP VERSION 
2.0, July 23, 2020 
PREVIOUS SAP VERSION 
AND DATE 
1.0, August 12, 2019 
IND NO. 
123659 
PHASE OF STUDY 
Phase 2a 
PROTOCOL NO. 
MN-001-NATG-201 
PROTOCOL VERSION AND 
DATE 
Amendment 3, August 14, 2017 
NCT NO. 
02681055 
REVISIONS 
Signature Page added 
Background, Rationale sections added 
General Statistical Considerations section added 
List of Tables and Listings was split into 2 Tables:  
Table of Tables, Table of Listings 
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2 SIGNATURES 
I give my approval for the Statistical Analysis Plan v2.0, for the study entitled, “An Open-Label 
Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of MN-001 
(tipelukast) on HDL (High Density Lipoprotein) Function and Serum Triglyceride Levels in 
Non-Alcoholic Steatohepatitis (NASH) and Non-Alcoholic Fatty Liver Disease (NAFLD) 
Subjects with Hypertriglyceridemia.” 
 
 
 
Kazuko Matsuda, M.D., Ph.D., M.P.H. 
Name 
Chief Medical Officer, MediciNova, Inc. 
Title 
 
 
 
Signature 
23 July 2020 
Date 
 
 
 
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3 TABLE OF CONTENTS 
1 
STATISTICAL ANALYSIS PLAN .............................................................................1 
2 
SIGNATURES .............................................................................................................2 
3 
TABLE OF CONTENTS .............................................................................................3 
4 
ABBREVIATIONS AND DEFINITIONS ...................................................................5 
5 
INTRODUCTION ........................................................................................................7 
5.1 
Background ...................................................................................................................7 
5.2 
Rationale .......................................................................................................................7 
6 
STUDY OBJECTIVES AND ENDPOINTS ................................................................7 
6.1 
Study Objectives ...........................................................................................................7 
6.2 
Study Endpoints (Outcome Variable) ...........................................................................8 
7 
STUDY DESIGN .........................................................................................................9 
7.1 
General Study Design and Plan ....................................................................................9 
7.2 
Inclusion-Exclusion Criteria and General Study Population ........................................9 
7.3 
Randomization and Blinding ........................................................................................9 
7.4 
Study Assessments ........................................................................................................9 
8 
GENERAL STATISTICAL CONSIDERATIONS ....................................................11 
8.1 
Determination of Sample Size ....................................................................................11 
8.2 
Statistical Software .....................................................................................................11 
8.3 
Precision .....................................................................................................................11 
9 
ANALYSIS POPULATION ......................................................................................11 
10 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS....................................12 
10.1 
Subject Disposition .....................................................................................................12 
10.2 
Protocol Deviations ....................................................................................................12 
10.3 
Demographics and Baseline Characteristics ...............................................................12 
10.4 
Medical History ..........................................................................................................13 
10.5 
Prior and Concomitant Medication .............................................................................13 
11 
EFFICACY ANALYSIS ............................................................................................13 
11.1 
Serum Triglyceride Level ...........................................................................................13 
11.2 
Cholesterol Efflux Capacity .......................................................................................13 
11.3 
Other Secondary Efficacy Analysis ............................................................................14 
12 
PHARMACOKINETICS ANALYSIS .......................................................................14 
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13 
SAFETY ANALYSIS ................................................................................................14 
13.1 
Adverse Events ...........................................................................................................14 
13.2 
Clinical Laboratory Assessments ...............................................................................15 
13.3 
Vital Signs ..................................................................................................................15 
13.4 
Electrocardiogram (ECG) ...........................................................................................15 
14 
DATA PRESENTATION ..........................................................................................15 
15 
TABLES AND LISTINGS .........................................................................................16 
15.1 
Table of Tables ...........................................................................................................16 
15.2 
Table of Listings .........................................................................................................17 
16 
REFERENCE .............................................................................................................18 
 
 
 
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4 ABBREVIATIONS AND DEFINITIONS 
ABBREVIATION 
AE 
Adverse Event 
ALP  
Alkaline Phosphatase  
ALT 
Alanine Aminotransferase 
AUC0→t 
Area Under the Concentration vs. Time 
Curve 
AUC0→∞ 
Area Under the Concentration Versus Time Curve, from Time 0 to Infinity  
Bid 
Twice Daily  
Cmin 
Minimum Concentration  
Cmax 
Maximum Concentration 
Clast 
Concentration at the time of the last measurable concentration  
CRF 
Case Report Form 
CSS 
Concentration Steady-State 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
ER 
Extended-Release  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H 
Hour 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IR 
Intermediate-Release 
IRB 
Institutional/independent Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities  
PD 
Pharmacodynamics  
PK 
Pharmacokinetics 
QD 
Once Daily  
QT 
Time Between the Beginning of the QRS Complex and the End of the T-
Wave 
QTcB 
QT interval using Bazette’s correction 
QTcF 
QT interval using Fridericia’s correction 
SAE 
Serious Adverse Event 
SD 
Standard Deviation  
SAP 
Statistical Analysis Plan 
t1/2 
Terminal Elimination Half Life 
tmax 
Time to Maximum Measured Concentration  
Tid 
Three Times Daily  
λz 
Terminal Elimination Rate Constant  
 
DEFINITIONS  
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Adverse Event  
An adverse event (AE) is any untoward medical occurrence in a subject 
administered a pharmaceutical product, regardless of causality 
assessment. 
Full Analysis Set 
Population 
Group of randomized subjects who received at least 14 days of study drug 
and had at least one post-dose efficacy measurement. 
Safety Analysis 
Set Population 
Group of subjects who received at least one dose of study drug and had at 
least one post-dose safety assessment. 
PK population  
PK sample collection of the first 6 subjects enrolled in the study.  
Serious AE 
An AE occurring at any dose that: results in death; is a life-threatening 
experience; requires inpatient hospitalization or prolongation of an 
existing hospitalization; results in a persistent or significant 
disability/incapacity; or is a congenital anomaly/birth defect in the 
offspring of a patient who received study drug. 
Treatment-
emergent AE 
 
AEs occurring from the time of first dose through 7 days after the last 
dose or that is already present prior to the first dose of study drug and 
becomes more severe post-dose 
 
 
 
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5 INTRODUCTION 
5.1 
Background 
The purpose of this statistical analysis plan (SAP) is to outline in detail the statistical methods, 
data derivations, and presentations of data so that valid conclusions can be reached to address the 
study objectives outlined in the MN-001-NATG-201 protocol Amendment 3, dated 14 August  
2017.  
The planned analyses identified in this statistical analysis plan (SAP) may be included in 
regulatory submissions and/or future manuscripts. Exploratory analyses, not identified in this 
SAP, may be performed to support the clinical development program. Any post-hoc or 
unplanned analyses that are performed but not identified in this SAP will be clearly identified in 
the clinical study report (CSR). 
5.2 
Rationale 
Preclinical and clinical studies have shown that MN-001 treatment improves lipid profile and 
protects the liver in patients with comorbidities of NASH or NAFLD and elevated serum 
triglyceride levels.   
In an in vivo NASH mouse model, MN-001 (10, 30 and 100 mg) or placebo was administered to 
male mice for 3 weeks. MN-001 significantly reduced fibrosis in a dose-dependent manner (P < 
.01) as demonstrated by a reduction in liver hydroxyproline content, supporting MN-001’s anti-
fibrotic properties. MN-001 improved NASH pathology by inhibiting hepatocyte damage (P < 
.01) and ballooning (P < .01).  
In a Phase 1 trial (Protocol no. MN-001-CL-003), the pharmacokinetics, safety, and tolerability 
of MN-001 at 750 mg BID vs 500 mg TID were evaluated in healthy volunteers. Additionally, 
sponsor conducted two Phase 2 trials to evaluate MN-001 in patients with asthma (Protocol no. 
MN-001-CL-001) and in patients with interstitial cystitis (MN-001-CL-002). Results from 
clinical laboratory assessments throughout these clinical trials , MN-001 showed a decrease in 
serum triglyceride levels, i.e., improvement, while subjects given placebo showed unchanged or 
increased serum triglyceride levels. These findings warranted a closer examination of MN-001’s 
potential utility as a treatment for hypertriglyceridemia.     
6 STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
Co-Primary Objectives: 
• To evaluate the effects of MN-001 on triglyceride levels in NASH and NAFLD subjects 
with hypertriglyceridemia; 
• To evaluate the effects of MN-001 on Cholesterol Efflux Capacity in NASH and NAFLD 
subjects with hypertriglyceridemia. 
Secondary Objectives: 
• To evaluate the safety and tolerability of MN-001; 
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• To evaluate PK profile of MN-001/MN-002 (metabolite) in first 6 enrolled subjects; 
• To evaluate the effect of MN-001 on lipid profile 
o HDL-C, LDL-C, total cholesterol level;  
• To evaluate the effect of MN-001/002 on liver enzymes; 
• To evaluate the effect of MN-001/002 on percentage of fat in the liver assessed using MRI 
at Week 12. 
6.2 
Study Endpoints (Outcome Variable) 
Co-Primary Outcome Variables 
• Mean change from baseline on serum triglyceride levels at Week 8  
The primary endpoint is to evaluate the effects of MN-001 on serum triglyceride level in NASH 
and NAFLD with hypertriglyceridemia. The serum triglycerides will be measured as the 
difference after 8 weeks of treatment from pre-treatment serum triglyceride levels. Pre-treatment 
triglyceride level will be defined as the highest value of serum triglyceride at screening visit or 
baseline visit. The data are expressed as the percent change from the baseline value and 
calculated using he equation: Change = [100%*(Endpoint value - Baseline Value)/Baseline 
Value] 
• Mean change from baseline on cholesterol efflux capacity at Week 12 
Cholesterol efflux capacity in the subjects will be quantified at National Institute of Biomedical 
Innovation, Osaka, Japan using the method previously reported (Ogura et al 2016). Percent 
efflux will be calculated by the following formula: [(μCi of 3H-cholesterol in mediums 
containing 2.8% apolipoprotein B–depleted serum –μCi of 3H-cholesterol in serum-free 
mediums)/μCi of 3H-cholesterol in cells extracted before the efflux step] × 100. All assays will 
be performed in duplicate. To correct for inter-assay variation across plates, a pooled serum 
control from eleven healthy volunteers was included on each plate, and values for serum samples 
from patients were normalized to the value of the pooled sample in subsequent analyses. 
Secondary Outcome Variables 
• Treatment-emergent adverse events (TEAEs) and Treatment-emergent serious adverse 
events (SAE); 
• Discontinuations of treatment for any reason; 
• Treatment discontinuations due to TEAEs; 
• Treatment discontinuations due to treatment-related AEs or SAEs; 
• Changes from baseline for safety clinical laboratory tests;  
• Changes from baseline in vital signs and 12-lead ECG; 
• Lipid profile (serum HDL-C, LDL-C, total cholesterol level), liver enzymes (ALT and 
AST) changes from baseline; 
• Changes of liver fat content (%) assessed by MRI from baseline to post treatment MRI.  
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7 STUDY DESIGN  
7.1 
General Study Design and Plan 
This is a multi-center, proof-of-principle, open-label study designed to evaluate the efficacy, 
safety, and tolerability of MN-001 in subjects diagnosed with non-alcoholic steatohepatitis 
(NASH) or NAFLD with hypertriglyceridemia.  Subjects will receive MN-001 250 mg qd for the 
first 4 weeks and will take 250 mg bid for an additional 8 weeks. Subjects will receive MN-001 
for a total of 12 weeks.  Anticipated enrollment is 20-40 subjects.  
7.2 
Inclusion-Exclusion Criteria and General Study Population 
Eligible subjects will consist of males and female participants ≥18 years of age.  To be eligible, 
subjects must have a histologically confirmed diagnosis of NASH within 36 months of baseline 
visit or NAFLD confirmed by imaging studies and an elevated serum triglyceride (>150 mg/dL) 
at screening. Diagnosis of other known cause of liver disease, current diagnosis or suspicion of 
hepatocellular carcinoma, decompensated or severe liver disease, and uncontrolled diabetes 
mellitus Type 2, are major exclusionary criteria.  
7.3 
Randomization and Blinding 
This is an open-label study; therefore, randomization and blinding are not applicable. 
7.4 
Study Assessments 
Please see Schedule of Events in Table 1. 
 
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Table 1 Schedule of Events 
* Baseline visit will be overnight stay for selected 6 subjects from whom PK samples will be obtained  
** ET: Early termination visit  
*** PK sample for MN-001/002 will be also obtained when subjects experience SAE  
**** Liver MRI can be scheduled on different day of each lab/clinic visit 
a Pre-treatment Liver MRI may be performed between Day -120 and Day -1prior to Baseline Day 1 
 
Phase 
Screening 
Treatment  
Follow-up   
 
Tests and Evaluations 
Day -120 
to Day -7 
 – 1 week 
± 5 days 
 
Baseline 
Day 1-2* 
 
Week 2  
± 3 days 
Week 4 
± 5 days 
 
Week 8 
± 5 days 
Week 12/ET** 
± 5 days 
Week 13  
± 5 days 
Type of Visit 
Clinic 
Lab 
Clinic 
Tel 
Clinic 
Clinic 
Clinic 
Clinic 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
X 
X 
X 
X 
Body height 
X 
 
 
 
 
 
 
 
Body weight/Waist circumference 
X 
 
X 
 
X 
X 
X 
X 
Vital signs 
X 
 
X 
 
X 
X 
X 
X 
Alcohol consumption 
questionnaire 
X 
 
 
 
 
 
X 
 
Pregnancy test (serum /urine)  
X (serum)  
X (serum)  
 
 
X 
X 
X 
 
12-lead ECG 
X 
 
X 
 
X 
X 
X 
 
Clinical labs (chemistry, incl CPK, 
hematology, lipid panel 
coagulation profile including INR, 
urinalysis) 
X 
X 
 
 
X 
X 
X 
X 
CK-18 biomarker  
X 
 
 
 
 
 
X 
 
Fib-4 Index calculation 
X 
 
 
 
 
 
 
 
NAFLD fibrosis score 
X 
 
 
 
 
 
 
 
Blood Sample for Cholesterol 
Efflux  
 
 
X 
 
 
 
X 
 
MN-001 plasma concentration *** 
 
 
X 
 
 
 
 
 
Liver MRIa 
X**** 
 
 
 
 
 
X**** 
 
Adverse event review 
 
 
X 
X 
X 
X 
X 
X 
Concom med review 
X 
 
X 
X 
X 
X 
X 
 
Study Drug Dispensing 
 
 
X 
 
 
 
 
 
Study Drug Accountability 
 
 
 
X 
X 
X 
X 
 
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8 GENERAL STATISTICAL CONSIDERATIONS 
8.1 
Determination of Sample Size 
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 20 subjects is deemed to be appropriate for this purpose. 
8.2 
Statistical Software 
Statistical analyses will be performed using SAS (SAS Institute, NC, USA). Cholesterol efflux 
capacity and percent (%) fat in liver assessed by MRI will be reported and calculated by EXCEL. 
Summary Statistics 
Data will be summarized with respect to disposition, demographics, pre-treatment 
characteristics, safety outcomes, tolerability, and efficacy outcomes. Summary statistics for 
continuous variables will include the number of subjects, the mean, median, standard deviation, 
and range. For categorical data, summaries will include counts and percentages. 
Biomarkers and clinical outcomes will be summarized longitudinally from baseline to Week 8 or 
Week 12, with means and standard deviations at each timepoint. 
8.3 
Precision 
Results will be reported to 3 significant figures. Percentages will be reported to 0.1 percentage 
points. P-values will be reported to two digits when ≥ .095, to three digits when ≥ .00095 and 
< .095, and as < .001 for all smaller values. 
9 ANALYSIS POPULATION 
For purposes of analysis, the following sets are defined: 
Population 
Description 
All Subjects 
All subjects enrolled 
 
Safety Analysis Set  
All subjects who received at least one dose of study drug and had at least one 
post dose safety assessment. 
Intent-to-treat Set 
All randomized subjects in the groups to which they are randomly assigned, 
regardless of their adherence to the inclusion-exclusion criteria, regardless of 
the treatment they actually received, and regardless of subsequent withdrawal 
from treatment or deviation from the protocol. 
Per Protocol Set  
All subjects who received at least one dose of study drug and no major 
protocol deviations. 
PK population 
All subjects who received at least 1 dose of study drug (MN-001) and have 
evaluable PK data, and complete scheduled post-dose PK measurements 
without protocol deviations, violations, or events include, but may not be 
limited to, vomiting occurring within 30 minutes following oral dosing, 
sample processing errors that lead to inaccurate bioanalytical results, and/or 
inaccurate dosing on the day of PK sampling. In the case of a significant 
protocol deviation, PK data collected during the affected treatment period will 
be excluded from summary statistics but will be included in individual subject 
listings.  
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10 DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
Two listings will be presented for Subject Disposition and Major Protocol Deviations as defined 
below. 
10.1 
Subject Disposition  
All enrolled subject disposition will be presented.  
Number of subjects in the following categories will be summarized as appropriate: 
• Enrolled 
• Safety Population 
• PK Population 
Additionally, a summary on study completion status will be presented:  
• 
Completed study among subjects enrolled; 
• 
Prematurely discontinued the study and the reasons for discontinuations as follows: 
o 
Adverse Event 
o 
Informed Consent Withdrawn  
o 
Lost to Follow-Up 
o 
Other reason, specify  
10.2 
Protocol Deviations 
The following will be considered as major protocol violations: 
Protocol deviations are collected and will further be evaluated by the sponsor to determine whether 
the violation affects the efficacy and/or safety measurements for the subject.  
Major deviations will be defined as the following: 
• Eligibility Criteria not met – any deviation from the inclusion / exclusion criteria in the 
protocol will be considered major 
• Informed consent – missing consent 
• Dose administration errors 
o Incorrect (high, low) dose administered to subject 
• Unreported SAEs 
• Any other instance in the opinion of the sponsor and investigator that adversely affects 
the safety of the subject or the integrity of the study data 
10.3 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects, including age, sex, 
race, ethnicity, Fib-4 Index score, and NAFLD score. Summary statistics (e.g., number of subjects, 
mean, median, standard deviation, and range) will be generated for continuous variables (e.g., age 
and weight) and the number and percentage of subjects within each category will be presented for 
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categorical variables (e.g., gender, ethnicity, and race). Age will be presented as captured in the 
Screening visit CRF.  
10.4 
Medical History 
Medical and surgical history will be coded according to the latest version of MedDRA and 
summarized by system organ class and preferred term.  
10.5 
Prior and Concomitant Medication 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced and categorized as follows: 
Prior medication is any medication that started before initial dosing of study drug, regardless 
of when it ended.  
Concomitant medication is any medication received at or after the dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of study 
drug, or medication with missing stop date. 
A given medication can be classified as a prior medication or a concomitant medication or both. 
If a medication has a missing or partial missing start/end date or time and it cannot be determined 
whether it was taken before initial dosing or concomitantly, it will be considered as both prior and 
concomitant. 
11 EFFICACY ANALYSIS  
11.1 
Serum Triglyceride Level 
The primary endpoint is to evaluate the effects of MN-001 on serum triglyceride level in NASH 
and NAFLD with hypertriglyceridemia. The serum triglycerides will be measured as the 
difference after 8 weeks of treatment from pre-treatment serum triglyceride levels. Pre-treatment 
triglyceride level will be defined as the highest value of serum triglyceride at screening visit or 
baseline visit.  The data are expressed as the percent change from the baseline value and 
calculated using the equation: Change = [100%*(Endpoint value - Baseline Value)/Baseline 
Value]. 
 
11.2 
Cholesterol Efflux Capacity 
Cholesterol efflux capacity in the subjects will be quantified at National Institute of Biomedical 
Innovation, Osaka, Japan using the method previously reported (Ogura et al 2016). Percent 
efflux will be calculated by the following formula: [(μCi of 3H-cholesterol in mediums 
containing 2.8% apolipoprotein B–depleted serum –μCi of 3H-cholesterol in serum-free 
mediums)/μCi of 3H-cholesterol in cells extracted before the efflux step] × 100. All assays will 
be performed in duplicate. To correct for inter-assay variation across plates, a pooled serum 
control from eleven healthy volunteers will be included on each plate, and values for serum 
samples from patients will be normalized to the value of the pooled sample in subsequent 
analyses.  
 
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11.3 
Other Secondary Efficacy Analysis 
Other secondary measures, lipid profile including serum HDL-C, LDL-C, total cholesterol level, 
liver enzymes (ALT and AST) will be measured by the change from baseline to Week 8 and 
Week 12. The percentage (%) of fat in the liver assessed by MRI will be measured by the 
changes from baseline MRI to post treatment MRI.  
12 PHARMACOKINETICS ANALYSIS 
Pharmacokinetic parameters of MN-001 and its metabolite, MN-002 will be calculated in a 
subset of 6 subjects. The following parameters are to be calculated from MN-001/MN-002 
plasma concentrations: 
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/λz where Clast is the last quantifiable concentration. 
13 SAFETY ANALYSIS  
Safety analyses will be based on the Safety Analysis Set. 
13.1 
Adverse Events 
All AEs occurring after the subject signed Informed Consent Form (ICF) will be reported and 
will be coded using the latest version of MedDRA dictionary.  
An overall summary of the number and percentage of subjects with AEs, subjects that lead to 
discontinuation of study drug, AEs related to study drug (the relationship will be categorized as 
“related” or “unrelated”, where “related” includes investigator terms of “Possibly Related” and 
“Probably Related”), SAEs, and SAEs related to study drug will be presented by treatment. Also, 
the AEs will be presented by SOC, PT and treatment. In addition, subjects with AEs in various 
severity categories (mild, moderate, severe, and life-threatening) will be presented based on the 
maximum severity of a specific AE for a subject.  
Listings of individual by-subject data for any subject experiencing an SAE will be provided 
separately. All AEs will also be presented in individual by-subject data listings. 
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13.2 
Clinical Laboratory Assessments 
For each subject, clinical laboratory parameters including hematology, chemistry 
 will be listed by visit.  
13.3 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure, respiration rate and pulse rate. Pre-
dose values, the values at the final visit, and changes from pre-dose will be summarized for each 
of the quantitative laboratory assessments.  
13.4 
Electrocardiogram (ECG) 
For standard 12-lead ECG, the summary statistics results for heart rate, QT interval, PR interval, 
QRS interval, QTcB, and QTcF, the values will be listed by subject, along with the overall clinical 
interpretation. 
14 DATA PRESENTATION 
Tables and listings will be prepared in accordance with the current ICH Guidelines. The 
information and explanatory notes to be provided in the “footer” or bottom of each table and 
listing will include the following information: 
• Date and time of output generation; 
• Program name; 
• Any other output specific details that require further elaboration. 
 
 
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15 TABLES AND LISTINGS  
15.1 
Table 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 
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 
Summary of Serum triglyceride – Mean Change from Baseline to Week 8  
14.2.2 
Summary of Serum Lipid Panel – Mean Change from Baseline to Week 8 
14.2.3 
Summary of Liver Enzymes (ALT, AST) – Mean Change from Baseline to Week 8 
14.3 
Safety Data 
14.3.1 
Display of Adverse Events 
14.3.1.1 
Number of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term (Safety Analysis Set) 
14.3.1.2 
Number of Subjects with Treatment-emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Analysis Set)  
14.3.1.3 
Number of Subjects with Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term, and Intensity (Safety Analysis Set) 
14.3.1.4 
Number of Subjects with Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship (Safety Analysis Set) 
14.3.1.5 
Number of Subjects with Treatment-emergent Serious Adverse Events by System Organ 
Class and Preferred Term (Safety Analysis Set) 
14.3.1.6 
Number of Subjects with Treatment-emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class and Preferred Term (Safety Analysis Set) 
14.3.2 
Listings of Serious and Significant Adverse Events 
14.3.3 
Narratives of Serious and Certain Other Significant Adverse Events 
14.3.4 
Abnormal Laboratory Value Listing (Each Subject) 
14.3.4.1   
Summary of Hematology by Visit (Safety Analysis Set)  
14.3.4.2 
Hematology – Shift from Baseline by Visit (Safety Analysis Set) 
14.3.4.3 
Summary of Serum Chemistry by Visit (Safety Analysis Set) 
14.3.4.4 
Serum Chemistry – Shift from Baseline by Visit (Safety Analysis Set) 
14.3.4.5  
Summary of Vital Signs by Visit (Safety Analysis Set)   
14.3.4.6 
Summary of Electrocardiogram Results by Visit (Safety Analysis Set)   
14.3.4.7 
Shift from Baseline in Electrocardiogram Finding and Overall Impression by Visit (Safety 
Analysis Set)   
14.3.4.8 
Abnormal QTc Interval (ms) by Visit (Safety Analysis Set)   
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15.2 
Table of Listings 
Listing 
Number 
Listing Description 
16.2 
Subject Data Listings 
16.2.1  
Discontinued Subjects 
16.2.1.1 
Disposition 
16.2.2 
Protocol Deviations 
16.2.2.1 
Major Protocol Deviations 
16.2.3 
Subjects Excluded from the Efficacy Analysis 
16.2.3.1 
Subject Eligibility 
16.2.4 
Demographic Data 
16.2.4.1  
Demographics and Baseline Characteristics  
16.2.4.2.1 
Medical History 
16.2.4.2.2 
Alcohol Consumption 
16.2.4.3.1 
Serum Pregnancy 
14.2.4.3.2 
Urine Pregnancy 
16.2.4.4 
Prior and Concomitant Medications 
16.2.5 
Study Drug Exposure  
16.2.6 
Individual Efficacy Response Data  
16.2.6.1 
Triglyceride Levels – Change from Baseline to Week 8 
16.2.6.2 
Cholesterol Efflux Capacity – Change from Baseline to post treatment  
16.2.6.3 
Lipid Profile (serum HDL-C, LDL-C, total cholesterol, Liver Enzymes (ALT, AST) – 
Changes from Baseline to Week 8 and to Week 12   
16.2.6.4 
Percent (%) fat in Liver – Change from Baseline to Post-treatment MRI  
16.2.7 
Adverse Event Listings (by Subject) 
16.2.7.1 
Treatment-emergent AEs 
16.2.7.2 
Treatment-emergent SAEs 
16.2.7.3 
Treatment-emergent AEs leading to study discontinuation, study drug interruption, or 
death 
16.2.7.5 
Treatment-related AEs 
16.2.7.6 
Treatment-related SAEs  
16.2.8 
Listing of Individual Laboratory Measurements by Subject, when Required by Regulatory 
Authorities 
16.2.8.1 
Hematology (all subjects) 
16.2.8.2 
Serum Chemistry (all subjects) 
16.2.8.3 
Vital Signs (all subjects) 
16.2.8.4 
Physical Examination (all subjects) 
16.2.8.6 
12-lead ECG (all subjects) 
16.3 
Case Report Forms 
16.3.1 
CRFs for Serious Adverse Events and Withdrawals for AE 
16.3.2 
Other CRFs Submitted 
16.4 
Individual Subject Data Listings (U.S. Archival Listings) 
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16 REFERENCE 
Ogura M, Hori M, Harada-Shiba M. Association between cholesterol efflux capacity and 
atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia. 
Arterioscler Thromb Vasc Biol 2016; 36:181-8. 
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CONFIDENTIAL
______________________________________________________________________________________________
MN-001/tipelukast
______________________________________________________________________________________________
IND 123659 / Sequence No. 0019
16.1.9 Statistical Analysis Plan - MN-001-NATG-201
MediciNova, Inc.