RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

Study Protocol(English translated version of the original Japanese protocol version 2.4 that was approvedby the Institutional Review Boards at sites)

Phase II/III Clinical trial

A multi-center, randomized, double-blind, placebo-controlled trial todetermine the efficacy of rituximab against a relapse of neuromyelitis optica
spectrum disorders with anti-aquaporin 4 antibody
Clinical trial Protocol Number: RIN-1
Clinical trial Protocol Version 2.4(Finalization date: December 12, 2018)

Clinical trial Coordinating Committee Chair:
Masayuki Tahara, M.D., Ph.D.
Department of Neurology, and Clinical Research Center,
National Hospital Organization, Utano National Hospital

The information in this document is provided only to parties directly involved in the clinical trial(study site head, clinical trial office, principal investigator/co-investigator, study collaborator, study
drug manager, and institutional review board (IRB), etc.).
Therefore, information cannot be disclosed to any third party unrelated to the study without the priorconsent of the principal investigator, except when informed consent is being obtained from patients
participating in the study.

This document, which contains unpublished scientific data, should be handled with care. This
document may not be transferred, reproduced, published or otherwise used, in whole or in part, without
prior written permission.

RIN-1 Clinical trial Protocol
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Clinical trial Summary Chart
Primary outcome: Time to the first relapse from randomization
Secondary outcomes: Change in EDSS and QOSI from baseline, and steroid reduction rate

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Table of contents

SUMMARY OF THE CLINICAL TRIAL PROTOCOL ................................................................. 8
1.

OBJECTIVES ...................................................................................................................... 122.

BACKGROUND AND RATIONALE ................................................................................... 12

3.

4.

5.

2.1

MEDICAL BACKGROUND ................................................................................................. 12

2.2

RATIONALE ................................................................................................................... 12

INVESTIGATIONAL PRODUCT ........................................................................................ 14
3.1

OVERVIEW OF INVESTIGATIONAL PRODUCT .................................................................... 14

3.2

IDENTITY OF INVESTIGATIONAL PRODUCT....................................................................... 14

3.3

CHEMICAL NAME, STRUCTURAL FORMULA, AND OTHER INFORMATION ON TEST DRUG ...... 14

3.4

CONTENTS OF INVESTIGATIONAL PRODUCT LABEL .......................................................... 14

3.5

STORAGE CONDITIONS FOR THE INVESTIGATIONAL PRODUCT .......................................... 14

3.6

RATIONALE FOR THE DOSAGE AND ADMINISTRATION OF THE INVESTIGATIONAL PRODUCT 15

ELIGIBILITY CRITERIA ................................................................................................... 15
4.1

INCLUSION CRITERIA...................................................................................................... 15

4.2

EXCLUSION CRITERIA..................................................................................................... 16

EXPLANATION PROVIDED TO PATIENTS AND OBTAINING INFORMED CONSENT17
5.1

PREPARATION OF EXPLANATORY DOCUMENTS AND INFORMED CONSENT FORMS............... 17

5.2

REVISION OF EXPLANATORY DOCUMENTS AND INFORMED CONSENT FORMS ..................... 17

5.3

TOPICS TO BE EXPLAINED TO PATIENTS ........................................................................... 17

5.4

TIMING AND METHOD OF OBTAINING INFORMED CONSENT ............................................... 18

5.5

IN THE EVENT THAT INFORMATION THAT MAY AFFECT THE PATIENT'S WILLINGNESS TO

PARTICIPATE OR CONTINUE PARTICIPATION IN THE STUDY BECOMES AVAILABLE ......................... 19

5.6

OBTAINING INFORMED CONSENT AGAIN AFTER REVISION OF EXPLANATORY DOCUMENTS

AND INFORMED CONSENT FORMS ................................................................................................ 19

5.7
6.

OBTAINING CONSENT FROM MINORS ............................................................................... 20

ENROLLMENT/RANDOMIZATION.................................................................................. 20
6.1

PROCEDURES FOR PATIENT ENROLLMENT (TENTATIVE ENROLLMENT, DEFNITIVEENROLLMENT, AND RANDOMIZATION) ........................................................................................ 20

6.1.1

Tentative enrollment................................................................................................... 20

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Definitive enrollment and randomization..................................................................... 20

6.1.2
6.2

RANDOMIZATION METHOD AND RANDOMIZATION ADJUSTMENT FACTORS ........................ 20

6.3

KEY CODE...................................................................................................................... 21

TREATMENT PLAN ........................................................................................................... 21

7.

7.1

PROTOCOL TREATMENT ................................................................................................. 21

7.2

RITUXIMAB MAINTENANCE (ADDITIONAL DOSES)............................................................. 21

7.3

CORTICOSTEROID TAPERING PROTOCOL ......................................................................... 22

7.4

RATIONALE FOR REDUCING CORTICOSTEROID DOSE ........................................................ 23

7.5

TREATMENT OPTIONS AT THE TIME OF "RELAPSE" (RELAPSE OF NMO AS DEFINED IN

SECTION 13) .............................................................................................................................. 23
7.6

STUDY DISCONTINUATION .............................................................................................. 24

7.7

RESTRICTED CONCOMITANT DRUGS AND THERAPIES ....................................................... 24

7.8

PROHIBITED CONCOMITANT DRUGS AND THERAPIES ........................................................ 24

ADVERSE EVENT ASSESSMENT AND REPORTING ...................................................... 25

8.

8.1

DEFINITION OF ADVERSE EVENTS .................................................................................... 25

8.2

ASSESSMENT AND REPORTING OF ADVERSE EVENTS ......................................................... 25

8.3

DEFINITION OF SERIOUS ADVERSE EVENTS ...................................................................... 25

8.4

EXPECTED ADVERSE EVENTS .......................................................................................... 25

8.4.1

Details of serious adverse reactions, frequency, and recommended measures ................ 25

8.4.2

Other adverse reactions and corresponding frequencies ............................................... 25

EXPEDITED REPORTING OF AND RESPONSE TO SERIOUS ADVERSE EVENTS ...... 26

9.

9.1

EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS AND RESPONSE TO THESE EVENTS .. 26

9.2

ESTABLISHMENT OF AN INDEPENDENT DATA MONITORING COMMITTEE ......................... 2610.

EMERGENCY UNBLINDING ......................................................................................... 27

11.

OBSERVATION, TESTING, AND REPORTING ITEMS AND SCHEDULE OF

ASSESSMENTS ........................................................................................................................... 27
11.1

OBSERVATION/TEST ITEMS AND TREATMENT INFORMATION TO BE REPORTED .................. 27

11.3

RATIONALE FOR PERFORMING OBSERVATIONS, TESTS, AND COLLECTING TREATMENT

INFORMATION TO BE REPORTED ................................................................................................. 28

11.4

OBSERVATION, TESTING AND REPORTING SCHEDULE AND ACCEPTABLE WINDOWS ............ 28

11.5

LABORATORY TESTS ...................................................................................................... 29

11.5.1

Test items ............................................................................................................... 29

11.5.2

Test methods .......................................................................................................... 29

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11.6

COLLECTION OF INFORMATION ON CONCOMITANT MEDICATION USE ............................... 29

11.7

END OF OBSERVATION (THE COMPLETION OF OBSERVATION WILL MARK THE END OF THE

STUDY) 29

TARGET SAMPLE SIZE AND STUDY DURATION ...................................................... 30

12.
12.1

TARGET SAMPLE SIZE..................................................................................................... 30

12.2

STUDY DURATION ........................................................................................................... 30
RELAPSE OF NEUROMYELITIS OPTICA ................................................................... 30

13.
13.1

DEFINITION OF RELAPSE................................................................................................. 30

13.2

EVALUATION AND TESTING AT THE TIME OF RELAPSE ...................................................... 30

13.3

RETREATMENT WITH RITUXIMAB AT THE TIME OF RELAPSE ............................................ 30
ENDPOINTS .................................................................................................................... 31

14.
14.1

EFFICACY ENDPOINTS .................................................................................................... 31

14.1.1Primary outcome .................................................................................................... 31

14.1.2

Secondary outcome................................................................................................. 31

14.2

SAFETY ENDPOINT.......................................................................................................... 31

15.

PREGNANCY .................................................................................................................. 31

16.

STATISTICAL ANALYSIS .............................................................................................. 31

16.1

RATIONALE FOR SETTING THE TARGET NUMBER OF PATIENTS.......................................... 31

16.2

POPULATION FOR EFFICACY AND SAFETY ANALYSES ........................................................ 33

16.3

PATIENT CLASSIFICATION .............................................................................................. 33

16.4

HANDLING DATA FROM DISCONTINUED PATIENTS AND DROPOUTS .................................... 33

16.5

HANDLING OF MISSING DATA .......................................................................................... 33

16.5.1

Handling of missing data in survival analyses .......................................................... 33

16.5.2

Handling of missing data in analyses other than survival analyses ............................ 33

16.6

DATABASE LOCK ............................................................................................................ 33

16.7

ANALYSIS PARAMETERS AND METHODS ........................................................................... 33

16.7.1

Breakdown of patients ............................................................................................ 33

16.7.2Treatment status ..................................................................................................... 34

16.7.3

Summary of the data............................................................................................... 34

16.7.4Significance level ................................................................................................... 34

16.7.5

Analysis of the Primary outcome and analysis method ............................................. 34

16.7.6

Analysis of Secondary outcomes and analysis method .............................................. 34

16.7.7

Analysis of safety endpoints and analysis method (comparison of adverse events) ...... 34

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16.8

ADVERSE EVENTS ........................................................................................................... 34

16.9

INTERIM ANALYSES ........................................................................................................ 35

16.10

STATISTICAL ANALYSIS PLAN ...................................................................................... 35

17.

COMPLETION AND SUBMISSION OF CASE REPORT FORMS ................................. 35

17.1

DATA ENTRY .................................................................................................................. 35

17.2

STORAGE METHOD ......................................................................................................... 35

18.

MONITORING ................................................................................................................ 35

18.1

DIRECT ACCESS.............................................................................................................. 35

18.2

TIMING OF DIRECT ACCESS ............................................................................................. 36

18.3

SOURCE DOCUMENTS SUBJECT TO DIRECT ACCESS........................................................... 36

19.

QUALITY CONTROL AND ASSURANCE ..................................................................... 3620.

KEY UNLOCKING (UNBLINDING) ............................................................................... 36

21.

ETHICAL CONSIDERATIONS ....................................................................................... 36

21.1

COMPLIANCE WITH THE DECLARATION OF HELSINKI AND GCP ...................................... 36

21.2

INSTITUTIONAL REVIEW BOARD ...................................................................................... 36

21.3

PROVISION OF NEW INFORMATION .................................................................................. 36

21.4

PROTECTION OF PATIENT HUMAN RIGHTS ....................................................................... 36

22.

COST BURDEN FOR THE CLINICAL TRIAL ............................................................... 37

22.1

FUNDING AND FINANCIAL RELATIONSHIPS ....................................................................... 37

22.2

EXPENSES RELATED TO THE CLINICAL TRIAL .................................................................. 37

22.3

PROVISION OF THE INVESTIGATIONAL PRODUCT.............................................................. 37

22.4

COMPENSATION FOR HEALTH INJURIES ........................................................................... 37

23.

PROTOCOL DEVIATIONS ............................................................................................. 38

23.1

DEVIATIONS FROM THE DATE OF ASSESSMENT ................................................................. 38

23.2

DEVIATIONS FROM THE STUDY PROTOCOL ...................................................................... 38

23.3

PREPARATION OF RECORDS OF PROTOCOL DEVIATIONS ................................................... 38

24.

AMENDMENTS TO THE CLINICAL TRIAL PROTOCOL ........................................... 38

25.

STUDY COMPLETION AND EARLY TERMINATION ................................................. 38

25.1

STUDY COMPLETION ...................................................................................................... 38

25.2

CRITERIA FOR PREMATURE TERMINATION OR SUSPENSION OF THE ENTIRE STUDY ............ 38

25.3

DISCONTINUATION OR SUSPENSION OF THE CLINICAL TRIAL AT STUDY SITES .................... 39

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26.
26.1

HANDLING OF STUDY DOCUMENTS .......................................................................... 39
RECORD RETENTION ...................................................................................................... 39

27.

PUBLICATION OF STUDY RESULTS ........................................................................... 39

28.

STUDY ADMINISTRATIVE STRUCTURE .................................................................... 39

29.

LITERATURE ................................................................................................................. 39

RIN-1 Clinical trial Protocol
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Summary of the Clinical Trial Protocol
Title: A multi-center, randomized, double-blind, placebo-controlled trial to determine the efficacyof rituximab against a relapse of neuromyelitis optica spectrum disorders with anti-aquaporin 4
antibody
Purpose: To evaluate the efficacy of rituximab (recombinant, anti-CD20 monoclonal antibody) in
preventing relapses in patients with neuromyelitis optica
Phase of Development: Phase II/III
Design: Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial
Treatment period: 72 weeks
Patient Eligibility: Patients with neuromyelitis optica who meet all of the following inclusion criteria
and does not meet any of the following exclusion criteria.
【Inclusion criteria】
1) Patients who are seropositive for anti-aquaporin 4 antibody (Patients who have previously been
seropositive are also included.).
2) Patients who have at least one episode of either optic neuritis or myelitis.
3) Patients who are treated with oral corticosteroids of a dosage of 5 mg /day or more, inprednisolone-conversion dose for 3 months before registration, and the dosage is fixed or change
within 10% of the dosage at the registration for 3 months.
4) EDSS between 0 and 7.0.
5) Patients who have no recurrence of NMO within a month before registration and areneurologically stable.
6) Patients between the ages of 16 and 80
7) Either male or female. Either inpatients or outpatients.
8) Women of childbearing ages can be involved if a pregnancy test on Visit 1 is negative and she
agree with contraception during the trial.
9) Patients who give written informed consent. Patients under 20 years of age are required parental
consent study collaborators study collaborators.
10) Patients who are able to follow the study protocol and schedule, and who can report their
symptoms.
【Exclusion Criteria】
1) Patients who have a history of hypersensitivity to mouse protein derivatives or anaphylactic
reaction to components of rituximab.
2) Patients infected with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, andthose having active infectious diseases.
3) Patients who have a history of severe recurrent or chronic infections.

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4) Patients who have used a live vaccine within 6 months before randomization.
5) Patients under treatment with oral corticosteroid drugs of dosage of 30 mg/day or more in
prednisolone-conversion dose.
6) Patients with previous use of cladribine or a monoclonal antibody, such as natalizumab orrituximab.
7) Patients with a history of radiation treatment (whole body irradiation or lymphoid irradiation) or astem cell transplant.
8) Patients who are treated with mitoxantrone or cyclophosphamide within 12 months before
randomization.
9) Patients who are treated with immunomodulatory drugs (interferon beta, glatiramer acetate) or
immunoglobulin therapy within 6 months before randomization.
10) Patients who are treated with oral immunosuppressive agents other than steroids (e.g.,azathioprine, tacrolimus, cyclosporine, cyclophosphamide, methotrexate, or fingolimod) within 3months before randomization.
11) Patients who have received plasma exchange or intravenous steroid pulse therapy within 3months before tentative enrollment.
12) Patients with autoimmune diseases, such as Sjögren's syndrome or systemic lupus
erythematosus, requiring treatment with immunosuppressants.
13) Patients who are pregnant or feeding a baby.
14) Patients who participate in other clinical trials.
15) Patients diagnosed as having a cancer.
16) Patients who are judged inappropriate for enrollment in the trial by the principal investigator /co-investigator.

Investigational drug: Rituximab
Control drugs: placebo undistinguished from the investigational drug
Expected clinical benefits: Prophylactic effect against relapses of neuromyelitis optica
Protocol Treatment[Induction therapy]
Investigational drug (rituximab 375mg /m2 or placebo) is administrated intravenously (the drug isdiluted 10-fold with saline), following pre-medication of an oral non-steroidal anti-inflammatory
drug and an anti-histamine drug (30 minutes before administration of the investigational drug).
In Visit 2, the intravenous administration described above is repeated weekly 4 times.

[Maintenance therapy]
In Visit 8 and Visit 14, study drug (1g rituximab or placebo) was intravenous biweekly (the drug is

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diluted 10-fold with saline), following premedication (a non-steroidal anti-inflammatory drug and ananti-histamine drug). Confirm no active infections before the drug administration.

Prohibited concomitant drugs and therapy: During the trial period, the combination of the following
drugs and therapies are prohibited.
1) Steroid pulse therapy (methylprednisolone 500 to 1000mg per day, 3 to 5 days)
2) Plasma exchange therapy (including simple plasma exchange and immunoadsorption therapy)3) Monoclonal antibodies (natalizumab, alemtuzumab, tocilizumab, etc.)
4) Intravenous immunoglobulin therapy5) immunosuppressive agents / anticancer agents (cladribine, mitoxantrone, cyclophosphamide,azathioprine, tacrolimus, cyclosporine, methotrexate, fingolimod, etc.)
6) Immunomodulatory (interferon beta, glatiramer acetate, etc.)
7) Live vaccine or live-attenuated vaccine
8) Study drugs except for the investigational drug of the current trial
Discontinued criteria: In case of any of the following conditions, the subjects will discontinue thetrial.
(1) When a prohibited concomitant drug is administered(2) When a prohibited concomitant therapy is performed(3) When the consent is withdrawn by participants(4) Adverse events that should be discontinued the trial occur(5) When the entire trial is discontinued due to the conditions of the investigational drug provider or
the trial(6) If the pregnancy of participants is confirmed(7) When it is judged appropriate to discontinue the trial by the principal investigator / coinvestigator for other reasons.
Efficacy evaluations:Primary outcome measure: time to the first NMO relapse in the trial
Secondary outcome measures: Score changes in EDSS and QOSI from the baseline, steroid
reduction rate from the baseline
Safety evaluations:
Frequency of adverse events
Frequency of severe adverse events

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List of abbreviations
AQP-4: aquaporin-4
EDC: electronic data capture
EDSS: Krutzke's expanded disability status scale
GCP: good clinical practice
Gd: gadolinium
HIV: human immunodeficiency virus
IDMC: Independent Data Monitoring Committee
IRB: Institutional review board
MRI: magnetic resonance imaging
MS: multiple sclerosis
NMO: neuromyelitis optica
NMOSD: neuromyelitis optica spectrum disorder
QOSI: quantification of optic nerve and spinal cord impairment
RCT: randomized control trial

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1.

Objectives

The objective of this study is to determine the efficacy of rituximab (a recombinant, anti-CD20
monoclonal antibody) in preventing relapses in patients with neuromyelitis optica (NMO) in a
multicenter, placebo-controlled, double-blind study. Study subjects are the patients with NMO who
fulfill the 2006 revised NMO diagnostic criteria (1) and those with anti-aquaporin 4 antibody-positive
neuromyelitis or optic neuritis (referred to as NMO spectrum disorders, hereafter, NMOsp) that areunder treatment with corticosteroids. During the observation period, steroids are tapered according to
the protocol. The primary outcome is the time to the first relapse from randomization, and thesecondary outcomes are changes in EDSS and QOSI from baselines, and steroid reduction rate.

2.

Background and rationale

2.1 Medical background
Background of NMO
The first report of NMO was a serious case of acute myelitis and optic neuritis in 1894 in a patient
who died after a month from diagnosis. At that time, NMO was thought to be a subtype of multiple
sclerosis (MS). The poor prognoses of NMO continued for a long time, according to a report of 1999,
half of the patients used wheelchairs within 5 years after the onset of symptoms, and 60% of patients
lost their eyesight (2). In 2004, autoantibodies were discovered in the sera of patients with NMO (3)and revealed to be antibodies to aquaporin 4 (AQP-4) that are water channels expressing in astrocytic
foot processes which form blood-brain barrier) (4). In addition, the loss of AQP-4 at NMO lesions
was pathologically proven (5); hence, NMO has been regarded as an immunological neurologicaldisorder, and anti-AQP-4 antibodies may play an important role for the disease.
Based on findings described above, the diagnostic criteria for NMO were revised (1). Most patientswith optico-spinal MS, which had been considered to account for about 30% of MS in Japan, werepositive for anti-AQP-4 antibodies, and NMO is not considered to be a rare disease in Japan. Patientswith NMO does not respond to clinical treatment for MS; interferon-β, treatment for MS, has beenshown to be ineffective or may even exacerbate disease in patients with NMO (6, 7).
The assessment of the efficacy of corticosteroids has been retrospectively conducted in a small numberof patients as a treatment for NMO (8); however, adequate evidence on the steroid efficacy has notbeen shown, and there is no guidance on dose reductions, raising concern about side effects due tolong-term steroid treatment. The incidence of NMO is higher in Japan than foreign countries and NMO
relapses can be fatal or may leave serious sequelae such as blindness or wheelchair-bound, andtherefore, it is urgent to develop effective therapies for the disease.
2.2 Rationale
Rituximab, originally a therapeutic agent for B-cell non-Hodgkin’s lymphoma, is a pharmaceuticalproduct that specifically depletes only anti-CD20 positive B cells. Therefore, rituximab is expected toRIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

be effective against autoimmune diseases in which B cells are considered to be involved in thepathogenesis. In clinical practice, the therapeutic effects on various autoimmune diseases including
rheumatoid arthritis and MS are confirmed.
In terms of the therapeutic effects in NMO, the annual relapse rate for NMO reportedly decreased
from 2.6 to 0 by rituximab in 8 patients with recurrent NMO (9). A subsequent retrospective reviewof the efficacy of rituximab in 25 patients with NMO (comparison of pre- and post-treatment) showedthat the annual relapse rate decreased from 1.7 (median, range 0.5-5) to 0 (range 0-3.2) (10). In
addition, in a similar retrospective study (11) and a prospective report of long-term efficacy, 10
patients with NMO were observed during the period of 10 to 45 months, for whom the mean annual
relapse rate was reduced from 2.4 (pre) to 0.93 (post) (12). We also reported that the annual relapse
rate decreased from 4.8 to 1.1 and EDSS improved from 8.7 to 8.0 in three patients with NMO (13).
Based on these results, rituximab, along with corticosteroids, is defined to be first-line therapy in the2010 guideline of the European Federation of Neurological Societies (EFNS) (14); however, none ofthese are approved in Japan.
Since then, no randomized controlled trials (RCTs) have been conducted, and only an open-label study
was conducted. In the study, 30 patients with NMO or NMOsp, who had experienced at least one
relapse in the 12 months prior to rituximab treatment, were enrolled and observed for 2 years. Annual
relapse rate, the primary outcome, was significantly reduced from 2.4 (0.4-8) to 0.3 (0-4) by rituximab
and there was statistical significance between the pre-treatment and the post-treatment periods(p<0.001), demonstrating a 70% complete response rate without relapse. As the Secondary outcome,
EDSS decreased significantly from 4.4 (1.0-8.5) to 3.0 (1.0-7.5) (p<0.001) and was stable or improvedin 97% of patients. No serious adverse reactions were reported in the report (15).
Preliminary we analyzed the data of 5 NMO patients treated with rituximab (a total of 20 courses wereconducted) at Utano National Hospital and found that the relapse was not observed in 17 of the 20
courses, demonstrating a very high response rate. The response rate to rituximab was 95% in the period
excluding the induction period until rituximab works and the period when the efficacy of rituximab
had expired.

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3.

Investigational product3.1 Overview of investigational product
The test drug used in this study is a clear and colorless injection drug containing anti-human CD20
monoclonal antibodies. The control drug is an injection drug that is indistinguishable from theaforementioned test drug in appearance and has no pharmacological effects.
3.2 Identity of investigational product
Test and control drugs will be provided in a dedicated box.
3.3 Chemical name, structural formula, and other information on test drug
Generic name: JAN (Japanese name) rituximab (recombinant product)(English name) rituximab (genetic recombinant)
INN rituximab
Chemical formula: C6426H9900N1700O2008S44
Molecular weight: 144,510 Daltons (1,328 amino acid residues)
Structural formula:

C1q Binding site

carbohydrate

3.4 Contents of investigational product label
The following information shall be displayed on the investigational product label.
Notice that the product is for the clinical trial
Name, title, and address of the head of the study coordinating committee
Medication number
Manufacturing number or manufacturing code
Storage conditions and shelf-life
3.5 Storage conditions for the investigational productThe investigational product is to be stored in a refrigerator and appropriately managed according to
the Procedure of the Investigational Product Management.

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3.6 Rationale for the dosage and administration of the investigational productInduction therapy: 375 mg/m2 four times weekly administration was adopted because a repeatedadministration could deplete B cells throughout the body (according to the protocol for the treatmentof B-cell non-Hodgkin’s lymphoma). We consider the protocol of lymphoma can be partially adopted
in patients with NMO.
Maintenance therapy: rituximab-induced B-cell depletion lasts at least 6 months but does not last 12
months in many patients; therefore, rituximab is to be re-administered at 6 months (Visit 8) and 12
months (Visit 14). Dosing is to be repeated twice, 1 g every other week.

4.

Eligibility criteria

4.1 Inclusion criteria(1) Patients who are seropositive for anti-aquaporin 4 antibody (Patients who have previously been
seropositive are also included.).
(2) Patients who have at least one episode of either optic neuritis or myelitis.
(3) Patients who are treated with oral corticosteroids of a dosage of 5 mg /day or more, inprednisolone-conversion dose for 3 months before registration, and the dosage is fixed orchange within 10% of the dosage at the registration for 3 months.
(4) EDSS between 0 and 7.0.
(5) Patients who have no recurrence of NMO within a month before registration and areneurologically stable.
(6) Patients between the ages of 16 and 80(7) Either male or female. Either inpatients or outpatients.
(8) Women of childbearing ages can be involved if a pregnancy test on Visit 1 is negative and she
agree with contraception during the trial.
(9) Patients who give written informed consent. Patients under 20 years of age are required parental
consent study collaborators study collaborators.
(10) Patients who are able to follow the study protocol and schedule, and who can report their
symptoms.
[Rationale](1) Anti-AQP-4 antibodies are extremely helpful in diagnosing NMO (specificity is reportedly close
to 100% and sensitivity >90% (1)). However, it is well-known that the antibodies frequently convert
to seronegative according to treatment or disease activity. Therefore patients who previously showed
antibody-positive are allowed to participate in the study. (2) Patients with positive AQP-4 antibodies
and either optic neuritis or myelitis are referred to as NMOsp and are considered as having localized
forms of NMO. In a study by Kittley et al., 86% of patients with positive anti-AQP-4 antibodies
experienced relapse, and the median for the time from onset of symptoms to relapse was reported toRIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018be 14 months (16). From these points, assuming that the pathophysiology was common to NMO
participation was allowed. (3) This was considered so that patients might participate without
discontinuing oral corticosteroid treatment, which is the current standard treatment for NMO. The
rationale for setting a lower limit of 5 mg for the steroid dose is due to the limited necessity to include
patients who are stable with very low doses of corticosteroids without causing a major issue in termsof adverse reactions. In addition, the range of fluctuation in dose was set for the reason that large dose
fluctuations of steroid may affect the efficacy assessment, although a fluctuation within 10% of thesteroid dose at the time of tentative enrollment was allowed for clinical purposes. (4) This was set
since severe neurological sequelae make appropriate assessment difficult. (5) This was set toaccurately evaluate the primary outcome of relapse. (6) The lower limit of age was set in accordancewith the patients' ability to give voluntary consent and the upper limit was set in terms of safety. (7)This was set for the reason that efficacy can be assessed in both hospitalized patients and outpatients.
In addition, since the tolerability and safety of the study drug and the expected benefits are not limited
to males or females, this criterion was set. (8) Since the safety of the test drug in pregnant women has
not been established, a decision was made to require women of childbearing potential to consent tothe use of contraception. (9) This was set to ensure that the patients' interests are not compromised
from an ethical point of view. (10) This was set to allow for appropriate assessments.
4.2 Exclusion criteria(1) Patients who have a history of hypersensitivity to mouse protein derivatives or anaphylactic
reaction to components of rituximab.
(2) Patients infected with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, andthose having active infectious diseases.
(3) Patients who have a history of severe recurrent or chronic infections.
(4) Patients who have used a live vaccine within 6 months before randomization.
(5) Patients under treatment with oral corticosteroid drugs of dosage of 30 mg/day or more in
prednisolone-conversion dose.
(6) Patients with previous use of cladribine or a monoclonal antibody, such as natalizumab orrituximab.
(7) Patients with a history of radiation treatment (whole body irradiation or lymphoid irradiation) ora stem cell transplant.
(8) Patients who are treated with mitoxantrone or cyclophosphamide within 12 months before
randomization.
(9) Patients who are treated with immunomodulatory drugs (interferon beta, glatiramer acetate) or
immunoglobulin therapy within 6 months before randomization.
(10) Patients who are treated with oral immunosuppressive agents other than steroids (e.g.,azathioprine, tacrolimus, cyclosporine, cyclophosphamide, methotrexate, or fingolimod) within

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

3 months before randomization.
(11) Patients who have received plasma exchange or intravenous steroid pulse therapy within 3months before tentative enrollment.
(12) Patients with autoimmune diseases, such as Sjögren's syndrome or systemic lupus erythematosus,
requiring treatment with immunosuppressants.
(13) Patients who are pregnant or feeding a baby.
(14) Patients who participate in other clinical trials.
(15) Patients diagnosed as having a cancer.
(16) Patients who are judged inappropriate for enrollment in the trial by the principal investigator /co-investigator.
[Rationale]
For the purpose of the safe conduct of the clinical trial, patients who meet criterion (1) should not be
included from the perspective of test drug administration.
In particular, since some patients died of fulminant hepatitis, patients with hepatitis virus infections or
those at high risk of infection according to (2), (3), and (4) should not be included in the study. (5) To
keep detection power of efficacy of rituximab, patients concomitantly using corticosteroids exceeding
the equivalent of 30 mg of prednisolone per day are excluded. Based on the necessity to exclude theeffects of immunosuppressive agents other than the investigational product on the clinical trial and inconsideration of an excessive immunosuppressive state, those meeting criteria (6), (7), (8), (9), and(10) are excluded. In addition, based on the potential impact of steroid pulse therapy on efficacy
assessments and to allow for an accurate assessment of disease status, criterion (11) and, to exclude
the impact of other diseases, criterion (12) were set. Considering the effects on pregnancy and breastfeeding, the criterion (13) should not be included. (Patients who are of childbearing potential should
not be excluded from the study if adequate contraception is being used). In addition, patients who meetcriteria (14), (15), and (16) are not included in the study to ensure the appropriate conduct of the study.

5.

Explanation provided to patients and obtaining informed consent

5.1 Preparation of explanatory documents and informed consent forms
The written explanatory documents and informed consent form will be prepared by the principal
investigator and approved by the IRB of each study site and will be used to obtain informed consent
from patients to participate in the clinical trial.
5.2 Revision of explanatory documents and informed consent forms
The principal investigator shall promptly revise the explanatory documents and informed consent form
and obtain IRB approval as soon as the principal investigator becomes aware of the need to revise theinformed consent form or other relevant information that may be relevant to the patients' consent.
5.3 Topics to be explained to patients

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

The explanatory documents and informed consent forms should include the following:

That the clinical trial involves researchStudy objectives

The name, title and contact information of the principal investigatorStudy methods

Expected benefits on patients' physical and mental health with the use of investigational product(or that such benefits cannot be expected if benefits are not expected) and potential disadvantages
to the patient (in particular, an explanation for the risk of progressive multifocal
leukoencephalopathy, one of the serious adverse reactions associated with the investigational
product, should be included)

Information regarding other treatments for NMO relapse

Duration of participation in the clinical trialThat the patient may withdraw from the clinical trial at any timeThat the patient will not receive unfavorable treatment due to not participating in the clinical trial
or by withdrawing the participation in the clinical trialThat source documents may be accessed by the monitor, auditor, and IRB, provided that theconfidentiality of patients is maintained

That the patient's identity will be kept confidentialThe contact information of the study site in the event of study-related injuriesThat necessary treatment will be provided to the patient in the event of study-related injuries

Information on compensation in the event of any study-related injury

Type of IRB reviewing and deliberating the appropriateness and other aspects of the clinical trial,
topics to be reviewed and deliberated by the IRB, and other matters related to the IRB reviewing
the clinical trial

The number of patients that will participate in the clinical trialThat, in the event that information that may affect the decision of the patient to continue
participation in the clinical trial is obtained, such information will be promptly communicated tothe patient

Requirements or reasons for discontinuing participation in the clinical trialIn the event that the patient is paid, the details regarding such payment



Instructions the patient must comply with

Other necessary matters concerning the clinical trial

5.4 Timing and method of obtaining informed consent
Written informed consent should be obtained from prospective participants prior to participating inthe study (on the day of Visit 1 or by the day prior) according to the following procedures.
(1) The principal/co-investigator will fully explain the information specified in "5.3 Topics to be

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

explained to patients" using explanatory documents and the informed consent form to patients
who are considered eligible to participate in the clinical trial. In addition, as necessary, clinicalresearch coordinators will provide additional explanation.
(2) Prior to obtaining consent, the principal/co-investigator will provide the patient with theopportunity to ask questions and sufficient time to decide whether or not to participate in the
study.
(3) Principal/co-investigators or clinical research coordinators providing supplementary explanations
should respond to all questions from prospective participants and ensure prospective participants
are satisfied with responses.
(4) If a prospective participant agrees to participate in the clinical trial, the principal/co-investigator
who provided the explanation and clinical research coordinators (when providing supplementary
explanations), and the prospective participant will sign and affix their seal or sign and date theconsent form.
(5) Prior to participation in the study, the principal investigator or co-investigator shall hand over a
copy of the informed consent form and explanatory documents to the prospective participant andretain the original informed consent form and explanatory documents at the participating studysite
5.5 In the event that information which may affect patient consent to participate or continue
participation in the study becomes available
In the event that information which may affect the patient's willingness to participate or continue
participation in the study (safety information, etc.) becomes available, the principal/co-investigator
will inform the patient of such information, confirm the patient's willingness to continue participationin the study, and document the decision and date of confirmation.
5.6 Obtaining informed consent again after revision of explanatory documents and informed
consent forms
If explanatory documents and informed consent forms are revised, the principal/co-investigator mustobtain informed consent from the patient according to the following procedures.
(1) The principal investigator or co-investigator shall inform patients who are already participatingin the study of the revision, confirm their willingness to continue participation in the study,
provide an explanation using the revised explanatory documents and informed consent and obtainwritten informed consent to continue participation in the study.
(2) Prior to obtaining consent, the principal/co-investigator will provide the patient with theopportunity to ask questions and sufficient time to decide whether or not to participate in the
study.
(3) Principal/co-investigators or clinical research coordinators providing supplementary explanations
should respond to all questions from patients and ensure participants are satisfied with responses.

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018(4) If a patient agrees to continue participation in the clinical trial, the principal/co-investigator who
provided the explanation and clinical research coordinators (when providing supplementary
explanations), and the participant will sign and date the consent form.
(5) The principal/co-investigator shall hand over a copy of the informed consent form andexplanatory documents to the patient, and the principal/co-investigator will retain the original
information consent form at the participating study site.
5.7 Obtaining consent from minors
If the patient is younger than 20 years of age, consent from the patient's legally acceptable
representative should be obtained.

6.

Enrollment/randomization

6.1 Procedures for patient enrollment (tentative enrollment, definitive enrollment, andrandomization)
6.1.1

Tentative enrollment

The principal investigator or co-investigator will provide an explanation to patients eligible for theclinical trial using specified documents and, if consent is obtained, shall enter the information required
for tentative enrollment into the electronic data capture (EDC) system, and perform tentativeenrollment.
The required information is as follows.
1) Date of birth2) Sex3) Race4) Date informed consent was obtained5) Form of consent obtained6) Age at the time informed consent was obtained7) Date of onset of NMO
8) Corticosteroid dose
6.1.2

Definitive enrollment and randomization

The principal investigator or a co-investigator will evaluate whether the patient meets the inclusion
criteria described in Section 4.1 and does not meet the exclusion criteria described in Section 4.2 after
the tentative enrollment and, at the time eligibility is confirmed, will enter the required information
for definitive enrollment in EDC and perform definitive enrollment.
6.2 Randomization method and randomization adjustment factors
Assuming that the allocation in Section 6.1.2 is performed using as stratification factors, the dose ofconcomitant corticosteroids entered in EDC (three strata: A (5-10 mg/day), B (11-20 mg/day), and C(21-30 mg/day) according to the steroid dose at the time of tentative enrollment) and the relapses inRIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018the 2 years prior to allocation (groups with or without relapse), patients formally enrolled will berandomized by the registration center to either the active treatment group or the placebo group. The
results of randomization (medication number) will be sent by the registration center to the principal/coinvestigator by FAX during the day of definitive enrollment, and the investigational product with theassigned medication number will subsequently be supplied by the investigational product provider.
6.3 Key code
The information linking each investigational product as an active drug or placebo is called a key code.
The key code will be retained by the allocation manager and will not be disclosed until the emergency
unblinding specified in Section 20 after the completion of the clinical trial, except for emergency
unblinding specified in Section 10.

7.

Treatment plan

7.1 Protocol treatment


Visit 2

For patients who have completed definitive enrollment, observations for "relapse" (relapse of NMO
as defined in Section 13) will be started and the investigational product will be administered. As ageneral rule, the investigational product should be administered in the hospital.


Investigational product administration

The investigational product should be administered within one week after definitive enrollment.
Rituximab 375 mg/m2 is administered as an intravenous drip infusion after 10-fold dilution withphysiological saline or placebo is administered as an intravenous drip infusion. Four repeated doses
are administered once a week. However, the 4th dose should be administered no later than the day
before Visit 3. Oral premedication (anti-inflammatory drugs, antihistamines) should be administered
30 minutes prior to administration. Administration method details are provided in Appendix 1.
Visit 4 and thereafter

The dose of corticosteroids should be reduced according to Section 7.3. At visits every 4 weeks, checks
for "relapses" based on neurologic findings and safety concerns are to be performed.


For visits every 12 weeks (Visit 5, 8-1, 11, 14-1, 17, 20), plain and Gd-enhanced cerebral MRI
are to be performed. At Visits 8-1, 14-1, and 20, plain and Gd-enhanced spinal cord MRI should
also be attempted.

7.2 Rituximab maintenance therapy (additional doses)

Visit 8, 14

Additional doses will be administered to maintain the efficacy of rituximab. Rituximab 1 g, diluted
10-fold with physiological saline, is administered as an intravenous drip infusion or placebo isadministered as an intravenous drip infusion. Two doses are given every other week. As with induction
therapy, planned premedication should be given 30 minutes prior to dosing.

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

Prior to administration, patients should be confirmed as not having active infection by checking for
pyrexia, examining physical findings, complete blood count, biochemistry tests, urinalysis, and chest
X-rays. If the attending physician decides that administration is inappropriate, a delay of up to 2 weeks
may be permitted; however, the second dose should be administered the day prior to Visit 9 or 15.
7.3 Corticosteroid tapering protocol
The dose of corticosteroids is converted to prednisolone equivalents as follows. The day after Visit 1,
the patient will be switched to prednisolone. However, if steroids are being administered as an everyother-day regimen, a dose close to the mean (rounded off) should be administered daily.
Prednisolone 5 mg = 25 mg of cortisone = 10 mg of cortisol = 5 mg of prednisone = 4 mg of
methylprednisolone = 4 mg of triamcinolone = 2 mg of paramethasone = 0.5 mg of dexamethasone =0.5 mg of betamethasone
For example: 12 mg of methylprednisolone is 15 mg (prednisolone equivalent).
Thereafter, prednisolone is tapered from Visit 4 (8 weeks after rituximab administration) until Visit
20 in both groups by 10% per month, to a minimum of 2 mg, if no relapse is observed. (In the instanceof dose reduction from a dose of 10 mg or less, dose reduction shall be by 1 mg steps). Reductions foreach visit are to be performed in the following order.
However, if the starting dose does not correspond to any of the following entries, the nearest doseshould be used as a starting point for reductions.
(In order of dose reduction, in terms of prednisolone [mg] equivalents)
30→27→24→22→20→18→16→14→13→12→11→10→9→8→7→6→5→4→3→2
Reductions in corticosteroid doses during the study are to be initiated at Visit 4.
The dose reduction steps based on the steroid dose at the time of tentative enrollment (when startingfrom 30 mg, 20 mg, 15 mg, 10 mg, and 5 mg in the figure, as shown in the bar graph on the left) are
as shown in the following figure.

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

Prednisolone (mg)

30
25
20
15
10
5

V2

(ra

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om
V4
i za
(s
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7.4 Rationale for reducing corticosteroid dose
There are no clear guidelines for the dosage and duration of use of corticosteroids for the preventionof relapse of NMO, as objective measures of NMO disease activity have not been established (14, 17).
In this clinical trial, the dose is to be gradually reduced to minimize the effect on NMO disease activity,
taking safety into consideration. The dose is to be reduced by 10% per month. At this dose reduction
rate, steroid rebound is considered to be less likely to occur and steroid withdrawal syndrome fromdose reductions can also be avoided. Analyses of our data showed that, assuming that thecorticosteroid dose (prednisolone equivalent) and risk of relapse was set to 1 when the dose was ≥21
mg/day, the risk of relapse increased with dose reduction to 3.58-fold when the dose was ≤20 mg/day
and 5.22-fold when the dose was ≤10 mg/day (refer to the subsequent table).
Based on this finding, assuming that the dose is reduced to 5 mg from 30 mg, there is an estimated 5fold increase in the frequency of relapse; however, this increase in the frequency of relapse is offset
to 0.11- to 0.15-fold with the administration of rituximab.
Based on these findings, the risk of relapse becomes negligible in the active treatment group even if
the dose is tapered from 30 mg and, even in the placebo group, the dose is gradually reduced in amanner comparable to typical clinical use, thus avoiding excessive burden on patients.
Medications

Steroid

Doses

OR (95% CI)P

5-10mg /day

5.22

(

1.08

-

25.25

)

0.04

11-20mg /day

3.58

(

0.52

-

24.56

)

0.20

21mg/day or more (Ref)1

7.5 Treatment options at the time of "relapse" (relapse of NMO as defined in Section 13)

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

After completing the observation period in this study, treatment with (1) below will be started
immediately, and concomitant use of (2) will be considered as necessary. If the treatment with (1) and(2) is considered difficult or does not improve outcome measures, other appropriate treatment should
be given.
(1) Steroid pulse therapy (methylprednisolone at a dose of 500 to 1000 mg for 3 to 5 days)(2) Plasmapheresis (irrespective of the type of plasmapheresis, immunoadsorption therapy, etc.)
7.6 Study discontinuation
Discontinue investigational product administration and remove the patient from the clinical trial if anyof the following occur.
(1) If prohibited concomitant drugs were administered(2) If prohibited concomitant therapy was administered/performed(3) If consent is withdrawn(4) In the event of an adverse event that requires discontinuation of treatment(5) If the study is discontinued at the discretion of the principal investigator or sponsor providing theinvestigational product(6) If the pregnancy of the patient is confirmed(7) If the principal or co-investigator determines it necessary to withdraw patients from the study forother reasons
If the patient discontinues the study, the principal/co-investigator will identify the reason forwithdrawal and enter this in EDC. The assessments described in Section 11.1 (at the time ofwithdrawal) should be performed as much as possible. Also, the outcome of any previous adverse
events will be followed for the required period of time. The required period will be determined at thediscretion of the principal/co-investigator.
7.7 Restricted concomitant drugs and therapies
For corticosteroids, Section 7.3 should be followed during the study period.
Steroid pulse therapy and plasmapheresis should not be used until the relapse of NMO as defined in
Section 13 is observed. If relapse of NMO as defined in Section 13 has not occurred and steroid pulse
therapy or plasmapheresis has been administered, withdraw the patient from the study (Section 7.6(1))
7.8 Prohibited concomitant drugs and therapies
The concomitant use of the following drugs and therapies is prohibited during the course of the clinical
trial.
1)

Steroid pulse therapy

2)

Plasmapheresis

3)

Monoclonal antibodies

4)High-dose immunoglobulin therapy

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

5)

Immunosuppressive agents/Anti-cancer drugs

6)

Immunomodulators

7)

Live or live-attenuated vaccines

8)

Investigational products other than the study drug

A list of drugs/therapies corresponding to 1-8) are shown in Appendix 2.

8.

Adverse event assessment and reporting

8.1 Definition of adverse events
Any disease and signs and symptoms that occur in a patient, for whom definitive enrollment has been
completed, are regarded as adverse events. Specifically, any untoward medical adverse event and its
signs (including abnormal laboratory changes), symptoms, or onset or worsening of disease in a patient,
for whom confirmed enrollment has been completed, whether or not considered related to theinvestigational product.
8.2 Assessment and reporting of adverse events
The principal/co-investigator will determine the presence or absence of an adverse event as defined in
Section "8.1 Definition of adverse events" based on the results of interviews, examinations, andlaboratory tests. If an adverse event occurs, this will be entered in EDC and severity will be evaluatedin accordance with the "Classification Criteria for Severity of Adverse Drug Reactions (Appendix 3)."
Serious adverse events occurring within 28 days of completion of protocol treatment should bereported and followed up.
8.3 Definition of serious adverse events
A serious adverse event is defined as follows.
(1) Death(2) Adverse events that may result in death(3) Adverse events requiring hospitalization in a hospital or clinic for treatment or requiring
prolongation of hospitalization (except for the relapse of NMO as defined in Section 13)(4) Permanent or severe* impairment or dysfunction (*refers to the degree of impairment in dailylife)(5) Adverse events that are considered serious based on the above events(6) Any congenital disease or abnormalities in the offspring of a treated patient
8.4 Expected adverse events
The main known serious adverse reactions of rituximab and the corresponding frequencies are as
follows.
8.4.1

Details of serious adverse reactions, frequency, and recommended measures

Refer to the description in the Investigator's Brochure.
8.4.2

Other adverse reactions and corresponding frequencies

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

Adverse reactions in Japanese clinical studies in non-Hodgkin’s lymphoma patients were observed in
147 out of 157 patients (93.6%). The most common adverse reactions (≥10%) were fever in 101
patients (64.3%), white blood cell count decreased in 75 patients (47.8%), neutrophil count decreasedin 72 patients (45.9%), chills in 54 patients (34.4%), pruritus in 34 patients (21.7%), headache in 33
patients (21.0%), hot flush in 32 patients (20.4%), increased blood pressure in 28 patients (17.8%),
tachycardia in 27 patients (17.2%), hyperhidrosis in 25 patients (15.9%), rash in 22 patients (14.0%),
and decreased blood pressure in 18 patients (11.5%), hemoglobin decreased in 18 patients (11.5%),
nausea and vomiting in 17 patients (10.8%), malaise in 17 patients (10.8%), pain in 17 patients (10.8%),
AST (GOT) increased in 17 patients (10.8%), and platelet count decreased in 16 patients (10.2%).

9.

Expedited reporting of and response to serious adverse events

9.1 Expedited reporting of serious adverse events and response to these events
1) In the event of a serious adverse event, the principal/co-investigator will consider medical
treatment/procedures as necessary to ensure the safety of patients.
2) If medical treatment becomes necessary, the principal/co-investigator will inform the patient of
the necessity of treatment.
3) The principal investigator will promptly report the occurrence of the events to the head of thestudy site and the study coordinating office regardless of relationship to the investigational
products.
4) The clinical trial coordinating office will report the information to the coordinating committee,
other principal investigators, and the investigational product provider. The coordinating
committee will consult with other principal investigators to determine whether the adverse event
meets Article 273 of the Enforcement Regulations of the Pharmaceutical Affairs Law. In the eventthat criteria are met, the principal investigator shall report the event to the Ministry of Health,
Labor and Welfare (MHLW) in accordance with the "Procedures for Handling of Safety
Information."5) The principal/co-investigator will confirm that the serious adverse event that occurred resolves or
stabilizes. In addition, the expectedness of the occurrence of this event in this patient will beassessed based on information on trends such as the onset or number of events, frequency, andconditions of onset based on the Investigator's Brochure, and events that cannot be predicted shallbe classified as unknown, and those that can be predicted classified as known.
9.2 Establishment of an Independent Data Monitoring Committee
The Independent Data Monitoring Committee (IDMC) will be called if any of the following events,(1) to (5), occurs to determine whether or not the study can be continued.
(1) First observation of relapse of NMO as defined in Section 13(2) If a relapse that leads to death or may lead to death is observed

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018(3) If an unknown adverse event that leads to death or may lead to death occurs(4) If there is a concern that the scientific validity of the investigational product development may
have been lost(5) Other than the above, if the coordinating committee or the principal investigators determine there
is a necessity
The members are shown in Appendix 4.

10.

Emergency unblinding

In the event of an emergency and there is a need to know what treatment the patient is receiving, theprincipal/co-investigator will discontinue administration of the investigational product to the patient
and report this to the coordinating committee. The coordinating committee will discuss this with theprincipal investigator to determine whether key code unlocking is necessary. If deemed necessary, thekey code will be unlocked only for the investigational product in question. In other words, theallocation manager will be instructed to unlock the code in writing and to notify the clinical trial
coordinating committee and the principal investigator of the results of unblinding in writing.

11. Observation, testing, and reporting items and schedule of assessments
11.1 Observation/test items and treatment information to be reported
Visit 1 (Screening tests)
Perform EDSS (Appendix 5) and QOSI (Appendix 6). Measure body temperature, blood pressure,pulse, and assess physical findings. Perform laboratory tests specified in Section 11.5 (complete bloodcount, biochemistry, urinalysis, human anti-chimeric antibodies (HACA) to rituximab, etc.), standard
12-lead electrocardiography (ECG), and chest X-ray.
Perform urine hCG pregnancy test for women who are premenopausal and <1 year after menopause.
Perform an ophthalmologic examination (including at least visual acuity, visual field test, and central
flicker value), visual evoked potential, and plain and Gd-enhanced brain (including optic neurography(plain)) and spinal cord MRI (imaging conditions are specified in Appendix 7)
Whenever feasible, assess somatosensory evoked potential and perform cerebrospinal fluid (CSF)
testing, which may be performed between Visit 1 and Visit 2.
Record the prescriptions for the day and collect the types and doses of medications other thancorticosteroids.
Measure and record weight and height. Collect information on relapses before and after starting oral
steroid administration, particularly the presence or absence and frequency of relapses during the twoyears prior to randomization, by Visit 2.
Visit 2 (definitive study enrollment)
Measure height and body weight, body temperature, blood pressure, pulse rate, assess physicalRIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

findings, perform EDSS and QOSI, clinical laboratory tests specified in Section 11.5 (blood tests,
urinalysis, anti-AQP-4 antibodies, lymphocyte subsets), record details on prescriptions for the day,medical history, and complications as medical background information.
Observation starts on this day. Start study administration within one week.
Visit 3 and thereafter
Measure body temperature, blood pressure, pulse rate, assess physical findings, perform EDSS andQOSI, and laboratory tests specified in Section 11.5 (such as blood tests and urinalysis) according to
the schedule shown in Appended Table 1. At Visits 5, 8-1, 11, 14-1, 17, and 20, perform
ophthalmologic examination (including visual evoked potential, if feasible), plain and Gd-enhanced
brain and spinal cord MRIs (preferably Gd-enhanced) to determine whether "relapse" (relapse of NMO,
as defined in Section 13) has occurred. If Visit 2-4 and Visit 3 are on the same day, perform
assessments specified in Visit 3 the day after administration of the investigational product in Visit 24.
At discontinuation of treatment
In principle, height and body weight, body temperature, blood pressure, and pulse are measured,
physical findings assessed, complete blood count, biochemistry test, urinalysis, EDSS, QOSI, ECG,
and chest X-ray are performed. If not performed, the brain (including optic neurography) and spinal
cord MRI, ophthalmologic examination, and visual evoked potential should also be evaluated. In
addition, record the details of prescriptions for the day.
If the patient is a woman of childbearing potential, a pregnancy test (urine hCG) should be performed,
and somatosensory evoked potential and CSF tests should be performed whenever possible. Theseshould be performed within 7 days after discontinuation.
11.2 Evaluation method
EDSS and QOSI are assessed by interview and neurologic examination. These are applicable to all
visits.
11.3 Rationale for performing observations, tests, and collecting treatment information to bereported
This information is collected to appropriately determine the relapse of NMO as defined in Section 13
and to collect information on the safety of the investigational product.
11.4 Observation, testing and reporting schedule, and acceptable windows
The schedule of observations, tests, and acceptable windows for each visit are shown in Appendix 1.
(e.g., +4D refers to up to 4 days after the specified visit and -4D refers to up to 4 days prior to thespecified visit)
These schedules were designed to ensure patient convenience and to adequately assess the primary
outcome of relapse. On Visits 8 and 14 of administration of the investigational product, an allowance(+14D) was set to ensure safe administration of the investigational product in instances where deferred

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

administration of the investigational product due to infectious diseases, etc. is deemed necessary.
11.5Laboratory tests
11.5.1 Test items
Laboratory test items are as follows.
(1) Lymphocyte subsets (CD19, 20) (*)(2) Anti-AQP-4 antibodies (*)(3) Complete blood count: white blood cell count, differential white blood count (neutrophils,
lymphocytes), red blood cell count, hemoglobin, hematocrit, and platelet count(4) Biochemistry (in serum): C-reactive protein (CRP), total protein, albumin, total bilirubin, AST(GOT), ALT (GPT), alkaline phosphatase, γ-GTP, creatine kinase (CK) (CPK), glucose,electrolytes (Na, K, Cl), total cholesterol, triglycerides, BUN, creatinine(5) Infectious disease tests (HBs antigen, HBs antibody, HBc antibody, HCV antibody, TPHA, RPR,
HIV, anti-JC virus antibody (*)) (*only at Visit 1)(6) Urinalysis (qualitative): urinary glucose, urinary protein, urinary occult blood(7) Urine hCG pregnancy test for women of childbearing potential (Visits 1, 8-1, 14-1, 20)(8) HACA in serum (Visits 1, 5, 8-1, 11, 14-1, 17, 20) (*)(9) CSF: cell counts, glucose, protein, chloride, oligoclonal bands, IgG index
11.5.2 Test methods
Laboratory tests will be performed at the study site except for those marked with * in Section 11.5.1.
Lymphocyte subsets, anti-AQP-4 antibodies, anti-JC virus antibodies, and HACA should be assayedon an outsourced basis. The results will not be disclosed to the participating study site until key
unblocking. In addition, sample collection and handling instructions for anti-AQP-4 antibody, anti-JC
virus antibody, and HACA samples are provided in Appendix 8.
11.6Collection of information on concomitant medication use
For concomitant medications after obtaining informed consent, details of prescriptions will berecorded at each visit.
11.7End of observation (the completion of observation will mark the end of the study)
The observation of patients in this study will be deemed complete in the following situations.
1)

Once specified assessments are completed at Visit 20. However, if the number of NMO relapses
during the entire study reaches the expected number of NMO relapses (13 relapses) as stipulated
in Section 16.1, the patient will be deemed as having reached the end of the study after completing
Visit 17.

2)

On the date of discontinuation. However, if adverse events have not resolved, the date ofcompletion of follow-up should be used.

3)

If relapse as defined in Section 13.1 is confirmed and the patient is enrolled in a separate rituximab
re-challenge study (clinical trial)RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

12. Target sample size and study duration
12.1Target sample size
The target sample size is a total of 40 patients, including 20 in the active treatment group and 20 in
the placebo group.
12.2Study duration
Informed consent will be obtained starting from May 10, 2014, and the enrollment period (planned)
will continue until August 15, 2017, with study completion by February 1, 2019.

13. Relapse of neuromyelitis optica
13.1Definition of relapse
Relapse is defined as any symptom reported by the patient or any new symptom that is consistent witha central nervous system lesion, such as the optic nerve or spinal cord, and that is associated with
objective abnormalities (new lesion in T2 or Gd-enhanced images) on MRI. However, the relapse of
optic neuritis will need to meet all of the following conditions, (1), (2), and (3).
(1) New abnormalities in ophthalmologic examinations (e.g., visual acuity, visual field testing, central
flicker levels, etc.)(2) Objective abnormalities on either MRI (new lesions on T2 or Gd-enhanced images) orelectrophysiologic testing (visual evoked potential)(3) The cause is presumably due to optic neuritis
This definition was established in accordance with the definition of relapse in the 2010 revised
McDonald diagnostic criteria for multiple sclerosis (18). In this clinical trial, only objectively provenrelapse is considered, and confirmation by either abnormal findings on MRI or electrophysiologicalexamination is required.
13.2Evaluation and testing at the time of relapse
The presence or absence of new neurologic findings is assessed by EDSS and QOSI. Plain andcontrast-enhanced MRI, ophthalmologic examination, and visual evoked potential are performed asneeded to objectively evaluate relapse. Body temperature, blood pressure, pulse rate, height, bodyweight, ECG, chest X-ray, pregnancy tests, anti-AQP-4 antibody, HACA, blood tests, urinalysis, andlymphocyte subset measurements (blinded) also need to be obtained. In addition, somatosensory
evoked potential and CSF testing are to be performed as much as possible. These procedures shouldbe performed within 7 days of relapse.
13.3Retreatment with rituximab at the time of relapse
Patients experiencing relapses identified during the course of the study, regardless of whether on active
treatment or placebo, may be enrolled in a separately-defined rituximab re-administration study,
provided consent is obtained from the patient (in this case, observation of the patient in this study

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protocol will be discontinued). The re-administration study will be conducted as an open study
associated with this clinical trial.

14. Endpoints
14.1Efficacy endpoints
14.1.1 Primary outcome
Time to the first relapse from randomization
The date of relapse will be as follows, whichever comes first.
(1) Date reported by the patient(2) Date of confirmed relapse based on objective tests such as MRI
14.1.2 Secondary outcome
Changes from baseline in EDSS and QOSI, and steroid reduction rate
14.2 Safety endpoint
The following items are subject to evaluation as safety endpoints.
Adverse events and adverse reactions, comparison of adverse events between the two groups

15. Pregnancy
If a patient has a positive urine hCG pregnancy test during the course of the study, the principal
investigator will report this to the coordinating office using a specified form and will follow-up on thestatus of pregnancy.
Patients who become pregnant during the study period will be withdrawn from the study. Pregnancies
are to be reported to the study coordinating office within 2 weeks of the day the principal investigatorbecomes aware of the pregnancy. Follow-up must be performed to determine outcomes and the statusof the mother and child. Pregnancy itself is not considered an adverse event or a serious adverse event;
however, pregnancy complications and termination for medical reasons should be reported as adverse
events or serious adverse events.

16. Statistical Analysis
16.1Rationale for setting the target number of patients
Setting the observation period
We estimated the risk of NMO relapse of both groups in the current study based on the previous reports.
However, we considered the difference in the relapse risk between the current trial and the previous
reports. In the previous reports the data were analyzed in patients with relapses within one year;
however, patients without recent relapses and those treated with oral steroids will be enrolled in thecurrent trial. Therefore, the disease activity and relapse risk are lower in the current study than in theprevious reports. We estimated the sample size conservatively as follows. First, the annual relapse rate

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in the placebo group was set to about 30% of that in the previous study. Next, calculated the required
number of relapses (expected number of events) would be observed by Week 60, although theobservation period was set up to Week 72. The reason why the observation period was shortened to
60 weeks in the calculation is to avoid disadvantages of patients. We can avoid the detriment of study
participants due to risk of relapse in the period between Weeks 60 and 72 when the statitistical power
is obtained in 60 weeks. If the expected number of events is not reached, the patient should be observed
up to Week 72.
Estimated annual relapse rate and cumulative OS at Week 60 in the placebo and rituximab
groupsThe mean annual NMO relapse rates before and after rituximab treatment for a total of 113 NMO
patients included in 7 previous reports (9-12, 15, 19, 20) were 2.65 per person-year prior to treatment
and 0.29 per person-year following treatment.
Estimation of survival rate at Week 60 in the placebo group
Based on these data, the annual relapse rate in the placebo group was estimated more conservatively,
assuming an annual relapse rate of 0.79 per person-year. In this instance, the cumulative survival rate
at Week 60 is estimated at 40%.
Estimation of survival rate at Week 60 in the rituximab group
We expect that rituximab suppresses NMO relapse 0.11-fold because the annualized relapse rate was
reduced from 2.64 to 0.29 in the previous reports. Therefore, the annual relapse rate in the active
treatment group was estimated to be 0.79 x 0.11 = 0.0869 per person-year.
Based on this result, the cumulative survival rate at Week 60 was estimated at 90%.
Sample size calculation (expected number of events and required number of study participants)
The significance level of the test was calculated with α=0.05 and power of 1-β=0.8.
Hazard ratioθ=log(0.90)= 0.115log(0.40)

Expected number of events e from the Freedman formula:2
θ+1 2
1.115 2e=(
) (Zα + Zβ ) = () × (1.960 + 0.842)2 = 12.5 ≅ 13
θ−1
0.885
2

Required entry size for each group𝑒n=(2−0.90−0.40) = 18.5 ≅ 19
Number of required patients and shortening of the observation period
Based on the above, the number of patients required for enrollment was 19 patients in each group, 38
in total, with the expected number of events being 13. As previously mentioned, if the cumulative
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observed up to Week 60, and observation will be completed after collecting the necessary data.
16.2Population for efficacy and safety analyses
The full analysis set (FAS) defined below will be used for analyses of endpoints in survival analyses.
When other analytical methods are used, both the FAS and the per protocol set (PPS) will be used as
analysis sets.
FAS definition: The FAS is defined as all randomized patients excluding those who were not assessedat any time after Visit 2.
PPS definition: The PPS is defined as all eligible patients, excluding those who were not assessed at
any time after Visit 2 or for whom a major deviation from the protocol was identified and werewithdrawn from the study, as defined below. Significant deviations include violations of eligibility
criteria found after randomization, discontinuation of the administration of the investigational product,and use of prohibited concomitant drugs. For each patient, handling will be determined after the
temporary database lock according to Section 16.7. Data handling will be specified separately for each
endpoint.
16.3Patient classification
Eligible patients: patients who meet all of the inclusion criteria and do not meet any of the exclusion
criteria
Discontinued patients: patients who were discontinued from the study due to discontinuation criteria
in Section 7.6.
Dropouts: patients for whom no further observations will be performed despite not meeting
discontinuation criteria in Section 7.6.
16.4Handling data from discontinued patients and dropouts
For both the FAS and PPS, actual values measured until the last observation time point regardless ofthe time of discontinuation or dropout will be used for evaluation.
16.5Handling of missing data
16.5.1 Handling of missing data in survival analyses
Discontinued patients will be treated as censored patients.
16.5.2 Handling of missing data in analyses other than survival analyses
For missing data for analyses except for survival analyses, the most recent prior assessment at the
specified time point will be used for both the FAS and PPS.
16.6Database lockPatients and data not specified above will be discussed and determined by the coordinating committee
and principal investigators, and the database will be locked.
16.7Analysis parameters and methods
16.7.1 Breakdown of patients
The FAS, PPS, and the number of discontinued patients will be listed along with group classifications.

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16.7.2 Treatment status
The status of active or placebo treatment will be summarized.
16.7.3 Summary of the data
Baseline statistics (maximum, median, minimum, 25%, 75%, mean value, standard deviation) will becalculated for all test values obtained as continuous values by treatment group at each assessment time
point. Baseline statistics will also be calculated for the change from baseline, and the time course ofindividual patients will be shown in a graph (broken line graph) and summarized in Box-Whisker plots.
In addition, the time course of data measured over time will also be summarized using Box-Whisker
plots. The categories of all test values obtained as categorical data will be tabulated by treatment groupand by assessment time point.
16.7.4 Significance level
Unless otherwise specified, a two-sided test of less than 5% will be considered statistically significant
in both tests.
16.7.5 Analysis of the primary outcome and analysis method
Time to the first relapse will be compared between the two groups. The start day of observation willbe the date of randomization and the observation period will be 72 weeks. Comparative survival
analyses will be performed between the placebo and active treatment groups. The analytical method
may be changed based on the statistical analysis plan prepared prior to the database lock considering
the progress of this study. However, if the number of relapses reaches the expected number of events(13 events) as described in Section 16.1, observation should be completed by Week 60.
16.7.6 Analysis of secondary outcomes and analysis method
The changes in EDSS and QOSI from baseline and steroid reduction rate will be compared between
the two groups. The method of analysis will be as per the statistical analysis plan.
16.7.7 Analysis of safety endpoints and analysis method (comparison of adverse events)
The frequency and severity of adverse events and adverse reactions will be summarized to determine
the differences between the rituximab and placebo groups.
Severity shall be classified into Grades 1, 2, and 3 according to the "Classification Criteria for
Seriousness of Adverse Drug Reactions" (Appendix 3) stipulated under the "Classification Criteria for
Seriousness of Adverse Drug Reactions of Pharmaceutical Products" (Notification No. 80 of the
Safety Division of the Pharmaceutical Affairs Bureau dated June 29, 1992).
Grade 1: Events considered minor adverse events
Grade 2: Non-serious adverse events but not minor adverse events
Grade 3: Events considered to be serious adverse events, in other words, depending on the patient's
constitution and condition at the time of onset, there is a risk of death or permanent disability that caninterfere with daily life
16.8 Adverse events

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Tabulations of adverse events will be by treatment group, and Fisher’s exact test will be used toperform a comparison of the incidence of each adverse event between two groups.
16.9Interim analyses
It will not be performed.
16.10

Statistical analysis planA statistical analysis plan will be prepared and will include technical details of the final analysis andprocedures after the clinical trial protocol is finalized. A blinded review will be conducted after the
final data collection, and the principal investigator will finalize the statistical analysis plan prior to thestudy database lock after discussion with the coordinating committee and the clinical trial statistician.

17. Completion and submission of case report forms
17.1 Data entry
For this clinical trial, an EDC system will be used for the case report forms. Data entry into the EDC
system shall be performed by the principal investigator or co-investigator. The data entry method shallcomply with the separately drafted manuals. Co-investigators or clinical research coordinators who
can enter data into EDC shall be individuals who have been entered into the pre-prepared "list of coinvestigators and clinical research coordinators." The study collaborator may enter details that do not
require medical judgment, such as transcribing laboratory values, patient characteristics, andprescription status of concomitant drugs. The principal investigator will review and electronically signthe EDC system entries and notify the coordinating committee. Data entered into the EDC system
based on original medical records should be consistent with the original medical records. If there areany discrepancies between the original medical records and entries, the principal investigator should
prepare a record explaining the reason for the discrepancy, appropriately store the record, andpromptly submit a copy to the coordinating committee.
17.2 Storage method
After completion of the data cleaning and the database lock, the revision history and EDC screens will
be recorded on a CD-R and retained at the study site. The principal investigator will confirm and signfor the information stored in the CD-R.

18. Monitoring
18.1 Direct access
The heads of participating study sites and the principal investigator will accommodate monitoring
visits and audits, as well as investigations by the IRB and regulatory authorities, and provide all studyrelated records, including source documents, for direct access. Direct access for monitoring will be
performed by clinical research associates assigned to this clinical trial. In addition, direct access foraudits shall be performed by the auditor.

RIN-1 Clinical trial Protocol
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The timing of direct access will be determined in consultation with the participating study site. In
addition, in the event of serious adverse events, source documents may be accessed as necessary toensure the safety of patients and to provide safety information to other participating study sites.
18.3 Source documents subject to direct access1)

Medical records, explanatory documents, and informed consent forms, and other medical datathat can be used to check EDC entries

2)

Other essential documents or records and related documents retained only at the study site

19. Quality control and assurance
The study site shall manage the quality of the clinical trial according to the standard operatingprocedures (SOPs) for investigator-initiated clinical studies. In addition, the auditing department will
check whether the clinical trial is being properly implemented in compliance with the protocol, theinvestigator-initiated clinical trial SOPs, and Good Clinical Practice (GCP). In addition, confirmationthat the clinical trial is being conducted appropriately and that the reliability of the data is sufficiently
maintained will be obtained by visiting study sites to directly access source documents as necessary.

20. Key unlocking (unblinding)
Unblinding will be performed according to the following procedures, with the exception of emergency
unblinding as specified in Section 10. After the database lock, the key code will be disclosed andunblinded.

21. Ethical considerations
21.1 Compliance with the Declaration of Helsinki and GCP
This study will be conducted in compliance with the ethical principles of the Declaration of Helsinki(partially revised in 2008) and GCP.
21.2 Institutional review board
This clinical trial will be conducted after undergoing review and obtaining approval from the IRB
prior to the implementation of the clinical trial at participating study sites.
21.3 Provision of new information
The investigator shall promptly notify the heads of participating study sites and the study coordinating
office of any information that may adversely affect the safety of patients, affect the conduct of theclinical trial, or change the approval status of the IRB regarding the continuation of the clinical trial.
The clinical trial coordinating office shall promptly notify the coordinating committee, other principal
investigators, and investigational product providers of the information.
21.4 Protection of patient human rights

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In order to protect the human rights of patients, the following must be observed during the course ofthis clinical trial. Individuals involved in this clinical trial shall fully consider the protection of thehuman rights of patients when handling consent forms, case report forms, source documents, and otherstudy-related documents, and publishing the results of the clinical trial. The discernment andidentification of individual patients will be performed using a patient identification code (referred toin this study as an anonymized ID). For records that may identify patients, the privacy andconfidentiality of patients should be taken into account.

22. Cost burden for the clinical trial
22.1Funding and financial relationships
This clinical trial is an investigator-initiated study, and the expenses involved in conducting theclinical trial will be subsidized by Practical Research Project for Rare/Intractable Diseases Health andLabor Science Research Grant (grant number H25/H26-Nanchi-Ippan-025) in 2013 to 2014, by theJapan Agency for Medical Research and Development (grant number 15/16/17ek0109090) from 2015
to 2017 and, from FY2018 onwards, by research funds from Zenyaku Kogyo Co., Ltd. In addition, as
stated in Section 22.3 Provision of the investigational product (including transportation expenses) andsome test items in Section 22.2 shall be borne by the investigation product provider. Details on
reducing the burden of expenses on patients are provided in Appendix 10.
An application was filed with the Conflict of Interest Committee of the National Hospital Organization
Utano National Hospital that established the clinical trial coordinating committee for approval of thestatus of conflict of interest occurring between the principal/co-investigator and Zenyaku Kogyo Co.,
Ltd., the provider of the investigational product in this clinical trial, and approval was obtained. In the
future, potential for conflicts of interest regarding the conduct and outcomes of the clinical trial will
be appropriately managed based on the conflict of interest management policy for each study site.
22.2Expenses related to the clinical trial
The costs of the clinical trial are covered by research grants from the Japan Agency for Medical
Research and Development. In addition, clinical laboratory tests (blood tests, urinalysis, ECGs,
imaging, etc.) performed during the administration of the investigational product are covered bynormal medical care insurance. However, the expenses for measuring and collecting anti-AQP-4
antibodies, anti-JC virus antibodies, and HACA will be borne by the investigational product provider.
22.3 Provision of the investigational productThe investigational product will be provided by Zenyaku Kogyo Co., Ltd.
22.4 Compensation for health injuries
In the event health injuries occur in patients due to the conduct of this clinical trial, the participating
study site will provide sufficient treatment and perform other appropriate measures. In addition,diseases, disabilities, etc. caused by adverse reactions, which are considered serious to a certain degree,

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will be covered by the clinical trial compensation insurance. The investigational product provider willassume the responsibility for the manufacture of the investigational product in case of health injuriescaused by the manufacture of the investigational product.

23. Protocol deviations
23.1 Deviations from the date of assessment
Deviations from the date of assessment exceeding the acceptable windows defined in Section 11.4
shall be reported as protocol deviations. Individual assessment should be performed as to whether
values measured on the deviating assessment day should be considered missing values.
23.2 Deviations from the study protocol
The principal/co-investigator may deviate from the protocol without prior approval from the IRB if
there are unavoidable medical circumstances, such as to avoid an immediate hazard to patients.
23.3 Preparation of records of protocol deviations
The principal/co-investigator will document all protocol deviations. If situations mentioned in Section
25.2 occur, the principal investigator shall prepare a record explaining the reason, submit this to theheads of participating study sites, and retain a copy.

24. Amendments to the clinical trial protocol
The principal investigator will revise the protocol as necessary whenever important new information
becomes available that may be relevant to the proper conduct of the clinical trial, such as informationon the quality, efficacy, and safety of the investigational product.
When revising the protocol, the principal investigator will submit the revised version of the protocol
to the heads of the participating study sites in advance. The heads of the participating study sites willconsult with the IRB regarding the protocol amendment.
If the protocol amendment results in revisions to the case report forms and informed consent form, theprincipal investigator shall also submit these documents to the heads of participating study sites assoon as possible, and the heads of the participating study sites shall consult with the IRB.

25. Study completion and early termination
25.1 Study completion
Once the clinical trial is completed, the principal investigator shall report the completion of the clinical
trial to the heads of the participating study sites.
25.2 Criteria for premature termination or suspension of the entire study
The principal investigator will terminate or suspend the entire study if any of the following situations
arise.
1)

If ethical or medical issues, such as ensuring the safety of patients, arise

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If the scientific validity of the clinical trial is lost25.3 Discontinuation or suspension of the clinical trial at study sites
The principal investigator or the heads of the participating study sites may prematurely terminate orsuspend the clinical trial at a participating study site if any of the following situations arise.
1)

Discovery of significant or persistent noncompliance by the principal/co-investigator or study site

2)

If continuation of the clinical trial is not feasible due to the transfer of the principal investigator

3)

Failure of the study site to continue to meet the requirements required for the proper conduct of
the clinical trial

26. Handling of study documents
26.1 Record retention
The retention period for essential documents shall be as per the policies of the participating study site.
The clinical trial coordinating office shall collectively manage the case report forms.

27. Publication of study results
The publication of study results may be led by the clinical trial coordinating committee and thecommittee may co-author the results along with researchers recommended by the researchorganization who meet the authorship criteria. There are no requirements for the investigational
product provider to publish results.

28. Study administrative structure
Refer to Appendix 9

29. Literature

1. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485-1489.
2. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999; 53: 11071114.
3. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.
Lancet 2004;
364: 2106-2112.
4. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp
Med 2005;
202: 473-477.
5. Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis.
Brain.
2007 ;130: 1224-1234.

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6. Interferon-beta (1b) treatment in neuromyelitis optica. Neurol. 2009;62(3):167-170.
7. B-cell activating factor of the TNF family is upregulated in neuromyelitis optica. Neurology.
2010 ;74:
177-178.
8. Low-dose corticosteroids reduce relapse regroup in neuromyelitis optica: a retrospective
analysis. Mult Scler.
2007 ;13: 968-974.
9. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005
12;64(7):1270-1272.
10. Treatment of Neuromyelitis Optica with Rituximab Retrospective Analysis of 25 Patients
ArchNeurol.
2008 ;65(11): 1443-1448
11. Impact of rituximab on relapse rate and disability in neuromyelitis optica. Multiple Sclerosis
Journal2011;17:1225-1230
12. Long-term follow-up of patients with neuromyelitis optica after repeated therapy withrituximab.
Neurology. 2011;76(15):1310-1315.
13. Trial of rituximab in three patients with neuromyelitis optica. Rinsho Shinkeigaku.
2009 ;49(8):457-462.
14. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol
2010;17:1019-1032

15. Repeated treatment with rituximab based on the assessment of peripheral circulating memory B
cells in patients with relapsing neuromyelitis optica over 2 years. Arch Neurol2011;68:1412-1420
16. Prognostic factors and course in aquaporin-4 antibody-positive patients withneuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain.
2012;135:1834-1849.
17. Treatment of Neuromyelitis Optica. Jpn.J. Clin. Immunol. 2012;35:129-135
18. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol.
2011;69:292-302.
19. Variable responses to rituximab treatment in neuromyelitis optica (Devic's disease). Neurol Sci.
2007;28:209-211.
20. Rituximab reduces attacks in Chinese patients with neuromyelitis optica spectrum disorders. J.

Neurol Sci. 2013;324:38-39._

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Appendix 1. Investigational product administration1.

Preparation of investigational product

(1)

Dose

Assuming that the investigational product would be administered at a dose of 375
mg/m2/administration, the body surface area should be calculated based on that measured at the timeof definitive enrollment using the DuBOIS equation below* (rounded to the first decimal place)* Body surface area (BSA) (m2) = weight (kg) 0.425 x height (cm) 0.725 x 0.007184(2)

Preparation method

Immediately prior to administration, dilute the investigational product (at a concentration of 10
mg/mL) with Japanese Pharmacopoeia (JP) physiological saline to prepare a 1 mg/mL concentration
solution. The entire volume of prepared infusion solutions should be fully administered within 24
hours. Do not use any diluent other than JP physiological saline.

2.

Premedications

To prevent infusion reactions, administer antihistamines and antipyretic analgesics as premedications
30 minutes prior to each administration of the investigational product.
Antihistamines: d-chlorpheniramine maleate 2 mg, etc.
Antipyretic analgesics: acetaminophen 400 mg, etc.

3.

Administration of the investigational product(1)

First administration in each course

The starting dose is 50 mg/h administered for 30 minutes. In the absence of adverse reactions such asallergic symptoms or infusion reactions, the infusion rate can be increased by 50 mg/h every 30
minutes up to a maximum dose of 400 mg/h.
However, in the case that the infusion rate cannot be increased every 30 minutes due to the onset of
infusion reactions or some other reasons, the reason should be recorded.
If adverse reactions are observed during administration of the investigational product, the infusion rateof the investigational product should be maintained, reduced, or temporarily interrupted, andappropriate supportive care should be provided as needed (Refer to "5. Reduction, interruption, andresumption of investigational product administration at the time of onset of adverse events" below).

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Figure 1. Infusion rate of the first administration of the investigational product in each course(2)

Second and subsequent administrations of the investigational product in each course

If adverse reactions such as allergic symptoms or infusion reactions that occurred during the previous
administration of study drug are Grade 2 or lower, the second and subsequent administrations can bestarted at 100 mg/h and increased by 100 mg/h every 30 minutes to a maximum of 400 mg/h. If adverse
reactions such as Grade 3 allergic symptoms or infusion reactions are observed during the previous
administration of the investigational product, set the starting infusion rate at 50 mg/h and administerfor 30 minutes and, if adverse reactions are not observed, can increase the starting infusion rate by 50
mg/h every 30 minutes up to a maximum dose of 400 mg/h. Patients should be closely monitored andextreme caution should be paid when increasing the infusion rate.
In the case that, the rate cannot be increased every 30 minutes due to the onset of infusion reactions
or some other reason, the reason should be recorded.
If adverse reactions such as allergic symptoms or infusion reactions are observed during administrationof the investigational product, the infusion rate of the investigational product should be maintained,
reduced, or temporarily interrupted, and appropriate supportive care should be provided as needed(Refer to "5. Reduction, interruption, and resumption of study drug administration at the time of onsetof adverse events" below).

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Figure 2. Infusion rate of second and subsequent administrations of the investigational product in eachcourseNote 1) Grade 2 infusion reaction: Requiring interruption of treatment or infusion, but responding
to treatment for symptoms (e.g., antihistamines, NSAIDs, narcotics, IV fluids)
Note 2) Grade 3 infusion reaction: Causes administration delays (e.g., not responding promptly tosymptomatic treatment and/or temporary interruption of infusion), relapses even after initial
improvement, requires hospitalization for sequelae

4.

After investigational product administration

After completion of investigational product administration, have patients rest for at least 30 minutes.

5.

Reduction, interruption, and resumption of investigational product administration at the timeof onset of adverse events(1)

If Grade 1 to 2 infusion reactions or other adverse reactions occur during administration of

the investigational product, maintain, reduce the infusion rate, or interrupt administration at thediscretion of the principal (or sub) investigator depending on the condition of the patient. Administer
supportive care as needed. If the infusion rate is to be reduced, reduce the infusion rate to 1/2 or lower.
After interrupting administration, administration may be resumed at the discretion of the principal (orsub) investigator. If administration is to be resumed, confirm that the reason for interruption, such as
infusion reactions, have resolved and resume administration at an infusion rate that is lower than orequivalent to 1/2 of the rate at the time of interruption.
(2)

If Grade 3 infusion reactions or other adverse reactions occur during administration of thestudy drug, immediately interrupt administration and actively treat the patient. After confirming thatthe reason for interruption, such as infusion reactions, have been resolved, administration may beresumed at the discretion of the principal (or sub) investigator. Resume administration at an infusion
rate that is lower than or equivalent to 1/2 of the rate at the time of interruption. If the same Grade 3

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event recurs within the same cycle, discontinue further investigational product administration.
(3)

If increasing the infusion rate is difficult due to the onset of infusion reactions, etc., theinvestigational product may be administered at a low infusion rate; however, complete theadministration of the entire volume of prepared investigational product within 24 hours of preparation.

6.

Measurement of vital signs (body temperature, blood pressure, pulse rate) at the time ofadministration of the investigational product(1)

Measure vital signs prior to the start and after the completion of investigational productadministration.
(2)

If the infusion rate is reduced or administration is interrupted due to the onset of adverse

events or for other reasons, record vital signs and subjective and objective symptoms at the time of
reduction or interruption.

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Appendix 2. Prohibited concomitant drugs and therapies
1.

Steroid pulse therapy (500 to 1,000 mg of methylprednisolone per dose, 3 to 5 consecutive

days)
2.

Plasmapheresis (irrespective of type of simple plasma exchange or immunoadsorption

therapy, etc.)
3.

Monoclonal antibodies (natalizumab, alemtuzumab, tocilizumab, etc.)

4.

High-dose immunoglobulin therapy

5.

Immunosuppressive agents/anticancer drugs (cladribine, mitoxantrone, cyclophosphamide,azathioprine, tacrolimus, cyclosporine, cyclophosphamide, methotrexate, fingolimod, etc.)
6.

Immunomodulators (interferon-β, glatiramer acetate, etc.)

7.

Live or live-attenuated vaccines

8.

Investigational product other than those used in this study

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Appendix 3. Criteria for classifying the severity of adverse reactions
The severity shall be classified into Grades 1, 2, and 3 according to the "Classification Criteria for
Seriousness of Adverse Drug Reactions" stipulated in the "Classification Criteria for Severity ofAdverse Drug Reactions of Pharmaceutical Products" (Notification No. 80 of the Safety Division of
the Pharmaceutical Affairs Bureau dated June 29, 1992).
Grade 1: Events considered minor adverse events
Grade 2: Non-serious adverse events but not minor adverse events
Grade 3: Events considered to be serious adverse events, in other words, depending on the patient's
constitution and condition at the time of onset, there is a risk of death or permanent disability that caninterfere with daily life.

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Appendix 4. Independent Data Monitoring Committee (IDMC) Members
1）

Department of Brain Pathophysiology, Graduate School of Medicine, Kyoto University,

Department of Clinical Neurology (Neurology)
Professor Ryosuke Takahashi
2）Director of Clinical Research Management, Center for Clinical Research, Kyoto University

Hospital
Professor Kazuo Matsubara
3）

Director, Health Science Center, Health Science Division, Japan Environmental Safety

Insurance Organization, Kyoto University
Professor Takashi Kawamura
4）

Director, Center for Brain Function Research, Graduate School of Medicine, Kyoto

University
Professor Hidenao Fukuyama

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Appendix 5. EDSS and FS
From EDSS 0 to 10, evaluations are in 0.5 increments.
From EDSS 0 to 5.5, evaluations also use FS (degree of functional impairment: pyramidal function,
cerebellar function, brain stem function, sensory function, bladder bowel function, visual function,
mental function, etc.) in the lower part of the following table in combination.
EDSS 6 to 10 is evaluated based on ADL, and EDSS 7 is wheelchair-level ADL, where the patientcannot walk more than 5 m without assistance.

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Appendix 6. QOSI (Adapted from Ref. 2)

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Appendix 7. Magnetic resonance imaging
Magnetic resonance imaging (MRI) scanners used should have a magnetic field strength of
1.5T or 3T in order to standardize the conditions between sites and scanners.
If more than one 1.5 or 3T MRI scanner are available, only one of them should be used for
imaging.
Check for any contraindications before using contrast media.
Perform scans using the parameters specified in the attached scanning parameter tables.
In the case that your facility uses 1.5T or 3T scanners of different models or from different
manufacturers, please develop protocols in accordance with the conditions shown in the tables.
Do not change the protocol developed when performing MRI scans in this study.
Perform MRI scans on the V1 brain area, as well as on the optic nerve (plain scan) for control
at the time of recurrence. If a recurrence of optic neuritis is observed, use a contrast agent.
MRI scans for suspected recurrence should only be performed with contrast enhancementwith the exception of plain MRI scans using the parameters defined for this clinical trial.

<Imaging targets>
Brain (plain → with contrast)
Entire spinal cord (plain cervicothoracic→ plain thoracolumbar → thoracolumbar with
contrast → cervicothoracic with contrast)*

Do not perform brain and entire spinal cord scans on the same day.

*Even if a scanner is available to cover the entire spinal cord in one scan, the scan for theentire spinal cord should divided into two scans to ensure that conditions between sites and scanners
are met.
Optic nerve (plain, but with contrast at the time of recurrence of optic neuritis)*

If optic neuritis is suspected during the course of the clinical trial and an MRI is performed,

administer a contrast agent according to the same sequence as that used in the protocol for optic nerve
imaging at the time of tentative enrollment, and start the Axial T1WI fatsat 10 minutes after thecompletion of administration of contrast agent.
(Perform image positioning scan and Axial T2WI fatsat within 10 minutes after completion ofadministration of contrast agent)<Procedure for brain MRI>
1

Positioning

Have the patient lay on the bed so that he/she can undergo the scan in the most comfortable position

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and align the eyebrows with the isocenter of the magnet.
2

Protocol2.1

Localizer

2.2

True mid-line sagittal Localizer (mid-sagittal）

2.3

Sagittal FLAIR

2.4

Axial FLAIR

2.5

Axial T1WI

2.6

Contrast agent administration

2.7

Axial T2WI

2.8

Axial T1WI

2-1.
This is a three-section scout used for positioning for the subsequent sequence.
2-2
Scan the mid-sagittal plane using a sequence allowing for definitely clear AC-PC lines.
2-3
Plan scans in parallel with imaging of the mid-sagittal plane in 2-2 (Fig. 1)
Figure 1

2-4., 2-5., 2-7., 2-8.
Use the images of the midline sagittal plane taken in 2-2 for positioning so that to align with the ACPC line (Fig. 2) and the upper edges of the slices as shown in Fig. 3.
Plan the second and subsequent images as closely as possible to the position of the first slice.

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Figure 2

Figure32-6.
Administer contrast medium intravenously at a dose of 0.2 ml/kg.
For post-contrast T1WI, start imaging 10 minutes after the completion of contrast agent infusion.
Image sequences using the parameters for 2-5 T1WI plain scans.
(Image the 2-7 Axial T2WI during the 10-minute waiting period.)*

Use the same contrast medium during the entire duration of the study.

<Procedure for spinal MRI>Divide the imaging for the entire spinal cord into two scans.

*

Include the entire spinal cord because the main assessment of the spinal cord is performedon the sagittal plane.
*

Position the junction between the cervicothoracic and thoracolumbar parts of spinal cord sothat there is overlap in one or more vertebral bodies (Fig. 4)*

If scoliosis is severe and the entire spinal cord cannot be imaged using the specified

procedure, change the angle and perform additional imaging (Fig. 5)

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Figure 4

Figure 5<Flow of imaging>
Cervicothoracic/thoracolumbar parts of spinal cord
1.

Positioning

Have the patient lie straight so that their spine is straightly aligned against the bed and align the xiphoidprocess of the manubrium/sternum such that the inferior border is 4 fingers wide from the isocenter ofthe magnet. Adjust the posture as much as possible so that the spinal cord forms an identical crosssectional image in the sagittal plane.

2.

ProtocolCervicothoracic (plain)
2-1. Localizer
2-2. Sagittal T1WI
2-3. Sagittal T2WI
Thoracolumbar (plain)
2-4. Localizer
2-5. Sagittal T1WIRIN-1 Clinical trial Protocol
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2-6. Sagittal T2WI
2-7. Contrast agent administration
Cervicothoracic (with contrast)
2-8. Sagittal T1WI
2-9. Axial T1WI
2-10. Axial T2WI
Thoracolumbar (with contrast)
2-11. Localizer
2-12. Sagittal T1WI
2-13. Axial T1WI
2-14. Axial T2WI

2-1., 2-4., 2-11
This is a three-section scout used to select the position of the subsequent sequence.
2-2., 2-3.
Select positioning to sufficiently include C1 relative to the upper border of the field of view (FOV).
After imaging, proceed to plain imaging of the thoracolumbar part of spinal cord.
2-5., 2-6.
Select positioning to sufficiently include S1 relative to the upper border of the FOV.
If the FOV380 does not overlap with at least one vertebral body at the thoracic spinal junction, widen
the FOV.
Ensure that the setting assures more than one vertebral body overlapping.
*If scoliosis is severe enough to make it difficult to capture the cervical thoracic spine andthoracolumbar part of spinal cord in the sagittal plane in two scans, additional imaging is taken withstandardized FOV to 300.
2-7. Contrast agent administration
Administer contrast medium intravenously at a dose of 0.2 ml/kg.
For 2-8. Sagittal T1WI, start imaging 10 minutes after the completion of contrast agent infusion.
Image sequences using the parameters for 2-5. Sagittal T1WI plain scans.
*

The flow of T1WI Sagittal imaging is to start 10 minutes after completion of administrationof the contrast medium. However, to shorten the time, the T2WI Sagittal imaging can be started first.
*

Use the same contrast medium during the entire duration of the study.

* 2-9., * 2-10.
Obtain axial images of new lesions or pre-existing lesions.
If no lesions are present, the axial view can be omitted.
2-11., 2-12., *2-13., *2-14.

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After completing thoracolumbar imaging, return to the cervicothoracic part of spinal cord and use thesame alignment as for plain imaging to obtain sagittal T1WI (with contrast) images.
Obtain axial images of new or pre-existing lesions, as well as the thoracolumbar part.
If no lesions are present, the axial image can be omitted.

<Submission of imaging data>
Create a CD containing images in DICOM format and submit the CD.

<Procedures for MRI of optic nerves>
1

Positioning

Have the patient lay in the bed so that they can undergo the scan in the most comfortable position,align the eye socket with the isocenter of the magnet, and ask the patient to gently close their eyes andnot move their eyeballs.

2

Protocol2.1

Localizer

2.2

Sagittal Localizer (sagittal section parallel to the right and left optic nerves)

2.3

Axial T2WI fatsat

2.4

Axial T1WI fatsat

2.5

Coronal T2WI fatsat

2.6

CoronalT1WI fatsat

2-1This is a three-section scout used to select the position of the subsequent sequence.

2-2
Scan sagittal sections parallel to the right and left optic nerves.

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2-3., 2-4.
Confirm the position of the right and left optic nerves in images of the sagittal section taken in 2-2
and, as much as possible, select the position to obtain axial images of the right and left optic nerves inthe same slice.

2-5., 2-6.
Plan to run directly along the optic nerve and select positioning to include the optic chiasm as muchas possible.

3

Contrast agent administration (in case of recurrence of optic neuritis)

Administer contrast medium intravenously at a dose of 0.2 ml/kg.
For T1WI fatsat, start imaging 10 minutes after the completion of contrast agent infusion.
Image sequences using the parameters used during the initial tentative enrollment.
*

Use the same contrast medium as that used for patients in the RIN-1 study.

<Submission of imaging data>
As with other sections, create a CD containing images in DICOM format and submit the CD.

RIN-1 Clinical trial Protocol
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(Precautions for brain protocol)
Do not apply a sensitivity-correction filter (normalizing filter).
Do not use parallel imaging.
Use Sequence Nos. 1 and 2 for the positioning sequence. Scan the sagittal sections using the sequence
allowing for clear visualization of CD-PC
Use the values shown in yellow in the following table.

(Precautions for spinal cord protocol)
Do not apply a sensitivity-correction filter (normalizing filter).
Do not use parallel imaging.
Use presaturation for the anterior spine.
Use Sequence No. 1 for the positioning sequence.
Use the values shown in yellow and red in the following table.

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RIN-1 Clinical trial Protocol
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Appendix 8. Handling of Anti-AQP-4 antibody, anti-JC virus antibody, and human antichimeric antibody (HACA) samples
Testing for anti AQP-4 antibodies, anti-JC virus antibodies, and human anti-chimeric antibodies(HACA) in blood in this clinical trial is outsourced. Blood sampling and sample storage should be
performed according to the procedures described below.
1.

Anti AQP4 antibodies and anti-JC-virus antibodies(1)

Collect 5 ml of whole blood samples in blood collection tubes at specified visits (Visit 1,

Visit 5, Visit 8, Visit 11, Visit 14, Visit 17, Visit 20, and at study discontinuation for anti-AQP
antibodies, and only at Visit 1 for anti-JC antibodies).
(2)

Invert and mix the blood collection tubes five times and allow the tubes to stand still for 30

minutes (room temperature).
(3)

Subsequently centrifuge immediately at room temperature (3,000 x g for 20 minutes).

(4)

Aspirate and dispense the supernatant into the appropriate storage tube.

(5)

Store storage tubes filled with the supernatant frozen at -20°C or below.

2.

HACA

(1)

Collect 10 ml of whole blood samples into blood collection tubes for HACA measurement

at specified visits (Visit 1, Visit 5, Visit 8, Visit 11, Visit 14, Visit 17, Visit 20, and at study
discontinuation).
(2)

Invert and mix the blood collection tubes five times and allow the tubes to stand still for 30

minutes (room temperature).
(3)

Subsequently centrifuge immediately at room temperature (3,000 x g for 20 minutes).

(4)

Aspirate and dispense equal volumes (minimum: 2 mL) of supernatant into two specified

storage tubes*.
(5)Store storage tubes filled with the supernatant frozen at -20°C or below.

The individual in charge of collection will collect the samples and request the designated contract
laboratory to conduct tests.

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Appendix 9. Study administrative structure
1. List of those conducting the clinical trial (principal investigators) and clinical trial sites
1) Department of Clinical Research Center, National Hospital Organization Utano National Hospital
Department of Neurology/Rehabilitation Medical Officer Masayuki Tahara (Principal Investigator(PI))
Vice-President Hideyuki Sawada
Director of Clinical Research Center Tomoko Oeda
Address 8 Ontoyama-cho, Kitaki-ku, Right-kyo-ku, Kyoto 616-8255
Phone 075-461-5121

2) Department of Neurology, Tokyo Women's Medical University
Specially Appointed Professor Yuko Shimizu (PI)
Address 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666
Phone 03-3353-8111

3) Department of Neurology, University of Occupational and Environmental Health
Associate Professor Kazumasa Okada (PI)
Address 1-1 Medical Sugaoka, Yahatanishi-ku, Kitakyushu 807-8555
Phone 093-603-1611

4) Department of Neurology and Sensory Diseases, Graduate School of Medicine, Tohoku University
Lecturer Tatsuro Misu (PI)Ichiro Nakashima (former PI)
Kazuo Fujihara
Address: 1-1, Seiryo-cho, Aoba-ku, Sendai 980-8574
Phone 022-717-7189

5) Departmentof Applied Life Sciences, Faculty of Medical, Dental and Pharmaceutical Health
Sciences, Hiroshima University
Professor Hirofumi Maruyama (PI)
Medical Lecturer Kazuhide Ochi (former PI)
Address 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
Phone 082-257-5555

6) Department of Neurology, Saitama Medical University Medical Center
Professor Kyoichi Nomura (PI)RIN-1 Clinical trial Protocol
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Associate Professor Hikoaki Fukaura
Address 1981 Kamoda, Kawagoe-shi, Saitama350-8550
Phone 049-228-3400
7) Department of Neurology, Nara Medical University
Lecturer Takao Kiriyama (PI)
Address 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
Phone 0744-22-3051

8) Department of Neurology, Graduate school of Medicine, Ciba University
Associate Professor Masahiro Mori (PI)
Address 1-8-1inohana, Chuo-ku, Chiba, Chiba 260-8670, Japan
Phone 043-222-7171[Responsibilities]
1)

Developing and amending the clinical trial protocol

2)

Developing and revising explanatory documents and informed consent forms

3)

Selecting study participants and obtaining their informed consent

4)

Guiding and supervising sub-investigators and study coordinators

5)

Providing materials and information, and providing help to monitoring and audits

6)

Handling deviations from or changes to the clinical trial protocol

7)

Reporting adverse events

8)

Preparing case report forms

9)

Storing study-related documents or records

10)

Other activities specified under Good Clinical Practice (GCP)

2. Clinical trial coordination committee
National Hospital Organaization Utano Hosipital Clinical Research Center
Chief Masayuki Tahara
Vice President Hideyuki Sawada
Director Tomoko Oeda
Address 8 Ondoyma-cho, Narutaki, Ukyo-ku, Kyoto, Kyoto 616-8255, Japan
Tel: 075-461-5121[Responsibilities]
1)

Developing and amending the clinical trial protocol

2)

Developing and revising explanatory documents and informed consent forms

3) Coordination and implementation of the details in the contents of the clinical trial Protocol andRIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018queries occurred during the trial at each facility, specified in the "Standard Operating Procedures of
the clinical trial coordination committee".

3. Clinical trial Statistician
Department of Internal Medicine, Kyoto Medical Center, National Hospital Organization
Masashi Goto, MD, PhD
Address 1-1 Fukasa-mukaihata-cho, Fushimi-ku, Kyoto 612-8555
Phone 075-641-9161[Responsibilities]
From a biostatistical point of view, advising all statistical aspects of this trial, such as the design ofclinical trials, the calculation of the number of required cases, the duration of clinical trials and analysis
methods.

4. Clinical trial coordination office
Clinical trial management office, Clinical Research Center, National Hospital Organization Utano
National Hospital
Address 8 Ontoyama-cho, Narutaki, Ukyo-ku, Kyoto 616-8255
Phone 075-461-5121[Responsibilities]
Under the direction of the clinical trial coordination committee, supporting the work conducted by theclinical trial coordination committee.

5. Clinical trial drug provider
Zenyaku kogyo Co., Ltd
Address 5-6-15 Otsuka, Bunkyo-ku, Tokyo 112-8650
Phone 03-3946-1113
Fax: 03-3946-1202[Responsibilities]
Provide clinical trial drugs, clinical trial drug outline, materials or information necessary for the
preparation of clinical trial protocol, etc., in an appropriate manner. In addition, provide informationon the safety of the clinical trial drugs provided, and information on the approval of manufacturing
and sales approval matters partly change approval application, etc., and other necessary informationin an appropriate manner.

6. Person in charge of assigning investigational drugs of clinical trial
DOT International Co., Ltd.

RIN-1 Clinical trial Protocol
Ver 2.4, December 12, 2018

Masato Nakata
Address 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo105-0021
Phone 03-3433-6060 / Fax:03-3433-6161[Responsibilities]
1.

Create, store, and manage key codes and key code tables

2.

Create, store, and manage emergency key codes

3.

Attaching drug numbers to clinical trials

4.

Confirmation of inability to identify clinical trials

5.

Check the seal status of the recovery trial drug before the key is opened

6.

Check the status of the emergency key code when opening and open the key code

7.

Check the seal status of the investigational drug after the key is opened

7. Person in charge of delivery of investigational drugs of clinical trial
Zenyaku kogyo Co., Ltd
Kazuhiro Endo
Masato Watanabe
Address 5-6-15 Otsuka, Bunkyo-ku, Tokyo 112-8650
Phone 03-3946-1113 / Fax: 03-3946-1202[Responsibilities]
Appropriately manage investigational drugs and deliver them to medical institutions

8. Registration Center
DOT International Co., Ltd.
Masato Nakata
Address 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo105-0021
Phone 03-3433-6060 / Fax:03-3433-6161[Responsibilities]
Central assignment is performed in a predetermined manner.

9. Data Management
DOT International Co., Ltd.
Hiroko Iijima
Address 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo105-0021
Phone 03-3433-6060 / Fax: 03-3433-6161[Responsibilities]
Entering, inspecting, and fixing CRF data into the database

RIN-1 Clinical trial Protocol
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Data validation and validation

10. Statistical analysis
DOT International Co., Ltd.
Tomonori Kimura
Address 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo105-0021
Phone 03-3433-6060 / Fax:03-3433-6161[Responsibilities]
Preparation of statistical analysis plan, execution of analysis based on statistical analysis plan,
preparation of analysis report

11. Monitoring
DOT International Co., Ltd.
Namiko Murao
Address 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo105-0021
Phone 03-3433-6060 / Fax:03-3433-6161[Responsibilities]
Collection and provision of information by visiting medical institutions, procedures for contracts,
collection of clinical trial investigational drugs, confirmation of clinical trial implementation status,
collection and investigation of case reports form, implementation of direct browsing, confirmation ofpreservation of documents, etc., eligibility survey of medical institutions and clinical trial responsible
physicians, Monitoring regularly implemented medical institutions

12. Medical WritingNone

13. Audit
DOT International Co., Ltd.
Harutoshi Kon
Address 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo105-0021
Phone 03-3433-6060 / Fax:03-3433-6161[Responsibilities]
Investigate whether the clinical trial is conducted in compliance with the clinical trial protocol,
standard operating procedure and GCP by the principal investigator and the clinical trial coordinating
committee (including the clinical trial coordination office), includeing consistency with the original
material by direct viewing.

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14. Management of clinical trials
DOT International Co., Ltd.
Tetsuya Orido
Address 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo105-0021
Phone 03-3433-6060 / Fax: 03-3433-6161[Responsibilities]
Based on the instructions of the clinical trial Coordinating Committee, supporting the clinical trial
coordination office.

15. Doctor-led clinical trial insurance
Mitsui Sumitomo Insurance Co., Ltd.
Liability claim Insurance amount: 100 million yen per person/accident, limit 300 million yen
No deductible
Liability insurance insurance amount Death 20 million yen (livelihood maintainer)
7 million yen (other than the livelihood maintainer)
disability grade (*)
1st class 30 million yen (livelihood maintainer) 20 million yen (non-livelihood maintainer)
2nd class 24 million yen (livelihood maintainer) 16 million yen (non-livelihood maintainer)*Pharmaceutical Side Effects Damage Relief System Standards
No deductible
Total payment limit 300 million yen[Responsibilities]
1. Payment of insurance for damages incurred by the subject of this trial due to the disability of thesubject of this trial and the insured person (the subject of insurance) is liable for legal liability.
2. Payment of insurance claims for "compensation liability" required by the Ethical Guidelines forClinical Research.
3. Liability insurance: Damages, dispute expenses (litigation fees, attorney's compensation, etc.)
Liability insurance: Death and disability 1st and 2nd gradeRIN-1 Clinical trial Protocol
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Table 1. Schedule