Clinical trial NCT04854096
Conditions: Primary Myelofibrosis Post-essential Thrombocythemia Myelofibrosis Post-polycythemia Vera Myelofibrosis
Sponsor: NS Pharma, Inc.
Start date: 2023-01-31; Completion date: 2024-05-16
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will enroll male and female subjects who are 18 years of age or older with Primary Myelofibrosis, post-polycythemia Vera Myelofibrosis, or post-essential Thrombocythemia Myelofibrosis with severe thrombocytopenia (platelet count \<50,000/µL) including subjects with intermediate-2 or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPSS).

Detailed description:
NS-018 will be self-administered orally at a dose of 300 mg BID. The BAT will be administered according to manufacturer's instructions and Investigator discretion. Subjects will complete study visits at Screening, Day 1 and Day 15 of Cycle 1, 2, 3, 4, 5, 6 and Day 1 of every cycle thereafter. At these visits, blood/urine sampling, spleen measurements, bone marrow assessments, patient-reported outcome (PRO) assessments, and safety assessments may be performed.

Arms: arm 1: Self-administered NS-018 300 mg orally, twice daily, preferably at the same time each day in consecutive 4-week (28-day) cycles arm 2: Single agent per Investigator discretion or no therapy
Interventions: intervention 1: NS-018 intervention 2: Best Available Therapy
Intervention descriptions: intervention 1: Experimental intervention 2: Active Comparator

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
1 
TITLE PAGE 
Protocol Title:  
A Phase 2b, Open-label, Multicenter, Randomized, Controlled, 2-Arm Study to Assess the Efficacy and 
Safety of Orally Administered NS-018 versus Best Available Therapy in Subjects with Primary 
Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis 
with Severe Thrombocytopenia (Platelet Count <50,000/μL)  
Protocol Number: NS-018-201 
Amendment Number: Protocol Version 3.0 
Product: NS-018 (Ilginatinib) 
Study Phase: Phase 2b 
Sponsor Name:  
NS Pharma, Inc. 
140 East Ridgewood Avenue, Suite 280S 
Paramus, NJ 07652 
USA 
Regulatory Agency Identifying Number(s):  
IND #: 109286 
EudraCT #: 2021-000369-34 
EU CT #: 2023-504462-39-00 
Date of Protocol: 07 August 2023 
 
 




CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment No. 
Substantial 
Region 
Version 3.0 
07 August 2023 
2 
Yes 
Europe, North America, 
Turkey, Poland, and Asia 
Version 2.0 
15 September 2022 
1 
Yes 
Poland, Turkey, North 
America, and Asia 
Original 
Protocol 
13 October 2021 
- 
- 
Europe, North America, and 
Asia. 
 
Amendment Protocol Global Version 3.0 (07 August 2023) 
Overall Rationale for the Global Amendment: 
The purpose of this global amendment from Protocol Version 2.0 is to harmonize the protocol 
language related to contraception per Clinical Trials Facilitation Group (CTFG) guidance and is 
aligned to harmonize with the European union (EU) submissions.  Changes that apply to all 
countries are harmonized throughout this amendment where applicable.  This global protocol 
amendment consolidates country-specific protocol changes requested by each country’s 
competent authority.   
The changes from Protocol Version 2.0 to this amendment are provided in the following table. 


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Final Protocol NS-018-201 - Protocol V3.0 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Updated Version 2.0 to 
Version 3.0, updated 
abbreviations, Appendix 
numbering, minor wording 
changes, and formatting as 
needed. 
Changed ilginatinib to NS-018 
Changed ‘no therapy’ to 
‘supportive care/therapy’ 
Changes required amendment with new 
version number and updates to text, 
appendices, formatting, drug name, etc. 
Title Page 
EU CT number added: 2023-
504462-39-00. 
EU CT number required. 
1.1 Synopsis, Best Available 
Therapy Dosage 
4.1 Overall Design, Best 
Available Therapy Dosage 
Added that the Investigator will 
decide the BAT that will be 
administered during the 
screening period and BAT 
must include one of the 
following; hydroxyurea, 
danazol, fedratinib, ruxolitinib, 
interferon, corticoid, 
erythropoietin, purinethol, 
thalidomide, lenalidomide or 
‘supportive care/therapy’.  
Clarification and BAT ‘no therapy’ 
replaced with BAT specific medication or 
‘supportive care/therapy’ to clarify that 
subjects are receiving other types of 
treatment for myelofibrosis.   
Added the list of BATs to meet the 
requirement of the new Clinical Trial 
Registration in EU. 
Added clarification that 
‘supportive care/therapy’ refers 
to blood products fluids 
(crystalloids), pain 
medications, and/or antibiotics, 
that subjects will need to 
manage myelofibrosis 
symptoms and complications. 
Clarification. 
Clarified that the dose and 
schedule for BAT will be 
decided by Investigator based 
on subject condition and 
according to manufacturer’s 
instruction or Investigator 
discretion. 
Clarification. 


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Section # and Name 
Description of Change 
Brief Rationale 
Added that subjects whose 
standard of care treatment is 
JAK inhibitor will be allowed 
in BAT group or as BAT.  
Clarification. 
Removed pacritinib, 
ruxolitinib, or fedratinib may 
be administered as a standard 
of care/BAT.  
Clarification. 
Modified text JAK inhibitor 
can be allowed as BAT if the 
JAK inhibitor was 
administered as a standard of 
care and that BAT may be 
changed at any time during the 
randomization period per the 
Investigator’s assessment.  
Clarification. 
1.1 Synopsis, Study Visits 
1.3 Global Schedule of 
Assessments 
4.1 Overall Design, Study 
Visits 
8.0 Study Assessments and 
Procedures 
8.2.4 Clinical Safety 
Laboratory Assessments 
Appendix 15 Schedule of 
Assessment for South Korea 
Only 
Appendix 16 Schedule of 
Assessments for UK Only 
Appendix 17 Schedule of 
Assessments for Germany 
Only 
Clarified safety laboratory 
assessments for each cycle and 
when a central laboratory can 
be used.  
Text was updated, as NS-018 has very 
limited clinical data to date, and an 
adjustment of the test plan to closely 
monitor safety of BAT subjects 
transitioning to NS-018 was required. 
This change is to clarify the schedule of 
safety laboratory assessments during the 
randomized period and after transition from 
BAT to NS-018 for all subjects.  
Added safety laboratory 
assessments that will be 
collected for South Korea only 
for the subjects transitioning 
from BAT to NS-018. 
Added at the request of Korea regulatory 
authority.  
Clarified when physical 
examinations, vital signs, and 
ECGs will be collected for 
each cycle. 
Clarification.  


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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, Study Visits 
4.1 Overall Design, Study 
Visits 
“JAK-inhibitor” was replaced 
with “ruxolitinib” while 
clarifying the washout period 
before starting NS-018 at Cycle 
1 and Cycle 7.  
Clarification. 
Added taper off or washout 
requirement for subjects 
transitioning from BAT to NS-
018. 
Clarification. 
1.1 Synopsis, Study Visits 
4.1 Overall Design, Study 
Visits 
Added that changes in MF-
directed treatment should be 
documented. 
Clarification. 
1.1 Synopsis 
1.2 Schema 
1.3 Global Schedule of 
Assessments 
4.1 Overall Design 
8.0 Study Assessments and 
Procedures 
Added cross reference to SoAs 
for South Korea, UK, and 
Germany for study visits and 
assessments. 
Provide SoAs for study assessments 
specific to each country.   
1.1 Synopsis, Number of 
Investigators and Study 
Centers 
Added additional study centers 
may be added. 
Text was added to support enrollment. 
1.2 Schema 
Revised footnote a to include 
subjects in the control group 
may receive BAT according to 
the Investigator’s discretionand 
based on the subject’s 
condition. 
Clarification. 
Revised footnote b to include 
BAT ‘supportive care/therapy’.  
Clarification. 


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Section # and Name 
Description of Change 
Brief Rationale 
Revised the Additional 
Assessment Guidance table 
after the Study Schema.  
 Added ECG details for 
UK only.  
 Removed MF-SAF, 
PROMIS, and EQ-5D-5L 
from the table. 
 Added safety laboratory 
assessments and timing 
for South Korea only.  
Clarification. 
1.3 Global Schedule of 
Assessments 
Modified the Visit Windows 
from plus/minus to only plus 3 
days. 
Clarification. 
Modified the bone marrow 
assessment at Cycle ≥ 7 to 
update from Cycles 7 to Cycle 
13.  
Clarification. 
Added therapies/procedures to 
Concomitant medication 
assessment. 
Clarification. 
Modified footnote b from 10 
days to 14 days for spleen 
measurement.  
Clarification. 
Added to footnote f 
clarification on safety 
laboratory assessments for 
subject transitions from BAT to 
NS-018.  
Added direct bilirubin for 
screening. 
Clarified total bilirubin for 
safety assessment.   
Clarification. 
Added footnote g to 12-lead 
ECG assessments in the table 
where appropriate.   
Clarification. 
Added to footnote g the 
collection of ECGs at each 
Cycle and Day.  
Clarification. 


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Section # and Name 
Description of Change 
Brief Rationale 
Modified footnote h from 3 
months to 6 months.   
Baseline bone marrow assessment was 
changed from 3 to 6 months to alleviate the 
subject burden of having BMA done at 3 
months before first dose. 
Added to footnote i 
clarification on collection of 
MF-SAF v4.0 assessment 
during screening and 
throughout the study.  
Clarification. 
Modified footnote n to clarify 
subjects receiving treatment 
other than ruxolitinib will 
undergo a washout period of 7 
days prior to treatment with 
NS-018.  
Clarification. 
Added footnote q and included 
“q” to the assessment of 
Concomitant 
therapies/procedures/medicatio
n assessment.  
Clarification. 
2.2 Background 
Revised “30 da” to survival 
Typographical error correction. 
Section 1.3, Global Schedule 
of Assessments 
4.1 Overall Design 
Appendix 3 Clinical 
Laboratory Tests 
Appendix 15 Schedule of 
Assessment for South Korea 
Only 
Appendix 16 Schedule of 
Assessment for UK Only 
Appendix 17 Schedule of 
Assessment for Germany 
Only 
Added that all subjects will be 
evaluated for active 
tuberculosis and inactive 
(latent) tuberculosis testing will 
be done in UK and South 
Korea by local laboratory. 
 
Clarified in footnote f that total 
bilirubin is collected for safety 
assessments.  
Added direct bilirubin for 
screening.  
Clarification. 
5.1 Inclusion Criteria #6 
Added that each platelet count 
result must be <50,000/µL. 
Clarification. 


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Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria #7 
Added subjects who are not 
benefitting from ruxolitinib 
may be enrolled per the 
Investigator’s discretion.  
JAK-inhibitor was replaced 
with ruxolitinib as MF-directed 
treatment, while clarifying the 
washout period before starting 
NS-018 at Cycle 1 Day 1 
Clarification. 
5.1 Inclusion Criteria #16 
Added specific contraception 
requirements and pregnancy 
testing for Germany and UK 
only for male and female 
subjects.  
Text was revised to clarify that male 
subjects must refrain from donating sperm 
for the duration of the study and for 
180 days after study completion or 
following discontinuation of study 
treatment. 
Text was revised to clarify that male 
subjects with partners who are WOCBP, 
pregnant or breastfeeding must agree to 
remain abstinent from penile vaginal 
intercourse throughout the study treatment 
period until 180 days from last study 
treatment. 
5.2 Exclusion Criteria  #1 
Added that the inactive (latent) 
tuberculosis testing to be done 
for UK and South Korea only.   
Clarification. 
5.2 Exclusion Criteria  #2 
Revised prior treatment with 1 
JAK inhibitors to 2 JAK 
inhibitors. 
To enhance enrollment. 
 
5.2 Exclusion Criteria  #3a 
and 3b 
Deleted the duration of 
treatment is cumulative and 
excludes dose interruptions and 
loss of spleen response. 
To enhance enrollment. 
5.2 Exclusion Criteria  #3 
Added subject receiving 
clinical benefit from JAK 
inhibitor is allowed per the 
investigator’s discretion.  
To enhance enrollment.  


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10 
Section # and Name 
Description of Change 
Brief Rationale 
5.4 Screen Failures 
Added that rescreened subjects 
should be given a new 
screening number and will 
require re-consenting.   
Clarification.  
6.1 Study Treatment(s) 
Administered 
Added subjects transitioning 
from BAT to NS-018 will 
receive study drug (NS-018) at 
Day 1 of every 3 cycles.  
Clarification. 
6.6 Dose Modification 
Added thrombocytopenia with 
active bleeding to Grade 4 for 
drug-related AEs and 
management of hematologic 
AEs.   
 
Added Grade 3 or Grade 4 non-
hematologic AEs will require 
dose interruption or dose 
reduction for non-hematologic 
AEs.   
Clarification. 
8.1.3 Bone Marrow 
Assessment 
Modified bone marrow 
assessment from 3 months to 6 
months.  
Deleted the timepoint for bone 
marrow assessment at Cycle 7 
Day 1. 
Baseline bone marrow assessment was 
changed from 3 to 6 months to alleviate the 
subject burden of having BMA done at 3 
months before first dose. 
8.1.4 Myelofibrosis 
Symptom Assessment Form 
Appendix 15 Schedule of 
Assessments for South Korea 
Only 
Added clarification on when 
MF-SAF v4.0 assessment will 
be collected during screening 
and throughout the treatment 
period. 
Removed the following text: 
Usability testing on selected 
electronic platforms should be 
completed in order to ensure 
that subjects can use the 
electronic devices 
appropriately. 
Clarification and was removed to reduce the 
complexity.  
 
 
 
The text was removed because usability 
testing is not a protocol requirement.  
Usability testing of the platforms was done 
during user acceptance testing of the device 
and platforms. 


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Section # and Name 
Description of Change 
Brief Rationale 
Removed the following text: 
Subjects transitioning from 
BAT to NS-018 treatment at 
any time before Cycle 7 Day 1 
will complete the MFSAF v4.0 
daily assessments for the first 7 
days prior to start of NS-018 
treatment. Additionally, 
MFSAF v4.0 assessments will 
be completed daily for 7 days 
after each cycle until the end of 
Cycle 12 (Day 336). 
The text was removed to reduce the 
complexity. 
8.1.5.2.1 Phospho-STAT3 
Assessments 
Revised collection of phospho-
STAT3 for Cycle 2 Day 1 from 
24 hours to 1 hour after 
administration of NS-018. 
Clarification. 
Added NS -018 arm only for 
participation in phospho-
STAT3 is optional and based 
on the site’s capability to 
process the sample prior to 
shipment to the central 
laboratory.   
Clarification. 
8.1.6.1 Patient-Reported 
Outcomes Measurement 
Information System 
(PROMIS) Fatigue Short 
Form (F-SF) 7b 
Removed the following text: 
Subjects transitioning from the 
BAT to NS-018 treatment at 
any time before Cycle 7 Day 1 
will complete PROMIS F-SF 
daily assessments for the first 7 
days prior to start of NS-018 
treatment. Additionally, this 
assessment will be completed 
daily for the last 7 days after 
each cycle until the end of 
Cycle 12 (Day 336). 
The text was removed to reduce the 
complexity. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
12 
Section # and Name 
Description of Change 
Brief Rationale 
8.2.1 Physical Examinations 
Added for subjects in UK only, 
a skin examination will also be 
conducted as part of the 
physical examination. 
 
Modified spleen measurement 
from 10 days to 14 days 
This was added as the ruxolitinib SmPC 
indicates that periodic skin examination is 
recommended for subjects.  The collection 
of skin cancer data as an AESI was 
considered insufficient to meet this 
requirement and to provide additional time 
for sites to upload the MRI scan for 
eligibility assessment for spleen 
measurement.  
8.2.3 Electrocardiograms 
Revised ECG is required at 
screening for all subjects and 
will be collected after 
randomization at Cycle 1 Day 
1, Cycle 1 Day 15, Cycle 2 
Day 1, Cycle 4 Day 1, and Day 
1 of every 3 cycles thereafter. 
Clarification. 
Clarified that subjects 
transitioning from BAT to NS-
018 will have ECG done on 
Day 1 and Day 15 of the first 
cycle of NS-018, Day 1 of the 
second and fourth cycles, and 
Day 1 of every three cycles 
thereafter.  
Clarification.  
Added for UK only and South 
Korea only, collection and 
timing of ECGs during Cycles.  
The additional ECG was in response to the 
competent authority’s request. 
Appendix 2 Regulatory, 
Ethical, and Study Oversight 
Considerations 
Added pSTAT3 assessment as 
a function and Cerba is the 
responsible organization.   
Clarification. 
Added mRNA assessment and 
Takara-Bio as responsible 
organization  
Clarification.  


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Final Protocol NS-018-201 - Protocol V3.0 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 3 Clinical 
Laboratory Tests 
Additional laboratory testing 
may be performed per the local 
standard of care. 
Clarified that latent TB test at 
Screening to be performed only 
for Korea and UK 
Clarified that local lab 
assessments will be performed 
per investigator’s discretion to 
monitor safety. 
Included “active TB test” at 
screening (except for the UK). 
Clarification. 
Appendix 6 Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Added intrauterine hormone-
releasing system (Italy only) 
for highly effective 
contraceptive methods. 
Clarification. 
Added Investigators are to 
collect data on all female 
subjects who become pregnant, 
definition of AE or SAE on 
pregnancy, and that any subject 
who becomes pregnant during 
the study will discontinue study 
treatment or be withdrawn 
from the study. 
Clarification. 
Added additional contraceptive 
guidance for male subjects. 
Clarification. 
Appendix 7 Contraceptive 
Guidance and Collection of 
Pregnancy Information for 
Germany and United 
Kingdom 
Added entire Appendix 7 for 
contraceptive guidance and 
collection of pregnancy 
information for Germany and 
United Kingdom. 
To reflect the changes requested by the UK 
Medicines & Healthcare products 
Regulatory Agency 
Appendix 9 Primary 
Myelofibrosis Definition 
Added Serum to LDH level. 
Clarification. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
14 
Section # and Name 
Description of Change 
Brief Rationale 
Appendix 15 Schedule of 
Assessments for South Korea 
Only 
Modified the Visit Windows 
from plus/minus to only plus 3 
days. 
To facilitate the collection of PROMIS 
diary data for the last 7 days of each cycle. 
 
 
Added footnote g to 12-lead 
ECG assessments in the table 
where appropriate.  
Clarification. 
Added to footnote i 
clarification on collection of 
MF-SAF v4.0 assessment 
during screening and 
throughout the study.  
Clarification. 
 
Added to footnote b 14 days 
for spleen measurement. 
To provide additional time for sites to 
upload the MRI scan for eligibility 
assessment. 
Modified footnote f to clarify 
safety laboratory assessments 
and timing.  
Clarification. 
Modified footnote g to clarify 
ECGs timing.  
Clarification. 


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Final Protocol NS-018-201 - Protocol V3.0 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Modified footnote h bone 
marrow assessment was 
modified from 3 months to 6 
months. 
 
Modified footnote n to clarify 
subjects receiving treatment 
other than JAK inhibitor will 
undergo a washout period of 7 
days prior to treatment with 
NS-018.  
Clarification. 
Additional assessment 
guidance was also added to 
South Korea SOA. 
Clarification. 
Appendix 16 Schedule of 
Assessments for UK only 
Added schedule of assessment 
specific to UK and additional 
guidance for UK only.  
Provided study assessment schedule to 
address UK site only.  
Appendix 17 Schedule of 
Assessments for Germany 
only 
Added schedule of assessment 
specific to Germany.  
Provided study assessment schedule to 
address Germany site only.  
Appendix 18 Protocol 
Amendment History 
Added protocol amendment 
summary of changes table from 
original protocol Version 1.0 to 
Version 2.0.  
Added document history of protocol 
amendment.  


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Final Protocol NS-018-201 - Protocol V3.0 
 
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The following country-specific protocols were consolidated in this amendment.  
Document  
Date 
Date of Approval by Competent 
Authority  
Italy Protocol V1.1 
28 October 2022 
07 February 2023 
United Kingdom Protocol V1.2 
19 July 2022 
02 November 2022 
Germany Protocol V1.2 
25 August 2022 
16 January 2023  
Changes that are country-specific for Germany, Italy, and UK are identified, respectively, in the 
following sections. 
Germany Protocol V1.2 
Germany protocol version 1.2, dated 25 August 2022, was amended based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union in a letter dated 19 May 2022, because it significantly impacts the safety or 
physical/mental integrity of subjects or the scientific value of the study, given the phase of this 
study, study population and expected menopausal status/use of contraception for the enrolled 
subjects.  
Overall Rationale for the Germany Amendment: 
The following table is the summary of changes requested and approved by the Germany Federal 
Institute for Drugs and Medical Devices in a letter dated 16 January 2023 and consolidated in 
this global amendment. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.2, Safety 
Assessments 
Appendix 17 Schedule of 
Assessment for Germany 
Only  
Added text under “Safety 
Assessments” to specify to closely 
monitor safety of BAT patients 
transitioning to NS-018. 
Text was updated, as NS-018 has very 
limited clinical data to date, and an 
adjustment of the test plan to closely 
monitor safety of BAT subjects 
transitioning to NS-018 was required.  
This change was not included in amendment 
version 1.1 as initially requested by the 
Germany Federal Institute for Drugs and 
Medical Devices in a letter dated 
10 Feb 2022 and is now included in this 
amendment version 1.2. 
Section 5.1, Inclusion 
Criteria 16 
Revised text. 
Text was revised to delete any specific 
information and to refer to protocol 
Appendix 7, to avoid conflicting 
information defined in Appendix 6 and to 
clarify the contraception requirements.  
Text referring to complete abstinence, 
double-barrier method, tubal ligation or 
vasectomy were removed. 
Section 11.0, Appendix 6 
(Contraceptive Guidance 
and Collection of 
Pregnancy Information) 
Revised text under “Male subjects” 
to clarify sperm donation and the 
use of condom. 
Text was revised to clarify that male 
subjects must refrain from donating sperm 
for the duration of the study and for 
180 days after study completion or the last 
dose of study treatment. 
Text was revised to clarify that male 
subjects with partners who are WOCBP, 
pregnant or breastfeeding must agree to 
remain abstinent from penile vaginal 
intercourse throughout the study treatment 
period until 180 days from last study 
treatment. 
The use of condom was also removed from 
the text given that it is not “highly effective” 
as per the CTFG contraception guidance – 
subsection 4.2. 


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Section # and Name 
Description of Change 
Brief Rationale 
 
Revised text under “Female 
subjects” to clarify contraceptive 
use. 
Text was revised for female subjects that 
they must use 2 highly effective 
contraceptive methods during the study and 
for 180 days after last dose of NS-018 as per 
Appendix 6 guidance for males, or for the 
duration required by product information of 
the comparator drug. 
 
Added text under “Female subjects” 
to follow the contraception 
requirements of comparator 
therapies. 
Added text to state that contraception 
requirements of comparator therapies must 
be followed.  As these comparator therapies 
are started in this protocol, this advice must 
be included in the protocol. 
 
Removed footnote b from table for 
“Highly Effective Contraceptive 
Methods” and replaced with revised 
text. 
Removed “hormonal contraception 
methods” clarifying that they cannot 
be used. 
Text was revised to state that hormonal 
contraception methods are not allowed to be 
used.  The IB indicates that NS-018 may be 
susceptible to drug-drug interactions and no 
results of clinical drug-drug interaction 
studies are provided.  Therefore, hormonal 
contraception will not be allowed, and this 
option was removed from the protocol. 
 
Added the following text under 
“Pregnancy Testing”: 
“Monthly pregnancy tests should be 
performed for WOCBP.  The serum 
pregnancy test should not be older 
than 72 hours before taking the first 
dose of study treatment.”. 
Text was revised based on incomplete 
preclinical toxicity testing program and 
related toxicity as described in the IB. 
Throughout 
Text edits. 
Minor editorial changes were made for 
consistency. 
 
 
 


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Italy Protocol Version 1.1 
Overall Rationale for the Italy Amendment: 
Italy protocol version 1.1, dated 28 October 2022, was amended to incorporate the changes 
requested from the Italian Medicines Agency, Agenzia Italiana del Farmaco (AIFA) in a letter 
dated 26 July 2022.  
The following table is the summary of changes requested and approved by the Italian Medicines 
Agency, Agenzia Italiana del Farmaco (AIFA) in a letter dated 07 February 2023 and 
consolidated in this global amendment. 


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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Updated with edits, such as 
replacing abbreviations with spelled 
out words and corrections of 
misspelled words, that were made 
in various sections throughout the 
protocol.  
For added clarity and per standard 
style guide. 
Section 1.1 Synopsis 
Section 4.1 Overall Design 
The following sentences were 
removed. 
Subjects treated with a JAK 
inhibitor will be required to taper of 
this treatment before initiation of 
NS 018 at Cycle 1 Day 1.  The dose 
of JAK inhibitor should be 
decreased every 7 days by up to 
50% until the smallest dose 
possible has been given for a 
minimum duration for the total 
tapering period of 14 days.  JAK 
inhibitor should then be stopped 1 
day before starting NS-018.  
Subjects who are taking 5 mg QD 
of a JAK inhibitor are already on 
the lowest dose possible; therefore, 
tapering is not applicable in this 
case.  If recurrence of MF-related 
symptoms (upon discontinuation of 
a JAK inhibitor therapy) is noted, it 
is strongly suggested that therapy 
with a JAK inhibitor be restarted.  
If restart is not possible, then 
prompt therapy with corticosteroids 
(eg, prednisone 60 mg QD) is 
recommended. 
To be consistent with inclusion 
criteria #7 that was changed as 
requested by the Italian Medicines 
Agency.   
Section 2.2 Background 
Replaced “30 da” with “survival” 
after “shortened” 
Typographical error correction. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion Criteria 
The following inclusion criteria #7 
was removed as it is only applicable 
for Italy.  
“Subjects treated with a JAK 
inhibitor will be required to taper of 
the JAK inhibitor before initiation 
of NS-018 at Cycle 1 Day 1.  The 
dose of JAK inhibitor should be 
decreased every 7 days by up to 
50% until the smallest dose 
possible has been given for a 
minimum duration for the total 
tapering period of 14 days.  JAK 
inhibitor should then be stopped 
1 day before starting NS-
018.  Subjects who are taking 5 mg 
QD of a JAK inhibitor are already 
on the lowest dose possible; 
therefore, tapering is not applicable 
in this case.  If recurrence of MF-
related symptoms (upon 
discontinuation of a JAK inhibitor 
therapy) is noted, it is strongly 
suggested that therapy with a JAK 
inhibitor be restarted.  If restart is 
not possible, then prompt therapy 
with corticosteroids (eg, prednisone 
60 mg QD) is recommended.”  
The following sentence was added.  
“Subjects who are not benefitting 
from ruxolitinib treatment may be 
enrolled in the study per the 
Investigator’s discretion.” 
Inclusion criteria #7 was changed 
as requested by the Italian 
Medicines Agency. 
Section 5.2 Exclusion Criteria 
The following criteria was added. 
3. Subjects receiving any clinical 
benefits from JAK inhibitor per the 
Investigator’s discretion. 
Exclusion criteria 3. was added to 
reinforce the change in inclusion 
criteria #7 as requested by the 
Italian Medicines Agency. 
 


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22 
United Kingdom Protocol Version 1.2 
Overall Rationale for the United Kingdom Amendment: 
United Kingdom (UK) protocol version 1.2, dated 19 July 2022, was amended to incorporate the 
changes requested by the UK Medicines and Healthcare products Regulatory Agency 
(MHRA) in a letter dated 26 May 2022.  
The following table is a summary of changes requested and approved by the MHRA in a letter 
dated 02 November 2022 and consolidated in this global amendment. 


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Final Protocol NS-018-201 - Protocol V3.0 
 
23 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1, Inclusion 
Criteria 16 
Revised text. 
Text was revised to delete any specific 
information and to refer to protocol 
Appendix 7, to avoid conflicting 
information defined in Appendix 6 and to 
clarify the contraception requirements.  
Text referring to complete abstinence, 
double-barrier method, tubal ligation or 
vasectomy were removed. 
Section 11.0, Appendix 6 
(Contraceptive Guidance 
and Collection of 
Pregnancy Information) 
Revised text under “Male subjects” 
to clarify sperm donation and the 
use of condom. 
Text was revised to clarify that male 
subjects must refrain from donating sperm 
for the duration of the study and for 
180 days after study completion or the last 
dose of study treatment. 
Text was revised to clarify that male 
subjects with partners who are WOCBP, 
pregnant or breastfeeding must agree to 
remain abstinent from penile vaginal 
intercourse throughout the study treatment 
period until 180 days from last study 
treatment. 
The use of condom was also removed from 
the text given that it is not “highly effective” 
as per the Clinical Trial Facilitation Group 
contraception guidance – subsection 4.2. 
 
Revised text under “Female 
subjects” to clarify contraceptive 
use. 
Text was revised for female subjects that 
they must use 2 highly effective 
contraceptive methods during the study and 
for 180 days after last dose of ilginatinib as 
per Appendix 6 guidance for males, or for 
the duration required by product 
information of the comparator drug. 
 
Added text under “Female subjects” 
to follow the contraception 
requirements of comparator 
therapies. 
Added text to state that contraception 
requirements of comparator therapies must 
be followed.  As these comparator therapies 
are started in this protocol, this advice must 
be included in the protocol. 


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24 
Section # and Name 
Description of Change 
Brief Rationale 
 
Removed footnote b from table for 
“Highly Effective Contraceptive 
Methods” and replaced with revised 
text. 
Removed “hormonal contraception 
methods” clarifying that they cannot 
be used. 
The text in footnote b was unclear and also 
made the unclarified recommendation to use 
2 highly effective methods, which could 
mean 2 types of hormonal methods, or 
1 type of hormonal method combined to 
another highly effective method.  
Text was revised to state that hormonal 
contraception methods are not allowed to be 
used.  The IB indicates that ilginatinib may 
be susceptible to drug-drug interactions and 
no results of clinical drug-drug interaction 
studies are provided.  Therefore, hormonal 
contraception will not be allowed, and this 
option was removed from the protocol. 
Throughout 
Text edits. 
Minor editorial changes were made for 
consistency 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................3 
TABLE OF TABLES .............................................................................................................28 
TABLE OF FIGURES ...........................................................................................................29 
1.0 
PROTOCOL SUMMARY ........................................................................................30 
1.1 
Synopsis ...........................................................................................................30 
1.2 
Schema ............................................................................................................36 
1.3 
Global Schedule of Assessments ...................................................................39 
2.0 
INTRODUCTION......................................................................................................46 
2.1 
Study Rationale ..............................................................................................46 
2.2 
Background ....................................................................................................48 
2.3 
Benefit/Risk Assessment ................................................................................49 
3.0 
OBJECTIVES AND ENDPOINTS ..........................................................................51 
4.0 
STUDY DESIGN ........................................................................................................53 
4.1 
Overall Design ................................................................................................53 
4.2 
Scientific Rationale for Study Design ...........................................................57 
4.3 
Justification for Dose .....................................................................................57 
4.4 
End of Study Definition .................................................................................58 
5.0 
STUDY POPULATION ............................................................................................59 
5.1 
Inclusion Criteria ...........................................................................................59 
5.2 
Exclusion Criteria ..........................................................................................60 
5.3 
Lifestyle Considerations ................................................................................63 
5.4 
Screen Failures ...............................................................................................63 
6.0 
STUDY TREATMENT .............................................................................................64 
6.1 
Study Treatment(s) Administered ................................................................64 
6.2 
Preparation/Handling/Storage/Accountability ...........................................66 
6.3 
Measures to Minimize Bias: Randomization and Blinding........................66 
6.4 
NS-018 Study Treatment Compliance .........................................................67 
6.5 
Concomitant Therapy ....................................................................................67 
6.6 
Dose Modification ..........................................................................................69 
6.7 
Treatment after the End of the Study ..........................................................70 


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7.0 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT  
DISCONTINUATION/WITHDRAWAL ................................................................71 
7.1 
Discontinuation of Study Treatment ............................................................71 
7.2 
Subject Withdrawal from the Study ............................................................71 
7.3 
Lost to Follow-up ...........................................................................................72 
7.4 
Procedures for Discontinuation in Relation to COVID-19 ........................72 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ....................................................74 
8.1 
Efficacy Assessments .....................................................................................75 
8.1.1 
Treatment Response ..........................................................................75 
8.1.2 
Spleen Volume Assessment ..............................................................75 
8.1.3 
Bone Marrow Assessment .................................................................76 
8.1.4 
Myelofibrosis Symptom Assessment Form .......................................76 
8.1.5 
Pharmacokinetics and Pharmacodynamics Assessments ..................77 
8.1.6 
Other Exploratory Assessments ........................................................78 
8.2 
Safety Assessments .........................................................................................79 
8.2.1 
Physical Examinations .......................................................................79 
8.2.2 
Vital Signs .........................................................................................79 
8.2.3 
Electrocardiograms ............................................................................79 
8.2.4 
Clinical Safety Laboratory Assessments ...........................................80 
8.3 
Adverse Events ...............................................................................................82 
8.3.1 
Time Period and Frequency for Collecting AE and SAE 
Information ........................................................................................82 
8.3.2 
Method of Detecting AEs and SAEs .................................................82 
8.3.3 
Follow-up of AEs and SAEs .............................................................82 
8.3.4 
Regulatory Reporting Requirements for SAEs .................................83 
8.3.5 
Pregnancy ..........................................................................................83 
8.3.6 
Adverse Events of Special Interest ....................................................83 
8.3.7 
Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs ......................................................................................84 
8.3.8 
Procedures in Relation to COVID-19 Infection ................................84 
8.4 
Treatment of Overdose ..................................................................................85 
8.5 
Pharmacokinetics ...........................................................................................85 
8.6 
Pharmacodynamics ........................................................................................86 
8.7 
Genetics ...........................................................................................................86 
8.8 
Biomarkers .....................................................................................................87 
8.9 
Health Economics/Medical Resource Utilization and Health 
Economics .......................................................................................................87 
9.0 
STATISTICAL CONSIDERATIONS .....................................................................88 
9.1 
Statistical Hypotheses ....................................................................................88 
9.2 
Sample Size Determination ...........................................................................88 
9.3 
Populations for Analyses ...............................................................................89 
9.4 
Statistical Analyses.........................................................................................89 
9.4.1 
Efficacy Analyses ..............................................................................89 
9.4.2 
Safety Analyses .................................................................................91 


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9.4.3 
Other Analyses ..................................................................................92 
9.4.4 
Missing Data ......................................................................................93 
9.5 
Interim Analyses ............................................................................................93 
9.6 
Independent Data Monitoring Committee ..................................................93 
10.0 
REFERENCES ...........................................................................................................94 
11.0 
APPENDICES ............................................................................................................97 
Appendix 1 
Abbreviations ....................................................................................98 
Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations .........101 
Appendix 3 
Clinical Laboratory Tests ..............................................................106 
Appendix 4 
Adverse Events: Definitions and Procedures for   
Recording, Evaluating, Follow-up, and Reporting .....................108 
Appendix 5 
Excluded Medications/Therapy ....................................................114 
Appendix 6 
Contraceptive Guidance and Collection of Pregnancy 
Information .....................................................................................117 
Appendix 7 
Contraceptive Guidance and Collection of Pregnancy 
Information for Germany and United Kingdom .........................120 
Appendix 8 
Genetics ...........................................................................................124 
Appendix 9 
Primary Myelofibrosis Definition .................................................125 
Appendix 10  Post-Polychythemia Vera Myelofibrosis Definition ....................126 
Appendix 11  Post-Essential Thrombocythemia Myelofibrosis Definition .......127 
Appendix 12  Dynamic International Prognostic Scoring System ....................128 
Appendix 13  Eastern Cooperative Oncology Group (ECOG) 
Performance Status ........................................................................129 
Appendix 14  Revised Response Criteria for Myelofibrosis: 
International Working Group-Myeloproliferative 
Neoplasms Research and Treatment (IWG-MRT) and 
European LeukemiaNet (ELN) Consensus Report .....................130 
Appendix 15  Schedule of Assessments for South Korea Only ..........................133 
Appendix 16  Schedule of Assessments for UK only ...........................................140 
Appendix 17  Schedule of Assessments for Germany Only ...............................147 
Appendix 18  Protocol Amendment History ........................................................155 
Appendix 19  Signature of Investigator ...............................................................161 
 


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TABLE OF TABLES 
Table 1 
Study Objectives and Endpoints ......................................................................51 
Table 2 
World Health Organization COVID-19 Case Definition Criteria ...................62 
Table 3 
Study Treatment Details ..................................................................................64 
Table 4 
Study Treatment Administration in Case of Dose Reduction ..........................69 
Table 5 
Items of Myelofibrosis Symptom Assessment Form v4.0 Diary .....................76 
Table 6 
Efficacy Analyses ............................................................................................90 
Table 7 
Study Administrative Structure ......................................................................103 
Table 8 
Protocol-required Safety Laboratory Assessments ........................................106 
 


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TABLE OF FIGURES 
Figure 1 
Study Schema...................................................................................................36 
 


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Final Protocol NS-018-201 - Protocol V3.0 
 
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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Phase 2b, Open-label, Multicenter, Randomized, Controlled, 2-Arm Study to Assess 
the Efficacy and Safety of Orally Administered NS-018 versus Best Available Therapy in Subjects with 
Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia 
Myelofibrosis with Severe Thrombocytopenia (Platelet Count <50,000/μL) 
Study Rationale:  
NS-018 is a potent and specific Janus kinase 2 (JAK2) inhibitor which was designed and synthesized by 
Nippon Shinyaku Co., Ltd.  NS-018 is being developed as a therapeutic agent for myeloproliferative 
neoplasm (MPN) including myelofibrosis (MF).  A Phase 1/Phase 2, multicenter, dose-escalation, open-
label study of NS-018 was conducted in subjects with primary myelofibrosis (PMF), post-polycythemia 
vera MF (PVMF), or post-essential thrombocythemia MF (ETMF) with 10 dosing cohorts (Study No. 
NS-018-101 [NCT01423851]).  A total of 48 evaluable subjects were enrolled in the Phase 1 part of the 
study.  The best response in palpable spleen size reduction of ≥50% observed was similar between 
subjects administered with 300 mg once daily (QD) and twice daily (BID), which is 56% (5/9) and 50% 
(3/6), respectively.  In terms of safety, both 300 mg QD and 300 mg BID were tolerable.  The safety data 
showed a difference between 300 mg QD (17%, 1/6) and 300 mg BID (50%, 4/8) in dose reduction or 
discontinuation up to Cycle 7 Day 1 (first dose cohort).  The 300 mg QD dose was selected as the dose 
for the Phase 2 part of Study NS-018-101.  A total of 29 evaluable subjects were enrolled in the Phase 2 
part of Study NS-018-101.  In the Phase 2 part of the study, spleen volume reduction (SVR) was 
measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan.  There were no 
safety concerns in subjects administered with 300 mg QD; however, only 1 subject with a baseline 
platelet count of <50,000/μL achieved ≥35% reduction in spleen size volume as measured by MRI at 
Cycle 7.  There was a trend, however, that subjects with higher area under the plasma concentration-time 
curve (AUC) obtained higher efficacy in terms of SVR and an improvement of symptoms.  In the Phase 1 
part of Study NS-018-101, there was no clear difference in drug-related hematological adverse events 
(AEs) between 300 mg QD and 300 mg BID (Grade 3/4 thrombocytopenia: 13% (2/15) and 8% (1/12), 
Grade 3/4 anemia: 0% and 17% (2/12), respectively.  The safety assessment of 300 mg QD showed no 
clear difference from 300 mg BID in terms of drug-related non-hematological AEs (gastrointestinal 
disorders 4/15 [27%] versus 6/12 [50%]; nervous system disorders 6/15 [40%] versus 5/12 [42%]), with 
dizziness and nausea the most common toxicities in these classes, respectively.   
In reviewing the available data, the following 3 factors were considered in the selection of subjects with 
severe thrombocytopenia (platelet count <50,000/μL) and the 300 mg BID dose that will be used in the 
NS-018-201 study: 1) 300 mg BID safety profile that was demonstrated in the Phase 1 part of Study 
NS-018-101 (n=12); 2) demonstrated efficacy of >35% SVR as measured by MRI at Cycle 7 in 1 subject 
with baseline platelet count of <50,000/μL who received 300 mg QD in the Phase 2 part of 
Study NS-018-101; and 3) detected trend in higher efficacy in SVR and improvement in symptoms in 
those subjects with higher AUC. 




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32 
care/therapy’.  The BAT should be administered according to the manufacturer’s instructions or the 
Investigator’s discretion.  The BAT is ‘supportive care/therapy’, and refers to use of blood products, 
fluids (crystalloids), pain medications, and/or antibiotics, that subjects will need to manage myelofibrosis 
symptoms and complications.  Subjects in the control group will receive BAT at doses and schedules 
selected by the Investigator based on the subject’s condition and according to the manufacturer’s 
instructions or the Investigator’s discretion.  The BAT must be a single agent and cannot be combined 
with other agents.  JAK inhibitor can be allowed as BAT if the JAK inhibitor was administered as a 
standard of care based on the product label or Investigator’s discretion.  The BAT may be changed at any 
time during the randomized treatment period based on the Investigator’s clinical assessment of the 
subject’s condition.  However, it is not allowed to change the BAT to JAK inhibitor if it was not used as 
standard of care treatment prior to study participation. .  No experimental agents (ie, those not approved 
for any indication) may be used at any time.  
Study Visits 
Subjects will have regular scheduled study visits at screening, Day 1, Day 15 of Cycles 1, 2, 3, 4, 5, and 
6, and Day 1 of every cycle thereafter.  One cycle is 28 days.  Subjects transitioning from BAT to NS-018 
before or at Cycle 7 Day 1 will have safety laboratory assessments performed on Day 1 and Day 15 of 
each cycle for 6 cycles.  Safety laboratory assessments will continue on Day 1 of the following cycles 
until the end of the study and will be done by a central laboratory (refer to Appendix 17 SoA for further 
details).  Additional local laboratory assessments may be performed per Investigator’s discretion to 
monitor safety and document AEs as per local standards of care.    
Subjects in South Korea only, safety laboratory assessments will be performed weekly at Cycle 1 on 
Day 1, Day 8, Day 15, and Day 22, and Cycles 2 through 6 will be performed on Days 1 and 15, and Day 
1 of each cycle thereafter.  Laboratory visits on Day 8 and Day 22 of Cycle 1 for subjects randomized to 
NS-018 or Cycle 1 after transitioning to NS-018 in subjects who transition to NS-018 will be performed 
at the institutional local laboratory (refer to Appendix 15 SoA for further details).   
Subjects who transition from BAT to NS-018 will have a physical examination done on Day 1 of each 
cycle for the first 4 cycles after transitioning to NS-018 and on Day 1 of every three cycles thereafter, as 
subjects are transitioned to NS-018.  Vital signs will be done on Day 1 of each cycle after transitioning to 
NS-018.  Vital signs will be taken within 3 hours before transitioning to NS-018.  Electrocardiogram 
(ECG) will be done on Day 1 and Day 15 of the first cycle and on Day 1 of the second and fourth cycles 
after transitioning to NS-018, and on Day 1 of every 3 cycles thereafter as subjects randomized to 
NS-018.  Each ECG measurement will be performed 2 hours (±10 minutes) postdose.   
Subjects treated with ruxolitinib will be required to taper off this treatment before initiation of NS-018 at 
Cycle 1 Day 1.  The dose of ruxolitinib should be decreased every 7 days by up to 50% until the smallest 
dose possible has been given for a minimum duration of total tapering period of 14 days.  Ruxolitinib 
should then be stopped 1 day before starting NS-018.  Subjects who are taking 5 mg QD of ruxolitinib as 
standard of care prior to study participation, are already on the lowest dose possible; therefore, tapering is 
not applicable in this case.  If recurrence of MF-related symptoms upon discontinuation of ruxolitinib 
therapy is noted, it is strongly suggested that therapy with ruxolitinib be restarted.  If restart is not 
possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg QD) is recommended.   


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Final Protocol NS-018-201 - Protocol V3.0 
 
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Eligible subjects will receive NS-018 or BAT according to treatment assignment from Cycles 1 to 6 until 
one of the following criteria for disease progression is met: 
1. Increase in spleen volume of ≥15% measured by MRI (or by CT for applicable subjects) from the 
baseline for subjects who are randomized to NS-018 or transitioned to NS-018. 
2. Splenic irradiation or splenectomy. 
3. Leukemic transformation defined by an increase in peripheral blood blast percentage to ≥20% 
that is sustained for at least 8 weeks. 
4. Leukemic transformation defined by bone marrow blast count of ≥20%. 
5. Death. 
Subjects who meet the criteria for increase in spleen volume of >15% measured by MRI (or by CT for 
applicable subjects), leukemic transformation, or have had splenic irradiation will be discontinued from 
the study treatment and will be asked to complete the end of study procedures.  Subjects randomized to 
the BAT arm (ie, subjects already on BAT or ‘supportive care/therapy’ and met all of the following 
criteria may transition to NS-018 treatment.   
 
Subject has completed at least 24 weeks on BAT or had progression of disease prior to Week 24; 
progression must be declared based only on an increase in splenic volume of >15% measured by 
MRI (or by CT for applicable subjects) from baseline. 
 
Subject has not undergone splenic irradiation or splenectomy. 
 
Subject does not meet criteria for leukemic transformation. 
There will be no MF-directed treatment (other than ruxolitinib) for at least 1 week (7 days) prior to 
initiation of NS-018 after completion of BAT.  Changes in the MF-directed treatment should be 
documented.  
Subjects randomized to receive either NS-018 or BAT may continue to receive NS-018 after completion 
of Cycle 6.  In the BAT treatment arm (control group), after subjects have completed treatment with BAT 
at the end of Cycle 6, the Investigator will determine whether subjects should continue BAT treatment 
outside the study (ie, withdrawn from the study) or discontinue BAT and transition to NS-018 at Cycle 7 
Day 1.  During this transition period, subjects treated with ruxolitinib will be required to taper off this 
treatment before initiation of NS-018.  The dose of ruxolitinib should be decreased every 7 days by up to 
50% until the smallest dose possible has been given for a minimum duration for the total tapering period 
of 14 days.  Ruxolitinib should then be stopped 1 day before starting NS-018.  Subjects who are taking 
5 mg QD of ruxolitinib are already on the lowest dose possible; therefore, tapering is not applicable in 
this case.  If recurrence of MF-related symptoms (upon discontinuation of ruxolitinib therapy) is noted, it 
is strongly suggested that therapy with ruxolitinib be restarted.  If restart is not possible, then prompt 
therapy with corticosteroids (eg, prednisone 60 mg QD) is recommended.   
Subjects receiving treatment other than ruxolitinib will undergo a minimum washout period of 1 week (7 
days) prior to start of NS-018 treatment. 
For subjects receiving BAT and transitioning to NS-018 before Cycle 7 Day 1, subjects will be required 
to taper off or washout this treatment before initiation of NS-018 as described above. 


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34 
Subjects may continue to receive treatment with NS-018 until the subject meets the discontinuation 
criteria of study treatment (see Section 7.1 of protocol), or until 3 years (expected) after the first subject is 
enrolled at any of the study centers, whichever comes first.  Dose modification is allowed for subjects 
who experience Grade 4 neutropenia, lymphopenia or bleeding, or Grade 3 or 4 non-hematologic AEs 
(see Section 6.6 of protocol).   
Visits for subjects in South Korea, UK, and Germany are detailed in a separate schedule of assessments 
(SoA) in Appendix 15, Appendix 16, and Appendix 17, respectively. 
Number of Investigators and Study Centers: 
A total of 65 Investigators and study centers in multiple countries are expected to participate in this study.  
Additional study centers may be added to support enrollment. 
Number of Subjects: 
A total of 120 subjects are expected to be enrolled and randomized 1:1 to either of the following treatment 
arms:  
 
NS-018 
 
BAT 
See Section 9.2 of the protocol. 
Treatment Groups and Duration: 
Individual subject participation will depend upon the ability to tolerate the treatment regimen and upon 
the time to a progression event mandating study withdrawal. 
The screening period is 28 days before start of treatment.  During screening, all subjects will be evaluated 
for active tuberculosis.  Additionally, inactive (latent) tuberculosis testing will be done in UK and South 
Korea by local laboratory for all subjects.  At Cycle 1 Day 1, before the subject starts study treatment, all 
eligibility criteria including the subject’s status for coronavirus disease 2019 (COVID-19) must be 
reviewed and confirmed.  All subjects will be treated from Cycle 1 Day 1 through the end of the study.  
There will be an indefinite period from Cycle 7 Day 1 until the subject meets the criteria of 
discontinuation of study treatment (see Section 7.1 of protocol), or until 3 years (expected) after the first 
subject is enrolled at any of the study centers, whichever comes first.  All subjects will have a follow-up 
visit within 30 days after study completion or early termination.  
Statistical Methods: 
Sample size: 
A total of 120 randomized subjects (60 subjects in each treatment arm) is planned.  The sample size 
determination is based on literature. 
Assuming a splenic response rate of 20% in the NS-018 arm and 1% in the BAT arm, there is 93.5% 
power at the final analysis to maintain a type I error rate of 5% (ie, a 2-sided significance level using 
Fisher’s exact test is 5%).  Similarly, assuming a symptom response rate of 33% in the NS-018 arm and 
8% in the BAT arm, the power of the final analysis to maintain a type I error rate of 5% is 91.0%.  
Assuming that there is no correlation between SVR and total symptom score (TSS) reduction, the power 
to reject the null hypothesis for both endpoints is 85.1%. 
 
 


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Final Protocol NS-018-201 - Protocol V3.0 
 
35 
Analysis Populations:  
The intent-to-treat (ITT) population will consist of all randomized subjects. 
The modified intent-to-treat (mITT) population will consist of all randomized subjects who receive at 
least 1 dose of study treatment and have a baseline assessment and at least 1 postbaseline efficacy 
assessment.  Subjects will be analyzed as randomized.  This will be the primary analysis population for 
the evaluation of efficacy. 
The safety (SAF) population will consist of all randomized subjects who receive at least 1 dose of study 
treatment.  For BAT subjects who do not receive therapy, a Cycle 1 Day 1 visit is required to be included 
in the SAF.  Subjects will be analyzed as treated.  This will be the primary analysis population for the 
evaluation of exposure and safety. 
A second safety (SAF2) population will consist of subjects randomized to BAT who complete BAT 
through 6 cycles and go on to receive at least 1 dose of NS-018.  Baseline will consist of the last data 
available prior to initiation of NS-018.  
The PK concentration population will consist of all randomized subjects who receive at least 1 dose of 
study treatment and have at least 1 plasma concentration value for study treatment. 
General Statistical Considerations:  
All statistical tests will be performed at a significance level of 0.05 with no corrections for multiple 
comparisons. 
The first primary endpoint of a proportion of subjects who achieve ≥35% SVR from baseline to Week 24 
will be compared between the NS-018 group and the BAT group using Firth-corrected logistic regression 
model.  Covariates of baseline spleen volume and a history of prior JAK inhibitor treatment will be 
included.  Model-based point estimates for the treatment effects, 95% confidence intervals, and p-values 
will be calculated.  Subjects who do not reach Week 24 will be considered treatment nonresponders 
(ie, did not achieve ≥35% SVR from baseline to Week 24).  No imputations will be made for missing 
data. 
Similar to the analysis of the first primary endpoint, the second primary endpoint of proportion of subjects 
who achieve ≥50% reduction in TSS from baseline to Week 24 as measured by MF-SAF v4.0 and the 
secondary endpoint of proportion of subjects who achieve ≥35% SVR any time up to Week 24 will be 
compared between the NS-018 group and the BAT group using Firth-corrected logistic regression model.  
Covariates of baseline spleen volume and a history of prior JAK inhibitor treatment will be included. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  For each study 
treatment, numbers of treatment-emergent AEs (TEAEs) and incidence rates will be tabulated by 
preferred term and system organ class.  
Treatment-emergent AEs by maximum severity, TEAEs by relationship to study treatment, serious 
adverse events (SAEs), TEAEs leading to death, and TEAEs leading to discontinuation of study treatment 
will be tabulated for each treatment group.  
All central and local laboratory test results, vital signs measurements, electrocardiogram results, physical 
examination, spleen size (by palpation), spleen volume (by MRI) and weight will be summarized for each 
treatment group using descriptive statistics at each visit for raw numbers and change from baseline. 


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Final Protocol NS-018-201 - Protocol V3.0 
 
36 
No interim analysis is planned for efficacy.  The primary efficacy analyses will be conducted after all 
subjects have completed assessments at Week 24 (Cycle 7 Day 1).  A final analysis will be conducted at 
the end of the study.  An additional analysis for futility may also be performed.  The statistical analysis 
plan will describe these analyses in greater detail. 
Independent Data Monitoring Committee (IDMC):  
An IDMC will be set up to oversee safety across the life span of the study and all specifics will be 
captured in the IDMC charter. 
1.2 
Schema 
Figure 1 
Study Schema 
 
Abbreviations: BAT=Best Available Therapy; BID=twice daily.; JAK=Janus kinase; MF=myelofibrosis. 
a Subjects in the control group may receive BAT at doses and schedules selected by the Investigator discretion and 
based on subject’s condition. 
b In the BAT treatment arm (control group), after subjects have completed treatment with BAT including BAT 
‘supportive care/therapy’, at the end of Cycle 6, the Investigator will determine whether subjects should continue 
BAT treatment outside the study or discontinue BAT and transition to NS-018 at Cycle 7 Day 1.  During this 
transition period, subjects must not receive any MF-directed treatment (other than ruxolitinib) for a minimum 
period of 1 week (7 days) prior to start of NS-018 treatment. 


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Final Protocol NS-018-201 - Protocol V3.0 
37
c Subjects treated with ruxolitinib will be required to taper off ruxolitinib before initiation of NS-018.  The dose of 
ruxolitinib should be decreased every 7 days by up to 50% until the smallest dose possible has been given for a 
minimum duration for the total tapering period of 14 days.  Ruxolitinib should then be stopped 1 day before 
starting NS-018.  Subjects who are taking 5 mg once daily (QD) of ruxolitnib, are already on the lowest dose 
possible; therefore, tapering is not applicable in this case.  If recurrence of MF-related symptoms (upon 
discontinuation of ruxolitinib therapy) is noted, it is strongly suggested that therapy with ruxolitinib be restarted. 
If restart is not possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg QD) is recommended. 
d Within 14 days after last dose of study treatment or within 14 days after withdrawal from the study. 
e The planned end of study is the scheduled date when the final subject enrolled completes the 30-day follow-up 
phone call after completion of the end of study procedures. 
f 
Indefinite period from Cycle 7 Day 1 until the subject experiences unacceptable toxicity that precludes any 
further treatment, disease progression, and/or loss of benefit from treatment, at the discretion of the Investigator, 
or until 3 years after the first subject in, whichever comes first. 
Overview of procedures for BAT subjects transitioning to NS-018 is provided below.  Sites in South 
Korea are to follow the SoA provided in Appendix 15.  Sites in UK are to follow the SoA provided 
in Appendix 16.  Sites in Germany are to follow the SoA provided in Appendix 17.  


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Final Protocol NS-018-201 - Protocol V3.0 
 
38 
Additional Assessment Guidance 
The table below clarifies the timing of specific assessment completion. 
 
BAT to NS-018 Before Cycle 7 Day 1 
BAT to NS-018 at Cycle 7 Day 1 
ECG  
Section 8.2.3 
Day 1 and Day 15 of the first cycle, Day 1 
of the second and fourth cycles, and on 
Day 1 of every three cycles thereafter 
 
Additionally for UK only, Day 1 on the 
third cycle predose (within 1 hour) and 1, 
2, and 4 (±10 minutes) hours after 
administration of NS-018 
Cycle 7 Day 1, Cycle 7 Day 15, Cycle 8 
Day 1, Cycle 10 Day 1 and thereafter every 
3 cycles 
 
For UK only, Cycle 9, Day 1 predose 
(within 1 hour) and 1, 2, and 4 (±10 
minutes) hours after administration of NS-
018 
PK 
Section 8.1.5.1 
No sample collection required 
No sample collection required 
MRI 
Section 8.1.2 
Cycle 4 Day 1 (only if subject transitions 
BEFORE Cycle 4 Day 1, if subject 
transitions AT or AFTER Cycle 4 Day 1 
then MRI is not required until Cycle 7 Day 
1)  
Cycle 7 Day 1, Cycle 10 Day 1, and Cycle 
13 Day 1.  
 
Safety Laboratory 
Assessments 
Section 8.2.4 
Day 1 and Day 15 at Cycles 1, 2, 3, 4, 5, 
and 6 of NS-018 and Day 1 of each cycle 
thereafter until the end of the study 
Day 1 and Day 15 at Cycle 7, 8, 9, 10, 11, 
12 and Day 1 of each cycle thereafter until 
end of the study 
 
Subjects in South Korea only, safety laboratory assessments will be performed 
weekly at Cycle 1 on Day 1, Day 8, Day 15, and Day 22, and Cycles 2 through 6 
will be performed on Days 1 and 15, and Day 1 of each cycle thereafter.  
Laboratory visits on Day 8 and Day 22 can be done at a local laboratory. . 
Abbreviations: BAT = best available therapy; C = cycle; C7D1 = Cycle 7 Day 1; D = Day;  
ECG = electrocardiogram; MRI= magnetic resonance imaging; PK = pharmacokinetics; UK = United Kingdom. 
 


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Final Protocol NS-018-201 - Protocol V3.0 
 
39 
1.3 
Global Schedule of Assessments 
All sites unless otherwise specified are to follow the Global SoA (Section 1.3).  Sites in South Korea are to follow the SoA provided in 
Appendix 15.  Sites in United Kingdom (UK) are to follow the SoA provided in Appendix 16.  Sites in Germany are to follow the SoA 
provided in Appendix 17.   
Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 
to  
Day 0 
Day 1 
(Day 1/ 
WK 0) 
Day 15 
(Day 15/ 
WK 2) 
Day 1 
(Day 29/ 
WK 4) 
Day 15 
(Day 43/ 
WK 6) 
Day 1 
(Day 57/ 
WK 8) 
Day 15 
(Day 71/ 
WK 10) 
Day 1 
(Day 85/ 
WK 12) 
Day 15 
(Day 99/ 
WK 14) 
Visit Window 
 
 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
Study Procedure 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Review/confirm eligibility criteria 
X 
X 
 
 
 
 
 
 
 
COVID-19 status verification 
X 
 
 
 
 
 
 
 
 
Genetic substudy informed consent (optional) 
X 
 
 
 
 
 
 
 
 
Medical history 
Xa 
 
 
 
 
 
 
 
 
Physical examination 
Xb 
 
 
Xc 
 
Xc 
 
Xc 
 
MRI/CT (spleen volume measurement) 
Xd 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
ECOG PS 
X 
Xe 
 
 
 
 
 
 
 
Active tuberculosis 
X 
 
 
 
 
 
 
 
 
Clinical laboratoryf 
(by central lab) 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) 
X 
 
 
 
 
 
 
 
 
12-lead ECG  
Xg 
Xg 
Xg 
Xg 
 
 
 
Xg 
 


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Final Protocol NS-018-201 - Protocol V3.0 
 
40 
Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 
to  
Day 0 
Day 1 
(Day 1/ 
WK 0) 
Day 15 
(Day 15/ 
WK 2) 
Day 1 
(Day 29/ 
WK 4) 
Day 15 
(Day 43/ 
WK 6) 
Day 1 
(Day 57/ 
WK 8) 
Day 15 
(Day 71/ 
WK 10) 
Day 1 
(Day 85/ 
WK 12) 
Day 15 
(Day 99/ 
WK 14) 
Visit Window 
 
 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
PK sampling (NS-018 treatment arm only) 
 
X 
 
X 
 
 
 
 
 
Bone marrow assessment 
Xh 
 
 
 
 
 
 
 
 
Response assessment (IWG-MRT and ELN) 
 
 
 
X 
 
X 
 
X 
 
Genetic profiling 
 
Xe 
 
 
 
 
 
 
 
Phospho-STAT3 
(NS-018 treatment arm only) 
 
Xe 
 
X 
 
 
 
 
 
mRNA sequencing 
(NS-018 treatment arm only) 
 
Xe 
 
X 
 
 
 
 
 
MF-SAF v4.0i 
 
 
 
 
 
 
 
 
 
PROMISj 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
Xe 
 
 
 
 
 
 
 
Randomization 
 
Xm 
 
 
 
 
 
 
Dispense study treatment/diary  
 
Xe 
 
X 
 
X 
 
X 
 
Administer study treatment 
(NS-018) 
 
 
 
 
 
 
 
 
 
Administer study treatment 
(BAT)n 
 
 
 
 
 
 
 
 
 
AEs 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies/procedures/medication 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
 


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Final Protocol NS-018-201 - Protocol V3.0 
 
41 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete End-
of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-up 
(Phone 
call)p 
Visit Window 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
± 1 week 
 
± 3 days 
Study procedure 
 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
Review/confirm eligibility criteria 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
Xc  
(Every 3 cycles) 
Xb 
 
MRI/CT (spleen volume measurement) 
 
 
 
 
X 
(Cycles 7, 10, 13) 
Xk 
 
Vital signs 
X 
 
X 
 
X 
X 
 
ECOG PS 
 
 
 
 
 
X 
 
Clinical laboratoryf 
(by central lab) 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (serum) 
 
 
 
 
 
X 
 
12-lead ECG (NS-018 treatment arm only 
at/after C1D1)g 
 
 
 
 
X 
(Every 3 cycles) 
X 
 
PK sampling (NS-018 treatment arm only) 
 
 
 
 
 
 
 
Bone marrow assessment 
 
 
 
 
X  
(Cycles 13; every 12 
cycles thereafter) 
 
 


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Final Protocol NS-018-201 - Protocol V3.0 
 
42 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete End-
of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-up 
(Phone 
call)p 
Visit Window 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
± 1 week 
 
± 3 days 
Response assessment (IWG-MRT and 
ELN) 
 
 
 
 
X  
(Every 3 cycles) 
X 
 
Genetic profiling 
 
 
 
 
 
 
 
Phospho-STAT3 (NS-018 treatment arm 
only) 
 
 
 
 
 
 
 
mRNA sequencing (NS-018 treatment arm 
only) 
 
 
 
 
 
 
 
MF-SAF v4.0i 
 
 
 
 
 
(Up to Cycle 12) 
 
 
PROMISj 
 
 
 
 
 
(Up to Cycle 12) 
 
 
EQ-5D-5L 
 
 
 
 
X  
(Every 6 cycles) 
 
 
Randomizationm 
 
 
 
 
 
 
 
Dispense study treatment/diary 
X 
 
X 
 
X  
(Every 3 cycles) 
 
 
Administer study treatment (NS-018) 
 
 
 
 
 
 
 
Administer study treatment (BAT)n 
 
 
 
 
(Transition to 
NS-018) 
 
 


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Final Protocol NS-018-201 - Protocol V3.0 
 
43 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete End-
of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-up 
(Phone 
call)p 
Visit Window 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
± 1 week 
 
± 3 days 
AE 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies/procedures/ 
medicationq 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AEs=adverse events; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BAT=Best Available Therapy; BUN=blood 
urea nitrogen; COVID-19=coronavirus disease 2019; eCRF=electronic case report form; CT=computed tomography; ECG=electrocardiogram; ECOG PS=Eastern Cooperative 
Oncology Group performance status; ELN=European LeukemiaNet; IWG-MRT=International Working Group for Myelofibrosis Research and Treatment; JAK=Janus 
kinase; LDH=lactate dehydrogenase; mRNA=messenger ribonucleic acid; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; MF=myelofibrosis; MF-
SAF v4.0=Myelofibrosis Symptom Assessment Form version 4.0; MRI=magnetic resonance imaging; mRNA=messenger ribonucleic acid; PK=pharmacokinetics; 
STAT3=signal transducer and activator of transcription 3; PROMIS=Patient-Reported Outcomes Measurement Information System; QD=once daily; STAT3=signal transducer 
and activator of transcription 3; WK=week; WOCBP=women of childbearing potential.  
NOTE: At Cycle 1 Day 1, before the subject starts study treatment, all eligibility criteria including the subject’s COVID-19 status should be reviewed and confirmed.   
NOTE: Verification of COVID-19 status is based on the World Health Organization diagnostic criteria (Public health surveillance for COVID-19.  Interim guidance, 
07 August 2020).  If a subject presents with clinical signs and symptoms consistent with COVID-19 infection, the Investigator should request a test where possible and this 
should be recorded in the AE field of the eCRF. 
a 
Including concomitant medications within 28 days prior to study treatment administration, blood products transfused within 3 months prior to study treatment administration, 
and concurrent baseline conditions. 
b 
Full physical examination including weight and spleen size by clinical assessment (palpation).  At screening, spleen size (palpation) measurement should be done on the same 
day the spleen volume is measured.  If the same day measurement is not feasible, the measurement should be assessed within 14 days prior to the first dose of the study 
treatment. 
c 
Directed physical examination including weight and spleen size by palpation. After transitioning to NS-018, the subjects will have physical examination on Day 1 of first 4 
cycles and thereafter, Day 1 of every 3 cycles. 
d 
Assess spleen volume within 14 days prior to the first dose of the study treatment.  
e 
Predose; may be obtained within 24 hours prior to study treatment administration.  AEs on Cycle 1 Day 1 will also be collected postdose. 


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Final Protocol NS-018-201 - Protocol V3.0 
 
44 
f 
Subjects transitioning from BAT to NS-018 before or at Cycle 7 Day 1 will have safety laboratory assessments performed on Day 1 and 15 of each cycle for 6 cycles.  Safety 
laboratory assessments will continue on Day 1 of the following cycles until the end of the study and will be done by a central laboratory.  Hematology includes erythrocytes, 
MCV, MCH, neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, leukocytes, hemoglobin, and hematocrit.  Serum chemistry includes BUN, LDH, 
creatinine, uric acid, total protein, albumin, glucose, direct bilirubin for screening, total bilirubin (for safety assessment), magnesium, ALP, AST, ALT, chloride, sodium, 
potassium, amylase, and lipase.  Urinalysis includes pH, protein, glucose, ketone, bilirubin, blood, and nitrite. Note: Additional local laboratory assessments may be performed 
per Investigator’s discretion to monitor safety and document AEs as per local standards of care. 
g 
For eligibility determination and centrally read for all subjects; median QTcF must be ≤480 msec.  For screening, Cycles 1 and 2, triplicate central reading, and then from Cycle 
4 onwards, single central reading.  ECG is required at screening for all subjects but only for NS-018 subjects at the remaining study visits.  ECGs for Cycle 1 Day 1: Predose 
(3 time points within 1 hour) and 1, 2, 4, 6, 8 (±10 minutes) hours after administration of NS-018, Cycle 1 Day 15: 2 (±10 minutes) hours after administration of NS-018, 
Cycle 2 Day 1: Predose (within 1 hour) and 1, 2, 4 (±10 minutes) hours after administration of NS-018, and Cycle 4 Day 1 and thereafter every 3 cycles: 2 (±10 minutes) hours 
after administration of NS-018. Subjects transitioning from BAT to NS-018 before or at Cycle 7 Day 1 will have ECG done at Cycle 7 Day 1 and will follow the same visit 
schedule (Cycle 7 Day 15, Cycle 8 Day 1, Cycle 10 Day 1 and thereafter Day 1 of every 3 cycles). 
h 
Within 28 days prior to the first dose of study drug.  However, bone marrow assessment performed within 6 months prior to the first dose can be used as baseline. 
i 
During the screening period, subject will complete the MF-SAF v4.0 assessment daily. The first 7 consecutive days of diary data will be used for eligibility assessment. Subject 
will complete the MF-SAF from Day −7 of Cycle 1 Day 1 to the end of Cycle 6 (Day 168) and the last 7 days in each cycle thereafter until the end of Cycle 12 (Day 336) for 
efficacy assessment. 
j 
The PROMIS questionnaire must be completed daily during the screening period and the last 7 days of each cycle until the end of Cycle 12 (Day 336).  This assessment will be 
performed for all subjects including subjects transitioning from BAT to NS-018. 
k 
If not done within the previous 8 weeks. 
l 
Within 14 days after last dose of study treatment or within 14 days after withdrawal from the study. 
m Randomization can be done within Day −4 so that the subject can start study treatment on the morning of Day 1. 
n 
In the BAT treatment arm (control group), after subjects have completed treatment with BAT at the end of Cycle 6, the Investigator will determine whether subjects should 
continue BAT treatment outside the study or discontinue BAT and transition to NS-018 at Cycle 7 Day 1.  During this transition period, subjects treated with ruxolitinib will be 
required to taper off this treatment before initiation of NS-018.  The dose of ruxolitinib should be decreased every 7 days by up to 50% until the smallest dose possible has been 
given for a minimum duration for the total tapering period of 14 days.  Ruxolitinib should then be stopped 1 day before starting NS-018.  Subjects who are taking 5 mg QD of 
ruxolitinib are already on the lowest dose possible; therefore, tapering is not applicable in this case.  If recurrence of MF-related symptoms (upon discontinuation of ruxolitinib 
therapy) is noted, it is strongly suggested that therapy with ruxolitinib be restarted.  If restart is not possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg 
QD) is recommended.  Subjects receiving treatment other than ruxolitinib will undergo a minimum washout period of 1 week (7 days) prior to start of NS-018 treatment. 
o 
Subjects who discontinue study treatment or withdraw from the study will be asked to complete the end of study procedures within 14 days after the last dose.  If the end of 
study procedures occur at a regular scheduled visit, these procedures may be performed at that time. 
p 
Follow-up phone call will be done 30 (±3) days after the completion of end of study procedures. 
q  Transfusion will be collected 12 weeks prior to Cycle 1 Day 1 and then throughout the study.  


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45 
Additional Assessment Guidance 
The table below clarifies the timing of specific assessment completion. 
 
Assessments 
Time restriction 
 
Predose 
Postdose 
Pharmacokinetics  
(NS-018 treatment arm 
only) 
Within 1 hour 
Cycle 1 Day 1 
0.5, 1, 2, 3, 4, 6, 8 hours (±10 min per time point) 
Cycle 2 Day 1 
0.5, 1, 2, 3, 4, 6, 8 hours (±10 min per time point) 
Vital signs 
Within 3 hours 
Not applicable  
ECOG performance status 
Within 24 hours 
Not applicable 
12-lead ECG (NS-018 
treatment arm only)  
Cycle 1 Day 1  
3 time points within 1 hour (eg, -45, -
30, -15 min) 
Cycle 2 Day 1 
Within 1 hour  
Cycle 1 Day 1 
5 time points: 1, 2, 4, 6, and 8 hours (±10 min per 
time point) 
Cycle 1 Day 15 
2 (±10 min) hours 
Cycle 2 Day 1 
3 time points: 1, 2, and 4 hours (±10 min per time 
point) 
Cycle 4 Day 1 and thereafter every 3 cycles 
2 (±10 min) hours 
Phospho-STAT3  
(NS-018 treatment arm 
only) 
Cycle 1 Day 1 
Within 24 hours 
Cycle 2 Day 1 
Within 1 hour 
Cycle 1 Day 1 
3 hours (±10 min)  
Cycle 2 Day 1 
3 hours (±10 min) 
mRNA sequencing  
(NS-018 treatment arm 
only) 
Cycle 1 Day 1 
Within 24 hours 
Cycle 2 Day 1 
Within 1 hour 
Cycle 1 Day 1 
8 hours (±10 min) 
Abbreviations: ECG=electrocardiogram; ECOG= Eastern Cooperative Oncology Group; min=minutes;  
mRNA=messenger ribonucleic acid sequencing; STAT3=signal transducer and activator of transcription 3. 
 


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Final Protocol NS-018-201 - Protocol V3.0 
 
46 
2.0 INTRODUCTION 
NS-018 (Ilginatinib) is a potent and specific Janus kinase 2 (JAK2) inhibitor which was designed 
and synthesized by Nippon Shinyaku Co., Ltd.  NS-018 is being developed as a therapeutic agent 
for myeloproliferative neoplasm (MPN) including myelofibrosis (MF). 
2.1 
Study Rationale 
A Phase 1/Phase 2, multicenter, dose-escalation, open-label study of NS-018 was conducted in 
subjects with primary myelofibrosis (PMF; defined in Appendix 9), post-polycythemia vera MF 
(PVMF; defined in Appendix 10), or post-essential thrombocythemia MF (ETMF; defined in 
Appendix 11) with 10 dosing cohorts (Study No. NS-018-101 [NCT01423851]).  A total of 
48 evaluable subjects were enrolled in the Phase 1 part of the study.  Sequential cohorts of 3 to 
6 subjects each were treated with escalating doses of NS-018.  Subjects self-administered 
NS-018 orally.  The starting dose of NS-018 was 75 mg daily.  The 10 dosing cohorts were: 
75 mg once daily (QD), 100 mg twice daily (BID), 125 mg QD, 200 mg QD, 200 mg BID, 
250 mg BID, 300 mg QD, 300 mg BID, 400 mg QD, and 400 mg BID.  Subjects were 
continuously treated with NS-018, administered daily therapy in 28-day cycles, until disease 
progression, whenever the product was tolerated.  The 300 mg QD dose was selected for use in 
the Phase 2 part of the study.  A total of 29 evaluable subjects were enrolled in the Phase 2 part 
of the study.  Subjects were continuously treated with NS-018, administered daily therapy in 
28-day cycles, until disease progression, whenever the product was tolerated.   
Responses  
In the Phase 1 part of Study NS-018-101, the best response in palpable spleen size reduction of 
≥50% observed was similar between subjects administered with 300 mg QD and BID, which is 
56% (5/9) and 50% (3/6), respectively.1  
In the Phase 2 part of Study NS-018-101, spleen volume reduction (SVR) was measured by 
magnetic resonance imaging (MRI) or computed tomography (CT) scan.  Only 1 subject had 
≥35% reduction in spleen size volume at Cycle 7 as measured by MRI and a baseline platelet 
count of <50,000/μL. 
Safety findings  
The maximum tolerated dose (MTD) was not reached during the Phase 1 part of 
Study NS-018-101 study; however, the Safety Review Committee (SRC) considered the 400 mg 
QD and BID cohorts not tolerable based on the proportion of drug-related neurological adverse 
events (AEs).  A treatment-emergent AE (TEAE) was reported for all 48 subjects (100%) during 
the study and Grade 3 or 4 TEAEs were reported for 35 of 48 subjects (72.9%).  The most 
frequently reported drug-related TEAEs were dizziness (11 of 48 subjects [22.9%]), anemia 
(10 of 48 subjects [20.8%]), thrombocytopenia (10 of 48 subjects [20.8%]),  


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Final Protocol NS-018-201 - Protocol V3.0 
 
47 
nausea (9 of 48 subjects [18.8%]), and diarrhea (7 of 48 subjects [14.6%]).  The majority of the 
drug-related TEAEs reported were Grade 3 in severity (16 of 48 subjects [33.3%]).  No deaths 
were reported during the study.  Any serious TEAEs were reported for 23 of 48 subjects (47.9%) 
and Grade 3 or 4 serious TEAEs were reported for 19 of 48 subjects (39.6%).  Treatment-
emergent AEs leading to discontinuation of study drug were reported for 14 of 48 subjects 
(29.2%).  There were no apparent dose-related trends in the incidence of TEAE across the 
treatment groups.  The SRC determined that 400 mg QD and BID were not tolerated based on 
the proportion of drug-related neurological AEs.  Dose-limiting toxicities were observed in 2 
subjects: Grade 3 QT prolongation in 1 subject in the 250 mg BID cohort and Grade 3 dizziness 
in 1 subject in the 400 mg BID cohort.  The subject with Grade 3 QT prolongation recovered 
following NS-018 discontinuation.  This was the only case of QT prolongation observed in the 
study.  This was also attributed to the subject’s prior cardiac history and the SRC concluded that 
it did not represent an overall issue for the study.  The most common drug-related hematologic 
events were thrombocytopenia and anemia.  Drug-related Grade 3/4 thrombocytopenia was 
reported for 13% (2/15) and 8% (1/12) in 300 mg QD and 300 mg BID, respectively.  Drug-
related Grade 3/4 anemia was reported for 0% and 17% (2/12) in 300 mg QD and 300 mg BID, 
respectively.  The safety assessment of 300 mg QD showed no clear difference from 300 mg 
BID in terms of drug-related non hematological AEs (gastrointestinal disorders 4/15 [27%] 
versus 6/12 [50%]; nervous system disorders 6/15 [40%] versus 5/12 [42%]), with dizziness and 
nausea the most common toxicities in these classes, respectively.   
In the Phase 2 part of Study NS-018-101, a TEAE was reported for all 29 subjects (100%) during 
the study.  The most frequently reported drug-related TEAEs were diarrhea (34.5%), anemia 
(27.6%), fatigue (24.1%).  The majority of the TEAEs reported were Grade 3 in severity 
(48.3%).  Drug-related Grade 3 anemia and Grade 3 thrombocytopenia were reported for 
21% and 3%, respectively.  No case of Grade 4 TEAE was reported.  A TEAE of Grade 5 in 
severity was reported for 1 of 29 subjects (3.4%). 
Pharmacokinetics 
The pharmacokinetics (PK) parameters of NS-018 were assessed in 43 subjects.  On Day 8, 
maximum plasma concentration (Cmax) was achieved 1 to 3 hours postdosing for all the dose 
cohorts.  Based on Cmax assessments on Day 8, systemic exposure of NS-018 was approximately 
dose proportional.  The half-life of NS-018 was 2 to 4 hours.  There was no evidence of drug 
accumulation as drug exposure was not substantially different between Day 8 and Day 29. 
Based on the efficacy, safety, and PK data of the Phase 1/Phase 2 study (Study No. NS-018-101), 
the 300 mg BID dose of NS-018 will be examined in this Phase 2b, open-label, multicenter, 
randomized, controlled, 2-arm study (Study No. NS-018-201). 


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48 
2.2 
Background 
Myelofibrosis is a BCR-ABL1-negative MPN characterized by bone marrow fibrosis, anemia, 
progressive splenomegaly, extramedullary hematopoiesis (EMH), debilitating constitutional 
symptoms, cachexia, leukemic progression, shortened survival, and compromised quality of life 
(QoL).2, 3, 4  Myelofibrosis may be de novo (PMF) or secondary to polycythemia vera or essential 
thrombocythemia.  Approximately 90% of patients with MF carry mutations in any of the 3 
driver genes: JAK2 in approximately 60% of cases, calreticulin in approximately 20%, and 
myeloproliferative leukemia virus oncogene in approximately 10%.5, 6  Mutant proteins activate 
the JAK/signal transducers and activators of transcription pathway and other pathways 
downstream, leading to myeloproliferation, proinflammatory cytokine expression, and bone 
marrow remodeling.7, 8  
Because MF is associated with a heterogenous clinical phenotype, stratifying patients by 
prognosis can facilitate choice of appropriate treatment and identify candidates for high-risk 
procedures such as transplant.9  The International Prognostic Scoring System (IPSS), used at 
diagnosis, utilizes 5 independent predictors of inferior survival to determine disease risk in 
primary MF: age >65 years, hemoglobin <10 g/dL, white cell count >25 × 109/L, circulating 
blasts ≥1%, and presence of constitutional symptoms.10  The presence of 0, 1, 2, or ≥3 adverse 
features indicates low-, intermediate 1-, intermediate 2-, or high-risk disease, respectively, and 
corresponding median survival times range from approximately 11.3 to 2.3 years.  The Dynamic 
International Prognostic Scoring System (DIPSS) can be used to stratify prognosis at any time 
during the disease course.11  The DIPSS includes the same 5 prognostic factors as the IPSS but 
ascribes greater weight to low hemoglobin (2 points instead of 1); risk scoring is modified 
accordingly, and corresponding median survival estimates for low-, intermediate 1-, 
intermediate 2-, and high-risk diseases range from not reached to 1.5 years (Appendix 12).  The 
subsequent DIPSS-Plus includes 3 additional independent prognostic factors: red blood cell 
(RBC) transfusion dependence, platelet count <100 × 109/L, and unfavorable karyotype.12  
Until 2019, ruxolitinib, a dual JAK1/JAK2 inhibitor that was approved by the United States (US) 
Food and Drug Administration (FDA) in 2011 and by the European Medicines Agency in 2012, 
was the only available drug indicated for treatment of intermediate- and high-risk MF.  Evidence 
suggests there may be a survival benefit with ruxolitinib compared with conventional therapies.  
Patients treated with ruxolitinib frequently experience gradual loss of response, have a 
suboptimal response or develop cytopenias during treatment, resulting in ruxolitinib 
discontinuation within a few months and therefore, a subsequent risk of disease rebound.  In the 
Phase III COMFORT-I and COMFORT-II trials, pooled ruxolitinib discontinuation rates at 
3 and 5 years were approximately 50% and approximately 70%, respectively.  Suboptimal 
ruxolitinib dosing to avoid treatment-related AEs, at least initially, appears to be relatively 
common.13, 14, 15, 16, 17  


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Final Protocol NS-018-201 - Protocol V3.0 
 
49 
Fedratinib is an oral, JAK2 inhibitor with activity against wild-type and mutationally activated 
JAK2 and FMS-like tyrosine kinase 3.18  In August 2019, the US FDA approved fedratinib for 
treatment of adult patients with intermediate-2 or high-risk primary or secondary MF.  The 
National Comprehensive Care Network (NCCN) clinical practice guidelines for treatment of 
MPNs now includes fedratinib as an option for patients with intermediate-2 or high-risk MF with 
platelet count ≥50 × 109/L, used as initial therapy or as second-line therapy for patients 
previously treated with ruxolitinib.19 
Despite the benefits reported with ruxolitinib as the first‑line treatment, a high proportion of 
patients discontinued treatment; the 1-, 2-, and 3-year discontinuation rates are 49%, 71%, and 
86%, respectively.20, 21  For patients who discontinue treatment with ruxolitinib, the median 
overall survival is dismal and ranges from 13 to 16 months.22, 23  There remains a great unmet 
need for patients who are nonresponsive to and have discontinued treatment with a JAK 
inhibitor. 
A detailed description of the chemistry, pharmacology, safety, and key findings of nonclinical 
and clinical studies for NS-018 is provided in the current Investigator’s Brochure (IB). 
2.3 
Benefit/Risk Assessment 
NS-018 is currently being developed as a therapeutic agent for MPN including MF.  NS-018 has 
been shown to have specificity for inhibiting activated JAK2 and is expected to have a wide 
therapeutic range, providing a satisfactory margin of safety between its efficacy and its safety.  
In the Phase 2 part of the Phase 1/Phase 2 study, 15 out of 20 subjects had an SVR of 0% to 50% 
at Cycle 7 since baseline.  One subject who had a baseline platelet count of <50,000/μL, 
achieved ≥35% SVR at Cycle 7.  The available safety data in the Phase 1/Phase 2 study indicate 
an overall acceptable safety and tolerability profile for NS-018.  Based on these data, NS-018 is 
considered to have a positive benefit-risk ratio for the treatment of subjects with MF and with 
platelet count of <50,000/μL.   
Treatment with specific therapy such as the JAK inhibitor, ruxolitinib, was observed in minority 
of patients with platelets below 100,000/µL, which is in line with previous reports.  Although 
there are case reports and series in which JAK inhibitors have been used successfully with 
improvement of platelet count,24, 25 JAK inhibitors are not recommended for patients with severe 
thrombocytopenia according to the NCCN clinical practice guidelines for treatment of MPNs.  
The management of severe thrombocytopenia remains unresolved, and future studies focused on 
patients with low platelets are deeply needed, to extend their extremely limited treatment 
armamentarium.  Several reports showed additional significant negative impact of severe 
thrombocytopenia (<50,000/µL) on prognosis of these patients,26, 27 but little is known about the 
impact of severe thrombocytopenia on the outcome of patients with PMF versus post-PVMF 
versus post-ETMF.  The fact that 1 subject with a baseline platelet count of <50,000/μL achieved 
≥35% SVR at Cycle 7 of the NS-018 clinical study as well as the current clinical situation 


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described above, it would be worth considering that NS-018 may have a positive benefit-risk 
ratio for the treatment of subjects with MF with platelet count of <50,000/μL. 
See Section 4.0 for details of study procedures, dose, and study design justification. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of NS-018 may be found in the IB.  




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Table 1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
 
Improvement in hemoglobin level without 
transfusion at Weeks 24 
 
To explore changes in the expression profile of 
mRNA by NS-018 versus baseline assessment 
 
Change of mRNA expressions by using mRNA 
sequencing 
 
To evaluate the splenic response and the effect on 
improvement of MF-associated symptoms and 
fatigue up to Week 48 
 
Improvement in splenic response, MF-associated 
symptoms and fatigue up to Week 48 by NS-018 
 
To evaluate the splenic response and the effect on 
improvement of MF-associated symptoms and 
fatigue after transitioning from BAT to NS-018 
 
Improvement in splenic response, MF-associated 
symptoms and fatigue by NS-018 after 
transitioning from BAT to NS-018 
Abbreviations: BAT=Best Available Therapy; BID=twice daily; CR=complete response; CT=computed 
tomography; ETMF=essential thrombocythemia myelofibrosis; F-SF = Fatigue Short Form; mRNA=messenger 
ribonucleic acid; IWG-MRT=International Working Group for Myelofibrosis Research and Treatment; 
MF=myelofibrosis; MF-SAF v4.0=Myelofibrosis Symptom Assessment Form version 4.0; MRI=magnetic 
resonance imaging; PD=progressive disease; PMF=primary myelofibrosis; PR=partial response; PROMIS = 
Patient-Reported Outcomes Measurement Information System; PVMF=polycythemia vera MF; QoL=quality of 
life; RBC=red blood cell; SD=stable disease.  


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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2b, open-label, multicenter, randomized, controlled, 2-arm study in subjects with 
PMF (Appendix 9), post-PVMF (Appendix 10), or post-ETMF (Appendix 11) to compare the 
efficacy and safety of NS-018 versus best available therapy (BAT).  Subjects will be stratified at 
baseline by spleen volume, and by history of prior JAK inhibitor treatment, and randomized to 
receive either NS-018 or BAT (control group).  The stratification factors will be as follows: 
1) spleen volume 
; 2) JAK inhibitor (naïve versus prior 
treatment).  There will be no MF-directed treatment (other than JAK inhibitor) for at least 
2 weeks prior to initiation of NS-018 or BAT.  A total of 120 subjects are expected to be enrolled 
and randomized 1:1 to either NS-018 or BAT. 
The population for this study includes male and female subjects who are 18 years of age or older 
with PMF, post-PVMF, or post-ETMF with severe thrombocytopenia (platelet count 
<50,000/µL), including subjects with DIPSS intermediate-2 or high-risk MF, and who require 
therapy.  Subjects must have a spleen volume of at least 450 cm3 measured by MRI (or by CT for 
applicable subjects) and have an Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤2 (Appendix 13) at study entry (screening).  Subjects may or may not have received 
prior therapy for MF including JAK inhibitor. 
Individual subject participation in the study will depend upon the ability to tolerate the treatment 
regimen and upon the time to a progression event mandating study withdrawal. 
The screening period is 28 days before start of treatment.  During screening, all subjects will be 
evaluated for active tuberculosis (except in UK).  Additionally, inactive (latent) tuberculosis 
testing will be done in UK and South Korea by local laboratory for all subjects.  At Cycle 1 Day 
1, before the subject starts study treatment, all eligibility criteria including the subject’s status for 
coronavirus disease 2019 (COVID-19) should be reviewed and confirmed.  All subjects will be 
treated from Cycle 1 Day 1 through the end of the study.  There will be an indefinite period from 
Cycle 7 Day 1 until the subject meets the criteria for the discontinuation of study treatment (see 
Section 7.1), or until 3 years (expected) after the first subject in, whichever comes first.  Subjects 
who complete the treatment period will complete the end of study procedures within 14 days 
after the last dose.   
Subjects who discontinue prior to completing the treatment period will be asked to complete the 
end of study procedures within 14 days after the last dose (see Schedule of Assessments [SoA], 
Section 1.3).  For sites in South Korea, UK, and Germany, see SoA in Appendix 15,  
Appendix 16, and Appendix 17, respectively. 
If the end of study procedures occurs at a regular scheduled visit, these procedures may be 
performed at that time.  


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A 30-day follow-up phone call will be scheduled after completion of the end of study 
procedures. 
NS-018 Dosage and Mode of Administration 
NS-018 will be self-administered orally at a dose of 300 mg BID.  The BAT will be administered 
according to product label and the Investigator’s discretion. 
Best Available Therapy Dosage 
The Investigator will decide the BAT that will be administered to the subject during the 
screening period based on subject’s condition.  The BAT must be one of the following: 
hydroxyurea, danazol, fedratinib, ruxolitinib, interferon, corticoid, erythropoietin, purinethol, 
thalidomide, lenalidomide or ‘supportive care/therapy’.  The BAT should be administered 
according to the manufacturer’s instructions or the Investigator’s discretion.  The BAT 
‘supportive care/therapy’, refers to use of blood products, fluids (crystalloids), pain medications, 
and/or antibiotics, that subjects will need to manage myelofibrosis symptoms and complications.  
Subjects in the control group will receive BAT at doses and schedules selected by the 
Investigator based on the subject’s condition and according to the manufacturer’s instructions or 
the Investigator’s discretion.  The BAT must be a single agent and cannot be combined with 
other agents.  JAK inhibitor can be allowed as BAT if the JAK inhibitor was administered as a 
standard of care based on the product label or Investigator’s discretion. The BAT may be 
changed at any time during the randomized treatment period based on the Investigator’s clinical 
assessment of the subject’s condition. However, it is not allowed to change the BAT to JAK 
inhibitor if it was not used as standard of care treatment prior to study participation.  No 
experimental agents (ie, those not approved for any indication) may be used at any time. 
Genetic Substudy 
In this study, DNA/RNA testing will be conducted.  In DNA testing, mutated genes are detected.  
The main purpose of DNA testing is to investigate a relationship between clinical benefit and 
genetic background.  In RNA testing, an expression of mRNAs is measured.  The main purpose 
of RNA testing is to investigate a more precise mechanism of action of NS-018 and/or explore 
currently unknown underlying pathophysiology of MPNs with special reference to treatment.  
This genetic substudy will be conducted after subjects have signed an optional genetic substudy 
consent form. 
Study Visits 
Subjects will have regular scheduled study visits at screening, Day 1 and Day 15 of 
Cycles 1, 2, 3, 4, 5, and 6, and Day 1 of every cycle thereafter.  One cycle is 28 days. Subjects 
transitioning from BAT to NS-018 before or at Cycle 7 Day 1 will have safety laboratory 
assessments performed on Day 1 and Day 15 of each cycle for 6 cycles.  Safety laboratory 
assessments will continue on Day 1 of the following cycles until the end of the study and will be 


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done by a central laboratory (refer to Appendix 17 SoA for further details).  Additional local 
laboratory assessments may be performed per the Investigator’s discretion to monitor safety and 
document AEs as per local standards of care.     
Subjects in South Korea only, safety laboratory assessments will be performed weekly at Cycle 1 
on Day 1, Day 8, Day 15, and Day 22, and Cycles 2 through 6 will be performed on Days 1 and 
15, and Day 1 of each cycle thereafter.   For subjects who transition to NS-018, safety laboratory 
assessments will be performed on Day 1 and Day 15 of each cycle for the first 6 cycles after 
transitioning to NS-018 (including the additional visits on Day 8 and Day 22 of the first cycle 
after transitioning).  Laboratory visits on Day 8 and Day 22  of Cycle 1 for subjects randomized 
to NS-018 or Cycle 1 after transitioning to NS-018 in subjects who transition to NS-018 will be 
performed at the institutional local laboratory (refer to Appendix 15 for further details).  
Subjects who transition from BAT to NS-018 will have a physical examination done on Day 1 of 
each cycle for the first 4 cycles after transitioning to NS-018 and on Day 1 of every three cycles 
thereafter, as subjects are transitioned to NS-018.  Vital signs will be done on Day 1 of each 
cycle after transitioning to NS-018.  Vital signs will be taken within 3 hours before transitioning 
to NS-018.  ECG will be done on Day 1 and Day 15 of the first cycle and on Day 1 of the second 
and fourth cycles after transitioning to NS-018, and on Day 1 of every 3 cycles thereafter as 
subjects randomized to NS-018.  Each ECG measurement will be performed 2 hours 
(±10 minutes) postdose (refer to Section 8.2.3 and Appendix 16 for further details for UK).   
Subjects treated with ruxolitinib will be required to taper off ruxolitinib before initiation of NS-
018 at Cycle 1 Day 1.  The dose of ruxolitinib should be decreased every 7 days by up to 50% 
until the smallest dose possible has been given for a minimum duration of total tapering period of 
14 days.  Ruxolitinib should then be stopped 1 day before starting NS-018.  Subjects who are 
taking 5 mg QD of ruxolinitb, are already on the lowest dose possible, therefore, tapering is not 
applicable in this case.  If recurrence of MF-related symptoms (upon discontinuation of 
ruxolitinib therapy) is noted, it is strongly suggested that therapy with ruxolitinib be restarted.  If 
restart is not possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg QD) is 
recommended. 
Eligible subjects will receive NS-018 or BAT according to treatment assignment from Cycles 1 
to 6 until one of the following criteria for disease progression is met: 
1. Increase in spleen volume of ≥15% measured by MRI (or by CT for applicable subjects) 
from the baseline for subjects who are randomized to NS-018 or transitioned to NS-018. 
2. Splenic irradiation or splenectomy. 
3. Leukemic transformation defined by an increase in peripheral blood blast percentage to 
≥20% that is sustained for at least 8 weeks. 
4. Leukemic transformation defined by bone marrow blast count of ≥20%. 
5. Death. 


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Subjects who meet the criteria for increase in spleen volume of ≥15% measured by MRI (or by 
CT for applicable subjects), leukemic transformation, or have had splenic irradiation will be 
discontinued from the study treatment and will be asked to complete the end of study procedures.  
Subjects randomized to the BAT arm (ie, subjects already on BAT or ‘supportive care/therapy’ 
and met all of the following criteria may transition to NS-018 treatment.   
 Subject has completed at least 24 weeks on BAT or had progression of disease prior to 
Week 24; progression must be declared based only on an increase in splenic volume of 
>15% measured by MRI (or by CT for applicable subjects) from baseline. 
 Subject has not undergone splenic irradiation or splenectomy. 
 Subject does not meet criteria for leukemic transformation. 
There will be no MF-directed treatment (other than ruxolitinib) for at least 1 week (7 days) prior 
to initiation of NS-018 after completion of BAT.  Changes in the MF-directed treatment should 
be documented.  
Subjects randomized to receive either NS-018 or BAT may continue to receive NS-018 after 
completion of Cycle 6.  In the BAT treatment arm (control group), after subjects have completed 
treatment with BAT at the end of Cycle 6, the Investigator will determine whether subjects 
should continue BAT treatment outside the study (ie, withdrawn from the study) or discontinue 
BAT and transition to NS-018 at Cycle 7 Day 1.  During this transition period, subjects treated 
with a ruxolitinib will be required to taper off this treatment before initiation of NS-018.  The 
dose of ruxolitinib should be decreased every 7 days by up to 50% until the smallest dose 
possible has been given for a minimum duration for the total tapering period of 14 days.  
Ruxolitinib should then be stopped 1 day before starting NS-018.  Subjects who are taking 5 mg 
QD of ruxolitinib, ruxolitinib, are already on the lowest dose possible; therefore, tapering is not 
applicable in this case.  If recurrence of MF-related symptoms (upon discontinuation of 
ruxolitinib therapy) is noted, it is strongly suggested that therapy with ruxolitinib be restarted.  If 
restart is not possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg QD) is 
recommended. 
Subjects receiving treatment other than ruxolitinib will undergo a minimum washout period of 1 
week (7 days) prior to start of NS-018 treatment.   
For subjects receiving BAT and transitioning to NS-018 before Cycle 7 Day 1, subjects will be 
required to taper off or washout this treatment before initiation of NS-018 as described above. 
Subjects may continue to receive treatment with NS-018 until the subject meets the criteria for 
discontinuation of study treatment (see Section 7.1), or until 3 years (expected) after the first 
subject is enrolled at any of the study centers, whichever comes first. 


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Visits for subjects in South Korea, UK, and Germany are detailed in a separate schedule of 
assessments (SoA) in Appendix 15, Appendix 16, and Appendix 17, respectively. 
4.2 
Scientific Rationale for Study Design 
This is a Phase 2b, open-label, multicenter, randomized, controlled, 2-arm study.  It will compare 
the efficacy and safety of NS-018 versus BAT in subjects with thrombocytopenia and primary 
MF, post-PVMF or post-ETMF.  A total of 120 eligible subjects are expected to be randomized 
in a 1:1 ratio to 1 of the 2 treatment arms. 
The NCCN clinical practice guidelines (2022 version 1.0) for treatment of MPNs recommends 
participating in clinical trial for patients with platelet counts of <50,000/μL.  In this study, both 
JAK inhibitor-naïve patients and patients who were previously treated with JAK inhibitor can be 
enrolled.  It is highly possible that symptoms and conditions differ very much among patients.  
Therefore, the BAT as comparator would be appropriate because the physician can select a 
treatment according to the subject’s disease status.    
4.3 
Justification for Dose 
The Maximum Tolerated Dose was not reached during the Phase 1 part of the NS-018-101 study; 
however, the Safety Review Committee considered the 400 mg QD and BID cohorts not 
tolerable based on the proportion of drug-related neurological AEs.  Therefore, 300 mg BID is 
the maximum dose which can be administrated. 
In the Phase 1 part of study NS-018-101, the best response in palpable spleen size reduction of 
≥50% observed was similar between subjects administered with 300 mg QD and BID, which is 
56% (5/9) and 50% (3/6), respectively.  However, based on the balance of efficacy and safety 
results in the Phase 1 part, the 300 mg QD dose was selected as the dose for the Phase 2 part of 
study NS-018-101.  
In the Phase 2 part of the study, SVR was measured by MRI or CT scan.  There were no safety 
concerns in subjects administered with 300 mg QD, however, only 1 subject with a baseline 
platelet count of <50,000/μL achieved ≥35% reduction in spleen size volume as measured by 
MRI at Cycle 7.  
The clinical diagnosis of splenomegaly is defined as the organ palpable below the costal margin 
during physical examination.  However, the recognition of the spleen enlargement by means of 
imaging methods such as MRI or CT was proven to be more accurate and reliable and was used 
to measure ≥35% SVR as primary end point in pivotal study for other JAK2 inhibitors 
(ruxolitinib, fedratinib, and pacritinib).  Based on this information, the best response in palpable 
spleen size reduction of ≥50% observed was similar between 300 mg QD and BID, which could 
have shown measurable differences with the use of MRI or CT scans.  In the Phase 2 part, it was 
observed that subjects with higher area under the plasma concentration-time curve (AUC) 


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obtained higher efficacy in terms of SVR and an improvement of symptoms.  This means that if 
SVR is measured by MRI/CT in the Phase 1 part, 300 mg BID might have had better efficacy 
data than 300 mg QD.  
Based on the efficacy, safety, and PK data of the Phase 1/Phase 2 study NS-018-101, 300 mg 
BID dose of NS-018 was determined for use in this Phase 2b study NS-018-201.  In case a dose 
reduction, dose interruption or dose re-escalation is necessary, the study treatment will be 
administered as described in Section 6.6. 
4.4 
End of Study Definition 
The planned end of study is defined as the scheduled date when the last subject enrolled 
completes the 30-day follow-up phone call after the completion of the end of study procedures.   
The total length of the study, from screening of the first subject to the 30-day follow-up phone 
call of the last subject, is expected to be 3 years. 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Able to provide written informed consent prior to enrollment into the study. 
2. Males and females ≥18 years of age. 
3. Primary MF, post-PVMF or post-ETMF according to the DIPSS risk categories of 
intermediate-2 or high-risk MF (see Appendix 12). 
4. Spleen volume of at least 450 cm3 measured by MRI (or by CT for applicable subjects).  
This baseline scan will be centrally reviewed for spleen volume. 
5. Total symptom score (TSS) ≥10 on MF-SAF v4.0.  The TSS from the first 7 consecutive 
days of entry through the screening period will be used for eligibility.  
6. Platelet count < 50,000/µL.  Two results taken at least 7 days apart during screening are 
needed.  Each result must be <50,000/µL. 
7. No MF-directed treatment (other than ruxolitinib) for at least 2 weeks prior to initiation 
of NS-018, including erythropoietic, thrombopoietic agent, or any use of corticosteroids 
for MF symptom or blood count management.  Low dose corticosteroids <10 mg/day 
prednisone or equivalent is allowed for non-MF purposes.  Subjects treated with 
ruxolitinib will be required to taper off ruxolitinib before initiation of NS-018 at Cycle 1 
Day 1.  The dose of ruxolitinib should be decreased every 7 days by up to 50% until the 
smallest dose possible has been given for a minimum duration for the total tapering 
period of 14 days.  Ruxolitinib should then be stopped 1 day before starting NS-018.  
Subjects who are taking 5 mg QD of ruxolitinib are already on the lowest dose possible; 
therefore, tapering is not applicable in this case.  If recurrence of MF-related symptoms 
(upon discontinuation of ruxolitinib therapy) is noted, it is strongly suggested that therapy 
with ruxolitinib be restarted.  If restart is not possible, then prompt therapy with 
corticosteroids (eg, prednisone 60 mg QD) is recommended.   
Subjects who are not benefitting from ruxolitinib treatment may be enrolled in the study 
per the Investigator’s discretion. 
8. ECOG performance status ≤2. 
9. QTcF ≤480 msec. 
10. Peripheral blood blast count <10%. 
11. Estimated creatinine clearance ≥40 mL/min/1.73 m2 calculated using the Cockcroft and 
Gault equation. 
12. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit 
of normal (ULN) and a direct bilirubin ≤1.5 × ULN. 
13. Absolute neutrophil count >500/μL. 


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14. Negative serum pregnancy test within 7 days prior to the first dose of study drug (if 
subject is a female of childbearing potential). 
15. No treatment with any investigational agent within 28 days or five times the half-life of 
the drug prior to initiation of NS-018, whichever is longer (not shorter).  COVID-19 
vaccines that are commercially available or approved by local regulatory authorities and 
are administered outside of an investigational clinical study are not considered as 
investigational agents (see Section 6.5). 
16. Male or non-pregnant, non-lactating female subjects.  Male and female subjects who are 
fertile and their partners must agree to use 2 highly effective methods of contraception 
from screening through 180 days (for male subjects with partners who are women of 
childbearing potential [WOCBP], pregnant or breast feeding) and 180 days (for females) 
following discontinuation of study treatment as outlined in Appendix 6. 
For Germany and UK Only: 
Male or non-pregnant, non-lactating female subjects.  Male and female subjects who are 
fertile and their partners must agree to use 2 highly effective methods of contraception 
from screening through 180 days for male subjects with partners who are WOCBP), 
pregnant or breast feeding) and 180 days for females following discontinuation of study 
treatment as outlined in Appendix 7. 
 
Male subjects should not father a child during treatment and for 180 days 
thereafter. 
 
Female partners must use highly effective contraceptive methods for 180 days 
thereafter. 
Additionally, monthly pregnancy tests should be performed for WOCBP.  The serum 
pregnancy test should not be older than 72 hours before taking the first dose. 
17. Life expectancy >6 months. 
5.2 
Exclusion Criteria 
Subjects are excluded from study participation if any of the following criteria apply: 
1. Active, uncontrolled systemic infection including active tuberculosis.  Inactive (latent) 
tuberculosis infection testing will be done for UK and South Korea only. 
2. Any prior treatment with more than 2 JAK inhibitors.  Subjects with any contraindication 
to BAT (see the product label) are excluded. 
3. Subjects receiving any clinical benefits from JAK inhibitor per the Investigator’s 
discretion. 
4. Previous treatment with NS-018.  Subjects with hypersensitivity to NS-018, any excipient 
of NS-018 tablets and to any JAK2 inhibitor will be excluded from study participation. 
5. Subjects actively receiving a concurrent investigational agent. 


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6. Subjects with any unresolved AE greater than Grade 1 other than hematological AEs 
from previous anticancer therapy. 
7. Potentially curative therapy is available: 
 
Candidates for hematopoietic stem cell transplant in which transplant is an 
available and viable option and of higher priority than this study are excluded. 
 
If the subject has declined hematopoietic stem cell transplant, has no donor for 
transplant, or in the judgment of the Investigator is not suitable for transplant, 
the subject may be enrolled. 
8. Currently taking medication that is substantially metabolized by cytochrome P450 (CYP) 
1A2 or CYP3A4 (see Appendix 5) or taking medication known to be strong inhibitors or 
inducers of CYP3A4 (see Appendix 5).  
9. Pregnancy or lactation. 
10. Radiation therapy for splenomegaly within 6 months prior to study entry (screening). 
11. History of splenectomy or planning to undergo splenectomy. 
12. Known HIV positive status. 
13. Known active hepatitis, or a history of viral hepatitis B or hepatitis C. 
14. Subjects with a serious cardiac condition within the past 6 months such as uncontrolled 
arrhythmias, myocardial infarction, angina, or heart disease as defined by the New York 
Heart Association Class III or IV. 
15. Subjects diagnosed with another malignancy within 2 years prior to an enrollment.  
Subjects with prior malignancies must have completed all treatments with no recurrence 
within 2 years to an enrollment.  Subjects with an early stage squamous cell carcinoma of 
the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia may be 
eligible for participation at the Investigator’s discretion. 
16. Subjects who have had surgery (other than placement of vascular access and bone 
marrow biopsy) within 4 weeks of study entry (screening), or subjects with incomplete 
recovery from any prior surgical procedures. 
17. Other concurrent disease and/or medical condition including cardiac condition, which, in 
the judgment of the Investigator, would prevent the subject’s participation. 
18. Unwilling or unable to comply with the protocol. 
19. Subjects with suspected (case definition A or B), probable, or confirmed diagnosis of 
COVID-19 based on the World Health Organization diagnostic criteria (Table 2). 


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Table 2 
World Health Organization COVID-19 Case Definition Criteria 
Suspected 
A. A person who meets the clinical AND epidemiological criteria:  
Clinical criteria:  
1. Acute onset of fever AND cough; 
OR  
2. Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, 
cough, general weakness/fatiguea, headache, myalgia, sore throat, coryza, dyspnea, 
anorexia/nausea/vomiting, diarrhea, altered mental status.  
AND  
Epidemiologic criteria:  
1. Residing or working in an area with high risk of transmission of the virus: for example, 
closed residential settings and humanitarian settings, such as camp and camp-like settings for 
displaced persons, any time within the 14 days prior to symptom onset;  
OR  
2. Residing in or travel to an area with community transmissionb anytime within the 14 days 
prior to symptom onset;  
OR  
3. Working in health setting, including within health facilities and within households, 
anytime within the 14 days prior to symptom onset.  
B. A patient with severe acute respiratory illness (acute respiratory infection with history of 
fever or measured fever of ≥38°C; and cough; with onset within the last 10 days; and who 
requires hospitalization). 
Probable 
A. A patient who meets clinical criteria above AND is a contact of a probable or confirmed 
case, or epidemiologically linked to a cluster of cases which has had at least 1 confirmed case 
identified within that cluster.  
B. A suspected case (described above) with chest imaging showing findings suggestive of 
COVID-19 disease*  
*Typical chest imaging findings suggestive of COVID-19 include the following28:  
•chest radiography: hazy opacities, often rounded in morphology, with peripheral and lower 
lung distribution  
•chest CT: multiple bilateral ground glass opacities, often rounded in morphology, with 
peripheral and lower lung distribution  
•lung ultrasound: thickened pleural lines, B lines (multifocal, discrete, or confluent), 
consolidative patterns with or without air bronchograms.  
C. A person with recent onset of anosmia (loss of smell) or ageusia (loss of taste) in the 
absence of any other identified cause.  
D. Death, not otherwise explained, in an adult with respiratory distress preceding death AND 
who was a contact of a probable or confirmed case or epidemiologically linked to a cluster 
which has had at least 1 confirmed case identified within that cluster.   
Confirmed 
A person with laboratory confirmation of COVID-19 infection, irrespective of clinical signs 
and symptoms. 
Source: Public health surveillance for COVID-19.  Interim guidance.  07 August 2020. 
Abbreviations: COVID-19=coronavirus disease 2019; CT = computerized tomography. 
a Signs separated with slash (/) are to be counted as 1 sign. 
b Community transmission: Countries/territories/areas experiencing larger outbreaks of local transmission defined 
through an assessment of factors including, but not limited to: large numbers of cases not linkable to transmission 
chains, large numbers of cases from sentinel lab surveillance or increasing positive tests through sentinel samples 
(routine systematic testing of respiratory samples from established laboratories), multiple unrelated clusters in 
several areas of the country/territory/area. 


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5.3 
Lifestyle Considerations 
No restrictions are required in this study. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to study treatment via the Interactive Web Response System 
(IWRS).  A minimal set of screen failure information is required to ensure transparent reporting 
of screen failure subjects to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened one time.  Rescreened subjects should be given a new screening number  and will 
require re-consenting.  . 






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6.2 
Preparation/Handling/Storage/Accountability 
NS-018 tablets should be stored 
 in a pharmacy or a locked and 
secure storage facility, accessible only to those individuals authorized by the Investigator to 
handle the study treatment. 
BAT storage requirements as described in the product insert(s) should be followed. 
Maintenance of a temperature log is mandatory. 
1. The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only subjects enrolled in the study may receive study treatment and only authorized 
study center staff may supply or administer study treatment.  All study treatments must 
be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the Investigator and authorized study center staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual.  
The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study treatment using the Drug 
Accountability Log.  These logs must be available for inspection at any time.  A Drug 
Accountability Log should also be maintained for the BAT(s) given to the subjects. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is a Phase 2b, open-label, multicenter, randomized, controlled 2-arm study.  If the subject is 
eligible to participate in the study, the subject will be assigned to receive either NS-018 or BAT.  
A total of 120 subjects are expected to be enrolled into the study and randomized in a 1:1 ratio to 
receive either NS-018 or BAT during the treatment period (Cycle 1 to Cycle 6).  Approximately 
60 subjects will be randomized to receive NS-018 and approximately 60 subjects will be 
randomized to receive BAT.   
Randomization will occur centrally by the IWRS.  Randomization will be stratified by spleen 
volume and a history of prior JAK inhibitor treatment (naïve versus prior treatment). 
Spleen volume will be assessed by the central reader who will be blinded to treatment 
assignments.  Details of the central assessments of spleen volume will be described in an 
imaging review charter. 


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6.4 
NS-018 Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed, except as 
defined in Section 6.6.  Any departures from the intended regimen must be recorded in the 
electronic case report form (eCRF). 
Subject compliance will be monitored by assessing the tablet count from each of the dispensed 
bottles and returned at each visit.  Subjects will complete a study treatment dosing diary that will 
document the time of day they took their study treatment.  Tablet counts will be compared by the 
site to the dosing diary to further assess compliance and aid subject education regarding 
compliance.  Documentation on the eCRF will account for subject compliance in each treatment 
arm.  Subjects will be instructed to return any unused study treatment when attending clinic visits 
or if the subject is discontinued before the study is complete. 
Subjects who take <80% of the expected prescribed regimen will be counseled on the importance 
of good compliance to the study dosing regimen.  If compliance is <80% during the first month 
of therapy, the subject will be counseled, remain on study treatment, and will follow the study 
assessment schedule.   
Noncompliance is defined as taking less than 80% (underdose) or more than 100% (overdose) of 
study treatment during any evaluation period (visit to visit).  Both these situations should also be 
considered as protocol deviations. 
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) taken within 14 days of study drug administration will be considered 
a concomitant medication.  The site will also enter the subject’s prior therapies for MF.  Subjects 
taking medications chronically should be maintained on the same dose and dosing schedule, if 
medically feasible.  The product label of comparator therapies must be consulted and followed 
regarding concomitant therapies. 
Necessary supportive measures for optimal medical care will be given throughout the study, 
including intravenous antibiotics to treat infections, blood components, antidiarrheals, and 
antiemetics.  Additional care will be administered as indicated by the treating physician and the 
subject’s medical need.  No concomitant cytotoxic therapy, whether conventional or 
investigational, will be allowed during this study.  All concomitant medications and supportive 
therapy must be recorded on the eCRF along with: 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency. 


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The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.   
A list of excluded medications/therapy is provided in Appendix 5. 
Routine prophylactic use of growth factors (granulocyte colony-stimulating factor, granulocyte 
macrophage-colony stimulating factor, and erythropoietin) or high dose steroids (>10 mg/day of 
prednisone or prednisone equivalent) is not permitted.  Therapeutic use should be considered at 
the treating physician’s discretion in subjects who develop complications secondary to 
cytopenias (eg, overt sepsis).  This should be discussed with the Medical Monitor, if at all 
possible, and documented.   
Blood products can be administered as needed.  
The potential for drugs which are metabolized by CYP enzymes to be affected by NS-018 is 
considered possible.  The plasma concentration of these drugs may increase or decrease when 
administered concomitantly with NS-018. 
Subjects currently taking medication that is substantially metabolized by CYP1A2 or CYP3A4 
(see Appendix 5) are not eligible for this study.  Every effort should be made to change these 
medications to acceptable alternatives to allow subject enrollment. 
Subjects taking strong CYP3A4 inducers or strong CYP3A4 inhibitors (see Appendix 5) who 
cannot be safely switched to an acceptable alternative are excluded from the study. 
Use of moderate or weak CYP3A4 inducers or moderate or weak CYP3A4 inhibitors (see 
Appendix 5) is discouraged (alternative therapies should be considered) during the study, but 
does not disqualify the subject from study participation and does not require dose modification. 
No other drugs that directly treat MF are allowed during this study.  No other investigational 
agents and anticancer agents are permitted while on study.  Herbal medications should be 
discontinued and not initiated while participating in the study. 
Live vaccines are not allowed within 30 days prior to the first dose of study treatment and while 
participating in the study.  In case of other type of vaccines, the subject must consult with the 
Investigator before vaccination.  Non-live COVID-19 vaccines can be used according to the local 
vaccination requirements and recommendations when considered appropriate by the Investigator.  
Any vaccines should be recorded in the eCRF as a concomitant medication, including 
manufacturer, brand name, lot number if available, doses administered (first dose, second dose, 
etc.) with administration dates. 


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6.6 
Dose Modification 
Subjects who present the following drug-related AEs must have study treatment interrupted and 
a dose reduction should be considered according to Table 4: 
 Grade 4 neutropenia 
 Grade 4 lymphopenia 
 Grade 4 thrombocytopenia with active bleeding 
 Grade 3 or 4 non-hematologic AEs except for nausea, vomiting and/or diarrhea adequately 
controlled with standard systemic medications (per “Management of non-hematologic AEs”).  
Additional information about AE grades (Common Terminology Criteria for AEs [CTCAE] 
version 5.0) is provided in Appendix 4.   
Study treatment administration may be interrupted for clinically significant AEs of ≥Grade 1 that 
do not meet the interruption criteria, at the discretion of the Investigator.  Once the AE has 
resolved to Grade 0 or 1, or to baseline level within 4 weeks of study drug interruption, the study 
treatment may be resumed at 1 dose level below.  
Subjects requiring a >4-week interruption in study treatment administration should be 
permanently discontinued from study participation.   
If a dose reduction is necessary, the study treatment will be administered as follows (Table 4): 
Table 4 
Study Treatment Administration in Case of Dose Reduction 
Starting dose 
300 mg BID 
Dose level −1 
200 mg BID 
Dose level −2 
100 mg BID 
Abbreviations: BID=twice daily. 
Dose reduction would be to the next lower dose level.  If the subject has been receiving starting 
dose, the next dose level will be level −1.  If the subject has already been receiving 200 mg BID, 
the next dose level will be level −2.  Further dose reductions are not allowed. 
Dose re-escalation is permitted upon resolution to ≤Grade 1 AEs, except for hematological AEs, 
if deemed appropriate by the Investigator and following discussion with the medical monitoring 
team and Sponsor.  In case of hematological AEs, dose re-escalation is determined by the 
Investigator and Medical Monitor. 
Dose delays or modifications for BAT should occur per Investigator’s discretion in accordance 
to approved prescribing information or institutional guidelines. 


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Management of non-hematologic AEs 
Grade 3 or Grade 4 non-hematologic AEs will require dose interruption or dose reduction per the 
above guidance.  For Grade 3 nausea, vomiting, and/or diarrhea should receive optimal treatment 
with antiemetics or antidiarrheals and persist for at least 72 hours despite the use of an optimal 
antiemetic or antidiarrheal regimen before being considered an AE requiring treatment 
interruption.  The optimal antiemetic regimen is to be determined by each Investigator and 
should at a minimum include a 5-hydroxytrptamine (5-HT3) antagonist (also called serotonin 
receptor antagonists or serotonin blockers).  The optimal antidiarrheal regimen is to be 
determined by each Investigator and should at a minimum include Imodium® (loperamide 
hydrochloride) or Lomotil® (diphenoxylate hydrochloride and atropine sulfate). 
Management of hematologic AEs 
NS-018 should be held for Grade 4 neutropenia, lymphopenia, or bleeding.  Treatment should be 
held until hematologic AE has resolved to baseline level within 4 weeks of study treatment 
interruption, or in a case of Grade 4 thrombocytopenia with active bleeding, until 1 week after 
the resolution of a bleed.  Upon restart, it is additionally recommended to reduce the dose 
according to Table 4.  If the treatment is interrupted for >4 weeks for recovery of hematologic 
toxicities, subjects will be permanently discontinued from the study.   
Blood products can be used as needed.  Use of growth factors (granulocyte colony-stimulating 
factor, granulocyte macrophage-colony stimulating factor, and erythropoietin) is not permitted. 
6.7 
Treatment after the End of the Study 
The Sponsor will evaluate the appropriateness of continuing to provide the study treatment to 
subjects who are benefiting from treatment.  Based on the benefit-risk profile, if the development 
of this investigational study treatment has not been discontinued and if not yet commercially 
available, post-study access may be provided in compliance with local regulations. 


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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Treatment 
Subjects will be permanently discontinued from the study under the following circumstances: 
 Clinical progression as determined by Investigator including but not limited to the following 
events as described in Section 4.1: 
 Leukemic transformation defined by an increase in peripheral blood blast percentage 
to ≥20% that is sustained for at least 8 weeks 
 Leukemic transformation defined by bone marrow blast count of ≥20% 
 Subject’s physician considers a change of therapy would be in the best interest of the subject 
 Death 
 Continued unacceptable AEs despite optimal treatment or dose reduction (see Section 6.6) 
 Need for any treatment not allowed by the protocol 
 Noncompliance with study treatment and/or study procedures, as judged by the Investigator 
and/or Sponsor (eg, failure to return for scheduled visits, failure to complete study 
assessments, failure to return study treatment, etc.) 
 Subjects requiring >4-week interruption in study treatment administration 
 Increase in spleen volume of ≥15% measured by MRI (or by CT for applicable subjects) 
from the baseline for subjects who are randomized to NS-018 or transitioned to NS-018. 
Subjects who are discontinued from study participation will be asked to undergo the end of study 
procedures within 14 days after the last dose of study treatment.  If the end of study procedures 
occurs at a regular scheduled visit, these procedures may be performed at that time.  Subjects 
who are discontinued will also be asked to undergo a 30-day follow-up phone call after 
completion of the end of study procedures (see SoA, Section 1.3).  If a subject who does not 
meet enrollment criteria is inadvertently enrolled, that subject must be discontinued from study 
treatment and the Sponsor/designee must be contacted immediately.  An exception may be 
granted in rare circumstances for which there is a compelling safety reason to allow the subject 
to continue.  In these rare cases, the Investigator must obtain documented approval from the 
Sponsor/designee to allow the subject to continue in the study. 
Subjects who discontinue study treatment will not be replaced. 
7.2 
Subject Withdrawal from the Study 
Subjects will be withdrawn from the study under the following circumstances: 
 Withdrawal of consent 


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 Noncompliance with study treatment and/or study procedures, as judged by the Investigator 
and/or Sponsor (eg, failure to return for scheduled visits, failure to complete study 
assessments, failure to return study treatment, etc.) 
 Female subjects who become pregnant during the study or who fail to use adequate birth 
control if applicable (refer to pregnancy section) 
 Sponsor decision to terminate study. 
Subjects who are withdrawn will be asked to undergo the end of study procedures within 14 days 
after withdrawal from the study.  If the end of study procedures occurs at a regular scheduled 
visit, these procedures may be performed at that time.  Subjects who are withdrawn from the 
study will also be asked to undergo a 30-day follow-up phone call after the completion of the end 
of study procedures (see SoA, Section 1.3).  For subjects who withdraw their consent, the end of 
study procedures and/or the 30-day follow-up phone call will not be performed.  
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.  If a subject withdraws 
from the study, the subject may request destruction of any samples taken and not tested, and the 
Investigator must document this in the study center study records. 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study center.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
 The study center must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
 Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods).  
These contact attempts should be documented in the subject’s medical record. 
 Should the subject continue to be unreachable, the subject will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up whenever possible.  
7.4 
Procedures for Discontinuation in Relation to COVID-19 
If a subject is diagnosed with COVID-19 or is suspected to have COVID-19 and an AE/SAE is 
reported (see Section 8.3.8), the Investigator should determine whether the subject’s study 
treatment should continue, be temporarily discontinued or permanently discontinued.   


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Subject safety is paramount, and the Investigator should continue to reassess the risk/benefit of 
continued study involvement for each subject.  
If a subject is unable to attend on-site visits for undergoing safety-related assessments as shown 
in the SoA (Section 1.3) for physical visits at study centers due to local public health rules, 
subject inability or subject/caregiver decision, the subject must be temporarily discontinued from 
study treatment, unless the safety-related assessments can be performed at the subject’s home by 
delegated study center staff. 
Such temporary discontinuation of study treatment does not mean discontinuation of follow-up.  
In case it is not possible to perform on-site visits, the study center staff should keep in close 
contact with the subject to maintain awareness of their status and on-site visits should be 
replaced by telephone contacts following the same procedures as detailed in the SoA 
(Section 1.3) for telephone visits. 
If a subject is temporarily discontinued from study treatment, every effort should be made to 
have the subject/caregiver return all unused study treatment and empty bottles to the study center 
and study center staff should perform accountability as described in Section 6.2. 
If this is not possible: 
 Subjects should be clearly instructed that, in case of any tablets leftover in bottles already 
dispensed to them, they are not allowed to take the study treatment if they are not visiting the 
study center. 
 Remaining study treatment should be returned during the first possible on-site visit. 
 Reasons for not returning the study treatment and instructions given to the subject should be 
thoroughly documented. 
According to the local public health rules and recommendations, as soon as the subject is able to 
undergo study protocol procedures, then the study treatment can be dispensed and treatment 
restarted. 
If a study center is impacted by COVID-19 in a way that results in an inability to perform study 
activities, the study monitor should be informed as soon as possible. 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Subjects will have regular scheduled study visits at screening, Day 1 and Day 15 of 
Cycles 1, 2, 3, 4, 5, and 6, and Day 1 of every cycle thereafter (see SoA, Section 1.3).  One cycle 
is 28 days.  
Subjects transitioning from BAT to NS-018 before or at Cycle 7 Day 1 will have safety 
laboratory assessments performed on Day 1 and Day 15 of each cycle for 6 cycles.  Safety 
laboratory assessments will continue on Day 1 of the following cycles until the end of the study 
and will be done by a central laboratory.  Additional local laboratory assessments may be 
performed per Investigator’s discretion to monitor safety and document AEs as per local 
standards of care.   
For subjects in South Korea only, safety laboratory assessments will be performed weekly at 
Cycle 1 on Day 1, Day 8, Day 15, and Day 22, and Cycles 2 through 6 will be performed on 
Days 1 and 15, and Day 1 of each cycle thereafter.  For subjects who transition to NS-018, safety 
laboratory assessments will be performed on Day 1 and Day 15 of each cycle for the first 6 
cycles after transitioning to NS-018 (including the additional visits on Day 8 and Day 22 of the 
first cycle after transitioning).  Laboratory visits on Day 8 and Day 22 of Cycle 1 for subjects 
randomized to NS-018 or Cycle 1 after transitioning to NS-018 in subjects who transition to NS-
018 will be performed at the institutional local laboratory.  
Subjects who transition from BAT to NS-018 will have a physical examination done on Day 1 of 
each cycle for the first 4 cycles after transitioning to NS-018 and on Day 1 of every three cycles 
thereafter, as subjects are transitioned to NS-018.  Vital signs will be done on Day 1 of each 
cycle after transitioning to NS-108.  Vital signs taken within 3 hours before transitioning to NS-
018. Subjects transitioning from BAT to NS-018 before or at Cycle 7 Day 1 will have ECG
done at Cycle 7 Day 1 and will follow the same visit schedule (Cycle 7 Day 15, Cycle 8 Day 1,
Cycle 10 Day 1 and thereafter Day 1 of every 3 cycles) as subjects randomized to NS-018.  Each
ECG measurement will be performed at 2 hours (±10 minutes) postdose.

At Cycle 1 Day 1, before the subject starts study treatment, all eligibility criteria, including 
the subject’s COVID-19 status, should be reviewed and confirmed.

Study procedures and their timing are summarized in the Global SoA (Section 1.3),  
(Appendix 15), UK SoA (Appendix 16), and Germany SoA (Appendix 17).

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
treatment.

Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.


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 All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.  The Investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will adhere to the clinical guidance of no 
more than 15% over an individual assessment or a weekly/monthly assessment draw.  Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
Visits for subjects in South Korea, UK and Germany are detailed in a separate SoA in  
Appendix 15, Appendix 16, and Appendix 17, respectively. 
8.1 
Efficacy Assessments  
8.1.1 
Treatment Response 
Treatment response will be assessed using the International Working Group for Myelofibrosis 
Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) during the study at 
Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 7 Day 1, and at every 3 cycles thereafter 
(Day 1) (see SoA, Section 1.3).  The criteria are provided in Appendix 14. 
8.1.2 
Spleen Volume Assessment 
Magnetic resonance imaging is the imaging modality of choice for the measurement of spleen 
volume.  Subjects who have contraindications to MRI or subjects at sites where MRI is not 
available will be evaluated with CT scans.  Both MRI and CT scans will be performed without 
injection of contrast material.  Consistent imaging, ie, the same modality (MRI or CT) and the 
same technique must be used for a given individual subject throughout the study unless a new 
contraindication develops (such as claustrophobia) or the availability for the originally selected 
method is no longer possible.  Spleen volume will be assessed by limited central readers who 
will be blinded to treatment assignments and centrally adjudicated.  The full details of the central 
assessments of spleen volume will be described in an imaging review charter. 
Spleen volume will be assessed by MRI (CT scan for subjects not able to tolerate MRI) in all 
randomized subjects.  Spleen size measurement will be done at baseline (screening), Cycle 4 
Day 1, Cycle 7 Day 1, Cycle 10 Day 1 and Cycle 13 Day 1.  Details regarding the MRI/CT 
protocol will be provided in the Study Reference Manual.   
Subjects transitioning to NS-018 from BAT at Cycle 7 Day 1 will also have spleen volume 
measurement by MRI at Cycle 7 Day 1, Cycle 10 Day 1, and Cycle 13 Day 1.  
Subjects transitioning to NS-018 from BAT before Cycle 7 Day 1 (see Section 4.1, Study Visits) 
will have spleen volume measurement by MRI at Cycle 4 Day 1 per schedule. 


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8.1.3 
Bone Marrow Assessment 
Bone marrow assessment will be performed in subjects who are randomized to either NS-018 or 
BAT treatment arm.  Bone marrow will be assessed by aspiration and biopsy, according to 
standard practice at the site at baseline (screening), Cycle 13 Day 1 and at every 12 cycles 
thereafter.  Bone marrow assessment performed within 6 months prior to the first dose can be 
used as baseline  
8.1.4 
Myelofibrosis Symptom Assessment Form 
Myelofibrosis is a highly symptomatic MPN and causes both splenomegaly-related and 
constitutional symptoms.29  In addition to reducing spleen size, relieving symptom severity is a 
key objective of the treatment of MF.   
The MF-SAF v4.0 assesses the severity of 7 core symptoms of myelofibrosis: fatigue, night 
sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and 
bone pain.  The MF-SAF v4.0 asks respondents to report symptom severity at its worst for each 
of the 7 items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale.  The MF-SAF v4.0 
is scored as a unidimensional scale to create a TSS.  The TSS for the 24-hour recall (ie, daily 
diary) format is calculated as the sum of the 7 individual item responses on the 0 to 10 scale for a 
possible TSS range of 0 to 70.   
The 24-hour recall (ie, daily diary) format will be used in this study.  The 24-hour recall (daily 
diary) format asks subjects to rate the severity of each symptom at its worst during the past 
24 hours (Table 5). 
Table 5 
Items of Myelofibrosis Symptom Assessment Form v4.0 Diary 
1. During the past 24 hours, how severe was your worst fatigue (weariness, tiredness)? 
2. During the past 24 hours, how severe were your worst night sweats (or feeling hot or flushed)? 
3. During the past 24 hours, how severe was your worst itching? 
4. During the past 24 hours, how severe was your worst abdominal discomfort (feeling pressure or 
bloating)? 
5. During the past 24 hours, how severe was the worst pain under your ribs on your left side? 
6. During the past 24 hours, what was the worst feeling of fullness you had after beginning to eat? 
7. During the past 24 hours, how severe was your worst bone pain (not joint or arthritis pain)? 
 
During the screening period, subjects will complete the MF-SAF v4.0 assessment daily. The first 
7 consecutive days of diary data will be used for eligibility assessment.  Subjects will complete 
the MF-SAF daily from Day −7 of Cycle 1 Day 1 to the end of Cycle 6 (Day 168) and the last 7 
days in each cycle thereafter until the end of Cycle 12 (Day 336) for efficacy assessment.  


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The MF-SAF v4.0 is designed for electronic data collection by the subject and the electronic 
version will be used in this study.   
8.1.5 
Pharmacokinetics and Pharmacodynamics Assessments 
The PK/pharmacodynamic assessments will be performed in subjects who are randomized to 
NS-018 only.  Instructions for the processing, handling, and shipment of samples for central 
analysis will be provided in the Study Reference Manual. 
8.1.5.1 
Pharmacokinetics Assessments 
Blood samples will be obtained for PK assessments to analyze NS-018 and its metabolite, 
MPD-6007.  The intended time points are specified below for the study (see SoA, Section 1.3).  
Blood samples will be collected from subjects assigned to the NS-018 arm (60 subjects) during 
the randomized phase of the study at Cycles 1 and 2. 
 Cycle 1 Day 1: Predose (within 1 hour) and 0.5, 1, 2, 3, 4, 6, and 8 hours (±10 minutes per 
time point) after administration of NS-018. 
 Cycle 2 Day 1: Predose (within 1 hour) and 0.5, 1, 2, 3, 4, 6, and 8 hours (±10 minutes per 
time point) after administration of NS-018. 
The PK parameters to be estimated include observed Cmax, time to maximum plasma 
concentration (Tmax), AUC, terminal elimination half-life (t1/2), and accumulation ratio (AR). 
8.1.5.2 
Pharmacodynamic Assessments 
8.1.5.2.1 
Phospho-STAT3 Assessments 
The intended time points for phospho-STAT3 assessments are specified below for the study (see 
SoA, Section 1.3). 
 Cycle 1 Day 1: Predose (within 24 hours) and 3 (±10 minutes) hours after administration of 
NS-018. 
 Cycle 2 Day 1: Predose (within 1 hour) and 3 (±10 minutes) hours after administration of 
NS-018. 
Participation in phospho-STAT3 analysis (for NS-018 arm only) is optional and based on the 
site’s capability to process the sample prior to shipment to the central laboratory.   
8.1.5.2.2 
mRNA Sequencing (optional genetic substudy) 
The intended time points for mRNA sequencing are specified below for the study (see SoA, 
Section 1.3). 
 Cycle 1 Day 1: Predose (within 24 hours) and 8 hours (±10 minutes) after administration of 
NS-018. 
 Cycle 2 Day 1: Predose (within 1 hour). 


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8.1.6 
Other Exploratory Assessments 
8.1.6.1 
Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue 
Short Form (F-SF) 7b 
The PROMIS F-SF is a suitable measure of fatigue.  The PROMIS Fatigue item banks assess a 
range of self-reported symptoms, from mild subjective feelings of tiredness to an overwhelming, 
debilitating, and sustained sense of exhaustion that likely decreases one’s ability to execute daily 
activities and function normally in family or social roles.  Fatigue is divided into the experience 
of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and 
social activities.   
The PROMIS F-SF 7b (daily) v1.0 will be used in this study.  The PROMIS 7b daily short form 
measures daily fatigue and asks the subject to evaluate the subject’s fatigue since waking up.   
The electronic version of the questionnaire must be completed daily by the subject during the 
screening period and the last 7 days of each cycle until the end of Cycle 12 (Day 336).30, 31  This 
assessment will be performed as defined in the SoA (Section 1.3) for all subjects including 
subjects transitioning from BAT to NS-018. 
8.1.6.2 
EQ-5D-5L 
The 5-level EQ-5D paper version (EQ-5D-5L; https://euroqol.org/eq-5d-instruments/eq-5d-5l-
about/) consists of 2 pages: the EQ-5D descriptive system and the EuroQoL visual analog scale 
(EQ VAS). 
The descriptive system comprises 5 dimensions: mobility, selfcare, usual activities, 
pain/discomfort, and anxiety/depression.  Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems.  The subject is asked to 
indicate the subject’s health state by ticking the box next to the most appropriate statement in 
each of the five dimensions.  This decision results in a 1-digit number that expresses the level 
selected for that dimension.  The digits for the 5 dimensions can be combined into a 5-digit 
number that describes the subject’s health state. 
The EQ VAS records the subject’s self-rated health on a vertical VAS, where the endpoints are 
labelled “The best health you can imagine” and “The worst health you can imagine.”  The VAS 
can be used as a quantitative measure of health outcome that reflect the subject’s own judgement. 
The EQ-5D-5L should be collected within 24 hours prior to first dose, at Cycle 7 Day 1 and 
every 6 cycles thereafter.  The subject should complete the questionnaire before any other 
scheduled procedures are performed and dosing occurs. 
Note: Every attempt should be made to have the questionnaires completed according to the SoA.  
Given the importance of having a baseline questionnaire as well as a questionnaire at end of 
treatment collected, if the subject discontinues treatment for reasons not due to disease 


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progression, questionnaires should be collected at the end of study visit (see Section 1.3 [SoA] 
for questionnaires to be collected).   
Subjects transitioning from the BAT to NS-018 treatment before Cycle 7 Day 1 will complete 
the EQ-5D-5L within 24 hours prior to administering NS-018, at Cycle 7 Day 1, and every 6 
cycles thereafter. 
8.2 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Physical Examinations 
Full physical examination, including weight and spleen size (by clinical assessment 
[palpation]), will be performed in accordance with the SoA (Section 1.3).   
For UK only, a skin examination will also be conducted as part of the physical examination 
(refer to Appendix 16 for further details). 
At screening, spleen size (palpation) measurement should be done on the same day the spleen 
volume is measured.  If the same day measurement is not feasible, the measurement should be 
assessed within 14 days prior to the first dose of study treatment.  
8.2.2 
Vital Signs 
The following vital signs will be assessed (within 3 hours predose) in accordance with the SoA 
(Section 1.3): 
 Blood pressure (systolic and diastolic [mmHg]) 
 Heart rate (beats per minute) 
 Body temperature (°C) 
 Respiration rate (breaths per minute). 
8.2.3 
Electrocardiograms 
Electrocardiogram  is required for all subjects at screening.  After screening, only subjects 
randomized to NS-018 will have ECGs done at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, 
Cycle 4 Day 1, and Day 1 of every 3 cycles thereafter as detailed below.  
 Cycle 1 Day 1: Predose (3 time points within 1 hour) and 1, 2, 4, 6, 8 (±10 minutes) 
hours after administration of NS-018 
 Cycle 1 Day 15: 2 (±10 minutes) hours after administration of NS-018. 
 Cycle 2 Day 1: Predose (within 1 hour) and 1, 2, 4 (±10 minutes) hours after 
administration of NS-018 
 Cycle 4 Day 1 and thereafter every 3 cycles: 2 (±10 minutes) hours after 
administration of NS-018 


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For UK only, ECGs Cycle 1 Day 1: predose (3 time points within 1 hour) and 1, 2, 4, 6, 8 (±10 
minutes) hours after administration of NS-018, Cycle 1 Day 15: 2 (±10 minutes) hours after 
administration of NS-018, Cycle 2 Day 1: predose (within 1 hour) and 1, 2, 4 (±10 minutes) 
hours after administration of NS-018, Cycle 3 Day 1 predose (within 1 hour) and 1, 2, and 4 
(±10 minutes) hours after administration of NS-018, and Cycle 4 Day 1 and thereafter every 
3 cycles: 2 (±10 minutes) hours after administration of NS-018. NOTE: An additional single 
ECG will be done at Cycle 3 and Cycle 9, Day 1 predose (within 1 hour) and 1, 2, and 4 (±10 
minutes) hours after administration of NS-018 .  Refer to Appendix 16 for UK SoA for 
further details. 
 At screening, ECG will be used for eligibility determination and centrally read for all 
subjects.  Median QTcF must be ≤480 msec. 
 Triplicate (for screening, Cycle 1 and Cycle 2) and single and Cycle 4 and thereafter) 12-lead 
ECG (central read) will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF 
intervals.   
 At each time point at which triplicate ECGs are required, 3 individual ECG tracings should 
be obtained as closely as possible in succession, but no more than 2 minutes apart.  The full 
set of triplicates should be completed in less than 4 minutes. 
When time points for ECG measurements coincide with the time points for PK sampling, 
triplicate ECG collection should take place immediately prior to the collection of the plasma 
sample for PK. 
All ECGs will be read centrally.  If actions are triggered based on local read by the 
Investigator/study center they should be documented in source documents and corresponding 
eCRF sections.  Details regarding the ECG collection and reading will be provided in the Study 
Reference Manual. 
Subjects transitioning from BAT to NS-018 before or at Cycle 7 Day 1 will have ECG done on 
Day 1 and Day 15 of the first cycle of NS-018, Day 1 of the second and fourth cycles, and on 
Day 1 of every three cycles thereafter as subjects randomized to NS-018.  Each ECG 
measurement will be performed at 2 hours (±10 minutes) postdose. 
8.2.4 
Clinical Safety Laboratory Assessments 
Safety laboratory assessments (hematology, chemistry, and urinalysis) will be performed for 
both BAT and NS-018 treatment arms by a central laboratory by means of their established 
methods.  Additional local laboratory assessments may be performed per Investigator’s 
discretion to monitor safety and document AEs as per local standards of care.  Before starting the 
study, the Investigator will supply the Sponsor with a list of the normal ranges and units of 
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Subjects transitioning from BAT to NS-018 will have safety laboratory assessments performed 
on Day 1 and Day 15 of each cycle for 6 cycles.  Safety laboratory assessments will continue on 
Day 1 of the following cycles until the end of the study and will be done by a central laboratory 
(refer to Section 1.3 and Appendix 16 SoA for further details).  Additional local laboratory 
assessments may be performed at the Investigator’s discretion to monitor safety and document 
AEs as per local standards of care.  
Subjects in South Korea only, safety laboratory assessments will be performed weekly at Cycle 1 
on Day 1, Day 8, Day 15, and Day 22, and Cycles 2 through 6 will be performed on Days 1 and 
15, and Day 1 of each cycle thereafter.   For subjects who transition to NS-018, safety laboratory 
assessments will be performed on Day 1 and Day 15 of each cycle for the first 6 cycles after 
transitioning to NS-018 (including the additional visits on Day 8 and Day 22 of the first cycle 
after transitioning).  Laboratory visits on Day 8 and Day 22  of Cycle 1 for subjects randomized 
to NS-018 or Cycle 1 after transitioning to NS-018 in subjects who transition to NS-018 will be 
performed at the institutional local laboratory.  Visits for subjects in South Korea are detailed in 
a separate SoA in Appendix 15.  
 See Appendix 3 for the list of clinical laboratory tests to be performed (refer to the SoA for 
the timing and frequency).  
 The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF.  The 
laboratory reports must be filed with the source documents.  Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the subject’s condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study treatment should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator or Medical Monitor. 
 If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
 All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the laboratory manual and the SoA. 
 If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in subject management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF. 
 
 


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8.3 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4. 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up all 
AEs/SAEs.  All AEs/SAEs, whether related or not, should be followed until resolution or until 
30 days post close of the study. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs, including SAEs, will be collected from the signing of the informed consent form (ICF) 
at the time points specified in the SoA (Section 1.3).  All preexisting medical conditions that are 
present prior to signing the ICF should be documented as part of the medical history. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 4.  The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation.  However, if the Investigator learns of any SAE, including a death, at any time 
after a subject has been discharged from the study, and considers the event to be reasonably 
related to the study treatment or study participation, the Investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4. 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts.  All SAEs, and serious or nonserious AEs of special interest (AESIs 
as defined in Section 8.3.6), will be followed until resolution, stabilization, the event is otherwise 
explained, or the subject is lost to follow-up (as defined in Section 7.3).  Further information on 
follow-up procedures is given in Appendix 4.  Following the 30-day window after last dose of 
study drug, only SAEs and AESIs considered as related/ potentially related to study drug should 
be reported. 


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8.3.4 
Regulatory Reporting Requirements for SAEs 
 Notification by the Investigator to the Sponsor/designee of an SAE within 24 hours is 
essential so that legal obligations and ethical responsibilities towards the safety of subjects 
and the safety of a study treatment under clinical investigation are met.  
 The Sponsor/designee has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The Sponsor/designee will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional Review 
Boards (IRB)/Independent Ethics Committees (IEC), and Investigators. 
 Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor/designee policy 
and forwarded to Investigators as necessary. 
 An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor/designee will 
review and document the review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment.   
The Investigator must follow the pregnancy either to term or termination and will collect data on 
both maternal and fetal outcomes until final outcome (ie, normal, abnormal including abortion).  
Pregnancy alone is not considered an AE. 
If pregnancy is reported, the Investigator should inform the Sponsor/designee within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
Adverse Events of Special Interest 
The AESIs for this study may include bleeding of any grade, cardiac events of any grade, 
non-melanoma skin cancer, opportunistic infections such as herpes zoster, progressive multifocal 
encephalopathy, and tuberculosis.  Any development of tuberculosis will be recorded as an 
AESI. 
The AESIs should be promptly recorded in the eCRF so that the Independent Data Monitoring 
Committee (IDMC) and Medical Monitor are notified.  Such events will be reviewed and 
documented by the IDMC and Medical Monitor to enable consideration of implications for other 
subjects. 


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The AESIs that qualify as SAEs should be reported according to Section 8.3.4 and Appendix 4. 
8.3.7 
Events and/or Disease-related Outcomes Not Qualifying as AEs or SAEs 
Events of progression of the underlying MF and events clearly related to the progression of the 
MF should not be reported as an AE or SAE.  These events will be recorded on the 
corresponding eCRF page in the subject’s eCRF. 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an AE or SAE if it meets the serious criteria:  
 The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual subject.  
OR 
 The Investigator considers that there is a reasonable possibility that the event was related to 
study treatment. 
Other events not considered SAEs for the purpose of this protocol are: 
 Overdose of study drug or concomitant medication unless associated with an SAE.  Note that 
these should be captured as an AE in the corresponding eCRF page. 
 Preplanned or elective hospitalization including social and/or convenience situations. 
 Hospital visits of less than 24 hours of duration which do not result in hospitalization. 
8.3.8 
Procedures in Relation to COVID-19 Infection 
If a subject presents with clinical signs and symptoms consistent with COVID-19 infection, the 
Investigator should request a test where possible and this should be recorded in the AE field of 
the eCRF as follows: 
 If test is positive, record as “COVID-19 confirmed”. 
 If test is negative, record the AE/SAE signs and symptoms and/or other diagnosis. 
 If test is not available and signs and symptoms, as judged by the Investigator, are highly 
suspicious of COVID-19 infection, record as “COVID-19 suspected”. 
If other concurrent diagnoses exist, eg, pneumonia, the Investigator should record as separate 
AEs. 
If an AE/SAE is associated with COVID-19, the Investigator should determine whether the 
subject’s treatment should continue, be temporarily interrupted, or permanently stopped.  Refer 
to Section 7.4 for discontinuation procedures in relation to COVID-19.  
All AE reporting instructions in this section and SAE reporting in Section 8.3 also apply to any 
AE/SAE associated with COVID-19. 


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8.4 
Treatment of Overdose 
For this study, any dose of NS-018 greater than 300 mg BID within a 24-hour time period will be 
considered an overdose.  For BAT, refer to the approved label/package insert for overdose 
information.   
The Sponsor does not recommend a specific treatment for an overdose.  In the event of an 
overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the subject for any AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 2 days). 
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of study 
treatment if possible and requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject. 
8.5 
Pharmacokinetics 
The PK parameters will include: 
Cycle 1 Day 1 
 Cmax  
 Tmax  
 Area under the plasma concentration-time curve (AUC0-24)  
 Terminal elimination phase rate constant (λz)   
 t½ 
 Apparent total body clearance (CL/F) 
 Apparent volume of distribution (Vz/F) 
 Lag time (Tlag) 
Cycle 2 Day 1 
 Cmax  
 Tmax  
 AUC0-24  
 λz  
 t½  
 AR = [AUC0-24] Cycle 2 Day 1/[AUC0-24] Cycle 1 Day 1  
 Average plasma concentration (Cav)  


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 Observed minimum plasma concentration (Cmin)   
 Percentage fluctuation  
 PTF % =100 × (Cmax − Cmin)/Cav 
 CL/F 
 Vz/F 
 Tlag 
 Whole blood samples of approximately 3 mL will be collected from subjects assigned to the 
NS-018 treatment arm only for measurement of plasma concentrations of NS-018 and 
MPD-6007 as specified in the SoA (Section 1.3).  A maximum of 8 samples may be collected 
including sample taken predose and samples taken at 0.5, 1, 2, 3, 4, 6, and 8 hours postdose.  
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor/designee.  The actual date and time (24-hour clock time) of each sample will be 
recorded.  The time and date of study treatment administration and the subject’s most recent 
ingestion of drugs will also be recorded. 
 Samples will be used to evaluate the PK of NS-018 and MPD-6007.  Each plasma sample 
will be divided into 5 aliquots (for 2 primary PK samples and 3 back-up PK samples).  
Analyses of NS-018 and MPD-6007 plasma concentration may also be used to evaluate 
safety, efficacy or PK aspects related to concerns arising during or after the study. 
 Genetic analyses will not be performed on these plasma samples.  Subject confidentiality will 
be maintained.  At visits during which plasma samples for the determination of NS-018 will 
be taken, 1 sample of sufficient volume can be used. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the 
Sponsor/designee and study center study files, but will not constitute a protocol amendment.  The 
IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF. 
If a subject refuses blood collection for PK analysis, this will not be considered a protocol 
violation as the PK analysis is a secondary objective. 
8.6 
Pharmacodynamics 
Venous blood samples will be collected for measurement of phospho-STAT3 assessments, and 
mRNA sequencing at the time points specified in the SoA (Section 1.3).  Details on processes for 
collection and shipment of these samples can be found in the study laboratory manual. 
8.7 
Genetics 
Blood samples for DNA isolation will be collected from subjects who have consented to 
participate in the genetic analysis component of the study.  Sample for genetic testing can be 


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collected at any time prior to first dose at Cycle 1 Day 1.  Participation is optional.  Subjects who 
do not wish to participate in the genetic research may still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject.  Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
See Appendix 7 for information regarding genetic research.  Details on processes for collection 
and shipment and destruction of these samples can be found in the study laboratory manual. 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 
Health Economics/Medical Resource Utilization and Health Economics 
Not applicable. 
 
 


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9.0 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
All statistical tests will be performed at a significance level of 0.05 with no corrections for 
multiple comparisons. 
The first primary endpoint is the proportion of subjects who achieve ≥35% SVR from baseline to 
Week 24 (splenic response).  The null hypothesis (H0) and the alternative hypothesis (HA) are: 
H0: The null hypothesis is that the proportion of subjects who achieve ≥35% SVR from 
baseline to Week 24 in each treatment arm is the same.  
HA: The alternative hypothesis is that the proportion of subjects who achieve ≥35% SVR 
from baseline to Week 24 is different by treatment arm. 
The second primary endpoint is the proportion of subjects who achieve ≥50% reduction in TSS 
from baseline to Week 24 as measured by MF-SAF v4.0. The null hypothesis (H0) and the 
alternative hypothesis (HA) are: 
H0: The null hypothesis is that the proportion of subjects who achieve ≥50% reduction in 
TSS from baseline to Week 24 as measured by MF-SAF v4.0 in each treatment arm is the 
same.  
HA: The alternative hypothesis is that the proportion of subjects who achieve 
≥50% reduction in TSS from baseline to Week 24 as measured by MF-SAF v4.0 is 
different by treatment arm. 
The efficacy of SVR and TSS, as co-primary endpoints, will be confirmed when the null 
hypotheses of SVR and TSS are rejected simultaneously.  
9.2 
Sample Size Determination 
A total of 120 randomized subjects (60 subjects in each treatment arm) is planned.  The sample 
size determination is based on literature.32, 33 
Assuming a splenic response rate of 20% in the NS-018 arm and 1% in the BAT arm, there is 
93.5% power at the final analysis to maintain a type I error rate of 5% (ie, a 2-sided significance 
level using Fisher’s exact test is 5%).  Similarly, assuming a symptom response rate of 33% in 
the NS-018 arm and 8% in the BAT arm, the power of the final analysis to maintain a Type I 
error rate of 5% is 91.0%.  Assuming that there is no correlation between SVR and TSS 
reduction, the power to reject the null hypothesis for both endpoints is 85.1%. 
 
 


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9.3 
Populations for Analyses 
The intent-to-treat (ITT) population will consist of all randomized subjects. 
The modified intent-to-treat (mITT) population will consist of all randomized subjects who 
receive at least 1 dose of study treatment and have a baseline assessment and at least 
1 postbaseline efficacy assessment.  Subjects will be analyzed as randomized.  This will be the 
primary analysis population for the evaluation of efficacy. 
The safety (SAF) population will consist of all randomized subjects who receive at least 1 dose 
of study treatment.  For BAT subjects who do not receive therapy, a Cycle 1 Day 1 visit is 
required to be included in the SAF.  Subjects will be analyzed as treated.  This will be the 
primary analysis population for the evaluation of exposure and safety. 
A second safety (SAF2) population will consist of subjects randomized to BAT who complete 
BAT through 6 cycles and go on to receive at least 1 dose of NS-018.  Baseline will consist of 
the last data available prior to initiation of NS-018. 
The PK concentration population will consist of all randomized subjects who received at least 
1 dose of study treatment and have at least 1 plasma concentration value for study treatment. 
9.4 
Statistical Analyses 
A more technical and detailed description of the statistical methods will be provided in the 
statistical analysis plan (SAP).  The SAP will be developed and finalized before database lock 
and will describe the subject analysis sets to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data.  This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints. 
9.4.1 
Efficacy Analyses 
The primary efficacy analyses will be performed on the mITT population (Table 6).  Efficacy 
data from the SAF2 population will be presented separately.  


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Table 6 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
First Primary 
The first primary endpoint of a proportion of subjects who achieve ≥35% SVR from baseline 
to Week 24 will be compared between the NS-018 group and the BAT group using 
Firth-corrected logistic regression model.  Covariates of baseline spleen volume and a history 
of prior JAK inhibitor treatment will be included.  Model-based point estimates for the 
treatment effects, 95% confidence intervals, and p-values will be calculated.  Subjects who do 
not reach Week 24 will be considered treatment nonresponders (ie, did not achieve 
≥35% SVR from baseline to Week 24).  No imputations will be made for missing data. 
Subgroup analyses may be performed by age, gender, race, stratification factors and other 
baseline characteristics. 
The primary efficacy analyses will be conducted after all subjects have completed 
assessments at Week 24 (Cycle 7 Day 1). 
Second Primary 
Similar to the analysis of the first primary endpoint, the second primary endpoint of 
proportion of subjects who achieve ≥50% reduction in TSS from baseline to Week 24 as 
measured by MF-SAF v4.0 will be compared between the NS-018 group and the BAT group 
using Firth-corrected logistic regression model.  Covariates of baseline spleen volume and a 
history of prior JAK inhibitor treatment will be included. 
Secondary 
Similar to the analysis of the primary endpoint, the secondary endpoint of proportion of 
subjects who achieve ≥35% SVR any time up to Week 24 will be compared between the 
NS-018 group and the BAT group using Firth-corrected logistic regression model.  Covariates 
of baseline spleen volume and a history of prior JAK inhibitor treatment will be included. 
Exploratory 
Will be described in the SAP finalized before database lock. 
Abbreviations: BAT=Best Available Therapy; JAK=Janus kinase; MF-SAF v4.0=Myelofibrosis Symptom 
Assessment Form version 4.0; SAP=statistical analysis plan; SVR=spleen volume reduction; TSS=total symptom 
score. 
The primary estimand is defined as: 
 Population of interest: Subjects with PMF, post-PVMF, or post-ETMF with severe 
thrombocytopenia defined by the inclusion/exclusion criteria. 
 Variables/endpoints of interest:  
 Proportion of subjects who achieve ≥35% SVR from baseline to Week 24. 
 Proportion of subjects who achieve ≥50% reduction in TSS from baseline to Week 24 
as measured by MF-SAF v4.0. 
 Intercurrent event handling strategy: 
 Death due to any cause: Subject death for any cause occurring prior to Week 24 will 
be considered as a non-response for the first and second primary endpoint definitions 
(ie, did not achieve ≥35% SVR from baseline to Week 24 and did not achieve ≥50% 
reduction in TSS from baseline to Week 24, respectively).  
 Prohibited medication: Subjects who take prohibited medication during the study will 
be analyzed by the treatment policy strategy, ie, data collected after the initiation of 
prohibited medications will be included in analysis as collected. 


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 Population-level summary measure:  
 Difference in proportion of subjects achieving ≥35% SVR from baseline to Week 24 
between the NS-018 group and the BAT group will be analyzed as described in 
Table 6. 
 Difference in proportion of subjects who achieve ≥50% reduction in TSS from 
baseline to Week 24 as measured by MF-SAF v4.0 between the NS-018 group and 
the BAT group will be analyzed as described in Table 6. 
The following sensitivity analysis will be planned for the primary estimand: 
 In the mITT population, subjects who experience death prior to Week 24, the last SVR will 
be imputed to Week 24 for the first primary endpoint. 
The following supplementary analysis will be planned for the primary estimand: 
 A per-protocol analysis consisting of all subjects without a major protocol violation that 
might affect the efficacy assessment (criteria will be specified prior to unblinding), following 
the same method as described for the primary estimand. 
Additional sensitivity and supplementary analysis will be explored in the SAP as appropriate. 
A similar intercurrent event handling strategy will be used for estimands related to the second 
primary endpoint of proportion of subjects who achieve ≥50% reduction in TSS from baseline to 
Week 24 as measured by MF-SAF v4.0 and the secondary endpoint of proportion of subjects 
who achieve ≥35% SVR any time up to Week 24. 
9.4.2 
Safety Analyses 
The primary safety analyses will be performed on the SAF population.  Safety data from the 
SAF2 population will be presented separately. 
Adverse Events 
Treatment-emergent AEs are defined as AEs that first occurred or worsened in severity after the 
first administration of study treatment and up to 30 days after the last administration of study 
treatment. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  For each 
study treatment, numbers of TEAEs and incidence rates will be tabulated by preferred term and 
system organ class.  
Treatment-emergent AEs by maximum severity, TEAEs by relationship to study treatment, 
AESIs, SAEs, TEAEs leading to death, and TEAEs leading to discontinuation of study treatment 
will be tabulated for each treatment group.  


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All central and local laboratory test results, vital signs measurements, ECG results, physical 
examination, spleen size (by palpation), spleen volume (by MRI) and weight will be summarized 
for each treatment group using descriptive statistics at each visit for raw numbers and change 
from baseline. 
9.4.3 
Other Analyses 
All analyses, summaries, and listings will be performed using SAS® software (version 9.4 or 
higher).  If not stated otherwise, all efficacy data will be summarized descriptively by treatment 
group and visit. 
The following descriptive statistics will be used as applicable to summarize the study data unless 
otherwise specified: 
 Continuous variables: sample size (n), mean, standard deviation, median, minimum (min), 
and maximum (max). 
 Categorical variables: frequencies and percentages. 
Individual subject data will be presented in listings.   
Pharmacokinetics, pharmacodynamics, and exploratory analyses will be described in the SAP 
finalized before database lock.  The population PK analysis and pharmacodynamic analyses will 
be presented separately from the main clinical study report.  
9.4.3.1 
Pharmacokinetics Analyses 
Blood samples for PK analysis of NS-018 will be collected at the designated study visits.  All PK 
analyses will be based on the PK population. 
Plasma concentrations of NS-018 will be summarized descriptively by time point of collection.  
Summary statistics including number of subjects, arithmetic mean, geometric mean, geometric 
coefficient of variation, coefficient of variation, standard deviation, minimum, maximum, 
median, and standard error of the mean will be presented.  Individual subject and mean plasma 
concentrations of NS-018 will be plotted versus time in linear and log-linear scale. 
Derived PK parameters will be listed and summarized using the same measures as for the plasma 
concentrations of NS-018. 
9.4.3.2 
Pharmacodynamic Analyses 
The pharmacodynamic analysis for phospho-STAT3 will be based on the pharmacodynamic 
population.  Phospho-STAT3 values at each time point and changes from baseline will be 
summarized descriptively and listed.   


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9.4.4 
Missing Data 
Data from subjects who withdraw from the study, including AEs and any follow-up, will be 
included in the analyses of primary and secondary outcomes. 
Sensitivity analyses of the primary endpoints to assess the impact of missing data and any 
imputation methods for secondary efficacy endpoints and partially missing dates will be 
described in the SAP. 
9.5 
Interim Analyses  
No interim analysis is planned for efficacy.  The primary efficacy analyses will be conducted 
after all subjects have completed assessments at Week 24 (Cycle 7 Day 1).  A final analysis will 
be conducted at the end of the study.  An additional analysis for futility may also be performed.  
The SAP will describe these analyses in greater detail. 
9.6 
Independent Data Monitoring Committee 
An IDMC will be set up to oversee safety across the life span of the study and all specifics will 
be captured in the IDMC charter. 


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10.0 REFERENCES 
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study of the JAK2 inhibitor NS-018 in patients with myelofibrosis.  Leukemia.  
2017b;31(2):393-402. 
2. Harrison CN, Schaap N, Vannucchi AM, et al.  Fedratinib in patients with myelofibrosis 
previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using 
stringent criteria for ruxolitinib failure.  Am J Hematol.  2020a;95(6):594-603. 
3. Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and 
management.  Am J Hematol.  2016;91(12):1262-71. 
4. Tefferi A, Cervantes F, Mesa R, et al.  Revised response criteria for myelofibrosis: 
International Working Group-Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) and European LeukemiaNet (ELN) consensus report.  Blood.  
2013;122(8):1395-8. 
5. Shammo JM, Stein BL.  Mutations in MPNs: prognostic implications, window to biology, 
and impact on treatment decisions.  Hematology Am Soc Hematol Educ Program.  
2016:552-60. 
6. Vannucchi AM, Lasho TL, Guglielmelli P, et al.  Mutations and prognosis in primary 
myelofibrosis.  Leukemia.  2013;27(9):1861-9. 
7. Palandri F, Palumbo GA, Iurlo A, et al.  Differences in presenting features, outcome and 
prognostic models in patients with primary myelofibrosis and post-polycythemia vera and/or 
post essential thrombocythemia myelofibrosis treated with ruxolitinib.  New perspective of 
the MYSEC-PM in a large multicenter study.  Semin Hematol.  2018;55(4):248-55. 
8. de Freitas RM, da Costa Maranduba CM.  Myeloproliferative neoplasms and the JAK/STAT 
signaling pathway: an overview.  Rev Bras Hematol Hemoter.  2015;37(5):348-53. 
9. O’Sullivan JM, Harrison CN.  Myelofibrosis: clinicopathologic features, prognosis, and 
management.  Clin Adv Hematol Oncol.  2018;16(2):121-131. 
10. Cervantes F, Dupriez B, Pereira A, et al.  New prognostic scoring system for primary 
myelofibrosis based on a study of the International Working Group for Myelofibrosis 
Research and Treatment.  Blood.  2009;113(13):2895-901. 
11. Passamonti F, Cervantes F, Vannucchi AM, et al.  A dynamic prognostic model to predict 
survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group 
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12. Gangat N, Caramazza D, Vaidya R, et al.  DIPSS plus: a refined Dynamic International 
Prognostic Scoring System for primary myelofibrosis that incorporates prognostic 
information from karyotype, platelet count, and transfusion status.  J Clin Oncol.  
2011;29(4):392-7. 
13. Harrison CN, Schaap N, Mesa RA.  Management of myelofibrosis after ruxolitinib failure.  
Ann Hematol.  2020b;99(6):1177-1191. 
14. Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al.  A pooled analysis of overall survival in 
COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the 
treatment of myeloﬁbrosis.  Haematologica.  2015;100:1139-45. 
15. Verstovsek S, Gotlib J, Mesa RA, et al.  Long-term survival in patients treated with 
ruxolitinib for myeloﬁbrosis: COMFORT-I and -II pooled analyses.  J Hematol Oncol.  
2017a;10:156. 
16. McLornan DP, Harrison CN.  Guidance on changing therapy choice in myeloﬁbrosis.  Blood 
Adv.  2020;4(4):607-610. 
17. Incyte Corporation.  Jakaﬁ® (ruxolitinib) prescribing information.  Wilmington, Delaware: 
Incyte Corporation.  2019. 
18. Celgene Corporation.  U.S.  FDA approves INREBIC (fedratinib) as first new treatment in 
nearly a decade for patients with myelofibrosis. 
19. National Comprehensive Cancer Network.  NCCN Clinical Practice Guidelines in 
Oncology-myeloproliferative neoplasms v3.2020.  Fort Washington, PA, USA: National 
Comprehensive Cancer Network; 2019. 
20. Abdelrahman RA, Begna KH, Al-Kali A, et al. Revised assessment of response and 
long-term discontinuation rates among 111 patients with myelofibrosis treated with 
momelotinib or ruxolitinib.  2015;29(2):498-500.  
https://pubmed.ncbi.nlm.nih.gov/25252872/ 
21. Mascarenhas J, Harrison C, Kiladjian J, et al.  Randomized open-label, Phase 3 study to 
evaluate imetelstat versus Best Available Therapy (BAT) in patients with intermediate-2 or 
high-risk myelofibrosis (MF) refractory to Janus kinase (JAK) inhibitor.  The American 
Society of Hematology.  2020; Abstract #2194. 
22. Kuykendall AT, Shah S, Talati C, et al.  Between a rux and a hard place: evaluating salvage 
treatment and outcomes in myelofibrosis after ruxolitinib discontinuation.  Ann Hematol.  
2018;97(3):435-41. 


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23. Schain F, Vago E, Song C, et al.  Survival outcomes in myelofibrosis patients treated with 
ruxolitinib: A population-based cohort study in Sweden and Norway.  Eur J Haematol.  
2019;103(6):614-19. 
24. Talpaz M, Paquette R, Afrin L, et al.  Interim analysis of safety and efficacy of ruxolitinib in 
patients with myelofibrosis and low platelet counts.  J Hematol & Oncol.  2013;6(1):81. 
25. Bjorn ME, Holmstrom MO, Hasselbalch HC.  Ruxolitinib is manageable in patients with 
myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients.  Leuk 
Lymphoma.  2016;57(1):125-8. 
26. Alhuraiji A, Bose P, Daver N, et al.  Clinical features and outcome of patients with 
poor-prognosis myelofibrosis based on platelet count <50 × 109/L: A single-center 
experience in 1100 myelofibrosis patients.  J Clin Oncol.  2016;(suppl. 15):7068. 
27. Hernandez-Boluda JC, Correa JG, Alvarez-Larran A, et al.  Clinical characteristics, 
prognosis and treatment of myelofibrosis patients with severe thrombocytopenia.  Br J 
Haematol.  2018;181(3):397-400. 
28. Manna S, Wruble J, Maron SZ, et al.  COVID-19: A multimodality review of radiologic 
techniques, clinical utility, and imaging features.  Radio Cardiothoracic Imaging.  
2020;1;2(3). 
29. Gwaltney C, Paty J, Kwitkowski V, et al.  Development of a harmonized patient-reported 
outcome questionnaire to assess myelofibrosis symptoms in clinical trials.  Leukemia Res.  
2017;59:26-31. 
30. Lai J-S, Cella D, Choi S, et al.  How item banks and their application can influence 
measurement practice in rehabilitation medicine: A PROMIS fatigue item bank example.  
Arch Phys Med Rehabil.  2011;S20-S27. 
31. Cessna J, Jim H, Sutton S, et al.  Evaluation of the psychometric properties of the PROMIS 
Cancer Fatigue Short Form with cancer patients.  J Psychosomatic Res.  2016;81:9-13.  
http://dx.doi.org/10.1016/j.jpsychores.2015.12.002. 
32. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including 
ruxolitinib, in patients with myelofibrosis: a randomized clinical trial.  JAMA Oncol.  
2018;4(5):652-59. 
33. Verstovsek S, Mesa R, Talpaz M, et al. Retrospective analysis of pacritinib in patients with 
myelofibrosis and severe thrombocytopenia.  Haematologica.  2021. Epub ahead of print. 


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11.0 APPENDICES 


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Appendix 1 
Abbreviations 
Abbreviation 
Definition 
λz 
terminal elimination phase rate constant 
ADL 
activities of daily living 
AESI 
adverse event of special interest 
AE 
adverse event 
ALT 
alanine aminotransferase 
AR 
accumulation ratio 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from time zero 
to 24 
BAT 
best available therapy 
BID 
twice daily (“bis in die” Latin) 
Cav 
average plasma concentration 
CI 
clinical improvement 
CL/F 
apparent total body clearance 
Cmax 
maximum concentration 
Cmin 
observed minimum plasma concentration 
CR 
complete response 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
eCRF 
electronic case report form 
CT 
computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events  
CYP 
cytochrome P450 
DIPSS 
Dynamic International Prognostic Scoring System 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMH 
extramedullary hematopoiesis 
ELN 
European leukemiaNet 
EQ VAS 
EuroQoL Visual Analog Scale 


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Abbreviation 
Definition 
ETMF 
essential thrombocythemia myelofibrosis 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
F-SF 
fatigue short form 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
mITT 
modified intent-to-treat 
IWG-MRT 
International Working Group for Myelofibrosis Research and 
Treatment 
IWRS 
interactive web response system 
JAK 
Janus kinase 
mRNA 
messenger ribonucleic acid 
MF 
myelofibrosis 
MF-SAF v4.0 
Myelofibrosis Symptom Assessment Form version 4.0 
MPN 
myeloproliferative neoplasm 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Care Network 
PD 
progressive disease 
PK 
pharmacokinetics 
PMF 
primary myelofibrosis 
PR 
partial response 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PVMF 
polycythemia vera myelofibrosis 


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Abbreviation 
Definition 
QD 
once daily 
QoL 
quality of life 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAF 
safety  
SAF2 
second safety 
SAP 
statistical analysis plan 
SoA 
Schedule of Assessments 
SRC 
Safety Review Committee 
STAT3 
signal transducer and activator of transcription (3) 
SUSAR 
suspected unexpected serious adverse reactions 
SVR 
spleen volume reduction 
TEAE 
treatment-emergent adverse event 
Tlag 
lag time 
Tmax 
time to maximum plasma concentration 
T½ 
terminal elimination half-life 
TSS 
total symptom score 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
Terms 
Definition 
BAT ‘supportive 
care/therapy’ 
Refers to use of blood products, fluids (crystalloids), pain 
medications, and/or antibiotics, that subjects will need to 
manage myelofibrosis symptoms and complications. 


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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
 Applicable laws and regulations. 
 The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
 Any amendments to the protocol will require IRB/IEC and regulatory authority approval, 
when applicable, before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to subjects.  
 The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
 Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
 After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 19).  The study will not 
start at any study center at which the Investigator has not signed the protocol. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 


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Insurance 
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects in this study.  The terms of the insurance will be kept in the study files. 
Informed Consent Process 
 The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorized representative and answer all questions regarding the study.  
 Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center.  
 The medical record must include a statement that written informed consent was obtained 
before the subject was entered in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICF. 
 Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
 A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
A subject who is rescreened will be required to sign another ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research.  The Investigator or authorized designee will explain to each 
subject the objectives of the exploratory research.  Subjects will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period.  A separate signature will be required to document a subject’s agreement to allow 
any remaining specimens to be used for exploratory research.  Subjects who decline to 
participate in this optional research will not provide this separate signature. 
Data Protection 
 Subjects will be assigned a unique identifier by the Sponsor/designee.  Any subject records 
or datasets that are transferred to the Sponsor/designee will contain the identifier only; 
subject names or any information which would make the subject identifiable will not be 
transferred.  
 The subject must be informed that his/her personal study-related data will be used by the 
Sponsor/designee in accordance with local data protection law.  The level of disclosure must 
also be explained to the subject.  


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 The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor/designee, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
 The Sponsor/designee or its representative will not provide individual genotype results to 
subjects, any insurance company, any employer, their family members, general physician, or 
any other third party, unless required to do so by law. 
 Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the subject.  In exceptional circumstances, however, certain individuals 
might see both the genetic data and the personal identifiers of a subject.  For example, in the 
case of a medical emergency, the Sponsor/designee or representative physician or an 
Investigator might know a subject’s identity and also have access to his or her genetic data.  
Also, regulatory authorities may require access to the relevant files. 
Administrative Structure 
Table 7 
Study Administrative Structure 
Function 
Responsible Organization 
Study Operations Management 
Medical Monitoring 
IQVIA Biotech 
Study Master File 
IQVIA Biotech 
Randomization Code 
Cenduit: IRT (Interactive Web Response System) 
Data Management 
IQVIA Biotech 
Clinical Supply Management 
Alcura 
Quality Assurance Auditing 
IQVIA Biotech 
Biostatistics 
Medical Writing 
IQVIA Biotech 
Electronic Clinical Outcome Assessment 
Signant Health 
Imaging (Magnetic Resonance Imaging) 
Clario (formerly Bioclinica) 
Laboratory Assessments 
Q2 Solutions 
Electrocardiogram Collection, Review, and Analysis 
Clario (formerly ERT) 
Pharmacokinetic Sample Testing 
Sumika Chemical Analysis 
Safety Monitoring Committee (see Section 9.6) 
IQVIA Biotech 
pSTAT3 Assessment 
Cerba 
mRNA 
Takara-Bio 
 


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Dissemination of Clinical Study Data 
The results of the study should be reported within 1 year from the end of the clinical study.  
Irrespective of the outcome, the Sponsor will submit to the EU database a summary of the results 
of the clinical study within 1 year from the end of the clinical study.  It shall be accompanied by 
a summary written in a manner that is understandable to laypersons. 
Data Quality Assurance 
 All subject data relating to the study will be recorded on printed or eCRFs unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data).  The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the case report form (CRF).  
 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized study center personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.  
 Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 10 years after the last approval of a marketing application 
in an ICH region unless local regulations or institutional policies require a longer retention 
period.  No records may be destroyed during the retention period without the written 
approval of the Sponsor.  No records may be transferred to another location or party without 
written notification to the Sponsor.  
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study center’s subjects.  Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete.  Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (eg, via an audit trail). 
 Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s study center. 
 Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 


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Investigator may need to request previous medical records or transfer records, depending on 
the study.  Also, current medical records must be available. 
 Definition of what constitutes source data can be found in the Clinical Monitoring Plan. 
Study and Study Center Closure 
The Sponsor designee reserves the right to close the study center or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study centers will be closed upon study 
completion.  A study center is considered closed when all required documents and study supplies 
have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but 
are not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines. 
 Inadequate recruitment of subjects by the Investigator. 
 Discontinuation of further study treatment development. 
 Unjustifiable risk and/or toxicity in risk-benefit analysis (decision taken by sponsor 
representative), eg, when adverse events occur, unknown to date in respect of their nature, 
severity, duration or frequency in relation to the current established safety profile (substantial 
changes in risk-benefit considerations), and therefore medical and/or ethical reasons affect 
the continued performance of the study.  
 New scientific evidence becomes available during the study that could affect the subject’s 
safety (benefit-risk analysis no longer positive), eg, new insights from other clinical trials.  
 Request of the sponsor or regulatory agency, eg, as a consequence of inspection.  
 In case of difficulties in the recruitment of the planned number of subjects in the indicated 
time (insufficient recruitment rate). 
 Withdrawal of the license to manufacture. 
Publication Policy 
The data generated by this study are confidential information of the Sponsor.  The Sponsor will 
make the results of the study publicly available.  The publication policy with respect to the 
Investigator and study center will be set forth in the Clinical Trial Agreement. 


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Appendix 3 
Clinical Laboratory Tests  
 The tests detailed in Table 8 will be performed by the central laboratory.   
 For South Korea, the tests detailed in Table 8 will be performed by the central laboratory at 
all timepoints, except for the assessments on Day 8 and Day 22 of the first cycle (or the first 
cycle after transition to NS-018), which will be performed in the local laboratory.   
 For South Korea and UK, the screening test for latent tuberculosis will be performed in the 
institutional local laboratory.  
 Additional local laboratory assessments may be performed per Investigator’s discretion to 
monitor safety and document AEs as per local standards of care. 
 Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5.0 of the protocol. 
 Additional tests may be performed at any time during the study as determined necessary by 
the Investigator, local standard of care, or required by local regulations. 
Table 8 
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
Mean corpuscular volume 
(MCV) 
Mean corpuscular 
hemoglobin (MCH) 
White Blood Cell Count 
with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red Blood Cell (RBC) 
Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Blood Urea 
Nitrogen (BUN) 
Potassium 
Aspartate 
aminotransferase 
(AST)/Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total bilirubin 
 
Creatinine 
Sodium 
Alanine 
aminotransferase 
 (ALT)/Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total protein 
 
Glucose 
(nonfasting) 
Chloride 
Alkaline 
phosphatase 
Lactate 
dehydrogenase 
 
Albumin 
Magnesium 
Amylase 
Lipase 
 
Uric acid 
 
 
 
Routine 
Urinalysisa 
 
Specific gravity 
 
pH, glucose, protein, blood, ketones, bilirubin, nitrite by dipstick 
 
Microscopic examination (if blood or protein is abnormal) 


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Table 8 
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Other Screening 
Tests 
 
Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
 
Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)a 
 
Serology (human immunodeficiency virus [HIV] antibody, hepatitis B surface antigen 
[HBsAg], and hepatitis C virus antibody) 
 
Active tuberculosis and country-specific requirement in South Korea and UK only: 
Inactive (latent) tuberculosis test (local laboratory) 
The results of each test must be entered into the (e)CRF. 
NOTES: 
a Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.   
 


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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
 
An AE is any untoward medical occurrence in a subject, temporally associated with the use of study 
treatment, whether or not considered related to the study treatment. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. 
 
Events Meeting the AE Definition  
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator (ie, not 
related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent preexisting condition including either an increase in frequency 
and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even though it may have been 
present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant 
medication.  Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent.  Such overdoses should be reported regardless of sequelae. 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or 
SAE.  Such instances will be captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE.   
 


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Events NOT Meeting the AE Definition  
 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the subject’s condition. 
 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).  Hospital visits of less than 24 hours of duration which do not result in 
hospitalization. 
 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term ‘life-threatening’ in the definition of “serious” refers to an event in which the subject was at risk of 
death at the time of the event.  It does not refer to an event, which hypothetically might have caused death, if it 
were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline is not 
considered an AE. 
d) Results in persistent disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 


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 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Other situations: 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition.  These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
 


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Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
 
The Investigator will then record all relevant AE/SAE information in the CRF.  Each event must be recorded 
separately. 
 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to 
Sponsor/designee in lieu of completion of the CRF page. 
 
There may be instances when copies of medical records for certain cases are requested by Sponsor/designee.  
In this case, all subject identifiers, with the exception of the subject number, will be redacted on the copies of 
the medical records before submission. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study according to 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf) 
or higher grading scale.  For AEs not covered by National Cancer Institute (NCI) CTCAE, the severity will be 
characterized as mild, moderate, severe, life-threatening, or fatal according to the following definitions: 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.  
 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
Activities of Daily Living (ADL)*.  
 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care ADL**.  
 
Grade 4: Life-threatening consequences; urgent intervention indicated.  
 
Grade 5: Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade.  
A single dash (-) indicates a grade is not available.  
Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 


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Assessment of Causality 
 
The Investigator is obligated to assess the relationship between study treatment and each occurrence of each 
AE/SAE.  The AE must be characterized as unrelated, unlikely to be related, possibly related, probably 
related, or definitely related. 
o 
“Definitely related” conveys the adverse event has a timely relationship to administration of study 
treatment and there is no apparent, potential alternate etiology. 
o 
“Probably related” conveys that there are facts, evidence, and/or arguments to suggest a causal 
relationship, rather than a relationship cannot be ruled out. 
o 
“Possibly related” suggests that the association of the AE with the study treatment is unknown; 
however, the AE is not reasonably supported by other conditions. 
o 
“Unlikely to be related” suggests that only a remote connection exists between the study treatment 
and the AE.  Other conditions, including chronic illness, progression or expression of the disease 
state or reaction to concomitant therapy, appear to explain the reported AE. 
o 
“Unrelated” is used if there is not a reasonable possibility that the study treatment caused the AE.  
 
The Investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study treatment administration will be considered and investigated. 
 
The Investigator will also consult the IB and/or Product Information, for marketed products, in his/her 
assessment. 
 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the AE/SAE 
and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred and the Investigator has minimal information to 
include in the initial report to the Sponsor/designee.  However, it is very important that the Investigator always 
make an assessment of causality for every event before the initial transmission of the SAE data to the 
Sponsor/designee. 
 
The Investigator may change his/her opinion of causality in light of follow-up information and send a SAE 
follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
o 
Events deemed “Unlikely to be related” and “Unrelated” will not be considered a SUSAR for 
regulatory reporting purposes. 
 


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Follow-up of AEs and SAEs 
 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by Sponsor/designee to elucidate the nature and/or causality 
of the AE or SAE as fully as possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 
New or updated information will be recorded in the originally completed CRF. 
 
The Investigator will submit any updated SAE data to the Sponsor/designee within 24 hours of receipt of the 
information. 
 
Reporting of SAEs 
SAE Reporting to Sponsor/designee via an Electronic Data Collection Tool 
 
The primary mechanism for reporting an SAE to Sponsor/designee will be the electronic data collection tool. 
 
If the electronic system is unavailable for more than 24 hours, then the study center will use the paper SAE 
data collection tool (see next section). 
 
The study center will enter the SAE data into the electronic system as soon as it becomes available. 
 
After the study is completed at a given study center, the electronic data collection tool will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a study center receives a report of a new SAE from a subject or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken off-line, then the study center can report 
this information on a paper SAE form (see next section) or to the Medical Monitor/SAE coordinator by 
telephone. 
 
Contacts for SAE reporting can be found in the Investigator Study Binder 
 
SAE Reporting to Sponsor/designee via Paper CRF 
 
E-mail transmission of the SAE paper CRF is the preferred method to transmit this information to 
Sponsor/designee with Facsimile transmission as back-up method. 
 
In rare circumstances and in the absence of e-mail/facsimile equipment, notification by telephone is acceptable 
with a copy of the SAE data collection tool. 
 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the SAE 
CRF pages within the designated reporting time frames. 
 
Contacts for SAE reporting can be found in the Investigator Study Binder.  Submission of paper CRF pages, 
in the event electronic data collection tool is unavailable, should be completed and submitted via e-mail to 
Safety-Inbox.Biotech@IQVIA.com or faxed to +1-919-313-1412. 


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Appendix 5 
Excluded Medications/Therapy 
Excluded medications/therapy is listed below.  The use of an excluded medication/therapy is a 
protocol violation and must be recorded in the eCRF. 
The tables below list many of the medications that are prohibited or cautioned.  See the website 
(http://medicine.iupui.edu/clinpharm/ddis/table.asp) for additional medications that may not be 
listed. 
CYP1A2 and CYP3A4 Substrates 
(Drugs Substantially Metabolized by CYP1A2 or CYP3A4) 
Use of these drugs is prohibited 
CYP1A2 Substrates 
 
amitriptyline 
ondansetron 
excessive caffeine 
phenacetin 
clomipramine 
propranolol 
clozapine 
riluzole 
cyclobenzaprine 
ropivacaine 
duloxetine 
tacrine 
estradiol 
theophylline 
fluvoxamine 
tizanidine 
haloperidol 
triamterene 
imipramine N-DeMe 
verapamil 
mexiletine 
warfarin 
naproxen 
zileuton 
olanzapine 
zolmitriptan 
CYP3A4 Substrates 
Macrolide antibiotics including clarithromycin, erythromycin and telithromycin (not azithromycin) 
Benzodiazepines including alprazolam, diazepam, midazolam, and triazolam 
Immune modulators including cyclosporine and tacrolimus 
Antihistamines including astemizole and chlorpheniramine. 
Calcium channel blockers including amlodipine, diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine, 
nitrendipine, verapamil 
HMG CoA reductase inhibitors (Statins) including atorvastatin, cerivastatin, lovastatin, simvastatin (not 
pravastatin and rosuvastatin) 


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Steroid 6beta-OH including estradiol, hydrocortisone, progesterone, and testosterone 
Miscellaneous: 
alfentanil 
 
 
eplerenone 
 
 
quinidine 
aprepitant 
 
 
fentanyl  
 
 
quinine 
aripiprazole 
 
 
finasteride 
 
 
risperidone 
buspirone 
 
 
haloperidol 
 
 
salmeterol 
cafergot  
 
 
LAAM  
 
 
sildenafil 
excessive caffeine 
 
lidocaine 
 
 
sirolimus 
cilostazol 
 
 
methadone 
 
 
tamoxifen 
cocaine  
 
 
nateglinide 
 
 
trazodone 
codeine N-demethylation  
ondansetron 
 
 
zaleplon 
dexamethasone  
 
pimozide 
 
 
ziprasidone 
dextromethorphan 
 
propranolol 
 
 
zolpidem 
domperidone 
 
 
quetiapine 
 


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CYP3A4 STRONG Inhibitors and Inducers 
Use of these drugs is prohibited 
CYP3A4 Inhibitors 
CYP3A4 Inducers 
clarithromycin  
rifampin 
itraconazole 
St. John's Wort 
ketoconazole 
 
nefazodone 
 
telithromycin 
 
CYP3A4 MODERATE Inhibitors and Inducers 
Use of these drugs is discouraged (alternative therapies should be considered) but does not disqualify subject 
participation in the study. 
CYP3A4 Inhibitors 
CYP3A4 Inducers 
aprepitant 
carbamazepine 
diltiazem 
 phenobarbital 
erythromycin 
phenytoin 
fluconazole 
pioglitazone 
grapefruit juice 
rifabutin 
verapamil 
troglitazone 
 


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Appendix 6 
Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with one of the following: 
a. Documented hysterectomy. 
b. Documented bilateral salpingectomy. 
c. Documented bilateral oophorectomy. 
Note: Documentation can come from the study center personnel’s: review of the subject’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
a. A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT).  However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.  
b. Females on HRT and whose menopausal status is in doubt will be required to use highly 
effective contraception methods if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment. 
Contraception Guidance 
Male subjects 
 Male subjects must refrain from donating sperm for the duration of the study and for 180 
days after study completion or the last dose of study treatment. 
 Male subjects with partners who are WOCBP, pregnant or breastfeeding must agree to 
remain abstinent from penile-vaginal intercourse throughout the study treatment period until 
180 days from last study treatment.  
 Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent. 
 Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant. 


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The following are not acceptable methods of contraception: 
 Periodic abstinence (calendar, symptom-thermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM). 
 Male condom with cap, diaphragm or sponge with spermicide. 
 Male and female condom cannot be used together. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use 2 highly 
effective methods of contraception consistently and correctly as described in the table below.  
Female subjects must use the permitted contraception during the study and for 180 days after the 
last dose of NS-018 or for the duration required by product information of the comparator drug.  
Contraception requirements in the product information of a comparator therapy must be 
followed. 
Highly Effective Contraceptive Methods 
Highly Effective Methods That Are User Independent a  
 
Intrauterine device. 
 
Intrauterine hormone-releasing system (Italy only). 
 
Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional highly effective method 
of contraception should be used.   
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment.  The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.   
NOTES:  
a Failure rate of less than 1% per year.  Typical use failure rates may differ from those when used consistently and 
correctly.  Use should be consistent with local regulations regarding the use of contraceptive methods for 
subjects participating in clinical studies.  
Two highly effective methods of contraception should be utilized during the treatment period and for 180 days (for 
females) and 180 days (for male subjects with partners who are women of childbearing potential [WOCBP], 
pregnant or breast feeding), corresponding to time needed to eliminate study treatments with genotoxic potential 
after the last dose of study treatment.  Hormonal contraception methods are not allowed to be used. 
 
 
 


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Pregnancy Testing: 
 WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test at times specified in the SoA (Section 1.3). 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant  
 The Investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is in this study.  This applies only to 
male subjects who receive study treatment. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor/designee within 24 hours of learning of the partner’s pregnancy.  
The female partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to the Sponsor/designee.  
Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.  
Female subjects who become pregnant  
 The Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study.  Information will be recorded on the appropriate 
form and submitted to the Sponsor/designee within 24 hours of learning of a subject’s 
pregnancy.  The subject will be followed to determine the outcome of the pregnancy.  The 
Investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor.  
 The Investigator must follow the pregnancy either to term or termination and will collect data 
on both maternal and fetal outcomes until final outcome (ie, normal, abnormal including 
abortion).  Pregnancy alone is not considered an AE. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  A spontaneous 
abortion is always considered to be an SAE and will be reported as such. 
 Any post-study pregnancy related SAE considered reasonably related to the study treatment 
by the Investigator will be reported to the Sponsor/designee as described in Section 8.3.4.  
While the Investigator is not obligated to actively seek this information in former subjects, he 
or she may learn of an SAE through spontaneous reporting.  
 Any female subject who becomes pregnant while participating in the study will discontinue 
study treatment or be withdrawn from the study. 
 


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Appendix 7 
Contraceptive Guidance and Collection of Pregnancy 
Information for Germany and United Kingdom 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
a. Documented hysterectomy. 
b. Documented bilateral salpingectomy. 
c. Documented bilateral oophorectomy. 
Note: Documentation can come from the study center personnel’s: review of the subject’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
a. A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT.  However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
b. Females on HRT and whose menopausal status is in doubt will be required to use 2 highly 
effective contraception methods as described in the table below if they wish to continue 
their HRT during the study.  Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Contraception Guidance 
Male subjects 
 In addition, male subjects must refrain from donating sperm for the duration of the study and 
for 180 days after study completion or the last dose of study treatment. 
Male subjects with partners who are WOCBP, pregnant or breastfeeding must agree to 
remain abstinent from penile-vaginal intercourse throughout the study treatment period until 
180 days from last study treatment.  
 
For UK only: Male subjects must use a condom during sexual intercourse with a female 
partner who is WOCBP during the study and for 180 days after the last dose of NS-018 or for 
the duration required by product information of the comparator drug. 
 


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Use a male condom plus partner use of an additional contraceptive method when having penile-
vaginal intercourse with a woman of childbearing potential who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use 2 highly 
effective methods of contraception consistently and correctly as described in the table below.  
Female subjects must use the permitted contraception during the study and for 180 days after the 
last dose of NS-018 or for the duration required by product information of the comparator drug.  
Contraception requirements in the product information of a comparator therapy must be 
followed. 
For UK only, female subjects must use the permitted contraception during the study and for 
180 days after the last dose of NS-018 as per Appendix 7 guidance for females, or for the 
duration required by product information of the comparator drug. 
The following are not acceptable methods of contraception: 
o Periodic abstinence (calendar, symptom-thermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method 
(LAM). 
o Male condom with cap, diaphragm or sponge with spermicide. 
o Male and female condom cannot be used together. 
Highly Effective Contraceptive Methods 
Highly Effective Methods That Are User Independent a  
 
Intrauterine device. 
 
Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional highly effective method 
of contraception should be used.   
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment.  The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.   
NOTES:  
a Failure rate of less than 1% per year.  Typical use failure rates may differ from those when used consistently and 
correctly.  




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Investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor.  
 The Investigator must follow the pregnancy either to term or termination and will collect data 
on both maternal and fetal outcomes until final outcome (ie, normal, abnormal including 
abortion).  Pregnancy alone is not considered an AE. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  A spontaneous 
abortion is always considered to be an SAE and will be reported as such. 
 Any post-study pregnancy related SAE considered reasonably related to the study treatment 
by the Investigator will be reported to the Sponsor/designee as described in Section 8.3.4.  
While the Investigator is not obligated to actively seek this information in former subjects, he 
or she may learn of an SAE through spontaneous reporting.  
Any female subject who becomes pregnant while participating in the study will discontinue 
study treatment or be withdrawn from the study. 
 


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Appendix 8 
Genetics 
Use/Analysis of DNA 
 Genetic variation may impact a subject’s response to study treatment, susceptibility to, and 
severity and progression of disease.  Variable response to study treatment may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting subjects. 
 DNA samples will be used for genetic mutation profiling.  
 The results of genetic mutation profiling may be reported in the clinical study report. 
 The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
 The samples will be discarded once this study is completed. 


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Appendix 9 
Primary Myelofibrosis Definition 
2016 WHO Diagnostic Criteria for PMF 
 
Primary myelofibrosis (PMF)a 
 
Prefibrotic/early PMF (pre-PMF) 
Overt PMF 
Major criteria 
1 
Megakaryocytic proliferation and atypiab, without 
reticulin fibrosis >grade 1c, accompanied by 
increased age-adjusted BM cellularity, granulocytic 
proliferation and often decreased erythropoiesis 
Megakaryocyte proliferation and atypiab 
accompanied by either reticulin and/or collagen 
fibrosis (Grade 2 or 3) 
2 
Not meeting WHO criteria for BCR-ABL1 + CML, 
PV, ET, MDS, or other myeloid neoplasm 
Not meeting WHO criteria for BCR-ABL1 + CML, 
PV, ET, MDS or other myeloid neoplasm 
3 
Presence of JAK2, CALR, or MPL mutation or in the 
absence of these mutations, presence of another 
clonal markerd or absence of minor reactive BM 
reticulin fibrosise 
Presence of JAK2, CALR, or MPL mutation or in the 
absence, the presence of another clonal markerd or 
absence of evidence for reactive BM fibrosisf 
Minor criteria 
1 
Presence of one or more of the following, confirmed 
in two consecutive determinations: 
 
Anemia not attributed to a comorbid 
condition 
 
Leukocytosis ≥11 × 109/L 
 
Palpable splenomegaly 
 
Serum LDH level above the upper limit of 
the institutional reference range 
Presence of one or more of the following confirmed 
in two consecutive determinations: 
 
Anemia not attributed to a comorbid 
condition 
 
Leukocytosis ≥11 × 109/L 
 
Palpable splenomegaly 
 
Serum LDH level above the upper limit of 
the institutional reference range 
 
Leukoerythroblastosis 
Abbreviations: BM=bone marrow; CML=chronic myeloid leukemia; LDH= lactate dehydrogenase; 
MDS=myelodysplastic syndrome; PMF = primary myelofibrosis; WHO=World Health Organization. 
a Diagnosis of prefibrotic/early PMF requires all three major criteria and at least one minor criterion.  Diagnosis of 
overt PMF requires meeting all three major criteria and at least one minor criterion. 
b Small-to-large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly 
folded nuclei and dense clustering. 
c In cases with Grade 1 reticulin fibrosis, the megakaryocyte changes must be accompanied by increased BM 
cellularity, granulocytic proliferation, and often decreased erythropoiesis (that is, pre-PMF). 
d In the absence of any of the three major clonal mutations, the search for the most frequent accompanying 
mutations (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the 
disease. 
e Minor (Grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory 
conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) 
myelopathies. 
f 
BM fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell 
leukemia, or other lymphoid neoplasm, metastatic malignancy or toxic (chronic) myelopathies. 
Source: Barbui T. Thiele J. Gisslinger H, et al.  The 2016 WHO classification and diagnostic criteria for 
myeloproliferative neoplasms: document summary and in-depth discussion.  Blood Cancer Journal.  2018;8:15; 
Arber DA, Orazi A, Hasserjian R, et al.  The 2016 revision to the World Health Organization classification of 
myeloid neoplasm and acute leukemia.  Blood.  2016;127(20):2391-405. 


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Appendix 10 
Post-Polychythemia Vera Myelofibrosis Definition 
2008 IWG-MRT Diagnostic Criteria for post-polycythemia vera myelofibrosis 
Required criteria: 
1. Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria 
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale) or grade 3–4 (on 0–4 scale)a 
Additional criteria (two are required): 
1. Anemiab or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) 
or cytoreductive treatment for erythrocytosis 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm (distance of 
the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly  
4. Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, 
unexplained fever (>37.5°C) 
Abbreviations: IWG-MRT=International Working Group for Myelofibrosis Research and Treatment; WHO=World 
Health Organization. 
a Grade 2–3 according to the European classification: diffuse, often coarse fiber network with no evidence of 
collagenization (negative trichrome stain) or diffuse, coarse fiber network with areas of collagenization (positive 
trichrome stain).  Grade 3–4 according to the standard classification: diffuse and dense increase in reticulin with 
extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse 
and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with 
significant osteosclerosis. 
b Below the reference range for appropriate age, sex, gender and altitude considerations. 
Source: Barosi G, Mesa RA, Thiele J, et al.  Proposed criteria for the diagnosis of pos-polycythemia vera and post-
essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for 
Myelofibrosis Research and Treatment.  Leukemia.  2008;22:437-438. 
 


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Appendix 11 
Post-Essential Thrombocythemia Myelofibrosis Definition 
2008 IWG-MRT Diagnostic Criteria for post-essential thrombocythemia myelofibrosis 
Required criteria: 
1. Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria 
2. Bone marrow fibrosis Grade 2–3 (on 0–3 scale) or grade 3–4 (on 0–4 scale)a 
Additional criteria (two are required): 
1. Anemiab and a ≥2 mg/mL decrease from baseline hemoglobin level 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm (distance of 
the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly 
4. Increased LDH (above reference level)  
5. Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, 
unexplained fever (>37.5°C) 
Abbreviations: IWG-MRT=International Working Group for Myelofibrosis Research and Treatment; LDH=lactate 
dehydrogenase; WHO=World Health Organization. 
a Grade 2–3 according to the European classification: diffuse, often coarse fiber network with no evidence of 
collagenization (negative trichrome stain) or diffuse, coarse fiber network with areas of collagenization (positive 
trichrome stain).  Grade 3–4 according to the standard classification: diffuse and dense increase in reticulin with 
extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse 
and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with 
significant osteosclerosis. 
b Below the reference range for appropriate age, sex, gender, and altitude considerations. 
Source: Barosi G, Mesa RA, Thiele J, et al.  Proposed criteria for the diagnosis of pos-polycythemia vera and post-
essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for 
Myelofibrosis Research and Treatment.  Leukemia.  2008;22:437-438. 
 


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Appendix 12 
Dynamic International Prognostic Scoring System 
The DIPSS includes the same 5 prognostic factors as the IPSS but ascribes greater weight to low 
hemoglobin (2 points instead of 1) while the other risk factors are counted as 1; risk scoring is 
modified accordingly, and corresponding median survival estimates for low-, intermediate 1-, 
intermediate 2-, and high-risk diseases range from not reached to 1.5 years. 
DIPSS Risk and Survival 
Risk category 
Number of risk factors  
Median survival (years) 
Low 
0 
Not reached 
Intermediate-1 
1-2 
14.2 
Intermediate-2 
3-4 
4 
High 
5-6 
1.5 
 
The 5 adverse prognostic factors identified as predictors of shortened survival are: 
 Age >65 years 
 Constitutional symptoms 
 Hemoglobin <10 g/dL 
 White blood cell count >25 × 109/L 
 Peripheral blood blasts ≥1% 
Subjects are assigned into one of 4 risk categories based on the number of risk factors present. 
DIPSS for Survival in Primary Myelofibrosis 
Prognostic variable 
Value 
0  
1 
2 
Age (years) 
≤65 
>65 
 
White blood cell count (× 109/L) 
≤25 
>25 
 
Hemoglobin (g/dL) 
≥10 
 
<10 
Peripheral blood blast (%) 
<1 
≥1 
 
Constitutional symptoms 
N 
Y 
 
The risk category is obtained adding up the values of each prognostic variable.  Risk categories are defined as 
low: 0; intermediate-1: 1 or 2; intermediate-2: 3 or 4; and high: 5 or 6. 
Source: Passamonti F, Cervantes F, Vannucchi AM, et al.  A dynamic prognostic model to predict survival in 
primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative 
Neoplasms Research and Treatment).  Blood.  2010;115(9):1703-8. 


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Appendix 13 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
These scales and criteria are used by doctors and researchers to assess how a subject’s disease is 
progressing, assess how the disease affects the daily living abilities of the subject, and determine 
appropriate treatment and prognosis.  They are included here for health care professionals to 
access. 
Grade 
ECOG Performance Status* 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed and chair. 
5 
Dead 
* As published in: Oken MM, Creech RH, Tormey DC, et al.  Am J Clin Oncol.  1982;5(6):649-55. 
Source: npcrc.org/files/new/ECOG_performance_status.pdf. 


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Appendix 14 
Revised Response Criteria for Myelofibrosis: International 
Working Group-Myeloproliferative Neoplasms Research 
and Treatment (IWG-MRT) and European LeukemiaNet 
(ELN) Consensus Report 
Response categories 
Required criteria (for all response categories, benefit must last for ≥12 
weeks to qualify as a response) 
Complete response (CR) 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† 
AND 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count 
≥1 × 109/L and <UNL; platelet count ≥100 × 109/L and <UNL; <2% 
immature myeloid cells‡ AND 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
Partial response (PR) 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count 
≥1 × 109/L and <UNL; platelet count ≥100 × 109/L and <UNL; <2% 
immature myeloid cells‡ AND 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
OR 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† 
AND 
Peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil 
count ≥1 × 109/L and <UNL; platelet count ≥50, but <100 × 109/L and 
<UNL; <2% immature myeloid cells‡ AND 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
Clinical improvement (CI) 
The achievement of anemia, spleen or symptoms response without 
progressive disease or increase in severity of anemia, thrombocytopenia, or 
neutropenia§ 
Anemia response 
Transfusion-independent subjects: a ≥20 g/L increase in hemoglobin level‖ 
Transfusion-dependent subjects: becoming transfusion-independent{ 
Spleen response# 
A baseline splenomegaly that is palpable at 5 to 10 cm, below the LCM, 
becomes not palpable** 
OR 
A baseline splenomegaly that is palpable at >10 cm, below the LCM, 
decreases by ≥50%** 
 
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not 
eligible for spleen response. 
A spleen response requires confirmation by MRI or computed tomography 
showing ≥35% spleen volume reduction. 
Symptoms response 
A ≥50% reduction in the MPN-SAF TSS†† 
Progressive disease‡‡ 
Appearance of a new splenomegaly that is palpable at least 5 cm below the 
LCM 
OR 
A ≥100% increase in palpable disease, below LCM, for baseline 
splenomegaly of 5 to 10 cm 
OR 
A 50% increase in palpable distance, below LCM, for baseline splenomegaly 
of 10 cm 
OR 


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Response categories 
Required criteria (for all response categories, benefit must last for ≥12 
weeks to qualify as a response) 
Leukemic transformation confirmed by a bone marrow blast count of ≥20% 
OR 
A peripheral blood blast content of ≥20% associated with an absolute blast 
count of ≥1 × 109/L that lasts for at least 2 weeks 
Stable disease 
Belonging to none of the above listed response categories 
Relapse 
No longer meeting criteria for at least CI after achieving CR, PR, or CI 
OR 
Loss of anemia response persisting for at least 1 month 
OR 
Loss of spleen response persisting for at least 1 month 
Recommendations for assessing treatment-induced cytogenic and molecular changes 
Cytogenetic remission 
At least 10 metaphases must be analyzed for cytogenetic response evaluation 
and requires confirmation by repeat testing within 6 months window. 
 
CR: eradication of a pre-existing abnormality 
PR: ≥50% reduction in abnormal metaphases (partial response applies only 
to subjects with at least 10 abnormal metaphases at baseline) 
Molecular remission 
Molecular response evaluation must be analyzed in peripheral blood 
granulocytes and requires confirmation by repeat testing within 6 months 
window. 
 
CR: Eradication of a pre-existing abnormality 
PR: ≥50% decrease in allele burden (partial response applies only to subjects 
with at least 20% mutant allele burden at baseline) 
Cytogenetic/molecular relapse 
Re-emergence of a pre-existing cytogenetic or molecular abnormality that is 
confirmed by repeat testing 
Abbreviations: EMH=extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or 
imaging study-proven nonhepatosplenic EMH); LCM=left costal margin; MF=myelofibrosis; UNL=upper 
normal limit. 
* Baseline and post-treatment bone marrow slides are to be interpreted locally at one sitting preferably by the same 
assessor.  Cytogenetic and molecular responses are not required for CR assignment. 
† Grading of MF is according to the European classification (Thiele et al.  European consensus on grading bone 
marrow fibrosis and assessment of cellularity.  Haematologica 2005;90:1128).  It is underscored that the 
consensus definition of a CR bone marrow is to be used only in those subjects in which all other criteria are met, 
including resolution of leukoerythroblastosis.  It should also be noted that it was a particularly difficult task for 
the working group to reach a consensus regarding what represents a complete histologic remission. 
‡ Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood 
cells.  In splenectomized subjects, 5% immature myeloid cells is allowed. 
§ See above for definitions of anemia response, spleen response, and progressive disease.  Increase in severity of 
anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in hemoglobin level 
from pretreatment baseline that lasts for at least 12 weeks.  Increase in severity of thrombocytopenia or 
neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil 
count, according to the CTCAE version 4.0.  In addition, assignment to CI requires a minimum platelet count of 
≥25,000 × 109/L and absolute neutrophil count of ≥0.5 × 109/L. 
|| Applicable only to subjects with baseline hemoglobin of <100 g/L.  In subjects not meeting the strict criteria for 
transfusion dependency at the time of study enrolment (see as follows), but have received transfusions within the 
previous month, the pretransfusion hemoglobin level should be used as the baseline. 


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{ Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood 
cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in the absence of 
bleeding or treatment-induced anemia.  In addition, the most recent transfusion episode must have occurred in the 
28 days prior to study enrollment.  Response in transfusion-dependent subjects requires absence of any PRBC 
transfusions during any consecutive “rolling” 12-week interval during the treatment phase, capped by a 
hemoglobin level of ≥85 g/L. 
# In splenectomized subjects, palpable hepatomegaly is substituted with the same measurement strategy. 
** Spleen or liver responses must be confirmed by imaging studies where a ≥35% reduction in spleen volume, as 
assessed by MRI or CT, is required.  Furthermore, a ≥35% volume reduction in the spleen or liver, by MRI or 
CT, constitutes a response regardless of what is reported with physical examination. 
†† Symptoms are evaluated by the MPN-SAF TSS.  The MPN-SAF TSS is assessed by the subjects themselves and 
this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal 
discomfort, weight loss, and fevers.  Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as 
bad as it can be) for each item.  The MPN-SAF TSS is the summation of all the individual scores (0-100 scale).  
Symptoms response requires ≥50% reduction in the MPN-SAF TSS. 
‡‡ Progressive disease assignment for splenomegaly requires confirmation by MRI or computed tomography 
showing a ≥25% increase in spleen volume from baseline.  Baseline values for both physical examination and 
imaging studies refer to pretreatment baseline and not to post-treatment measurements. 
Source: Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working 
Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) 
consensus report.  Blood 2013;122:1395-1398. 


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Appendix 15 
Schedule of Assessments for South Korea Only 
Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 to  
Day 0 
Day 1 
(Day 
1/ 
WK 
0) 
Day 8 
(Day 
8/Wk 
1) 
Day 
15 
(Day 
15/ 
WK 
2) 
Day 
22 
(Day 
8/Wk 
3) 
Day 1 
(Day 
29/ 
WK 
4) 
Day 
15 
(Day 
43/ 
WK 
6) 
Day 1 
(Day 57/ 
WK 8) 
Day 
15 
(Day 
71/ 
WK 
10) 
Day 
1 
(Day 
85/ 
WK 
12) 
Day 
15 
(Day 
99/ 
WK 
14) 
Visit Window 
 
 
+3 
days 
+3 
days 
+3 
days 
+3 
days 
+3 
days 
+3  
days 
+3 
days 
+3 
days 
+3 
days 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Review/confirm eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
COVID-19 status verification 
X 
 
 
 
 
 
 
 
 
 
 
Genetic substudy informed consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
Xa 
 
 
 
 
 
 
 
 
 
 
Physical examination 
Xb 
 
 
 
 
Xc 
 
Xc 
 
Xc 
 
Inactive (latent) TB test (local laboratory) 
X 
 
 
 
 
 
 
 
 
 
 
MRI/CT (spleen volume measurement) 
Xd 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
 
 
X 
 
X 
 
X 
 
ECOG PS 
X 
Xe 
 
 
 
 
 
 
 
 
 
Clinical laboratoryf 
 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Active tuberculosis (local lab) 
 
X 
 
 
 
 
 
 
 




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Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 to  
Day 0 
Day 1 
(Day 
1/ 
WK 
0) 
Day 8 
(Day 
8/Wk 
1) 
Day 
15 
(Day 
15/ 
WK 
2) 
Day 
22 
(Day 
8/Wk 
3) 
Day 1 
(Day 
29/ 
WK 
4) 
Day 
15 
(Day 
43/ 
WK 
6) 
Day 1 
(Day 57/ 
WK 8) 
Day 
15 
(Day 
71/ 
WK 
10) 
Day 
1 
(Day 
85/ 
WK 
12) 
Day 
15 
(Day 
99/ 
WK 
14) 
Visit Window 
 
 
+3 
days 
+3 
days 
+3 
days 
+3 
days 
+3 
days 
+3  
days 
+3 
days 
+3 
days 
+3 
days 
Administer study treatment 
(NS-018) 
 
 
 
 
 
 
 
 
 
 
 
Administer study treatment 
(BAT)n 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
Xe 
 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant therapies/procedures/medication 
X 
Xe 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete 
End-of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-
up 
(Phone 
call)p 
Visit Window 
+3 days 
+3 days 
+3 days 
+3 days 
1 week 
 
3 days 
Physical examination 
 
 
 
 
Xc  
(Every 3 cycles) 
Xb 
 


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Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete 
End-of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-
up 
(Phone 
call)p 
Visit Window 
+3 days 
+3 days 
+3 days 
+3 days 
1 week 
 
3 days 
MRI/CT (spleen volume measurement) 
 
 
 
 
X 
(Cycles 7, 10, 13) 
Xk 
 
Vital signs 
X 
 
X 
 
X 
X 
 
ECOG PS 
 
 
 
 
 
X 
 
Clinical laboratoryf 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (serum) 
 
 
 
 
 
X 
 
12-lead ECGg  
 
 
 
 
X 
(Every 3 cycles) 
X 
 
Bone marrow assessment 
 
 
 
 
X  
(Cycles 13; every 
12 cycles 
thereafter) 
 
 
Response assessment (IWG-MRT and ELN) 
 
 
 
 
X  
(Every 3 cycles) 
X 
 
MF-SAF v4.0i 
 
 
 
 
 
(Up to Cycle 12) 
 
 
PROMISj 
 
 
 
 
 
 
(Up to Cycle 12) 
 
 


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Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete 
End-of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-
up 
(Phone 
call)p 
Visit Window 
+3 days 
+3 days 
+3 days 
+3 days 
1 week 
 
3 days 
EQ-5D-5L 
 
 
 
 
X  
(Every 6 cycles) 
 
 
Dispense study treatment/diary 
X 
 
X 
 
X  
(Every 3 cycles) 
 
 
Administer study treatment (NS-018) 
 
 
 
 
 
 
 
Administer study treatment (BAT)n 
 
 
 
 
(Transition to 
NS-018) 
 
 
AE 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies/procedures/ medication 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AEs=adverse events; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BAT=Best Available Therapy; BUN=blood 
urea nitrogen; COVID-19=coronavirus disease 2019; eCRF=electronic case report form; EQ-5D-5L = 5-level EQ-5D version; CT=computed tomography; 
ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group performance status; ELN=European LeukemiaNet; IWG-MRT=International Working Group for 
Myelofibrosis Research and Treatment; LDH=lactate dehydrogenase; mRNA=messenger ribonucleic acid; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular 
volume; MF-SAF v4.0=Myelofibrosis Symptom Assessment Form version 4.0; MRI=magnetic resonance imaging; PK=pharmacokinetics; PROMIS=Patient-Reported 
Outcomes Measurement Information System; QD=once daily; STAT3=signal transducer and activator of transcription 3; WK=week.  
NOTE: At Cycle 1 Day 1, before the subject starts study treatment, all eligibility criteria including the subject’s COVID-19 status should be reviewed and confirmed.   
NOTE: Verification of COVID-19 status is based on the World Health Organization diagnostic criteria (Public health surveillance for COVID-19.  Interim guidance; 
07 August 2020).  If a subject presents with clinical signs and symptoms consistent with COVID-19 infection, the Investigator should request a test where possible and this 
should be recorded in the AE field of the eCRF. 
a 
Including concomitant medications within 28 days prior to study treatment administration, blood products transfused within 3 months prior to study treatment administration, 
and concurrent baseline conditions. 
b 
Full physical examination including weight and spleen size by clinical assessment (palpation).  At screening, spleen size (palpation) measurement should be done on the same 
day the spleen volume is measured by MRI.  If the same day measurement is not feasible, the measurement should be assessed within 14 days prior to the first dose of the study 
treatment. 


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Final Protocol NS-018-201 - Protocol V3.0 
 
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c 
Directed physical examination including weight and spleen size by palpation.  
d 
Assess spleen volume within 14 days prior to the first dose of the study treatment. 
e 
Predose; may be obtained within 24 hours prior to study treatment administration.  AEs on Cycle 1 Day 1 will also be collected postdose. 
f 
Safety laboratory assessments will be performed on Cycle 1 Days 1, 8, 15, and 22, Cycle 2 through Cycle 6 on Days 1 and 15, and Day 1 of each cycle thereafter at minimum.  
For subjects who transition to NS-018, safety laboratory assessments will be performed on Day 1 and Day 15 of each cycle for the first 6 cycles after transitioning to NS-018 
(including the additional visits on Day 8 and Day 22 of the first cycle after transitioning).  Hematology includes erythrocytes, MCV, MCH, neutrophils, eosinophils, basophils, 
lymphocytes, monocytes, platelets, leukocytes, hemoglobin, and hematocrit.  Serum chemistry includes BUN, LDH, creatinine, uric acid, total protein, albumin, glucose, direct 
bilirubin for screening, total bilirubin (for safety assessment), magnesium, ALP, AST, ALT, chloride, sodium, potassium, amylase, and lipase.  Urinalysis includes pH, protein, 
glucose, ketone, bilirubin, blood, and nitrite.  Assessments on Day 8 and Day 22 of Cycle 1 for subjects randomized to NS-018 or Cycle 1 after transitioning to NS-018 in 
subjects who transition to NS-018 will be performed at the institutional local laboratory.  All other safety laboratory assessments will be performed at the central laboratory.  
Additional local laboratory assessments may be performed per Investigator’s discretion to monitor safety and document AEs as per local standards of care. 
g 
For eligibility determination; median QTcF must be ≤480 msec.  For screening, Cycles 1 and 2, triplicate central reading, and then from Cycle 4 onwards, single central 
reading.  ECGs for Cycle 1 Day 1: Predose (3 time points within 1 hour) and 1, 2, 4, 6, 8 (±10 minutes) hours after administration of NS-018, Cycle 1 Day 15: 2 (±10 minutes) 
hours after administration of NS-018, Cycle 2 Day 1: Predose (within 1 hour) and 1, 2, 4 (±10 minutes) hours after administration of NS-018, and Cycle 4 Day 1 and thereafter 
every 3 cycles: 2 (±10 min) hours after administration of NS-018. 
h 
Within 28 days prior to the first dose of study drug.  However, bone marrow assessment performed within 6 months prior to the first dose can be used as baseline. 
i 
 During the screening period, subjects will complete the MF-SAF v4.0 assessment daily. The first 7 consecutive days of diary data will be used for eligibility assessments. 
Subjects will complete the MF-SAF daily  from Day −7 of Cycle 1 Day 1 to the end of Cycle 6 (Day 168) and the last 7 days in each cycle thereafter until the end of Cycle 12 
(Day 336) for efficacy assessment. 
j 
The PROMIS questionnaire must be completed daily during the screening period and the last 7 days of each cycle until the end of Cycle 12 (Day 336).  This assessment will be 
performed for all subjects including subjects transitioning from BAT to NS-018. 
k 
If not done within the previous 8 weeks. 
l 
Within 14 days after last dose of study treatment or within 14 days after withdrawal from the study. 
m Randomization can be done within Day −4 so that the subject can start study treatment on the morning of Day 1. 
n 
In the BAT treatment arm (control group), after subjects have completed treatment with BAT at the end of Cycle 6, subjects will discontinue BAT and transition to NS-018 at 
Cycle 7 Day 1.  During this transition period, subjects treated with ruxolitinib will be required to taper off this treatment before initiation of NS-018.  The dose of ruxolitinib 
should be decreased every 7 days by up to 50% until the smallest dose possible has been given for a minimum duration for the total tapering period of 14 days.  Ruxolitinib 
should then be stopped 1 day before starting NS-018.  Subjects who are taking 5 mg QD of ruxolitinib are already on the lowest dose possible; therefore, tapering is not 
applicable in this case.  If recurrence of MF-related symptoms (upon discontinuation of ruxolitinib therapy) is noted, it is strongly suggested that therapy with ruxolitinib be 
restarted.  If restart is not possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg QD) is recommended.  Subjects administered with treatment other than 
ruxolitinib will undergo a minimum washout period of 1 week (7 days) prior to start of NS-018 treatment. 
o 
Subjects who discontinue study treatment or withdraw from the study will be asked to complete the end of study procedures within 14 days after the last dose.  If the end of 
study procedures occur at a regular scheduled visit, these procedures may be performed at that time. 
P 
Follow-up phone call will be done 30 (±3) days after the completion of end of study procedures. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
139 
Additional Assessment Guidance 
The table below clarifies the timing of specific assessment completion. 
Assessments 
Time restriction 
 
Predose 
Postdose 
Pharmacokinetics  
(NS-018 treatment arm only) 
Within 1 hour 
Cycle 1 Day 1 
0.5, 1, 2, 3, 4, 6, 8 hours (±10 min per time point) 
Cycle 2 Day 1 
0.5, 1, 2, 3, 4, 6, 8 hours (±10 min per time point) 
Vital signs 
Within 3 hours 
Not applicable  
ECOG performance status 
Within 24 hours 
Not applicable 
12-lead ECG (NS-018 treatment 
arm only) 
Cycle 1 Day 1  
3 time points within 1 hour (eg, -45, -30, -15 min) 
Cycle 2 Day 1 
Within 1 hour  
 
Cycle 1 Day 1 
5 time points: 1, 2, 4, 6, and 8 hours (±10 min per time point) 
Cycle 1 Day 15 
2 (±10 min) hours 
Cycle 2 Day 1 
3 time points: 1, 2, and 4 hours (±10 min per time point) 
Cycle 4 Day 1 and thereafter every 3 cycles 
2 (±10 min) hours 
Phospho-STAT3  
(NS-018 treatment arm only) 
Cycle 1 Day 1 
Within 24 hours 
Cycle 2 Day 1 
Within 1 hour 
Cycle 1 Day 1 
3 hours (±10 min)  
Cycle 2 Day 1 
3 hours (±10 min) 
mRNA sequencing  
(NS-018 treatment arm only) 
Cycle 1 Day 1 
Within 24 hours 
Cycle 2 Day 1 
Within 1 hour 
Cycle 1 Day 1 
8 hours (±10 min) 
Abbreviations: ECG=electrocardiogram; ECOG= Eastern Cooperative Oncology Group; min=minutes; mRNA=messenger ribonucleic acid sequencing; 
STAT3=signal transducer and activator of transcription 3. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
140 
Appendix 16 
Schedule of Assessments for UK only 
Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 
to  
Day 0 
Day 1 
(Day 1/ 
WK 0) 
Day 15 
(Day 15/ 
WK 2) 
Day 1 
(Day 29/ 
WK 4) 
Day 15 
(Day 43/ 
WK 6) 
Day 1 
(Day 57/ 
WK 8) 
Day 15 
(Day 71/ 
WK 10) 
Day 1 
(Day 85/ 
WK 12) 
Day 15 
(Day 99/ 
WK 14) 
Visit Window 
 
 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
Study Procedure 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Review/confirm eligibility 
criteria 
X 
X 
 
 
 
 
 
 
 
COVID-19 status verification 
X 
 
 
 
 
 
 
 
 
Genetic substudy informed 
consent (optional) 
X 
 
 
 
 
 
 
 
 
Medical history 
Xa 
 
 
 
 
 
 
 
 
Physical examination 
Xb 
 
 
Xc 
 
Xc 
 
Xc 
 
Inactive (latent) TB test (local 
laboratory) 
X 
 
 
 
 
 
 
 
 
MRI/CT (spleen volume 
measurement) 
Xd 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
ECOG PS 
X 
Xe 
 
 
 
 
 
 
 
Clinical laboratoryf 
(by central lab) 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum)q 
X 
 
 
X 
 
X 
 
X 
 
12-lead ECG 
Xg 
Xg 
Xg 
Xg 
 
Xg 
 
Xg 
 
PK sampling (NS-018 treatment 
arm only) 
 
X 
 
X 
 
 
 
 
 
Bone marrow assessment 
Xh 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
141 
Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 
to  
Day 0 
Day 1 
(Day 1/ 
WK 0) 
Day 15 
(Day 15/ 
WK 2) 
Day 1 
(Day 29/ 
WK 4) 
Day 15 
(Day 43/ 
WK 6) 
Day 1 
(Day 57/ 
WK 8) 
Day 15 
(Day 71/ 
WK 10) 
Day 1 
(Day 85/ 
WK 12) 
Day 15 
(Day 99/ 
WK 14) 
Visit Window 
 
 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
Study Procedure 
 
 
 
 
 
 
 
 
 
Response assessment 
(IWG-MRT and ELN) 
 
 
 
X 
 
X 
 
X 
 
Genetic profiling 
 
Xe 
 
 
 
 
 
 
 
Phospho-STAT3 
(NS-018 treatment arm only) 
 
Xe 
 
X 
 
 
 
 
 
mRNA sequencing 
(NS-018 treatment arm only) 
 
Xe 
 
X 
 
 
 
 
 
MF-SAF v4.0i 
 
 
 
 
 
 
 
 
 
PROMISj 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
Xe 
 
 
 
 
 
 
 
Randomization 
 
Xm 
 
 
 
 
 
 
Dispense study treatment/diary  
 
Xe 
 
X 
 
X 
 
X 
 
Administer study treatment 
(NS-018) 
 
 
 
 
 
 
 
 
 
Administer study treatment 
(BAT)n 
 
 
 
 
 
 
 
 
 
AEs 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
therapies/procedures/medication 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
142 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete End-
of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-up 
(Phone 
call)p 
Visit Window 
+3 days 
+3 days 
+3 days 
+3 days 
1 week 
 
3 days 
Study Procedure 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
Xc  
(Every 3 cycles) 
Xb 
 
MRI/CT (spleen volume measurement) 
 
 
 
 
X 
(Cycles 7, 10, 13) 
Xk 
 
Vital signs 
X 
 
X 
 
X 
X 
 
ECOG PS 
 
 
 
 
 
X 
 
Clinical laboratoryf 
(by central lab) 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (serum)q 
X 
 
X 
 
X 
X 
 
12-lead ECG 
 
 
 
 
X 
(Every 3 cycles)g 
X 
 
PK sampling (NS-018 treatment arm only) 
 
 
 
 
 
 
 
Bone marrow assessment 
 
 
 
 
X  
(Cycles 13; every 12 
cycles thereafter) 
 
 
Response assessment (IWG-MRT and 
ELN) 
 
 
 
 
X  
(Every 3 cycles) 
X 
 
Genetic profiling 
 
 
 
 
 
 
 
MF-SAF v4.0i 
 
 
 
 
 
(Up to Cycle 12) 
 
 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
143 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete End-
of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-up 
(Phone 
call)p 
Visit Window 
+3 days 
+3 days 
+3 days 
+3 days 
1 week 
 
3 days 
Study Procedure 
 
 
 
 
 
 
 
PROMISj 
 
 
 
 
 
(Up to Cycle 12) 
 
 
EQ-5D-5L 
 
 
 
 
X  
(Every 6 cycles) 
 
 
Dispense study treatment/diary 
X 
 
X 
 
X  
(Every 3 cycles) 
 
 
Administer study treatment (NS-018) 
 
 
 
 
 
 
 
Administer study treatment (BAT)n 
 
 
 
 
(Transition to 
NS-018) 
 
 
AE 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies/procedures/ 
medication 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AEs=adverse events; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BAT=Best Available Therapy; BUN=blood 
urea nitrogen; COVID-19=coronavirus disease 2019; eCRF=electronic case report form; CT=computed tomography; ECG=electrocardiogram; ECOG PS=Eastern Cooperative 
Oncology Group performance status; ELN=European LeukemiaNet; EQ-5D-5L=5-level EQ-5D version;IWG-MRT=International Working Group for Myelofibrosis Research 
and Treatment; LDH=lactate dehydrogenase; MF=myelofibrosis; mRNA=messenger ribonucleic acid; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
MF-SAF v4.0=Myelofibrosis Symptom Assessment Form version 4.0; MRI=magnetic resonance imaging; PK=pharmacokinetics; PROMIS=Patient-Reported Outcomes 
Measurement Information System; QD=once daily; STAT3=signal transducer and activator of transcription 3; TB=tuberculosis; WOCBP=women of childbearing potential; 
WK=week.  
NOTE: At Cycle 1 Day 1, before the subject starts study treatment, all eligibility criteria including the subject’s COVID-19 status should be reviewed and confirmed.   
NOTE: Verification of COVID-19 status is based on the World Health Organization diagnostic criteria (Public health surveillance for COVID-19.  Interim guidance, 
07 August 2020).  If a subject presents with clinical signs and symptoms consistent with COVID-19 infection, the Investigator should request a test where possible and this 
should be recorded in the AE field of the eCRF. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
144 
a 
Including concomitant medications within 28 days prior to study treatment administration, blood products transfused within 3 months prior to study treatment administration, 
and concurrent baseline conditions. 
b 
Full physical examination including weight and spleen size by clinical assessment (palpation).  At screening, spleen size (palpation) measurement must be done on the same 
day the spleen volume is measured by MRI. 
c 
Directed physical examination including weight and spleen size by palpation.  A skin examination will also be conducted as part of the physical examination.  
d 
Assess spleen volume within 14 days prior to the first dose of the study treatment. 
e 
Predose; may be obtained within 24 hours prior to study treatment administration.  AEs on Cycle 1 Day 1 will also be collected postdose. 
f 
Subjects transitioning from BAT to NS-018 before or at Cycle 7 Day 1 will have safety laboratory assessments performed on Day 1 and 15 of each cycle for 6 cycles. Safety 
laboratory assessments will continue on Day 1 of the following cycles until the end of the study.  Hematology includes erythrocytes, MCV, MCH, neutrophils, eosinophils, 
basophils, lymphocytes, monocytes, platelets, leukocytes, hemoglobin, and hematocrit.  Serum chemistry includes BUN, LDH, creatinine, uric acid, total protein, albumin, 
glucose, direct bilirubin (for screening)  total bilirubin (safety assessment), magnesium, ALP, AST, ALT, chloride, sodium, potassium, amylase, and lipase.  Urinalysis includes 
pH, protein, glucose, ketone, bilirubin, blood, and nitrite. Note: Additional local laboratory assessments may be performed per Investigator’s discretion to monitor safety and 
document AEs as per local standards of care. 
g 
For eligibility determination; median QTcF must be ≤480 msec.  For screening, Cycles 1 and 2, triplicate central reading, and then from Cycle 4 onwards, single central 
reading.  ECGs Cycle 1 Day 1: Predose (3 time points within 1 hour) and 1, 2, 4, 6, 8 (±10 minutes) hours after administration of NS-018, Cycle 1 Day 15: 2 (±10 minutes) 
hours after administration of NS-018, Cycle 2 Day 1: Predose (within 1 hour) and 1, 2, 4 (±10 minutes) hours after administration of NS-018, Cycle 3 Day 1 predose (within 1 
hour) and 1, 2, and 4 (±10 minutes) hours after administration of NS-018, and Cycle 4 Day 1 and thereafter every 3 cycles: 2 (±10 minutes) hours after administration of NS-
018.  NOTE: An additional single ECG will be done at Cycle 3 and Cycle 9, Day 1 predose (within 1 hour) and 1, 2, and 4 (±10 minutes) hours after administration of NS-018.   
h 
Within 28 days prior to the first dose of study drug.  However, bone marrow assessment performed within 6 months prior to the first dose can be used as baseline. 
i 
During the screening period, subjects will complete the MF-SAF v4.0 assessment daily. The first 7 consecutive days of diary data will be used  for eligibility assessments. 
Subjects will complete the MF-SAF daily  from Day −7 of Cycle 1 Day 1 to the end of Cycle 6 (Day 168) and the last 7 days in each cycle thereafter until the end of Cycle 12 
(Day 336) for efficacy assessment. 
j 
The PROMIS questionnaire must be completed daily during the screening period and the last 7 days of each cycle until the end of Cycle 12 (Day 336).  This assessment will be 
performed for all subjects including subjects transitioning from BAT to NS-018. 
k 
If not done within the previous 8 weeks. 
l 
Within 14 days after last dose of study treatment or within 14 days after withdrawal from the study. 
m Randomization can be done within Day −4 so that the subject can start study treatment on the morning of Day 1. 
n 
In the BAT treatment arm (control group), after subjects have completed treatment with BAT at the end of Cycle 6, subjects will discontinue BAT and transition to NS-018 at 
Cycle 7 Day 1.  During this transition period, subjects treated with ruxolitinib will be required to taper off this treatment before initiation of NS-018.  The dose of ruxolitinib 
should be decreased every 7 days by up to 50% until the smallest dose possible has been given for a minimum duration for the total tapering period of 14 days.  Ruxolitinib 
should then be stopped 1 day before starting NS-018.  Subjects who are taking 5 mg QD of ruxolitinib are already on the lowest dose possible; therefore, tapering is not 
applicable in this case.  If recurrence of MF-related symptoms (upon discontinuation of ruxolitinib therapy) is noted, it is strongly suggested that therapy with ruxolitinib be 
restarted.  If restart is not possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg QD) is recommended.  Subjects administered with treatment other than 
ruxolitinib will undergo a minimum washout period of 1 week (7 days) prior to start of NS-018 treatment. 
o 
Subjects who discontinue study treatment or withdraw from the study will be asked to complete the end of study procedures within 14 days after the last dose.  If the end of 
study procedures occur at a regular scheduled visit, these procedures may be performed at that time. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
145 
P 
Follow-up phone call will be done 30 (±3) days after the completion of end of study procedures. 
q 
For WOCBP only, a negative serum pregnancy test will be required within 7 days prior to dosing on Cycle 1 Day 1, and a negative urine and/or serum pregnancy test will be 
required within 7 days prior to dosing on Day 1 of each cycle (local laboratory).  Of note to sites, if the urine test is the choice and is positive or cannot be confirmed as 
negative, a serum pregnancy test must be completed to confirm pregnancy result.  
WOCBP will have pregnancy tests done monthly for early detection of pregnancy and discontinuation of study drugs. 
 
 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
146 
Additional Assessment Guidance 
The table below clarifies the timing of specific assessment completion. 
Assessments 
Time restriction 
 
Predose 
Postdose 
Pharmacokinetics  
(NS-018 treatment arm only) 
Within 1 hour 
Cycle 1 Day 1 
0.5, 1, 2, 3, 4, 6, 8 hours (±10 min per time point) 
Cycle 2 Day 1 
0.5, 1, 2, 3, 4, 6, 8 hours (±10 min per time point) 
Vital signs 
Within 3 hours 
Not applicable  
ECOG performance status 
Within 24 hours 
Not applicable 
12-lead ECG 
Cycle 1 Day 1  
3 time points within 1 hour (eg, -45, -30, -15 min) 
Cycle 2 Day 1 
Within 1 hour  
Cycle 3 Day 1 (for UK only) 
Within 1 hour 
Cycle 1 Day 1 
5 time points: 1, 2, 4, 6, and 8 hours (±10 min per time point) 
Cycle 1 Day 15 
2 (±10 min) hours 
Cycle 2 Day 1 
3 time points: 1, 2, and 4 hours (±10 min per time point) 
Cycle 3 Day 1 
3 time points: 1, 2, and 4 hours (±10 min per time point) 
Cycle 4 Day 1 and thereafter every 3 cycles 
2 (±10 min) hours 
Phospho-STAT3  
(NS-018 treatment arm only) 
Cycle 1 Day 1 
Within 24 hours 
Cycle 2 Day 1 
Within 1 hour 
Cycle 1 Day 1 
3 hours (±10 min)  
Cycle 2 Day 1 
3 hours (±10 min) 
mRNA sequencing  
(NS-018 treatment arm only) 
Cycle 1 Day 1 
Within 24 hours 
Cycle 2 Day 1 
Within 1 hour 
Cycle 1 Day 1 
8 hours (±10 min) 
Abbreviations: ECG=electrocardiogram; ECOG= Eastern Cooperative Oncology Group; min=minutes; mRNA=messenger ribonucleic acid sequencing; STAT3=signal transducer and activator of 
transcription 3. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
147 
Appendix 17 
Schedule of Assessments for Germany Only 
Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 
to  
Day 0 
Day 1 
(Day 1/ 
WK 0) 
Day 15 
(Day 15/ 
WK 2) 
Day 1 
(Day 29/ 
WK 4) 
Day 15 
(Day 43/ 
WK 6) 
Day 1 
(Day 57/ 
WK 8) 
Day 15 
(Day 71/ 
WK 10) 
Day 1 
(Day 85/ 
WK 12) 
Day 15 
(Day 99/ 
WK 14) 
Visit Window 
 
 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
Study Procedure 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Review/confirm eligibility 
criteria 
X 
X 
 
 
 
 
 
 
 
COVID-19 status verification 
X 
 
 
 
 
 
 
 
 
Genetic substudy informed 
consent (optional) 
X 
 
 
 
 
 
 
 
 
Medical history 
Xa 
 
 
 
 
 
 
 
 
Physical examination 
Xb 
 
 
Xc 
 
Xc 
 
Xc 
 
MRI/CT (spleen volume 
measurement) 
Xd 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
ECOG PS 
X 
Xe 
 
 
 
 
 
 
 
Active tuberculosis 
X 
 
 
 
 
 
 
 
 
Clinical laboratoryf 
(by central lab) 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) (local 
laboratory) 
X 
X 
 
X 
 
X 
 
X 
 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
148 
Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 
to  
Day 0 
Day 1 
(Day 1/ 
WK 0) 
Day 15 
(Day 15/ 
WK 2) 
Day 1 
(Day 29/ 
WK 4) 
Day 15 
(Day 43/ 
WK 6) 
Day 1 
(Day 57/ 
WK 8) 
Day 15 
(Day 71/ 
WK 10) 
Day 1 
(Day 85/ 
WK 12) 
Day 15 
(Day 99/ 
WK 14) 
Visit Window 
 
 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
12-lead ECG 
Xg 
Xg 
Xg 
Xg 
 
 
 
Xg 
 
PK sampling (NS-018 treatment 
arm only) 
 
X 
 
X 
 
 
 
 
 
Bone marrow assessment 
Xh 
 
 
 
 
 
 
 
 
Response assessment 
(IWG-MRT and ELN) 
 
 
 
X 
 
X 
 
X 
 
Genetic profiling 
 
Xe 
 
 
 
 
 
 
 
Phospho-STAT3 
(NS-018 treatment arm only) 
 
Xe 
 
X 
 
 
 
 
 
mRNA sequencing 
(NS-018 treatment arm only) 
 
Xe 
 
X 
 
 
 
 
 
MF-SAF v4.0i 
 
 
 
 
 
 
 
 
 
PROMISj 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
Xe 
 
 
 
 
 
 
 
Randomization 
 
Xm 
 
 
 
 
 
 
Dispense study treatment/diary  
 
Xe 
 
X 
 
X 
 
X 
 
Administer study treatment 
(NS-018) 
 
 
 
 
 
 
 
 
 
Administer study treatment 
(BAT)n 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
149 
Visit Timing 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Day −28 
to  
Day 0 
Day 1 
(Day 1/ 
WK 0) 
Day 15 
(Day 15/ 
WK 2) 
Day 1 
(Day 29/ 
WK 4) 
Day 15 
(Day 43/ 
WK 6) 
Day 1 
(Day 57/ 
WK 8) 
Day 15 
(Day 71/ 
WK 10) 
Day 1 
(Day 85/ 
WK 12) 
Day 15 
(Day 99/ 
WK 14) 
Visit Window 
 
 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
+3 days 
AEs 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
therapies/procedures/medication 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete End-
of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-up 
(Phone 
call)p 
Visit Window 
+3 days 
+3 days 
+3 days 
+3 days 
1 week 
 
3 days 
Study procedure 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
Xc  
(Every 3 cycles) 
Xb 
 
MRI/CT (spleen volume measurement) 
 
 
 
 
X 
(Cycles 7, 10, 13) 
Xk 
 
Vital signs 
X 
 
X 
 
X 
X 
 
ECOG PS 
 
 
 
 
 
X 
 
Clinical laboratoryf 
(by central lab) 
X 
X 
X 
X 
X 
X 
 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
150 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete End-
of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-up 
(Phone 
call)p 
Visit Window 
+3 days 
+3 days 
+3 days 
+3 days 
1 week 
 
3 days 
Pregnancy test (serum)q 
X 
 
X 
 
X 
X 
 
12-lead ECG 
 
 
 
 
X 
(Every 3 cycles)g 
X 
 
Bone marrow assessment 
 
 
 
 
X  
(Cycles 13; every 12 
cycles thereafter) 
 
 
Response assessment (IWG-MRT and 
ELN) 
 
 
 
 
X  
(Every 3 cycles) 
X 
 
MF-SAF v4.0i 
 
 
 
 
 
(Up to Cycle 12) 
 
 
PROMISj 
 
 
 
 
 
(Up to Cycle 12) 
 
 
EQ-5D-5L 
 
 
 
 
X  
(Every 6 cycles) 
 
 
Dispense study treatment/diary 
X 
 
X 
 
X  
(Every 3 cycles) 
 
 
Administer study treatment (NS-018) 
 
 
 
 
 
 
 
Administer study treatment (BAT)n 
 
 
 
 
(Transition to 
NS-018) 
 
 
AE 
X 
X 
X 
X 
X 
X 
X 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
151 
Visit Timing 
Cycle 5 
Cycle 6 
Cycle ≥7 
Complete End-
of-Study 
Proceduresl, o 
End of 
Study 
Day 1 
(Day 113/ 
WK16) 
Day 15 
(Day 127/ 
WK18) 
Day 1 
(Day 141/ 
WK20) 
Day 15 
(Day 155/ 
WK22) 
Day 1 
(Every 
+Day28/WK4) 
30-Day 
Follow-up 
(Phone 
call)p 
Visit Window 
+3 days 
+3 days 
+3 days 
+3 days 
1 week 
 
3 days 
Concomitant therapies/procedures/ 
medication 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AEs=adverse events; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BAT=Best Available Therapy; BUN=blood 
urea nitrogen; COVID-19=coronavirus disease 2019; eCRF=electronic case report form; CT=computed tomography; ECG=electrocardiogram; ECOG PS=Eastern Cooperative 
Oncology Group performance status; ELN=European LeukemiaNet; EQ-5D-5L = 5-level EQ-5D version; IWG-MRT=International Working Group for Myelofibrosis 
Research and Treatment; LDH=lactate dehydrogenase; mRNA=messenger ribonucleic acid; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
MF=myelofibrosis; MF-SAF v4.0=Myelofibrosis Symptom Assessment Form version 4.0; MRI=magnetic resonance imaging; PK=pharmacokinetics; STAT3=signal 
transducer and activator of transcription 3; PROMIS=Patient-Reported Outcomes Measurement Information System; QD=once daily; WK=week; WOCBP = women of 
childbearing potential.  
NOTE: At Cycle 1 Day 1, before the subject starts study treatment, all eligibility criteria including the subject’s COVID-19 status should be reviewed and confirmed.   
NOTE: Verification of COVID-19 status is based on the World Health Organization diagnostic criteria (Public health surveillance for COVID-19.  Interim guidance; 
07 August 2020).  If a subject presents with clinical signs and symptoms consistent with COVID-19 infection, the Investigator should request a test where possible and this 
should be recorded in the AE field of the eCRF. 
NOTE: Monthly pregnancy tests should be performed for women of childbearing potential.  The serum pregnancy test should not be older than 72 hours before taking the first dose 
and can be done locally.  The subsequent monthly serum pregnancy tests should be done at Day 1 of each Cycle until the end of the study. 
NOTE: Subjects transitioning from BAT to NS-018 must be monitored as closely as subjects who are initially randomized to NS-018 with physical examination, vital signs, safety 
laboratory assessments and 12-lead ECG, etc., for the first cycles after transition to the NS-018 following the SoA from Cycle 1 Day 1. 
a 
Including concomitant medications within 28 days prior to study treatment administration, blood products transfused within 3 months prior to study treatment administration, 
and concurrent baseline conditions. 
b 
Full physical examination including weight and spleen size by clinical assessment (palpation).  At screening, spleen size (palpation) measurement must be done on the same 
day the spleen volume is measured by MRI. If the same day measurement is not feasible, the measurement should be assessed within 14 days prior to the first dose of the study 
treatment. 
c 
Directed physical examination including weight and spleen size by palpation. 
d 
Assess spleen volume within 14 days prior to the first dose of the study treatment. 
e 
Predose; may be obtained within 24 hours prior to study treatment administration.  AEs on Cycle 1 Day 1 will also be collected postdose. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
152 
f 
Subjects transitioning from BAT to NS-018 before or at Cycle 7 Day 1 will have safety laboratory assessments performed on Day 1 and 15 of each cycle for 6 cycles. Safety 
laboratory assessments will continue on Day 1 of the following cycles until the end of the study.  Hematology includes erythrocytes, MCV, MCH, neutrophils, eosinophils, 
basophils, lymphocytes, monocytes, platelets, leukocytes, hemoglobin, and hematocrit.  Serum chemistry includes BUN, LDH, creatinine, uric acid, total protein, albumin, 
glucose, direct bilirubin for screening, total bilirubin (for safety measurement), magnesium, ALP, AST, ALT, chloride, sodium, potassium, amylase, and lipase.  Urinalysis 
includes pH, protein, glucose, ketone, bilirubin, blood, and nitrite. Additional local laboratory assessments may be performed per Investigator’s discretion to monitor safety and 
document AEs as per local standards of care. 
g 
For eligibility determination; median QTcF must be ≤480 msec.  For screening, Cycles 1 and 2, triplicate central reading, and then from Cycle 4 onwards, single central 
reading.  ECGs for Cycle 1 Day 1: Predose (3 time points within 1 hour) and 1, 2, 4, 6, 8 (±10 minutes) hours after administration of NS-018, Cycle 1 Day 15: 2 (±10 minutes) 
hours after administration of NS-018, Cycle 2 Day 1: Predose (within 1 hour) and 1, 2, 4 (±10 minutes) hours after administration of NS-018, and Cycle 4 Day 1 and thereafter 
every 3 cycles: 2 (±10 min) hours after administration of NS-018.  
h 
Within 28 days prior to the first dose of study drug.  However, bone marrow assessment performed within 6 months prior to the first dose can be used as baseline. 
i 
During the screening period, subjects will complete the MF-SAF v4.0 assessment daily. The first 7 consecutive days of diary data will be used for eligibility assessments. 
Subjects will complete the MF-SAF daily from Day −7 of Cycle 1 Day 1 to the end of Cycle 6 (Day 168) and the last 7 days in each cycle thereafter until the end of Cycle 12 
(Day 336) for efficacy assessment. 
j 
The PROMIS questionnaire must be completed daily during the screening period and the last 7 days of each cycle until the end of Cycle 12 (Day 336).  This assessment will be 
performed for all subjects including subjects transitioning from BAT to NS-018. 
k 
If not done within the previous 8 weeks. 
l 
Within 14 days after last dose of study treatment or within 14 days after withdrawal from the study. 
m Randomization can be done within Day −4 so that the subject can start study treatment on the morning of Day 1. 
n 
In the BAT treatment arm (control group), after subjects have completed treatment with BAT at the end of Cycle 6, subjects will discontinue BAT and transition to NS-018 at 
Cycle 7 Day 1.  During this transition period, subjects treated with ruxolitinib will be required to taper off this treatment before initiation of NS-018.  The dose of ruxolitinib 
should be decreased every 7 days by up to 50% until the smallest dose possible has been given for a minimum duration for the total tapering period of 14 days.  Ruxolitinib 
should then be stopped 1 day before starting NS-018.  Subjects who are taking 5 mg QD of ruxolitinib are already on the lowest dose possible; therefore, tapering is not 
applicable in this case.  If recurrence of MF-related symptoms (upon discontinuation of ruxolitinib therapy) is noted, it is strongly suggested that therapy with ruxolitinib be 
restarted.  If restart is not possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg QD) is recommended.  Subjects administered with treatment other than 
ruxolitinib will undergo a minimum washout period of 1 week (7 days) prior to start of NS-018 treatment. 
o 
Subjects who discontinue study treatment or withdraw from the study will be asked to complete the end of study procedures within 14 days after the last dose.  If the end of 
study procedures occur at a regular scheduled visit, these procedures may be performed at that time. 
P 
Follow-up phone call will be done 30 (±3) days after the completion of end of study procedures. 
q  For WOCBP only, a negative serum pregnancy test will be required within 7 days prior to dosing on Cycle 1 Day 1, and a negative urine and/or serum pregnancy test will be 
required within 7 days prior to dosing on Day 1 of each cycle (local lab).  Of note to sites, if the urine test is the choice and is positive or cannot be confirmed as negative, a 
serum pregnancy test must be completed to confirm pregnancy result.  WOCBP will have pregnancy tests done monthly for early detection of pregnancy and discontinuation of 
study drugs. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
153 
Additional Assessment Guidance 
The table below clarifies the timing of specific assessment completion. 
 
Assessments 
Time restriction 
 
Predose 
Postdose 
Pharmacokinetics  
(NS-018 treatment arm only) 
Within 1 hour 
Cycle 1 Day 1 
0.5, 1, 2, 3, 4, 6, 8 hours (±10 min per time point) 
Cycle 2 Day 1 
0.5, 1, 2, 3, 4, 6, 8 hours (±10 min per time point) 
Vital signs 
Within 3 hours 
Not applicable  
ECOG performance status 
Within 24 hours 
Not applicable 
12-lead ECG 
Cycle 1 Day 1  
3 time points within 1 hour (eg, -45, -30, -15 min) 
Cycle 2 Day 1 
Within 1 hour  
 
Cycle 1 Day 1 
5 time points: 1, 2, 4, 6, and 8 hours (±10 min per time point) 
Cycle 1 Day 15 
2 (±10 min) hours 
Cycle 2 Day 1 
3 time points: 1, 2, and 4 hours (±10 min per time point) 
Cycle 4 Day 1 and thereafter every 3 cycles 
2 (±10 min) hours 
Phospho-STAT3  
(NS-018 treatment arm only) 
Cycle 1 Day 1 
Within 24 hours 
Cycle 2 Day 1 
Within 1 hour 
Cycle 1 Day 1 
3 hours (±10 min)  
Cycle 2 Day 1 
3 hours (±10 min) 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
154 
Assessments 
Time restriction 
 
Predose 
Postdose 
mRNA sequencing  
(NS-018 treatment arm only) 
Cycle 1 Day 1 
Within 24 hours 
Cycle 2 Day 1 
Within 1 hour 
Cycle 1 Day 1 
8 hours (±10 min) 
Abbreviations: ECG=electrocardiogram; ECOG= Eastern Cooperative Oncology Group; min=minutes; mRNA=messenger ribonucleic acid sequencing; STAT3=signal transducer 
and activator of transcription 3. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
155 
Appendix 18 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment version 3.0 is 
located directly before the table of contents. 
Protocol Amendment Summary of Change Table 
DOCUMENT HISTORY 
 
 
Document 
Date 
Substantial 
Region 
Version 2.0 
15 September 2022 
Yes 
Poland, Turkey, 
North America, 
and Asia 
Original Protocol 
13 October 2021 
 
Europe, North 
America, and 
Asia 
 
Amendment Global Version 2.0 (15 September 2022) 
This amendment for all sites participating in this study is considered substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union because it significantly impacts the safety or physical/mental 
integrity of subjects, the scientific value of the study, given the phase of this study, study 
population and expected menopausal status/use of contraception for the enrolled subjects. 
Overall Rationale for the Amendment: 
This amendment to the original protocol version 1.0 (dated 13 October 2021), was amended to 
consolidate the changes requested by the Food and Drug Administration (FDA South Korean 
Competent Authority).  Additionally, the protocol language related to contraception per Clinical 
Trials Facilitation Group (CTFG) guidance has been aligned to harmonize with EU submissions.  
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Updated version from 
original to Version 2.0, 
updated abbreviations and 
formatting as needed. 
Changes required amendment and new version and 
updates to text, tables, formatting. 
Sponsor Signatory page 
Removed statement 
regarding medical monitor. 
Removed names and contacts from Appendix 2 in 
accordance with template standards. 
1.1 Synopsis 
Sentence revised to clarify 
that additional safety 
laboratory assessments 
will be performed on Day 
8 and Day 22 of the first 
cycle (for subjects who are 
randomized to NS-018 and 
Added at the request of South Korea regulatory 
authority  


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
156 
Section # and Name 
Description of Change 
Brief Rationale 
subjects who switch to 
NS-018 from BAT) 
Changed ‘all central 
laboratory test results to 
‘all clinical laboratory test 
results’ in the safety 
analysis text  
Added at the request of South Korea regulatory 
authority 
1.1 Synopsis 
1.3 Schedule of 
Assessments 
4.1 Overall Design 
Added that sites in South 
Korea to follow a separate 
schedule of assessments in 
Appendix 14. 
Added for Clarification that South Korean sites 
follow a different schedule of assessments. 
1.1 Synopsis, Best 
Available Therapy Dosage 
4.1 Overall Design 
Specified BAT that may 
be used; added text 
regarding use of JAK 
inhibitors as standard of 
care. 
Modified for Clarification. 
Added that pacritinib is 
not allowed for BAT and 
subjects who are treated 
with pacritinib are not 
eligible to participate in 
the study.  
Clarification.  
1.1 Synopsis, Study Visits 
4.1 Overall Design 
Provided example of JAK 
inhibitor 
Modified for Clarification. 
1.1 Synopsis, Study Visits 
Added criteria of increase 
in spleen volume, clarified 
that subjects randomized 
to BAT arm (already on 
BAT or no therapy) and 
moved criteria that 
subjects need to meet 
criteria of at least 24 
weeks on BAT or disease 
progression, has not 
undergone splenic 
irradiation or splenectomy 
and does not meet criteria 
for leukemic 
transformation. 
Modified for Clarification. 
1.1 Synopsis, Study Visits 
1.2 Schema, study schema 
1.3 Schedule of 
Assessments 
4.1 Overall Design 
Added Investigator 
discretion for continuing 
BAT outside of the study 
if discontinued from the 
study and how long NS-
018 treatment may be 
continued. 
Modified for Clarification.   
1.1 Synopsis 
9.4.2 Safety Analyses  
Added that both central 
and local laboratory test 
results will be summarized 
for each treatment group. 
Modified for Clarification. 
1.1 Synopsis 
Added to overview of 
procedures timing of EQ-
5D-5L. 
Modified for Clarification. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
157 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Assessments 
Added overview of 
procedures table for BAT 
subjects for pre- and post-
Cycle 7. 
Modified for Clarification. 
1.3 Schedule of 
Assessments, footnote b 
Changed to 14 days 
Modified to match MRI assessment. 
1.3 Schedule of 
Assessments, footnote g 
Additional assessment 
guidance  
8.2.3 Electrocardiograms 
Added in SOA that 12-
lead ECG to be performed 
in all subjects at screening, 
after C1D1 for NS-018 
treatment arm only, and in 
additional assessment 
guidance that only for NS-
018 treatment arm; 
additional details added in 
ECG procedure section. 
Modified for Clarification. 
1.3 Schedule of 
Assessments, footnote b 
8.2.1 Physical 
Examinations 
Modified text for 
requirements for 
measurement of spleen by 
physical examination and 
timing pre-dose. 
To allow for flexibility if MRI and palpation cannot 
be done the same day. 
1.3 Schedule of 
Assessments, footnote d 
8.2.1 Physical 
Examinations 
Timing of spleen volume 
changed from 10 to 14 
days. 
Correction. 
4.0 Study Design 
Text was updated to 
clarify that additional 
safety laboratory 
assessments will be 
performed on Day 8 and 
Day 22 of the first cycle 
(for subjects who are 
randomized to NS-018 and 
subjects who switch to 
NS-018 from BAT).   
Added at the request of South Korea regulatory 
authority  
4.1 Overall Study Design, 
Best Available Therapy 
Dosage 
Specified BAT therapies 
and requirements to allow 
use of JAK inhibitor as 
BAT 
Modified for Clarification. 
4.1 Overall Study Design, 
Study Visits 
Added increase in spleen 
volume criteria. 
Preliminary results of this study indicated this to be 
relevant clinical marker. 
4.2 Scientific Rationale 
for Study Design 
Added year and version 
for NCCN clinical practice 
guidelines 
Updated guidelines available. 
4.3 Justification for Dose 
Removed previous text 
and added available data 
from completed Phase 1 
part of Study NS-018-101, 
recommendations of 
Safety Review Committee 
for justification of dose in 
this study. 
Clarified justification for the dose selection of NS-
018 300 mg BID in this study (Study NS-018-201).   


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
158 
Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria  
 
#6 Removed “average” for 
platelet count and 
modified timing. 
Modified for Clarification. 
#15 In addition to no 
investigational agent 
within 28 days, added 
number of half-lives and 
criteria of which to use. 
Modified for Clarification. 
5.1 Inclusion Criteria #16 
Modified contraception 
language requirements. 
To align with CTFG requirements and FDA guidance 
for genotoxic drugs of 180 days. 
5.2 Exclusion Criteria #1 
Added “including active 
tuberculosis infection.” 
Requested by South Korean regulatory authority. 
5.2 Exclusion Criteria #2 
Added contraindication 
language for BAT 
Modified for Clarification. 
5.2 Exclusion Criteria #4 
Added hypersensitivity to 
NS-018 or excipients. 
Modified for Clarification. 
4.1 Overall Design 
Table 3 
Modified BAT reference 
from manufacturer’s 
information to product 
label throughout. 
Modified for Clarification. 
6.5 Concomitant Therapy 
Added guidance to follow 
product label of any 
comparator therapies. 
Modified for Clarification. 
8.0 Study Assessments 
and Procedures 
Text was updated to 
clarify that additional 
safety laboratory 
assessments will be 
performed on Day 8 and 
Day 22 of the first cycle 
(for subjects who are 
randomized to NS-018 and 
subjects who switch to 
NS-018 from BAT)  
Added at the request of South Korea regulatory 
authority  
8.0 Study Assessments 
and Procedures 
Added that additional 
visits required for subjects 
in South Korea and cross 
reference to Appendix 14. 
Additional assessments added at the request of South 
Korea regulatory authority and are specific to this 
country. 
8.1.3 Bone Marrow 
8.2.4 Clinical Laboratory 
Safety Assessments 
Subjects transitioning from 
BAT to NS-018 before or 
at Cycle 7 Day 1 will 
follow the same visit 
schedule as subjects 
randomized to NS-018 
Modified for Clarification. 
8.1.6.1 Patient-Reported 
Outcomes Measurement 
Information System 
(PROMIS) Fatigue Short 
Form (F-SF) 7b 
Added that assessment to 
be performed as defined in 
SOA and including all 
subjects transitioning from 
BAT to NS-018. 
Modified for Clarification. 
8.2.1 Physical 
Examinations 
Modified text for physical 
examination details; added 
window for measurement 
relative to first dose. 
Modified for consistency with Schedule of 
Assessments. 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
159 
Section # and Name 
Description of Change 
Brief Rationale 
8.2.4 Clinical Laboratory 
Assessments 
Sentence revised to clarify 
that except for the 
assessments on Day 8 and 
Day 22 of the first cycle, 
all other safety laboratory 
assessments will be 
performed at the central 
laboratory  
Added at the request of South Korea regulatory 
authority  
8.2.4 Clinical Laboratory 
Assessments 
Appendix 3 
Added that additional 
visits required for subjects 
in South Korea and tests to 
be performed by local vs. 
central laboratory. 
Added at the request of South Korea regulatory 
authority and are specific to this country. 
8.3.6 Adverse Events of 
Special Interest 
Removed extrapulmonary 
and added development of 
TB.  Added reference to 
Appendix 4. 
Modified to collect any development of tuberculosis 
not only extrapulmonary tuberculosis.  Reference to 
Appendix 4 added to guide to definition of AESI. 
Section 9.4.2. Safety 
Analysis  
Changed ‘all central 
laboratory test results to 
‘all clinical laboratory test 
results’ in the safety 
analysis text 
Added at the request of South Korea regulatory 
authority 
Appendix 2 
Removed contact 
information for medical 
monitor and sponsor 
medical representative. 
Removed in accordance with template standards. 
Appendix 2, 
Administrative Structure 
Changed imaging and 
ECG collection, review, 
and analysis to Clario. 
Changed vendors. 
Appendix 2, Data Quality 
Assurance 
Records retention changed 
to 10 years. 
Changed per current NSP records retention policy. 
Appendix 2, Study and 
Study Center Closure 
Added requirements 
regarding unjustifiable 
risk, new scientific 
evidence, 
sponsor/regulatory request, 
insufficient recruitment, 
and withdrawal of license 
to manufacture. 
Clarified additional requirements. 
Appendix 3 
Sentence revised to clarify 
that all tests detailed in 
Table 8 will be performed 
by the central laboratory at 
all timepoints, except for 
the assessments on Day 8 
and Day 22 of the first 
cycle, and the screening 
test for latent tuberculosis, 
which will be performed 
by the local laboratory.   
Added at the request of South Korea regulatory 
authority 
Table updated to include 
latent tuberculosis test at 
screening 
Added at the request of South Korea regulatory 
authority 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
160 
Section # and Name 
Description of Change 
Brief Rationale 
Appendix 6 
Added to notes, failure rate 
clarification and modified 
guidance to 180 days post 
last dose for WOCBP; 
extended sperm donation 
interval, abstinence from 
intercourse for male 
subjects with WOCBP, 
and female subject 
contraception requirements 
(removed hormonal 
contraception) for 
participation in the study.   
Modified to harmonize the protocol language related 
to contraception per Clinical Trials Facilitation Group 
(CTFG) guidance and has been aligned to harmonize 
with EU submissions. 
Appendix 13 
Modified requirements 
from central review to 
local assessment of bone 
marrow.   
Clarified bone marrow assessments will be done 
locally. 
Appendix 14 
Added schedule of 
assessments specific to 
South Korea. 
Provided study assessments schedule to address 
requests made by South Korea regulatory authority. 
Appendix 14 
Schedule of Assessments 
was revised to indicate that 
additional safety 
laboratory assessments 
will be performed on Day 
8 and Day 22 of the first 
cycle (for subjects who are 
randomized to NS-018 and 
subjects who switch to 
NS-018 from BAT)  
Added at the request of South Korea regulatory 
authority  
A test for latent 
tuberculosis was added at 
screening  
Added at the request of South Korea regulatory 
authority 
 
 
 
 
 


CONFIDENTIAL 
Final Protocol NS-018-201 - Protocol V3.0 
 
161 
Appendix 19 
Signature of Investigator 
PROTOCOL TITLE:  A Phase 2b, Open-label, Multicenter, Randomized, Controlled, 2-Arm 
Study to Assess the Efficacy and Safety of Orally Administered NS-018 Versus Best Available 
Therapy in Subjects with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or 
Post-Essential Thrombocythemia Myelofibrosis with Severe Thrombocytopenia (Platelet Count 
<50,000/μL) 
PROTOCOL NO: 
NS-018-201 
VERSION:  
 
Protocol Version 3.0 
This protocol is a confidential communication of NS Pharma, Inc, I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol.  I will also work consistently 
with the ethical principles that have their origin in the Declaration of Helsinki and that are 
consistent with Good Clinical Practices and the applicable laws and regulations.  Acceptance of 
this document constitutes my agreement that no unpublished information contained herein will 
be published or disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, title, and the name of the study 
center in which the study will be conducted.  Return the signed copy to the CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      __________________________            Date:  ________________ 
Printed Name:                         __________________________ 
Investigator Title:                   __________________________ 
 
Name/Address of Center:        __________________________ 
 
 
 
 
 __________________________ 
 
 
 
 
 __________________________ 
 

SAP_001.pdf: 




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CONTENTS
I.Introduction ........................................................................................................................... 7
A. Background ........................................................................................................... 7
B. Protocol and Amendment History...................................................................... 9
II.Protocol Objectives........................................................................................................... 10
A. Primary Objectives............................................................................................. 10
B. Secondary Objectives........................................................................................ 10
C. Exploratory Objectives....................................................................................... 10
III.Study Endpoints and Estimands ................................................................................... 11
A. Primary Endpoints.............................................................................................. 11
B. Secondary Endpoints ........................................................................................ 11
C. Exploratory Endpoints ....................................................................................... 11
D. Estimands Considerations................................................................................ 12
IV.Study Design.................................................................................................................... 13
A. Design Overview ................................................................................................ 13
B. Study Population ................................................................................................ 15
C. Sample Size Predictions ................................................................................... 15
D. Treatment Randomization and Blinding ......................................................... 16
E. Assessment Schedule....................................................................................... 16
V.Interventions...................................................................................................................... 18
A. Clinical Trial Material (CTM)............................................................................. 18
B. Study Procedures............................................................................................... 19
VI.General Analytical Considerations ............................................................................... 20
A. Data Sources ...................................................................................................... 20
B. Visit Windows...................................................................................................... 20
C. Definition of Baseline......................................................................................... 20
D. Missing Data ....................................................................................................... 21
E. Multiple Study Centers ...................................................................................... 22
F. Covariate Adjustment in Primary Analysis ..................................................... 22
G. Multiplicity Adjustment....................................................................................... 22
H. Interim Analyses or Timing of Analyses ......................................................... 22
I.
Analysis Populations.......................................................................................... 23
J. Data Display Characteristics ............................................................................ 24
VII.Subject Accountability ................................................................................................... 24
A. Disposition........................................................................................................... 24
B. Protocol Deviations and Population Inclusions ............................................. 25
C. Subject Characteristics...................................................................................... 26


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VIII.Efficacy Analyses.......................................................................................................... 27
A. Definition of Efficacy Outcomes....................................................................... 27
B. Analysis Methods for Primary Efficacy Analysis ........................................... 32
C. Sensitivity and Supporting Analysis ................................................................ 33
D. Analysis Methods for Secondary Efficacy Analysis ...................................... 33
E. Analysis Methods for Exploratory Analysis .................................................... 33
IX.Safety Analyses............................................................................................................... 35
A. Exposure to NS-018 .......................................................................................... 35
B. Exposure to BAT ................................................................................................ 37
C. Adverse Events................................................................................................... 37
D. Clinical Laboratory Results............................................................................... 38
E. Vital Signs............................................................................................................ 40
F. Physical Examination ........................................................................................ 40
G. Prior and Concomitant Medications ................................................................ 40
H. Electrocardiograms (ECG)................................................................................ 41
X.Pharmacokinetic and Pharmacodynamic Analyses.................................................... 41
A. Pharmacokinetics............................................................................................... 41
B. Pharmacodynamics ........................................................................................... 42
XI.References ....................................................................................................................... 42
Appendix 1
Revised Response Criteria for Myelofibrosis : International Working Group-
Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European 
LeukemiaNet (ELN) Consensus Report ........................................................................... 44


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List of abbreviations terms and Definitions of Terms
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BAT
best available therapy
BCR-ABL1
Breakpoint Cluster Region- Abelson 1
BID
twice daily (“bis in die” Latin)
Cmax
maximum concentration
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
Contract Research Organization
CT
computed tomography
CTCAE v5.0
Common Terminology Criteria for Adverse Events version 5.0
CYP
cytochrome P450
DIPSS
Dynamic International Prognostic Scoring System
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ET
essential thrombocythemia
EMH
extramedullary hematopoiesis
ETMF
essential thrombocythemia myelofibrosis
FLT3
Fibromyalgia syndrome -like tyrosine kinase 3
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IPSS
International Prognostic Scoring System
ITT
Intention-to-treat
IWG
International Working Group
IWG-MRT
International Working Group for Myelofibrosis Research and Treatment
IWRS
interactive web response system
JAK
Janus kinase 
MF
myelofibrosis
MFSAF v4.0
Myelofibrosis Symptom Assessment Form version 4.0
mITT
Modified intention-to-treat
MPN
myeloproliferative neoplasm
MRI
magnetic resonance imaging
PcD
pharmacodynamic(s)
PK
pharmacokinetics


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Abbreviation
Definition
PMF
primary myelofibrosis
PV
polycythemia vera
PVMF
polycythemia vera myelofibrosis
QD
once daily
QoL
Quality of Life
QTcF
QT Interval Corrected Using Fridericia's Correction
RNA
ribonucleic acid
mRNA
messenger ribonucleic acid
SAE
serious adverse event
SAF
safety population
SAP
statistical analysis plan
STAT3
signal transducer and activator of transcription (3)
SVR
spleen volume reduction
TEAE
treatment-emergent adverse event
TSS
total symptom score
ULN
upper limit of normal
WHO
World Health Organization


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I. Introduction
A. Background
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm 
(MPN) characterized by bone marrow fibrosis, anemia, progressive 
splenomegaly, extramedullary hematopoiesis (EMH), debilitating 
constitutional symptoms, cachexia, leukemic progression, shortened 
survival, and compromised quality of life (QoL). Myelofibrosis may be de 
novo or secondary to polycythemia vera (PV) or essential 
thrombocythemia (ET).  Approximately 90% of subjects with MF carry 
mutations in any of the 3 driver genes: Janus kinase 2 (JAK2) in 
approximately 60% of cases, calreticulin in approximately 20%, and 
myeloproliferative leukemia virus oncogene in approximately 10%. Mutant 
proteins activate the JAK/signal transducers and activators of 
transcription pathway and other pathways downstream, leading to 
myeloproliferation, proinflammatory cytokine expression, and bone 
marrow remodeling. 
MF is associated with a heterogenous clinical phenotype, stratifying 
subjects by prognosis can facilitate choice of appropriate treatment and 
identify candidates for high-risk procedures such as transplant. The 
International Prognostic Scoring System (IPSS), used at diagnosis, 
utilizes 5 independent predictors of inferior survival to determine disease 
risk in primary MF: age >65 years, hemoglobin <10 g/dL, white cell count 
>25 × 109/L, circulating blasts ≥1%, and presence of constitutional 
symptoms. The presence of 0, 1, 2, or ≥3 adverse features indicates low-, 
intermediate 1-, intermediate 2-, or high-risk disease, respectively, and 
corresponding median survival times range from approximately 11.3 to 
2.3 years.  The Dynamic International Prognostic Scoring System 
(DIPSS) can be used to stratify prognosis at any time during the disease 
course.  The DIPSS includes the same 5 prognostic factors as the IPSS 
but ascribes greater weight to low hemoglobin (2 points instead of 1); risk 
scoring is modified accordingly, and corresponding median survival 
estimates for low-, intermediate 1-, intermediate 2-, and high-risk 
diseases range from not reached to 1.5 years. The subsequent DIPSS-
Plus includes 3 additional independent prognostic factors: red blood cell 
(RBC) transfusion dependence, platelet count <100 × 109/L, and 
unfavorable karyotype. 
Until 2019, ruxolitinib, a dual JAK1/JAK2 inhibitor that was approved by 
the United States (US) Food and Drug Administration (FDA) in 2011 and 
by the European Medicines Agency in 2012, was the only available drug 


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indicated for treatment of intermediate- and high-risk MF.  Evidence 
suggests there may be a survival benefit with ruxolitinib compared with 
conventional therapies. Subjects treated with ruxolitinib frequently 
experience gradual loss of response, have a suboptimal response, or 
develop cytopenias during treatment, resulting in ruxolitinib 
discontinuation within a few months and therefore, a subsequent risk of 
disease rebound. In the Phase III COMFORT-I and COMFORT-II trials, 
pooled ruxolitinib discontinuation rates at 3 and 5 years were 
approximately 50% and approximately 70%, respectively. Suboptimal 
ruxolitinib dosing to avoid treatment-related AEs, at least initially, appears 
to be relatively common. 
Fedratinib is an oral JAK2 inhibitor with activity against wild-type and 
mutationally activated JAK2 and Fibromyalgia syndrome-like tyrosine 
kinase 3 (FLT3).  In August 2019, the US FDA approved fedratinib for 
treatment of adult subjects with intermediate-2 or high-risk primary or 
secondary MF.  The National Comprehensive Care Network (NCCN) 
clinical practice guidelines for treatment of MPNs now includes fedratinib 
as an option for subjects with intermediate-2 or high-risk MF with platelet 
count ≥50 × 109/L, used as initial therapy or as second-line therapy for 
subjects previously treated with ruxolitinib.
Despite the benefits reported with ruxolitinib as the first-line treatment, a 
high proportion of subjects discontinue treatment; the 1-, 2-, and 3-year 
discontinuation rates are 49%, 71%, and 86%, respectively.  For subjects 
who discontinue treatment with ruxolitinib, the median overall survival is 
dismal and ranges from 13 to 16 months.  There remains a great unmet 
need for subjects who are nonresponsive to and have discontinued 
treatment with a JAK inhibitor.
A detailed description of the chemistry, pharmacology, safety, and key 
findings of nonclinical and clinical studies for NS-018 is provided in the 
current Investigator’s Brochure (IB).
NS-018 is currently being developed as a therapeutic agent for MPN
including MF.  NS-018 has been shown to have specificity for inhibiting 
activated JAK2 and is expected to have a wide therapeutic range, 
providing a satisfactory margin of safety between its efficacy and its 
safety.  In the Phase 2 part of the Phase 1/Phase 2 study, 15 out of 20 
subjects had an SVR of 0% to 50% at Cycle 7 since baseline.  One 
subject who had a baseline platelet count of <50,000/μL, achieved ≥35% 
SVR at Cycle 7.  The available safety data in the Phase 1/Phase 2 study 
indicate an overall acceptable safety and tolerability profile for NS-018.  
Based on these data, NS-018 is considered to have a positive benefit-risk 
ratio for the treatment of subjects with MF and with platelet count of 
<50,000/μL.


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Treatment with specific therapy such as the JAK inhibitor, ruxolitinib, was 
observed in minority of subjects with platelets below 100,000/μL, which is 
in line with previous reports.  Although there are case reports and series 
in which JAK inhibitors have been used successfully with improvement of 
platelet count, JAK inhibitors are not recommended for subjects with 
severe thrombocytopenia according to the NCCN clinical practice 
guidelines for treatment of MPNs.  The management of severe 
thrombocytopenia remains unresolved, and future studies focused on 
subjects with low platelets are deeply needed, to extend their extremely 
limited treatment armamentarium.  Several reports showed additional 
significant negative impact of severe thrombocytopenia (<50,000/μL) on 
prognosis of these subjects, but little is known about the impact of severe 
thrombocytopenia on the outcome of subjects with PMF versus
post-PVMF versus post-ETMF. The fact that 1 subject with a baseline 
platelet count of <50,000/μL achieved ≥35% SVR at Cycle 7 of the NS-
018 clinical study as well as the current clinical situation described above, 
it would be worth considering that NS-018 may have a positive benefit-
risk ratio for the treatment of subjects with MF with platelet count of 
<50,000/μL.
The protocol, NS-018-201, describes the general approach to analysis of 
data from the study.  This Statistical Analysis Plan outlines the statistical 
principles which will be used to analyze and present the data, including 
definition of endpoints, stopping rules, and analysis populations. Table, 
Figure, and Listing shells will be supplied in an accompanying document. 
B. Protocol and Amendment History
This Statistical Analysis Plan (SAP) is based on the Protocol Amendment 
version 3.0 dated 07 August 2023.
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Document
Date
Amendment 
No.
Substantial
Region
Version 3.0
07 August 2023
2
Yes
Europe, North America, 
Turkey, Poland, and Asia
Version 2.0
15 September 
2022
1
Yes
Poland, Turkey, North America, 
and Asia
Original 
Protocol
13 October 
2021
-
-
Europe, North America, and 
Asia.


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This SAP will govern the analysis of data from this study. The plan can be 
modified up to the database lock to reflect any changes to the protocol 
because of amendments. Any amendments to the protocol, which do not 
affect the statistical analyses, will not necessitate an update to this 
document. Additional post-hoc or unplanned analyses, which are not 
defined in this SAP, may be performed to support the clinical 
development program. Such analyses will be documented in the CSR as 
deviations from the analysis plan. 
II. Protocol Objectives
A. Primary Objectives
The primary objective is to compare the efficacy of the dose of 300 mg bis 
in die (BID) of NS-018 to the Best Available Therapy (BAT) in subjects 
with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis 
(post-PVMF), or post essential thrombocythemia myelofibrosis (post-
ETMF) with severe thrombocytopenia and to also compare the effect of 
the dose of 300 mg BID of NS-018 on MF-associated symptoms as 
measured by Myelofibrosis Symptom Assessment Form version 4.0 
(MFSAF v4.0) to the BAT.
B. Secondary Objectives
Secondary objectives of the study are to evaluate whether the dose of
300 mg BID of NS-018 is safe and demonstrates probable benefit for the 
best splenic response as compared to BAT.
C. Exploratory Objectives
Exploratory objectives of the study are:

To evaluate the effect of NS-018 on fatigue, on health-related QoL 
and utility using the EQ-5D-5L, on a bone marrow fibrosis, 
phosphorylation of STAT3, on platelet, RBC, and transfusion. 

To evaluate plasma PK of NS-018 in the study population.

To evaluate efficacy, as measured by the rates of complete 
response (CR), partial response (PR), clinical improvement, stable 
disease (SD), progressive disease (PD) and relapse, based on the 
IWG-MRT response criteria.

To explore changes in the expression profile of mRNA by NS-018 
versus baseline assessment.


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
To evaluate the splenic response and the effect on improvement of 
MF-associated symptoms and fatigue up to Week 48.

To evaluate the splenic response and the effect on improvement of 
MF-associated symptoms and fatigue after transitioning from BAT 
to NS-018.
III. Study Endpoints and Estimands
A. Primary Endpoints
The study has co-primary endpoints:

Proportion of subjects who achieve ≥35% reduction in spleen 
volume from baseline to Week 24 as measured by MRI (or by CT 
for applicable subjects). 

Proportion of subjects who achieve ≥50% reduction in total 
symptom score from baseline to Week 24 as measured by the 
MFSAF v4.0.
B. Secondary Endpoints
The protocol describes as secondary endpoints the following:

Proportion of subjects who achieve ≥35% reduction in spleen 
volume from baseline at any time up to Week 24 as measured by 
MRI (or by CT for applicable subjects)

Comparison of the safety of NS-018 versus BAT
C. Exploratory Endpoints
The following exploratory endpoints will be evaluated:

Improvement in fatigue as measured by Patient-Reported 
Outcomes Measurement Information System (PROMIS) Fatigue 
Short Form (F-SF) 7b.

Change on health-related QoL and utility using EQ-5D-5L

Plasma concentration of NS-018.

Improvement of bone marrow fibrosis.

Inhibition of phospho-STAT3.

Rates of CR, PR, clinical improvement, SD, PD and relapse as 
measured by the IWG-MRT response criteria.

Proportion of subjects with platelet count of ≥50,000/μL at 
Weeks 12 and 24.

Proportion of platelet transfusion-independent subjects at 
baseline with improvement in grade of thrombocytopenia at 
Week 24.




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Co-Primary
The co-primary 
estimand of this study 
is the effect of NS-
018 compared to the 
BAT as measured by 
≥50% reduction in 
total symptom score 
of MFSAF v4.0 from 
baseline to Week 24 
Subjects with 
PMF, PPV-
MF, or PET-
MF.
Proportion of 
responders, 
defined as subjects 
who achieved at 
least 50% 
reduction in total 
symptom score at 
Week 24 
compared to 
baseline.
Difference in 
proportion of 
responders for the 
key secondary 
endpoint between 
NS-018 and BAT 
treatment arms will 
be analyzed as 
described in 
Section VIII.B
Intercurrent events are patient-level events that either change the 
meaning of a patient’s data or make it impossible to collect that data. 
Values of endpoints can also be missing for reasons other than 
intercurrent events. Consideration of intercurrent events and strategies to 
assess their impact are described here:
x
Subjects who take prohibited medication during the study will be 
analyzed by the treatment policy strategy, i.e., data collected after the 
initiation of prohibited medications will be included in analysis as 
collected.
x
Subjects with dosing adjustments, missing doses or severe treatment 
non-compliance during the study will be analyzed by the treatment 
policy strategy.
x
Any major protocol deviations that could influence spleen size or TSS 
will be analyzed with a composite strategy:  1) The Main Analytical 
Approach: Treatment Policy strategy; 2) Supplementary Analyses: 
exclusion from Per Protocol (PP) set.  
x
Week 24 spleen size or TSS data are not available.  For example, a 
subject withdraws from the study prior to Week 24 with or without 
giving a reason or becomes lost to follow-up. A composite strategy will 
be adopted:  The Main Analytical Approach is, per the protocol and to 
be conservative, subjects missing the Week 24 assessments will be 
considered as non-responders for the Primary Analysis.  In addition, 
sensitivity analysis related to imputation of missing data will be 
performed, as described in Section VIII.C. 
IV.Study Design
A. Design Overview


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This is a Phase 2b, open-label, multicenter, randomized, controlled, 2-
arm study intended to compare the efficacy and safety of NS-018 versus 
BAT in subjects with PMF, post-PVMF, or post-ETMF. A total of 120 
subjects who meet eligibility criteria and consent to participate in the 
study will be stratified at baseline by spleen volume and by history of prior 
JAK inhibitor treatment and randomly assigned in a 1:1 ratio to receive 
either NS-018 or BAT (control arm). The stratification factors will be as 
follows:
1) spleen volume (≥
 cm3 vs <
 cm3)
2) JAK inhibitor (naïve vs prior treatment).
Subjects will have regularly scheduled study visits at Screening, Day 1 
and Day 15 of Cycles 1, 2, 3, 4, 5, and 6, and Day 1 of every cycle 
thereafter. 
Subjects in South Korea only will have additional visits on Day 8 and Day 
22 of the first cycle for safety laboratory assessments. 
The screening period is 28 days before start of treatment. One cycle is 28 
days.
During screening, all subjects will be evaluated for active tuberculosis 
(except in UK).  Additionally, inactive (latent) tuberculosis testing will be 
done in UK and South Korea by local laboratory for all subjects. At Cycle 
1 Day 1, before the subject starts study treatment, all eligibility criteria 
including the subject’s status for coronavirus disease 2019 (COVID-19) 
should be reviewed and confirmed. All subjects will be treated from Cycle 
1 Day 1 through the end of the study. There will be an indefinite period 
from Cycle 7 Day 1 until the subject meets the criteria for the 
discontinuation of study treatment (see protocol Section 7.1), or until 3 
years (expected) after the first subject is enrolled at any of the study 
centers, whichever comes first.
Subjects who complete the treatment period will complete the end of 
study procedures within 14 days after the last dose.
Subjects who discontinue prior to completing the treatment period will be 
asked to complete the end of study procedures within 14 days after the 
last dose.
If the end of study procedures occurs at a regularly scheduled visit, these 
procedures may be performed at that time.
A 30-day follow-up phone call will be scheduled after completion of the 
end of study procedures.
≥


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An IDMC will be set up to oversee safety across the life span of the study 
and all specifics will be captured in the IDMC charter. IDMC data review 
meetings will be scheduled quarterly intervals during the study timeline, 
resulting in a minimum of eight (8) planned data review meetings. The 
first data review meeting will happen after 3 subjects randomized to NS-
018 treatment arm have been enrolled and completed Cycle 2 Day 1 of 
the study. Subsequent meetings will be held quarterly.
The IDMC will also review the results of the interim analysis for futility.
B. Study Population
Eligible subjects for this study are male or female (non-pregnant and non-
lactating female for Germany and UK) aged 18 years or older who have 
been diagnosed with the DIPSS risk categories of intermediate -2 or high-
risk PMF, post-PVMF, or post-ETMF with severe thrombocytopenia 
(platelet count <50,000/μL) with life expectancy >6 months. Subjects
must have had no MF-directed (other than JAK inhibitor) for at least 2 
weeks prior to initiation of NS 018 or BAT and met pre-specified 
laboratory values for selected parameters (spleen volume of at least 450 
cm3 measured by MRI or by CT, TSS ≥10 on MFSAF v4.0, Peripheral 
blood blast count <10%, Estimated creatinine clearance ≥40 mL/min/1.73 
m2, AST and ALT ≤3 × ULN and a direct bilirubin ≤1.5 × ULN, Absolute 
neutrophil count >500/μL ) in addition to multiple other required eligibility 
criteria (ECOG performance status ≤2, QTcF ≤480 msec). Subjects may 
or may not have received prior therapy for MF including JAK inhibitor.
Subjects who are not eligible for this study are subjects with Active, 
uncontrolled systemic infection including active tuberculosis infection, 
subjects with active hepatitis A, B, C or who are HIV-positive, and 
subjects with serious cardiac condition within the past 6 months or who 
have been diagnosed with another malignancy within 2 years prior to 
enrollment or who have had surgery within 4 weeks of screening.
Subjects with suspected, probable, or confirmed diagnosis of COVID-19 
are excluded from study participation.
C. Sample Size Predictions
A total of 120 randomized subjects (60 in each treatment arm) is planned. 


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Assuming a splenic response rate of 20% in the NS-018 arm and 1% in 
the BAT arm, there is 93.5% power at the final analysis to maintain a type 
I error rate of 5% (i.e., a 2-sided significance level using Fisher’s exact 
test is 5%).  Similarly, assuming a symptom response rate of 33% in the 
NS-018 arm and 8% in the BAT arm, the power of the final analysis to 
maintain a type I error rate of 5% is 91.0%. Assuming that there is no 
correlation between spleen volume reduction and TSS reduction, the 
power to reject the null hypothesis for both endpoints is 85.1%.
D. Treatment Randomization and Blinding
This study is an open-label design in which Investigators, subjects, 
Sponsor and CRO will know the treatment assignment.
When screening assessments are completed and eligibility is confirmed, 
subjects will be randomized to a study arm in 1:1 ratio using centralized 
IWRS.
Randomization will be stratified by spleen volume (≥
 cm3 vs 
cm3) and a history of prior JAK inhibitor treatment (naïve vs prior 
treatment).
Spleen volume will be assessed by the central reader who will be blinded 
to treatment assignments.
E. Assessment Schedule
All subjects will be treated from Cycle 1 Day 1 through the end of the 
study. The acceptable visit window for scheduled visits is ± 3 days.  
The following table provides the different assessment across the visit 
schedules.
Table 2 : Summary of the schedule of study procedures.
Visit Timing
Study procedure
Screening 
Day -28 to Day 0 
Informed consent, Review/confirm eligibility criteria, COVID-19 status 
verification, Genetic substudy informed consent (optional), Medical 
history, Physical examination, MRI/CT (spleen volume measurement), 
Vital signs, ECOG PS, Active tuberculosis, Clinical laboratory (by 
central lab), Latent tuberculosis** (local laboratory), Pregnancy test, 
12-lead ECG, Bone marrow assessment, AEs, Concomitant 
therapies/procedures/medication.


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Cycle 1
Day 1 (Day 1/ WK 0)
Review/confirm eligibility criteria, Vital signs, ECOG PS, Clinical 
laboratory (by central lab), 12-lead ECG, Genetic profiling, 
EQ-5D-5L, Randomization, Dispense study treatment/diary, AEs, 
Concomitant therapies/procedures/medication.
NS-018 treatment arm only: PK sampling, Phospho-STAT3, mRNA 
sequencing.
Day 8 (Day 8/ WK 1)
Clinical laboratory*(by local lab)
Day 15 (Day 15/ WK 2) 
Clinical laboratory (by central lab), 12-lead ECG, AEs, Concomitant 
medication.
Day 22 (Day 22/WK3)
Clinical laboratory*(by local lab)
Cycle 2
Day 1 (Day 29/ WK 4)
Physical examination, Vital signs, Clinical laboratory, 12-lead ECG, 
Response assessment (IWG MRT and ELN), Dispense study 
treatment/diary, AEs, Concomitant therapies/procedures/medication.
NS-018 treatment arm only: PK sampling, Phospho-STAT3, mRNA 
sequencing.
Day 15 (Day 43/ WK 6) 
Clinical laboratory (by central lab), AEs, Concomitant medication
Cycle 3
Day 1 (Day 57/ WK 8)
Physical examination, Vital signs, Clinical laboratory, Response 
assessment (IWG MRT and ELN), Dispense study treatment/diary, 
AEs, Concomitant medication
Day 15 (Day 71/ WK 10) 
Clinical laboratory (by central lab), AEs, Concomitant medication
Cycle 4
Day 1 (Day 85/ WK 12)
Physical examination, MRI/CT (spleen volume measurement), Vital 
signs, Clinical laboratory, 12-lead ECG, Response assessment (IWG 
MRT and ELN), Dispense study treatment/diary, AEs, Concomitant 
medication
Day 15 (Day 99/ WK 14) 
Clinical laboratory (by central lab), AEs, Concomitant medication
Cycle 5
Day 1 (Day 113/ WK 16)
Vital signs, Clinical laboratory (by central lab), Dispense study 
treatment/diary, AEs, Concomitant medication
Day 15 (Day 127/ WK 18) 
Clinical laboratory (by central lab), AEs, Concomitant medication
Cycle 6
Day 1 (Day 141/ WK 20)
Vital signs, Clinical laboratory (by central lab), Dispense study 
treatment/diary, AEs, Concomitant medication
Day 15 (Day 155/ WK 22) 
Clinical laboratory (by central lab), AEs, Concomitant medication
Cycle >=7
Day 1 (Every +Day 28/ WK 4)
Vital signs, Clinical laboratory (by central lab), AEs, Concomitant 
medication.
Cycle 7 and Every 3 cycles: Physical examination, 12-lead ECG, 
Response assessment (IWG-MRT and ELN), Dispense study 
treatment/diary. 
Cycles 7, 10 and 13: MRI/CT (spleen volume measurement)
Cycle 7 and Every 6 cycles: EQ-5D-5L
Cycles 7, 13 and every 12 cycles: Bone marrow assessment 


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Complete End-of-Study Procedures
Physical examination, MRI/CT (spleen volume measurement), Vital 
signs, ECOG PS, Clinical laboratory (by central lab), Pregnancy test 
(serum), 12-lead ECG, Response assessment (IWG MRT and ELN), 
AEs, Concomitant medication
End of Study 30-Day Follow-up (Phone call)
AEs, Concomitant medication
* For South Korean Sites Only.
** For UK and South Korean Sites Only.
During the screening period, subject will complete the MF-SAF v4.0
assessment daily. The first 7 consecutive days of diary data will be used for 
eligibility assessment. Subject will complete the MF-SAF from Day −7 of 
Cycle 1 Day 1 to the end of Cycle 6 (Day 168) and the last 7 days in each 
cycle thereafter until the end of Cycle 12 (Day 336) for efficacy assessment.
The PROMIS questionnaire must be completed daily during the screening 
period and the last 7 days of each cycle until the end of Cycle 12 (Day 336). 
This assessment will be performed for all subjects including subjects 
transitioning from BAT to NS-018.
V. Interventions
A. Clinical Trial Material (CTM)
The drug product is NS-018 (ilginatinib), a potent and specific JAK2 
inhibitor which was designed and synthesized by Nippon Shinyaku Co., 
Ltd. NS-018 is being developed as a therapeutic agent for MPN including 
MF.
NS-018 is provided in film-coated tablets orally administrated. The tablet 
contains 100 mg of active NS-018 drug substance and the following 
inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, hydroxypropyl cellulose, and magnesium 
stearate. Additionally, the coating film Opadry OY-L-28900 contains 
polyethylene glycol, hypromellose, titanium dioxide and lactose 
monohydrate.
Subjects will self-administer 300 mg BID of NS-018 2 hours or more after 
the last meal and at least 1 hour before the next meal. Each dose must 
be administered 8 to16 hours apart.
The BAT will be administered according to manufacturer’s instructions 
and Investigator discretion. The Investigator will decide the BAT that will 
be administered to the subject during the screening period based on 


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subject’s condition.  The BAT may include hydroxyurea, danazol, 
fedratinib, ruxolitinib, interferon, corticoid, erythropoietin, purinethol, 
thalidomide, lenalidomide or ‘supportive care/therapy’. The BAT 
‘supportive care/therapy’ refers to use of blood products, fluids 
(crystalloids), pain medications, and/or antibiotics, that subjects will need 
to manage myelofibrosis symptoms and complications.  Subjects in the 
control group will receive BAT at doses and schedules selected by the 
Investigator based on the subject’s condition and according to the 
manufacturer’s instructions or the Investigator’s discretion.  The BAT 
must be a single agent and cannot be combined with other agents.  JAK 
inhibitor can be allowed as BAT if the JAK inhibitor was administered as a 
standard of care based on the product label or Investigator’s discretion. 
The BAT may be changed at any time during the randomized treatment 
period based on the Investigator’s clinical assessment of the subject’s 
condition.  However, it is not allowed to change the BAT to JAK inhibitor if 
it was not used as standard of care treatment prior to study participation. 
No experimental agents (those not approved for any indication) may be 
used at any time.
B. Study Procedures
Subjects meeting the eligibility criteria were screened for the study after 
the nature and purpose of the protocol were explained to them, and they 
or a legally authorized representative voluntarily granted written informed 
consent to participate.
Subjects will receive NS-018 or BAT according to treatment assignment 
from Cycles 1 to 6 until one of the following criteria for disease 
progression is met:
1.
Increase in spleen volume of ≥15% measured by MRI (or by CT 
for applicable subjects) from the baseline for subjects who are 
randomized to NS-018 or transitioned to NS-018. 
2.
Splenic irradiation or splenectomy.
3.
Leukemic transformation defined by an increase in peripheral 
blood blast percentage to ≥20% that is sustained for at least 8 weeks.
4.
Leukemic transformation defined by bone marrow blast count of 
≥20%.
5.
Death.
Subjects who meet the criteria for increase in spleen volume of >15% 
measured by MRI (or by CT for applicable subjects), leukemic 
transformation, or have had splenic irradiation will be discontinued from 


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the study treatment and will be asked to complete the end of study 
procedures.  Subjects randomized to the BAT arm (ie, subjects already 
on BAT or ‘supportive care/therapy’) and met all of the following criteria 
may transition to NS-018 treatment:  
x
Subject has completed at least 24 weeks on BAT or had 
progression of disease prior to Week 24; progression must be 
declared based only on an increase in splenic volume of >15% 
measured by MRI (or by CT for applicable subjects) from baseline.
x
Subject has not undergone splenic irradiation or splenectomy.
x
Subject does not meet criteria for leukemic transformation.
For subjects receiving BAT and transitioning to NS-018 before Cycle 7 
Day 1, subjects will be required to taper off or washout this treatment 
before initiation of NS-018.
Procedures conducted at each visit time to assess the study drug safety, 
pharmacodynamics, and pharmacokinetics to achieve the study 
objectives are summarized in the Study procedure column of the Table 2
in section IV.E.
VI.General Analytical Considerations
A. Data Sources
All data are collected via electronic case report forms (eCRFs) defined by 
and provided by the Sponsor or designee through remote data entry;
subject data necessary for analysis and reporting will be entered into a 
validated database or data system. Appendix 2 of the protocol provides 
additional details regarding data recording and handling.
B. Visit Windows 
The visit number for analysis purposes will be the visit number assigned 
by the investigator at the time of the visit (i.e., nominal visits).
C. Definition of Baseline
Cycle 1 Day 1 is the date of initiation of NS-018.The day before initiation 
of NS-018 will be Day -1.
For analysis purposes, baseline is defined as of the last data available 
within 28 days prior to initiation of NS-018. For BAT, unless otherwise 


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specified, it is the last data available up to and including the Cycle 1 Day 
1 visit.
Bone marrow assessment performed within 6 months prior to the first 
dose can be used as baseline.
For spleen size (palpation) and spleen volume assessment, baseline 
values should be obtained within 14 days prior to the first dose of study 
treatment.
MFSAF v4.0 assessment will be assessed daily for the first 7 consecutive 
days of entry through the screening period for eligibility.
For Genetic Profiling, Phospho-STAT3 and mRNA sequencing 
assessment, baseline will be the value on Cycle 1 Day 1 and may be 
obtained within 24 hours prior to study treatment administration.
For SAF2 (Second Safety) population, baseline will consist of the last 
data available prior to initiation of NS-018.
D. Missing Data
Any subjects who discontinue study treatment will not be replaced. If the 
subject withdraws consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. If a subject withdraws from the study, the subject
may request destruction of any samples taken and not tested, and the 
Investigator must document this in the study center study records.
Subjects who do not reach Week 24 will be considered treatment non-
responders (i.e., did not achieve ≥35% SVR from baseline to Week 24).
Unless stated otherwise, missing data will not be replaced with imputed 
values.
If a medication has incomplete start or stop dates, dates will be imputed 
to determine whether a medication should be considered prior or 
concomitant. If a medication start date is incomplete, the first day of the 
month will be imputed for missing day and January will be imputed for 
missing month. If a medication stop date is incomplete, the last day of the 
month will be imputed for missing day and December will be imputed for 
missing month. 


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“COVID-19 VACCINE” and AEs missing date will be analyzed under the 
same rule as above.
Incomplete start and stop dates will be listed as collected without 
imputation.
E. Multiple Study Centers
There will be no adjustment for multiple study centers in the analysis.
F. Covariate Adjustment in Primary Analysis
This study uses a stratified randomization schedule when enrolling 
subjects. The stratification factors will be included as covariates in 
efficacy analysis. The main statistical analyses of primary and secondary 
efficacy outcomes comparing NS-018 with BAT will be adjusted by spleen 
volume strata (≥
cm3 vs <
 cm3), and history of prior JAK 
inhibitor strata (naïve vs prior treatment).
G. Multiplicity Adjustment
The efficacy of SVR and TSS, as co-primary endpoints, will be confirmed 
when the null hypotheses of SVR and TSS are rejected simultaneously.
As we have co-primary endpoints, multiplicity issue can arise and then 
the adjustment needs to be made. Hochberg procedure for multiple 
comparisons will be used for the evaluation of the primary endpoints. For 
the two endpoints, the Hochberg procedure results in the following rule: if 
the maximum of the two p-values is less than 0.05 (2-sided tests), then 
both hypotheses are rejected and claim the statistical significance for both 
endpoints. Otherwise, the minimum of the two p-values needs to be less 
than 0.025 for claiming the statistical significance.
If both primary endpoints are significant, then the secondary efficacy 
endpoint will be tested at 0.05 significance level (two-sided).
H. Interim Analyses or Timing of Analyses
The primary efficacy analyses will be conducted after all subjects have 
completed assessments at Week 24 (Cycle 7 Day 1).
 


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An Interim Analysis for CSR will be conducted after all subjects have 
reached 24 weeks of follow-up. 
A final analysis will be conducted at the end of the study.  
An IDMC will be set up to oversee safety across the life span of the study 
and all specifics will be captured in the IDMC charter. The scope of the 
analysis will be Demographics, disposition, AE/SAE, VS and Lab data.
According to the IDMC Charter, 
An interim analysis for futility on splenic response will be carried out when 
60 subjects (50% of randomized subjects) have completed assessments 
at Week 24 (Cycle 7 Day 1). The IDMC will additionally review the results 
of the interim analysis for futility and will make appropriate 
recommendations based on those results. Conditional power will be used 
as the statistical rule to guide the decision of whether to stop the trial 
early for futility. 
Note (details) on Conditional Power (CP) [4]:
Conditional power quantifies the probability that the null hypothesis of no 
treatment effect will be rejected at the end of the study with a given statistical test, 
given the primary endpoint data observed thus far.If this quantity is very small, a 
conclusion can be reached that it would be futile to continue the investigation[3].
I.
Analysis Populations 
Analysis sets define the subjects to be included in an analysis.
Six analysis sets/populations will be defined for use with various analyses
and their definitions are provided in this section. The analysis set will be 
identified and included as a subtitle of each table, figure, and listing.
Intent-to-treat (ITT) Population. The ITT population will include all
randomized subjects.
Modified Intent-to-treat (mITT) Population.The mITT population will 
consist of all randomized subjects who receive at least 1 dose of study 
treatment and have a baseline assessment and at least 1 post-baseline 
efficacy assessment. Subjects will be analyzed as randomized.
This will be the primary analysis population for the evaluation of efficacy.
Safety (SAF) Population. All randomized subjects who receive at least 
one dose of the study treatment will be included in the (SAF) population. 


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For BAT subjects who do not receive therapy, a Cycle 1 Day 1 visit is
required to be included in the SAF. Subjects will be analyzed as treated.
This will be the primary analysis population for the evaluation of exposure 
and safety.
Second safety (SAF2) population. A SAF2 population will consist of 
subjects randomized to BAT who complete BAT through 6 cycles and go 
on to receive at least 1 dose of NS-018. Baseline will consist of the last 
data available prior to initiation of NS-018.
Per-Protocol population (PP). The PP population consist of subjects
treated for the first 4 weeks without a major protocol violation that might 
affect the efficacy assessment.
PK concentration Population. The PK concentration population will 
consist of all randomized subjects who received at least 1 dose of study 
treatment and have at least 1 plasma concentration value forNS-018. The 
population PK analysis and pharmacodynamic analyses will be presented 
separately from the main clinical study report.
J. Data Display Characteristics
Data displays produced for this study will include three types—summary 
tables, data listings, and figures. 
All observed and derived variables (e.g., change from baseline, 
percentage change from baseline, and response status) that are analyzed 
or summarized will be listed by subject. Descriptive statistics will provide 
an overview of the efficacy and safety results. For categorical parameters, 
the number and percentage of subjects in each category will be 
presented. The denominator for percentage will be appropriate for the 
purpose of the analysis. For continuous parameters, descriptive statistics 
will include number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum.
The summaries and listings will be separated by treatment arm.
All calculations and analyses will be conducted using SAS® Version 9.4.
VII.
Subject Accountability
A. Disposition


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Enrolled. A hierarchical table of the populations will summarize the 
relationship of the analysis populations. Given population definitions, the 
ITT population will be treated as the starting, parent population. The 
summary will present the number and percentage of subjects in each of 
the categories listed below:

Subjects Signed Inform Consent (Overall only)

Screen Failures (Overall only)

Screened and Randomized subjects (ITT)

The numbers and percentages of mITT population will be 
presented for each treatment arm.

The numbers and percentages of SAF population will be presented 
for each treatment arm.

The numbers and percentages of SAF2 population will be 
displayed only for NS-018 arm.
For each column, the denominator for the percentage calculation will be 
the total number of randomized subjects analyzed (ITT) for that column.
An additional summary of enrolled subjects will display the numbers and 
percentages of the disposition including the following:

Primary reason subjects discontinued of study treatment

Primary reason subjects’ withdrawal from the study
Percentages of subjects who withdrew for each of these reasons will be 
calculated using all members of the relevant population in the relevant 
treatment arm for the denominator.
In addition, the number of patients by site and investigator will be 
presented by treatment group and overall.
B. Protocol Deviations and Population Inclusions
A major protocol deviation is a protocol deviation that may significantly 
affect the completeness, accuracy, and/or reliability of the study data 
(major data protocol deviation) or that may significantly affect a subject’s 
rights, safety, or well-being (major GCP protocol deviation). Prior to 
database lock, all documented protocol deviations will be reviewed to 
identify major protocol deviations by a data review team including 
representatives from clinical operations, medical, data management, and 
statistics. Major protocol deviations will be categorized as either major 
data protocol deviations or major GCP protocol deviations.


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All protocol deviations will be listed. Major protocol deviations will be 
flagged. A listing will identify subjects who were enrolled even though 
they did not meet one or more eligibility criteria, and subjects who met 
withdrawal criteria discernible from recorded data during the study but 
were not withdrawn. A separate listing of subjects in the ITT population 
who were excluded from the Efficacy Population will indicate the reason 
for the exclusions.
C. Subject Characteristics
Demography. Subject demographic variable including age, gender
(Male, Female), ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not 
Reported) and race (White, Black or African American, Asian, American 
Indian or Alaska Native, Native Hawaiian or other Pacific Islander, Other, 
Unknown) and will be summarized by treatment arm and overall by 
appropriate descriptive statistics for all ITT, mITT and Safety populations. 
Where date of birth is collected, age will be calculated as the number of 
years between the date of birth and the date of informed consent. Where 
date of birth is not collected due to country-specific regulations, the 
subject’s age as provided by the investigator will be used. 
A by-subject demographic listing will be provided by subject ID number in 
ascending order.
Other Baseline Characteristics. Baseline characteristics including 
weight at baseline, ECOG performance status (score =0, 1, 2, 3, 4), 
spleen volume, history of prior JAK inhibitor treatment and transfusion 
dependence status (Yes, No) will be summarized by treatment arm and 
overall using descriptive statistics for continuous variables and using 
number and percentage of subjects for categorical variables.
A by-subject listing of other baseline characteristics will be provided by 
subject ID number in ascending order.
Disease history. Disease history and disease characteristics include 
type of MF, time since initial diagnosis, diagnostic classification, DIPSS 
Adverse Prognostic Factors, DIPSS risk category, time since DIPSS 
Assessment, screening platelet results - based on 2 consecutive 
measurements (first platelet count, second platelet count and average 
platelet count at screening). 


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Qualitative data will be described using frequency and percentages and 
continuous data will be summarized by appropriate descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum). 
A by-subject listing will be provided.
Medical History.
Subjects with any condition entered on medical-history elements prior to 
consent will be listed with the description of medical condition and onset 
and resolution dates.
Surgical History
A by-subject listing with any disease-specific surgical procedures prior to 
consent will be provided with the description of surgical procedure and 
the procedure start and end dates.
Prior Disease Treatment. Any prior myelofibrosis therapy including 
transfusions prior to consent will be presented with the number (lines) of 
the therapy, its indication (PMF, post-PMF, post-ETMF and other), the 
time (month) between last treatment and the start of the study treatment, 
the number of days of interruption and its reason, and the best response 
of the therapy. Also, it will be indicated if the therapy is a JAK inhibitor.
In addition, a by-subject listing of other prior disease treatment will be 
provided by subject ID number in ascending order.
COVID-19 Assessment. The number and percentages of subjects 
assessed for COVID-19 infection with their vaccination status will be 
tabulated and a by-subjects listing of COVID-19 status will be provided. 
VIII. Efficacy Analyses 
Efficacy data collected after Week 24 will be presented separately
A. Definition of Efficacy Outcomes
Reduction of ≥35% in spleen volume. Subjects who achieve ≥35% 
reduction in spleen volume from baseline to Week 24 as measured by 
MRI (or by CT for applicable subjects) will be defined as a responder, 
otherwise they will be considered as a non-responder. The responder rate 
will be based on the percentage change in spleen volume (SpV) from 
baseline (B) in the 24 Week treatment (T), which is defined as follows:


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% SpV Change = [(SpV (T) - SpV (B)) / SpV (B)] x100%
Reduction of ≥50% in TSS. Subjects who achieve ≥50% reduction in 
Total Symptom Score from baseline to Week 24 as will be defined as a 
responder, otherwise they will be considered as a non-responder. The 
responder rate will be based on the percentage change in TSS from 
baseline (B) in the 24 Week treatment (T), which is defined as follows:
% TSS Change = [(TSS (T) - TSS (B)) / TSS (B)] x100%
The MFSAF v4.0 assesses the severity of 7 core symptoms of 
myelofibrosis: fatigue, night sweats, pruritus, abdominal discomfort, pain 
under the ribs on the left side, early satiety, and bone pain. The MFSAF 
v4.0 asks respondents to report symptom severity at its worst for each of 
the 7 items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating 
scale. The MFSAF v4.0 is scored as a unidimensional scale to create a 
TSS.
The TSS for the 24-hour recall (i.e., daily diary) format is 
calculated as the sum of the 7 individual item responses on the 0 
to 10 scale for a possible TSS range of 0 to 70.

The daily TSS is the sum of the scores for the following 
symptoms: tiredness, early satiety, abdominal discomfort, night 
sweats, pruritus, bone pain, and pain under ribs on the left side 
(excludes the inactivity score).

The baseline TSS is the mean of the daily TSS over the 7 
consecutive days prior to the start of treatment. A similar approach 
will be performed when defining the TSS values for Cycles 7, 8, 9, 
10, 11 and 12. Missing values during these days are handled as 
described below.

Week 24 TSS is the mean of the daily TSS obtained during the 28 
consecutive days at Cycle 6. A similar approach will be performed 
when defining the TSS values for Cycles 2, 3, 4 and 5.
Handling of Missing TSS Values

If any of the seven individual symptoms scores are missing, the 
TSS for that day will be considered as missing.

The baseline TSS is set to missing if fewer than 4 daily TSS are 
available out of the 7 consecutive days prior to the start of study 


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treatment. A similar approach will be performed when defining the 
TSS values for Weeks 28, 32, 36, 40, 44 and 48.

The Week 24 TSS is set to missing if fewer than 20 daily TSS are 
available out of the 28 consecutive days prior to Week 24 spleen 
volume scan date (or Week 24 visit date if scan date is missing). 
In sensitivity analyses where Week 24 TSS is derived from the 
mean of 7 consecutive days of daily TSS, the Week 24 TSS is set 
to missing if fewer than 4 daily TSS are available out of the 7
consecutive days prior to Week 24 spleen volume scan date (or 
Week 24 visit date if scan date is missing). Missing TSS at other 
post-baseline time-points is similarly handled. A similar approach 
will be performed when defining the TSS values for Weeks 8, 12, 
16 and 20.
Best splenic response. Subjects who achieve ≥35% reduction in spleen 
volume (SpV) from baseline (B) compared to Cycle 4 Day 1 or Cycle 7 
Day 1 will be considered as responders.   subjects who do not achieve 
≥35% reduction in spleen volume (SpV) from baseline (B) compared to 
Cycle 4 Day 1 and Cycle 7 Day 1 will be considered as non-responders.
% SpV Change (i) = [(SpV (Ti) - SpV (B)) / SpV (B)] x100%
Improvement in fatigue. Fatigue will be measured daily by PROMIS F-
SF 7b and subjects will be asked to evaluate their fatigue since waking 
up. The PROMIS Fatigue item banks assess a range of self-reported 
symptoms, from mild subjective feelings of tiredness to an overwhelming, 
debilitating, and sustained sense of exhaustion that likely decreases 
one’s ability to execute daily activities and function normally in family or 
social roles. Fatigue is divided into the experience of fatigue (frequency, 
duration, and intensity) and the impact of fatigue on physical, mental, and 
social activities. Improvement in fatigue will be indicated by a negative 
deviation over baseline.
Change on Health-Related (H-R) QoL and utility using EQ-5D-5L. The 
EQ-5D-5L questionnaire is a generic measure of health status that 
provides a descriptive profile and a simple index value. It includes 5 items 
assessing mobility, self-care, usual activities, pain / discomfort, anxiety / 
depression. Each dimension has 5 levels response scored on a scale of 1 
to 5: no problems, slight problems, moderate problems, severe problems, 
and extreme problems. For each item, a lower score indicates better 
health status. A negative change in outcome measures at a post-baseline 
visit indicates an improvement of H-R QoL over the baseline.


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Improvement of bone marrow fibrosis. Bone marrow will be assessed 
by aspiration and biopsy, according to standard practice at the site at 
baseline (Screening), Cycle 7 Day 1, Cycle 13 Day 1 and at every
12 cycles thereafter. The parameters in cellular composition of the bone 
marrow aspirate and biopsy include %Blasts, Cellularity (Cellularity, 
%Cellularity), Morphology (M:E Ratio, Megakaryocytes, Degree of 
Dysplasia Present), Cell differential (Total Cells Counted, Promyelocytes, 
Myelocytes, Mature Granulocytes, Eosinophils, Erythroid Cells, 
Monocytes). Also, as a part of Bone marrow assessment, Fibrosis score 
(grade) will be graded using European Consensus Criteria for Grading 
Myelofibrosis (Thiele et al., 2005) and reported from worst case to better 
case scale as MF-0, MF-1, MF-2, and MF-3 in Bone Marrow Biopsy. Shift 
in fibrosis Grade in the bone marrow from Baseline is defined as the 
status change of fibrosis at time of worst/best response (whenever it 
occur) compared to fibrosis status at baseline.
Treatment response. Treatment response will be assessed during the 
study at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 7 Day 1, and 
at every 3 cycles thereafter (Day 1) using the IWG-MRT and ELN 
Response Criteria for treatment response in myelofibrosis. The criteria 
are provided in 


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Appendix 1. The response, to be assessed following each bone marrow 
sampling, will be categorized as Complete Response (CR), Partial 
Response (PR), Clinical Improvement (CI), Anaemia Response, Spleen 
Response, Symptoms Response, Progressive Disease (PD), Stable 
Disease (SD), Relapse, Cytogenetic Remission, Molecular Remission, 
Cytogenetic/Molecular Relapse. The subject who discontinues without 
post-baseline response assessment will be categorized as Not Evaluable 
(NE) during final data analysis. Objective response rate (ORR) is the 
proportion of responders with MF. Clinical advantage rate (CAR) is the 
proportion of MF subjects with clinical benefit (Complete Remission (CR), 
Partial Remission (PR), Clinical Improvement (CI), Anaemia Response, 
Spleen Response, Symptoms Response, Stable Disease).
Change in platelet counts. Subjects with platelet count of ≥50,000/μL at 
Weeks 12 and 24 will be defined as a responder, otherwise they will be 
considered as a non-responder.
Change in blood transfusion dependency. For the purposes of this 
assessment, we will consider these following definitions.

Transfusion dependence at baseline will be defined as subject
who received at least 6 units of packed red blood cells (PRBC), in 
the 12 weeks prior to first study drug, for a hemoglobin level of <85 
g/L, in the absence of bleeding or treatment-induced anemia. In 
addition, the most recent transfusion episode must have occurred 
in the 28 days prior to study drug administration.

Transfusion dependence at Week 24 will be defined as the use 
of 6 or more units of red blood cell product(s) during any 
consecutive 12 weeks prior to Week 24 for a hemoglobin level of 
<85 g/L, in the absence of bleeding or treatment-induced anemia.

Transfusion independency at baseline will be defined as subject
who didn’t meet the definition of transfusion dependence at 
baseline.

Transfusion independency at Week 24 will be defined as no (0) 
use of PRBC during any consecutive rolling 12 weeks interval 
during the treatment phase, capped by a hemoglobin level of ≥85 
g/L for subjects who met the definition of transfusion dependence 
at baseline. Subjects who were not transfusion-dependent at 
baseline and who required transfusions during the study, but not 
during the last 12 weeks of observation, will be considered 
transfusion independent.

Improvement in platelet count is marked by an increase of 
platelet count from baseline. 


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
Improvement grade of thrombocytopenia is marked by an 
increase in the number of platelets which make change in grade 
defined as Grade 3 (<50,000/μL), Grade 2 (50,000 -<75,000/μL), 
Grade 1 (75,000/μL – <LLN).

Improvement in hemoglobin level is indicated by an increase of 
hemoglobin level.

Rate of RBC transfusion at Week 24. Rate of RBC transfusion 
will be calculated as the total number of RBC units across all 
subjects divided by the total exposure time among these subjects 
through Week 24. excluding cases due to overt bleeding per 
subject month from the first dose.

Improvement grade of hemoglobin is marked by an increase in 
the level of hemoglobin which make change in grade defined as 
Grade 3 (<8 – 6.5 g/dL), Grade 2 (<10 – 8 g/dL), Grade 1 (10 g/dL 
– <LLN).
Pharmacokinetics and Pharmacodynamics. The PK and PcD 
assessments will be performed with PK population. The PK parameters to 
be estimated include observed Cmax, time to maximum plasma 
concentration (Tmax), AUC, terminal elimination half-life (t1/2), and 
accumulation ratio (AR).  The PcD assessment include Phospo-STAT3 
assessment and mRNA sequencing. 
B. Analysis Methods for Primary Efficacy Analysis
The study has co-primary endpoints. The primary efficacy analyses will 
be performed on the mITT population.
A Firth-corrected logistic regression model will be used to compare the 
proportion of subjects who achieve ≥35% SVR from baseline to 
Week 24 and the proportion of subjects who achieve ≥50% reduction 
in TSS from baseline to Week 24 between the NS-018 arm and the BAT 
arm. Baseline spleen volume and a history of prior JAK inhibitor treatment 
as recorded on the CRF will be included as covariates. A secondary 
analysis using the stratification factors at the time of randomization may 
be added. Model-based point estimates for the treatment effects, and p-
values, and odds ratio with its 95% confidence interval will be reported for 
each treatment arm.
The null hypothesis (H0) and the alternative hypothesis (HA) are:
H0: The proportion of subjects who achieve ≥35% SVR (resp. ≥50% 
reduction in TSS as measured by MFSAF v4.0) from baseline to Week 24 in 
each treatment arm is the same. 


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HA: The alternative hypothesis is that the proportion of subjects who achieve 
≥35% SVR (respectively ≥50% reduction in TSS as measured by MFSAF 
v4.0) from baseline to Week 24 is different by treatment arm.
Subgroup analyses may be performed by age, gender, stratification 
factors, diagnostic classification and DIPSS risk category. Other baseline 
characteristics may be included in the analysis depending on the data.
Subjects who do not reach Week 24 for any cause including death prior to 
Week 24 will be considered treatment nonresponders (i.e., did not 
achieve ≥35% SVR from baseline to Week 24 and did not achieve ≥50% 
reduction in TSS from baseline to Week 24, respectively).
As descriptive purposes, the count and the percentage of subjects who 
achieve ≥35% SVR from baseline to Week 24 and subjects who achieve 
≥50% reduction in TSS from baseline to Week 24 will bepresented by 
treatment arm. In addition, descriptive statistics will be presented by 
treatment arm for Spleen Volume and TSS as measured by MFSAF 
v4.0 will be summarized by using descriptive statistics. The actual value, 
the change and the percentage change from baseline will be presented.
C. Sensitivity and Supporting Analysis
Using the mITT population, as sensitivity analysis of the primary endpoint
of SVR at Week 24, imputation will be used to evaluate the impact of 
missing data. Subjects who experience death from any cause prior to 
Week 24, the last SVR will be imputed to Week 24 for the first primary 
endpoint.
A second sensitivity analysis will be performed for missing Week 24 
spleen volume/TSS where subject data will be imputed using the last non-
missing value, except for death or initiation of other MF or anti-cancer 
therapy where missing will be imputed as non-responders.
The analysis described above (Section B) will be repeated for the PP 
Population.
Other supporting analysis will include Fisher’s exact test, chi-square test 
and Cochran-Mantel-Haenszel (CMH) test of the co-primary and key 
secondary endpoints.
D. Analysis Methods for Secondary Efficacy Analysis


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The proportion of subjects who achieve ≥35% SVR at any time up to 
Week 24 will be compared between the NS-018 arm and the BAT arm 
using Firth-corrected logistic regression model. Covariates of baseline 
spleen volume and a history of prior JAK inhibitor treatment will be 
included.
Subjects who do not reach Week 24 for any cause including death prior to 
Week 24 will be considered treatment nonresponders (i.e., did not 
achieve ≥35% SVR at any time up to Week 24).
E. Analysis Methods for Exploratory Analysis
For EQ-5D scores and each of PROMIS symptoms/items scores, for 
each of the parameters in cellular composition of the bone marrow
aspirate and biopsy, descriptive statistics will be presented by treatment 
arm for actual value, change from baseline, and percentage change from 
baseline by visit, and for the maximum and minimum percentage change 
from baseline.
In addition, the mean and its 95% confidence interval (CI) will be 
presented for the actual value, its change from baseline, and its 
percentage change from baseline by visit; and for the maximum and 
minimum percentage change from baseline. 
Also, For EQ-5D scores and each of PROMIS symptoms/items scores, 
and bone marrow fibrosis grade, the shift of the score from baseline to 
post-baseline will be summarized by the visit day and greatest reduction. 
Additionally, change from baseline will also be displayed using a line plot 
with time point (scheduled visit) on the x-axis, mean change score on the 
y-axis, and standard errors around each mean score. Separate lines will 
be presented for each treatment arm.
The counts and the percentage of subjects showing improvement
compared to baseline (i.e., the responder) will be presented for each visit 
for QoL, for fatigue, for bone marrow fibrosis grade and for platelet 
counts. 
The overall response rate will be presented by treatment arm and the 
numbers and percentages of subjects who have best overall response as 
CR, PR, CI, SD, and PD will also be provided. ORR and CAR and their 
Binomial exact 95% confidence interval will be presented.


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Descriptive statistic of rate of RBC transfusion through Week 24, 
independence and dependence RBC transfusion rate at Week 24 will 
be presented by treatment arm. Transfusions due to clinically overt 
bleeding will be excluded from this analysis.
The count and the percentage of subjects showing improvement in 
platelet count without transfusion will be presented by treatment arm
for each visit.
The proportion of subjects whose transfusion status (dependent or 
independent) changed over baseline (from dependent to independent or 
vice versa), will be tabulated with summary statistics.
The number and percent of subjects who received any blood component 
transfusions will be summarized by blood component (PRBC (Packed 
Red Blood Cells), platelets), and visit when the transfusion data were 
collected.
Proportion of platelet transfusion-independent subjects at baseline 
with improvement in grade of thrombocytopenia at Week 24; 
proportion of transfusion-dependent subjects at baseline who achieve 
transfusion independence and 50% reduction in transfusion rate at 
Week 24 will be tabulated with summary statistics.
A by-subject listing will be provided by treatment arm and visit for all the 
items cited above.
IX.Safety Analyses
The primary safety analyses will be performed on the safety (SAF) 
population. Safety data from the SAF2 population will be presented 
separately.
A. Exposure to NS-018
Exposure to the NS-018 will be summarized as the duration of exposure, 
the amount of drug exposure and the compliance. Study drug in this 
section refers to NS-018. 
Duration of Exposure to Study Drug. The duration of study drug 
administration is defined as the time interval from first (non -zero) 


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dose of study drug administration to last study drug administration date 
(i.e., last known study drug administration date).
The following algorithm will be used to calculate the duration of study 
drug exposure for subjects who took at least 1 dose of study drug: 
Duration of exposure (days) = [(last dosing date) – (first dosing date) + 1 day]
The duration includes the periods of temporary study drug interruption. 
For subjects who did not take any study drug, the duration of exposure is 
defined as zero.
If the last study drug dosing date is missing, the following rule should be 
used for the imputation of the last dosing date: 

If the study drug is permanently withdrawn, the latest date among 
the study drug end date (in EOT) will be used.

If the study drug completion status is unknown the date of death 
will be used for analysis.

If the stop date is partial then the stop date will be imputed with the 
earliest of the last day of the month (if only day is missing) or the 
last month of the year (if day and month are missing), or the death 
date if applicable.

If the dose end date is completely missing and there is no EOT 
page and no death date, the subject is considered as on-going: 
The subject should be treated as on-going, and the cut-off date 
should be used as the last dosing date. 
After imputation the imputed date will be compared with the start date of 
treatment, if the imputed date is less than the start date of treatment: the 
treatment start date will be used.
If start date is missing, then end-date should not be imputed (subjects 
with missing start dates are to be considered missing and no imputation 
will be made).
Amount of drug exposure. The total number of tablets administered, the 
cumulative dose, the dose intensity and the relative dose intensity will be 
summarized using descriptive statistics (n, mean, sd, median, min-max) 
by treatment arm.
The presumed total number of tablets administered to a subject will be 
determined by the data collected on the drug accountability CRF using 
the following formula:
Total number of Dose Administrated = (No. of Tablets Dispensed – No. of Tablets 
Returned.) * 100mg


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If a tablet is not returned or returned with unknown number of tablets, it is 
assumed that subject did not consume any tablet from this tablet.
Cumulative dose is defined as the total sum of all doses taken per subject
for each cycle and during the study drug exposure.
Dose Intensity (mg/day) and Relative Dose Intensity (% of planned) will 
be calculated for per subject for each cycle as 
Dose intensity (DI) = Cumulative dose (mg) / Duration of exposure (days)
Relative dose intensity= [dose intensity / planned dose intensity] *100),
Dose Modification. The number and percentage of subjects who had 
dose increase, dose reduction and/or dose interruption, drug permanently 
withdrawn, and overdose along with corresponding reasons for each will 
be summarized by treatment arm and overall.
Compliance. Dispensation and accountability will be presented in a by-
subject listing with the planned total daily dose, the actual total daily dose, 
the dose action, and the reason for the dose action. 
B. Exposure to BAT
Exposure to BAT will be summarized by the number and percentage of 
subjects with corresponding therapy types and the number of therapy 
cycles for which BAT was administered.   
The dose and frequency of BAT therapy will be presented in a by-subject 
listing, including dose actions (dose interrupted, dose 
decreased/increased/overdose, drug withdrawn) and the reason of dose 
action.
C. Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.0
will be used to classify all safety events with respect to system organ 
class (SOC) and preferred term (PT). Within each system organ class, 
the tables will display the counts and percentages of subjects reporting at 
least one AE, as designated by the preferred terms. 
AE summaries will include treatment-emergent AEs (TEAEs), that is, AEs 
that first occurred or worsened in severity after the first administration of 


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study treatment, and up to 30 days after the last administration of study
treatment. The following AE summaries will be produced:

All TEAEs: for each study treatment, numbers of TEAEs and 
incidence rates will be tabulated by preferred term and system 
organ class.

Serious TEAEs by System Organ Class and Preferred Term 

Serious TEAEs by Preferred Term 

TEAEs leading to death

TEAEs leading to discontinuation of study treatment. This subset 
includes TEAEs with an Action Taken of “Drug Withdrawn.”

TEAEs by Severity. On this table, treatment arms will be 
subdivided into five potential grades of AE severity— Mild (Grade 
1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 
4) or Death (Grade 5) based on CTCAE v5.0 and one additional 
category for subjects included in Grade 3-5. TEAEs missing a 
severity grade will not be included. An AE reported by a subject
more than once will be represented in the most severe category.

TEAEs related to CTM. This table will include TEAEs with a drug 
relationship of “Insufficient Data,” “Possible,” “Probable,” and 
“Highly Probable.”  It will also include TEAEs with missing drug 
relationships. An AE reported by a subject more than once will be 
included in this table if at least one of the drug association grades 
is one of the grades listed here.

AESIs that are AEs of special interest which may include bleeding 
of any grade, cardiac events of any grade, non-melanoma skin 
cancer, opportunistic infections such as herpes zoster, progressive 
multifocal encephalopathy, and tuberculosis. Any development of 
tuberculosis will be recorded as an AESI.
Subgroup analysis of TEAE and AESIs. Subgroup analysis of TEAE 
and AESIs will be prepared for the following factors: age group, gender, 
stratification factors, diagnostic classification, DIPSS risk category.
Listings will be presented as follows:

All AEs

Serious AEs

Serious AEs related to Study Treatment.

AEs Leading to Study Treatment Discontinuation 

AEs Leading to Death

AESIs
A hierarchical listing will display the MedDRA system organ classes 
represented in the data. Within each system organ class, the listing will 


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display each unique preferred term. Within each preferred term, the listing 
will display each unique verbatim (recorded) term. Listed terms will be 
ordered alphabetically. The listing will be sorted such that each AE and its 
associated changes appear together. Within that constraint, the listing will 
display AEs for each subject in order of onset date.
A listing of SAEs will display the recorded term from the CRF and, 
adjacent to that, the MedDRA preferred term that appears in the tables.  
SAEs for each subject will appear in order of onset date.
D. Clinical Laboratory Results
The descriptive statistics will be provided for the clinical laboratory 
parameters including hematology, chemistry, and urinalysis:

Hematology: Basophils, %; Basophils, Absolute; Eosinophils, %; 
Eosinophils, Absolute; Ery. Mean Corpuscular Volume (MCV); Ery. 
Mean Corpuscular Hemoglobin (MCH); Erythrocyte (RBC); 
Hematocrit; Hemoglobin; Lymphocytes, %; Lymphocytes, 
Absolute; Monocytes, %; Monocytes, Absolute; Neutrophils, %; 
Neutrophils, Absolute; Platelets; White Blood Cells (WBC). 

Clinical Chemistry: Alanine Aminotransferase (ALT/SGPT); 
Albumin; Alkaline Phosphatase (ALP); Aspartate Aminotransferase 
(AST/SGOT); Amylase; Blood Urea Nitrogen (BUN); Chloride; 
Creatinine; Glucose; Lactate Dehydrogenase (LDH); Lipase; 
Magnesium; Potassium; Sodium; Total Bilirubin; Total Protein; Uric 
Acid (Urate).

Urinalysis: Specific gravity; PH; Protein; Glucose; Ketones; Blood; 
Nitrite by Dipstick; Bilirubin; Microscopic examination (if blood or 
protein is abnormal).
Summaries of baseline values and values at each postbaseline visit,
postbaseline maximum and minimum value, change from baseline (CFB)
and percentage CFB by visit, and the maximum and minimum change 
from baseline will be presented by treatment arm for each assessment 
visit. 
Number and percentage of subjects with worst post-baseline CTC grade 
(regardless of the baseline status) will be provided. Each subject will be 


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counted only for the worst grade observed post-baseline.
In addition, shift tables using CTC grades to compare baseline to the 
worst post-baseline value will be produced for laboratory parameters with 
CTC grades. For laboratory parameters where CTC grades are not 
defined, shift tables to the worst post-baseline value will be produced 
using the low/normal/high classifications based on laboratory reference 
ranges.
Shift tables for laboratory values with respect to normal range (low, 
normal, high) and CTCAE toxicity grade, compared to baseline, will be 
summarized by visit. Overall laboratory result shift from baseline (Normal, 
Abnormal clinically significant (CS), and Abnormal non-clinically 
significant (NSC)) will be summarized.
Shift tables summarizing the counts and percentages of subjects who 
were normal at baseline, but who became abnormal subsequently, will 
also be displayed.
A by-subject listing of laboratory values will be provided by laboratory 
parameter. A separate listing will display notable laboratory abnormalities.
These following Others Protocol-required Screening Tests will be
summarized and presented in a by-subject listing: 

Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only)

Pregnancy test: serum or urine human chorionic gonadotropin 
(hCG) (as needed for women of childbearing potential)

Serology: human immunodeficiency virus [HIV] antibody, hepatitis 
B, surface antigen [HBsAg], and hepatitis C virus antibody
E.
Vital Signs
The vital signs include:

Blood pressure (systolic and diastolic [mmHg])

Heart rate (beats per minute)

Body temperature (°C)

Respiration rate (breaths per minute).
Weight and vital sign assessments will be summarized for the actual 
values, change from baseline, and percentage change from baseline by 
visit, and for the maximum and minimum change from baseline.


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A by-subject listing including the date of visit and the result of each 
parameter will be provided.
F. Physical Examination
Physical examination (PE) includes weight and spleen size by clinical 
assessment (palpation). 
The spleen size numerical results will be summarized by descriptive 
statistics. Categories of findings (normal, abnormal, not evaluated) on 
spleen size will be summarized as counts and percentages.
Additionally, for Cycle 2, Cycle 3 Day 1, Cycle 4 Day 1, Cycle7 and every 
3 Cycle thereafter and Early Termination, the counts and percentages of 
subjects who were normal at Baseline but who presented abnormal 
clinically significant findings at a subsequent visit will be provided for the 
spleen size.
A by-subject listing will be provided including the date of visit and the 
spleen size assessment results for subjects whose spleen was palpable 
and measurable.
G. Prior and Concomitant Medications
Prior medications are defined as any medications with a stop date prior to 
the date of first dose of NS-018.
Concomitant medications are defined as medications or therapies taken 
within 14 days of study drug administration.
Medications may be flagged as both prior and concomitant if the start 
date is prior to the date of the first dose of NS-018 and the medication 
continued after the first dose of NS-018.
Each medication will be coded to a preferred name and an Anatomic 
Therapeutic Classification using the most updated version of WHO Drug
at the time of study initiation (up-versioning will not occur).
The number (%) of subjects using prior, prior and concomitant, and 
concomitant medications will be summarized by preferred name.


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A by-subject listing will be provided with the line and the name of the 
therapy, the reason for use, the dates of administration including start and 
end dates and the dosage information including dose and frequency.
H. Electrocardiograms (ECG)
The normality or abnormality of the ECG tracing will be summarized using 
shift tables of numbers of subjects who have a normal/abnormal ECG 
tracing at each scheduled time of assessment.
A by-subject listing of overall ECG evaluation by visit will also be created
with all relevant information and derived variables.
X. Pharmacokinetic and Pharmacodynamic Analyses
A. Pharmacokinetics 
PK analysis will be performed for subjects on the PK population.
At the Cycle 1 Day 1 (C1D1) and Cycle 2 Day 1 (C2D1) visit, blood 
sample will be collected at predose, 0.5, 1, 2, 3, 4, 6 and 8 hours 
postdose from the PK population to evaluate the plasma concentration of 
NS-018 and MPD-6007. 
The following table displays the PK parameters assessed according to 
the time of visit:
PK parameters
Cycle 1 Day 1
Cycle 2 Day 1
Observed maximum plasma concentration (Cmax)
X
X
Time to maximum plasma concentration (Tmax)
X
X
Area under the plasma concentration-time curve (AUC0-24)
X
X
Terminal elimination phase rate constant (λz)
X
X
Terminal elimination half-life (t½)
X
X
Accumulation ratio (AR = [AUC0-24] C2 D1/[AUC0-24] C1 D1)
X
Average plasma concentration (Cav)
X
Observed minimum plasma concentration (Cmin)
X
Percentage fluctuation
X
PTF % =100 × (Cmax − Cmin)/Cav
X
Apparent total body clearance (CL/F)
X
X
Apparent volume of distribution (Vz/F)
X
X
Lag time (Tlag)
X
X


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PK parameters will be summarized descriptively at each time point of 
collection. 
Individual subject and mean plasma concentrations of NS-018 and its 
metabolite MPD-6007 will be plotted versus time in linear and log-linear 
scale.
Derived PK parameters will be listed and summarized using the same 
measures as for the plasma concentrations of NS-018 and MPD-6007.
B. Pharmacodynamics
Pharmacodynamics assessments include phospho-STAT3 assessment 
and mRNA sequencing. The PcD analysis will be based on PK 
population.
Phospho-STAT3 values at each time point and changes from baseline will 
be summarized descriptively and listed.
XI.References
1. Altman DG, Dore CJ.  Randomization and baseline comparisons in 
clinical trials.  Lancet 1990; 335(8682): 149-53
2. Senn S.  Testing for baseline balance in clinical trials.  Stat Med 1994; 
13(17): 1715-26.
3. Lachin JM. A review of methods for futility stopping based on 
conditional power. Stat Med. 2005 Sep 30;24(18):2747-64.
4. Kundu, M.G., Samanta, S. & Mondal, S. Review of calculation of 
conditional power, predictive power and probability of success in 
clinical trials with continuous, binary and time-to-event endpoints. 
Health Services and Outcomes Research Methodology (2023).


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Appendix 1
Revised Response Criteria for Myelofibrosis :
International Working Group-Myeloproliferative Neoplasms 
Research and Treatment (IWG-MRT) and European LeukemiaNet 
(ELN) Consensus Report
Response categories
Required criteria (for all response categories, benefit must last for 
≥12 weeks to qualify as a response)
Complete response (CR)
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF†
AND
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count 
≥1 × 109/L and <UNL; platelet count ≥100 × 109/L and <UNL; <2% 
immature myeloid cells‡ AND
Clinical: Resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH
Partial response (PR)
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count 
≥1 × 109/L and <UNL; platelet count ≥100 × 109/L and <UNL; <2% 
immature myeloid cells‡ AND
Clinical: Resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH
OR
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF†
AND
Peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil 
count ≥1 × 109/L and <UNL; platelet count ≥50, but <100 × 109/L and 
<UNL; <2% immature myeloid cells‡ AND
Clinical: Resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH
Clinical improvement (CI)
The achievement of anemia, spleen or symptoms response without 
progressive disease or increase in severity of anemia, thrombocytopenia, 
or neutropenia§
Anemia response
Transfusion-independent subjects: a ≥20 g/L increase in hemoglobin 
levelǁ
Transfusion-dependent subjects: becoming transfusion-independent{
Spleen response#
A baseline splenomegaly that is palpable at 5 to 10 cm, below the LCM, 
becomes not palpable**
OR
A baseline splenomegaly that is palpable at >10 cm, below the LCM, 
decreases by ≥50%**
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not 
eligible for spleen response.
A spleen response requires confirmation by MRI or computed 
tomography showing ≥35% spleen volume reduction.


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Response categories
Required criteria (for all response categories, benefit must last for 
≥12 weeks to qualify as a response)
Symptoms response
A ≥50% reduction in the MPN-SAF TSS††
Progressive disease‡‡
Appearance of a new splenomegaly that is palpable at least 5 cm below 
the LCM
OR
A ≥100% increase in palpable disease, below LCM, for baseline 
splenomegaly of 5 to 10 cm
OR
A 50% increase in palpable distance, below LCM, for baseline 
splenomegaly of 10 cm
OR
Leukemic transformation confirmed by a bone marrow blast count of 
≥20%
OR
A peripheral blood blast content of ≥20% associated with an absolute 
blast count of ≥1 × 109/L that lasts for at least 2 weeks
Stable disease
Belonging to none of the above listed response categories
Relapse
No longer meeting criteria for at least CI after achieving CR, PR, or CI
OR
Loss of anemia response persisting for at least 1 month
OR
Loss of spleen response persisting for at least 1 month
Recommendations for assessing treatment-induced cytogenic and molecular changes
Cytogenetic remission
At least 10 metaphases must be analyzed for cytogenetic response 
evaluation and requires confirmation by repeat testing within 6 months 
window.
CR: eradication of a pre-existing abnormality
PR: ≥50% reduction in abnormal metaphases (partial response applies 
only to subjects with at least 10 abnormal metaphases at baseline)
Molecular remission
Molecular response evaluation must be analyzed in peripheral blood 
granulocytes and requires confirmation by repeat testing within 6 months 
window.
CR: Eradication of a pre-existing abnormality
PR: ≥50% decrease in allele burden (partial response applies only to 
subjects with at least 20% mutant allele burden at baseline)
Cytogenetic/molecular relapse
Re-emergence of a pre-existing cytogenetic or molecular abnormality that 
is confirmed by repeat testing


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Abbreviations: EMH=extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or 
imaging study-proven nonhepatosplenic EMH); LCM=left costal margin; MF=myelofibrosis; UNL=upper 
normal limit.
*
Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review 
process.  Cytogenetic and molecular responses are not required for CR assignment.
†
Grading of MF is according to the European classification (Thiele et al.  European consensus on grading 
bone marrow fibrosis and assessment of cellularity.  Haematologica  2005;90:1128).  It is underscored that 
the consensus definition of a CR bone marrow is to be used only in those subjects in which all other criteria 
are met, including resolution of leukoerythroblastosis.  It should also be noted that it was a particularly 
difficult task for the working group to reach a consensus regarding what represents a complete histologic 
remission.
‡
Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red 
blood cells. In splenectomized subjects, 5% immature myeloid cells is allowed.
§
See above for definitions of anemia response, spleen response, and progressive disease. Increase in severity 
of anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in hemoglobin 
level from pretreatment baseline that lasts for at least 12 weeks.  Increase in severity of thrombocytopenia or 
neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute 
neutrophil count, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
In addition, assignment to CI requires a minimum platelet count of ≥25,000 × 109/L and absolute neutrophil 
count of ≥0.5 × 109/L.
||
Applicable only to subjects with baseline hemoglobin of <100 g/L.  In subjects not meeting the strict criteria 
for transfusion dependency at the time of study enrolment (see as follows), but have received transfusions 
within the previous month, the pretransfusion hemoglobin level should be used as the baseline.
{
Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red 
blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in the 
absence of bleeding or treatment-induced anemia.  In addition, the most recent transfusion episode must 
have occurred in the 28 days prior to study enrollment.  Response in transfusion-dependent subjects requires 
absence of any PRBC transfusions during any consecutive “rolling” 12-week interval during the treatment 
phase, capped by a hemoglobin level of ≥85 g/L.
#
In splenectomized subjects, palpable hepatomegaly is substituted with the same measurement strategy.
** Spleen or liver responses must be confirmed by imaging studies where a ≥35% reduction in spleen volume,
as assessed by MRI or CT, is required.  Furthermore, a ≥35% volume reduction in the spleen or liver, by 
MRI or CT, constitutes a response regardless of what is reported with physical examination.
†† Symptoms are evaluated by the MPN-SAF TSS.  The MPN-SAF TSS is assessed by the subjects themselves 
and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal 
discomfort, weight loss, and fevers.  Scoring is from 0 (absent/as good as it can be) to 10 (worst 
imaginable/as bad as it can be) for each item.  The MPN-SAF TSS is the summation of all the individual 
scores (0-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS.
‡‡ Progressive disease assignment for splenomegaly requires confirmation my MRI or computed tomography 
showing a ≥25% increase in spleen volume from baseline.  Baseline values for both physical examination 
and imaging studies refer to pretreatment baseline and not to posttreatment measurements.
Source: Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International 
Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European 
LeukemiaNet (ELN) consensus report.  Blood 2013;122:1395-1398.