Clinical trial NCT02990806
Conditions: Rheumatoid Arthritis
Sponsor: Nichi-Iko Pharmaceutical Co., Ltd.
Start date: 2017-01-19; Completion date: 2019-05-20
Enrollment: 683 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study was to demonstrate similarity of NI-071 (proposed biosimilar to infliximab) to US REMICADE® (reference product) in terms of safety and efficacy in participants with rheumatoid arthritis (RA) not adequately responding to methotrexate (MTX).

Detailed description:

Arms: arm 1: Participants received intravenous (IV) infusion of NI-071 at a dose of 3 milligrams/kilograms (mg/kg) at Weeks 0, 2, 6, 14 during stage 1 and at Weeks 22, 30, 38, 46, and 54 during stage 2. Participants were followed up to Week 62 (Stage 3). arm 2: Participants received IV infusion of Remicade-US (infliximab) at a dose of 3 mg/kg at Weeks 0, 2, 6, 14 during stage 1. arm 3: Participants who received Remicade US during stage 1; were re-randomized during stage 2 to continue Remicade-US dose 3 mg/kg from Week 22 through Week 54 with every 8 weeks dosing intervals. Participants were followed up to Week 62 (Stage 3). arm 4: Participants who received Remicade US during stage 1; were re-randomized during stage 2 and received IV infusion of NI-071 at Week 22 followed by Remicade-US at Week 30, followed by NI-071 at Weeks 38, 46, and 54. Participants were followed up to week 62 (Stage 3).
Interventions: intervention 1: NI-071 intervention 2: Remicade
Intervention descriptions: intervention 1: IV infusion. intervention 2: IV infusion.

Protocol documents:
Prot_000.pdf: 
16 APPENDICES 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
The latest version of the protocol used during the study is provided in this section. Previous 
versions of the protocol are available on request. 
 
Clinical Study Protocol (NI071F2) Version 4.0 dated 09 August 2017 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 1 of 96






1LFKL,NR3KDUPDFHXWLFDO&R/WG
),1$/&/,1,&$/678'<35272&2/
3URWRFRO1XPEHU1,)
$5DQGRPL]HG'RXEOH%OLQG0XOWLFHQWHU6WDJH(IILFDF\DQG
6DIHW\6WXG\RI1,DQG86/LFHQVHG5HPLFDGH,QIOL[LPDE
IRUWKH7UHDWPHQWRI3DWLHQWVZLWK5KHXPDWRLG$UWKULWLV

,1'1XPEHU

(XGUD&71XPEHU

1DPHRI3URGXFW
1,SURSRVHGLQIOL[LPDEELRVLPLODU
3KDVHRI'HYHORSPHQW

,QGLFDWLRQ
5KHXPDWRLG$UWKULWLV
6SRQVRU&RQWDFW
3K'

1LFKL,NR3KDUPDFHXWLFDO&R/WG
6RJDZD7R\DPD&LW\
7R\DPD3UHIHFWXUH-DSDQ
7HO
)D[
3URWRFRO9HUVLRQ
)LQDO9HUVLRQ
3URWRFRO'DWH
$XJXVW

&21),'(17,$/
7KLVGRFXPHQWDQGLWVFRQWHQWVDUHWKHSURSHUW\RIDQGFRQILGHQWLDOWR1LFKL,NR
3KDUPDFHXWLFDO&R/WG$Q\XQDXWKRUL]HGFRS\LQJRUXVHRIWKLVGRFXPHQW
LVSURKLELWHG
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 2 of 96
PPD
PPD
PPD
PPD




Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 3 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree: 
 
To assume responsibility for the proper conduct of the study at this site. 
 
To conduct the study in compliance with this protocol, any future amendments, and 
with any other study conduct procedures provided by Nichi-Iko Pharmaceutical Co., 
Ltd. 
 
Not to implement any changes to the protocol without written agreement from 
Nichi-Iko Pharmaceutical Co., Ltd., and prior review and written approval from the 
Regulatory Authorities and the Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC), except where necessary to eliminate an immediate hazard to 
patients. 
 
That I am thoroughly familiar with the appropriate use of the study drug, as described 
in this protocol and any other information provided by Nichi-Iko Pharmaceutical Co., 
Ltd., including, but not limited to, the current Investigator’s Brochure (IB).  
 
That I am aware of, and will comply with, International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines and all applicable 
regulatory requirements. 
 
To ensure that all persons assisting me with the study are adequately informed about 
the Nichi-Iko Pharmaceutical Co., Ltd., study drug and of their study-related duties 
and functions as described in the protocol. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 4 of 96


1LFKL,NR3KDUPDFHXWLFDO&R/WG
1,)
1,
)LQDO3URWRFRO9HUVLRQ

$XJXVW





3DJH

&217$&7/,67
6SRQVRU
1LFKL,NR3KDUPDFHXWLFDO&R/WG
6RJDZD7R\DPD&LW\
7R\DPD3UHIHFWXUH-DSDQ
6SRQVRU¶V5HVSRQVLEOH6WXG\
0DQDJHU

1LFKL,NR3KDUPDFHXWLFDO&R/WG
7HOHSKRQH

&RQWUDFW5HVHDUFK2UJDQL]DWLRQ
&526WXG\0DQDJHU


LQ9HQWLY+HDOWK
&DUQHJLH&HQWHU
3ULQFHWRQ1-86
7HOHSKRQH



LQ9HQWLY+HDOWK
6WRUNVWUDDW
/%/HXVGHQ
7KH1HWKHUODQGV
7HOHSKRQH


&520HGLFDO0RQLWRU
0'03+
LQ9HQWLY+HDOWK
&DUQHJLH&HQWHU
3ULQFHWRQ1-86
7HOHSKRQH


&526DIHW\3KDUPDFRYLJLODQFH
5HSRUWLQJ
LQ9HQWLY+HDOWK3KDUPDFRYLJLODQFH
7HOHSKRQHKRWOLQH
)D[IRU1RUWK$PHULFD
)D[IRUDOORWKHUFRXQWULHV
6DIHW\39#LQYHQWLYKHDOWKFRP
&OLQLFDO/DERUDWRU\
7REHSURYLGHGLQWKHODERUDWRU\PDQXDO
3.DQG,PPXQRJHQLFLW\/DERUDWRU\
7REHSURYLGHGLQWKHODERUDWRU\PDQXDO

______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 5 of 96
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 5 
 
1 
SYNOPSIS 
Title of Study: 
A Randomized, Double-Blind, Multicenter, 3-Stage, Efficacy 
and Safety Study of NI-071 and US-Licensed Remicade® 
(Infliximab) for the Treatment of Patients with Rheumatoid 
Arthritis 
Protocol Number: 
NI071F2 
Investigators/Study Sites: 
Approximately 160 sites in the United States (US; including 
Puerto Rico), Western Europe, and Eastern Europe. 
Phase of Development: 
3 
Objectives: 
Stage 1 (Biosimilarity Stage) 
Primary: 
 To investigate the biosimilarity of NI-071 (proposed 
infliximab biosimilar) and US-licensed Remicade® 
(infliximab; Remicade-US) in terms of efficacy in 
patients with rheumatoid arthritis (RA) not adequately 
responding to methotrexate (MTX), by determining the 
percentages of patients achieving ACR20-CRP (a 20% 
improvement from baseline in the American College of 
Rheumatology [ACR] core set criteria using C-reactive 
protein [CRP] as the acute-phase reactant) 
Secondary: 
 To evaluate safety and immunogenicity of NI-071 and 
Remicade-US 
 To evaluate efficacy based on other rates of 
improvement in the ACR criteria, on the DAS28 
(disease activity score involving 28 joints) and the 
RAPID3 (routine assessment of patient index data 3), 
and on changes in health-related quality of life 
Stage 2 (Interchangeability Stage) 
Primary: 
 To investigate the interchangeability between NI-071 
and Remicade-US by evaluating key pharmacokinetic 
(PK) parameters in each treatment group following 
treatment switches 
Secondary: 
 To evaluate the safety, efficacy, and immunogenicity of 
NI-071 and Remicade-US  
Stage 3 (Safety Follow-up Stage) 
Primary: 
 To evaluate the safety of long-term treatment 
(follow-up through Week 62)  
Study Design: 
This Phase 3, randomized, double-blind, multicenter, 
biosimilarity, interchangeability, and safety study is designed 
to evaluate NI-071 versus Remicade-US for the treatment of 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 6 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 6 
 
patients with RA.  Following a screening period, there will be 
3 stages:  the biosimilarity stage (Stage 1), the 
interchangeability stage (Stage 2), and the safety follow-up 
stage (Stage 3).   
The screening period, approximately 4 weeks long for each 
patient, will be used to assess eligibility.  At baseline 
(Week 0), approximately 585 patients who are eligible will be 
randomized in a 2:1 ratio to the Remicade-US and NI-071 
groups, respectively.  This initial randomization will be 
stratified by CRP level (≤2, >2 mg/dL).  During Stage 1, 
patients will receive their randomized treatment at Weeks 0, 2, 
6, and 14.  Primary biosimilarity efficacy assessments 
(specifically ACR20-CRP) will be performed at Week 22. 
During Stage 2, at Week 22, patients in the original 
Remicade-US group are re-randomized (1:1) to a 
Remicade-US group and a Switch group.  The Switch group 
will receive NI-071 at Week 22, Remicade-US at Week 30, 
and NI-071 at Weeks 38, 46, and 54; the Remicade-US group 
will continue to receive Remicade-US from Week 22 through 
Week 54 every 8 weeks.  The original NI-071 group will 
continue to receive NI-071 from Week 22 through Week 54 
every 8 weeks.  To evaluate interchangeability, a full PK 
similarity analysis (specifically AUCtau [area under the 
concentration-time curve over the dosing interval] and Cmax 
[maximum concentration]) will be performed for all treatment 
groups from samples drawn at 11 time points from pre-dose 
Week 46 to pre-dose Week 54. 
During Stage 3, the last dose of study treatment will be given 
at Week 54, and patients will return for 2 additional safety 
follow-up visits through Week 62 (end of study visit). 
Efficacy and safety evaluations, including assessments of 
anti-drug antibodies (ADAs), will be performed throughout the 
study.  In addition, samples for determining trough 
concentrations will be collected prior to each infusion in the 
study and at the end of the study (Week 62). 
Selection of Patients: 
Inclusion Criteria: 
1. Patients with a diagnosis of RA as defined by the 2010 
ACR and European League Against Rheumatism 
(EULAR) classification criteria8 
2. Patients have active RA, as confirmed by the following 
criteria: 
 ≥6 swollen joints and ≥6 tender joints at screening 
and baseline (28-joint count), and 
 Either CRP ≥0.7 mg/dL (≥7.0 mg/L) or erythrocyte 
sedimentation rate (ESR) ≥28 mm/h at screening 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 7 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 7 
 
3. Patients taking MTX (oral or parenteral) for at least 
3 months prior to screening and at a stable dose of 
between 10 and 25 mg/week for at least 8 weeks.  
Concomitant folic/folinic acid at a dose of at least 
5 mg/week is to be taken during the study; patients can 
start treatment with folic/folinic acid at screening if not 
already receiving it. 
4. If the patient is currently taking non-steroidal 
anti-inflammatory drugs (NSAIDs), the patient must be 
on a stable dose for at least 4 weeks prior to screening 
and during the study. 
5. Patients with a body weight of ≥40 kg and ≤120 kg at 
screening  
6. Patients who are ≥18 and ≤75 years of age at screening  
7. Women of childbearing potential (WOCBP) and men 
(if their sexual partners are WOCBP) must use at least 
1 highly effective form of birth control throughout the 
study and for 6 months after the last dose of study 
treatment.  Highly effective methods of birth control 
include true sexual abstinence (defined as refraining 
from heterosexual intercourse during the entire period 
of risk, in line with the preferred and usual lifestyle of 
the patient), surgery (bilateral tubal ligation or 
occlusion, vasectomized partner), progestogen-only or 
estrogen/progestogen hormonal contraceptive 
associated with inhibition of ovulation (oral, patch, 
injectable, implantable, or intravaginal), intrauterine 
device (IUD), or intrauterine hormone-releasing system 
(IUS).  See Section 8.7 for a definition of WOCBP and 
a complete description of contraceptive requirements. 
8. Patients with the ability to read and understand the 
informed consent form and to provide written consent 
Exclusion Criteria: 
1. Patients who are rated as Class IV according to the 
1991 ACR revised criteria for classification of global 
functional status (see Section 16, Appendix 1) 
2. Patients who have received disease-modifying 
antirheumatic drugs (DMARDs), other than MTX, 
within a period prior to screening shorter than the 
washout period appropriate to the pharmacodynamic 
profile of the specific drug; see Section 16, Appendix 2 
for a list of DMARDs and their washout periods.  
(These patients may be re-screened after the 
appropriate washout period.) 
3. Patients who have received immunosuppressive drugs 
within 4 weeks prior to screening.  Patients on a stable 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 8 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 8 
 
dose of oral corticosteroids (≤10 mg/day prednisone or 
equivalent) for ≥4 weeks prior to screening are 
permitted.  
4. Patients who have received intra-articular, 
intramuscular, intravenous, or epidural injection of 
corticosteroids within 4 weeks prior to screening  
5. Patients who have received intra-articular sodium 
hyaluronate injections within 4 weeks prior to 
screening 
6. Patients who have received surgical therapy for RA 
such as synovectomy or arthroplasty within 6 months 
prior to screening 
7. Patients who have received arthrocentesis within 
4 weeks prior to screening  
8. Patients who have had prior treatment with infliximab 
9. Patients who have had prior treatment with more than 
1 biological drug other than infliximab (e.g., 
adalimumab, rituximab, abatacept, etanercept) for RA 
either as part of clinical management or during a 
clinical study.  Patients who have had prior treatment 
with more than 1 protein kinase inhibitor (e.g., 
tofacitinib) for RA either as part of clinical 
management or during a clinical study.  Patients who 
have had prior treatment with 1 biological drug AND 
1 protein kinase inhibitor are allowed in the study. 
10. Patients who have had prior treatment with a tumor 
necrosis factor alpha (TNF-α) inhibitor for RA who had 
lack of efficacy as per clinical judgment (primary 
failure).  Primary failure is defined as never having 
achieved an adequate response, whereas secondary 
failure is the loss of response over time.  Patients who 
have received prior treatment with no more than 
1 biological DMARD and who have received not more 
than 1 prior TNF-α inhibitor (other than infliximab) and 
have failed it because of loss of efficacy (secondary 
failure) or intolerance (e.g., mild injection site 
reactions) are allowed in the study.  Patients who have 
discontinued TNF-α inhibitors for RA (other than 
infliximab) because their insurance no longer covered 
the cost of treatment or they could no longer afford the 
cost or copays for the treatment are allowed in the 
study.  
11. Patients who had prior treatment with 
cyclophosphamide or other cytotoxic agents 
12. Patients who received investigational drugs in other 
clinical studies within 12 weeks or 5 half-lives of the 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 9 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 9 
 
drug prior to screening, whichever is longer 
13. Patients with a concomitant or past history of 
autoimmune connective tissue diseases other than RA, 
for example, systemic lupus erythematosus, Sjogren's 
syndrome, polymyositis, dermatomyositis, and mixed 
connective tissue disease 
14. Patients with a history of hypersensitivity to the 
components of NI-071 or mouse-derived protein (e.g., 
mouse, chimeric, and humanized antibody) 
15. Patients with the following concomitant or past history: 
 Chronic or recurrent infectious disease (e.g., 
bronchiectasis, sinusitis) 
 Demyelinating disease (e.g., multiple sclerosis) 
 Presence of New York Heart Association (NYHA) 
Class III/IV heart failure (see Section 12.5) 
 Lymphoproliferative disorder (e.g., Epstein-Barr 
virus [EBV]-related lymphoproliferative disorder, 
lymphoma, or leukemia) or myelodysplastic 
syndrome 
 Cancer other than successfully treated 
non-melanoma skin cancer or localized carcinoma 
in situ of the cervix 
 Interstitial lung disease 
16. Presence of chronic or acute infection at screening, 
including positive result for active tuberculosis (TB) 
(e.g., positive QuantiFERON® test result without any 
prior history of active or latent TB and without 
evidence of active infection) where the patient is not 
willing to undergo prophylactic treatment.  (These 
patients may be re-screened after appropriate treatment 
for TB [see Section 12.3]). 
17. Patients with an acute infection requiring parenteral 
antibiotics within 4 weeks of study dosing or requiring 
oral/topical antibiotics within 2 weeks of study dosing. 
(These patients may be re-screened after the 
appropriate washout period.) 
18. Patients with mycobacterial infection or opportunistic 
infection (e.g., cytomegalovirus infection or invasive 
fungal infection such as histoplasmosis, blastomycosis, 
or coccidiomycosis) or who have resided in or traveled 
to regions where such infections are prevalent within 
6 months prior to the initial administration of the 
investigational drug 
19. Patients who have active or past infection or suspected 
infection in prosthetic joints that have not been 
removed or replaced 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 10 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 10 
 
20. Patients with positive results of hepatitis B surface 
antigen (HBsAg), hepatitis B surface antibody 
(HBsAb), hepatitis B core antibody (HBcAb), 
hepatitis C antibody (HCV Ab), and/or human 
immunodeficiency virus antibody (HIV Ab) tests at 
screening (excluding patients who are tested positive 
for HBsAb alone due to a hepatitis B vaccination) 
21. Patients who received a live vaccine within 12 weeks 
prior to study dosing, or who plan to receive a live 
vaccine during the study period or within 6 months 
after the last dose of study treatment.  (If received prior 
to study dosing, these patients may be re-screened after 
the appropriate washout period.) 
22. Patients with laboratory test results at screening that 
meet any of the following reference levels: 
 Hemoglobin ≤8.5 g/dL 
 White blood cells (WBCs) ≤3,500/mm3 
 Lymphocytes ≤1,000/mm3 
 Platelet count ≤100,000/mm3 
 Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥ upper limit of normal 
(ULN) x 1.5 
 Serum creatinine ≥ULN x 1.5 
 Glycated hemoglobin (HbA1c) ≥9.0% 
 Positive anti-double-stranded deoxyribonucleic acid 
(anti-dsDNA) assay 
 β-D-glucan ≥80 pg/mL (positive) 
23. History of clinically significant cardiac, respiratory, 
renal, hepatic, hematologic, gastrointestinal, 
neurologic, endocrinologic, psychiatric, or any other 
uncontrolled medical illness 
24. Female patients who are pregnant, wish to become 
pregnant, or are breastfeeding 
25. Male patients who plan to donate sperm during the 
study or within 6 months after the last dose.  Female 
patients who plan to donate eggs or undergo in vitro 
fertilization treatment during the study or within 
6 months after the last dose. 
26. Patients who are taking part in other clinical studies at 
screening or planning to take part in other clinical 
studies during the study period 
27. Patients with a drug or alcohol dependence 
28. Patients who are determined by the Investigator to be 
unsuitable for study enrollment for other reasons 
Planned Sample Size: 
The sample size required to be randomized in Stage 1 was 
derived with consideration of the required sample size needed 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 11 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 11 
 
for PK analysis at the end of Stage 2 and assumes a 25% 
drop-out of patients during Stages 1 and 2.  Stage 3 will follow 
patients for safety after the final dose and does not have sample 
size requirements. 
To show PK similarity, the 90% geometric confidence 
intervals (CIs) of the ratio (Switch/Remicade-US) of the least 
squares means from the analysis of variance (ANOVA) of the 
ln-transformed AUCtau and Cmax must be within 80.00% and 
125.00%.  For the PK interchangeability analysis at the end of 
Stage 2, assuming coefficients of variation (CVs) of 49% and 
33% for AUCtau and Cmax, respectively, and CIs of the ratios 
between 95% and 105%, at least 109 patients per treatment 
group are required for an 80% powered trial.  
In order to meet this Stage 2 requirement, in Stage 1 (at 
Week 0), approximately 585 patients are expected to be 
randomized in a ratio of 2:1 to Remicade-US (390 patients) 
and NI-071 (195 patients).  This sample size will provide over 
90% power to test for equivalence, using an asymmetric 
margin (-12%, 15%) and a two 1-sided test (TOST) analysis 
with α=0.05 for each 1-sided statistical test.  Greater than 90% 
power is achieved when the ACR20-CRP response rate for 
Remicade-US at Week 22 is assumed to be 79.4% (the 
Remicade-US ACR20-CRP result at Week 22 from Study 
NI071F1 using the study’s modified intent-to-treat population). 
Assuming a 25% drop-out rate during Stage 1, at least 292 
patients in the Remicade-US group and 146 patients in the 
NI-071 group are expected to complete Stage 1 of the study.  
In Stage 2 (at Week 22), patients in the original Remicade-US 
group (about 292 patients) will be re-randomized in a 1:1 ratio 
to a Remicade-US group (146 patients) and a Switch group 
(146 patients).  Assuming a 25% drop-out rate during Stage 2, 
approximately 109 patients per treatment group will be 
available for the PK analysis at the end of Stage 2. 
Investigational Therapy: 
NI-071 (proposed infliximab biosimilar) is provided as a white 
lyophilized pellet in a vial.  Each 20-mL vial contains 100 mg 
of NI-071 for a final reconstitution volume of 10 mL.  NI-071 
is to be administered by IV infusion at a dose of 3 mg/kg at 
Weeks 0, 2, 6, 14, 22, 30, 38, 46, and 54. 
Reference Therapy: 
Remicade-US (infliximab) is provided as a white lyophilized 
pellet in a vial.  Each 20-mL vial contains 100 mg of 
Remicade-US for a final reconstitution volume of 10 mL.  
Remicade-US is to be administered by IV infusion at a dose of 
3 mg/kg at Weeks 0, 2, 6, 14, 22, 30, 38, 46, and 54. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 12 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 12 
 
Switch Therapy: 
Remicade-US and NI-071, administered by IV infusion at a 
dose of 3 mg/kg.  In Stages 2 and 3, the Switch group will 
receive NI-071 at Week 22, Remicade-US at Week 30, and 
NI-071 at Weeks 38, 46, and 54. 
Treatment Duration: 
The approximate maximum duration of treatment for each 
patient is 55 weeks (Week 0 through 54), and the approximate 
maximum duration of the study is 67 weeks (screening of 4 
weeks, treatment of 55 weeks, follow-up of 8 weeks). 
Criteria for Evaluation: 
Clinical Efficacy: 
Clinical efficacy will be assessed by determining ACR core set 
values (tender joint count, swollen joint count, patient pain 
assessment, patient global assessment of disease activity, 
physician global assessment of disease activity, 
patient-completed Health Assessment Questionnaire Disability 
Index [HAQ-DI], CRP, and ESR) at specific visits; the 
DAS28-CRP and DAS28-ESR scores (DAS28 scores 
calculated with CRP and ESR values, respectively) at specific 
visits; the RAPID3 scores at specific visits; and the Medical 
Outcome Study 36-Item Short-Form Health Survey (SF-36) 
scores at specific visits.  ACR20, ACR50, and ACR70 
response rates will be evaluated and are defined as the 
percentage of patients having 20%, 50%, and 70% 
improvement from Week 0 (baseline) scores; these response 
rates will be determined using CRP changes (e.g., ACR20-
CRP) and ESR changes (e.g., ACR20-ESR).  Biosimilarity will 
be based on the ACR20-CRP at Week 22. 
Pharmacokinetics: 
Interchangeability will be assessed from full PK sampling and 
similarity analysis (specifically AUCtau and Cmax) during the 
dosing interval of Weeks 46 to 54.  The following samples will 
be taken for determining the full PK profile:  Week 46 
pre-dose, 1 h after infusion start, at the end of infusion (EOI), 
at 4 h and 24 h after infusion start, and at 4 days, 7 days 
(Week 47), 14 days (Week 48), 28 days (Week 50), 42 days 
(Week 52), and 56 days (Week 54) post-dose. 
Safety: 
Safety will be assessed by adverse event (AE) reporting, 
physical examinations, vital signs, electrocardiograms (ECGs), 
clinical laboratory values, and immunogenicity assessments.  
Blinded patient safety data will be monitored on a monthly 
basis by the clinical team to ensure patient safety. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 13 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 13 
 
Study Endpoints: 
Clinical Efficacy 
Primary endpoint:   
 ACR20-CRP at Week 22 
Secondary endpoints:  
 Change from baseline in DAS28-CRP and DAS28-ESR 
scores 
 ACR20-CRP (at time points other than Week 22), 
ACR20-ESR, ACR50-CRP, ACR50-ESR, 
ACR70-CRP, and ACR70-ESR 
 Change from baseline in each item of ACR core set 
 Change from baseline in RAPID3 scores 
 Change from baseline in SF-36 domain subscores and 
summary scores 
Pharmacokinetics 
Primary endpoints: 
 AUCtau and Cmax during the dosing interval of 
Weeks 46 to 54 
Secondary endpoints: 
 Minimum concentration (Cmin) and time at maximum 
concentration (tmax) during the dosing interval of 
Weeks 46 to 54 
Safety 
The safety endpoints of this study are as follows: 
 Incidence of treatment-emergent AEs (TEAEs) and 
serious AEs (SAEs) 
 Incidence and risk difference between treatment groups 
of AEs of special interest, including serious infections, 
malignancies, infusion-related reactions, 
hepatotoxicity, heart failure, and cytopenias 
 Incidence of ADAs and neutralizing antibodies 
 Clinically significant changes in laboratory values, vital 
signs, weight, ECG, and physical examination results 
Statistical Methods and 
Planned Analyses: 
Five analysis populations are being defined for this study: 
 The intent-to-treat (ITT) population will include all 
patients who are randomized, irrespective of any 
deviation from the protocol or premature 
discontinuation.  Patients will be analyzed according to 
the treatment group assigned at the Stage 1 
randomization.  The ITT population will serve as the 
basis for the primary efficacy analysis in Stage 1. 
 The safety population will include all ITT patients who 
receive at least 1 dose of study drug.  Patients will be 
analyzed according to the actual treatment they receive 
rather than as randomized.  This population will be 
used for the analysis of safety.  
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 14 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 14 
 
 The full analysis set (FAS) will include all patients in 
the safety population with at least 1 post-baseline 
ACR20 efficacy assessment.  Patients will be analyzed 
according to the treatment group assigned at the most 
recent randomization.  This population will be used for 
the secondary efficacy analyses, as well as a sensitivity 
analysis for the primary efficacy endpoint.   
 The per-protocol (PP) population will include all 
patients in the FAS with no major protocol deviations 
in Stage 1, and sufficient time in study.  Sufficient time 
will be defined as having at least the Week 22 
ACR20-CRP efficacy assessment and all study drug 
administrations up to and including the Week 14 study 
drug administration.  Since this population excludes 
patients with major protocol deviations, patients will be 
analyzed according to the treatment they were 
randomized to and received during Stage 1.  This 
population will be used for a sensitivity analysis of the 
primary efficacy analysis. 
 The PK population will include all patients in the FAS 
population in Stage 1 who have valid PK assessments 
through Stage 2.  This includes only patients who have 
received all and complete treatments required per 
protocol through Stage 2.  This population will be used 
for the analysis of interchangeability in Stage 2. 
Clinical Efficacy 
The primary clinical efficacy endpoint for biosimilarity, the 
ACR20-CRP response rate at Week 22, will be analyzed using 
the ITT population.  Patients who do not have an ACR20-CRP 
assessment at Week 22, as well as patients who do not receive 
study drug up to and including the Week 14 administration, 
will be considered to have not achieved ACR20-CRP.  
Because these patients are considered non-responders for this 
analysis, the primary analysis is considered an analysis on the 
composite endpoint of both ACR20-CRP response and 
adherence to study drug treatment. 
To determine biosimilarity, two standard 1-sided asymptotic 
Wald tests of the difference between NI-071 and Remicade-US 
response rates will be performed.  If the null hypotheses of 
both tests are rejected at α=0.05, the equivalence in efficacy is 
achieved.  The hypotheses that will be evaluated are stated, as 
follows, where PNI-071 is the response rate in the NI-071 arm 
and PRemicade-US is the response rate in the Remicade-US arm: 
Ho: PNI-071 – PRemicade-US ≤-12% 
Ho: PNI-071 – PRemicade-US ≥15% 
Ha: -12% <(PNI-071 – PRemicade-US) <15% 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 15 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 15 
 
Sensitivity analyses of the primary efficacy endpoint will be 
performed. 
Secondary clinical endpoints include ACR20-CRP (at time 
points other than Week 22), ACR20-ESR, ACR50-CRP, 
ACR50-ESR, ACR70-CRP, ACR70-ESR, ACR core set items, 
DAS28-CRP, DAS28-ESR, RAPID3 scores, and SF-36 scores.  
Summary statistics (including number of patients, mean, 
standard deviation, minimum, median, maximum) of numerical 
endpoints for DAS28-CRP and DAS28-ESR (value and change 
from baseline for visit) will be calculated and presented by 
visit and treatment group.  Point estimate and 95% CI of 
differences between NI-071 and Remicade-US for 
DAS28-CRP and DAS28-ESR will also be presented.  
Frequency tables of the number and percentage of patients 
achieving ACR20-CRP, ACR20-ESR, ACR50-CRP, 
ACR50-ESR, ACR70-CRP, and ACR70-ESR will be 
calculated and presented by visit and treatment group.  ACR 
core set items will be summarized (value and change from 
baseline for visit) descriptively.  RAPID3 scores will be 
summarized (value and change from baseline for visit) 
descriptively.  SF-36 domain subscores and summary scores 
will be summarized (value and change from baseline for visit) 
descriptively. 
Pharmacokinetics 
To determine PK similarity, the 90% CIs of the ratios 
(Switch/Remicade-US) of least squares means from the 
ANOVA of the ln-transformed AUCtau and Cmax will be 
evaluated at the alpha level of 0.05 for the PK population 
during the dosing interval of Weeks 46 to 54.  If the CI is 
within the range of 80.00% to 125.00%, PK similarity is 
achieved.  Secondary PK parameters include Cmin and tmax 
during this dosing interval.  Wilcoxon’s test will be performed 
on tmax, and Cmin will be summarized descriptively.  Additional 
PK analyses may be performed. 
Interim Analysis 
An interim analysis of the primary clinical efficacy endpoint, 
the ACR20-CRP response rate, will be performed after the last 
patient has completed the last visit in Stage 1, the Week 22 
visit (the visit of the assessments for the primary efficacy 
endpoint).  This analysis will be performed by an unblinded 
statistician not otherwise affiliated with the study.  An 
independent data monitoring committee (IDMC) will be 
established to assess the results and determine whether the 
study should continue or be stopped for futility. 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 16 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 16 
 
Multiplicity 
A hierarchical procedure will be applied to account for 
multiplicity of the confirmatory nature of the study.  The 
Stage 2 interchangeability assessment will be regarded as 
confirmatory in nature only if the biosimilarity assessment at 
Stage 1 is positive.  With this approach, no adjustment for 
multiplicity of the Stage 2 analysis will need to be performed. 
No adjustments for multiplicity are necessary following the 
interim analysis because the interim analysis will be checking 
for a stop for futility reasons only.  Further, the PK analysis for 
the interchangeability assessment in Stage 2 is based solely on 
objective variables (plasma concentration data); hence, the 
introduction of additional bias can be excluded. 
Safety 
AEs will be tabulated by treatment group according to the 
Medical Dictionary for Regulatory Activities (MedDRA).  
TEAEs and treatment-related TEAEs will be summarized by 
system organ class and preferred term.  SAEs, AEs of special 
interest, and AEs resulting in treatment discontinuation will be 
summarized.  The risk difference between treatment groups 
will be determined for AEs of special interest.  Results and 
changes in laboratory data, ADAs, and vital signs will be 
summarized descriptively.  Duration of treatment will be 
summarized by treatment group. 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 17 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 17 
 
2 
TABLE OF CONTENTS 
1 
SYNOPSIS ...................................................................................................................... 5 
2 
TABLE OF CONTENTS ............................................................................................ 17 
IN-TEXT TABLES .............................................................................................. 21 
IN-TEXT FIGURES ............................................................................................. 22 
3 
LIST OF ABBREVIATIONS ..................................................................................... 23 
4 
INTRODUCTION ....................................................................................................... 26 
4.1 
Background on Rheumatoid Arthritis and Treatment .........................................26 
4.2 
Background on NI-071 .......................................................................................27 
4.2.1 
Nonclinical Studies ..............................................................................27 
4.2.2 
Clinical Studies ....................................................................................28 
4.3 
Potential Benefits and Risks ...............................................................................29 
4.4 
Rationale .............................................................................................................30 
5 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 32 
5.1 
Study Objectives .................................................................................................32 
5.1.1 
Stage 1 (Biosimilarity Stage) Objectives .............................................32 
5.1.2 
Stage 2 (Interchangeability Stage) Objectives .....................................32 
5.1.3 
Stage 3 (Safety Follow-up Stage) Objective ........................................32 
5.2 
Study Endpoints ..................................................................................................32 
5.2.1 
Clinical Efficacy Endpoints .................................................................32 
5.2.2 
Pharmacokinetic Endpoints .................................................................33 
5.2.3 
Safety Endpoints ..................................................................................33 
6 
INVESTIGATIONAL PLAN ..................................................................................... 33 
6.1 
Description of Overall Study Design and Plan ...................................................33 
6.2 
Discussion of Study Design ................................................................................34 
7 
SELECTION AND WITHDRAWAL OF PATIENTS ............................................ 35 
7.1 
Inclusion Criteria ................................................................................................35 
7.2 
Exclusion Criteria ...............................................................................................35 
7.3 
Withdrawal, Removal, and Replacement of Patients..........................................39 
7.4 
Follow-Up for Drug Discontinuation/Patient Withdrawal from Study ..............40 
8 
TREATMENTS ........................................................................................................... 40 
8.1 
Details of Study Treatments................................................................................40 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 18 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 18 
 
8.2 
Dosage Schedule .................................................................................................42 
8.3 
Study Treatment Assignment ..............................................................................43 
8.4 
Blinding...............................................................................................................43 
8.5 
Treatment Accountability and Compliance ........................................................43 
8.6 
Prior and Concomitant Illnesses and Medications ..............................................44 
8.6.1 
Prior and Concomitant Illnesses ..........................................................44 
8.6.2 
Prior and Concomitant Medications ....................................................44 
8.7 
Study Restrictions ...............................................................................................46 
9 
STUDY PROCEDURES ............................................................................................. 47 
9.1 
Patient Informed Consent ...................................................................................51 
9.2 
Patient Re-Screening ...........................................................................................51 
9.3 
Procedures by Week ...........................................................................................51 
9.3.1 
Screening..............................................................................................51 
9.3.2 
Week 0 (Baseline) ................................................................................52 
9.3.3 
Weeks 2, 6, and 14 ...............................................................................53 
9.3.4 
Week 18 ...............................................................................................54 
9.3.5 
Week 22 ...............................................................................................55 
9.3.6 
Weeks 26, 30, 34, 38, and 42 ...............................................................55 
9.3.7 
Weeks 46, 50, 54, and 58 .....................................................................57 
9.3.8 
Week 62 (End of Study Visit or Early Discontinuation Visit) ............58 
9.3.9 
Unscheduled Visits ..............................................................................59 
10 
EFFICACY ASSESSMENTS ..................................................................................... 59 
10.1 
Primary Efficacy Variable ..................................................................................59 
10.1.1 
Tender and Swollen Joint Counts ........................................................59 
10.1.2 
Assessments Using Visual Analog Scales ...........................................60 
10.1.3 
HAQ-DI ...............................................................................................60 
10.1.4 
Acute-Phase Reactants .........................................................................60 
10.2 
Secondary Efficacy Variables .............................................................................60 
10.2.1 
DAS28-CRP and DAS28-ESR ............................................................60 
10.2.2 
RAPID3................................................................................................61 
10.2.3 
SF-36 ....................................................................................................61 
10.3 
Other Disease Assessments (at Screening) .........................................................62 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 19 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 19 
 
11 
PHARMACOKINETIC ASSESSMENTS ................................................................ 62 
12 
SAFETY ASSESSMENTS .......................................................................................... 62 
12.1 
Vital Signs, Height, and Weight .........................................................................62 
12.2 
Physical Examination..........................................................................................62 
12.3 
Tuberculosis Screening .......................................................................................63 
12.4 
Electrocardiogram ...............................................................................................63 
12.5 
New York Heart Association Classification .......................................................63 
12.6 
Clinical Laboratory Parameters ..........................................................................64 
12.7 
Immunogenicity Assessments .............................................................................65 
12.8 
Adverse Events ...................................................................................................66 
12.8.1 
Adverse Events ....................................................................................66 
12.8.2 
Serious Adverse Events .......................................................................71 
12.8.3 
Serious Adverse Event Reporting ........................................................71 
12.8.4 
Suspected Unexpected Serious Adverse Reactions .............................72 
12.8.5 
Pregnancy .............................................................................................72 
12.8.6 
Overdose ..............................................................................................73 
13 
STATISTICAL ANALYSIS ....................................................................................... 73 
13.1 
Determination of Sample Size ............................................................................73 
13.2 
Analysis Populations ...........................................................................................75 
13.3 
Demographic and Baseline Characteristics ........................................................76 
13.4 
Efficacy Analysis ................................................................................................76 
13.4.1 
Analysis of Primary Efficacy Endpoint ...............................................76 
13.4.1.1 Sensitivity Analyses of the Primary Efficacy Endpoint ......76 
13.4.2 
Analysis of Secondary Efficacy Endpoints..........................................78 
13.5 
Pharmacokinetic Analysis ...................................................................................78 
13.6 
Accounting for Multiplicity ................................................................................78 
13.7 
Safety Analysis ...................................................................................................79 
13.7.1 
Adverse Events ....................................................................................79 
13.7.2 
Vital Signs, Weight, Physical Examination, and ECG ........................79 
13.7.3 
Clinical Laboratory Parameters ...........................................................79 
13.7.4 
Anti-drug Antibodies and Neutralizing Antibodies .............................79 
13.7.5 
Prior and Concomitant Medications ....................................................79 
13.8 
Interim Analysis ..................................................................................................80 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 20 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 20 
 
13.9 
Independent Data Monitoring Committee ..........................................................80 
14 
STUDY MANAGEMENT ........................................................................................... 80 
14.1 
Approval and Consent.........................................................................................80 
14.1.1 
Regulatory Guidelines .........................................................................80 
14.1.2 
Institutional Review Board/Independent Ethics Committee................80 
14.1.3 
Informed Consent.................................................................................80 
14.2 
Data Handling .....................................................................................................81 
14.3 
Source Documents ..............................................................................................81 
14.4 
Record Retention ................................................................................................81 
14.5 
Monitoring ..........................................................................................................82 
14.6 
Definition of the End of Trial .............................................................................82 
14.7 
Quality Control and Quality Assurance ..............................................................82 
14.8 
Protocol Amendment and Protocol Deviation ....................................................83 
14.8.1 
Protocol Amendment ...........................................................................83 
14.8.2 
Protocol Deviations ..............................................................................83 
14.9 
Ethical Considerations ........................................................................................83 
14.10 Financing and Insurance .....................................................................................83 
14.11 Publication Policy / Disclosure of Data ..............................................................83 
15 
REFERENCES............................................................................................................. 85 
16 
APPENDICES .............................................................................................................. 88 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 21 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 21 
 
IN-TEXT TABLES 
Table 1 
Details of Study Treatments ....................................................................................41 
Table 2 
Schedule of Assessments ........................................................................................48 
Table 3 
New York Heart Association Classification ...........................................................64 
Table 4 
Clinical Laboratory Parameters ..............................................................................65 
Table 5 
List of Anticipated AEs with Study Drug (AEs Reported with Remicade) ............67 
Table 6 
Classification of Adverse Events by Intensity ........................................................70 
Table 7 
Classification of Adverse Events by Relationship to Study Drug ..........................70 
Table 8 
Sensitivity Analyses of the Primary Efficacy Endpoint ..........................................77 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 22 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 22 
 
IN-TEXT FIGURES 
Figure 1 NI071F2 Study Design ............................................................................................31 
 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 23 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 23 
 
3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACPA 
Anti-citrullinated protein antibody 
ACR 
American College of Rheumatology 
ACR20 (50, 70)-
CRP 
20% (50%, 70%) improvement from baseline in the ACR core set 
criteria using C-reactive protein as the acute-phase reactant 
ACR20 (50, 70)-
ESR 
20% (50%, 70%) improvement from baseline in the ACR core set 
criteria using erythrocyte sedimentation rate as the acute-phase 
reactant 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
Anti-dsDNA 
Anti-double-stranded deoxyribonucleic acid 
ANOVA 
Analysis of variance 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase) 
AUC 
Area under the concentration-time curve 
BCG 
Bacillus Calmette-Guérin 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CPMP 
EMA Committee for Proprietary Medicinal Products, now known as 
the Committee for Medicinal Products for Human Use 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
DAS28-CRP 
Disease activity score based on 28 joints calculated with CRP value 
DAS28-ESR 
Disease activity score based on 28 joints calculated with ESR value 
DMARD 
Disease-modifying antirheumatic drug 
DNA 
Deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOI 
End of infusion 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 24 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 24 
 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
HbA1c 
Glycated hemoglobin 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV Ab 
Hepatitis C antibody 
HIV Ab 
Human immunodeficiency virus antibody 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
Independent data monitoring committee 
IGRA 
Interferon Gamma Release Assay 
IEC 
Independent ethics committee 
IND 
Investigational new drug  
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
IVRS/IWRS 
Interactive voice or web response system 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTX 
Methotrexate 
NRI 
Non-responder imputation 
NSAID 
Non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
PK 
Pharmacokinetic 
PP 
Per protocol 
PPD 
Purified protein derivative (skin test for TB) 
PT 
Preferred term 
RA 
Rheumatoid arthritis 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 25 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 25 
 
RAPID3 
Routine assessment of patient index data 3 
RF 
Rheumatoid factor 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-36 
Medical Outcomes Study 36-Item Short-Form Health Survey 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
tmax 
Time at maximum concentration 
TNF-α 
Tumor necrosis factor alpha 
TOST 
Two 1-sided test analysis 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analog scale 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 26 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 26 
 
4 
INTRODUCTION 
4.1 
Background on Rheumatoid Arthritis and Treatment 
Rheumatoid arthritis (RA), the most common autoimmune inflammatory arthritis in adults, is 
characterized by the persistent and progressive inflammation of multiple synovial 
membranes, causing symptoms of joint pain, swelling, stiffness, and redness, and often 
ultimately leading to the erosion and destruction of cartilage and bone.  RA causes increasing 
disability and decreases patients’ ability to perform daily activities, thus reducing their 
economic and social quality of life.  RA is associated with increased mortality and 
comorbidities (most commonly, cardiovascular disease, infections, mental health conditions, 
and malignancies).  There is no cure, but effective treatments are increasingly available to 
treat RA.  In patients with early RA, treatment usually starts with non-biologic 
disease-modifying antirheumatic drugs (DMARDs) that help reduce disease activity and 
prevent joint deformity.  Over time as the disease activity increases, combination treatment 
with non-biologic and biologic DMARDs are introduced.1,2 
Biologic therapies are designed to modify or regulate specific mechanisms involved in the 
proinflammatory cytokine overproduction that plays a key role in inflammatory diseases.  
Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine that is involved in 
normal inflammatory and immune response, but overexpressed TNF-α has been implicated in 
the pathogenesis of RA and other immunological diseases.  Elevated TNF-α levels have been 
found in the joints of RA patients and correlate with elevated disease activity; elevated levels 
are also found in patients with Crohn’s disease, ulcerative colitis, ankylosing spondylitis, 
psoriatic arthritis, and plaque psoriasis.3,4 
US-licensed Remicade® (infliximab; Remicade-US), one of the biologics used to treat RA, is 
a chimeric human-murine IgG1 monoclonal antibody specific for human TNF-α produced in 
murine hybridoma cells by recombinant deoxyribonucleic acid (DNA) technology.  
Infliximab neutralizes the biological activity of TNF-α by binding with high affinity to the 
soluble and transmembrane forms of TNF-α and inhibits binding of TNF-α with its receptors.  
Infliximab inhibits the functional activity of TNF-α in a wide variety of in vitro bioassays.  
Also, infliximab prevented disease in transgenic mice that develop polyarthritis as a result of 
constitutive expression of human TNF-α and when administered after disease onset, it 
allowed eroded joints to heal.  In vivo, infliximab rapidly forms stable complexes with 
human TNF-α, a process that parallels the loss of TNF-α bioactivity.  In RA, treatment with 
infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well 
as expression of molecules mediating cellular adhesion, chemo-attraction, and tissue 
degradation.  Also after infliximab treatment, patients exhibited decreased levels of serum 
interleukin 6 and C-reactive protein (CRP).3,4 
Remicade-US is approved for use in the United States (US) for the treatment of adult patients 
with moderately to severely active RA, in combination with methotrexate (MTX), for 
reducing signs and symptoms, inhibiting the progression of structural damage, and improving 
physical function.  In addition, Remicade-US is approved for the treatment of the following 
other indications in the US:3 
 Adult Crohn’s Disease (indicated for reducing signs and symptoms and inducing and 
maintaining clinical remission in adult patients with moderately to severely active 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 27 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 27 
 
disease who have had an inadequate response to conventional therapy and for 
reducing the number of draining enterocutaneous and rectovaginal fistulas and 
maintaining fistula closure in adult patients with fistulizing disease) 
 Pediatric Crohn’s Disease (indicated for reducing signs and symptoms and inducing 
and maintaining clinical remission in pediatric patients with moderately to severely 
active disease who have had an inadequate response to conventional therapy)  
 Adult Ulcerative Colitis (indicated for reducing signs and symptoms, inducing and 
maintaining clinical remission and mucosal healing, and eliminating corticosteroid 
use in adult patients with moderately to severely active disease who have had an 
inadequate response to conventional therapy) 
 Pediatric Ulcerative Colitis (indicated for reducing signs and symptoms and inducing 
and maintaining clinical remission in pediatric patients with moderately to severely 
active disease who have had an inadequate response to conventional therapy) 
 Ankylosing Spondylitis (indicated for reducing signs and symptoms in patients with 
active disease) 
 Psoriatic Arthritis (indicated for reducing signs and symptoms of active arthritis, 
inhibiting the progression of structural damage, and improving physical function) 
 Plaque Psoriasis (indicated for treatment of adult patients with chronic severe (i.e., 
extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy 
and when other systemic therapies are medically less appropriate) 
Nichi-Iko Pharmaceutical Co., Ltd., (the Sponsor) is developing NI-071, a proposed 
biosimilar of Remicade-US containing the active substance infliximab.  The indications for 
NI-071 are proposed to be the same as currently approved for Remicade-US, and the dosage 
forms, route of administration, and dosing regimens for NI-071 are to be the same as for 
Remicade-US for each indication.5 
4.2 
Background on NI-071 
NI-071 is a chimeric human/murine monoclonal antibody specific for human TNF-α.  Each 
molecule is composed of 2 heterodimers in which each heterodimer consists of a heavy 
polypeptide chain of 450 amino acids and a light polypeptide chain of 214 amino acids.  The 
complex intra- and inter-chain disulfide linkages contribute to the conserved folding, 
structural stability, and the unique function of the IgG1 molecule.  The Sponsor has 
performed extensive analytical and functional assay testing between NI-071 and 
Remicade-US as part of the similarity assessment of NI-071 to the reference product.   
4.2.1 Nonclinical Studies 
In vitro functional assays were performed to assess whether NI-071 possesses similar 
biological activity to Remicade-US.  A comprehensive panel of binding assays and bioassays 
was conducted to test functionality.  The results from these assays have demonstrated that 
NI-071 is similar analytically to Remicade-US in primary in vitro pharmacodynamics.  
Further information on the nonclinical studies of NI-071 is presented in the Investigator’s 
Brochure (IB).5 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 28 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 28 
 
4.2.2 Clinical Studies 
Two studies have been completed in Japan using Remicade-US as the reference product.  A 
Phase 1 study of NI-071 and Remicade-US was performed to study pharmacokinetics and 
safety, and a Phase 3 clinical study in RA patients was performed to evaluate efficacy in 
NI-071 and Remicade-US, and to provide immunogenicity and pharmacokinetic (PK) 
information.5,24 
In the Phase 1 study, 96 healthy male adult volunteers were randomized and given a single 
dose of 3 mg/kg NI-071 or Remicade-US as a 2-hour intravenous (IV) infusion (48 subjects 
in the NI-071 group, and 48 subjects in the Remicade-US group).  The least-squares means 
ratios (NI-071/Remicade-US), the 90% geometric confidence intervals (CIs), and coefficients 
of variation (CVs) were determined for AUC0-t (area under the concentration-time curve 
from time zero to the last non-zero concentration), AUC0-inf (area under the 
concentration-time curve from time zero to infinity), and maximum concentration (Cmax).  As 
shown by the CIs of the AUC0-t and AUC0-inf, PK similarity following a single dose was 
demonstrated.  Single-dose administration of a 3 mg/kg dose of NI-071 resulted in slightly 
greater immunogenic potential based on the incidence of anti-drug antibody (ADA)-positive 
subjects and detected increases in antibody titer and neutralizing antibody activity.  No 
difference was observed between the 2 groups in the severity and incidence of adverse events 
(AEs). 
The Phase 3 study evaluated Japanese RA patients for whom MTX was inadequately 
effective, and had a screening period and a treatment period (a double-blind period in Stage I 
and an open-label period in Stage II).  The study design in Stage I (from randomization to 
before administration at Week 30) was a randomized, double-blind, positive-control, 
parallel-group trial, comparing the efficacy, safety, and pharmacokinetics of NI-071 and 
Remicade-US.  NI-071 or Remicade-US was administered at a dose of 3 mg/kg by IV 
infusion on the first administration day, at 2 weeks, at 6 weeks, then every 8 weeks.  If the 
effect was insufficient or decreased, the dose could be increased and the dosing interval 
could be shortened after the evaluation at Week 14.  If the dose was increased, it was to be 
done stepwise and the upper limit of the dose per 1 kg body weight was to be 10 mg (if the 
dosing interval was 8 weeks) or 6 mg (if the dosing interval was 4 weeks).  If the dosing 
intervals were shortened, the intervals were to be 4 weeks.  The study design in Stage II 
(from administration at Week 30) was an open-label study in which NI-071 was administered 
to all patients who transitioned to Stage II to evaluate the long-term safety of NI-071. 
In this study, 242 patients (126 patients in the NI-071 group, 116 patients in the 
Remicade-US group) were randomized, and the investigational product was administered to 
all 242 randomized patients. Overall, 238 (98.3%) patients completed the protocol to 
14 weeks, which was the main evaluation point for efficacy, and 222 (91.7%) patients 
completed Stage I, which was the double-blind period (from randomization to before the 
administration at Week 30).  The average value (standard deviation) of change in 
DAS28-ESR (disease activity score [DAS] measured with 28 joints and erythrocyte 
sedimentation rate [ESR]) from baseline to Week 14, which was the primary efficacy 
endpoint, was -2.15 (1.19) in the NI-071 group and -2.13 (1.18) in the Remicade-US group.  
The difference in average values between the NI-071 group and the Remicade-US group and 
the 95% CI were calculated for the change in DAS28-ESR, using analysis of covariance with 
DAS28-ESR at the start of administration as the covariant.  As a result, the least squares 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 29 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 29 
 
average values (standard errors) of the 2 groups were -2.13 (0.106) in the NI-071 group and -
2.16 (0.112) in the Remicade-US group.  The difference was 0.02, and its 95% CI was -0.280 
to 0.328.  The previously stipulated standard for equivalence (95% CI of the difference in 
average values to fall in the range -0.6 to 0.6) was satisfied.  Therefore, the results indicated 
that the efficacy of NI-071 measured with DAS28-ESR was similar to Remicade-US.   
The ACR20-CRP, ACR50-CRP, and ACR70-CRP response rates (percentages of patients 
achieving a 20%/50%/70% improvement from baseline in the American College of 
Rheumatology [ACR] core set criteria) using CRP at Week 14 in the NI-071 group were 
73.2% (90 of 123 patients), 45.5% (56 of 123 patients), and 21.1% (26 of 123 patients), 
respectively.  In the Remicade-US group, they were 69.4% (77 of 111 patients), 53.2% (59 of 
111 patients), and 26.1% (29 of 111 patients), respectively.  At Week 22, the ACR20-CRP, 
ACR50-CRP, and ACR70-CRP response rates in the NI-071 group were 84.7% (100 of 118 
patients), 61.9% (73 of 118 patients), and 32.2% (38 of 118 patients), respectively.  In the 
Remicade-US group, they were 79.4% (85 of 107 patients), 59.8% (64 of 107 patients), and 
37.4% (40 of 107 patients), respectively.  Similarly, ACR20-CRP, ACR50-CRP, and 
ACR70-CRP response rates at Week 30 in the NI-071 group were 86.8% (99 of 114 
patients), 69.3% (79 of 114 patients), and 40.4% (46 of 114 patients), respectively.  In the 
Remicade-US group, they were 84.3% (86 of 102 patients), 64.7% (66 of 102 patients), and 
45.1% (46 of 102 patients), respectively. Thus, no clear difference was observed between the 
2 groups. 
Through Week 30 of the study, treatment-emergent AEs (TEAEs) were observed in 92 (73%) 
patients in the NI-071 group and 89 (76.7%) patients in the Remicade-US group.  TEAEs 
considered related to study drug were observed in 57 (45.2%) patients in the NI-071 group 
and in 49 (42.2%) patients in the Remicade-US group.  TEAEs seen with relatively high 
frequency (in at least 5% of patients in either group) were nasopharyngitis (NI-071 group: 
18.3%, Remicade-US group: 23.3%), infusion-related reaction (8.7%, 6.0%), elevated 
alanine aminotransferase (ALT) (6.3%, 6.0%), and eczema (3.2%, 5.2%).  Serious TEAEs 
were observed in 9 (7.1%) patients in the NI-071 group and 4 (3.4%) patients in the 
Remicade-US group.  Each of the events was reported in only 1 patient.  Serious TEAEs 
considered related to study drug were pancytopenia, female breast cancer, enterocolitis, 
peritonitis, interstitial lung disease, and pneumonia in the NI-071 group; and pyelonephritis, 
duodenal perforation, and Pneumocystis jiroveci pneumonia in the Remicade-US group.  No 
deaths were reported.  TEAEs that led to discontinuation of study treatment were reported in 
11 (8.7%) patients in the NI-071 group and 10 (8.6%) patients in the Remicade-US group. 
In the open-label stage (from Week 30 through Week 54) of the study, TEAEs were observed 
in 108 (85.7%) patients in the NI-071 group and 99 (85.3%) patients in the switch group (the 
patients who switched from Remicade-US to NI-071 at Week 30).  There was no difference 
between the 2 groups in terms of the incidence of TEAEs.  Moreover, the types of TEAEs 
did not change characteristically between up to Week 30 and Week 30 to Week 54.  Thus, 
there was no clinical safety concern with the long-term administration of NI-071 and the 
switching from Remicade-US to NI-071. 
4.3 
Potential Benefits and Risks 
In the Phase 1 study in healthy volunteers and in the Phase 3 study in patients with RA in 
Japan, the PK, clinical efficacy, and safety results were similar between the NI-071 and 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 30 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 30 
 
Remicade-US groups.  NI-071 is expected to have a similar benefit/risk profile to 
Remicade-US in patients with diseases indicated for treatment, as the active substance of 
NI-071 is essentially the same biological substance as the marketed formulation of 
infliximab.  
Infliximab neutralizes the biological function of TNF-α by blocking its interaction with cell 
surface TNF-α receptors, and modulates biological responses that are induced or modified by 
TNF-α.  The benefit of this immunosuppression is that RA patients who have inadequate 
disease control can enter the study and be treated with a TNF-α inhibitor recommended by 
ACR treatment guidelines.1  The main risk accompanies the same immunosuppression:  an 
increased risk of infections and possibly malignancies.  Other serious risks include 
hypersensitivity, hepatotoxicity, heart failure, and cytopenias.  The most commonly reported 
AEs with Remicade-US have been mild to moderate infusion-related reactions and upper 
respiratory tract infections, which are easily monitored and treated.3  Patients with a history 
of chronic or acute infection, including a positive test for hepatitis or untreated latent 
tuberculosis (TB), will not be permitted to enter the study.  Patients will be monitored during 
the study for development of serious infections and, if required, study treatment will be 
promptly discontinued. 
4.4 
Rationale 
To address any residual uncertainty in the proposed similarity of NI-071 and Remicade-US, 
this Phase 3 protocol will examine the therapeutic biosimilarity, the PK interchangeability, 
and the safety after multiple doses of double-blind study treatment.  This study in the 
sensitive population of patients with RA will serve as the benchmark study that addresses the 
clinical impact of the proposed biosimilar compared with the reference biologic for all adult 
indications currently approved for Remicade-US. 
Following a screening period, there are 3 stages:  the biosimilarity stage (Stage 1), the 
interchangeability stage (Stage 2), and the safety follow-up stage (Stage 3).  Clinical efficacy 
will be evaluated by the ACR20-CRP response rate at Week 22, which was the primary 
efficacy variable analyzed in the Phase 3 RA trials for Remicade-US.  At Week 22, half of 
the original Remicade-US patients will be randomly assigned to a Switch group to assess the 
effects of switching from the reference product to the investigational product.  During 
Stage 2, (Weeks 22 to 54), the Switch group will receive NI-071, then Remicade-US, then 
NI-071; the other half of the original Remicade-US group will continue on Remicade-US, 
and the NI-071 group will continue on NI-071.  To evaluate interchangeability, a full PK 
similarity analysis will be performed for all treatment groups from samples drawn at 11 time 
points from pre-dose Week 46 to pre-dose Week 54.  During Stage 3, the last dose of study 
treatment will be given at Week 54, and patients will return for 2 additional safety follow-up 
visits through Week 62.  A schematic of the study design is provided in Figure 1.  
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 31 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
 
 
 
 
 
NI071F2 
NI-071 
 
 
                    Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
 
 
 
 
 
 
Page 31 
 
Figure 1 NI071F2 Study Design 
 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 32 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 32 
 
5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Study Objectives 
5.1.1 Stage 1 (Biosimilarity Stage) Objectives 
Primary: 
 To investigate the biosimilarity of NI-071 (proposed infliximab biosimilar) and 
Remicade-US (infliximab) in terms of efficacy in patients with RA not adequately 
responding to MTX, by determining the percentages of patients achieving 
ACR20-CRP 
Secondary: 
 To evaluate safety and immunogenicity of NI-071 and Remicade-US 
 To evaluate efficacy based on other rates of improvement in the ACR criteria, on the 
DAS28 and the RAPID3 (routine assessment of patient index data 3), and on changes 
in health-related quality of life 
5.1.2 Stage 2 (Interchangeability Stage) Objectives 
Primary: 
 To investigate the interchangeability between NI-071 and Remicade-US by 
evaluating key PK parameters in each treatment group following treatment switches 
Secondary: 
 To evaluate the safety, efficacy, and immunogenicity of NI-071 and Remicade-US 
5.1.3 Stage 3 (Safety Follow-up Stage) Objective 
Primary: 
 To evaluate the safety of long-term treatment (follow-up through Week 62) 
5.2 
Study Endpoints 
5.2.1 Clinical Efficacy Endpoints 
Primary: 
 ACR20-CRP at Week 22 
Secondary: 
 Change from baseline in DAS28-CRP and DAS28-ESR scores (DAS28 scores 
calculated with CRP and ESR values, respectively) 
 ACR20-CRP (at time points other than Week 22), ACR20-ESR, ACR50-CRP, 
ACR50-ESR, ACR70-CRP, and ACR70-ESR 
 Change from baseline in each item of the ACR core set 
 Change from baseline in RAPID3 scores 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 33 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 33 
 
 Change from baseline in the Medical Outcomes Study 36-Item Short-Form Health 
Survey (SF-36) domain subscores and summary scores 
5.2.2 Pharmacokinetic Endpoints 
Primary: 
 AUCtau and Cmax during the dosing interval of Weeks 46 to 54 
Secondary: 
 Minimum concentration (Cmin) and time at maximum concentration (tmax) during the 
dosing interval of Weeks 46 to 54 
5.2.3 
Safety Endpoints 
The safety endpoints of this study are as follows: 
 Incidence of TEAEs and serious AEs (SAEs) 
 Incidence and risk difference between treatment groups of AEs of special interest, 
including serious infections, malignancies, infusion-related reactions, hepatotoxicity, 
heart failure, and cytopenias 
 Incidence of ADAs and neutralizing antibodies 
 Clinically significant changes in laboratory values, vital signs, weight, ECG, and 
physical examination results 
6 
INVESTIGATIONAL PLAN 
6.1 
Description of Overall Study Design and Plan 
This Phase 3, randomized, double-blind, multicenter, biosimilarity, interchangeability, and 
safety study is designed to evaluate NI-071 versus Remicade-US for the treatment of patients 
with RA.  Following a screening period, there will be 3 stages:  the biosimilarity stage 
(Stage 1), the interchangeability stage (Stage 2), and the safety follow-up stage (Stage 3). 
The screening period, approximately 4 weeks long for each patient, will be used to assess 
eligibility.  At baseline (Week 0), approximately 585 patients who are eligible will be 
randomized in a 2:1 ratio to the Remicade-US and NI-071 groups, respectively.  This initial 
randomization will be stratified by CRP level (≤2, >2 mg/dL).  During Stage 1, patients will 
receive their randomized treatment at Weeks 0, 2, 6, and 14.  Primary biosimilarity efficacy 
assessments (specifically ACR20-CRP) will be performed at Week 22. 
During Stage 2, at Week 22, patients in the original Remicade-US group are re-randomized 
(1:1) to a Remicade-US group and a Switch group.  The Switch group will receive NI-071 at 
Week 22, Remicade-US at Week 30, and NI-071 at Weeks 38, 46, and 54; the Remicade-US 
group will continue to receive Remicade-US from Week 22 through Week 54 every 8 weeks.  
The original NI-071 group will continue to receive NI-071 from Week 22 through Week 54 
every 8 weeks.  To evaluate interchangeability, a full PK similarity analysis (specifically 
AUCtau and Cmax) will be performed for all treatment groups from samples drawn at 11 time 
points from pre-dose Week 46 to pre-dose Week 54.  During Stage 3, the last dose of study 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 34 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 34 
 
treatment will be given at Week 54, and patients will return for 2 additional safety follow-up 
visits through Week 62 (end of study visit). 
Efficacy and safety evaluations, including assessments of ADAs, will be performed 
throughout the study.  In addition, samples for determining trough concentrations will be 
collected prior to each infusion in the study and at the end of the study. 
6.2 
Discussion of Study Design 
This Phase 3 study of NI-071 is designed to examine biosimilarity and interchangeability 
with Remicade-US in terms of efficacy, safety, and pharmacokinetics.  This randomized, 
double-blind study in patients with RA is designed to evaluate the same primary efficacy 
endpoint as in the Phase 3 Remicade-US studies (ACR20-CRP), pharmacokinetics, and 
safety, including immunogenicity.  The design includes primary efficacy evaluations at 
Week 22, followed by PK, efficacy, and safety assessments over an additional 32 weeks of 
treatment, and includes a randomized Switch arm that switches from Remicade-US to NI-071 
to Remicade-US to NI-071.  This switching of treatments in the Switch arm allows a study of 
the effect of interchangeability of Remicade-US and NI-071 on the pharmacokinetics, 
efficacy, and safety.  The immunogenicity of NI-071 is assessed during the biosimilarity and 
interchangeability stages of the study. 
The recommended therapeutic dose of Remicade-US for adults with RA is 3 mg/kg 
administered IV at Weeks 0, 2, and 6, then every 8 weeks.  As NI-071 is being developed as 
a similar medicinal product to Remicade-US, it is appropriate to also administer NI-071 at a 
dose of 3 mg/kg IV on the same schedule.  Hence, the duration of the switching intervals is 
also 8 weeks in the interchangeability stage of the study.  During this stage, the 16 weeks on 
NI-071 (2 doses starting from Week 38) in the Switch group ensures a washout of the 
reference product before the PK analysis is performed after the final dose of study treatment 
at Week 54 (for the Stage 2 PK endpoint). 
The Committee for Medicinal Products for Human Use draft “Guideline on clinical 
investigation of medicinal products other than non-steroidal anti-inflammatory drugs 
(NSAIDs) for the treatment of RA” (CPMP/EWP/556/95 Rev.2) indicates that combined 
measures are to be used in the documentation of efficacy in studies of RA.  Validated 
composite endpoints that are regarded as acceptable in this guideline include the ACR 
response rate and the DAS28 score.6  Both the ACR20 and DAS28 are accepted, validated 
endpoints that have been widely used in studies to assess DMARDs (biological and 
non-biological) for the treatment of RA.7  The timing of the ACR20-CRP endpoint at 
Week 22 is consistent with previous studies evaluating the efficacy of biological agents to 
improve the signs and symptoms of RA. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 35 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 35 
 
7 
SELECTION AND WITHDRAWAL OF PATIENTS 
7.1 
Inclusion Criteria 
Patients must meet all of the following criteria in order to be included in the study: 
1. Patients with a diagnosis of RA as defined by the 2010 ACR and European League 
Against Rheumatism (EULAR) classification criteria8 
2. Patients have active RA, as confirmed by the following criteria: 
 ≥6 swollen joints and ≥6 tender joints at screening and baseline (28-joint count), 
and 
 Either CRP ≥0.7 mg/dL (≥7.0 mg/L) or ESR ≥28 mm/h at screening 
3. Patients taking MTX (oral or parenteral) for at least 3 months prior to screening and 
at a stable dose of between 10 and 25 mg/week for at least 8 weeks.  Concomitant 
folic/folinic acid at a dose of at least 5 mg/week is to be taken during the study; 
patients can start treatment with folic/folinic acid at screening if not already receiving 
it. 
4. If the patient is currently taking NSAIDs, the patient must be on a stable dose for at 
least 4 weeks prior to screening and during the study. 
5. Patients with a body weight of ≥40 kg and ≤120 kg at screening  
6. Patients who are ≥18 and ≤75 years of age at screening  
7. Women of childbearing potential (WOCBP) and men (if their sexual partners are 
WOCBP) must use at least 1 highly effective form of birth control throughout the 
study and for 6 months after the last dose of study treatment.  Highly effective 
methods of birth control include true sexual abstinence (defined as refraining from 
heterosexual intercourse during the entire period of risk, in line with the preferred and 
usual lifestyle of the patient), surgery (bilateral tubal ligation or occlusion, 
vasectomized partner), progestogen-only or estrogen/progestogen hormonal 
contraceptive associated with inhibition of ovulation (oral, patch, injectable, 
implantable, or intravaginal), intrauterine device (IUD), or intrauterine hormone-
releasing system (IUS).  See Section 8.7 for a definition of WOCBP and a complete 
description of contraceptive requirements. 
8. Patients with the ability to read and understand the informed consent form (ICF) and 
to provide written consent 
7.2 
Exclusion Criteria 
Patients meeting any of the following criteria are ineligible to participate in this study: 
1. Patients who are rated as Class IV according to the 1991 ACR revised criteria for 
classification of global functional status (see Section 16, Appendix 1) 
2. Patients who have received DMARDs, other than MTX, within a period prior to 
screening shorter than the washout period appropriate to the pharmacodynamic 
profile of the specific drug (see Section 16, Appendix 2, for a list of DMARDs and 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 36 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 36 
 
their washout periods).  (These patients may be re-screened after the appropriate 
washout period.) 
3. Patients who have received immunosuppressive drugs within 4 weeks prior to 
screening.  Patients on a stable dose of oral corticosteroids (≤10 mg/day prednisone or 
equivalent) for ≥4 weeks prior to screening are permitted.  
4. Patients who have received intra-articular, intramuscular, IV, or epidural injection of 
corticosteroids within 4 weeks prior to screening  
5. Patients who have received intra-articular sodium hyaluronate injections within 
4 weeks prior to screening 
6. Patients who have received surgical therapy for RA such as synovectomy or 
arthroplasty within 6 months prior to screening 
7. Patients who have received arthrocentesis within 4 weeks prior to screening  
8. Patients who have had prior treatment with infliximab 
9. Patients who have had prior treatment with more than 1 biological drug other than 
infliximab (e.g., adalimumab, rituximab, abatacept, etanercept) for RA either as part 
of clinical management or during a clinical study.  Patients who have had prior 
treatment with more than 1 protein kinase inhibitor (e.g., tofacitinib) for RA either as 
part of clinical management or during a clinical study.  Patients who have had prior 
treatment with 1 biological drug AND 1 protein kinase inhibitor are allowed in the 
study. 
10. Patients who have had prior treatment with a tumor necrosis factor alpha (TNF-α) 
inhibitor for RA who had lack of efficacy as per clinical judgment (primary failure).  
Primary failure is defined as never having achieved an adequate response, whereas 
secondary failure is the loss of response over time.  Patients who have received prior 
treatment with no more than 1 biological DMARD and who have received not more 
than 1 prior TNF-α inhibitor (other than infliximab) and have failed it because of loss 
of efficacy (secondary failure) or intolerance (e.g., mild injection site reactions) are 
allowed in the study.  Patients who have discontinued TNF-α inhibitors for RA (other 
than infliximab) because their insurance no longer covered the cost of treatment or 
they could no longer afford the cost or copays for the treatment are allowed in the 
study. 
11. Patients who had prior treatment with cyclophosphamide or other cytotoxic agents 
12. Patients who received investigational drugs in other clinical studies within 12 weeks 
or 5 half-lives of the drug prior to screening, whichever is longer 
13. Patients with a concomitant or past history of autoimmune connective tissue diseases 
other than RA, for example, systemic lupus erythematosus, Sjogren's syndrome, 
polymyositis, dermatomyositis, and mixed connective tissue disease 
14. Patients with a history of hypersensitivity to the components of NI-071 or 
mouse-derived protein (e.g., mouse, chimeric, and humanized antibody) 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 37 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 37 
 
15. Patients with the following concomitant or past history: 
 Chronic or recurrent infectious disease (e.g., bronchiectasis, sinusitis) 
 Demyelinating disease (e.g., multiple sclerosis) 
 Presence of New York Heart Association (NYHA) Class III/IV heart failure (see 
Section 12.5) 
 Lymphoproliferative disorder (e.g., Epstein-Barr virus (EBV)-related 
lymphoproliferative disorder, lymphoma, or leukemia) or myelodysplastic 
syndrome 
 Cancer other than successfully treated non-melanoma skin cancer or localized 
carcinoma in situ of the cervix 
 Interstitial lung disease 
16. Presence of chronic or acute infection at screening, including positive result for active 
tuberculosis (TB) (e.g., positive QuantiFERON® test result without any prior history 
of active or latent TB and without evidence of active infection) where the patient is 
not willing to undergo prophylactic treatment.  (These patients may be re-screened 
after appropriate treatment for TB [see Section 12.3]). 
17. Patients with an acute infection requiring parenteral antibiotics within 4 weeks of 
study dosing or requiring oral/topical antibiotics within 2 weeks of study dosing.  
(These patients may be re-screened after the appropriate washout period.) 
18. Patients with mycobacterial infection or opportunistic infection (e.g., 
cytomegalovirus infection or invasive fungal infection such as histoplasmosis, 
blastomycosis, or coccidiomycosis) or who have resided in or traveled to regions 
where such infections are prevalent within 6 months prior to the initial administration 
of the investigational drug 
19. Patients who have active or past infection or suspected infection in prosthetic joints 
that have not been removed or replaced 
20. Patients with positive results of hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (HBsAb), hepatitis B core antibody (HBcAb), hepatitis C antibody 
(HCV Ab), and/or human immunodeficiency virus antibody (HIV Ab) tests at 
screening (excluding patients who are tested positive for HBsAb alone due to a 
hepatitis B vaccination) 
21. Patients who received a live vaccine within 12 weeks prior to study dosing, or who 
plan to receive a live vaccine during the study period or within 6 months after the last 
dose of study treatment.  (If received prior to study dosing, these patients may be 
re-screened after the appropriate washout period.) 
22. Patients with laboratory test results at screening that meet any of the following 
reference levels: 
 Hemoglobin ≤8.5 g/dL 
 White blood cells (WBCs) ≤3,500/mm3 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 38 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 38 
 
 Lymphocytes ≤1,000/mm3 
 Platelet count ≤100,000/mm3 
 Aspartate aminotransferase (AST) or ALT ≥ upper limit of normal (ULN) x 1.5 
 Serum creatinine ≥ULN x 1.5 
 Glycated hemoglobin (HbA1c) ≥9.0% 
 Positive anti-double-stranded deoxyribonucleic acid (anti-dsDNA) assay 
 β-D-glucan ≥80 pg/mL (positive) 
23. History of clinically significant cardiac, respiratory, renal, hepatic, hematologic, 
gastrointestinal, neurologic, endocrinologic, psychiatric, or any other uncontrolled 
medical illness 
24. Female patients who are pregnant, wish to become pregnant, or are breastfeeding 
25. Male patients who plan to donate sperm during the study or within 6 months after the 
last dose.  Female patients who plan to donate eggs or undergo in vitro fertilization 
treatment during the study or within 6 months after the last dose. 
26. Patients who are taking part in other clinical studies at screening or planning to take 
part in other clinical studies during the study period 
27. Patients with a drug or alcohol dependence 
28. Patients who are determined by the Investigator to be unsuitable for study enrollment 
for other reasons 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 39 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 39 
 
7.3 
Withdrawal, Removal, and Replacement of Patients 
Patients will be considered to have completed the study if they complete treatment and 
assessments through Week 62.  Patients who are withdrawn from the study for any reason 
will not be replaced. 
A patient’s study treatment should be discontinued if any of the following situations occurs: 
 The Investigator believes that for safety reasons it is in the best interest of the patient 
to stop treatment. 
 The patient becomes pregnant. 
 The patient is diagnosed with a malignancy, with the exception of no more than 
2 localized basal cell skin cancers that are treated with no evidence of recurrence or 
residual disease. 
 The patient is deemed ineligible according to 1 of the following TB criteria:  
a diagnosis of active TB is made; a patient has symptoms suggestive of active TB, but 
the patient cannot or will not undergo further evaluation; or a patient undergoing 
evaluation has a QuantiFERON test with evidence of active TB. 
 The patient initiates a protocol-prohibited medication (see Section 8.6.2). 
 If the patient requires parenteral antibiotics, the patient will be withdrawn from 
treatment but followed for resolution of the AE.  If it is necessary to interrupt study 
drug dosing for longer than 2 weeks for treatment of an infection with an oral or 
topical antibiotic, the patient will be withdrawn from treatment but followed for 
resolution of the AE. 
 The patient is noncompliant with the study visit schedule or other protocol 
requirements. 
 The patient develops a severe allergic reaction that occurs following study treatment 
administration. 
 The patient has a reaction resulting in myalgia and/or arthralgia with fever and/or rash 
(suggestive of serum sickness) occurring 1 to 14 days after an injection of study 
treatment. 
Also, discontinuation of study treatment should be considered for patients who develop a 
serious or opportunistic infection, congestive heart failure, demyelinating disease, lupus-like 
syndrome, cytopenia (for example, anemia, leukopenia, or neutropenia), or liver 
abnormalities. 
A patient may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following: 
 Patient withdrawal of consent:  At any time, a patient's participation in the study may 
terminate at his/her request.  The specific reason for patient withdrawal will be noted 
on the electronic case report form (eCRF).  
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 40 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 40 
 
 Lost to follow-up:  The patient stops coming for visits, and study personnel are 
unable to contact the patient after repeated attempts (e.g., telephone calls, mail, or 
email). 
 This study may be terminated at the discretion of the Sponsor or any regulatory 
agency.  An Investigator may elect to discontinue or stop the study at his or her site 
for any reason including safety or low enrollment. 
7.4 
Follow-Up for Drug Discontinuation/Patient Withdrawal from Study 
If a patient’s study treatment is discontinued during Stage 1 and the patient maintains consent 
to contribute additional outcome information, the patient should continue to be followed 
through Week 22 for all key safety and efficacy assessments.  Investigators will be trained 
about the importance of retention and steps to prevent missing data. 
When a patient withdraws or is withdrawn before completing the study, the date and reason 
for withdrawal are to be documented in the eCRF.  The study site must immediately notify 
the medical monitor.  Patients who withdraw prematurely are to attend an early 
discontinuation visit if possible, at which time they will complete all assessments described 
in Table 2 under the Week 62 visit. 
In the event that a patient discontinues prematurely from the study due to a TEAE or serious 
TEAE, the TEAE or serious TEAE will be followed until it resolves (returns to normal or 
baseline values) or stabilizes, or until it is judged by the Investigator to be no longer 
clinically significant. 
Once a patient is withdrawn from the study, the patient may not re-enter the study. 
8 
TREATMENTS 
8.1 
Details of Study Treatments 
NI-071 is a proposed infliximab biosimilar to be administered as an IV infusion.  Each 
20-mL vial contains 100 mg of NI-071 in the form of a lyophilized (freeze-dried) white 
pellet, for a final reconstitution volume of 10 mL and a final concentration of 10 mg/mL.  
Excipients include sucrose, polysorbate 80, monobasic sodium phosphate, and dibasic 
sodium phosphate. 
Remicade-US (infliximab) is the reference product to be administered as an IV infusion.  
Only US-licensed Remicade will be used in this study.  Each 20-mL vial contains 100 mg of 
infliximab in the form of a lyophilized (freeze-dried) white pellet, for a final reconstitution 
volume of 10 mL and a final concentration of 10 mg/mL.  Excipients include sucrose, 
polysorbate 80, monobasic sodium phosphate, and dibasic sodium phosphate. 
Basic information about the study treatments is provided in Table 1.  All vials of study drug 
will be provided by the Sponsor. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 41 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 41 
 
Table 1 Details of Study Treatments 
 
Preparations to be Administered 
 
NI-071 
Remicade (All US-licensed) 
Manufacturer 
Binex, Co., Ltd. 
7-48, Song do-dong Yeonsu-Gu, 
Incheon, 406-840 
Republic of Korea 
Janssen Biotech, Inc.  
Horsham, PA, US 
Active ingredient 
NI-071 
Infliximab 
Dosage 
3 mg/kg at Weeks 0, 2, and 6, then 
every 8 weeks 
3 mg/kg at Weeks 0, 2, and 6, then 
every 8 weeks 
Route 
IV 
IV 
Formulation 
Each 20-mL vial contains 100 mg of 
NI-071 (as a lyophilized pellet) for a 
final reconstitution volume of 10 mL 
and a final concentration of 
10 mg/mL. 
Each 20-mL vial contains 100 mg of 
infliximab (as a lyophilized pellet) 
for a final reconstitution volume of 
10 mL and a final concentration of 
10 mg/mL. 
Storage Instructions 
Each vial of study treatment is individually packaged in a carton.  Store unopened vials in a 
refrigerator at 2° to 8°C (36° to 46°F).  Do not freeze.  Do not use any vial beyond the 
expiration date.  The study treatments do not contain preservatives.  Detailed storage 
instructions will be provided in the pharmacy manual. 
Instructions for Use 
The reconstituted infusion solution should be prepared by a pharmacist or other trained 
medical professional using aseptic technique with the following procedures3 (detailed 
instructions will be available in the pharmacy manual): 
 Calculate the dose, total volume of reconstituted study drug solution required and the 
number of study drug vials needed. 
 Within 3 h prior to the planned patient infusion, reconstitute each vial with 10 mL 
sterile water for injection, using a syringe equipped with a 21-gauge or smaller 
needle.  After removing the top from the vial and wiping the top with an alcohol 
swab, insert the needle into the vial through the center of the rubber stopper and direct 
the stream of liquid to the glass wall of the vial.  Gently swirl the solution by rotating 
the vial to dissolve the drug.  Avoid prolonged or vigorous agitation (do not shake).  
Allow to stand for 5 minutes after dissolution.   
 The solution should be colorless to light yellow or opalescent, and there may be a few 
translucent particles, as this is a protein preparation.  Do not use if the lyophilized 
pellet has not fully dissolved, or if opaque particles, discoloration, or other foreign 
particles are present. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 42 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 42 
 
 Dilute the total volume of the reconstituted study drug solution to 250 mL with 0.9% 
sodium chloride for infusion.  This can be done by withdrawing a volume of the 
sodium chloride solution from the 250 mL infusion bottle or bag equal to the volume 
of reconstituted study drug.  Slowly add the total volume of reconstituted study drug 
solution to the infusion bottle or bag.  Gently mix.  
 Label the infusion bottle or bag in a blinded manner per the pharmacy manual and 
give to the appropriate blinded study staff for patient infusion. 
The blinded Investigator or designated study staff will administer the study drug in the 
following manner: 
 Start IV administration within 3 h after reconstitution and dilution.  Use an 
independent line for administration.  Do not mix the study drug with other infusion 
solutions.  Use an infusion set with an in-line, sterile, nonpyrogenic, 
low-protein-binding filter (pore size of 1.2 µm or less).   
 Prior to administration, visually inspect the infusion solution for particulates or 
discoloration.  If opaque particles, discoloration, or other foreign particles are present, 
do not use the solution. 
 Prior to administration of the study drug, patients may be given antihistamines and/or 
acetaminophen (paracetamol) per standard of care.  Emergency equipment, such as 
adrenaline, antihistamines, corticosteroids, and an artificial airway must be available 
in the event of infusion-related reactions. 
 Administer the infusion solution over a period of 2 h.  Observe the patient for at least 
30 minutes post-infusion for acute infusion-related reactions, including anaphylaxis.  
See Section16, Appendix 3 for guidelines on diagnosing anaphylaxis. 
 Do not store or reuse any unused portion of the infusion solution.  Any unused 
product or waste material should be disposed of in accordance with local 
requirements. 
8.2 
Dosage Schedule 
Study treatment is to be administered by IV infusion at a dose of 3 mg/kg at Weeks 0, 2, 6, 
14, 22, 30, 38, 46, and 54. 
Every effort should be made to adhere to the dosing schedule.  However, a scheduled dose 
should not be administered if a patient has an infection for which systemic anti-infectives are 
indicated or the patient has signs or symptoms of an infection or other AE that, in the 
Investigator’s opinion, warrants holding the dose.  If the patient requires parenteral 
antibiotics, the patient will be withdrawn from treatment but followed for resolution of the 
AE.  If it is necessary to interrupt study drug dosing for longer than 2 weeks for treatment of 
an infection with an oral or topical antibiotic, the patient will be withdrawn from treatment 
but followed for resolution of the AE. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 43 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 43 
 
8.3 
Study Treatment Assignment 
Each patient will be allocated a unique patient number at screening and will retain this 
number throughout the study.  At baseline (Week 0), upon confirmation of eligibility, the 
study staff will randomize an eligible patient using an interactive voice or web response 
system (IVRS/IWRS).  Patients will be randomized in a 2:1 ratio to receive Remicade-US or 
NI-071, respectively, for Stage 1 treatments in the study (at Weeks 0, 2, 6, and 14).  This 
initial randomization will be stratified by CRP level (≤2, >2 mg/dL). 
At Week 22, patients in the original Remicade-US group will be re-randomized (1:1) to a 
Remicade-US group or a Switch group; the treatment assignments for all patients will remain 
blinded.  For Stage 2 and Stage 3 treatments, the Switch group will receive NI-071 at 
Week 22, Remicade-US at Week 30, and NI-071 at Weeks 38, 46, and 54; the Remicade-US 
group will continue to receive Remicade-US from Week 22 through Week 54 every 8 weeks.  
The original NI-071 group will continue to receive NI-071 from Week 22 through Week 54 
every 8 weeks.  As the blinded re-randomization of the original Remicade-US group to a 
Switch group and a Remicade-US group will occur within the IVRS/IWRS, the clinical 
procedure for handling study treatment will remain unchanged throughout the study.  
8.4 
Blinding 
At each dosing visit, the Investigator or designee will access the IVRS/IWRS to receive the 
specific study drug number for the patient; this number will be provided to the unblinded 
pharmacist or designee for preparing the study treatment.  
The pharmacist or designee who prepares the infusion will be unblinded and not otherwise 
involved in the study.  This staff member will prepare the study drug according to the study 
drug number issued by the IVRS/IWRS for each patient at each dosing visit.  The prepared 
infusion solutions will be identical in appearance, and the preparer will label the bag or bottle 
in a blinded manner to include, at a minimum, the protocol number, “For Investigational Use 
Only”, the patient number, and the solution concentration.  All other study staff, all patients, 
and the Sponsor and its designees conducting the study will be blinded to treatment 
assignments during the study.  
In a medical emergency, if unblinding is required in the interest of the safety of a patient, the 
Investigator may break the randomization code for that patient using the IVRS/IWRS.  The 
Investigator must inform the medical monitor and/or the Sponsor as soon as possible that the 
randomization code has been broken for that patient.  The reason for unblinding must be 
documented in the eCRF.  
8.5 
Treatment Accountability and Compliance 
The study drug supplies will be stored at the site in a locked facility with monitored 
temperature.  Only authorized personnel will be allowed access.  The pharmacist or other 
designated unblinded individual will maintain records of study treatment delivered to the 
study site; the inventory at the site; the distribution to and use by each patient; and the return 
of materials to the Sponsor for storage or disposal.  These records should include dates, 
quantities, batch/serial numbers, expiration dates, in-clinic temperature log, and unique code 
numbers assigned to the product and study patients.   
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 44 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 44 
 
Administration of study drugs will be performed by blinded study personnel.  Infusion rates, 
volume of study drug infused, start times, and stop times will be recorded.  If any study drug 
is discarded, the reason will be recorded in the eCRF. 
8.6 
Prior and Concomitant Illnesses and Medications 
8.6.1 Prior and Concomitant Illnesses 
Investigators should document all prior significant medical history.  Additional illnesses 
present at the time when informed consent is given and up to the time of first dosing 
(Week 0) are to be regarded as concomitant illnesses.  Illnesses first occurring or detected 
during the study and/or worsening of a concomitant illness during the study are to be 
documented as AEs in the eCRF. 
8.6.2 Prior and Concomitant Medications 
All medications and other treatments (including over-the-counter treatments and preventative 
vaccines) taken by the patient during the study, including those treatments initiated prior to 
the start of the study, must be recorded in the eCRF.  The entry must include the dose, 
regimen, route, indication, and dates of use. 
Permitted Concomitant Medications 
All patients are required to take concomitant MTX and folic/folinic acid during this study.  
Patients must have taken MTX (oral or parenteral) for at least 3 months and at a stable dose 
of 10 to 25 mg/week for at least 8 weeks immediately prior to screening.  Patients are to 
continue on this stable dose during the study.  The route of administration of MTX should 
not change throughout the study.  The patient’s MTX dose can be reduced for toxicity only.  
If toxicity occurs, this should be recorded as an AE.  The folic/folinic acid dose should be at 
least 5 mg/week during the study.  Folic/folinic acid can be started at screening if the patient 
is not already receiving it.  These required concomitant medications will not be provided by 
the Sponsor. 
To minimize the risk of allergic reactions, patients may be given an antihistamine and/or 
acetaminophen (paracetamol) prior to each study drug infusion per standard care of the study 
site (For the antihistamine, 2 to 4 mg chlorpheniramine or equivalent, or 10 mg cetirizine, 
30 to 60 minutes prior to dosing). 
Oral corticosteroids (≤10 mg/day prednisone or equivalent) are permitted during the study if 
the dose has been stable for at least 4 weeks prior to screening and is continued at the same 
dose during the study.  An increase in oral corticosteroid dose is permitted to treat 
concomitant conditions, e.g., asthma, only.  The reason for any such increase in dose should 
be recorded as an AE (e.g., asthma flare).  The dose must be tapered back down as soon as 
medically viable and within 2 weeks. 
NSAIDs up to the maximum approved dose are permitted during the study if the dose has 
been stable for at least 4 weeks prior to screening.  Patients should continue to take this stable 
dose during the study.  The NSAID dose can be increased (not above the maximum approved 
dose) for up to 2 weeks to treat an RA flare.  This should be documented as a change in the 
concomitant medication.  The dose must be tapered back down as soon as medically viable 
and within 2 weeks.  Patients who are not receiving NSAIDs may be treated with an NSAID 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 45 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 45 
 
for up to 2 weeks, or an additional NSAID may be added to an existing NSAID regimen for 
up to 2 weeks to treat an RA flare.   
Analgesics up to the maximum approved dose are permitted during the study but should not 
be taken in the 24 hours prior to efficacy evaluations (except in cases of severe pain).  Other 
analgesics could include paracetamol/acetaminophen, combinations, alternative treatments, 
and psychotropic agents. 
For states and countries where medical marijuana is legal, patients can take medical 
marijuana while in the study according to the analgesic rule above. 
Patients with evidence or suspicion of latent TB at screening (see Section 12.3), may be 
enrolled provided that they begin prophylactic antimycobacterial treatment at least 4 weeks 
prior to randomization (or longer, if local guidelines specify) and commit to completing the 
course of treatment.  The treatment should be according to local guidelines.  If needed, such 
patients may be re-screened (see Section 9.2). 
Prohibited Medications 
The following treatments are prohibited during the study: 
 Immunization with a live or attenuated vaccine is prohibited within 12 weeks prior to 
study dosing, for the duration of study, and for 6 months after administration of the 
last dose. 
 Treatment with another investigational drug is prohibited during the study and within 
12 weeks or 5 half-lives of the drug prior to screening, whichever is longer. 
 Treatment with intra-articular or parenteral steroids within 28 days prior to study 
dosing and during the study is prohibited.  If a patient is treated with an intra-articular 
steroid injection during the study, the Investigator should discontinue study treatment 
and withdraw the patient from the study.  If this occurs during Stage 1 and the patient 
maintains consent to contribute additional outcome information, the patient should 
continue to be followed through Week 22 for all key safety and efficacy assessments. 
 Treatment with DMARDs (other than MTX), including traditional non-biologic 
drugs, biologic drugs, and protein kinase inhibitors, is prohibited during the study and 
within a period prior to screening (a washout period) appropriate to the 
pharmacodynamic profile of the specific drug.  See Section 16, Appendix 2, for a list 
of traditional non-biologic drugs, biologic drugs, and protein kinase inhibitors, along 
with their washout periods.  If the Investigator wishes to treat a patient with a 
DMARD other than MTX during the study, the patient must be withdrawn from study 
treatment, and the reason for withdrawal must be documented in the eCRF. 
 Surgical therapy and radiosynovectomy for RA is prohibited.  If surgery is performed 
on a joint, the joint will be unevaluable (excluded from joint counts) for the 
remainder of the study. 
 Arthrocentesis is prohibited during the study and within 4 weeks prior to screening. 
 Treatment with an agent that might confound efficacy or safety evaluation in this 
study (e.g., RANKL [receptor activator of nuclear factor kappa-B ligand] inhibitors 
for osteoporosis and immunomodulators for asthma) is prohibited within 5 half-lives 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 46 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 46 
 
of the drug concerned prior to the first dose of study treatment and during the study.  
Examples of RANKL inhibitors include Prolia/Xgeva (denosumab) for osteoporosis 
and Xolair (omalizumab) for asthma. 
 Cytapheresis is prohibited during the study. 
8.7 
Study Restrictions 
All WOCBP and all men (if their sexual partners are WOCBP) must use at least 1 highly 
effective method of contraception during the study and for 6 months after the last dose of 
study treatment.  A woman is considered as a WOCBP (fertile) following menarche and until 
becoming postmenopausal unless permanently sterile.  Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  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.  However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient.  A man is considered fertile after puberty unless 
permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception include the following: 
 Combined (containing estrogen and progestogen) hormonal contraception associated 
with inhibition of ovulation.  Delivery may be oral, intravaginal, or transdermal. 
 Progestogen-only hormonal contraception associated with inhibition of ovulation.  
Delivery may be oral, injectable, or implantable. 
 Intrauterine device (IUD). 
 Intrauterine hormone-releasing system (IUS). 
 Bilateral tubal ligation or occlusion. 
 Vasectomy (provided that the male has a medical assessment of surgical success). 
 True sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk, in line with the preferred and usual lifestyle of the patient). 
All patients will be strongly advised that they (or the female partners of male patients) should 
not become pregnant while on study treatment or for 6 months after the last dose.  Female 
patients will be advised that if they believe they may be pregnant, they must report 
immediately to the study site for pregnancy testing and appropriate management. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 47 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
          Page 47 
 
9 
STUDY PROCEDURES 
Table 2 outlines the timing of procedures, and assessments to be performed throughout the 
study.  Additional details of study procedures are provided in Sections 10, 11, and 12. 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 48 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
 
 
 
 
 
NI071F2 
NI-071 
 
 
                    Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
 
 
 
 
 
 
Page 48 
 
Table 2 Schedule of Assessments 
Screening 
Stage 1 
Stage 2 
Stage 3 
 
Visit at Week (±3 days) 
(Day -28 
to Day -7) 
0 
(Day 1) 2 
6 
14 18 
22 
26 
30 
34 
38 
42 
46 
50 
54 
58 
62a  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, weight, heighto 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-ray 
Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
Xb 
 
Physical examination 
X 
Xc 
Xc Xc Xc Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
Clinical laboratory testsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum immunology testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
QuantiFERON TB test 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
RF and ACPA testsg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Joint assessmentg,h,i,m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2010 ACR/EULAR RA classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP testg,h,i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESR testg,h,i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAQ-DIh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient global assessmenth,i,j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient pain assessmenth,j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
RAPID3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physician global assessmenth,j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 49 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
 
 
 
 
 
NI071F2 
NI-071 
 
 
                    Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
 
 
 
 
 
 
Page 49 
 
Screening 
Stage 1 
Stage 2 
Stage 3 
 
Visit at Week (±3 days) 
(Day -28 
to Day -7) 
0 
(Day 1) 2 
6 
14 18 
22 
26 
30 
34 
38 
42 
46 
50 
54 
58 
62a  
SF-36 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Concomitant medication review 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X* 
 
 
 
 
X** 
 
 
 
 
 
 
 
 
 
 
 
Administration of study drug 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
MTX and folic acid reminder 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-drug antibodies (pre-dose) 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Trough PK samplek (pre-dose) 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Full PK samplek (Weeks 46 to 54) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Abbreviations:  ACPA=anti-citrullinated protein antibody; ACR=American College of Rheumatology; ACR20(50, 70)=a 20%(50%, 70%) improvement from 
baseline in the ACR core set criteria; anti-dsDNA=anti-double-stranded deoxyribonucleic acid; CRP=C-reactive protein; DAS28=disease activity score involving 
28 joints; EOI=end of infusion; ESR=erythrocyte sedimentation rate; EULAR=European League Against Rheumatism; HAQ-DI=Health Assessment 
Questionnaire-Disability Index;HbA1c=glycated hemoglobin; HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B 
surface antigen; HCV Ab=hepatitis C antibody; HIV Ab=human immunodeficiency virus antibody; NYHA=New York Heart Association; PK=pharmacokinetic; 
RA=rheumatoid arthritis; RAPID3=routine assessment of patient index data 3; RF=rheumatoid factor; SF-36=Medical Outcomes Study 36-Item Short-Form 
Health Survey; TB=tuberculosis 
aOr early discontinuation visit. 
bChest x-rays (anterior-posterior and lateral views) are to be done only if the TB test is positive; also, at screening, only if the patient has not had x-rays within 12 
weeks prior to screening. 
cA limited physical examination to verify continued patient eligibility and to follow up any changes (symptom-driven) will be performed at these visits. 
dStandard hematology, blood chemistry, and urinalysis tests; at screening, also HbA1C. 
eScreening serum immunology tests include HBsAg, HBsAb, HBcAb, HCV Ab, HIV Ab, anti-dsDNA, and β-D-glucan. 
fOnly in women of childbearing potential.  Serum test is to be done at screening; urine test is to be done locally at other specified time points.  
gAssessment contributes to the 2010 ACR and EULAR RA classification at screening. 
hAssessment contributes to the ACR core set criteria for determining ACR20, ACR50, and ACR70 at all post-screening visits. 
iAssessment contributes to the DAS28 scores at all post-screening visits. 
jMeasured on a visual analog scale (VAS) of 0 to 100 mm.  VAS for patient assessment of pain goes from “no pain” to “pain as bad as it can be”; VAS for patient 
global assessment of disease activity goes from “very well” to “very poor”; VAS for physician global assessment of disease activity goes from “none” to 
“extremely active.” 
kTrough PK sampling should be done within 1 h prior to dosing.  Full PK sampling during Weeks 46 to 54 includes the following time points:  pre-dose, 1 h after 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 50 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
 
 
 
 
 
NI071F2 
NI-071 
 
 
                    Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
 
 
 
 
 
 
Page 50 
 
Screening 
Stage 1 
Stage 2 
Stage 3 
 
Visit at Week (±3 days) 
(Day -28 
to Day -7) 
0 
(Day 1) 2 
6 
14 18 
22 
26 
30 
34 
38 
42 
46 
50 
54 
58 
62a  
infusion start, at the end of infusion (EOI), at 4 h and 24 h after infusion start, and at 4 days, 7 days (Week 47), 14 days (Week 48), 28 days (Week 50), 42 days 
(Week 52), and 56 days (Week 54) post-dose.  Sampling windows for the blood draws are ±15 minutes for the 1 h time point, +15 minutes for the EOI, and 
±15 minutes for the 4 h time point; ±2 h for the 24 h time point; and ±24 h for the subsequent time points. 
lAt early discontinuation visit only. 
mJoint assessment includes determination of tender joints and swollen joints.  At screening, counts of tender and swollen joints out of 28 selected joints will be 
performed (for the 2010 ACR and EULAR classification criteria).  At all subsequent visits, counts of tender and swollen joints out of 68 and 66 selected joints, 
respectively, will be performed (for the ACR core set criteria and the DAS28).  
nAt screening, prior medications will also be reviewed. 
oRecord height at screening only. 
*Initial blinded randomization is to be performed after all inclusion/exclusion criteria are reconfirmed at Week 0. 
**Blinded re-randomization.  At Week 22, the original Remicade-US group is to be randomized 1:1 to a Switch group and a Remicade-US group.  The 
Remicade-US group will continue on Remicade-US from Week 22 through Week 54 every 8 weeks.  At Week 22, the Switch group will receive NI-071; at 
Week 30, this group will receive Remicade-US; and at Weeks 38, 46, and 54, this group will receive NI-071.  The original NI-071 group will continue on NI-071 
from Week 22 through Week 54 every 8 weeks. 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 51 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 51 
 
9.1 
Patient Informed Consent 
Prior to performing any study-related procedures, the Investigator (or his/her designated staff 
member) will obtain written informed consent from the patient.  
9.2 
Patient Re-Screening 
A patient who is screened and does not meet the study entry criteria may be re-screened once 
only.  Investigator discretion should be exercised in determining who may be re-screened.  
Patients who otherwise meet entry criteria but require a longer washout period for a 
DMARD, antibiotics, or vaccination; or require time for stabilization of the MTX regimen; 
or require time for starting prophylaxis treatment for latent TB (see Section 12.3) will be able 
to re-screen.  All patients who are eligible to be re-screened must be fully consented a second 
time before the second set of screening assessments take place, and they will keep their 
original patient numbers.  The re-screening process to follow in the IVRS/IVWS will be 
detailed in the study manual. 
In the case of doubt about the accuracy of screening laboratory value(s), the laboratory test(s) 
may be repeated provided that this can be done within the 4-week screening period without 
the need to repeat all other screening procedures (i.e., no re-screening). 
9.3 
Procedures by Week 
Assessments are to be performed as outlined in the following subsections.  For visits at 
Weeks 2 through 62, there will be a window of ±3 days, except for the blood draw visits 
during the full PK sampling interval following the Week 46 dose.  Sampling windows for 
these blood draw time points are ±15 minutes for 1 h after start of infusion, +15 minutes for 
the end of infusion (EOI), ±15 minutes for 4 h after start of infusion, ±2 h for 24 h after start 
of infusion, and ±24 h for the subsequent time points. 
9.3.1 Screening 
The screening visit will occur within Day -28 to Day -7 prior to the Week 0 visit.  If needed, 
patients may be re-screened once (see Section 9.2).  The following procedures will be 
performed during screening: 
 Obtain written informed consent. 
 Obtain demographic data. 
 Record medical history and current conditions, including an evaluation of the risk of 
TB infection (e.g., prior history of active or latent TB, possible exposure to 
individuals with active TB) and smoking history.  
 Record prior and concomitant medications for RA and other indications.  
 Measure vital signs (blood pressure, pulse, oral/tympanic body temperature) and 
weight.  Record height at screening only. 
 Perform a 12-lead electrocardiogram (ECG).  
 Perform a physical examination.  
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 52 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 52 
 
 Assess the NYHA classification.  
 Collect a blood sample for a QuantiFERON TB test.  
 Perform chest x-rays (anterior-posterior and lateral views) if the QuantiFERON TB 
test is positive, unless there are recent x-rays available (done within 12 weeks prior to 
screening).  
 Collect blood and urine samples for standard clinical laboratory tests (including 
HbA1C at screening). 
 Collect blood for a serum pregnancy test (females of childbearing potential only).  
 Collect blood for screening serum immunology tests, rheumatoid factor (RF) test, and 
anti-citrullinated protein antibody (ACPA) test. 
 Collect blood for CRP. 
 Collect blood to perform ESR locally (site personnel must enter the ESR result for 
each patient into the eCRF). 
 Administer the patient global assessment of disease activity on a visual analog scale 
(VAS).  
 Assess 28 joints for tenderness and swelling and ask the patient about the duration of 
synovitis (pain, swelling, tenderness) in the joints that are tender/swollen (for use in 
the 2010 ACR RA classification). 
 Ascertain 
patient 
eligibility 
by 
evaluating 
patient 
results 
against 
the 
inclusion/exclusion criteria. 
 Ask patients to avoid taking analgesics during the 24 h prior to a clinic visit. 
 Remind patients that they are required to stay on their stable regimens of MTX and 
folic/folinic acid throughout the study. 
9.3.2  
Week 0 (Baseline) 
Patients who meet the inclusion/exclusion criteria at screening will continue to the Week 0 
visit (baseline).  The following procedures will be performed: 
 Measure vital signs and weight, and perform a limited physical examination. 
 Record concomitant medications. 
 Administer the patient pain assessment, the patient global assessment of disease 
activity, the Health Assessment Questionnaire Disability Index (HAQ-DI), the 
RAPID3, and the SF-36.  
 Assess 68 joints for tenderness and 66 for swelling (for use in the ACR core set and 
DAS28). 
 Perform the physician global assessment of disease activity (VAS). 
 Reconfirm eligibility. 
 Randomize the patient using IVRS/IWRS. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 53 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 53 
 
 Collect blood and urine samples for standard clinical laboratory tests. 
 Collect urine to perform pregnancy test locally (females of childbearing potential 
only). 
 Collect blood for CRP. 
 Collect blood to perform ESR locally. 
 Collect blood for trough PK and ADA assessments. 
 Obtain the blinded study drug number from IVRS/IWRS for the unblinded 
pharmacist or designee to prepare the study treatment. 
 Prior to administration of the study drug, patients may be given antihistamines and/or 
acetaminophen (paracetamol) per standard care.  
 Administer study treatment. 
 Monitor for AEs.  Observe the patient for at least 30 minutes after dosing for 
symptoms of infusion-related reactions and allergic reactions, including anaphylaxis 
(see Section 16, Appendix 3). 
 Instruct the patient on recognition of delayed serious allergic reactions, including 
anaphylaxis.  Advise the patient to seek immediate medical attention if he or she 
experiences any symptoms of severe allergic reactions. 
 Remind patients to avoid taking analgesics during the 24 h prior to a clinic visit. 
 Remind patients that they are required to stay on their stable regimens of MTX and 
folic/folinic acid throughout the study. 
9.3.3 Weeks 2, 6, and 14 
The following procedures will be performed at Weeks 2, 6, and 14: 
 Measure vital signs and weight, and perform a limited physical examination. 
 Record concomitant medications. 
 Administer the patient pain assessment, the patient global assessment of disease 
activity, the HAQ-DI, and the RAPID3.  
 At Week 14 only, administer the SF-36. 
 Assess 68 joints for tenderness and 66 for swelling (for use in the ACR core set and 
DAS28). 
 Perform the physician global assessment of disease activity (VAS). 
 Collect blood and urine samples for standard clinical laboratory tests. 
 Collect urine to perform pregnancy test locally (females of childbearing potential 
only). 
 Collect blood for CRP. 
 Collect blood to perform ESR locally. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 54 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 54 
 
 Collect blood for trough PK and ADA assessments. 
 Obtain the blinded study drug number from IVRS/IWRS for the unblinded 
pharmacist or designee to prepare the study treatment. 
 Prior to administration of the study drug, patients may be given antihistamines and/or 
acetaminophen (paracetamol) per standard care. 
 Administer study treatment. 
 Monitor for AEs.  Observe the patient for at least 30 minutes after dosing for 
symptoms of infusion-related reactions and allergic reactions, including anaphylaxis 
(see Section 16, Appendix 3). 
 Remind the patient on recognition of delayed serious allergic reactions, including 
anaphylaxis.  Advise the patient to seek immediate medical attention if he or she 
experiences any symptoms of severe allergic reactions. 
 Remind patients to avoid taking analgesics during the 24 h prior to a clinic visit. 
 Remind patients that they are required to stay on their stable regimens of MTX and 
folic/folinic acid throughout the study. 
9.3.4 Week 18 
At Week 18, the following procedures will be performed: 
 Measure vital signs and weight, and perform a limited physical examination. 
 Record concomitant medications. 
 Administer the patient pain assessment, the patient global assessment of disease 
activity, the HAQ-DI, and the RAPID3.  
 Assess 68 joints for tenderness and 66 for swelling (for use in the ACR core set and 
DAS28). 
 Perform the physician global assessment of disease activity (VAS). 
 Collect blood and urine samples for standard clinical laboratory tests. 
 Collect blood for CRP. 
 Collect blood to perform ESR locally. 
 Monitor for AEs. 
 Remind patients to avoid taking analgesics during the 24 h prior to a clinic visit. 
 Remind patients that they are required to stay on their stable regimens of MTX and 
folic/folinic acid throughout the study. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 55 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 55 
 
9.3.5 Week 22 
The Week 22 visit is the primary efficacy time point for assessing biosimilarity (the last visit 
in Stage 1) and the first dosing visit for Stage 2.  As the blinded re-randomization will occur 
within the IVRS/IWRS, the clinical procedure for handling study treatment will remain 
unchanged throughout the study. 
The following procedures will be performed at Week 22: 
 Measure vital signs and weight, and perform a limited physical examination. 
 Record concomitant medications. 
 Administer the patient pain assessment, the patient global assessment of disease 
activity, the HAQ-DI, the RAPID3, and the SF-36.  
 Assess 68 joints for tenderness and 66 for swelling (for use in the ACR core set and 
DAS28). 
 Perform the physician global assessment of disease activity (VAS). 
 Collect blood and urine samples for standard clinical laboratory tests. 
 Collect urine to perform pregnancy test locally (females of childbearing potential 
only). 
 Collect blood for CRP. 
 Collect blood to perform ESR locally. 
 Collect blood for trough PK and ADA assessments. 
 Obtain the blinded study drug number from IVRS/IWRS for the unblinded 
pharmacist or designee to prepare the study treatment. 
 Prior to administration of the study drug, patients may be given antihistamines and/or 
acetaminophen (paracetamol) per standard care. 
 Administer study treatment. 
 Monitor for AEs.  Observe the patient for at least 30 minutes after dosing for 
symptoms of infusion-related reactions and allergic reactions, including anaphylaxis 
(see Section 16, Appendix 3). 
 Remind the patient on recognition of delayed serious allergic reactions, including 
anaphylaxis.  Advise the patient to seek immediate medical attention if he or she 
experiences any symptoms of severe allergic reactions. 
 Remind patients to avoid taking analgesics during the 24 h prior to a clinic visit. 
 Remind patients that they are required to stay on their stable regimens of MTX and 
folic/folinic acid throughout the study. 
9.3.6 Weeks 26, 30, 34, 38, and 42 
Visits at Weeks 26, 30, 34, 38, and 42 will have the following safety and efficacy 
assessments.  In addition, at Weeks 30 and 38, pre-dose PK and ADA assessments will be 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 56 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 56 
 
done, and study treatment will be administered (see below).  At Week 30, there will also be 
additional safety assessments (see below). 
 Measure vital signs and weight, and perform a limited physical examination. 
 Record concomitant medications. 
 Administer the patient pain assessment, the patient global assessment of disease 
activity, the HAQ-DI, and the RAPID3.  
 At Week 38 only, administer the SF-36. 
 Assess 68 joints for tenderness and 66 for swelling (for use in the ACR core set and 
DAS28). 
 Perform the physician global assessment of disease activity (VAS). 
 Collect blood and urine samples for standard clinical laboratory tests. 
 Collect blood for CRP. 
 Collect blood to perform ESR locally. 
 Monitor for AEs. 
 Remind patients to avoid taking analgesics during the 24 h prior to a clinic visit. 
 Remind patients that they are required to stay on their stable regimens of MTX and 
folic/folinic acid throughout the study. 
At Weeks 30 and 38 only: 
 Collect urine to perform pregnancy test locally (females of childbearing potential 
only). 
 Collect blood for trough PK and ADA assessments. 
 Obtain the blinded study drug number from IVRS/IWRS for the unblinded 
pharmacist or designee to prepare the study treatment. 
 Prior to administration of the study drug, patients may be given antihistamines and/or 
acetaminophen (paracetamol) per standard care. 
 Administer study treatment. 
 Monitor for AEs.  Observe the patient for at least 30 minutes after dosing for 
symptoms of infusion-related reactions and allergic reactions, including anaphylaxis 
(see Section 16, Appendix 3). 
 Remind the patient on recognition of delayed serious allergic reactions, including 
anaphylaxis.  Advise the patient to seek immediate medical attention if he or she 
experiences any symptoms of severe allergic reactions. 
At Week 30 only: 
 Collect a blood sample for a QuantiFERON TB test.  
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 57 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 57 
 
 Perform chest x-rays (anterior-posterior and  lateral views) if the QuantiFERON TB 
test is positive. 
9.3.7 Weeks 46, 50, 54, and 58 
At the Week 46 visit, the dosing interval begins for assessing the full PK profile (Week 46 to 
Week 54).  In addition to the pre-dose trough sample, blood draws will be required at the 
following time points:  1 h after infusion start, at the EOI, at 4 h and 24 h after infusion start, 
and at 4 days, 7 days (Week 47), 14 days (Week 48), 28 days (Week 50), 42 days (Week 52), 
and 56 days (Week 54) post-dose.  Sampling windows for the blood draws are ±15 minutes 
for the 1 h time point, +15 minutes for the EOI, and ±15 minutes for the 4 h time point; ±2 h 
for the 24 h time point; and ±24 h for the subsequent time points.  The clinic will need to 
schedule patients to return to the clinic on these days. 
Visits at Weeks 46, 50, 54, and 58 will have the following safety and efficacy assessments.  
In addition, at Weeks 46 and 54, pre-dose PK and ADA assessments will be done, and study 
treatment will be administered (see below).  At Week 46, there will also be the additional 
post-dose blood draws for PK assessments (see below). 
 Measure vital signs and weight, and perform a limited physical examination. 
 Record concomitant medications. 
 Administer the patient pain assessment, the patient global assessment of disease 
activity, the HAQ-DI, and the RAPID3.  
 Assess 68 joints for tenderness and 66 for swelling (for use in the ACR core set and 
DAS28). 
 Perform the physician global assessment of disease activity (VAS). 
 Collect blood and urine samples for standard clinical laboratory tests. 
 Collect blood for CRP. 
 Collect blood to perform ESR locally. 
 Monitor for AEs. 
 Remind patients to avoid taking analgesics during the 24 h prior to a clinic visit. 
 Remind patients that they are required to stay on their stable regimens of MTX and 
folic/folinic acid throughout the study. 
At Weeks 46 and 54 only: 
 Collect urine to perform pregnancy test locally (females of childbearing potential 
only). 
 Collect blood for trough PK and ADA assessments. 
 Obtain the blinded study drug number from IVRS/IWRS for the unblinded 
pharmacist or designee to prepare the study treatment. 
 Prior to administration of the study drug, patients may be given antihistamines and/or 
acetaminophen (paracetamol) per standard care. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 58 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 58 
 
 Administer study treatment. 
 Monitor for AEs.  Observe the patient for at least 30 minutes after dosing for 
symptoms of infusion-related reactions and allergic reactions, including anaphylaxis 
(see Section 16, Appendix 3). 
 Remind the patient on recognition of delayed serious allergic reactions, including 
anaphylaxis.  Advise the patient to seek immediate medical attention if he or she 
experiences any symptoms of severe allergic reactions. 
At Week 46 only: 
 Perform blood draws at 1 h after infusion start, at the EOI, and at 4 h after infusion 
start. 
 Schedule patients for returning to the clinic at the following post-dose time points:  
24 h, 4 days, 7 days (Week 47), 14 days (Week 48), 28 days (Week 50), 42 days 
(Week 52), and 56 days (Week 54). 
9.3.8 Week 62 (End of Study Visit or Early Discontinuation Visit) 
The following procedures will be done at the end of study (Week 62) visit, or if a patient is 
prematurely withdrawn from the study, at the early discontinuation visit: 
 Measure vital signs and weight, and perform a limited physical examination. 
 Perform a 12-lead ECG (early discontinuation visit only). 
 Record concomitant medications. 
 Administer the patient pain assessment, the patient global assessment of disease 
activity, the HAQ-DI, the RAPID3, and the SF-36.  
 Assess 68 joints for tenderness and 66 for swelling (for use in the ACR core set and 
DAS28). 
 Perform the physician global assessment of disease activity (VAS). 
 Collect blood and urine samples for standard clinical laboratory tests. 
 Collect blood for CRP. 
 Collect blood to perform ESR locally. 
 Collect blood for trough PK and ADA assessments. 
 Collect urine to perform pregnancy test locally (females of childbearing potential 
only). 
 Collect a blood sample for a QuantiFERON TB test.  
 Perform a chest x-ray if the QuantiFERON TB test is positive. 
 Monitor for AEs. 
Patients who prematurely withdraw from the study for any reason should complete the early 
discontinuation visit requirements.  If the early discontinuation visit is not done, the reason(s) 
will be recorded in the eCRF.  
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 59 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 59 
 
9.3.9 Unscheduled Visits 
The Investigator may at his/her discretion arrange for a patient to have an unscheduled 
assessment, especially in the case of adverse events (AEs) that require follow-up or an AE 
considered by the Investigator to be possibly related to the use of study drug.  The 
unscheduled visit page in the eCRF must be completed.   
10 EFFICACY ASSESSMENTS 
10.1 Primary Efficacy Variable 
The primary efficacy variable, the ACR20-CRP response rate at Week 22, is based on a 20% 
improvement from baseline (Week 0) in specific elements of the ACR core set criteria.9,10  
The core set criteria consist of 7 elements: 
1. Tender joint count (out of 68 joints) 
2. Swollen joint count (out of 66 joints) 
3. Patient pain assessment (VAS/100 mm) 
4. Patient global assessment of disease activity (VAS/100 mm) 
5. Physician global assessment of disease activity (VAS/100 mm) 
6. Patient-completed HAQ-DI 
7. Acute-phase reactant (CRP or ESR; CRP will be evaluated for the primary endpoint) 
Achieving ACR20 is defined by a 20% improvement in tender and swollen joint counts, plus 
a 20% improvement in 3 out of the remaining 5 items. 
ACR core set criteria will be measured at the time points indicated in the schedule of 
assessments in Table 2.  The following subsections describe these criteria. 
10.1.1 Tender and Swollen Joint Counts 
At screening, counts of tender and swollen joints out of 28 selected joints will be performed 
(for the 2010 ACR and EULAR classification criteria).  At all subsequent visits, counts of 
tender and swollen joints out of 68 and 66 selected joints, respectively, will be performed 
(for the ACR core set criteria and the DAS28).  Counts will be performed by a trained and 
qualified joint assessor using standardized techniques recommended by EULAR.11  Results 
will be recorded immediately on a tablet device provided (constituting source data).  For each 
patient, efforts will be made to use the same blinded joint evaluator at all visits.  The blinded 
joint evaluator will perform only the joint counts and will not perform other assessments in 
the study.  To maintain consistency, 2 or 3 joint evaluators per site will be trained on how to 
assess joints for the purpose of the study using a number of training opportunities.  The 
training opportunities may include, but not be limited to, attendance at the Investigators’ 
Meeting, the site initiation visit, a video, and a written manual detailing how to perform the 
joint assessment.  Training will be documented by certificates kept in the site file.  
If a joint is unevaluable for any reason, the joint will be recorded as such on the tablet device.  
If this is due to amputation, the joint will automatically be recorded as unevaluable for the 
remainder of the study.  If a joint is unevaluable for any other reason (such as infection, 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 60 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 60 
 
injury, or surgery), the joint should be re-assessed for evaluability at each visit by the joint 
examiner.  Criteria for excluding such joints from the joint count used to calculate the 
ACR20/50/70 and the DAS28 will be detailed in the Statistical Analysis Plan (SAP).  
10.1.2 Assessments Using Visual Analog Scales 
Patient pain assessment VAS (ranging from no pain to pain as bad as it can be), patient 
global assessment of disease activity VAS (ranging from very well to very poor), and 
physician global assessment of disease activity VAS (ranging from none to extremely active) 
will be assessed on 100-mm scales at the visits specified in the schedule of assessments.36,37  
All of these assessments are part of the ACR core set criteria.  In addition, the patient global 
assessment of disease activity with the 100-mm scale is used to calculate the DAS28-CRP 
and DAS28-ESR scores. 
VAS data will be recorded on a tablet device and will be regarded as source data. 
10.1.3 HAQ-DI 
The HAQ-DI to be used for the ACR core set criteria is the version without questions 
concerning the use of aids or assistance from others.  The questionnaire is a 20-question, self-
administered instrument that measures the patient’s functional ability on a 4-level difficulty 
scale (0 to 3, with 0 representing normal or no difficulty, and 3 representing inability to 
perform).  Eight categories of functioning are included:  dressing/grooming, arising, eating, 
walking, hygiene, reach, grip, and usual activities.12,13 
The HAQ-DI questionnaire will be completed by the patient on the tablet device at the visits 
indicated in the schedule of assessments. 
10.1.4 Acute-Phase Reactants 
Serum CRP levels analyzed by the central laboratory and ESR analyzed locally are the 
acute-phase reactants included in the ACR core set criteria; CRP is used to determine the 
ACR 20/50/70-CRP response rates, and ESR is used to determine the ACR 20/50/70-ESR 
response rates.  These levels are also used in calculating the DAS28-CRP and the 
DAS28-ESR. 
10.2 Secondary Efficacy Variables 
Secondary efficacy variables include the ACR20-CRP response rate at time points other than 
Week 22; the ACR50-CRP, ACR50-ESR, ACR70-CRP, and ACR70-ESR response rates 
(50% and 70% improvements calculated in the same way as the ACR20), and change from 
baseline in each of the ACR core set criteria (see ACR variables described in Section 10.1).  
Other secondary efficacy variables include the DAS28-CRP and DAS28-ESR, the RAPID3 
score, and the SF-36. 
10.2.1 DAS28-CRP and DAS28-ESR 
The DAS28 scores are based on the extent of pain and swelling of 28 specific joints, 
including the shoulders, elbows, wrists, metacarpophalangeal joints, proximal carpal joints, 
and knees.7  In addition, the score includes the patient global assessment of disease activity 
VAS and the CRP or ESR value.  In this study, both DAS28-CRP and DAS28-ESR scores 
will be calculated for each patient.  The greater the numerical score, the higher the disease 
activity.  A score of <2.6 indicates minimum disease activity (remission), a score of ≥2.6 to 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 61 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 61 
 
<3.2 indicates low activity, a score of ≥3.2 to ≤5.1 indicates moderate activity, and a score of 
>5.1 indicates highly active RA.1 
10.2.2 RAPID3 
The RAPID3 is an increasingly used assessment in both RA clinical trials and clinical 
practice.  The RAPID3 has recently been used in clinical trials with methotrexate, 
leflunomide, adalimumab, and abatacept.29,30,31  In clinical practice, the ease of use and the 
short time (<30 seconds) for patient completion of the RAPID3 are key advantages over 
other indices.32,33  RAPID3 scores have been shown to correlate well with DAS28 scores in 
clinical trials and clinical care.34 
The RAPID3 score is a composite disease activity index consisting of 3 patient-reported 
outcomes:  disability, pain, and global assessment of disease activity.  For the RAPID3, 
disability is measured using the first 10 questions of the physical function section of the 
multidimensional HAQ (MD-HAQ), with each question about physical tasks performed over 
the past week scored from 0 (without any difficulty) to 3 (unable to do); the total score from 
the 10 questions is divided by 10, then multiplied by 3.33 to obtain the weighted disability 
score in the range of 0-10 for the RAPID3.  The pain intensity score for the RAPID3 is based 
on the following question:  How much pain have you had because of your condition over the 
past week?  The numerical scale with 0.5 increments ranges from 0 (no pain) to 10 (pain as 
bad as it could be).  The patient global assessment of disease activity score for the RAPID3 is 
based on the following statement:  Considering all the ways in which illness and health 
conditions may affect you at this time, please indicate below how you are doing.  The 
numerical scale with 0.5 increments ranges from 0 (very well) to 10 (very poorly).35 
For the calculation of the RAPID3 score, the results from the 3 parts are summed:  MD-HAQ 
physical function (range 0–10), pain intensity score (range 0–10), and patient global 
assessment of disease activity score (range 0–10).  Thus, the range of the RAPID3 score is 
0-30, and disease activity categories are as follows:  remission 0 to 3, low >3.1 to 6, 
moderate >6.1 to 12, and high >12.34 
The RAPID3 will be completed by the patient on the tablet device at the visits indicated in 
the schedule of assessments. 
10.2.3 SF-36 
The SF-36 is a 36-item, short-form health survey that has 8 subscales divided across physical 
and psychological health-related quality of life domains:  physical function, role physical, 
bodily pain, global health, vitality, social function, role emotional, and mental health.  Scores 
on these subscales can be combined to form 2 higher-order summary scores, the physical 
component summary and the mental component summary.  As the SF-36 is a generic tool 
instead of one that targets a specific disease or population, it can be used to compare the 
quality of life between diseases and in comparison to healthy populations.  The SF-36 has 
been found to be a valid and reliable measure in RA, correlating well with the HAQ-DI.19,20 
The SF-36 will be completed by the patient on the tablet device at the visits indicated in the 
schedule of assessments. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 62 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 62 
 
10.3 Other Disease Assessments (at Screening) 
Two classifications used to assess the RA of each patient at screening include (1) the 2010 
ACR and EULAR classification criteria used to confirm that a patient has definite RA,8 and 
(2) the 1991 ACR revised criteria for classification of global functional status (see 
Section 16, Appendix 1).14 
11 PHARMACOKINETIC ASSESSMENTS 
Interchangeability will be assessed from the analysis (specifically AUCtau and Cmax) of blood 
samples collected during the dosing interval of Week 46 to Week 54.  The specific time 
points for collecting these PK samples are presented in Table 2. 
Trough sampling will be done at the visits specified in Table 2.  In addition, if a patient 
discontinues from the study at any time, he/she will need to provide a blood sample for 
trough analysis at the early discontinuation visit. 
The actual date and time of each blood sample collection will be recorded in the eCRF.  The 
timing of PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring. 
A laboratory manual that contains detailed information on sample collection and 
handling/shipping of the samples will be provided to the sites. 
12 SAFETY ASSESSMENTS 
Safety assessments (vital signs, weight, physical examinations, ECG recordings, AEs, routine 
clinical laboratory tests (hematology, blood chemistry, and urinalysis), pregnancy tests, 
antibody assays, and QuantiFERON TB tests (and chest x-rays, if applicable) are to be 
performed at the visits specified in the schedule of assessments in Table 2. 
12.1 Vital Signs, Height, and Weight 
Vital signs (oral/tympanic body temperature, pulse, systolic and diastolic blood pressure 
measurements) will be evaluated at the visits indicated in the schedule of assessments.  All 
vital signs will be measured after the patient has been resting in a sitting position for at least 
5 minutes.  Blood pressure measurements are to be taken in the same arm for the duration of 
the study.  Body weight (without shoes) will be recorded whenever vital signs are recorded, 
and height (without shoes) will be recorded at screening only. 
Vital sign measurements will be repeated if clinically significant or machine/equipment 
errors occur.  Out-of-range blood pressure and pulse measurements will be repeated at the 
Investigator’s discretion.  Any confirmed, clinically significant vital sign measurements must 
be recorded as AEs. 
12.2 Physical Examination 
A complete physical examination (head, eyes, ears, nose, throat, heart, lungs, abdomen, skin, 
cervical and axillary lymph nodes, neurological, and musculoskeletal systems) will be 
performed at screening.  In addition, medical history (including smoking history) will be 
recorded at screening. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 63 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 63 
 
A limited physical examination to verify continued patient eligibility and to follow up any 
change in medical history will be performed at the visits indicated in the schedule of 
assessments.  Symptom-driven physical examinations will be performed as clinically 
indicated at any study visit.  All changes not present at baseline or described in the past 
medical history and identified as clinically noteworthy must be recorded as AEs. 
12.3 Tuberculosis Screening 
At screening, a QuantiFERON test will be done to screen for latent TB.  If the test is positive, 
a chest x-ray is to be performed at screening unless a recent x-ray is available (done within 
12 weeks prior to screening). 
A patient who tests positive for latent TB (with a positive or indeterminate QuantiFERON 
test, plus a chest x-ray negative for active TB) will be allowed to enroll if prior prophylactic 
treatment was documented or if prophylactic treatment for TB was initiated at least 4 weeks 
prior to baseline (first dose of study drug).  If the result is indeterminate, the test may first be 
repeated, or purified protein derivative (PPD) testing may be done.  If confirmed 
indeterminate, the patient should be managed as though they have a positive test result or 
excluded from the study. 
If necessary, a patient may be re-screened once to allow for this prophylactic treatment 
period.  Prophylactic treatment should be according to local guidelines, which may vary 
depending upon the sensitivity of strains of M. tuberculosis present locally.  As a guide, the 
US Centers for Disease Control and Prevention recommendations are available online.15  
Patients with latent TB should receive appropriate treatment for at least 4 weeks prior to 
baseline and should be committed to completing the course of antimycobacterial therapy 
during the study. 
In case of any doubt as to the diagnosis of latent TB and the appropriate course of 
antimycobacterial therapy, it is advised that a local physician with expertise in the treatment 
of TB is consulted. 
All patients will be retested at Week 30 and Week 62 (or at the early discontinuation visit). 
For further information about TB screening, see Section 16, Appendix 4. 
12.4 Electrocardiogram 
A 12-lead resting ECG will be obtained at screening and at the early discontinuation visit, if 
applicable.  At screening, the Investigator will examine the ECG traces for signs of cardiac 
disease that could exclude the patient from the study.  An assessment of normal or abnormal 
will be recorded and if the ECG is considered abnormal, the abnormality will be documented 
in the eCRF.  ECGs will be repeated if clinically significant abnormalities are observed or 
artifacts are present. 
12.5 New York Heart Association Classification 
Patients will be evaluated at screening for cardiac disease by means of the NYHA functional 
classification (see Table 3).  If patients have Class III or IV cardiac disease, they will be 
excluded from the study. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 64 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 64 
 
Table 3 New York Heart Association Classification 
Class 
New York Heart Association Classification 
I 
Patients have cardiac disease but without the resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
II 
Patients have cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
III 
Patients have cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Patients have cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
Source:  Raphael C, Briscoe C, Davies J, et al.16  
12.6 Clinical Laboratory Parameters 
Samples for assessing clinical laboratory parameters (Table 4) are to be obtained at the visits 
designated in the schedule of assessments. 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 65 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 65 
 
Table 4 Clinical Laboratory Parameters 
Hematology 
Serum chemistry 
Urine analysis 
(dipstick) 
Full and differential blood count 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Mean corpuscular hemoglobin 
(MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count 
with differential  
Glycated hemoglobin (HbA1C) (at 
screening only) 
Albumin 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) or urea 
Creatinine 
Electrolytes (Na, K, Cl, Ca, P) 
Gamma-glutamyl transpeptidase 
(GGT) 
Glucose  
Lactate dehydrogenase (LDH) 
Total bilirubin 
Direct bilirubin 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood 
and WBCs 
Urobilinogen 
Serum immunology tests:  At screening, HBsAg, HBsAb, HBcAb, HCV Ab, HIV Ab, 
anti-dsDNA, and β-D-glucan (using the Fungitell® assay) will be measured. 
RA tests:  Rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) tests will be 
done at screening. 
Pregnancy test:   For women of childbearing potential, a serum pregnancy test will be done at 
screening, and urine dipstick tests will be done at all dosing visits and at Week 62 (or the early 
discontinuation visit). 
QuantiFERON TB test:  This test will be performed for all patients at screening, Week 30, and 
Week 62 (or the early discontinuation visit).  A dedicated incubator must be available at the site for 
storing samples at 37ºC prior to shipping them to the central laboratory (at room temperature or 
refrigerated) within 3 days. 
C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) tests:  CRP and ESR levels 
will be analyzed at every visit.  CRP will be analyzed by the central laboratory, and ESR will be 
analyzed locally. 
Blood and urine samples will be analyzed at a central laboratory facility, unless indicated 
otherwise.  Urine samples will be analyzed by dipstick, and a microscopic analysis will be 
performed if the results of the dipstick indicate abnormalities to be further investigated.   
The Investigator must review all laboratory reports and document the review.  Any 
laboratory test result or change considered by the Investigator to be clinically significant 
should be considered an AE and recorded in the AE eCRF.  Clinically significant abnormal 
values occurring during the study will be followed until repeat test results return to normal, 
stabilize, or are no longer clinically significant.  
12.7 Immunogenicity Assessments 
The detection and characterization of antibodies to study drug (Remicade-US and NI-071) 
will be performed using a validated immunoassay method.  Positive immunogenicity samples 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 66 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 66 
 
will be further examined to confirm the specificity of binding.  If the sample is confirmed to 
be positive for specific ADAs, the neutralizing capacity of these antibodies will be 
investigated. 
Blood samples will be collected at the time points indicated in the schedule of assessments 
(pre-dose at dosing visits).  In addition, if a patient discontinues from the study at any time, 
he/she will need to provide a sample at the early discontinuation visit.  A laboratory manual 
that contains detailed information on sample collection and handling/shipping of the samples 
will be provided to the sites. 
12.8 Adverse Events 
12.8.1 Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the 
study or, if present at screening, worsens during the study, regardless of the suspected cause 
of the event.  All medical and psychiatric conditions (except those related to the indication 
under study) present at screening will be documented in the medical history eCRF.  Changes 
in these conditions and new symptoms, physical signs, syndromes, or diseases should be 
noted on the AE eCRF during the rest of the study.  Clinically significant laboratory 
abnormalities should also be recorded as AEs.  Surgical procedures that were planned before 
the patient enrolled in the study are not considered AEs if the conditions were known before 
study inclusion; the medical condition should be reported in the patient’s medical history. 
Additionally, anticipated AEs for this study population are reported in Table 5 and are based 
on AEs reported with Remicade from the premarketing clinical studies as well as from 
post-marketing experience.  Anticipated AEs must be reported by Investigators to the 
Sponsor but will not necessarily be expedited on an individual basis.  Instead these AEs will 
be reviewed in aggregate every month by the medical monitor.  This aggregate review may 
result in an expedited safety report. 
Adverse events of special interest include serious infections, malignancies, hepatotoxicity, 
heart failure, cytopenias, and infusion-related reactions (any AE reported during an infusion 
or within 1 h after an infusion).  As anaphylaxis may occur at any time during or after 
infusion, Investigators are to observe patients during and after infusions for anaphylactic 
reactions as defined by the criteria in Section 16, Appendix 3.17 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 67 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 67 
 
Table 5 List of Anticipated AEs with Study Drug (AEs Reported with Remicade) 
System Organ 
Class 
Frequencya 
Adverse Reaction 
Infections and 
infestations 
Very 
common 
Viral infections (e.g., influenza, herpes virus) 
 
Common 
Bacterial infections (e.g., sepsis, cellulitis, abscess) 
 
Uncommon 
Tuberculosis, fungal infections (e.g., candidiasis) 
 
Rare 
Meningitis, opportunistic infections (such as invasive fungal 
infections, bacterial infections, and viral infections), parasitic 
infections, hepatitis B reactivation 
 
Not known 
Vaccine breakthrough infection 
Neoplasms 
benign, 
malignant, and 
unspecified 
Rare 
Lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s disease, 
leukemia, melanoma, cervical cancer 
 
Not known 
Hepatosplenic T-cell lymphoma, Merkel cell carcinoma 
Blood and 
lymphatic 
system 
disorders 
Common 
Neutropenia, leucopenia, anemia, lymphadenopathy,  
 
Uncommon 
Thrombocytopenia, lymphopenia, lymphocytosis 
 
Rare 
Agranulocytosis, thrombotic thrombocytopenic purpura, 
pancytopenia, hemolytic anemia, idiopathic thrombocytopenic 
purpura 
Immune system 
disorder 
Common 
Allergic respiratory symptom 
 
Uncommon 
Anaphylactic reaction, lupus-like syndrome, serum sickness or 
serum sickness-like reaction 
 
Rare 
Anaphylactic shock, vasculitis, sarcoid-like reaction 
Psychiatric 
disorders 
Common 
Depression, insomnia 
 
Uncommon 
Amnesia, agitation, confusion, somnolence, nervousness 
 
Rare 
Apathy 
Nervous system 
disorders 
Very 
common 
Headache 
 
Common 
Vertigo, dizziness, hypoesthesia, paresthesia 
 
Uncommon 
Seizure, neuropathy 
 
Rare 
Transverse myelitis, central nervous system demyelinating 
disorders, peripheral demyelinating disorders 
Eye disorders 
Common 
Conjunctivitis 
 
Uncommon 
Keratitis, periorbital edema, hordeolum 
 
Rare 
Endophthalmitis 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 68 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 68 
 
System Organ 
Class 
Frequencya 
Adverse Reaction 
 
Not known 
Transient visual loss occurring during or within 2 h of infusion 
Cardiac 
disorders 
Common 
Tachycardia, palpitation 
 
Uncommon 
Cardiac failure (new onset or worsening), arrhythmia, syncope, 
bradycardia 
 
Rare 
Cyanosis, pericardial effusion 
 
Not known 
Myocardial ischemia/myocardial infarction occurring during or 
within 2 h of infusion 
Vascular 
disorders 
Common 
Hypotension, hypertension, ecchymosis, hot flush, flushing 
 
Uncommon 
Peripheral ischemia, thrombophlebitis, hematoma 
 
Rare 
Circulatory failure, petechia, vasospasm 
Respiratory, 
thoracic, and 
mediastinal 
disorders 
Very 
common 
Upper respiratory tract infection, sinusitis 
 
Common 
Lower respiratory tract infection (e.g., bronchitis, pneumonia), 
dyspnea, epistaxis 
 
Uncommon 
Pulmonary edema, bronchospasm, pleurisy, pleural effusion 
 
Rare 
Interstitial lung disease (including rapidly progressive disease, 
lung fibrosis, and pneumonitis) 
Gastrointestinal 
disorders 
Very 
common 
Abdominal pain, nausea 
 
Common 
Gastrointestinal hemorrhage, diarrhea, dyspepsia, 
gastroesophageal reflux, constipation 
 
Uncommon 
Intestinal perforation, intestinal stenosis, diverticulitis, 
pancreatitis, cheilitis 
Hepatobiliary 
disorders 
Common 
Hepatic function abnormal, transaminases increased 
 
Uncommon 
Hepatitis, hepatocellular damage, cholecystitis 
 
Rare 
Autoimmune hepatitis, jaundice 
 
Not known 
Liver failure 
Skin and 
subcutaneous 
tissue disorders 
Common 
New onset or worsening psoriasis including pustular psoriasis 
(primarily palm and soles), urticarial, rash, pruritus, 
hyperhidrosis, dry skin, fungal dermatitis, eczema, alopecia 
 
Uncommon 
Bullous eruption, onychomycosis, seborrhea, rosacea, skin 
papilloma, hyper keratosis, abnormal skin pigmentation 
 
Rare 
Toxic epidermal necrolysis, Stevens-Johnson syndrome, 
erythema multiforme, furunculosis 
 
Not known 
Worsening of symptoms of dermatomyositis 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 69 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 69 
 
System Organ 
Class 
Frequencya 
Adverse Reaction 
Musculoskeletal 
and connective 
tissue disorders  
Common 
Arthralgia, myalgia, back pain 
Renal and 
urinary 
disorders 
Common 
Urinary tract infection 
 
Uncommon 
Pyelonephritis 
Reproductive 
system and 
breast disorders 
Uncommon 
Vaginitis 
General 
disorders and 
administration 
site conditions 
Very 
common 
Infusion-related reaction, pain 
 
Common 
Chest pain, fatigue, fever, injection site reaction, chills, edema 
 
Uncommon 
Impaired healing 
 
Rare 
Granulomatous lesion 
Investigations 
Uncommon 
Autoantibody positive 
 
Rare 
Complement factor abnormal 
aVery common: ≥10%; Common: ≥1% and <10%; Uncommon: ≥0.1% to <1%; Rare:≥0.01% to <0.1%; 
Very Rare: <0.01%; Not known: cannot be determined from the available data.  Within each frequency 
group, adverse reactions are presented in order of decreasing seriousness. 
Source: Remicade EMA EPAR Product Information4  
 
All SAEs must be reported to the Sponsor or Sponsor designee immediately after the 
Investigator becomes aware of the event, along with a determination as to whether it is 
associated with the study drug. 
Patients will be instructed to report AEs at each study visit.  All AEs are to be followed until 
resolution or until a stable clinical endpoint is reached. 
Each AE is to be documented in the eCRF with reference to date of onset, duration, 
frequency, severity, relationship to study drug, action taken with study drug, treatment of 
event, and outcome.  Furthermore, each AE is to be classified as being serious or 
non-serious.  Changes in AEs and resolution dates are to be documented in the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from 
the time the patient gives informed consent through Week 54 (or early discontinuation visit).  
Follow-up of the AE is required until the event resolves or stabilizes at a level acceptable to 
the Investigator. 
Specific guidelines for classifying AEs by intensity and relationship to study drug are given 
in Table 6 and Table 7. 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 70 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 70 
 
Table 6 Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the patient, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 
Table 7 Classification of Adverse Events by Relationship to Study Drug 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc.). 
UNLIKELY:  This category applies to those AEs that are judged to be unrelated to the study drug, but for 
which no extraneous cause may be found.  An AE may be considered unlikely to be related to study drug if or 
when it meets 2 of the following criteria:  (1) it does not follow a reasonable temporal sequence from 
administration of the study drug; (2) it could readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient; (3) it does not follow a 
known pattern of response to the study drug; or (4) it does not reappear or worsen when the drug is 
re-administered. 
POSSIBLY: This category applies to those AEs for which a connection with the study drug administration 
appears unlikely but cannot be ruled out with certainty.  An AE may be considered possibly related if or when it 
meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the drug; 
(2) it could not readily have been produced by the patient’s clinical state, environmental or toxic factors, or 
other modes of therapy administered to the patient; or (3) it follows a known pattern of response to the study 
drug. 
PROBABLY: This category applies to those AEs that the Investigator feels with a high degree of certainty are 
related to the study drug.  An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the patient; (3) it disappears or decreases on cessation or reduction in 
dose (note that there are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-
relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or tardive 
dyskinesia); or (4) it follows a known pattern of response to the study drug. 
DEFINITELY: This category applies to those AEs that the Investigator feels are incontrovertibly related to 
study drug.  An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the patient; (3) it disappears or decreases on cessation or reduction in 
dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a known pattern of response 
to the study drug. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the event should be noted.  If the intensity category changes over a 
number of days, then those changes should be recorded separately (with distinct onset dates). 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 71 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 71 
 
12.8.2 Serious Adverse Events 
An AE is considered serious if in the view of either the Investigator or Sponsor, it meets 1 or 
more of the following criteria:  
 Is fatal 
 Is life-threatening 
 Results in inpatient hospitalization or prolongation of existing hospitalization 
 Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
 Is a congenital anomaly/birth defect 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization, based upon appropriate medical judgment, are considered SAEs if 
they are thought to jeopardize the patient and/or require medical or surgical intervention to 
prevent one of the outcomes defining an SAE.  Since SAEs are critically important for the 
identification of significant safety problems, it is important to take into account both the 
Investigator’s and the Sponsor’s assessment.  If either the Sponsor or the Investigator 
believes that an event is serious, the event must be considered serious and evaluated by the 
Sponsor for expedited reporting. 
12.8.3 Serious Adverse Event Reporting 
An SAE occurring during the study or within 8 weeks after stopping the treatment must be 
reported to the inVentiv Health Pharmacovigilance Group and will be communicated to the 
Sponsor.  Any such SAE due to any cause, whether or not related to the study drug, must be 
reported within 24 hours of occurrence or when the Investigator becomes aware of the event.  
Notification can be made with the SAE reporting form by using the dedicated fax line or by 
scanning and emailing to the safety mailbox for the inVentiv Health Pharmacovigilance 
Group: 
inVentiv Health Pharmacovigilance Fax Numbers:   
North America:  +1-866-880-9343 
All other countries:  +44-1628-461184 
inVentiv Health Pharmacovigilance Email:  SafetyPV@inventivhealth.com 
If notification cannot be made via these means due to technical delivery problems, initial 
notification may be made by telephone, using the SAE Hotline number: 
inVentiv Health Pharmacovigilance Hotline:  +1-888-750-8020 
A telephone call to the SAE Hotline does not substitute for the site’s responsibility to submit 
a written SAE reporting form to inVentiv Health.  If the Investigator makes initial contact by 
telephone, then a written report must follow within 24 hours and is to include a full 
description of the event and sequelae in the format detailed in the SAE reporting form. 
The event must also be recorded on the standard AE eCRF.  Preliminary reports of SAEs 
must be followed by detailed descriptions later on, including clear and anonymized 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 72 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 72 
 
photocopies of hospital case reports, consultant reports, autopsy reports, and other documents 
when requested and applicable.  SAE reports must be made whether or not the Investigator 
considers the event to be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded.  Clinical, laboratory, and diagnostic measures should be employed as needed in 
order to determine the etiology of the problem.  The Investigator must report all additional 
follow-up evaluations to the inVentiv Health Pharmacovigilance Group within 10 calendar 
days.  All SAEs will be followed until the Investigator and Sponsor agree the event is 
satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the patient’s 
participation in the study is to be followed until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the 
study drug or procedures. 
12.8.4 Suspected Unexpected Serious Adverse Reactions 
Adverse events that meet all of the following criteria will be classified as suspected 
unexpected serious adverse reactions (SUSARs) and will be reported to the appropriate 
regulatory authorities in accordance with applicable regulatory requirements for expedited 
reporting: 
 Serious 
 Unexpected (i.e., the event is not consistent with the safety information in the IB) 
 There is at least a reasonable possibility that there is a causal relationship between the 
event and the study treatment. 
The Investigator will assess whether an event is causally related to study treatment.  The 
Sponsor (or inVentiv Health) will consider the Investigator’s assessment and determine 
whether the event meets the criteria for being reportable as a 7-day or 15-day safety report.  
SUSARs that are fatal or life-threatening must be reported to the regulatory authorities and 
the IEC/IRBs (where required) within 7 days after the Sponsor (or inVentiv Health) has first 
knowledge of them, with a follow-up report submitted within a further 8 calendar days.  
Other SUSARs must be reported to the relevant regulatory authorities and the IEC/IRBs 
within 15 calendar days after the Sponsor (or inVentiv Health) has first knowledge of them. 
The Sponsor (or inVentiv Health) is responsible for reporting SUSARs to the regulatory 
authorities and for informing Investigators of reportable events, in compliance with 
applicable regulatory requirements within specific timeframes.  Investigators will notify the 
relevant IEC/IRBs of reportable events within the applicable timeframes. 
12.8.5 Pregnancy 
Female patients of childbearing potential must have a negative serum pregnancy test at 
screening.  Following administration of study drug, any known cases of pregnancy in female 
patients will be reported until the patient completes or withdraws from the study.  The 
pregnancy will be reported immediately by phone and by faxing/emailing a completed 
Pregnancy Report to the Sponsor (or designee) within 24 hours of knowledge of the event.  
The pregnancy will not be processed as an SAE; however the Investigator will follow the 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 73 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 73 
 
patient until completion of the pregnancy and must assess the outcome in the shortest 
possible time but not more than 30 days after completion of the pregnancy.  The Investigator 
should notify the Sponsor (or designee) of the pregnancy outcome by submitting a follow-up 
Pregnancy Report.  If the outcome of the pregnancy meets the criteria for immediate 
classification of an SAE (e.g., spontaneous or therapeutic abortion [any congenital anomaly 
detected in an aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator will report the event by phone and by faxing a completed SAE 
form to the Sponsor (or designee) within 24 hours of knowledge of the event. 
12.8.6 Overdose 
The Investigator must immediately notify the Sponsor of any occurrence of overdose with 
study drug.  The patient will be monitored for any signs or symptoms of adverse reactions or 
effects, and appropriate symptomatic treatment will be given. 
13 STATISTICAL ANALYSIS 
A SAP will be prepared after the protocol is approved.  This document will provide further 
details regarding the definition of analysis variables and analysis methodology to address all 
study objectives.  The SAP will supersede planned analyses in the protocol in the case of any 
differences. 
The statistical evaluation will be performed using SAS® Version 9.3 or higher (SAS Institute, 
Cary, NC).  All data will be listed, and summary tables will be provided.  Summary statistics 
will be presented by treatment group according to study stage.  For continuous variables, data 
will be summarized with the number of patients (N), mean, standard deviation, median, 
minimum, and maximum by treatment group.  For categorical variables, data will be 
tabulated with the number and proportion of patients for each category by treatment group 
according to study stage.  
The treatment groups according to study stages are as follows:  2 treatment groups in Stage 1 
(i.e., Remicade-US and NI-071) and 3 treatment groups in Stage 2 (i.e., NI-071 throughout 
the study, Remicade-US throughout the study, and the Switch group [patients who were 
originally allocated to Remicade-US during Stage 1, then were re-randomized to alternate 
between treatments with NI-071 and Remicade-US in Stage 2]).  In addition, a combined 
group will be displayed. 
An interim analysis is planned in order to decide if the study should continue or be stopped 
for futility after Stage 1 (see Section 13.8). 
13.1 Determination of Sample Size 
The sample size required to be randomized in Stage 1 was derived with consideration of the 
required sample size needed for PK analysis at the end of Stage 2 and assumes a 25% 
drop-out of patients during Stages 1 and 2.  Stage 3 will follow patients for safety after the 
final dose and does not have sample size requirements.  
To show PK similarity, the 90% geometric CIs of the ratio (Switch/Remicade-US) of the 
least squares means from the analysis of variance (ANOVA) of the ln-transformed AUCtau 
and Cmax must be within 80.00% and 125.00%.  For the PK interchangeability analysis at the 
end of Stage 2, assuming coefficients of variation (CVs) of 49% and 33% for AUCtau and 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 74 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 74 
 
Cmax, respectively, and CIs of the ratios between 95% and 105%, at least 109 patients per 
treatment group are required for an 80% powered trial. (Note: The CV assumptions for the 
PK sample size estimations were derived from a multiple-dose PK study conducted in 
ankylosing spondylitis patients for the Remsima™ infliximab biosimilar.18  In the Phase 1 
single-dose PK study of NI-071 and Remicade-US in 96 healthy Japanese male volunteers, 
the CVs were quite low, about 24% for AUC and 15% for Cmax, possibly due to the 
homogeneity of the healthy population and to no or little impact from ADA formation after a 
single dose.  Using the data from the multiple-dose Remsima study in 222 patients with 
ankylosing spondylitis provides a more appropriate basis for this planned multiple-dose study 
in patients with RA.) 
In order to meet this Stage 2 requirement, in Stage 1 (at Week 0), approximately 585 patients 
are expected to be randomized in a ratio of 2:1 to Remicade-US (390 patients) and NI-071 
(195 patients).  This sample size will provide over 90% power to test for equivalence, using 
an asymmetric margin (-12%, 15%) and a two 1-sided test (TOST) analysis with α=0.05 for 
each 1-sided statistical test.  Greater than 90% power is achieved when the ACR20-CRP 
response rate for Remicade-US at Week 22 is assumed to be 79.4% (the Remicade-US 
ACR20-CRP result at Week 22 from Study NI071F1 using the study’s modified 
intent-to-treat population).  
Assuming a 25% drop-out rate during Stage 1, at least 292 patients in the Remicade-US 
group and 146 patients in the NI-071 group are expected to complete Stage 1 of the study.  In 
Stage 2 (at Week 22), patients in the original Remicade-US group (about 292 patients) will 
be re-randomized in a 1:1 ratio to a Remicade-US group (146 patients) and a Switch group 
(146 patients).  Assuming a 25% drop-out rate during Stage 2, approximately 109 patients 
per treatment group will be available for the PK analysis at the end of Stage 2.  
The asymmetric margins (-12%, 15%) were selected based on the following justifications. 
The lower -12% margin is justified for the following reasons:  
 Combest et al. (2014) indicated “From a clinical perspective, an equivalence margin 
of [±]15% or less is not a clinically meaningful difference based on a meta-analysis of 
both infliximab and adalimumab trials with a focus on Phase III trials.”25  
 Smolen et al. (2014), in a review that considered the ACR20 and other responses 
across a broad range of therapies, suggested that when comparing treatment effects 
between products, any differences in the effects of one RA treatment on the ACR20 
endpoint that are -12% or less (i.e., -12% to -1%) then effects seen with the 
comparator product would not be considered to represent clinical meaningful 
differences in effects.27  
 A lower margin of -12% is more conservative than a -15% lower margin, which was 
used to test equivalence between a study product and infliximab in patients with RA, 
as reported by Yoo et al. (2013),28 and more conservative than a -18% lower margin, 
which was used to test noninferiority in patients with RA, as reported by Ogata et al. 
(2014).26 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 75 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 75 
 
The upper 15% margin is justified for the following reasons:  
 Combest et al. (2014) indicated “From a clinical perspective, an equivalence margin 
of [±]15% or less is not a clinically meaningful difference based on a meta-analysis of 
both infliximab and adalimumab trials with a focus on Phase III trials.”25  
 Van Vollenhoven et al. (2012) reported results from testing a product against a 
placebo looking for 20% improvement in ACR20.21  This suggests that differences in 
ACR20 that are not at least 20% or more should not be considered to be clinically 
meaningful.  Therefore, a product having a treatment effect that is not more than 15% 
greater than that observed with a reference comparator product could be considered to 
be equivalent with the comparator product. 
Of note, the power analysis for equivalence was performed using PASS v13.0 and performed 
using all enrollees; enrollment sample sizes have not been reduced for considerations of loss 
to follow-up or protocol deviations because the primary evaluation of efficacy is planned 
using the intent-to-treat (ITT) population, defined as all randomized and treated patients, 
regardless of loss to follow-up.  This is consistent with van Vollenhoven (2012) and Schiff 
(2008).21,22 
13.2 Analysis Populations 
Five analysis populations are being defined for this study, as follows. 
Intent-To-Treat Population 
The ITT population will include all patients who are randomized, irrespective of any 
deviation from the protocol or premature discontinuation.  Patients will be analyzed 
according to the treatment group assigned at the Stage 1 randomization.  The ITT population 
will serve as the basis for the primary efficacy analysis in Stage 1. 
Safety Population 
The safety population will include all ITT patients who receive at least 1 dose of study drug.  
Patients will be analyzed according to the actual treatment they receive rather than as 
randomized.  This population will be used for the analysis of safety.   
Full Analysis Set 
The full analysis set (FAS) will include all patients in the safety population with at least 
1 post-baseline ACR20 efficacy assessment.  Patients will be analyzed according to the 
treatment group assigned at the most recent randomization.  This population will be used for 
the secondary efficacy analyses, as well as a sensitivity analysis for the primary efficacy 
endpoint.   
Per-Protocol Population 
The per-protocol (PP) population will include all patients in the FAS with no major protocol 
deviations in Stage 1, and sufficient time in the study.  Sufficient time will be defined as 
having at least the Week 22 ACR20-CRP efficacy assessment and all study drug 
administrations up to and including the Week 14 study drug administration.  Since this 
population excludes patients with major protocol deviations, patients will be analyzed 
according to the treatment they were randomized to and received during Stage 1.  This 
population will be used for a sensitivity analysis of the primary efficacy analysis. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 76 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 76 
 
Pharmacokinetic Population 
The PK population will include all patients in the FAS population in Stage 1 who have valid 
PK assessments through Stage 2.  This includes only patients who have received all and 
complete treatments required per protocol through Stage 2.  This population will be used for 
the analysis of interchangeability in Stage 2. 
13.3 Demographic and Baseline Characteristics 
Demographic variables to be recorded include age, gender, race, ethnicity, body height, and 
body weight. 
Demographic information will be presented in listings, and summarized in tables using 
descriptive statistics or counts and percentages. 
13.4 Efficacy Analysis 
The efficacy analyses will focus on the ACR core set criteria, the ACR20/50/70-CRP and 
ACR20/50/70-ESR (20%/50%/70% improvements from baseline in the ACR core set criteria 
using CRP and ESR, respectively) response rates, and DAS28 (both DAS28-CRP and 
DAS28-ESR) scores recorded throughout the study.  In addition, the SF-36 scores will be 
analyzed to evaluate health-related quality of life. 
13.4.1 Analysis of Primary Efficacy Endpoint 
The primary clinical efficacy endpoint for biosimilarity, the ACR20-CRP response rate at 
Week 22, will be analyzed using the ITT population.  Patients who do not have an 
ACR20-CRP assessment at Week 22, as well as patients who do not receive study drug up to 
and including the Week 14 administration, will be considered to have not achieved 
ACR20-CRP.  Because these patients are considered non-responders for this analysis, the 
primary analysis is considered an analysis on the composite endpoint of both ACR20-CRP 
response and adherence to study drug treatment. 
To determine biosimilarity, two standard 1-sided asymptotic Wald tests of the difference 
between NI-071 and Remicade-US response rates will be performed.  If the null hypotheses 
of both tests are rejected at α=0.05, the equivalence in efficacy is achieved.  The hypotheses 
that will be evaluated are stated, as follows, where PNI-071 is the response rate in the NI-071 
arm and PRemicade-US is the response rate in the Remicade-US arm:  
Ho: PNI-071 – PRemicade-US ≤-12% 
Ho: PNI-071 – PRemicade-US ≥15% 
Ha: -12% <(PNI-071 – PRemicade-US) <15% 
13.4.1.1 Sensitivity Analyses of the Primary Efficacy Endpoint 
Five types of sensitivity analyses will be performed for the primary efficacy endpoint.  These 
analyses are outlined in Table 8 and described in detail in the SAP.  
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 77 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 77 
 
Table 8 Sensitivity Analyses of the Primary Efficacy Endpoint 
Description 
Purpose 
Population 
Repeat of the primary 
analysis (Wald-test) 
Rather than applying the non-responder imputation 
(NRI) for patients who did not receive all treatments 
through Week 14, the data actually collected will be 
used to determine response status at Week 22.  This 
sensitivity analysis addresses the composite nature 
of the primary endpoint. 
ITT 
Repeat of the primary 
analysis (Wald-test) 
The primary analysis will be performed for different 
populations.  For the FAS, 2 analyses will be done: 
with and without NRI for patients who discontinue 
study drug. 
FAS, PP 
Repeat of the primary 
analysis (Wald-test) 
The primary analysis will be performed using a 
different imputation method.  Rather than not 
allowing for imputation of missing ACR20 
components, the mixed component last observation 
carried forward (LOCF) method for calculating 
ACR20 response status will be employed. 
ITT, FAS, PP 
Logistic regression model 
of the primary endpoint 
Modeling will be performed to evaluate if there is 
any impact on the primary analysis from baseline 
disease status or geographical region.  The model 
will use ACR20-CRP at Week 22 as a dependent 
variable, and treatment group, baseline CRP values, 
and region as covariates. 
ITT, FAS, PP 
Tipping point analysis of 
the primary endpoint 
A tipping point analysis will be performed if the 
primary analysis for the ITT population concludes 
similarity.  The purpose is to identify the 
hypothetical response rates required among the 
patients with missing data in order to produce 
statistics that no longer support similarity. To start, 
instead of assuming a 0% response rate for patients 
with missing data, the observed response rate for the 
Remicade-US arm in the PP population will be 
assumed for both treatment groups.  Through 
iterative steps of increasing the number of 
non-responders in the NI-071 group, the analysis 
will assess where the response conclusion switches 
direction. 
ITT 
Abbreviations: ACR20-CRP=20% improvement from baseline in the American College of Rheumatology core 
set criteria using C-reactive protein as the acute-phase reactant; FAS=full analysis set; ITT=intent-to-treat; 
LOCF=last observation carried forward; NRI=Non-responder imputation; PP=per protocol. 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 78 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 78 
 
13.4.2 Analysis of Secondary Efficacy Endpoints 
Secondary clinical efficacy endpoints include ACR20-CRP (at time points other than 
Week 22), ACR20-ESR, ACR50-CRP, ACR50-ESR, ACR70-CRP, ACR70-ESR, ACR core 
set items, DAS28-CRP, and DAS28-ESR.  Summary statistics (including number of patients, 
mean, standard deviation, minimum, median, maximum) of numerical endpoints for 
DAS28-CRP and DAS28-ESR (value and change from baseline for visit) will be calculated 
and presented by visit and treatment group.  Point estimate and 95% CI of differences 
between NI-071 and Remicade-US for DAS28-CRP and DAS28-ESR will also be presented.  
Frequency tables of the number and percentage of patients achieving ACR20-CRP, 
ACR20-ESR, ACR50-CRP, ACR50-ESR, ACR70-CRP, and ACR70-ESR will be calculated 
and presented by visit and treatment group.  ACR core set items will be summarized (value 
and change from baseline for visit) descriptively.  RAPID3 scores will be summarized (value 
and change from baseline for visit) descriptively.  SF-36 domain subscores and summary 
scores will be summarized (value and change from baseline for visit) descriptively. 
These secondary analyses are considered exploratory, as the power of the trial, designed for 
the primary endpoint, is not sufficient for the secondary endpoints. 
13.5 Pharmacokinetic Analysis 
To determine PK similarity, using the GLM procedure in SAS, the 90% CIs of the ratios 
(Switch/Remicade-US) of least squares means from the ANOVA of the ln-transformed 
AUCtau and Cmax will be evaluated at the alpha level of 0.05 for the PK population during the 
dosing interval of Weeks 46 to 54.  If the CI is within the range of 80.00% to 125.00%, PK 
similarity is achieved.  Secondary PK parameters include Cmin and tmax during this dosing 
interval.  Wilcoxon’s test will be performed on tmax, and Cmin will be summarized 
descriptively.  Additional PK analyses may be performed.  
A complete description of the PK statistical analyses to be performed will be presented in the 
SAP.  
13.6 Accounting for Multiplicity 
To maintain the overall significance level of 0.05 for this study, a hierarchical test procedure 
is applied, where the results of the interchangeability assessment performed at Stage 2 by the 
PK analysis will be regarded as confirmatory in nature only if the results of the biosimilarity 
assessment at Stage 1 have shown significant results.  By this hierarchical approach, the 
significance level of the PK analysis does not need further adjustments to account for 
multiplicity. 
No adjustments for multiplicity are necessary following the interim analysis because the 
interim analysis will be checking for a stop for futility reasons only.  Further, the PK analysis 
for the interchangeability assessment in Stage 2 is based solely on objective variables 
(plasma concentration data); hence, the introduction of additional bias can be excluded. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 79 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 79 
 
13.7 Safety Analysis 
13.7.1 Adverse Events 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The incidence of TEAEs (events with onset dates on or after the start of the 
study drug) and treatment-related TEAEs will be summarized by system organ class (SOC) 
and preferred term (PT).  Events with missing onset dates will be included as treatment-
emergent.  If a patient experiences more than 1 occurrence of the same AE, the occurrence 
with the greatest severity and the closest association with the study drug will be used in the 
summary tables.  SAEs and AEs that result in treatment discontinuation will be summarized.  
AEs of special interest will be summarized by SOC and PT; categories of AEs of special 
interest include serious infections, malignancies, infusion-related reactions, hepatotoxicity, 
heart failure, and cytopenias.  In addition, CIs will be calculated for the difference in 
incidence of these AEs of special interest to determine the risk difference between the NI-071 
and Remicade-US groups. 
All AEs will be listed by patient, along with information regarding onset, duration, 
relationship and severity to study drug, action taken with study drug, treatment of event, and 
outcome. 
13.7.2 Vital Signs, Weight, Physical Examination, and ECG 
Vital signs and weight will be summarized using descriptive statistics including mean values 
and mean change from baseline values, as well as numbers of patients with values outside 
limits of the normal range at each time point. 
Physical examination results at screening will be listed, and changes from screening values 
will be documented at each time point.  
ECG parameters (heart rate and cardiac intervals) at screening and early discontinuation will 
be listed. 
13.7.3 Clinical Laboratory Parameters 
Clinical laboratory data will be summarized using descriptive statistics including mean 
values and mean change from baseline values, as well as numbers of patients with values 
outside limits of the normal range at each time point. 
13.7.4 Anti-drug Antibodies and Neutralizing Antibodies 
Positive immunogenicity results will be listed.  The incidence of circulating ADAs and the 
incidence of neutralizing antibodies will be summarized, and the titer of ADA will be 
summarized over time by treatment group. 
13.7.5 Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary.  Summary 
tables will be provided for prior medications recorded at screening and concomitant 
medications continued and/or initiated during the study period. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 80 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 80 
 
13.8 Interim Analysis 
This study was designed using a hierarchical approach, where the results of the 
interchangeability assessment (PK analysis) performed at the end of Stage 2 will be regarded 
as confirmatory in nature only if the results of the biosimilarity assessment at the end of 
Stage 1 have shown significant results.  An interim analysis is planned in order to decide if 
the study should continue or be stopped for futility after Stage 1. 
The interim analysis of the primary clinical efficacy endpoint, the ACR20-CRP response 
rate, will be performed after the last patient has completed the last visit in Stage 1, the 
Week 22 visit (the visit of the assessments for the primary efficacy endpoint).  This analysis 
will be performed by an unblinded statistician not otherwise affiliated with the study.  An 
independent data monitoring committee (IDMC) will be established to assess the results and 
determine whether the study should continue or be stopped for futility.  An IDMC charter 
will be prepared to describe the details of the outputs available to the IDMC as well as to 
describe the decision tree for the IDMC meeting. 
13.9 Independent Data Monitoring Committee 
An IDMC will be established by the Sponsor or its designee to evaluate the results of a 
formal interim efficacy analysis.  Members will include experts in RA and biostatistics who 
are not participating in this study and do not have affiliation with the Investigators or the 
Sponsor.  The IDMC can recommend in writing to the Sponsor whether to continue or stop 
the clinical study on the basis of the results of the interim analysis.  The IDMC’s specific 
duties as well as statistical monitoring guidelines and procedures will be fully described in an 
IDMC charter. 
14 STUDY MANAGEMENT 
14.1 Approval and Consent 
14.1.1 Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of 
Title 21 of the US Code of Federal Regulations (CFR), and in compliance with the 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. 
14.1.2 Institutional Review Board/Independent Ethics Committee 
The conduct of the study must be approved the Regulatory Authorities and by an 
appropriately constituted Institutional Review Board (IRB)/ Independent Ethics Committee 
(IEC).  Approval is required for the study protocol, investigational drug brochure, protocol 
amendments, ICFs, and patient information sheets.   
14.1.3 Informed Consent 
For each study patient, written informed consent will be obtained prior to any 
protocol-related activities.  As part of this procedure, the Investigator or one of his/her 
associates must explain orally and in writing the nature, duration, and purpose of the study, 
and the action of the drug in such a manner that the patient is aware of the potential risks, 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 81 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 81 
 
inconveniences, or adverse effects that may occur.  The patient should be informed that 
he/she may withdraw from the study at any time, and the patient will receive all information 
that is required by local regulations and ICH guidelines.  The Investigator will provide the 
Sponsor or its representative with a copy of the IRB/IEC-approved ICF prior to the start of 
the study. 
14.2 Data Handling 
Any data to be recorded directly in the eCRFs (to be considered as source data) will be 
identified at the start of the study.  Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained.  Source data should be recorded contemporaneously with the activities performed. 
Clinical data will be entered on eCRFs for transmission to the Sponsor.  Data on eCRFs 
transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to 
the databases for which no other original or source documentation is maintained.  In such 
cases, the study site should document which eCRFs are subject to direct data entry and 
should have in place procedures to obtain and retain copies of the information submitted by 
direct data entry.  All study forms and records transmitted to the Sponsor must carry only 
coded identifiers such that personally identifying information is not transmitted.  The primary 
method of data transmittal is via the secure, internet-based electronic data capture (EDC) 
system maintained by inVentiv Health.  Access to the EDC system is available to authorized 
users via the study’s Internet web site, where an assigned username and password are 
required for access.  Any changes made to data after collection will be made through the use 
of data clarification forms.  Electronic CRFs will be considered complete when all missing 
and/or incorrect data have been resolved. 
All study data are to be captured in the eCRF with the exception of clinical laboratory, PK, 
and immunogenicity data, which will be provided electronically by the laboratories, and data 
recorded on tablet devices provided to the sites.  Reports received by the site from the central 
laboratory should be printed, retained as source documentation and signed by a medically 
qualified Investigator, indicating which values are considered clinically significant and to be 
reported as AEs.  All data recorded on the tablet devices will be regarded as source data. 
14.3 Source Documents 
Source documents are considered to be all information in original records and certified 
copies of original records of clinical findings, observations, data, or other activities in a 
clinical study necessary for the reconstruction and evaluation of the study. 
14.4 Record Retention 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other 
records transmitted outside the clinical site will be identified by a patient’s identification 
number or coded number.  All study records, source medical records, and code sheets or logs 
linking a patient’s name to an identification number will be kept in a secure location.  Study 
records such as eCRFs may be maintained electronically and require the same security and 
confidentiality as paper.  Clinical information will not be released without written permission 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 82 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 82 
 
of the patient/legal representative, except as specified in the ICF (e.g., necessary for 
monitoring by regulatory authorities or the Sponsor of the clinical study).  The Investigator 
must also comply with all applicable privacy regulations (e.g., US Health Insurance 
Portability Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
The study site (and the Investigator) will retain the essential documents specified in the ICH 
GCP (e.g., source document such as medical records, contract, signed ICF).  Essential 
documents should be retained at the study site for at least 15 years following completion of 
the study, or per regulatory obligations if longer, and thereafter destroyed only after 
agreement with the Sponsor.  However, this is not always applied to those that are not 
preserveable such as blood samples.  In the event of any inconsistency between the above 
mentioned contents and the contract with the study site, the contract shall prevail.  These 
documents should be retained for a longer period, however, if needed by the Sponsor, and the 
specific period and method of retention will be separately discussed between the study site 
and the Sponsor.  The Sponsor should notify the head of the study site in writing when the 
study-related records are no longer needed.  The records should be managed by a responsible 
person appointed by the head of the study site. 
14.5 Monitoring 
The study will be monitored to ensure that it is conducted and documented properly 
according to the protocol, GCP, and all applicable regulatory requirements.  
On-site monitoring visits will be made at appropriate times during the study.  Clinical 
monitors must have direct access to source documentation in order to check the 
completeness, clarity, and consistency of the data recorded in the eCRFs for each patient. 
The Investigator will make available to the clinical monitor source documents and medical 
records necessary to complete eCRFs.  In addition, the Investigator will work closely with 
the clinical monitor and, as needed, provide them appropriate evidence that the conduct of 
the study is being done in accordance with applicable regulations and ICH GCP guidelines.  
14.6 Definition of the End of Trial 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and have completed the study as stated in 
the regulatory application (i.e., clinical trial application) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the clinical 
trial application) by a Member State is not a reason for premature termination but is 
considered a normal conclusion to the study in that Member State. 
End of Trial in all other participating countries is defined as Last Patient Last Visit. 
14.7 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities 
of this study; however, responsibility for the accuracy, completeness, and reliability of the 
study data presented to the Sponsor lies with the Investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure 
that the study is being conducted in compliance with the protocol, standard operating 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 83 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 83 
 
procedures, ICH GCP, and all applicable regulatory requirements.  Audits will be 
independent of and separate from the routine monitoring and quality control functions.  
Quality assurance procedures will be performed at study sites and during data management to 
assure that safety and efficacy data are adequate and well documented.  
14.8 Protocol Amendment and Protocol Deviation  
14.8.1 Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no impact 
on the safety of patients or the conduct of the study will be classed as administrative 
amendments and will be submitted to the IRB/IEC for information only.  The Sponsor will 
ensure that acknowledgement is received and filed.  Amendments that are classed as 
substantial amendments must be submitted to the appropriate Regulatory Authorities and the 
IRBs/IECs for approval. 
14.8.2 Protocol Deviations 
Should a protocol deviation occur, inVentiv Health will inform the Sponsor as soon as 
possible.  Protocol deviations and/or violations and the reasons they occurred will be 
included in the clinical study report.  Reporting of protocol deviations to the IRB/IEC and in 
accordance with applicable Regulatory Authority mandates is an Investigator responsibility.  
Prospective protocol waivers are strictly prohibited. 
14.9 Ethical Considerations 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant US federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the US CFR, the EU Directive 2001/20/EC, all other applicable 
country regulations, and in compliance with ICH GCP guidelines. 
IRBs/IECs will review and approve this protocol and the ICF.  All patients are required to 
give written informed consent prior to participation in the study.   
14.10 Financing and Insurance 
Prior to the study commencing, the Sponsor (or its designee) and the Investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study.  This agreement 
will be documented in a financial agreement that will be signed by the Investigator (or the 
institution signatory) and the Sponsor (or its designee).  
The Investigator is required to have adequate current insurance to cover claims for 
negligence and/or malpractice.  The Sponsor will provide insurance coverage for the clinical 
study as required by national regulations. 
14.11 Publication Policy / Disclosure of Data  
Both the use of data and the publication policy are detailed within the clinical study 
agreement.  Intellectual property rights (and related matters) generated by the Investigator 
and others performing the clinical study will be subject to the terms of a clinical study 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 84 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 84 
 
agreement that will be agreed between the Institution and the Sponsor or their designee.  
With respect to such rights, the Sponsor or its designee will solely own all rights and interests 
in any materials, data, and intellectual property rights developed by Investigators and others 
performing the clinical study described in this protocol, subject to the terms of any such 
agreement.  In order to facilitate such ownership, Investigators will be required to assign all 
such inventions either to their Institution or directly to the Sponsor or its designee, as will be 
set forth in the clinical study agreement. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 85 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 85 
 
15 REFERENCES 
1. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology 
guideline for the treatment of rheumatoid arthritis. Arthritis and Rheum. 
2016;68(1):1-26.  
2. Centers for Disease Control and Prevention website:  Rheumatoid arthritis. Available 
at http://www.cdc.gov/arthritis/basics/rheumatoid.htm  Accessed 03 Feb 2016. 
3. Remicade (US package insert), Horsham, PA:  Janssen Biotech; Oct 2015. 
4. Remicade (EMA European Public Assessment Report [EPAR] Product Information), 
Leiden, The Netherlands:  Janssen Biologics BV; Nov 2015. 
5. NI-071 Investigator’s Brochure, Version 2.0. Nichi-Iko; July 2016. 
6. Guideline on clinical investigation of medicinal products other than NSAIDs for 
treatment of rheumatoid arthritis. EMA CPMP/EWP/556/95 Rev 2. Committee for 
Medicinal Products for Human Use; 20 Mar 2015. 
7. Fransen J and van Riel PL. The disease activity score and the EULAR response 
criteria. Clin Exp Rheumatol. 2005;23(39):S93-S99. 
8. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid Arthritis Classification 
Criteria:  An ACR/EULAR Collaborative Initiative. Arthritis and Rheum. 2010; 
62(9):2569-2581. 
9. Pincus T. The ACR core data set and derivative patient-only indices to assess 
rheumatoid arthritis. Clin Exp Rheumatol. 2005;23(39):S109-113. 
10. Felson DT and LaValley MP. The ACR20 and defining a threshold for response in 
rheumatic diseases:  too much of a good thing. Arthritis Research and Therapy. 
2014;16(101):1-5. 
11. Scott DL, van Riel PL, van Derheijde D, et al. Assessing in disease activity in 
rheumatoid arthritis: The EULAR handbook of standard methods.  EULAR Standing 
Committee for International Clinical Studies, 1993. 
12. Maska L, Anderson J, Michaud K. Measures of functional status and quality of life in 
rheumatoid arthritis. Arthritis Care and Research. 2011;63(S11):S4-S13. 
13. Stanford Patient Education Research Center website: Health assessment questionnaire 
disability scale. Available at: http://patienteducation.stanford.edu/research/haq20.html  
Accessed on 03 Feb 2016. 
14. Hochberg MC, Chang RW, Dwosh I, et al. The ACR 1991 revised criteria for the 
classification of global functional status in rheumatoid arthritis. Arthritis Rheum. 
1992;35(5):498-502. 
15. Centers for Disease Control and Prevention publications page: Latent tuberculosis 
infection: 
a 
guide 
for 
primary 
health 
care 
providers. 
Available 
at 
http://www.cdc.gov/tb/publications/ltbi/treatment.htm.  Accessed 03 Feb 2016. 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 86 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 86 
 
16. Raphael C, Briscoe C, Davies J, et al. Limitations of the New York Heart Association 
functional classification system and self-reported walking distances in chronic heart 
failure. Heart. 2007;93:476-482. 
17. Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report—Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. Ann Emerg Med. 2006;47(4):373-380. 
18. Remsima (EMA European Public Assessment Report). Budapest, Hungary: Celltrion 
Healthcare; 27 Jun 2013. 
19. Ware JE. SF-36 health survey update. Available at: 
http://www.sf-36.org/tools/sf36.shtml.  Accessed 12 Feb 2016. 
20. Matcham F, Scott IC, Rayner L, et al. The impact of rheumatoid arthritis on quality-
of-life assessed using the SF-36:  A systematic review and meta-analysis. Semin 
Arthritis Rheum. 2014;44:123-130. 
21. Van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab 
versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367:508-519. 
22. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or 
infliximab vs placebo in ATTEST:  a phase III, multi-centre, randomised, double-
blind, placebo-controlled study in patients with rheumatoid arthritis and an 
inadequate response to methotrexate. Ann Rheum Dis. 2008;67:1096-1103. 
23. Smolen JS, van der Heijde D, Machold KP, et al. Proposal for a new nomenclature of 
disease-modifying antirheumatic drugs. Ann Rheum Dis. 2014;73:3-5. 
24. Nichi-Iko Clinical Study Report (Data of Period I) for Protocol NI071F1 (Phase III 
Clinical Study of NI-071 in Patients with Rheumatoid Arthritis), Version 1.0, 
04 Sep 2015. 
25. Combest AJ, Wang S, Healey BT, et al. Alternative statistical strategies for biosimilar 
drug development. GaBI Journal. 2014;3(1):13-20. 
26. Ogata A, Tanimura K, Sugimoto T, et al. Phase III study of the efficacy and safety of 
subcutaneous versus intravenous tocilizumab monotherapy in patients with 
rheumatoid arthritis. Arthritis Care and Research. 2014;66(3):344-354. 
27. Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in rheumatoid 
arthritis on the basis of achievement of stable low disease activity with adalimumab 
plus methotrexate or methotrexate alone:  the randomised controlled OPTIMA trial. 
Lancet. 2014;383:321-332. 
28. Yoo DH, Hrycaj P, Miranda P. A randomised, double-blind, parallel-group study to 
demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator 
infliximab when coadministered with methotrexate in patients with active rheumatoid 
arthritis:  the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613-1620. 
29. Pincus T, Strand V, Koch G, et al. An index of the three core data set patient 
questionnaire measures distinguishes efficacy of active treatment from placebo as 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 87 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 87 
 
effectively as the American College of Rheumatology 20% response criteria (ACR20) 
or the disease activity score (DAS) in a rheumatoid arthritis clinical trial. Arthritis 
Rheum. 2003;48:625-630. 
30. Pincus T, Chung C, Segurado OG, et al. An index of patient self-reported outcomes 
(PRO index) discriminates effectively between active and control treatment in 
4 clinical 
trials 
of 
adalimumab 
in 
rheumatoid 
arthritis. 
J 
Rheumatol. 
2006;33:2146-2152. 
31. Pincus T, Bergman MJ, Yazici Y, et al. An index of only patient-reported outcome 
measures, routine assessment of patient index data 3 (RAPID3), in two abatacept 
clinical trials: similar results to disease activity score (DAS28) and other RAPID 
indices that include physician-reported measures. Rheumatology. 2008;47:345–349. 
32. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity 
measures:  American College of Rheumatology recommendations for use in clinical 
practice. Arthritis Care and Research. 2012;64(5):640-647. 
33. Pincus T, Swearingen CJ, Bergman MJ, et al. RAPID3 (routine assessment of patient 
index data 3), a rheumatoid arthritis index without formal joint counts for routine 
care:  proposed severity categories compared to DAS and CDAI categories. 
J Rheumatol. 2008;35:2136-2147. 
34. Pincus T, Yazici Y, Bergman MJ. RAPID3, an index to assess and monitor patients 
with rheumatoid arthritis without formal joint counts: similar results to DAS28 and 
CDAI in clinical trials and clinical care. Rheum Dis Clin N Am. 2009;35:773-778. 
35. RAPID3 sample forms, 
Available at http://www.rheumatology.org/Practice-
Quality/Clinical-Support/Quality-Measurement/Disease-Activity-Functional-Status-
Assessments Accessed on 17 June 2016. 
36. Burckhardt CS and Jones KD. Adult measures of pain. Arthritis Care and Research. 
2003;49(5S):S96-S104. 
37. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European 
League Against Rheumatism Provisional Definition of Remission in Rheumatoid 
Arthritis for Clinical Trials. Ann Rheum Dis. 2011;70:404-413. 
38. Mazurek GH, Jereb J, Vernon A, et al. Updated Guidelines for Using Interferon 
Gamma Release Assays to Detect Mycobacterium tuberculosis Infection—United 
States, 2010. MMWR (Recommendations and Reports) 2010;59(RR-5):1-25. 
 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 88 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 88 
 
16 APPENDICES 
 
 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 89 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 89 
 
Appendix 1:  American College of Rheumatology Revised Criteria for the Classification 
of Functional Status in Rheumatoid Arthritis 
 
Class I 
Completely able to perform usual activities of daily living (self-care, 
vocational, and avocational)a 
Class II 
Able to perform usual self-care and vocational activities, but limited in 
avocational activities 
Class III 
Able to perform usual self-care activities, but limited in vocational and 
avocational activities 
Class IV 
Limited ability to perform usual self-care, vocational, and avocational 
activities 
aUsual self-care activities include dressing, feeding, bathing, grooming, and toileting.  Avocational 
(recreational and/or leisure) and vocational (work, school, homemaking) activities are patient-desired 
and age- and sex-specific. 
Source:  Hochberg MC, Chang RW, Dwosh I, et al.14 
 
 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 90 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 90 
 
Appendix 2:  Prohibited DMARDs 
Treatment with DMARDs (other than MTX), including traditional non-biologic drugs, 
biologic drugs, and protein kinase inhibitors, is prohibited during the study and within a 
period prior to screening (a washout period) appropriate to the pharmacodynamic profile of 
the specific drug.  The following table is a list of these prohibited drugs and the appropriate 
washout periods.23 
Traditional Non-biologic DMARDs Prohibited during the Study 
Drug 
Washout Period Prior to Screening 
Azathioprine 
4 weeks 
Chlorambucil 
12 weeks 
Chloroquine 
4 weeks 
Cyclosporine 
8 weeks 
Gold (oral or injectable) 
6 months 
Hydroxychloroquine 
4 weeks 
Leflunomide 
12 weeks or 4 weeks with 11 days standard 
cholestyramine washout 
Mycophenolate mofetil 
12 weeks 
Penicillamine 
6 months 
Sulfasalazine 
4 weeks 
Tacrolimus 
12 weeks 
Marketed Biologic DMARDs Prohibited during the Study 
Drug 
Target 
Washout Period Prior to Screening 
Abatacept 
CTLA-4 
12 weeks 
Adalimumab 
TNF-α 
12 weeks 
Anakinra 
IL-1 
1 month 
Certolizumab pegol 
TNF-α 
12 weeks 
Etanercept 
TNF-α 
4 weeks 
Golimumab 
TNF-α 
12 weeks 
Infliximab 
TNF-α 
no prior use allowed 
Rituximab 
CD20 
12 months 
Tocilizumab 
IL6 
12 weeks 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 91 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 91 
 
Marketed Protein Kinase Inhibitors 
Drug 
Target 
Washout Period Prior to Screening 
Tofacitinib 
PKI 
12 weeks 
 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 92 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 92 
 
Appendix 3:  Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is defined as a serious allergic reaction that is rapid in onset and may cause 
death.  The following criteria were outlined by Sampson et al from the Second Symposium 
on the Definition and Management of Anaphylaxis (a 2005 meeting of the National Institute 
of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network).17  
Anaphylaxis is highly likely when any 1 of the following 3 criteria are met: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) AND at least 1 of the following: 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia) 
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia) 
c. Reduced BP or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a. Infants and children:  low systolic BP (age-specific) or greater than 30% 
decrease in systolic BP.  Low systolic BP for children is defined as less than 
70 mmHg from 1 month to 1 year, less than (70 mmHg + [2 x age]) from 1 to 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 93 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 93 
 
10 years, and less than 90 mmHg from 11 to 17 years. 
b. Adults:  systolic BP of less than 90 mmHg or greater than 30% decrease from 
that person’s baseline 
 
 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 94 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 94 
 
Appendix 4:  TB Screening Information 
Immunosuppressant biologic treatments have been shown to increase the risk of TB infection 
or to cause conversion from latent to active TB in some circumstances.  Because of this, and 
in accordance with the approved prescribing instructions for Remicade, patients must be 
screened for active or latent TB prior to entry into this study.  
Definitions 
Active TB is a disease caused by M. tuberculosis in any part of the body and that is in an 
active state as determined by either a smear or culture taken from any source in the person’s 
body which tests positive for TB or by radiographic evidence.  Individuals with active TB are 
symptomatic, depending upon the location of the disease (most commonly in the lungs but 
also possibly in the brain, kidneys, spine, or elsewhere), and can spread the infection to 
others.  
Latent TB is said to exist when an individual is infected with M. tuberculosis, as evidenced 
by a positive Interferon Gamma Release Assay (IGRA), such as QuantiFERON-TB Gold, or 
by a positive purified protein derivative (PPD) skin test, but is asymptomatic and has no 
evidence of active infection on screening pathology or radiographic tests.  Such individuals 
do not pass the disease to others and should commence a course of prophylactic 
antimycobacterial treatment to eliminate the infection at least 4 weeks prior to randomization 
(or longer, if local guidelines specify) and commit to completing the course of treatment.  
TB Screening 
Ideally, as part of the medical history, the patient should be asked if they have presented with 
active or latent TB in the past and whether they have received a Bacillus Calmette-Guérin 
(BCG) vaccination.  They should also be asked if they have been in contact with any 
individuals known to have active TB, or been placed in any circumstances that may have 
exposed them to an increased risk of TB infection, such as travels to TB endemic regions, 
close contact with persons with active TB, or workplace risk (e.g., prison, hospitals).  
In this study, a patient who tests positive for latent TB (with a positive or indeterminate 
QuantiFERON test, plus a chest x-ray negative for active TB) will be allowed to enroll if 
prior prophylactic treatment was documented or if prophylactic treatment for TB was 
initiated at least 4 weeks prior to baseline (first dose of study drug).  If the result is 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 95 of 96


Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
NI-071 
Final Protocol Version 4.0 
 
09 August 2017 
 
 
 
 
 
         Page 95 
 
indeterminate, the test may first be repeated, or PPD testing may be done if the patient has 
not received a BCG vaccination.  If confirmed indeterminate, the patient should be managed 
as though they have a positive test result or excluded from the study. 
Updated Guidelines for Using IGRA38 
https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm 
 
_
_
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 96 of 96

SAP_001.pdf: 
16.1.9 
Documentation of Statistical Methods 
The document listed below is provided in this section. 
Statistical Analysis Plan (NI071F2) Version 5.0 dated 27 June 2019 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 1 of 47






STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
CONFIDENTIAL 
Final 5.0: 2019-Jun-27 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 1 
1.
INTRODUCTION............................................................................................................................. 3
2.
STUDY OBJECTIVES ..................................................................................................................... 5
2.1 
Study Objectives .............................................................................................................................. 5 
2.1.1 
Stage 1 (Biosimilarity Stage) Objectives ............................................................................. 5 
2.1.2 
Stage 2 (Interchangeability Stage) Objectives ..................................................................... 5 
2.1.3 
Stage 3 (Safety Follow-up Stage) Objective ........................................................................ 5 
3.
STUDY DESIGN .............................................................................................................................. 5
4.
ANALYSIS POPULATIONS ........................................................................................................... 8
4.1 
Intent-To-Treat Population .............................................................................................................. 8 
4.2 
Safety Population ............................................................................................................................. 8 
4.3 
Full Analysis Set .............................................................................................................................. 8 
4.4 
Per-Protocol Population ................................................................................................................... 8 
4.5 
Pharmacokinetic Set ........................................................................................................................ 8 
5.
STUDY ENDPOINTS ...................................................................................................................... 9
5.1 
Clinical Efficacy Endpoints ............................................................................................................. 9 
5.2 
Pharmacokinetic Endpoints ............................................................................................................. 9 
5.3 
Safety Endpoints .............................................................................................................................. 9 
6.
DEFINITIONS AND DERIVED VARIABLES ............................................................................. 10
6.1 
ACR20/50/70 ................................................................................................................................. 10 
6.2 
DAS28 ........................................................................................................................................... 10 
7.
STATISTICAL METHODOLOGY................................................................................................ 11
7.1 
Statistical and Analytical Issues .................................................................................................... 11 
7.1.1 
Statistical Methods............................................................................................................. 11 
7.1.2 
Handling of Dropouts and Missing Data ........................................................................... 12 
7.1.3 
Pooling of Investigative Sites ............................................................................................ 15 
7.1.4 
Determination of Sample Size ........................................................................................... 15 
7.1.5 
Adjustment for Multiplicity ............................................................................................... 17 
7.2 
Patient Characteristics ................................................................................................................... 17 
7.2.1 
Patient Disposition ............................................................................................................. 17 
7.2.2 
Protocol Deviations ........................................................................................................... 18 
7.2.3 
Background and Demographic Characteristics .................................................................. 18 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 4 of 47


 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
7.2.4 
Treatment Exposure and Compliance ................................................................................ 19 
7.2.5 
Prior and Concomitant Medications and Therapies ........................................................... 19 
7.2.6 
Medical Histories ............................................................................................................... 19 
7.3 
Efficacy Analysis ........................................................................................................................... 19 
7.3.1 
Primary Efficacy Analysis ................................................................................................. 19 
7.3.2 
Secondary Efficacy Analysis ............................................................................................. 20 
7.3.3 
Subgroup Analysis of Efficacy Endpoints ......................................................................... 23 
7.3.4 
Sensitivity Analysis of Efficacy Endpoints ....................................................................... 24 
7.4 
Safety Analysis .............................................................................................................................. 27 
7.4.1 
Adverse Events .................................................................................................................. 27 
7.4.2 
Physical Examination ........................................................................................................ 28 
7.4.3 
Vital Signs and Body Weight ............................................................................................ 28 
7.4.4 
Screening Tests .................................................................................................................. 28 
7.4.5 
Electrocardiogram.............................................................................................................. 29 
7.4.6 
Laboratory Parameters ....................................................................................................... 29 
7.5 
Anti-drug Antibodies and Neutralizing Antibodies ....................................................................... 31 
7.6 
PK/PD Analysis ............................................................................................................................. 31 
7.6.1 
Handling of the BLQ and the No Reportable Concentration Values ................................. 31 
7.6.2 
Handling of the Difference between the Scheduled and the Actual Sampling Times ....... 31 
7.6.3 
Pharmacokinetic Parameters .............................................................................................. 31 
7.6.4 
Statistical Analyses ............................................................................................................ 32 
7.7 
Analysis of Other Assessments ..................................................................................................... 32 
7.8 
Interim Analysis ............................................................................................................................ 33 
7.9 
Data Monitoring Committee .......................................................................................................... 33 
7.10 
Changes to Methods Planned in the Protocol ............................................................................ 33 
8. 
TABLES, LISTINGS, AND FIGURES .......................................................................................... 34 
8.1 
Preparation of Tables ..................................................................................................................... 34 
8.2 
Preparation of Data Listings .......................................................................................................... 34 
9. 
REFERENCES ................................................................................................................................ 35 
10. 
APPENDICES ................................................................................................................................ 37 
 
 
 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 5 of 47


 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 1 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ACPA 
Anti-citrullinated protein antibody 
ACR 
American College of Rheumatology 
ACR20 (50, 70)-
CRP 
20% (50%, 70%) improvement from baseline in the ACR core set 
criteria using C-reactive protein as the acute-phase reactant 
ACR20 (50, 70)-
ESR 
20% (50%, 70%) improvement from baseline in the ACR core set 
criteria using erythrocyte sedimentation rate as the acute-phase 
reactant 
AE 
Adverse event 
Anti-dsDNA 
Anti-double-stranded deoxyribonucleic acid 
ANCOVA 
Analysis of co-variance 
ANOVA 
Analysis of variance 
AUC 
Area under the concentration-time curve 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
DAS28-CRP 
Disease activity score based on 28 joints calculated with CRP value 
DAS28-ESR 
Disease activity score based on 28 joints calculated with ESR value 
DMARD 
Disease-modifying anti-rheumatic drug 
DNA 
Deoxyribonucleic acid 
ESR 
Erythrocyte sedimentation rate 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
HbA1c 
Glycated hemoglobin 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV Ab 
Hepatitis C antibody 
HIV Ab 
Human immunodeficiency virus antibody 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 6 of 47


 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 2 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
ICH 
International Conference on Harmonization 
IDMC 
Independent data monitoring committee 
ITT 
Intent-to-treat 
NRI 
Non-responder imputation 
LOCF 
Last observation carried forward 
MDHAQ 
Multidimensional health assessment questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTX 
Methotrexate 
NRI 
Non-responder imputation 
PK 
Pharmacokinetic 
PP 
Per protocol 
PT 
Preferred term 
RA 
Rheumatoid arthritis 
RAPID3 
Routine assessment of patient index data 3 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error 
SF-36 
Medical Outcomes Study 36-Item Short-Form Health Survey 
SOC 
System organ class 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
tmax 
Time at maximum concentration 
TNF-α 
Tumor necrosis factor alpha 
TOST 
Two 1-sided test analysis 
US 
United States 
VAS 
Visual analog scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 7 of 47


 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 3 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
1. INTRODUCTION 
Rheumatoid arthritis (RA), the most common autoimmune inflammatory arthritis in 
adults, is characterized by the persistent and progressive inflammation of multiple 
synovial membranes, causing symptoms of joint pain, swelling, stiffness, and redness, 
and often ultimately leading to the erosion and destruction of cartilage and bone. RA 
causes increasing disability and decreases patients’ ability to perform daily activities, thus 
reducing their economic and social quality of life. RA is associated with increased 
mortality and comorbidities (most commonly, cardiovascular disease, infections, mental 
health conditions, and malignancies). There is no cure, but effective treatments are 
increasingly available to treat RA. In patients with early RA, treatment usually starts with 
non-biologic disease-modifying antirheumatic drugs (DMARDs) that help reduce disease 
activity and prevent joint deformity. Over time as the disease activity increases, 
combination treatment with non-biologic and biologic DMARDs are introduced.1,2 
Biologic therapies are designed to modify or regulate specific mechanisms involved in 
the proinflammatory cytokine overproduction that plays a key role in inflammatory 
diseases. Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine that is 
involved in normal inflammatory and immune response, but overexpressed TNF-α has 
been implicated in the pathogenesis of RA and other immunological diseases. Elevated 
TNF-α levels have been found in the joints of RA patients and correlate with elevated 
disease activity; elevated levels are also found in patients with Crohn’s disease, ulcerative 
colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.3,4 
Remicade® (infliximab), one of the biologics used to treat RA, is a chimeric human-
murine IgG1 monoclonal antibody specific for human TNF-α produced in murine 
hybridoma cells by recombinant deoxyribonucleic acid (DNA) technology. Infliximab 
neutralizes the biological activity of TNF-α by binding with high affinity to the soluble 
and transmembrane forms of TNF-α and inhibits binding of TNF-α with its receptors. 
Infliximab inhibits the functional activity of TNF-α in a wide variety of in vitro 
bioassays. Also, infliximab prevented disease in transgenic mice that develop 
polyarthritis as a result of constitutive expression of human TNF-α and when 
administered after disease onset, it allowed eroded joints to heal. In vivo, infliximab 
rapidly forms stable complexes with human TNF-α, a process that parallels the loss of 
TNF-α bioactivity. In RA, treatment with infliximab reduced infiltration of inflammatory 
cells into inflamed areas of the joint as well as expression of molecules mediating cellular 
adhesion, chemo-attraction, and tissue degradation. Also after infliximab treatment, 
patients exhibited decreased levels of serum interleukin 6 and C-reactive protein 
(CRP).3,4 
Remicade is approved for use in the United States (US) for the treatment of adult patients 
with moderately to severely active RA, in combination with methotrexate (MTX), for 
reducing signs and symptoms, inhibiting the progression of structural damage, and 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 8 of 47


 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 4 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
improving physical function. In addition, Remicade is approved for the treatment of the 
following other indications in the US:3 
• Adult Crohn’s Disease (indicated for reducing signs and symptoms and inducing 
and maintaining clinical remission in adult patients with moderately to severely 
active disease who have had an inadequate response to conventional therapy and 
for reducing the number of draining enterocutaneous and rectovaginal fistulas and 
maintaining fistula closure in adult patients with fistulizing disease) 
• Pediatric Crohn’s Disease (indicated for reducing signs and symptoms and 
inducing and maintaining clinical remission in pediatric patients with moderately 
to severely active disease who have had an inadequate response to conventional 
therapy)  
• Adult Ulcerative Colitis (indicated for reducing signs and symptoms, inducing 
and maintaining clinical remission and mucosal healing, and eliminating 
corticosteroid use in adult patients with moderately to severely active disease who 
have had an inadequate response to conventional therapy) 
• Pediatric Ulcerative Colitis (indicated for reducing signs and symptoms and 
inducing and maintaining clinical remission in pediatric patients with moderately 
to severely active disease who have had an inadequate response to conventional 
therapy) 
• Ankylosing Spondylitis (indicated for reducing signs and symptoms in patients 
with active disease) 
• Psoriatic Arthritis (indicated for reducing signs and symptoms of active arthritis, 
inhibiting the progression of structural damage, and improving physical function) 
• Plaque Psoriasis (indicated for treatment of adult patients with chronic severe 
[i.e., extensive and/or disabling] plaque psoriasis who are candidates for systemic 
therapy and when other systemic therapies are medically less appropriate) 
Nichi-Iko Pharmaceutical Co., Ltd., (the Sponsor) is developing NI-071, a biosimilar of 
Remicade containing the active substance infliximab. The indications for NI-071 are 
proposed to be the same as currently approved for US-licensed Remicade, and the dosage 
forms, route of administration, and dosing regimens for NI-071 are to be the same as for 
Remicade for each indication.5 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 9 of 47


 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 5 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
2. STUDY OBJECTIVES 
2.1 Study Objectives 
2.1.1 Stage 1 (Biosimilarity Stage) Objectives 
Primary: 
• To investigate the biosimilarity of NI-071 (infliximab biosimilar) and US-licensed 
Remicade (infliximab) in terms of efficacy in patients with RA not adequately 
responding to MTX, by determining the percentages of patients achieving 
ACR20-CRP (a 20% improvement from baseline in the American College of 
Rheumatology [ACR] core set criteria using CRP as the acute-phase reactant) 
Secondary: 
• To evaluate safety and immunogenicity of NI-071 and Remicade-US 
• To evaluate efficacy based on other rates of improvement in the ACR criteria, on 
the DAS28 (disease activity score involving 28 joints), and the RAPID3 (routine 
assessment of patient index data 3), and on changes in health-related quality of 
life 
2.1.2 Stage 2 (Interchangeability Stage) Objectives 
Primary: 
• To investigate the interchangeability between NI-071 and Remicade-US by 
evaluating key pharmacokinetic (PK) parameters in each treatment group 
following treatment switches 
Secondary: 
• To evaluate the safety, efficacy, and immunogenicity of NI-071 and Remicade-
US 
2.1.3 Stage 3 (Safety Follow-up Stage) Objective 
Primary: 
• To evaluate the safety of long-term treatment (follow-up through Week 62) 
3. STUDY DESIGN  
This Phase 3, randomized, double-blind, multicenter, biosimilarity, interchangeability, 
and safety study is designed to evaluate NI-071 versus Remicade-US for the treatment of 
patients with RA. Following a screening period, there will be 3 stages:  the biosimilarity 
stage (Stage 1), the interchangeability stage (Stage 2), and the safety follow-up stage 
(Stage 3). A schematic of the study design is provided in Figure 1. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 10 of 47


 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 6 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
The screening period, approximately 4 weeks long for each patient, will be used to assess 
eligibility. At baseline (Week 0), approximately 585 patients who are eligible will be 
randomized in a 2:1 ratio to the Remicade-US and NI-071 groups, respectively. This 
initial randomization will be stratified by CRP level (≤2, >2 mg/dL). During Stage 1, 
patients will receive their randomized treatment at Weeks 0, 2, 6, and 14. Primary 
biosimilarity efficacy assessments (specifically ACR20-CRP) will be performed at 
Week 22. 
During Stage 2, at Week 22, patients in the original Remicade-US group are re-
randomized (1:1) to a Remicade-US group and a Switch group. The Switch group will 
receive NI-071 at Week 22, Remicade-US at Week 30, and NI-071 at Weeks 38, 46, and 
54; the Remicade-US group will continue to receive Remicade-US from Week 22 
through Week 54 every 8 weeks. The original NI-071 group will continue to receive NI-
071 from Week 22 through Week 54 every 8 weeks. To evaluate interchangeability, a full 
PK similarity analysis (specifically AUCtau and Cmax) will be performed for all treatment 
groups from samples drawn at 11 time points from pre-dose Week 46 to pre-dose Week 
54. During Stage 3, the last dose of study treatment will be given at Week 54, and 
patients will return for 2 additional safety follow-up visits through Week 62. 
Efficacy and safety evaluations, including assessments of ADAs, will be performed 
throughout the study. In addition, samples for determining trough concentrations will be 
collected prior to each infusion in the study and at the end of the study. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 11 of 47


 
 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 7 
 
 
CONFIDENTIAL 
 
 
 
Final 5.0: 2019-Jun-27 
 
Figure 1 NI071F2 Study Design 
 
___________________________
___________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 12 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 8 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
4. ANALYSIS POPULATIONS 
4.1 Intent-To-Treat Population 
The intent-to-treat (ITT) population will include all patients who are randomized, 
irrespective of any deviation from the protocol or premature discontinuation. Patients will 
be analyzed according to the treatment group assigned at the Stage 1 randomization. The 
ITT population will serve as the basis for the primary efficacy analysis in Stage 1. 
4.2 Safety Population 
The safety population will include all ITT patients who receive at least 1 dose of study 
drug. Patients will be analyzed according to the actual treatment they receive rather than 
as randomized. This population will be used for the analysis of safety.  
4.3 Full Analysis Set 
The full analysis set (FAS) will include all patients in the safety population with at least 
1 post-baseline ACR20 efficacy assessment. Patients will be analyzed according to the 
treatment group assigned at the most recent randomization. This population will be used 
for the secondary efficacy analyses, as well as a sensitivity analysis for the primary 
efficacy endpoint.  
4.4 Per-Protocol Population 
The per-protocol (PP) population will include all patients in the FAS with no major 
protocol deviations in Stage 1 that have an impact on the primary efficacy endpoint, ie, 
ACR20-CRP response at Week 22, and sufficient time in study. Sufficient time will be 
defined as having at least the Week 22 ACR20-CRP efficacy assessment and all study 
drug administrations up to and including the Week 14 study drug administration. Since 
this population excludes patients with such major protocol deviations as defined above, 
patients will be analyzed according to the treatment they were randomized to and 
received during Stage 1. This population will be used for a sensitivity analysis of the 
primary efficacy analysis. 
4.5 Pharmacokinetic Set  
The PK population will include all patients in the FAS population in Stage 1 who have 
valid PK assessments through Stage 2. This includes only patients who have received all 
and complete treatments required per protocol through Stage 2. This population will be 
used for the analysis of interchangeability in Stage 2. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 13 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 9 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
5. STUDY ENDPOINTS 
5.1 Clinical Efficacy Endpoints 
Primary: 
• ACR20-CRP at Week 22 
Secondary: 
• Change from baseline in DAS28-CRP and DAS28-ESR scores (DAS28 scores 
calculated with CRP and erythrocyte sedimentation rate (ESR) values, 
respectively) 
• ACR20-CRP (at time points other than Week 22), ACR20-ESR, ACR50-CRP, 
ACR50-ESR, ACR70-CRP, and ACR70-ESR 
• Change from baseline in each item of the ACR core set 
• Change from baseline in RAPID3 scores 
• Change from baseline in the Medical Outcomes Study 36-Item Short-Form Health 
Survey (SF-36) domain subscores and summary scores 
5.2 Pharmacokinetic Endpoints 
Primary: 
• AUCtau and Cmax during the dosing interval of Weeks 46 to 54 
Secondary: 
• Minimum concentration (Cmin) and time at maximum concentration (tmax) during 
the dosing interval of Weeks 46 to 54 
5.3 Safety Endpoints 
The safety endpoints of this study are as follows: 
• Incidence of TEAEs and serious AEs (SAEs) 
• Incidence and risk difference between treatment groups of AEs of special interest, 
including 
serious 
infections, 
malignancies, 
infusion-related 
reactions, 
hepatotoxicity, heart failure, and cytopenias 
• Incidence of ADAs and neutralizing antibodies 
• Clinically significant changes in laboratory values, vital signs, weight, ECG, and 
physical examination results 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 14 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 10 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
6. DEFINITIONS AND DERIVED VARIABLES 
Derivation of visit windows can be found in Appendix A. Other definitions of derived 
variables not listed below can be found in applicable subsections of the statistical 
methodology section (Section 7) of this document. 
6.1 ACR20/50/70 
ACR20 will be defined as a dichotomous variable, for which a patient is defined as either 
a responder or a non-responder. Patients will be defined as a responder if all of the 
following criteria are met: 
• A 20% improvement from baseline in the tender/painful joint count. 
• A 20% improvement from baseline in the swollen joint count. 
• A 20% improvement from baseline in at least 3 of the following 5 variables: 
o Patient global assessment of disease activity (VAS) 
o Physician global assessment of disease activity (VAS) 
o Patient pain assessment (VAS) 
o HAQ-DI 
o CRP when calculating ACR20-CRP, or ESR when calculating ACR20-
ESR 
ACR50 and ACR70 are similarly defined, except 50% and 70% improvement is required, 
respectively. 
6.2 DAS28 
DAS28-CRP and DAS-ESR will be defined as a continuous variable based on 28-count 
subsets of tender/painful joints and swollen joints, together with either CRP or ESR, 
respectively. These variables will be calculated as follows: 
• If the patient global assessment of disease activity on the 100 mm VAS is not 
missing at the visit, then the following calculations are used: 
o DAS28(ESR) = (0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR) + 
0.014*GH 
o DAS28(CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) 
+ 0.014*GH + 0.96 
• If the patient global assessment of disease activity on the 100 mm VAS is missing 
at the visit, then the following calculations are used: 
o DAS28(ESR) = [0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 
0.70*ln(ESR)]*1.08 + 0.16 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 15 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 11 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
o DAS28(CRP) = [0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 
0.36*ln(CRP+1)] * 1.10 + 1.15, 
where TJC28 is number of painful joints out of 28 joints, SJC28 is number of swollen 
joints out of 28 joints, GH is the score of the patient global assessment of disease activity, 
ln is the natural logarithm, ESR is in mm/first hour, and CRP is in mg/L. 
7. STATISTICAL METHODOLOGY 
7.1 Statistical and Analytical Issues 
7.1.1 Statistical Methods 
The statistical evaluation will be performed using the Statistical Analysis Software 
(SAS®) Version 9.3 or higher (SAS Institute, Cary, NC). For all inferential analyses and 
all modeling type analyses, original SAS outputs will be provided to be included as 
appendices to the CSR. 
All data will be listed, and summary tables will be provided. The data listings will be 
sorted by treatment group, site number, patient screening number and visit. Any data 
collected on patients who were screened but subsequently not randomized will be 
presented within a non-randomized group. 
Baseline is generally defined as the last assessment taken prior to treatment. This 
typically occurs at the baseline visit. If the value from the baseline visit is missing for any 
given parameter, values from the screening visits (or any unscheduled visits that occurred 
later, but still before the first administration of study medication) will be applied as 
baseline. In no case, will baseline be imputed with assessments performed after the first 
application of study medication. If no pre-treatment assessments are available, baseline 
will be missing. 
As shown in Figure 1, the treatment groups according to study stages are as follows: 
2 treatment groups in Stage 1 (i.e., the Remicade-US and NI-071 groups), 3 treatment 
groups in Stage 2 (the NI-071 group, continuing to receive NI-071; the Remicade-US 
group, continuing to receive Remicade-US; and the Switch group, receiving NI-071 at 
Week 22, Remicade-US at Week 30, and NI-071 at Weeks 38 and 46); and the same 3 
treatment groups in Stage 3 (the NI-071 group, the Remicade-US group, and the Switch 
group [receiving NI-071 at Week 54]).  
The treatment group labels for all tables, figures and listings will be: NI-071, Remicade-
US, Switch, or Overall. 
Data will be summarized by treatment group; a total/overall column will be included to 
summarize all patients, where appropriate. Also, data will be summarized by visit, where 
appropriate.  
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 16 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 12 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
P-values will be rounded to 4 decimal places. P-values less than 0.0001 will be reported 
as “<0.0001” in tables. Unless otherwise specified, two-sided statistical tests will be 
performed with a significance level of 0.05, and one-sided tests will be performed with a 
significance level of 0.025.  
Categorical variables will be summarized using frequencies and percentages. Percentages 
will be presented to 1 decimal place. In cases where the percentage calculated is >0% and 
<0.1%, “<0.1%” will be presented. Percentage of 100% will be displayed without a 
decimal place, zero-incidences (i.e., where n=0) will not show a percentage value. 
Continuous variables will be summarized using descriptive statistics (number of patients 
with an observation [n], mean, standard deviation [SD], median, minimum [min] and 
maximum [max]) where n ≥2. Unless otherwise specified, the mean, SD, and median for 
a continuous variable will be presented with 1 more decimal place than the original (raw) 
values. The min and max will be presented with the same number of decimal places as 
the original values. 
7.1.2 Handling of Dropouts and Missing Data 
Patients who drop out will not be replaced in this study. 
As a general rule, unless specified otherwise, missing data for efficacy and safety 
assessments will not be imputed, assuming that these values are missing at random. 
Furthermore, all available data collected from patients who drop out of the study or 
discontinue study drug treatment will be included in the analyses. 
7.1.2.1 ACR20, ACR50, and ACR70 
Because the ACR20, ACR50, and ACR70 variables (determined with either CRP or 
ESR) are based on several component variables (the ACR core set criteria), it is possible 
that the values may still be calculated even if the component variables have some missing 
values. In this case, no imputation method is needed. If the ACR responder status still 
cannot be determined with the available visit specific data, an imputation method will be 
applied, except for the ACR20-CRP analyses done at Week 22 (the primary endpoint). 
If the ACR responder status is missing due to some missing (but not all) ACR core set 
criteria values, the method of last observation carried forward (LOCF) will be used to 
carry forward any of the individually missing component values, and from that mix of 
actual and carried-forward values, the ACR responder status will be determined. 
This type of LOCF method will be known as “LOCF mixed components,” since it is 
based on determining the ACR responder status with a mixture of values at the visit and 
values carried forward from previous visits.  
After the LOCF imputation has been applied, missing values due to a patient dropping 
from the study for any reason will be handled by setting the ACR responder status 
(ACR20, ACR50, and ACR70) to nonresponsive for future visits onward. For the 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 17 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 13 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
primary analysis performed, a patient who stays in the study but discontinues study drug 
treatment on or before Week 14 will also be regarded as nonresponsive. Note that this 
method also goes by the name non-responder imputation, NRI. NRI is the term to be used 
in the study report. 
If for some reason the ACR responder status still cannot be determined, including the 
case where baseline data is missing, then its value will be set to non-responder. 
Of note, the ACR responder status is aligned to a specific study week (defined in 
Appendix A); although the individual components might be assessed on different 
individual days, as long as the assessments are assigned to the specific visit/week, the 
ACR responder status will be determined with all assessments at that visit/week and for 
that specific visit/week. 
7.1.2.2 DAS28 
The DAS28-CRP and DAS28-ESR endpoints are calculated from several components 
(Section 6.2). As with ACR20/50/70, the DAS28 endpoints can be calculated even when 
one of the components is missing, specifically when the patient’s global assessment is 
missing. If more than the patient’s global assessment is missing, then the LOCF mixed 
component method will be used to calculate the endpoints. DAS28 scores that cannot be 
calculated from the LOCF mixed component method will not be imputed, but rather they 
will be set to missing; it is assumed that these values are missing at random. 
Of note, the DAS28 is aligned to a specific study week; although the individual 
components might be assessed on different individual days, as long as the assessments 
are assigned to the specific visit/week, the DAS28 will be calculated with all assessments 
at that visit/week and for that specific visit/week. 
7.1.2.3 HAQ-DI and SF-36 
The Health Assessment Questionnaire-Disability Index (HAQ-DI) and SF-36 endpoints 
are calculated from validated questionnaires. Each endpoint has a unique scoring method. 
The methods that will be employed for handling missing data from these assessments are 
intricate and related the unique scoring method for each. The rules for handling the 
missing data related to these questionnaires are presented in Section 7.3.2.4 for HAQ-DI 
and in Section 7.3.2.7 for SF-36. 
7.1.2.4 Tender and Swollen Joint Counts 
Handling of missing/unevaluable joint data is dependent on the reason (missing versus 
unevaluable) and the time point (baseline versus follow-up).  
• If baseline, and the joint is marked as “unevaluable”, then it is NOT counted as 
tender/swollen. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 18 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 14 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
• If follow-up, and the joint was evaluable at baseline, then it IS counted as 
tender/swollen. 
• If follow-up, and the joint was unevaluable at baseline, then it is NOT counted as 
tender/swollen. 
• If follow-up, and the evaluation is missing (not marked as “unevaluable”), then 
the classification of the joint (tender/swollen) will be based on LOCF, except for 
the ACR20-CRP analyses done at Week 22 (the primary endpoint). 
7.1.2.5 Visual Analog Scales 
Patients with missing scores at baseline will not be included in the analysis. Missing 
scores at follow-up will be based on LOCF, except for the ACR20-CRP analyses done at 
Week 22 (the primary endpoint). 
7.1.2.6 Safety 
As stated above, missing data will not be imputed for any safety analyses, except for 
missing AE relationship to study drug, AE severity, and AE seriousness. If AE 
relationship to study drug is missing, the relationship will be imputed to be “related” in 
any pertinent summary tables, severity will be imputed to be “severe”, and seriousness to 
be “serious.” This will be footnoted in the listings.  
7.1.2.7 Missing and Partially Missing Dates 
For any scheduled assessment at a specific study visit/week, if the date is completely 
missing, then the actual visit date (if available) or the target visit date (if actual is 
unavailable) will be used (see Appendix A for target date definitions). If the date is 
partially missing, then the date will be imputed to using the date of the actual visit (if 
available) or target date (if actual is unavailable). If a partial date is given that contradicts 
the actual/target date by specifying a different month/year, the imputed date will be set to 
the closest day to the target visit date including the given information. 
Missing start or end dates for events not aligned to a specific visit/week such as adverse 
events, medications reported, etc., will be imputed using the following rules: 
• A completely missing start date of an event will be set to the date of the first dose 
of study medication, unless it is clearly indicated that this is an event happening 
pretreatment. In this case, it will be set to the day before the first dose of study 
medication. 
• A completely missing stop date will not be imputed, but the event will be 
assumed to be ongoing. 
• Partially missing dates where the year is known will be set to 01 January of that 
year or the first dose of study medication date, if the first dose of study 
medication occurred in that year. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 19 of 47








 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 18 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
Patient disposition information will be tabulated by stage, summarizing the number of 
patients screened, randomized, initiated treatment, completed, and discontinued. Also, 
patient counts in each analysis population will be presented: ITT (Stage 1 only), safety, 
FAS, PP, and PK (Stage 2 only) populations. This disposition summary will be presented 
overall and by region. 
Patient discontinuation information will be presented by stage, summarizing the reasons 
for discontinuation (e.g., AE, patient consent withdrawal). This discontinuation table will 
be presented overall and by region. 
7.2.2 Protocol Deviations 
As specified in the definition of the PP population, individuals with major deviations 
concerning the primary efficacy endpoint ACR20-CRP response at Week 22 will be 
excluded from this analysis set. All decisions regarding major deviations will be 
discussed and finalized during a Blinded Data Review Meeting (BDRM) prior to 
breaking the treatment blind and commencing the final analysis on the locked database. 
Participants of the BDRM will include as a minimum the lead CRA, project manager, 
statistician, data manager, and the study physician. The decisions will be documented in 
the BDRM minutes and signed by the Sponsor and the CRO. 
For the BDRM, a blinded listing of possible protocol deviations (events sorted by patients 
and dates of events) will be created to include descriptions of the possible protocol 
deviation events. At least the following programmatic checks will be made to identify 
individuals deviating from the protocol:  checks for patients not meeting all inclusion 
criteria and for meeting any exclusion criteria, checks on the use of prohibited 
concomitant medications, checks on visit window deviations. Other types of protocol 
deviations that are detected during the course of the study may be added. This listing will 
be reviewed in the BDRM immediately prior to data lock. The listing will be used to 
mark the review committee’s decision of each possible protocol deviation event as a 
major or minor protocol deviation. The BDRM determinations of each event will be used 
by the biostatistician to create population flags for the analysis populations described in 
Section 4.  
A frequency table of the major protocol deviations will be presented by stage for the ITT 
population. In addition, a by-patient listing of all protocol deviations (identified as major 
and minor) will be provided. 
7.2.3 Background and Demographic Characteristics 
Demographic data including age, gender, race, ethnicity, body weight and height, and 
BMI will be listed and summarized descriptively by treatment group and overall using 
the ITT, safety, FAS, PP, and PK populations. 
Other baseline characteristic data such as disease history, medical conditions, HAQ-DI, 
CRP (as continuous and categorized parameters), smoking status, and DAS28 (CRP and 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 23 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 19 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
ESR, as continuous and categorized parameters) will be summarized descriptively using 
the FAS and ITT populations. 
7.2.4 Treatment Exposure and Compliance 
For patients in the ITT population, duration of study treatment exposure (days), the 
number of infusions, and the percent compliance (derived as the number of infusions 
received at applicable study visits divided by the number of applicable study visits) will 
be listed and summarized separately by stage, treatment group, and overall. 
Duration of study treatment exposure (days) will be derived as (date of last infusion) – 
(date of first infusion) + 1. 
In addition, the percent compliance will be categorized (>=120%, 80-120%, 60-<80%, 
40-<60%, 20-<40% and <20%) and summarized with frequency counts and percentages, 
by treatment group and overall. 
7.2.5 Prior and Concomitant Medications and Therapies 
All prescription medications and over-the-counter drugs including vitamins and blood 
transfusions taken prior to the start of and throughout the study will be recorded and 
coded using the WHO Drug Dictionary (WHO-DD) version March 2016. Prior 
medications include medications started before enrollment and stopped prior to the start 
of study treatment. Concomitant medications include medications taken on or after the 
start of study treatment.  
Prior and concomitant medications will be summarized according to the Anatomical 
Therapeutic Chemical (ATC) classification system, and tables of descriptive statistics 
(frequency counts and percentages of patients using these medications) will be provided 
for the ITT population.  
All prior and concomitant medications will be listed by patient. The listing will include 
verbatim descriptions and coded terms, and flags for prior medications.  
7.2.6 Medical Histories 
A listing of medical history will be presented by patient. 
7.3 Efficacy Analysis 
7.3.1 Primary Efficacy Analysis 
The primary efficacy analysis will be performed using the ITT population. The primary 
efficacy endpoint is the ACR20-CRP response at Week 22, and will be calculated as 
described in Section 6.1. Patients with a missing ACR20-CRP assessment at Week 22, as 
well as patients who did not receive all study drug treatments thru Week 14, will be 
considered as having no response (NRI). Because these patients are considered Non-
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 24 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 20 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
responders for this analysis, the primary endpoint is considered a composite of both 
ACR20-CRP response and adherence to study drug treatment. 
To determine biosimiliarity, 2 asymptotic one-sided Wald tests of the difference between 
NI-071 and Remicade-US response rates will be performed. If the null hypotheses of both 
tests are rejected at α = 0.05, the equivalence in efficacy is achieved. The hypotheses that 
will be evaluated are stated, as follows, where PNI-071 is the response rate in the NI-071 
arm and PRemicade  is the response rate in the Remicade-US arm. 
Ho: PNI-071 – PRemicade ≤-12% 
Ho: PNI-071 – PRemicade ≥15% 
Ha: -12% < (PNI-071 – PRemicade) <15% 
The z test statistic for the Wald tests will be calculated as z=(d+margin)/SE(d), where d = 
PNI-071 – PRemicade, and the standard error (SE) of d is calculated as: 
SE(d) = √(PNI-071(1- PNI-071)/n1 + PRemicade(1- PRemicade)/n2) 
7.3.2 Secondary Efficacy Analysis 
The secondary efficacy analysis will be performed using the FAS population. In addition 
to the analyses described in the following subsections, all data will be listed. 
7.3.2.1 ACR20, ACR50, and ACR70 
Response according to ACR20/50/70 will be derived as described in Section 6.1 and 
analyzed as a dichotomous, categorical variable. Of note, ACR20-CRP at Week 22 will 
not be included here, but is analyzed using the same method for a sensitivity analysis 
(described in Section 7.3.4). 
Summary statistics (including frequency count, percentage, and 95% CIs) for these items 
will be presented by visit and treatment group. In addition, these secondary efficacy items 
will be analyzed using a logistic model, with CRP value at baseline (as a continuous 
variable), region, and treatment arm as covariates. From this model, adjusted point 
estimates for response rates and risk ratios will be calculated and presented by visit 
(along with associated 95% CIs for each). These will be presented both in table format 
and a figure. The Hosmer-Lemeshow test will be performed to assess goodness of fit of 
the logistic model; fit will not be considered good if the p-value is rejected at the 5% 
level. 
Histograms will be provided for the above to visualize ACR20/50/70 response over time. 
7.3.2.2 Tender and Swollen Joint Counts 
Counts of tender (ranging 0-68) and swollen (ranging 0-66) joints will be analyzed, using 
continuous and categorical methods. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 25 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 21 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
Summary statistics for these items and change from baseline will be calculated and 
presented by visit and treatment group. In addition, these secondary efficacy items will be 
analyzed using an ANCOVA, with CRP value at baseline (as a continuous variable), 
region, and treatment arm as covariates. From this model, adjusted point estimates of the 
mean count for each treatment group and the difference in mean count between treatment 
groups with associated 95% CIs will be calculated and presented by visit. 
7.3.2.3 Visual Analog Scales 
Three VAS items will be analyzed as continuous variables.  
• Patient global assessment of disease activity VAS (ranging from very well to very 
poor; 0-100) 
• Physician global assessment of disease activity VAS (ranging from none to 
extremely active; 0-100) 
• Patient pain assessment VAS (ranging from no pain to pain as bad as it can be; 
0-100) 
Summary statistics for these scales and change from baseline will be calculated and 
presented by visit and treatment group. In addition, these secondary efficacy items will be 
analyzed using an ANCOVA, with CRP value at baseline (as a continuous variable), 
region, and treatment arm as covariates. From this model, adjusted point estimates of the 
mean score (least squares mean) for each treatment group and the difference in mean 
score between treatment groups with associated 95% CIs will be calculated and presented 
by visit. 
7.3.2.4 Disability measured with the HAQ-DI 
Disability will be analyzed as a continuous variable based on the HAQ-DI which contains 
20 questions that measure the patient’s functional ability on a 4-level difficulty scale (0 to 
3, with 0 representing normal or no difficulty, and 3 representing inability to perform). 
Eight categories of functioning are included: dressing/grooming, arising, eating, walking, 
hygiene, reach, grip, and usual activities. Analysis will be performed for the overall index 
score. 
The score for each of the eight functional categories will be the single response within the 
category with the highest score (greatest difficulty). For example, in the "Walking" 
category, there are 2 component questions (1 for each item). If "Walk outdoors on flat 
ground" is marked as "3" and "Climb up five steps" is marked as "0", then the score for 
the "Walking" category would be "3" (the response indicating the greatest difficulty 
within the category). If a component question is left blank or the response is too 
ambiguous to assign a score, then the score for that category is determined by the 
remaining completed question(s), per HAQ-DI scoring instructions. If responses to all 
component questions are missing, then scores will be based on LOCF.  
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 26 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 22 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
The score for the overall disability index is the mean of the eight category scores. If 2 or 
more of the categories are missing, then the mean score will be based on LOCF. If only 1 
of the categories is missing, then the mean is calculated by dividing the sum of the 
categories by 7 (instead of 8). Higher scores indicate greater disability. 
Summary statistics for the overall disability index and change from baseline will be 
calculated and presented by visit and treatment group. In addition, this secondary efficacy 
item will be analyzed using an ANCOVA, with CRP value at baseline (as a continuous 
variable), region, and treatment arm as covariates. From this model, adjusted point 
estimates of the mean index (least squares means) for each treatment group and the 
difference in mean index between treatment groups with associated 95% CIs will be 
calculated and presented by visit. 
7.3.2.5 DAS28-CRP and DAS28-ESR 
The DAS28 variables will be calculated as described in Section 6.2 and will be analyzed 
using continuous and categorical methods. 
Summary statistics for the DAS28 variables and change from baseline will be presented 
by visit and treatment group. In addition, these secondary efficacy variables will be 
analyzed using an ANCOVA, with CRP value at baseline (as a continuous variable), 
region, and treatment arm as covariates. From this model, adjusted point estimates of the 
mean value (least squares means) for each treatment group and the difference in mean 
value between treatment groups with associated 95% CIs will be calculated and presented 
by visit. 
In addition to providing the continuous-based analysis (above), values will be stratified 
into 4 disease activity categories: minimum (defined as values <2.6), low (defined as ≥2.6 
to <3.2), moderate (defined as values ≥3.2 to ≤5.1), and high (defined as >5.1). A 
frequency with counts and percentages will be presented for each category. These 
analyses will be presented by visit and treatment group. Additionally, shift tables from 
Baseline will be provided by visit and treatment group. 
7.3.2.6 RAPID3 
The RAPID3 score will be calculated by summing responses from the 3 parts:  
multidimensional HAQ (MDHAQ) physical function (range 0–10), pain intensity score 
(range 0–10), and patient global assessment of disease activity score (range 0–10). Thus, 
the range of the RAPID3 score is 0-30, and disease activity categories are as follows:  
remission 0 to 3, low >3.1 to 6, moderate >6.1 to 12, and high >12.  
This variable will be analyzed using continuous and categorical methods. Summary 
statistics for the variable and change from baseline will be presented by visit and 
treatment group. In addition, this secondary efficacy variable will be analyzed using an 
ANCOVA, with CRP value at baseline (as a continuous variable), region, and treatment 
arm as covariates. From this model, adjusted point estimates of the mean values (least 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 27 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 23 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
squares means) for each treatment group and the difference in mean values between 
treatment groups with associated 95% CIs will be calculated and presented by visit. 
In addition to providing the continuous-based analysis (above), values will be stratified 
into 4 disease activity categories (remission, low, moderate, and high). A frequency with 
counts and percentages will be presented for each category. These analyses will be 
presented by visit and treatment group. Additionally, shift tables from Baseline will be 
provided by visit and treatment group. 
7.3.2.7 SF-36 
Patient health-related quality of life will be analyzed as a continuous variable based on 
the SF-36 which contains 36 questions that measure how patients’ physical and 
psychological states affect their lives. Eight quality of life sub-scales are included: 
physical function, role physical, bodily pain, global health, vitality, social function, role 
emotional, and mental health. Analysis will be performed for the overall score, for 
2 higher-order summary scores (i.e., the physical component summary and the mental 
component summary), and for each of the eight sub-scales. Derivation of these scores 
will be done by reverse coding some question responses so that high scores indicate 
better health, summing scores across responses in the same sub-scale (raw scale score), 
and transforming the raw scale scores to a 0-100 scale .12 
Summary statistics for the scores and change from baseline will be presented by visit 
(Weeks 14, 22, 38, and 62) and treatment group. In addition, these secondary efficacy 
variables will be analyzed using an ANCOVA, with CRP value at baseline (as a 
continuous variable), region, and treatment arm as covariates. From this model, adjusted 
point estimates of the mean score for each treatment group and the difference in mean 
value between treatment groups with associated 95%CIs will be calculated and presented 
by visit. Mean changes from baseline by treatment group will also be represented in a bar 
graph or a figure for the overall and sub-scale scores. 
Data from SF-36 questionnaires collected at unscheduled visits will be listed.  
Regarding missing data, if an individual question response is missing, then the response 
will be based on LOCF. After individual LOCF, if more than 20% of the individual 
questions used to derive a sub-scale score are missing, then the sub-scale sore will be 
based on LOCF. If 2 or more of the sub-scale scores are missing, then the overall mean 
score, as well as the 2 higher-order summary scores, will be based on LOCF. 
7.3.3 Subgroup Analysis of Efficacy Endpoints 
Subgroup analyses will be performed for the primary efficacy analysis of ACR20-CRP at 
Week 22. These analyses will be performed using the FAS population. Summary 
statistics (including frequency counts, percentages, and 95% CIs) will be presented by 
treatment group. Furthermore, the difference between treatment groups and 95% CIs for 
the difference will be presented. A forest plot will be provided. For subgroups with more 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 28 of 47




 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 25 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
The first type of sensitivity analysis will be repeating the analysis described in 
Section 7.3.1 in a descriptive manner using the ITT population. However rather than 
applying the non-responder imputation (NRI) for patients who did not receive all 
treatments through Week 14, data actually collected will be used to determine response 
status at Week 22. This sensitivity analysis addresses the composite nature of the primary 
endpoint. 
The second type of sensitivity analysis will be repeating the analysis described in 
Section 7.3.1 in a descriptive manner using the FAS and PP populations, rather than the 
ITT population. For the FAS-based analysis, both types of approaches will be presented, 
i.e., with and without NRI for patients who discontinue study drug on or before Week 14. 
The third type of sensitivity analysis will be repeating the analysis described in 
Section 7.3.1 in a descriptive manner using the ITT, FAS, and PP populations. However,  
rather than not allowing for imputation of missing ACR20 components, the mixed 
component LOCF method for calculating ACR20 response status will be employed. 
The fourth type of sensitivity analysis will be modeling to evaluate if there is any impact 
on the primary analysis from baseline disease status or geographical region, using the 
ITT, FAS, and PP populations. To adjust for any impact due to baseline disease status 
and/or region, a logistic regression model will be used with ACR20-CRP at Week 22 as a 
dependent variable, and treatment group, baseline CRP values, and region as covariates. 
From this model, adjusted point estimates for ACR20-CRP response rates and risk ratio 
will be calculated and presented by visit (along with associated 95% CIs for each). The 
Hosmer-Lemeshow test will be performed to assess goodness of fit. The fit will not be 
considered good if the p-value is rejected at the 5% level. For this analysis, the NRI will 
be applied as done for the primary analysis. 
 
The fifth type of sensitivity analysis will be a tipping point analysis to be performed if the 
primary analysis in the ITT population concludes biosimilarity (i.e., rejection of both 
Wald tests using asymmetric margins -12% and 15%). This analysis will be performed to 
identify the hypothetical response rates required among the patients with missing data in 
order to produce statistics that no longer support similarity (patients who stop treatment 
but continue to be followed and have an efficacy evaluation at Week 22 are not 
considered to have missing data). In the planned primary analysis, a 0% response rate is 
assumed in both treatment groups of all patients randomized with missing data at 
Week 22 (i.e., all patients with missing data are considered non-responders). For the first 
step of this sensitivity analysis, instead of assuming a 0% response rate, the observed 
response rate for the Remicade-US arm in the PP population will be assumed for both 
treatment groups. Using the new Remicade-US response rate assumption, the primary 
analysis will be conducted, and the Wald p-values will be recorded; it is expected that 
this initial step will result in 2 significant p-values to accept the alternative hypothesis 
(i.e., difference within -12% and 15%), consistent with the finding of the primary 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 30 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 26 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
analysis. The second step of this sensitivity analysis will assign non-response status to 
one more NI-071 patient than in the first step. Using this unbalanced response rate, the 
primary analysis will be conducted, and the Wald p-values will be recorded. The 
remaining steps of this sensitivity analysis will iterate as described in the second step 
(each time re-assigning non-response status to one more NI-071 patient, considering the 
patient to be a non-responder rather than a responder). These steps will continue until the 
maximum number of NI-071 patients is achieved, or the Wald test shows non-similarity 
(p >0.05). The maximum number of patients will be defined as the total number of 
missing patients in the NI-071 arm. For each iteration of this sensitivity analysis, the 
following statistics will be presented:  frequency count and response rate percentage by 
treatment arm at Week 22, both overall and by missing-status; Wald p-values; and the 
percent difference in response rates within the original missing subset. Percent difference 
will be calculated as: (response rate in the Remicade-US arm minus response rate in the 
NI-071 arm) divided by the response rate in the Remicade-US arm. An example of 
interpretation of this percentage follows:  if Remicade-US response rate is 79% and NI-
071 response rate is 50% at the tipping point, then it may be stated that if the NI-071 
response was 36.7% lower (i.e., (79-50)/79 = 0.367) than the Remicade-US arm among 
the patients with missing values at Week 22, biosimilarity could not be concluded. Also, 
the difference in response rate between patients with missing data and patients with non-
missing data will be presented for each iteration. 
 
 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 31 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 27 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
The following tabulation summarizes the above mentioned sensitivity analyses: 
 
Description 
Purpose 
Population 
Imputation of 
missing data 
1 
Primary analysis 
(Wald-test) 
Repeat for different population 
/ use of collected data from  
patients who discontinued 
study drug 
ITT 
No NRI for 
patients who 
discontinued 
study drug. 
2 
Primary analysis 
(Wald-test) 
Repeat for different population 
FAS / PP 
With and 
without NRI for 
FAS 
3 
Primary analysis 
(Wald-test) 
Applying new imputation 
method 
ITT / FAS 
/ PP 
Mixed 
component 
LOCF method 
4 
Logistic 
regression model 
To adjust for any impact due to 
baseline disease status and/or 
region 
ITT / FAS 
/ PP 
NRI as for the 
primary 
analysis 
5 
Tipping point 
analysis 
Assess where the conclusion 
switches direction 
ITT 
NRI as for the 
primary 
analysis / Based 
on the 
Remicade-US 
PP population 
response rate 
7.4 Safety Analysis 
The analysis planned for each safety evaluation/endpoint is described in the following 
subsections and will be performed using the safety population.  
7.4.1 Adverse Events 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA version 19.0). The incidence of TEAEs (events with onset dates on or after the 
start of the study drug) and treatment-related TEAEs will be summarized by system 
organ class (SOC) and preferred term (PT). Events with missing onset dates will be 
included as treatment-emergent, assuming onset on the first day of study treatment. If a 
patient experiences more than 1 occurrence of the same AE, the occurrence with the 
greatest severity and the closest association with the study drug will be used in the 
summary tables. SAEs and AEs that result in treatment discontinuation will be 
summarized. AEs of special interest will be summarized by SOC and PT; categories of 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 32 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 28 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
AEs of special interest include serious infections, malignancies, infusion-related 
reactions, hepatotoxicity, heart failure, and cytopenias. In addition, CIs will be calculated 
for the difference in incidence of these AEs to determine the risk difference between the 
NI-071 and Remicade-US groups. 
All AEs will be listed by patient, along with information regarding onset, duration, 
severity, relationship with study drug, action taken with study drug, treatment of event, 
and outcome. 
In addition to the overall analysis described above, TEAEs and AEs of special interest 
will be summarized by system organ class and preferred term separately for each Stage 
(Stage 1, Stage 2, and Stage 3). These by-stage analyses will be stratified into 3 
timing/severity categories: (1) stage-emergent (onset date within the stage), (2) persistent 
without increasing severity within the stage, and (3) persistent with increasing severity 
within the stage. One AE may be reported as “stage-emergent” in the analysis of Stage 2 
and also be reported as “persistent with increasing severity” in the analysis of Stage 3. 
Stages (for this safety analysis of AEs) will be defined according to the following table: 
Stage 
Beginning Date 
Ending Date 
Stage 1 
First treatment in Stage 1 
One day prior to first treatment in Stage 2 
Stage 2 
First treatment in Stage 2 
One day prior to first treatment in Stage 3 
Stage 3 
First treatment in Stage 3 
Day of study completion 
7.4.2 Physical Examination 
Physical examinations will be performed at visits according to the assessment schedule 
(Appendix B). A detailed data listing of abnormal physical examination findings will be 
provided. 
7.4.3 Vital Signs and Body Weight 
Vital signs data (oral body temperature, pulse rate, systolic and diastolic blood pressure 
measurements) and body weight, as well as change from baseline in vital sign and weight 
data, will be presented using the summary statistics for continuous variables, by treatment 
group and overall.  
7.4.4 Screening Tests 
At screening, Week 30, and Week 62 (or at the early discontinuation visit), a tuberculosis 
test will be performed, and a chest x-ray will be performed when applicable. Summary 
statistics (patient count and frequency) for the TB results (positive/negative) will be 
presented by treatment group and overall. 
For women of childbearing potential, a serum pregnancy test will be performed at 
screening, and urine pregnancy tests will be performed at all dosing visits and at Week 62 
(or at the early discontinuation visit). Summary statistics (patient count and frequency) 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 33 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 29 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
for the pregnancy results (positive/negative) will be presented by treatment group and 
overall. 
7.4.5 Electrocardiogram 
At screening and at the early discontinuation visit (if applicable), patients will have an 
electrocardiogram. Summary statistics (patient count and frequency) for results 
(normal/abnormal) will be presented by treatment group and overall. 
7.4.6 Laboratory Parameters 
Samples for assessing the clinical laboratory parameters listed in the following table are 
to be obtained at the visits designated in the schedule of assessments.  
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 34 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 30 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
Hematology 
Serum chemistry 
Urine analysis 
(dipstick) 
Full and differential blood count 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Mean corpuscular hemoglobin 
(MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count 
with differential  
Glycated hemoglobin (HbA1C) (at 
screening only) 
Albumin 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) or urea 
Creatinine 
Electrolytes (Na, K, Cl, Ca, P) 
Gamma-glutamyl transpeptidase 
(GGT) 
Glucose  
Lactate dehydrogenase (LDH) 
Total bilirubin 
Direct bilirubin 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood 
and WBCs 
Urobilinogen 
Serum immunology tests:  At screening, HBsAg, HBsAb, HBcAb, HCV Ab, HIV Ab, 
anti-dsDNA, and β-D-glucan (using the Fungitell® assay) will be measured. 
RA tests:  Rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) tests will be 
done at screening. 
Pregnancy test:   For women of childbearing potential, a serum pregnancy test will be done at 
screening, and urine dipstick tests will be done at all dosing visits and at Week 62 (or the early 
discontinuation visit). 
QuantiFERON tuberculosis (TB) test:  This test will be performed for all patients at screening, 
Week 30, and Week 62 (or the early discontinuation visit). A dedicated incubator must be 
available at the site for storing samples at 37ºC prior to shipping them to the central laboratory (at 
room temperature or refrigerated) within 3 days. 
C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) tests:  CRP and ESR 
levels will be analyzed at every visit. CRP will be analyzed by the central laboratory, and ESR 
will be analyzed locally. 
Data for each hematology and serum chemistry parameter will be summarized using the 
summary statistics for continuous data, by visit and treatment group. The change from 
baseline to each visit will be calculated and summarized. Urinalysis data will be 
summarized using counts and percentage, by visit and treatment group.  
Shift tables from baseline to final visit (indicating any shifts) will be produced. 
For hematology and serum chemistry, by-patient listings of all laboratory results will be 
produced (abnormal values and clinically significant values as rated by the investigator 
will be flagged).  
In addition, listing of abnormal laboratory results will be produced, clinically significant 
values as rated by the investigator will be flagged.  
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 35 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 31 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
7.5 Anti-drug Antibodies and Neutralizing Antibodies 
Positive immunogenicity results will be listed. The incidence of ADAs and the incidence 
of neutralizing antibodies will be summarized, and the titer of ADA will be summarized 
over time by treatment group. 
7.6 PK/PD Analysis 
The PK population will be used for the analysis of PK data.  
7.6.1 Handling of the BLQ and the No Reportable Concentration Values 
All concentration values BLQ will be set to zero. Samples with no reportable value will 
be set to missing for tabulation, graphical representation and calculation purposes. 
7.6.2 Handling of the Difference between the Scheduled and the Actual Sampling 
Times 
The actual clock time for dosing and the actual clock time for each collection time for the 
PK samples will be recorded in the eCRF. For all sampling times, the actual sampling 
times will be calculated as the difference between the sample collection actual clock time 
and the actual clock time of dosing. The actual post-dose sampling times expressed in 
hours and rounded off to three decimal digits will be used to calculate the PK parameters, 
except for pre-dose samples occurring prior to dosing, which will always be reported as 
zero (0.000), regardless of the time difference. Scheduled sampling times will be 
presented in concentration tables and mean graphs, while actual sampling times will be 
presented in the individual graphs in the PK section of the report.  
A listing of the actual times for PKs will be provided for PK samples. Actual sampling 
times will be used in all cases for PK analyses; however samples taken out of windows 
will be listed as deviations in the report.  
7.6.3 Pharmacokinetic Parameters  
Trough PK samples will be collected at Weeks 0, 2, 6, 14, 22, 30, 38, 46, 54, and 62. 
Trough PK sampling should be done within 1 h prior to dosing. 
Full PK sampling during Weeks 46 to 54 includes the following time points:  pre-dose, 1 
h after infusion start, at the end of infusion (EOI), at 4 h and 24 h after infusion start, and 
at 4 days, 7 days (Week 47), 14 days (Week 48), 28 days (Week 50), 42 days (Week 52), 
and 56 days (Week 54) post-dose. Sampling windows for the blood draws are ±15 
minutes for the 1 h time point, +15 minutes for the EOI, and ±15 minutes for the 4 h time 
point; ±2 h for the 24 h time point; and ±24 h for the subsequent time point. 
Infliximab serum concentrations collected on Weeks 46 to 54 will be used to calculate the 
following parameters by standard non-compartmental methods: 
AUCtau: 
area under the concentration-time curve for one dosing interval 
(tau=8 weeks) 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 36 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 32 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
Cmax: 
maximum concentration 
Cmin: 
minimum concentration  
T1/2: 
terminal half life 
Kel: 
elimination rate constant 
CL: 
total clearance 
Vd: 
volume of distribution 
tmax: 
time of observed Cmax ss at steady-state 
Some PK parameters may not be calculated for all or some patients, at the discretion of 
the Syneos Health pharmacokineticist, if the concentration data is not deemed to be 
amenable to evaluation. Explanations for PK parameters that could not be estimated will 
be provided in the CSR report. 
7.6.4 Statistical Analyses  
Individual and mean concentration versus time curves will be presented using linear and 
semi-log scales for infliximab. Descriptive statistics of the serum concentrations versus 
time will be presented, including trough concentrations, as well as for all PK parameters 
(AUCtau, Cmax, Cmin, Kel, CL, Vd, and tmax) by treatment group.  
Using GLM procedures in SAS, an ANCOVA will be performed on ln-transformed 
AUCtau and Cmax with TREATMENT as fixed effect and REGION as categorical 
covariate at the alpha level of 0.05. Based on pairwise comparisons of the ln-transformed 
AUCtau and Cmax data, the geometric least-squares means for each treatment, the ratios 
(Switch/Remicade, Switch/NI-071, and NI-071/Remicade) of the geometric least-squares 
means, calculated according to the formula “e(X-Y) * 100”, as well as the corresponding 
90% geometric confidence intervals will be determined. Coefficient of variation will be 
estimated.  
Wilcoxon rank sum test will be performed on tmax for each comparison.  
The analysis for each comparison (Switch versus Remicade, Switch versus NI-071, and 
NI-071 versus Remicade) will be conducted excluding the data from the treatment that is 
not relevant for the comparison. 
Criteria for Interchangeability Assessment 
The 90% geometric confidence intervals of the ratio (Switch/Remicade) of least-squares 
means from the ANCOVA of the ln-transformed AUCtau and Cmax must be within 
80.00% to 125.00%. ANCOVA will be performed with TREATMENT as fixed effect 
and REGION as categorical covariate. 
7.7 Analysis of Other Assessments 
No other analyses are planned. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 37 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 33 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
7.8 Interim Analysis 
An interim analysis is planned in order to decide if the study should continue or be 
stopped for futility after Stage 1. 
This study was designed using a hierarchical approach, where the results of the 
interchangeability assessment (PK analysis) performed at the end of Stage 2 will be 
regarded as confirmatory in nature only if the results of the biosimilarity assessment at 
the end of Stage 1 have shown significant results. An interim analysis is planned in order 
to decide if the study should continue or be stopped for futility after Stage 1. 
The interim analysis of the primary clinical efficacy endpoint, the ACR20-CRP response 
rate, will be performed after the last patient has completed the last visit in Stage 1, the 
Week 22 visit (the visit of the assessments for the primary efficacy endpoint). This 
analysis will be performed by an unblinded statistician not otherwise affiliated with the 
study. An independent data monitoring committee (IDMC) will be established to assess 
the results and determine whether the study should continue or be stopped for futility. An 
IDMC charter will be prepared to describe the details of the outputs available to the 
IDMC as well as to describe the decision tree for the IDMC meeting. 
7.9 Data Monitoring Committee  
An IDMC will be established by the Sponsor or its designee to evaluate the results of a 
formal interim efficacy analysis. Members will include experts in RA and biostatistics 
who are not participating in this study and do not have affiliation with the Investigators or 
the Sponsor. The IDMC can recommend in writing to the Sponsor whether to continue or 
stop the clinical study on the basis of the results of the interim analysis. The IDMC’s 
specific duties as well as statistical monitoring guidelines and procedures will be fully 
described in an IDMC charter. 
7.10 Changes to Methods Planned in the Protocol  
No changes to the methods described in the protocol are planned. 
However, the definition of the per protocol population in Section 4.4 have been updated 
to only exclude such patients from the per protocol population that have major protocol 
deviations that are classified as having an impact on the primary efficacy outcome 
ACR20-CRP at Week 22 as defined during the BDRM before unblinding of the study.  
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 38 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 34 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
8. TABLES, LISTINGS, AND FIGURES 
The mock tables, listings, and figures will be presented in a separate document. 
The general layout of the tables, figures and listing (TFLs) will be as follows. 
Orientation 
Landscape 
Paper Size 
A4 
Margins 
Top: 3.2 cm  
Bottom: 2.5 cm 
Left: 2.5 cm 
Right: 2.5 cm 
Font 
Courier New 9pt 
Headers 
(alignment) 
Sponsor name and Protocol number (Center) 
Page X of Y (Right) 
TFL Number and Title (Center) 
Footers 
(alignment) 
SAS program path and file name (Left) 
Date output generated (Right) 
 
The font size may be reduced as necessary to allow additional columns to be presented, 
but not at the expense of clarity. Also, the orientation may be changed to portrait, if 
appropriate.  
All tables and data listings will be generated using SAS® v9.3 or higher.  
The date format for all presentations will be ddMmmyyyy.  
8.1 Preparation of Tables 
Certain data will be collated into summary tables; however, in general, most tables will 
present summary data stratified by treatment group. Some tables may be stage-specific, 
while others will present comprehensive data spanning all stages.  
8.2 Preparation of Data Listings 
The data listings will be sorted by treatment group, site number, patient screening 
number, and visit. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 39 of 47


STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 35 
CONFIDENTIAL 
Final 5.0: 2019-Jun-27 
9. REFERENCES
1. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology 
guideline for the treatment of rheumatoid arthritis. Arthritis and Rheum.
2016;68(1):1-26. Available at
www.rheumatology.org/Portals/0/Files/ACR%202015%20RA%20Guideline.pdf
2. Centers for Disease Control and Prevention website:  Rheumatoid arthritis. 
Available at http://www.cdc.gov/arthritis/basics/rheumatoid.htm  Accessed
03 Feb 2016.
3. Remicade (US package insert), Horsham, PA:  Janssen Biotech; Oct 2015.
4. Remicade (EMA European Public Assessment Report [EPAR] Product 
Information), Leiden, The Netherlands:  Janssen Biologics BV; Nov 2015.
5. NI-071 Investigator’s Brochure, Version 1.0. Nichi-Iko; March 2016.
6. Combest AJ, Wang S, Healey BT, et al. Alternative statistical strategies for 
biosimilar drug development. GaBI Journal. 2014;3(1):13-20.
7. Ogata A, Tanimura K, Sugimoto T, et al. Phase III study of the efficacy and 
safety of subcutaneous versus intravenous tocilizumab monotherapy in patients 
with rheumatoid arthritis. Arthritis Care and Research. 2014;66(3):344-354.
8. Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in rheumatoid 
arthritis on the basis of achievement of stable low disease activity with 
adalimumab plus methotrexate or methotrexate alone:  the randomised controlled 
OPTIMA trial. 2014;383:321-332.
9. Yoo DH, Hrycaj P, Miranda P. A randomised, double-blind, parallel-group study 
to demonstrate equivalence in efficacy and safety of CT-P13 compared with 
innovator infliximab when coadministered with methotrexate in patients with 
active rheumatoid arthritis:  the PLANETRA study. Ann Rheum Dis.
2013;72(10):1613-1620.
10. Van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab 
versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367:508-519.
11. Koch G and Gansky S. Statistical considerations for multiplicity in confirmatory 
protocols. Drug Information Journal. 1996;30:523–533.
12. Ware JE, Kosinski M, Dewey JE, and Gandek B. SF-36 health survey: manual 
and interpretation guide. 2000; Quality Metric Inc.
13. Remsima (EMA European Public Assessment Report). Budapest, Hungary: 
Celltrion Healthcare; 27 Jun 2013.
14. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or 
infliximab vs placebo in ATTEST:  a phase III, multi-centre, randomised, double-
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 40 of 47


STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 36 
CONFIDENTIAL 
Final 5.0: 2019-Jun-27 
blind, placebo-controlled study in patients with rheumatoid arthritis and an 
inadequate response to methotrexate. Ann Rheum Dis. 2008;67:1096-1103. 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 41 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 37 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
10. APPENDICES 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 42 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 38 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
Appendix A. Definitions of Visit Windows 
As described in the protocol, for visits at Weeks 2 through 62, there will be a target visit 
window of ±3 days.  
The following visit windows will be used for efficacy analysis, where day is defined as 
Visit Date minus date of first infusion at Stage 1. For analysis, the window definitions are 
derived to provide non-overlapping, consecutive windows. For example, Week 16 is the 
midpoint between Week 14 and Week 18; therefore, the end of the Week 14 window is 
7 days multiplied by 16, and the beginning of the next window is +1 day. 
Window Label 
Target Day 
Target Window (±3 days) 
Window Definition (days) 
Baseline 
1 
Not applicable 
(-3) – 1 
Week 2 
14 
11-17 
2-28 
Week 6 
42 
39-45 
29-70 
Week 14 
98 
95-101 
71-112 
Week 18 
126 
123-129 
113-140 
Week 22 
154 
151-157 
140- 168 
Week 26 
182 
179-185 
169-196 
Week 30 
210 
207-213 
197-224 
Week 34 
238 
235-241 
225-252 
Week 38 
266 
263-269 
253-280 
Week 42 
294 
291-297 
281-308 
Week 46 
322 
319-325 
309-336 
Week 50 
350 
347-353 
337-364 
Week 54 
378 
375-381 
365-392 
Week 58 
406 
403-409 
393-420 
Week 62 
434 
431-437 
>420 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 43 of 47


 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
Page 39 
 
 
CONFIDENTIAL 
 
Final 5.0: 2019-Jun-27 
 
Appendix B. Schedule of Assessments 
______________________________________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 44 of 47


 
 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
                                             Page 40 
 
 
CONFIDENTIAL 
 
         Final 5.0: 2019-Jun-27 
 
Schedule of Assessments 
 
Screening 
Stage 1 
Stage 2 
Stage 3 
 
Visit at Week (±3 days) 
(Day -28 
to Day -7) 
0 
(Day 1) 2 
6 
14 18 
22 
26 
30 
34 
38 
42 
46 
50 
54 
58 
62a  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, weight, heighto 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-ray 
Xb 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
Xb 
 
Physical examination 
X 
Xc 
Xc Xc Xc Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
Clinical laboratory testsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum immunology testse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
QuantiFERON TB test 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
RF and ACPA testsg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Joint assessmentg,h,i,m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2010 ACR/EULAR RA classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP testg,h,i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESR testg,h,i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
___________________________
___________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 45 of 47


 
 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
                                             Page 41 
 
 
CONFIDENTIAL 
 
         Final 5.0: 2019-Jun-27 
 
Screening 
Stage 1 
Stage 2 
Stage 3 
 
Visit at Week (±3 days) 
(Day -28 
to Day -7) 
0 
(Day 1) 2 
6 
14 18 
22 
26 
30 
34 
38 
42 
46 
50 
54 
58 
62a  
HAQ-DIh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient global assessmenth,i,j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient pain assessmenth,j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
RAPID3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physician global assessmenth,j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SF-36 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Concomitant medication review 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X* 
 
 
 
 
X** 
 
 
 
 
 
 
 
 
 
 
 
Administration of study drug 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
MTX and folic acid reminder 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-drug antibodies (pre-dose) 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Trough PK samplek (pre-dose) 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Full PK samplek (Weeks 46 to 54) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Abbreviations:  ACPA=anti-citrullinated protein antibody; ACR=American College of Rheumatology; ACR20(50, 70)=a 20%(50%, 70%) improvement from baseline in the ACR 
core set criteria; anti-dsDNA=anti-double-stranded deoxyribonucleic acid; CRP=C-reactive protein; DAS28=disease activity score involving 28 joints; EOI=end of infusion; 
ESR=erythrocyte sedimentation rate; EULAR=European League Against Rheumatism; HAQ-DI=Health Assessment Questionnaire-Disability Index;HbA1c=glycated hemoglobin; 
HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B surface antigen; HCV Ab=hepatitis C antibody; HIV Ab=human immunodeficiency 
virus antibody; NYHA=New York Heart Association; PK=pharmacokinetic; RA=rheumatoid arthritis; ; RAPID3=routine assessment of patient index data 3; RF=rheumatoid 
factor; SF-36=Medical Outcomes Study 36-Item Short-Form Health Survey; TB=tuberculosis 
aOr early discontinuation visit. 
bChest x-rays (anterior-posterior and lateral views) are to be done only if the TB test is positive; also, at screening, only if the patient has not had x-rays within 12 weeks prior to 
screening. 
___________________________
___________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 46 of 47


 
 
 
STATISTICAL ANALYSIS PLAN 
Nichi-Iko Pharmaceutical Co., Ltd. 
NI071F2 
                                             Page 42 
 
 
CONFIDENTIAL 
 
         Final 5.0: 2019-Jun-27 
 
Screening 
Stage 1 
Stage 2 
Stage 3 
 
Visit at Week (±3 days) 
(Day -28 
to Day -7) 
0 
(Day 1) 2 
6 
14 18 
22 
26 
30 
34 
38 
42 
46 
50 
54 
58 
62a  
cA limited physical examination to verify continued patient eligibility and to follow up any changes (symptom-driven) will be performed at these visits. 
dStandard hematology, blood chemistry, and urinalysis tests; at screening, also HbA1C. 
eScreening serum immunology tests include HBsAg, HBsAb, HBcAb, HCV Ab, HIV Ab, anti-dsDNA, and β-D-glucan. 
fOnly in women of childbearing potential. Serum test is to be done at screening; urine test is to be done locally at other specified time points.  
gAssessment contributes to the 2010 ACR and EULAR RA classification at screening. 
hAssessment contributes to the ACR core set criteria for determining ACR20, ACR50, and ACR70 at all post-screening visits. 
iAssessment contributes to the DAS28 scores at all post-screening visits. 
jMeasured on a visual analog scale (VAS) of 0 to 100 mm. VAS for patient assessment of pain goes from “no pain” to “pain as bad as it can be”; VAS for patient global assessment 
of disease activity goes from “very well” to “very poor”; VAS for physician global assessment of disease activity goes from “none” to “extremely active.” 
kTrough PK sampling should be done within 1 h prior to dosing. Full PK sampling during Weeks 46 to 54 includes the following time points:  pre-dose, 1 h after infusion start, at 
the end of infusion (EOI), at 4 h and 24 h after infusion start, and at 4 days, 7 days (Week 47), 14 days (Week 48), 28 days (Week 50), 42 days (Week 52), and 56 days (Week 54) 
post-dose. Sampling windows for the blood draws are ±15 minutes for the 1 h time point, +15 minutes for the EOI, and ±15 minutes for the 4 h time point; ±2 h for the 24 h time 
point; and ±24 h for the subsequent time points. 
lAt early discontinuation visit only. 
mJoint assessment includes determination of tender joints and swollen joints. At screening, counts of tender and swollen joints out of 28 selected joints will be performed (for the 
2010 ACR and EULAR classification criteria). At all subsequent visits, counts of tender and swollen joints out of 68 and 66 selected joints, respectively, will be performed (for the 
ACR core set criteria and the DAS28).  
nAt screening, prior medications will also be reviewed. 
oRecord height at screening only. 
*Initial blinded randomization is to be performed after all inclusion/exclusion criteria are reconfirmed at Week 0. 
**Blinded re-randomization. At Week 22, the original Remicade-US group is to be randomized 1:1 to a Switch group and a Remicade-US group. The Remicade-US group will 
continue on Remicade-US from Week 22 through Week 54 every 8 weeks. At Week 22, the Switch group will receive NI-071; at Week 30, this group will receive Remicade-US; 
and at Weeks 38, 46, and 54, this group will receive NI-071. The original NI-071 group will continue on NI-071 from Week 22 through Week 54 every 8 weeks. 
 
 
___________________________
___________________________________________________________________
Nichi-Iko Pharmaceutical Co., Ltd. 
NI-071 (proposed infliximab biosimilar)
NI071F2 
Final Clinical Study Report
This document is confidential.
27 April 2020
Page 47 of 47