Clinical Trials Register

Summary
EudraCT Number:	2016-001064-11
Sponsor's Protocol Code Number:	NI071F2
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-31
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2016-001064-11

A.3

Full title of the trial

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

Randomizovaná, dvojitě zaslepená, multicentrická, 3stupňová, účinnostní a bezpečnostní studie NI-071 a schváleného v USA Remicadu® (Infliximabu) pro léčbu pacientů s revmatickou artritidou

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy and safety study of Remicade® (infliximab) and NI-071 (a proposed infliximab biosimilar) for the treatment of patients with rheumatoid arthritis

A.4.1

Sponsor's protocol code number

NI071F2

A.5.4

Other Identifiers

Name:

IND number

Number:

126520

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Nichi-Iko Pharmaceutical Co., Ltd.
B.1.3.4	Country	Japan
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Nichi-Iko Pharmaceutical Co., Ltd.
B.4.2	Country	Japan
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Nichi-Iko Pharmaceutical Co., Ltd.
B.5.2	Functional name of contact point	Biosimilar Development Department
B.5.3	Address:
B.5.3.1	Street Address	11th Floor, Sumitomo Fudosan Nihonbashi Bldg
B.5.3.2	Town/ city	5-4 Nihonbashi-Honcho 1-chome, Chuo-ku
B.5.3.3	Post code	103-0023
B.5.3.4	Country	Japan
B.5.6	E-mail	kenji-matsuyama@nichiiko.co.jp

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NI-071
D.3.2	Product code	NI-071
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INFLIXIMAB
D.3.9.1	CAS number	170277-31-3
D.3.9.2	Current sponsor code	NI-071
D.3.9.4	EV Substance Code	SUB02681MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Remicade
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen Biotech, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Remicade
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INFLIXIMAB
D.3.9.1	CAS number	170277-31-3
D.3.9.3	Other descriptive name	Remicade
D.3.9.4	EV Substance Code	SUB02681MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid Arthritis

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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)
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
Stage 3 (Safety Follow-up Stage)
Primary:
• To evaluate the safety of long-term treatment (follow-up through Week 62)

E.2.2

Secondary objectives of the trial

Stage 1 (Biosimilarity Stage)
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)
Secondary:
• To evaluate the safety, efficacy, and immunogenicity of NI-071 and Remicade-US

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients with a diagnosis of RA as defined by the 2010 ACR and European League Against Rheumatism (EULAR) classification criteria8
- 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
- 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.
- 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.
- Patients with a body weight of ≥40 kg and ≤120 kg at screening
- Patients who are ≥18 and ≤75 years of age at screening
- 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.

Refer to protocol for more inclusion criteria

E.4

Principal exclusion criteria

- Patients who have had prior treatment with infliximab
- 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.
- 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.
- Patients who had prior treatment with cyclophosphamide or other cytotoxic agents
- 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
- Patients with a history of hypersensitivity to the components of NI-071 or mouse-derived protein (e.g., mouse, chimeric, and humanized antibody)
- 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
- 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
- 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.)
- Female patients who are pregnant, wish to become pregnant, or are breastfeeding.
- 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.

Refer to protocol for more exclusion criteria

E.5 End points

E.5.1

Primary end point(s)

Clinical Efficacy
Primary endpoint:
• ACR20-CRP at Week 22

Pharmacokinetics
Primary endpoints:
• AUCtau and Cmax during the dosing interval of Weeks 46 to 54

E.5.1.1

Timepoint(s) of evaluation of this end point

Clinical Efficacy
• ACR20-CRP at Week 22

Pharmacokinetics
• AUCtau and Cmax during the dosing interval of Weeks 46 to 54

Please refer to the Schedule of Assessments in the protocol.

E.5.2

Secondary end point(s)

Clinical Efficacy
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
Secondary endpoints:
• Minimum concentration (Cmin) and time at maximum concentration (tmax) during the dosing interval of Weeks 46 to 54

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the Schedule of Assessments in the protocol.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Czech Republic

Poland

Puerto Rico

Russian Federation

Spain

Ukraine

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last Visit of the Last Subject (LVLS)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

497

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

111

F.4.2.2

In the whole clinical trial

585

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Investigators will explain the safest way to end subject´s participation, which may involve the completion of some final key safety and efficacy assessments. Investigators will provide subjects with the best course of continuing care.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	National Institute for Health Research
G.4.3.4	Network Country	United Kingdom

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-05-10

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IMP with orphan designation in the indication
Orphan Designation Number:
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