| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active Rheumatoid Arthritis |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 19.0 |
| 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 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1
• To find the optimal dose of CT-P13 SC over the first 30 weeks as determined by the area under the concentration-time curve (AUCτ) at steady state between Week 22 and Week 30
Part 2
• To demonstrate that CT P13 SC is noninferior to CT-P13 IV at Week 22, in terms of efficacy, as determined by clinical response according to change from baseline in disease activity measured by Disease Activity Score using 28 joint counts (DAS28) (CRP)
• To demonstrate that CT-P13 SC is noninferior to CT-P13 IV in terms of PK, as determined by the AUCτ at steady state between Week 22 and Week 30
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| E.2.2 | Secondary objectives of the trial |
Part 1
• To evaluate efficacy, pharmacokinetics (PK), pharmacodynamics (PD), overall safety of CT P13 SC in comparison with CT-P13 IV up to Week 54
Part 2
• To evaluate efficacy, PK, PD and overall safety of CT-P13 SC in comparison with CT-P13 IV (over the first 30 weeks)
• To evaluate efficacy, PK, PD and overall safety of CT-P13 SC up to Week 54
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female aged 18 to 75 years old, inclusive.
2. Patient has a diagnosis of RA according to the 2010 ACR/EULAR classification criteria [Aletaha et al. 2010] for at least 6 months prior to the first administration of the study drug (Day 0).
3. Patient has active disease as defined by the presence of 6 or more swollen joints (of 28 assessed), 6 or more tender joints (of 28 assessed), and a serum CRP concentration > 0.6 mg/dL.
4. Patient who has completed at least 3 months of treatment of oral or parenteral dosing with methotrexate between 12.5 to 25 mg/week and on stable dosing with methotrexate between 12.5 to 25 mg/week for at least 4 weeks prior to the first administration of the study drug (Day 0).
5. Patient has adequate renal and hepatic function at Screening as defined by the following clinical chemistry results:
• Serum creatinine <1.5 × upper limit of normal (ULN) or an estimated creatinine clearance level >50 mL/min (by Cockcroft-Gault formula)
• Serum alanine aminotransferase <2.5 × ULN
• Serum aspartate aminotransferase <2.5 × ULN
• Serum total bilirubin <2 × ULN
6. Patient has the following hematology laboratory test results at Screening:
• Hemoglobin ≥8.5 g/dL (SI [Système International d'Unités] units: ≥85 g/L or 5.28 mmol/L)
• White blood cell count ≥3.5 × 103 cells/µL (SI units: ≥3.5 × 109 cells/L)
• Neutrophil count ≥1.5 × 103 cells/µL (SI units: ≥1.5 × 109 cells/L)
• Platelet count ≥100 × 103 cells/µL (SI units: ≥100 × 109 cells/L)
7. Patient has the ability to comprehend the full nature and purpose of the study, including possible risks and side effects, to cooperate with the investigator, to understand verbal and/or written instructions, and to comply with the requirements of the entire study.
8. Patient (or legal guardian, if applicable) is informed of the full nature and purpose of the study, including possible risks and side effects, and given ample time and opportunity to read and understand this information, signed and dated the written informed consent before inclusion in the study.
9. For both male and female patients, the patient and their partners of childbearing potential either agree to use one of the following medically acceptable methods of contraception during the course of the study and for 6 months following discontinuation of study drug (excluding women who are not of childbearing potential and men who have been sterilized):
• Barrier contraceptives (male condom, female condom, or diaphragm with a spermicidal gel)
• Hormonal contraceptives (implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings)
• Intrauterine device
Male and female patients and their partners who have been surgically sterilized for less than 6 months prior to the date of informed consent must agree to use any medically acceptable methods of contraception.
Menopausal females must have experienced their last period more than 12 months prior to the date of informed consent to be classified as not of childbearing potential.
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| E.4 | Principal exclusion criteria |
1. Patient who has previously received a biological agent for the treatment of RA
2. Patient who has allergies to any of the excipients of infliximab or any other murine and/or human proteins or patient with a hypersensitivity to immunoglobulin product.
3. Patient who has a current or past history of following infection:
• Current or past history of chronic infection with hepatitis C or human immunodeficiency virus-1 or-2 or current infection with hepatitis B
• Acute infection requiring oral antibiotics within 2 weeks prior to the first administration of the study drug (Day 0)
• Other serious infection within 6 months prior to the first administration of the study drug (Day 0)
• Recurrent herpes zoster or other chronic or recurrent infection within 6 weeks prior to the first administration of the study drug (Day 0)
• Past or current granulomatous infections or other severe or chronic infection (such as sepsis, abscess or opportunistic infections, or invasive fungal infection such as histoplasmosis)
4. Patient who has a medical condition including one or more of the following:
• Classified as obese (body mass index ≥30 kg/m2)
• Diabetes mellitus unless on a stable dosing treatment for at least 4 weeks prior to the first administration of the study drug (Day 0)
• Uncontrolled hypertension (as defined by systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg)
• Any other inflammatory or rheumatic diseases
• History of any malignancy within the 5 years prior to the first administration of the study drug (Day 0)except completely excised and cured squamous carcinoma of the uterine cervix in situ, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma
• History of lymphoma or lymphoproliferative disease or bone marrow hyperplasia
• NYHA class III or IV heart failure, severe uncontrolled cardiac disease (unstable angina or clinically significant electrocardiogram [ECG] abnormalities), or myocardial infarction within the 6 months prior to the first administration of the study drug (Day 0)
• History of organ transplantation, including corneal graft/transplantation
• Any uncontrolled, clinically significant respiratory disease (in the opinion of the investigator), including but not limited to chronic obstructive pulmonary disease, asthma, bronchiectasis, or pleural effusion.
• Previous diagnosis or symptoms suggestive of demyelinating disorders, including multiple sclerosis and Guillain-Barré syndrome
• Severe physical incapacitation (unable to perform routine self-care, has RA ACR functional status class 4 [Arnett et al 1988], or who cannot benefit from medication)
• Any conditions significantly affecting the nervous system (ie, neuropathic conditions or nervous system damage) if it may interfere with the investigator’s assessment on disease activity scores including joint counts
• Any other serious acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or that may interfere with the interpretation of study results.
5. Patient who has received or has plan to receive any of following prohibited medications or treatment:
• Any biological agents for the treatment of RA during the study period
• Corticosteroids, except oral glucocorticoids, of maximum equivalent daily dose of 10 mg of prednisolone within 4 weeks prior to the first administration of the study drug (Day 0)
• Disease-modifying antirheumatic drugs (DMARDs), other than methotrexate, including hydroxychloroquine, chloroquine, or sulfasalazine, within 4 weeks prior to the first administration of the study drug (Day 0)
• Alkylating agents within 12 months prior to the first administration of the study drug (Day 0) and/or during the study period
• Live or live-attenuated vaccine within 8 weeks the first administration of the study drug (Day 0) and/or during the study period
• Any planned live or live-attenuated vaccination at the time of the first administration of the study drug (Day 0) and/or during the study period
• Any surgical procedure, including bone or joint surgery or synovectomy (including joint fusion or replacement) within 12 weeks prior to the first administration of the study drug (Day 0) or planned within 6 months after the first administration of the study drug (Day 0)
6. Patient who has a current or past history of drug or alcohol abuse.
7. Patient who has had treatment with any other investigational device or medical product within 4 weeks prior to the first administration of the study drug (Day 0) or 5 half-lives, whichever is longer.
8. Female patient who is currently pregnant, breastfeeding, or planning to become pregnant or breastfeed within 6 months of the last dose of study drug.
9. Patient who, in the opinion of his or her general practitioner or investigator, should not participate in the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The following primary PK endpoint will be assessed at steady state between Week 22 and 30:
• AUCτ Area under the concentration-time curve at steady state between Week 22 and Week 30
Part 2
• Change from baseline in disease activity measured by DAS28(CRP) at Week 22
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary pharmacokinetic endpoint evaluation will be conducted during the Maintenance Phase between Week 22 to Week 30. |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoint evaluations are:
• Individual components of the DAS28
• DAS28(CRP) and DAS28(erythrocyte sedimentation rate [ESR])
• Individual components of the ACR
• ACR 20, 50 and 70
• Hybrid ACR response
• Proportion of patients with a good response, defined according to the EULAR response criteria
• SDAI and CDAI
• Health assessment questionnaire (HAQ)
• 36-item short form health survey (SF-36) (Part 2 only)
Secondary Endpoint for both Part 1 and Part 2
The following secondary PK endpoints will be assessed between Week 22 and Week 30:
• Cmax Observed maximum serum concentration
• MRT Mean residence time
• CL Clearance after IV dosing
• CL/F Apparent clearance after SC dosing
• BA Bioavailability (absolute and/or relative)
The following secondary PK endpoint will be assessed up to Week 54:
• Ctrough Trough concentration
The following PD parameters for CT-P13 SC and CT-P13 IV will be determined as secondary PD endpoints (up to Week 54):
• Rheumatoid Factor (RF)
• Anti-cyclic citruliinated peptide (anti-CCP)
• CRP
• ESR
Safety assessments will be performed on immunogenicity, hypersensitivity monitoring (including delayed hypersensitivity monitoring), vital sign measurements (including blood pressure, heart and respiratory rates and body temperature), weight, interferon-γ release assay, hepatitis B and C and HIV-1 and -2 status, physical examination findings, ECGs, AEs (including serious AEs), adverse events of special interest (infusion related reactions/hypersensitivity/anaphylactic reactions, delayed hypersensitivity, injection site reactions, infection and malignancies), clinical laboratory analyses, pregnancy testing, and previous and concomitant medications.
In case of delayed hypersensitivity occurred after 24 hours of study drug administration, including serum sickness-like reactions (myalgia with fever or rash, arthralgia, lymphadenopathy, skin eruption or edema), following assessments will be additionally performed to determine Serum Sickness during the study period;
• Immunogenicity
• Clinical Laboratory Analyses
• Complement (C3, C4) and Total Haemolytic Complement
In addition, local site pain using 10 cm Visual Analogue Scale (VAS) will be assessed.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary pharmacokinetic endpoint evaluations will be conducted during the Dose-Loading Phase and Maintenance Phase up to Week 54, with blood samples for analysis obtained at the time points specified in the schedule of events and secondary PK endpoint evaluations will be conducted during the Treatment Period up to Week 54. Secondary efficacy endpoints will be assessed at Weeks 0, 2, 6, 14, 22, 30 and 54 (or the End-of Study visit if not obtained at Week 54). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I/III to evaluate efficacy, pharmacokinetics and safety in patients with active RA |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 | No |
| 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 |
| Bosnia and Herzegovina |
| Bulgaria |
| Czech Republic |
| Estonia |
| Hungary |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Poland |
| Russian Federation |
| South Africa |
| Ukraine |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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