| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
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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 |
| The primary objective of this study is to demonstrate that CT P13 is equivalent to Remicade up to Week 30, in terms of efficacy as determined by clinical response according to the American College of Rheumatology (ACR) definition of a 20% improvement (ACR20). |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to evaluate long term efficacy, pharmacokinetics, pharmacodynamics, and overall safety of CT P13 in comparison with Remicade reference product 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 was diagnosed with active RA according to the revised 1987 ACR classification criteria [Arnett et al 1987] for at least 1 year prior to Screening.
3. Patients have active disease as defined by the presence of 6 or more swollen joints, and 6 or more tender joints, and at least two of the following: morning stiffness lasting at least 45 minutes, an erythrocyte sedimentation rate greater than 28 mm/h, and a serum C reactive protein (CRP) concentration greater than 2.0 mg/dL (Maini et al 1999).
4. Patients who have 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 Screening.
5. Both male and female patients and their partners of childbearing potential must agree to use 2 medically accepted methods of contraception (eg, barrier contraceptives [male condom, female condom, or diaphragm with a spermicidal gel], hormonal contraceptives (implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings), and intrauterine devices) during the course of the study and for 6 months following discontinuation of study treatments (excluding women who are not of childbearing potential and men who have been sterilized).
6. Male and female patients and their partners who have been surgically sterilized for less than 6 months prior to study entry must agree to use 2 medically accepted methods of contraception as per inclusion criterion 5.
7. Menopausal females must have experienced their last period more than 12 months prior to study entry to be classified as not of childbearing potential.
8. Patients have adequate renal and hepatic function at Screening as defined by the following clinical chemistry results:
• Serum creatinine <1.7 × upper limit of normal (ULN) or an estimated creatinine clearance level >75 mL/min
• Serum alanine aminotransferase <2 × ULN
• Serum aspartate aminotransferase <2 × ULN
9. Patients have the following hematology laboratory test results at Screening:
• Hemoglobin ≥8.0 g/dL
• White blood cell count ≥3.5 × 103 cells/µL (SI: ≥3.5 × 109 cells/L)
• Neutrophil count ≥1.5 × 103 cells/µL (SI: ≥1.5 × 109 cells/L)
• Platelet count ≥100 × 103 cells/µL (SI: ≥100 × 109 cells/L)
10. Patients are permitted to receive both oral glucocorticoids equivalent to ≤10 mg daily prednisolone and NSAIDS, if they have received a stable dose for at least 4 weeks prior to Screening. In addition, patients are permitted to receive low potency topical, otic, and ophthalmic glucocorticoid preparations provided the preparations are administered per the instructions on the product label.
11. Patients have 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 written instructions, and to comply with the requirements of the entire study.
12. 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.
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| E.4 | Principal exclusion criteria |
1. Patients who have previously been administered a biological agent for the treatment of RA.
2. Patients who have allergies to any of the excipients of infliximab or any other murine and human proteins and patients with a hypersensitivity to immunoglobulin product.
3. Patients who have a current or past history of chronic infection with hepatitis B, hepatitis C, or infection with human immunodeficiency virus 1 or 2 or who have a positive result to the screening test for those infections.
4. Patients who have a current diagnosis of tuberculosis (TB) or other severe or chronic infection (such as sepsis, abscess or opportunistic infections, or invasive fungal infection such as histoplasmosis) or a past diagnosis without sufficient documentation of complete resolution following treatment.
5. Patients who have had recent exposure to persons with active TB, or who have a positive result to the screening test for latent TB defined as a positive result of interferon-γ release assay with a negative examination of chest x-ray, and who have not received at least the first 30 days of country-specific TB therapy and do not intend to complete the entire course of that therapy. Patients with an abnormal chest x-ray must be discussed with the medical monitor before randomization.
6. Patients who have had an infection requiring oral antibiotics in the 2 weeks before Screening, parenteral injection of antibiotics in the 4 weeks before Screening, or serious infection in the 6 months before Screening, or who have a history of recurrent herpes zoster or other chronic or recurrent infection.
7. Patients who have a current or past history of drug or alcohol abuse.
8. Patients who have a medical condition including one or more of the following:
• Classified as obese
• Bone marrow hypoplasia
• Diabetes mellitus unless on a stable dosing regimen for at least 4 weeks prior to Screening
• Hypertension at Screening
• Any other inflammatory or rheumatic diseases, including but not limited to psoriatic arthritis (PsA), AS, spondyloarthritis, systemic lupus erythematosus, Lyme disease, or fibromyalgia, that may confound the evaluation of the effect of the study drug.
• History of any malignancy within the previous 5 years except completely excised and cured squamous carcinoma of the uterine cervix, cutaneous basal cell carcinoma, or squamous cell carcinoma
• History of lymphoma or lymphoproliferative disease
• History of congestive heart failure (New York Heart Association [NYHA] Class III/IV) or unstable angina
• History of organ transplantation
• History of severe hypersensitivity
• Severe physical incapacitation (Unable to perform routine self care, have RA ACR functional status Class 4 (Arnett et al 1988), or who cannot benefit from medication)
• Any clinically significant respiratory disease, 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-Barre syndrome
• Any condition 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, which may increase the risk associated with study participation or investigational product administration, or that may interfere with the interpretation of study results.
9. Patients taking any of the following concomitant medications:
• Corticosteroids, except oral glucocorticoids of maximum equivalent daily dose of 10 mg of prednisolone within 4 weeks prior to Screening. (Patient are permitted to receive low potency topoical, otic, and ophthalmic glococorticoid preparations provided the preparations are administered per the instructions on the product label.)
• Disease-modifying antirheumatic drugs (DMARDs), other than methotrexate, including hydroxychloroquine, chloroquine, or sulfasalazine, within 4 weeks prior to Screening. Patients who discontinued leflunomide and have had successful chelation with 8 g of cholestyramine (3 times daily) for 11 days must wait 4 weeks prior to Screening. Patients who discontinued leflunomide and did not have cholestyramine washout must wait 12 weeks after last dose of leflunomide before Screening
• Alkylating agents within 12 months prior to Screening
• Live or live-attenuated vaccine within 8 weeks of Screening
• Any biological agents for the treatment of RA
For criteria 10 to 13 please see protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the proportion of patients achieving clinical response according to the ACR20 criteria at Week 30. A patient is defined as a responder according to ACR20 criteria if the following are fulfilled:
•A decrease of at least 20% in the number of tender joints
•A decrease of at least 20% in the number of swollen joints and
•A 20% improvement in three of the following:
•Patient’s assessment of pain on the VAS
•Patient and physician global assessment of disease status (VAS)
•Health assessment questionnaire estimate of physical ability
•Serum CRP concentration
•ESR
The VAS range is from 0 to 100 mm, with higher scores indicating poorer status or more severe pain.
For the derivation of ACR20 at Week 30 the following categories of patients are considered nonresponders:
•Patients with an improvement according to the ACR criteria of less than 20%
•Patients who discontinue the study prior to Week 30 except for safety reasons
•Patients with missing or incomplete data for the evaluation of ACR20 at Week 30
•Patients with protocol prohibited changes in medication including initiation therapy with a new DMARD, increase in dose of RA medication (methotrexate or corticosteroid) and administration of intra articular corticosteroids in more than 1 joint
•Patients requiring a surgical joint procedure during the study
This approach should also be used for other time points where ACR20 is derived.
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Yes |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 | Information not present in EudraCT |
| 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 |
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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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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