| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes
inflammation and deformity of the joints. Other problems may also develop, including inflammation in various parts of the body. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10039075 |
| E.1.2 | Term | Rheumatoid arthritis and associated conditions |
| E.1.2 | System Organ Class | 100000004870 |
|
| 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 Part 1 of the study is:
"To evaluate and compare pharmacokinetics in terms of area under the serum concentration-time curve from zero to time of last quantifiable concentration (AUC0-last), AUC from zero to infinity (AUC0-∞) and maximum serum concentration (Cmax) (after the second infusion) of CT-P10 to Rituxan, CT-P10 to MabThera and Rituxan to MabThera during the first course of treatment (over the first 24 weeks)."
The primary objective of Part 2 of the study is:
• To demonstrate that CT-P10 is similar to reference products (Rituxan and MabThera) 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) (C-reactive protein [CRP]) at Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of Part 1 of the study are:
• To assess the additional PK variables of CT-P10, Rituxan and MabThera during the first course of treatment (over the first 24 weeks).
• To evaluate the pharmacodynamics and safety of CT-P10, Rituxan and MabThera (over the first 24 weeks).
The secondary objective of Part 2 of the study is:
• To evaluate the additional PK (up to Week 48), efficacy, PD, overall safety, and biomarkers of CT-P10 compared with reference products. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following criteria to be enrolled in this study:
1. Patient is male or female between 18 and 75 years old, inclusive.
2. Patient has a diagnosis of RA according to the revised 1987 ACR classification criteria (Arnett et al 1988) for at least 6 months prior to randomization.
3. Patient has active disease as defined by the presence of 6 or more swollen joints (of 66 assessed) and 6 or more tender joints (of 68 assessed), and serum CRP ≥1.5 mg/dL (≥15 mg/L) or an ESR ≥28 mm/hour.
4. Patient has experienced an inadequate response to previous or current treatment with the anti-TNF agents infliximab (≥3 mg/kg; at least 3 infusions for at least 3 months), golimumab (50 mg once a month for at least 12 to 14 weeks or 2 mg/kg IV infusion for at least 3 months), adalimumab (40 mg every other week for at least 3 months), or etanercept (25 mg twice weekly or 50 mg once weekly for at least 3 months), or was intolerant to at least 1 administration of these agents. Patients who discontinued etanercept for at least 4 weeks, infliximab or adalimumab for at least 8 weeks, or golimumab for at least 10 weeks prior to randomization are permitted to enter the study.
Patients who received any other anti-TNF agents not in this list can be enrolled if the patient discontinued the treatment at least 4 weeks or 5 half-lives prior to randomization, whichever is longer.
5. Patient has a proper discontinuation period after treatment with interleukin-1 receptor (IL-1R) antagonist, interleukin-6 receptor (IL-6R) antibody, or abatacept. Patients who discontinued IL-1R antagonist for at least 4 weeks, abatacept for at least 8 weeks, or IL-6R antibody for at least 17 weeks prior to randomization are permitted to enter the study.
Patients who had any other biological drugs not in this list can be enrolled if the patient discontinued the treatment at least 4 weeks or 5 half-lives prior to randomization, whichever is longer.
6. Patient has received MTX treatment (7.5 to 25 mg/week orally or parenterally) for at least the past 12 weeks, with the last 4 weeks at a stable dose before Screening.
7. Patient has the following hematology laboratory test results at Screening:
• Hemoglobin ≥8.0 g/dL
• White blood cell count ≥3.5 × 10 3 cells/μL (SI [Système International d'Unités] units: ≥3.5 × 10 9 cells/L)
• Neutrophil count ≥1.5 × 10 3 cells/μL (SI units: ≥1.5 × 10 9 cells/L)
• Platelet count ≥75× 10 3 cells/μL (SI units: ≥75 × 10 9 cells/L)
8. 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
9. 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.
10. Patient (or legal guardian, if applicable) has been 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, and provide signed and dated written informed consent before inclusion in the study.
11. For both male and female patients, the patient and their partners of childbearing potential either agree to practice total abstinence or use 2 of the following medically acceptable methods of contraception during the course of the study and for 12 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 2 medically acceptable methods of contraception or to practice total abstinence.
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. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from the study:
1. Patient has taken more than 2 biologic agents.
2. Patient has previously been administered Rituximab or participated in a Rituximab biosimilar study.
3. Patient has allergies or hypersensitivity to murine, chimeric, human, or humanized proteins.
4. Patient has current or past history of chronic infection with hepatitis B, hepatitis C, or infection with human immunodeficiency virus (HIV)-1 or -2 or who has a positive result to the screening test for these infections.
5. Patient has an infection requiring oral antibiotics 2 weeks before randomization,
parenteral injection of antibiotics 4 weeks before randomization, other serious infection 6 months before randomization, a history of recurrent herpes zoster or other chronic or recurrent infection 6 weeks before randomization.
6. Patient has a past or current diagnosis of tuberculosis (TB), recent exposure to person with active TB, examination findings indicating the presence of TB, defined as a positive result for interferon-γ release assay, or other severe or chronic infection (such as sepsis, abscess or opportunistic infection, or invasive fungal infection such as histoplasmosis). A patient who has a past diagnosis with sufficient documentation of prophylaxis or complete resolution following treatment can be enrolled.
7. Patient is receiving any of the following medications or therapies:
• Previous treatment within 6 months of IV gamma globulin or the Prosorba Column
• Any surgical procedure, including bone or joint surgery or synovectomy (including
joint fusion or replacement) within 12 weeks prior to randomization or planned within 6 months after randomization
• Intra-articular corticosteroids within 8 weeks prior to randomization. Patients are permitted to receive either oral or parenteral glucocorticoids (≤10 mg daily of
prednisone/prednisolone or equivalent), and nonsteroidal anti-inflammatory drug, if they have received a stable dose for at least 4 weeks prior to randomization. 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.
• Disease-modifying antirheumatic drugs, other than MTX, including
hydroxychloroquine, chloroquine, or sulfasalazine, within 4 weeks prior to randomization. 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 randomization. Patients who discontinued leflunomide and did not have a
cholestyramine discontinuation period must wait 12 weeks after last dose of
leflunomide before randomization.
• Live or live-attenuated vaccine within 8 weeks prior to randomization, and killed
vaccines within 4 weeks prior to randomization
• History of any biologic agent causing B-cell depletion or targeting B-cells
8. Patient has a medical condition including one or more of the following:
• Uncontrolled diabetes mellitus, even after insulin treatment
• Uncontrolled hypertension at the discretion of the investigator
• Any other inflammatory or rheumatic disease, including but not limited to psoriatic arthritis, ankylosing spondylitis, spondyloarthritis, systemic lupus erythematosus, Lyme disease, or fibromyalgia, that may confound the evaluation of the effect of study drug
• History of any malignancy within the previous 5 years prior to date of informed
consent except completely excised or cured squamous carcinoma of the uterine cervix, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma
• History of lymphoma, lymphoproliferative disease, or bone marrow hypoplasia
• Patients with New York Heart Association class III or IV heart failure, severe
uncontrolled cardiac disease (unstable angina, arrhythmias, clinically significant
electrocardiogram [ECG] abnormalities), or myocardial infarction within the previous 6 months prior to date of consent
• History of organ transplantation, including corneal graft/transplantation
• Severe physical incapacitation (unable to perform routine self-care), has RA ACR
functional status class 4, or no expected benefit from medication
• 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
• Any condition significantly affecting the nervous system (i.e., neuropathic conditions or nervous system damage) if it may interfere with the investigator’s assessment of disease assessment scores including joint counts.
Please Refer to the Protocol Section 4.1.2 Exclusion Criteria for a full list of Exclusion Criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The following PK parameters for the study drug (CT-P10, Rituxan and MabThera) will be determined as co-primary PK endpoints in Part 1 (over the first 24 weeks):
• AUC0-last: area under the serum concentration-time curve covering both infusions, time to the last measurable concentration
• AUC0-∞: area under the serum concentration-time curve covering both infusions, time zero to infinity
• Cmax: maximum concentration after the second infusion
The following efficacy parameter for the study drug (CT-P10 and reference products [Rituxan and MabThera]) will be determined as the primary efficacy endpoint:
• The change from Baseline in disease activity measured by DAS28 (CRP) at Week 24
• The proportion of patients achieving clinical response (according to the ACR20 criteria) at Week 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to E.5.1 and also the protocol |
|
| E.5.2 | Secondary end point(s) |
The following PK parameters for the study drug (CT-P10, Rituxan and MabThera) will be determined as secondary PK endpoints in Part 1 (over the first 24 weeks):
• AUC0-day14: area under the serum concentration-time curve covering both infusion, time zero to day 14
• Vd: volume of distribution
• CL: total clearance
• t1/2: terminal elimination half-life after the second infusion
• Tmax: time to Cmax after both the first and second infusions
• Cmax, 1: maximum concentration after the first infusion
• Cmin: concentration at Week 24
• Ctrough: trough concentration prior to the second infusion
The following PK parameters for the study drugs (CT-P10 and reference products [Rituxan and MabThera]) will be determined as secondary PK endpoints in Part 2 (up to Week 48 or over the first 24 weeks if second course of treatment is not administered):
• Tmax: time to Cmax after both the first and second infusions
• Cmax: maximum concentration after both the first and second infusions
• Cmin: concentration at Weeks 24 and 48
• Ctrough: trough concentration prior to the second infusion
The following efficacy parameters for the study drugs will be determined as secondary efficacy endpoints:
• ACR20, ACR50 and ACR 70 at Week 24, Week 48 and Extension Week 24
• Individual components of the ACR criteria compared with Baseline at Week 24 , Week 48 and Extension Week 24
• Time to onset of ACR20 response over 24 weeks
• Mean change from Baseline in disease activity measured by DAS28 (CRP) at Weeks 12 and 48 and Extension Week 24 and DAS28 (ESR) at Weeks 12, 24 and 48 and Extension Week 24
• Proportion of patients with a good response, defined according to the European League Against Rheumatism (EULAR) response criteria at Week 24, Week 48 and Extension Week 24
• Hybrid ACR response at Week 24, Week 48 and Extension Week 24
• SDAI and CDAI at Week 24, Week 48 and Extension Week 24
• Joint damage progression based on radiographic evaluations, van der Heijde modification of the Sharp scoring system at Week 48, Extension Week 24 and the EOS visit
• Functional disability (HAQ disability index) at Week 24, Week 48 and Extension Week 24
• Health-related quality of life (SF-36 health survey score) compared with Baseline at Week 24, Week 48 and Extension Week 24
The following safety parameters for the study drug (CT-P10, Rituxan and MabThera) will be determined as secondary safety endpoints:
• Immunogenicity testing
• Immunoglobulin (IgM, IgG and IgA) testing
• Hypersensitivity monitoring via vital sign measurements (including blood pressure, heart and respiratory rates, and temperature) and ECGs
• Vital sign measurements
• ECGs
• Signs and symptoms of TB monitoring
• Physical examination findings
• AEs
• Infections
• Infusion related reactions (IRRs)
• Clinical laboratory analyses
• Pregnancy testing
• Concomitant medications
The following PD parameters for the study drug (CT-P10, Rituxan and MabThera) will be determined as PD endpoints:
• B-cell kinetics over time including depletion and recovery
• CRP and ESR at Week 24, Week 48 and Extension Week 24
• Rheumatoid factor and anti-CCP at Week 24, Week 48 and Extension Week 24
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to E.5.2 and also the protocol |
|
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 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 | 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 |
| Austria |
| Bosnia and Herzegovina |
| Bulgaria |
| Chile |
| Colombia |
| Germany |
| Greece |
| Hungary |
| Israel |
| Korea, Republic of |
| Latvia |
| Mexico |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Ukraine |
|
| 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
|
| The date when last patient completes the last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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