| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe active rheumatoid arthritis (RA) diagnosed according to the 2010 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria (Aletaha et al., 2010) for at least 24 weeks, who have inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). |
|
| E.1.1.1 | Medical condition in easily understood language |
| moderate to severe active rheumatoid arthritis (RA) |
|
| 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 | 23.1 |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate that CT-P47 is equivalent to RoActemra, in terms of efficacy as determined by clinical response according to the change from baseline in disease activity measured by Disease Activity Score using 28 joint counts (DAS28) (Erythrocyte-Sedimentation Rate [ESR]) at Week 12. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate additional efficacy, pharmacokinetics (PK), and overall safety, including immunogenicity. |
|
| 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 aged 18 to 75 years old, both inclusive.
2. Patient has had a diagnosis of RA according to the 2010 ACR/EULAR classification criteria (Aletaha et al., 2010) for at least 24 weeks prior to the first administration of the study drug (Day 1).
3. Patient must have moderate to severe disease activity as defined by all of the following at Screening:
• 6 or more swollen joints (of 66 assessed)
• 6 or more tender joints (of 68 assessed)
• either an ESR ≥28 mm/hour or a serum C-reactive protein (CRP) concentration ≥1.0 mg/dL (≥10 mg/L)
• DAS28 (ESR or CRP) ≥3.2
4. Patient who has been receiving oral or parenteral MTX for at least 12 weeks and who has been on a stable dose and route of MTX between 10 to 25 mg/week for at least 8 weeks prior to the first administration of the study drug (Day 1).
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) (SI [Système International d'Unités] units: 0.84 mL/s)
• Serum alanine aminotransferase ≤2.0 × ULN
• Serum aspartate aminotransferase ≤2.0 × ULN
• Serum total bilirubin ≤1.5 × ULN
6. Patient has the following hematology laboratory test results at Screening:
• Absolute neutrophil count ≥2,000/mm3 (2.0×103/μL)
• Platelet count ≥100,000/mm3 (100.0×103/μL)
7. Patient and their partner of childbearing potential must agree to use following highly effective method of contraception consistent with local regulations throughout the study and for 6 months after the last dose of assigned treatment. A man or woman is of childbearing potential if, in the opinion of the investigator, he or she is biologically capable of having children and is sexually active (i.e., a man is fertile after puberty unless permanently sterile by bilateral orchidectomy or a woman is fertile, following menarche and until becoming postmenopausal unless permanently sterile).
Combined (estrogen and progestogen containing) or progestogen-only hormonal contraceptives associated with inhibition of ovulation
Intrauterine device or system
True abstinence, when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to investigational drug, and withdrawal are not acceptable methods of contraception.
Double contraceptive methods (e.g., male condom in addition to use of hormonal or barrier method in female); for male patient with his female partner of childbearing potential only.
If patient or their partner has been surgically sterilized for less than 24 weeks prior to the date of informed consent, they must agree to use any medically acceptable methods of contraception. Postmenopausal females must have experienced their last menstrual period more than 1 year prior to the date of informed consent without an alternative medical cause to be classified as not of childbearing potential.
8. Patient (or legal guardian, if applicable) is informed of the full nature and purpose of the study, including possible risks and side effects, has the ability to cooperate with the investigator and is given ample time and opportunity to read and understand verbal and/or written instructions, and signs the written informed consent form with date prior to participation in the study. |
|
| E.4 | Principal exclusion criteria |
A patient meeting any of the following criteria will be excluded from the study:
1. Patient who has previously received investigational or licensed product; targeted synthetic DMARD(s) (e.g., tofacitinib, baricitinib) for the treatment of RA and/or an interleukin-6 (IL-6) inhibitor for any purposes.
2. Patient who has previously received more than 1 biologic agents approved for the treatment of RA.
3. Patient who has allergies to any of the excipients of study drug or any other murine and human proteins, or patient with a hypersensitivity to immunoglobulin products.
4.Patient who currently has, or has a history of, any of the following infections:
• A known infection with hepatitis B (active or carrier of hepatitis B) or hepatitis C, or infection with human immunodeficiency virus (HIV). However, a patient with past hepatitis B virus is allowed if resolved (confirmed by negative HBsAg and HBV DNA).
• Acute infection requiring oral antibiotics within 2 weeks or parenteral injection of antibiotics within 4 weeks prior to the first administration of the study drug (Day 1)
• Recurrent herpes zoster or other chronic or recurrent infection within 6 weeks prior to the first administration of the study drug (Day 1)
• Past or current granulomatous infections or other severe or chronic infections (such as sepsis, abscess, opportunistic infections, or invasive fungal infections such as histoplasmosis). However, a patient who has a past diagnosis with sufficient documentation of complete resolution of the infection can be enrolled in the study.
• Other serious infections within 24 weeks prior to the first administration of the study drug (Day 1)
5.Patient who currently has, or has a history of, any of the following tuberculosis (TB):
• Patient who has current or a history of active TB. Patient who has any evidence of history of active TB cannot be enrolled despite sufficient documentation of complete resolution of active TB.
• Patient who has signs or symptoms suggestive of active TB.
• Patient who has had exposure to a person with active TB such as first-degree family members or co-workers within 16 weeks prior to the first administration of the study drug (Day 1).
• Patient who has a past diagnosis of latent TB unless they have documentation of completing TB prophylaxis, or have received at least the first 3 weeks of country-specific TB prophylaxis prior to the first administration of the study drug (Day 1) and intends to complete its entire course can be enrolled.
• Patient who has a current diagnosis of latent TB (defined as a positive result of interferon-γ release assay [IGRA] with a negative examination of chest X-ray) at Screening without a history of active TB or latent TB. However, a patient who has received at least the first 3 weeks of country-specific TB prophylaxis prior to the first administration of the study drug (Day 1) and intends to complete its entire course can be enrolled.
• Patient who is without a history of active TB or latent TB and has an indeterminate result of IGRA with a negative examination of chest X-ray at Screening. If the result of IGRA is indeterminate at Screening, 1 retest will be allowed during the Screening Period. Depending on the result of retest, the enrollment will be determined as follows:
- If the repeated IGRA result is negative, the patient can be enrolled.
- If the repeated IGRA result is positive, the patient who has received at least the first 3 weeks of country-specific TB prophylaxis prior to the first administration of the study drug (Day 1) and intends to complete its entire course can be enrolled.
- If the repeated IGRA result is again indeterminate, the patient cannot be enrolled.
6. Severe physical incapacitation .
7. Female patient who is currently pregnant or breastfeeding, or plans to become pregnant or breastfeed within 6 months of the last dose of study drug. Male patient who is planning to donate sperm or father a child within 6 months of the last dose of study drug.
8. Patient who currently abuses alcohol or drugs or has a history of alcohol or drug abuse within 1 years from Screening.
9. Patient is vulnerable.
10. Patient who, in the opinion of the investigator, should not participate in the study.
Please refer to the protocol to see the whole list of exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The difference of mean change from baseline of DAS28 (ESR) score at week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The following secondary efficacy endpoints will be assessed up to Week 52:
• ACR20, ACR50 and ACR70
• Individual components of the ACR
• Hybrid ACR response
• DAS28 (CRP)
• DAS28 (ESR) (except for Week 12)
• Individual components of the DAS28
• EULAR response
• Simplified disease activity index (SDAI) and clinical disease activity index (CDAI)
• ACR/EULAR remission (Boolean-based definition)
• 36-item short form health survey (SF-36)
• Joint damage progression based on radiographic evaluations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| 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 | 2 |
| 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 | 22 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 end of trial is defined as the date that the final database lock with no further database change for the final CSR. |
|
| 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 | 29 |
| 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 | 29 |
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