| 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 is a chronic inflammatory disease causing pain and swelling in the joints. The cause of the disease is unknown. In addition, the disease can involve other tissues of the body. |
|
| 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 | 18.0 |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy between infliximab-Pfizer and infliximab-EU in subjects with moderately to severely active RA who are treated with infliximab in combination with methotrexate. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the overall safety and tolerability of infliximab-Pfizer and infliximab-EU.
- To evaluate the immunogenicity of infliximab-Pfizer and infliximab-EU.
- To evaluate the overall safety, tolerability and immunogenicity of infliximab-Pfizer after treatment transition from infliximab-EU to infliximab-Pfizer.
- To evaluate the population pharmacokinetics (PK) of infliximab-Pfizer and infliximab-EU.
- To evaluate the pharmacodynamic (PD) response to infliximab-Pfizer and infliximab-EU.
- To evaluate the individual ACR parameters of clinical response to infliximab-Pfizer and infliximab-EU. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male and female subjects aged 18 years or older at the time of informed consent. Where required by regulations, consent from a legal representative is required for all subjects who are younger than 20 years of age.
4. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 6 months after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
Female subjects who are not of childbearing potential must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum FSH level in the laboratory’s reference range for postmenopausal females.
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy.
c. Have medically confirmed ovarian failure.
All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy or bilateral oophorectomy) will be considered to be of childbearing potential.
5. Diagnosis of rheumatoid arthritis (RA) based on 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR)
classification criteria (see Appendix 1) for RA for at least a 4 month duration.
6. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA (see Appendix 2).
7. Moderately to severely active RA disease as defined by the following criteria:
a. ≥ 6 tender joints (of 68 assessed) at both Screening and Baseline, and
b. ≥ 6 swollen joints (of 66 assessed) at both Screening and Baseline, and
c. Hs-CRP ≥10 mg/L (≥1 mg/dL) at Screening, performed by a central
laboratory. Subjects who do not meet this entry criteria but satisfy all other study entry criteria may have serum hs-CRP concentration re-tested once within 14 days and, if the repeat hs-CRP concentration is ≥10 mg/L
(≥1 mg/dL), will be eligible to enroll into the study provided all other
inclusion/exclusion criteria are met.
8. Stable dose of oral or parenteral methotrexate of 10 to 25 mg/week. Subjects who cannot tolerate 10 to 25 mg/week methotrexate may take a lower dose of as low as 7.5 mg/week. In geographic regions where specified by local guidance or standard of care, a stable dose of as low as 6mg/week is allowed. Subjects must have received methotrexate for at least 12 weeks and be on a stable dose for at least 4 weeks prior to first dose of study drug.
9. Stable dose of oral folic or folinic acid (≥5 mg once per week) supplementation for at least 21 days prior to the first dose of study drug.
10. If receiving an oral corticosteroid, subjects must be on a stable dose of ≤ 10 mg/day of prednisone (or equivalent) for 4 weeks prior to the first dose of study drug, without any intramuscular (IM) or intra-articular (IA) corticosteroids within the 4 weeks prior to the first dose of study drug.
11. If receiving a NSAID/Cox-2 inhibitor, subject must be on a stable dose of only one NSAID/Cox-2 inhibitor drug for 4 weeks prior to the first dose of study drug at a dosage less than or equal to the maximum recommended dose in the product information. In addition, a cardiovascular dose of aspirin (≤325 mg/day) is permitted. Topical NSAIDs (in addition to one NSAID/Cox-2 inhibitor drug) are allowed, prior to and during the study. Topical NSAIDs should not be used within 24 hours prior to joint assessments. |
|
| E.4 | Principal exclusion criteria |
1. Pregnant females and breastfeeding females; males and females of childbearing potential who are unwilling or unable to use a highly effective method of contraception for the duration of the study and for at least 6 months after last dose of investigational product. Females must not breastfeed for at least 6 months after last dose of investigational product.
2. Clinically significant laboratory abnormalities at Screening, including but not limited to inadequate bone marrow, liver, renal and immune system functions.
3. Evidence or history of moderate or severe heart failure (NYHA class III/IV, see Appendix 11 for NYHA classification of congestive heart failure) and subjects who are contraindicated for treatment with infliximab in accordance with the approved local label.
4. Evidence of current or recent history of uncontrolled, clinically significant infectious, hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease.
5. Evidence or history of seizures, or nervous system demyelinating diseases.
6. Evidence or history of a malignancy within the past 5 years with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin, or cervical carcinoma in situ with no evidence of recurrence.
7. History of any lymphoproliferative disorder
8. History of recurrent (more than one episode) limited herpes zoster or disseminated (a single episode) herpes zoster or herpes simplex. History of disseminated or recurrent infection of EBV or human papilloma virus (HPV) (a single, limited episode in the past is not exclusionary)
9. Infection requiring hospitalization or parenteral antimicrobial therapy judged clinically significant by the investigator within 6 months prior to first dose of study drug.
10. History of an infected joint prosthesis at any time.
11. History of recurrent inflammatory joint disease other than RA (eg, post infectious arthritis, gout, etc.) or history of any other autoimmune rheumatic diseases (eg, vasculopathies, spondyloarthropathies, etc.) other than Sjogren’s syndrome.
12. Evidence of untreated or inadequately treated latent, or inadequately treated or active infection with tuberculosis (TB). Subjects currently receiving treatment for active or latent TB are excluded.
13. Chest radiography with evidence of active TB, fungal infections, or other clinically significant abnormalities taken at Screening or within 12 weeks prior to first dose of study drug on Day 1.
14. Any current or prior treatment for the following DMARDs within the relevant washout period.
15. Current or prior treatment with infliximab or lymphocyte depleting therapies (eg, Rituximab, Campath). Prior exposure to biologic therapy for RA (with exception of up to 2 doses of one biologic therapy for RA, including anti-TNF therapies (other than infliximab). For prior exposure to a biologic therapy for RA, a washout period of at least 12 weeks of 5 half lives (whichever is longer) is required prior to the first dose of study drug.
16. Known requirement for treatment with prohibited concomitant medications during study.
17. Significant trauma or surgical procedure within 4 weeks prior to first dose of study drug.
18. Known or Screen test positive human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
19. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results.
20. Positive urine drug test at Screening for substances of abuse that is not due to prescribed medication.
21. Past or current history of addiction or dependence on non-prescribed substances within 12 months prior to Screening.
22. History of allergic or hypersensitivity reaction to active or inactive components of the study drug or any murine, chimeric or human proteins.
23. Exposure to any live vaccines within 4 weeks prior to administration of the first dose of study drug or lack of willingness to avoid exposure to any live vaccines during the trial and for at least 3 months after the last dose of study drug.
24. Participation in other studies involving investigational drug(s) (Phase 1-4) within at least 4 weeks or 5 half-lives from last dose, whichever is longer, before the current study begins and/or during study participation.
25. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. (Shortened. For full exclusion criteria refer to protocol section 4.2) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ACR20 response (≥ 20% improvement by ACR criteria) at Week 14. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At week 14. In addition, point estimates and 95% CIs in difference of
ACR20 response rates between the two treatment arms at Weeks 2, 4, 6, 12, 22, and 30, will be used to support the primary efficacy analysis. |
|
| E.5.2 | Secondary end point(s) |
- Categorical and continuous measures of clinical efficacy, including ACR20 (other than Week 14), ACR50, ACR70, change in DAS28-CRP (Disease Activity Score-28 4 components based on CRP), DAS remission (≤2.6), EULAR (European League Against Rheumatism) response, ACR/EULAR remission, and change in HAQ-DI.
- Safety measures characterized by type, incidence, severity, timing, seriousness and relatedness of adverse events and laboratory abnormalities.
- Change from baseline in individual components of ACR response.
- Incidence and titers of anti-drug antibodies (ADA) and neutralizing antibodies (Nab) in response to infliximab-Pfizer and infliximab-EU.
- Serum drug concentrations. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At Week 14 and other protocol-defined time points up to Week 30. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
Immunogenicity
Biosimilar |
|
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Argentina |
| Australia |
| Bosnia and Herzegovina |
| Brazil |
| Canada |
| Colombia |
| European Union |
| Georgia |
| Guatemala |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Morocco |
| Peru |
| Philippines |
| Russian Federation |
| Serbia |
| South Africa |
| Tunisia |
| Ukraine |
| 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
|
| End of Trial in all participating countries is defined as Last Subject Last Visit. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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