| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe rheumatoid arthritis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003268 |
| E.1.2 | Term | Arthritis rheumatoid |
| 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 |
The primary objectives of this study in adult subjects with moderate to severe RA responding inadequately to MTX are as follows:
• To demonstrate the superiority of short term (Week 12) treatment in CZP+MTX randomized subjects as compared with ADA+MTX randomized subjects
• To demonstrate the superiority of long term (Week 104) treatment in CZP+MTX randomized subjects as compared with ADA+MTX randomized subjects, with subjects who switch treatment (Week 12 Non Responders) counted as treatment failures. |
|
| E.2.2 | Secondary objectives of the trial |
• To investigate whether a Week 12 decision point is better at predicting the long term (Week 104) treatment success with CZP+MTX as compared with a Week 12 decision point with ADA+MTX
• To compare the percentage of subjects who meet ACR20 criteria at Week 6 between the CZP+MTX- and ADA+MTX randomized arms
• To compare the percentage of subjects with DAS28(ESR) LDA at Week 6 between the CZP+MTX- and ADA+MTX randomized arms
• To compare the percentage of subjects with DAS28(ESR) LDA at Week 12 between the CZP+MTX- and ADA+MTX randomized arms
• To evaluate the percentage of subjects reaching DAS28(ESR) LDA at Week 104 in subjects responding (in accordance with the Week 12 Responder definition) at both Week 6 and Week 12 when treated with CZP+MTX compared with ADA+MTX
• To evaluate the efficacy of CZP+MTX versus ADA+MTX in the physical function of Week 12 Responders at Week 104
• To evaluate the time to discontinuation in Week 12 Responders treated with CZP+MTX versus ADA+MTX |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Subjects will be given the option to participate in a genetics, genomics, and proteomics sub-study. Subjects who decide to participate in the sub-study must complete a separate Informed Consent Form for Pharmacogenomics and Pharmacogenetics at Screening following the same procedure and given the same considerations as the main Informed Consent Form. Each subject’s willingness to participate in the sub-study will be independent from his/her consent to participate in the main study. |
|
| E.3 | Principal inclusion criteria |
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form is signed and dated by the subject.
2. Subject is considered reliable and capable of adhering to the protocol (eg, able to understand and complete diaries), visit schedule or medication intake according to the judgment of the Investigator.
3. Subject is ≥18 years of age at Screening.
4. Subject must have a diagnosis of RA at Screening, as defined by the 2010 EULAR/ACR classification criteria (Aletaha D et al, 2010).
5. Subject must have a positive rheumatoid factor (RF) and/or a positive anti cyclic citrullinated peptide antibody (anti-CCP) at Screening.
6. Subject must have moderate to severe RA disease at Screening and Baseline as defined by:
• ≥4 swollen joints (of 28 prespecified joints).
• DAS28(ESR) >3.2.
• CRP concentration >10mg/L (or 1.0mg/dL) and/or ESR (Westergren) ≥28mm/hr.
7. Subject must have inadequately responded previously to MTX. Methotrexate-inadequate response is defined as not having achieved DAS28(ESR) ≤3.2 during the 3 to 6 months prior to the Screening Visit according to the Investigator.
8. Subject is using MTX 15 to 25mg/week orally or subcutaneously at Baseline and has used the same MTX regimen (dose and route) during the 56 days prior to Baseline. A MTX dose at a minimum of 10mg/wk orally or subcutaneously is acceptable for subjects considered by the Investigator to be intolerant to a higher dose of MTX.
9. Subject, if using oral corticosteroids at Baseline, is receiving at a stable dose of ≤10mg (unchanged for at least 28 days prior to Baseline).
10. The subject, if female, must be either postmenopausal for at least 1 year, surgically incapable of childbearing, or effectively practicing an acceptable method of contraception (oral/parenteral/implantable hormonal contraceptives, intrauterine device, or barrier and spermicide). Abstinence only is not an acceptable method. Subjects must agree to use adequate contraception from Screening through at least 10 weeks (or longer if required by local regulations) after the final dose of IMP. Male subjects must agree to ensure they or their female partner(s) use adequate contraception from Screening through at least 10 weeks (or longer if required by local regulations) after the final dose of IMP. |
|
| E.4 | Principal exclusion criteria |
1. Subject has previously participated in this study or subject has previously received any bDMARD during another clinical study or independent of another clinical study.
2. Subject has participated in another study of medication or a medical device within the previous 3 months or is currently participating in another study of a medication or medical device under investigation.
3. If a female subject, is breastfeeding, pregnant, or plans to become pregnant during the study or within 10 weeks following final dose of IMP or thereafter according to local regulations.
4. Subject has a known hypersensitivity to any components of CZP or ADA, or a history of an adverse reaction to polyethylene glycol (PEG).
5. Subject has a contraindication to the use of CZP, ADA, or MTX.
6. Subject must not have a secondary, noninflammatory type of musculoskeletal condition (eg, osteoarthritis or fibromyalgia) that in the Investigator’s opinion is symptomatic enough to interfere with evaluation of the effect of the IMP on the subject’s primary diagnosis of RA.
7. Subject must not have a diagnosis of any other inflammatory arthritis (eg, psoriatic arthritis or ankylosing spondylitis) or have a Steinbrocker IV functional capacity.
8. Subject must not have previously received any experimental nonbiological therapy.
9. Subject must be free of prohibited use or a limited use of concomitant medication as detailed in Table 6:1 of the Protocol.
10. Subject with concurrent malignancy or a history of malignancy (subjects with fewer than 3 excised basal cell carcinomas or with cervical carcinoma in situ successfully surgically treated more than 5 years prior to Screening may be included).
11. Subject with a history of a lymphoproliferative disorder including lymphoma or signs and symptoms suggestive of lymphoproliferative disease.
12. Subjects with a history of blood dyscrasias.
13. Subject with a current or recent history, as determined by the Investigator, of severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, or cerebral disease or other significant immunological/inflammatory disease including systemic lupus erythematosus or irritable bowel syndrome.
14. Subject with class III or IV congestive heart failure as defined by the New York Heart Association 1964 classification criteria.
15. Subject with a history of, or suspected, demyelinating disease of the central nervous system (eg, multiple sclerosis or optic neuritis).
16. Subject with any other condition (ie, clinically significant laboratory values) which, in the judgment of the Investigator, would make the subject unsuitable for inclusion in the study.
17. Subject with a value ≥1.2xULN for any of the following liver function tests (LFTs):
• Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase [GOT]).
• Alanine aminotransferase (ALT) (glutamate pyruvate transaminase [GPT]).
• Gamma-glutamyl transferase (GGT).
18. Subject has history of chronic alcohol or drug abuse within the previous 6 months.
19. Subject has any medical or psychiatric condition that, in the opinion of the Investigator, can jeopardize or would compromise the subject’s ability to participate in this study.
20. Subject with history of or current clinically active infection (including chest x-ray) with Histoplasma, Coccidioides, Paracoccidioides, Pneumocystis, Mycobacteria (other than tuberculosis), Blastomyces, or Aspergillus.
21. Subject with a history of chronic or recurrent infections (>3 episodes requiring antibiotics or antivirals during the preceding year), recent serious or life threatening infection within the 6 months prior to the Baseline Visit (including Herpes zoster), hospitalization for any infection in the previous 6 months, or any current sign or symptom that may indicate an infection.
22. Subject at a high risk of infection (eg, subject has leg ulcers, indwelling urinary catheter, or persistent or recurrent chest infections; or subject who is permanently bedridden or wheelchair bound).
23. Subject with concurrent acute or chronic viral Hepatitis B or C infection.
24. Subject with known human immunodeficiency virus infection.
25. Subject receiving live or attenuated vaccination during the 8 weeks (56 days) prior to Baseline. Live or attenuated vaccines are not allowed to be used concurrently with CZP or ADA during the study.
26. Subjects with known Tuberculosis (TB) disease, high risk of acquiring TB infection, or latent TB infection as defined in the Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Percentage of subjects meeting ACR20 criteria [American College of Rheumatology 20% criteria] in the CZP+MTX randomized group compared with the ADA+MTX randomized group;
2) Percentage of subjects with DAS28(ESR) LDA [Disease Activity Score-28 joint count(erythrocyte sedimentation rate) Low disease activity] in the CZP+MTX randomized group compared with the ADA+MTX randomized group (Group A versus Group C using all randomized subjects in the FAS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Among the others:
1) The percentage of subjects with DAS28(ESR) LDA at Week 104 comparing the Week 12 Responder groups (Group A versus Group C).
2) The percentage of subjects with DAS28(ESR) LDA at Week 6 using all subjects, comparing the CZP+MTX randomized arm and the ADA+MTX randomized arm
3) The percentage of subjects with DAS28(ESR) LDA at Week 12 using all subjects, comparing randomized treatment groups CZP+MTX and ADA+MTX
4) The percentage of subjects with DAS28(ESR) LDA at Week 104 comparing the Week 12 Responder groups (Group A versus Group C), who also responded at Week 6 (ie, DAS28(ESR) ≤3.2 or a DAS28(ESR) CFB reduction of ≥1.2) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Week 104
2) Week 6
3) Week 12
4) Week 104 |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | Yes |
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 |
| Australia |
| Canada |
| Mexico |
| Switzerland |
| Turkey |
| United States |
|
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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