| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003268 |
| E.1.2 | Term | Arthritis rheumatoid |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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, 12 and 52 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 compare physical function at Week 104 between the CZP+MTX- and ADA+MTX-randomized arms
• 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) as determined by the central laboratory at Screening.
6. Subject must have moderate to severe RA disease at Screening and Baseline defined as:
a) Screening (all criteria required): i. ≥4 swollen joints (of 28 prespecified joints). ii. DAS28(ESR) >3.2. iii. CRP concentration ≥10mg/L (or 1.0mg/dL) and/or ESR (Westergren) ≥28mm/hr. b) Baseline (both criteria required): i. ≥4 swollen joints (of 28 prespecified joints). ii. DAS28(ESR) >3.2.
7. Subject is considered by the Investigator to be responding inadequately to treatment with MTX. An inadequate response to MTX is based on the opinion of the Investigator and following a minimum 12-week course of MTX therapy prior to the Screening Visit.
8. Subject is using MTX 15 to 25mg/week orally or subcutaneously at Screening and has used the same MTX regimen (dose and route) for a minimum of 28 days prior to Baseline
9. If using oral corticosteroids at Baseline, the subject is using a stable dose of ≤10mg (unchanged for at least 28 days prior to Baseline). However, when deemed clinically necessary, 1 dose adjustment of no more than ±2.5mg during the 28 days prior to Baseline is acceptable provided the total dose does not exceed 10mg.
10. The subject, if female, must be either postmenopausal for at least 1 year, surgically sterile, or practicing an acceptable method of contraception, such as:
a. oral / parenteral / implantable hormonal contraceptives, intrauterine device, or barrier and spermicide.
b. Subjects must agree to use adequate forms of contraception from Screening through at least 10 weeks (or longer if required by local regulations as reflected by local product labelling) after the final dose of IMP.
c. 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 as reflected by local product labelling) after the final dose of IMP. Note: Abstinence is not an acceptable method of
contraception; therefore, subjects engaging or intending to engage in sexual activity must agree to employ 1 of the aforementioned acceptable methods of contraception.
11. Subject must have completed the Washout Periods for analgesics and nonbiologic DMARDs (except MTX) in accordance with Table 6.1 of the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Subject has previously participated in this study (except when rescreening criteria apply) or subject (sbj) has received treatment with any biologic DMARD or has received treatment with cyclophosphamide,chlorambucil,Janus kinase,spleen tyrosine kinase or phosphodiesterase 4 inhibitors or investigational agents such as spleen tyrosine kinase. 2. Sbj was randomized in another study of medication or a med. device within the previous 3 months or is currently participating
in another study of a medication or med. device under investigation
[Criterion 3-4-5-6: please refer to the protocol – not modified by this amendment]
7. Sbj must not have a diagnosis of any other inflammatory arthritis (eg psoriatic arthritis, ankylosing spondylitis or systemic lupus erythematosus/lupus nephritis) or have a Steinbrocker IV functional
capacity. Sbj with Sjogren's Syndrome, as assessed by the PI to be limited to mild or moderate sicca symptoms that are considered to be a manifestation of secondary Sjogren's Syndrome related to RA, may be enrolled. However, systemic manifestations attributable to primary Sjogren's Syndrome are still considered exclusionary
8. Sbj must not have received any experimental biological or nonbiological therapy for immuno inflammatory indications
9. The subject may not use prohibited medications and may only use (if needed) medications within protocol defined limitations as outlined in IC 11 and Table 6.1
10. Sbj with active malignancy or a history of cancer. Exceptions are subjects with: no more
than 2 basal cell carcinomas excised prior to study entry - cervical carcinoma in situ successfully surgically treated more than 5 yrs prior to Screening
11. Sbj with a history of a lymphoproliferative disorder including lymphoma or signs and symptoms suggestive of lymphoproliferative disease
12. Sbj with a history of blood dyscrasias
13. Sbj with a recent history or existing condition, as determined by the PI, of severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac,
neurological, or cerebral disease or other significant immunological/inflammatory disease including but not limited to inflammatory bowel disease
[Criterion 14-15-16-17-18-19: please refer to the protocol - not modified by this amendment]
20. Sbj with a history or active systemic/respiratory infection due to fungal, parasitic, or
mycotic pathogens including but not limited to histoplasmosis, coccidiosis, paracoccidiosis, pneumocystis, blastomyces, aspergillus and nontuberculus mycobacteria. Radiographic findings suggestive of infections such as apical fibrosis, pleural thickening, pulmonary nodules (including any pulmonary nodules of unspecified significance), fibrotic scars, calcified granulomas, upper lobe infiltrates, cavitations and pleural effusions, calcified lung nodules, calcified hilar lymph nodes, and
pericardial calcification or any other finding that could be suggestive of inactive TB or active TB, are sufficient grounds for exclusion. Radiographs will be assessed by a radiologist whose review of the
radiograph includes a deliberate assessment of the presence or absence of TB infection, granulomatous disease, etc. Any abnormal radiographic findings should be discussed with the Sponsor and/or Medical Monitor prior to subject enrollment
21. Sbj with a history of chronic or recurrent infections such as: - more than 3 episodes requiring antibiotics or antivirals during the preceding 6 months) or - recent serious or life threatening infection within the 12 months prior to the Baseline Visit (including Herpes zoster) or - hospitalization for any infection in the previous 6 months, or - any sign or symptom that may indicate an infection
22. Sbj at a high risk of infection (eg sbj has leg ulcers, indwelling urinary catheter, or persistent or recurrent chest infections; or sbj who is permanently bedridden or wheelchair bound)
23. Sbj with concurrent acute or chronic viral Hepatitis B or C infection including a
positive test for any of the following are exclusionary: - Hepatitis B core antibody; - Hepatitis B surface antigen, - Hepatitis C antibody
24. Sbj with known human immunodeficiency virus infection
25. Sbj receiving live or attenuated vaccination during the 8 weeks (56 days) prior to Baseline. Live or attenuated vaccines are not permitted to be administered to be used concurrently with CZP or ADA during the study
26. Sbj with known TB infection, at high risk of acquiring TB infection, or latent TB infection are exclusionary, as defined in the Protocol.
27. Subject must not have been exposed to more than 4 different nonbiological DMARDs over their lifetime
28. Subject has a positive urine drug screen at the Screening Visit for marijuana and its metabolites,
controlled substances that are not legally prescribed for the subject, and/or illegal substances. |
|
| 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)
5) The percentage of subjects with DAS28(ESR) LDA at Week 52 using all subjects, comparing randomized treatment groups CZP+MTX and ADA+MTX (where subjects who switch treatment at Week 12 are considered non-responders at Week 52)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Week 104
2) Week 6
3) Week 12
4) Week 104
5) Week 52 |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 96 |
| 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 |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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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