| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early active rheumatoid arthritis |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003268 |
| E.1.2 | Term | Arthritis rheumatoid |
| E.1.2 | System Organ Class | 100000004859 |
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| 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 |
PERIOD 1
To demonstrate that the combination of CZP + MTX is superior to PBO + MTX in achieving sustained remission by Week 52.
PERIOD 2
to demonstrate that both CZP + MTX dosing frequencies (the standard maintenance dose CZP 200mg every 2 weeks + MTX and the reduced frequency maintenance dose CZP 200mg every 4 weeks + MTX) are superior to CZP stopped dosing + MTX in maintaining subjects in LDA at Week 104 |
|
| E.2.2 | Secondary objectives of the trial |
PER. 1
• To demonstr. that in DMARD-naïve subj with adult-onset, early active RA present for less than 1y, the combination CZP+MTX is superior to PBO+MTX in achieving sustained LDA at W 52 • To compare the efficacy of CZP+MTX to PBO+MTX based on: - Radiographic progress. - Clinical response - Pt reported outcomes - Productivity within/outside home.
PER. 2 • To demonstr. that for subj achieving sustained remission treated with CZP+MTX during PER.1, both CZP+MTX dosing frequencies (std dose /reduced one + MTX) are superior to CZP stopped dosing +MTX in maint. subj in remission at 104 W. • To evaluate for subj who achieved sust. LDA at W 52 the efficacy of 3 treatm. options: - Radiographic progress. - Clinical response - Proportion of subj (also who flared once) in LDA at W 104 - Time to flare using DAS28(ESR) in PER.2 - Pt reported outcomes - Productivity within/outside home. • To evaluate the continued effect of initial treat. with CZP + MTX vs initial treat. with PBO+MTX up to W 104. |
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| 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. The purpose is to explore candidate gene expression/DNA biomarkers/candidate blood borne protein biomarkers relative to risk, prognosis, and response to treatment with CZP. Each subject’s willingness to participate in the sub-study will be independent from his/her consent to participate in the main study. |
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| E.3 | Principal inclusion criteria |
1. An IRB/ IEC approved written Informed Consent form is signed and dated by the subject prior to any study procedure. 2. This criterion is only applicable for the sub-study and does not impact the eligibility of the subject for the main study: to allow collection of blood samples for the genomic, genetic and proteomic analysis the subjects must have signed and dated an IRB/ IEC approved written Pharmacogenomics Informed Consent form.
3. 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.
4. Subject is male or female and must be at least 18 years old at the Screening Visit.
5. Female subjects must be either postmenopausal for at least 1 year, surgically incapable of childbearing, or effectively practicing an acceptable method of contraception (either oral/parenteral/implantable hormonal contraceptives, intrauterine device or barrier method and spermicide) at Screening. Abstinence only is not an acceptable method. Subjects must agree to use adequate contraception during the study and for at least 3 months (United States/Canada) or 6 months (Europe, Australia and Latin-America) after the last dose of study treatment. Male subjects must agree to ensure they or their female partner(s) use adequate contraception during the study and for at least 3 months (United States/Canada) or 6 months (Europe, Australia and Latin-America) after the subject receives their last dose of study treatment.
6. Subjects must have a time since diagnosis of adult-onset RA less than 1 year as defined by the 2010 ACR / EULAR classification criteria from Screening Visit.
7. Subjects must be DMARD-naïve at Screening and Baseline (except antimalarials, see Section 6.2.2 of the protocol).
8. Subjects must have a positive RF or positive ACPA result at Screening.
9. Subjects must have active RA disease as defined in the study protocol. |
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| E.4 | Principal exclusion criteria |
1. Female subjects who are breastfeeding, pregnant, or plan to become pregnant during the study or within 6 months following last dose of study drug.
2. The subject has previously participated in this study and has received CZP treatment, or has previously received CZP in or outside of another clinical study.
3. The subject has participated in another study of a medication or a medical device under investigation within the last 3 months or is currently participating in another study of a medication or medical device under investigation.
4. The subject has a known hypersensitivity to any components of CZP or with a history of an adverse reaction to polyethylene glycol (PEG).
5. Subjects must not have a secondary, noninflammatory type of musculoskeletal condition that in the Investigator’s opinion is symptomatic enough to interfere with evaluation of the effect of study drug on the subject’s primary diagnosis of RA.
6. Subjects must not have a diagnosis of any other inflammatory arthritis nor have a Steinbrocker IV functional capacity.
7. Subjects must not have received any experimental nonbiological therapy in the 3 past months or within 5 half-lives prior to Baseline (whichever is longer).
8. Subjects must not have received any experimental or approved biological agent prior to Baseline.
9. Subjects must not have used indicated medications in table 6.1 of the Protocol.
10. Concurrent malignancy or a history of malignancy.
11. Subjects 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. Subjects 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, inflammatory bowel disease.
14. Subjects with congestive heart failure as defined by the New York Heart Association 1994 classification criteria.
15. Subjects with a history of, or suspected, demyelinating disease of the central nervous system.
16. Subjects with any other condition which in the Investigator’s judgment would make the subject unsuitable for inclusion in the study.
17. Subject with a value >1.5x ULN for any of the following liver function tests (LFTs) at Screening: • Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase [GOT]); • Alanine aminotransferase (ALT) (glutamate‑pyruvate transaminase [GPT]).
18. Subject has history of chronic alcohol or drug abuse within the last 1 year.
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. Subjects with history of or current clinically active infection (including infections verified by chest X-ray) with histoplasma, coccidiodes, paracoccidioides, pneumocystis, nontuberculous mycobacteria, blastomyces, or aspergillus.
21. Subjects 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 last 6 months or any current sign or symptom that may indicate an infection.
22. Subjects at a high risk of infection (eg, leg ulcers, indwelling urinary catheter, and persistent or recurrent chest infections and subjects who are permanently bedridden or wheelchair bound).
23. Subjects with concurrent acute or chronic viral hepatitis B or C.
24. Subjects with known human immunodeficiency virus (HIV) infection.
25. Subjects receiving live or attenuated vaccination within 8 weeks prior to Baseline. Live or attenuated vaccines are not allowed to be used concurrently with CZP during the period of the study.
26.Subjects with known TB disease (pulmonary or extra pulmonary), high risk of acquiring TB infection, or latent TB infection as defined in the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PERIOD 1
1) proportion of subjects in sustained remission (defined as DAS28[ESR] <2.6 at Week 40 and Week 52 visits)
PERIOD 2
2) proportion of subjects who maintain LDA (DAS28[ESR] ≤3.2) from Week 52 through Week 104 without flaring |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Week 52
2) Week 52 through Week 104 |
|
| E.5.2 | Secondary end point(s) |
PERIOD 1
1) proportion of subjects in sustained LDA (defined as DAS28[ESR] ≤3.2 at Week 40 and Week 52 visits).
2) Radiographic variables: • change in the van der Heijde modified total sharp score (mTSS), • proportion of subjects with radiographic nonprogression, defined as change in mTSS ≤ 0.5; • change in joint erosion score; • change in joint narrowing score.
3) Clinical variables: •American College of Rheumatology (ACR)20, ACR50, ACR70 response rates in relation to Baseline, • Proportion of subjects achieving LDA (DAS28[ESR] ≤3.2); • proportion of subjects achieving a good or moderate EULAR clinical response (according to the DAS28(ESR)-based EULAR response criteria), • changes from Baseline in individual components of the ACR criteria, including tender joint count (TJC), swollen joint count (SJC), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient Assessment of Arthritis Pain (PtAAP)-Visual Analog Scale(VAS), Patient Global Assessment of Disease Activity (PtGADA), Physician Global Assessment of Disease Activity (PhGADA), CRP (ratio to Week 0) and erythrocyte sedimentation rate (ESR, ratio to Week 0), • changes from Baseline in DAS28(ESR), Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI), • proportion of subjects in remission as defined by 5 separate criteria: - the new ACR/EULAR 2011 remission criteria (TJC ≤1, SJC ≤ 1, CRP ≤10mg/L and PtGADA ≤10 [on a scale of 0 to 100]); - the new ACR/EULAR 2011 remission criteria simplified for clinical practice (TJC ≤ 1, SJC ≤ 1 and PtGADA ≤10 [on a scale of 0 to 100]); - DAS28(ESR) <2.6;- CDAI ≤2.8; - SDAI ≤3.3.
4) Patient-reported variables: • proportion of subjects reaching normative physical function (HAQ-DI score ≤0.5), • change from Baseline in Bristol RA Fatigue Multidimensional Questionnaire (BRAF–MDQ) total, • scores of the individual questions of the Work Productivity Survey RA (WPS-RA).
PERIOD 2
5) the proportion of subjects who are in sustained remission at Week 52 and maintain their remission (DAS28[ESR] <2.6) from Week 52 through Week 104 without flaring.
6) Radiographic variables: • change in the van der Heijde modified total sharp score (mTSS), • proportion of subjects with radiographic nonprogression, defined as change in mTSS ≤ 0.5, • change in joint erosion score, • change in joint narrowing score.
7) Clinical variables: • ACR20, ACR50, ACR70 response rates in relation at Week 0, • Proportion of subjects achieving LDA (DAS28[ESR] ≤3.2); • proportion of subjects achieving a good or moderate EULAR clinical response (according to the DAS28[ESR]-based EULAR response criteria), • changes from Week 0 and from Week 52 in individual components of the ACR criteria, including TJC, SJC, HAQ-DI, PtAAP, PtGADA, PhGADA, CRP (ratio to Week 0) and ESR (ratio to Week 0), • changes from Week 0 and from Week 52 in DAS28(ESR), CDAI and SDAI, • proportion of subjects in remission as defined by 5 separate criteria: - the new ACR/EULAR 2011 remission criteria (TJC ≤1, SJC ≤1, CRP ≤10mg/L and PtGADA ≤10 [on a scale of 0 to 100]); - the new ACR/EULAR 2011 remission criteria simplified for clinical practice (TJC ≤1, SJC≤ 1 and PtGADA ≤10 [on a scale of 0 to 100]); - DAS28(ESR) <2.6; - CDAI ≤2.8; - SDAI ≤3.3; • proportion of subjects in LDA (including all subjects who had a single flare but were brought back into LDA), • time to flare, defined as an increase of DAS28(ESR) ≥0.6 above Week 52 DAS28(ESR) level, having a DAS28(ESR) ≥3.2 and judged by the Investigator as due to RA and all 3 criteria confirmed at an additional visit 2 weeks thereafter, from Week 52 onwards.
8) Patient-reported variables: • proportion of subjects reaching normative physical function (HAQ-DI score ≤0.5), • change from Week 0 in BRAF–MDQ total, • scores of the individual questions of the Work Productivity Survey RA (WPS-RA)
9) Pharmacokinetic and immunological variables: to evaluate the Autoantibody (ANA and anti-dsDNA antibodies) levels |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Week 52
2) Baseline-Week 52
3) Week 12-24-52/withdrawal visit
4) Week 12-24-52/withdrawal visit
5) Week 52 through Week 104
6) Week 0 to Week 104/withdrawal visit or Week 52 to Week 104/withdrawal visit
7) Week 104/withdrawal visit
8) Week 104/withdrawal visit |
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| 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 | 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) | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 104 |
| 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 |
| Brazil |
| Canada |
| Colombia |
| 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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