Study designed to demonstrate the efficacy and safety of Certolizumab pegol in combination with Methotrexate in the treatment of subjects suffering from early, progressive active rheumatoid arthritis

INTERVENTION:

Trade Name: Cimzia Product Name: Certolizumab pegol Product Code: CDP870 Pharmaceutical Form: Solution for injection INN or Proposed

INN:

CERTOLIZUMAB PEGOL CAS Number: 428863‐50‐7 Current Sponsor code: CDP870 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 200‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Trade Name: Trexan Product Name: Methotrexate Pharmaceutical Form: Tablet INN or Proposed

INN:

METHOTREXATE CAS Number: 59‐05‐2 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5‐

CONDITION:

Early active rheumatoid arthritis ; MedDRA version: 14.1 Level: LLT Classification code 10003268 Term: Arthritis rheumatoid System Organ Class: 100000004859 Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05]

PRIMARY OUTCOME:

Main Objective: 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 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 Secondary Objective: P1; • In DMARD‐naïve subj. with adult‐onset early active RA present for less than 1 year that the combination therapy of CZP+MTX is superior to PBO+MTX in sustained LDA at W52 • Compare the efficacy of CZP+MTX to PBO+MTX based on: Radiographic progression/Clinical response/Pt. reported outcomes/Productivity within/outside home ; P2; • Those subj. achieving sustained remission and treated with CZP+MTX during PER.1 both CZP+MTX dosing frequencies (standard dose/reduced one + MTX) are superior to CZP stopped dosing +MTX in maint. subj in remission at 104 W • Evaluate for subjects who achieved sustained LDA at W 52 the efficacy of 3 different treatment options: Radiographic progression; Clinical response; The proportion of subjects (also counting subjects who flared once) in LDA at W 104; Time to flare using DAS28(ESR) in PER.2; Pt reported outcomes; Productivity within/outside home • Evaluate the continued effect of initial treat. with CZP + MTX vs initial treat. with PBO+MTX up to W 104. Timepoint(s) of evaluation of this end point: 1) Week 52; 2) Week 52 through Week 104

SECONDARY OUTCOME:

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. ; 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. ; 9) Pharmacokinetic and immunological variables: to evaluate the Autoantibody (ANA and anti‐dsDNA antibodies) levels Timepoint(s) of evaluation of this end point: 1) Week 52 ; 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. ; 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) ; 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 ; 9) Baseline and Weeks 2, 8, 12, 20, 24, and 52/104/Withdrawal Visit

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 contracep