This study is intended to evaluate the efficacy and safety of Certolizumab Pegol (CZP) in combination with Methotrexate (MTX) for inducing and sustaining clinical response in the treatment of Disease Modifying Antirheumatic Drug (DMARD)-naïve adults with early 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
BACKGROUND/PURPOSE: Early stages of rheumatoid arthritis (RA) may provide a therapeutic window in which biologic agents are most effective.1 C-EARLY (NCT01519791) is a phase 3 study in DMARD-naïve patients (pts) with severe, active, progressive RA assessing efficacy and safety of certolizumab pegol (CZP)+MTX vs placebo (PBO)+MTX treatment in inducing and maintaining sustained clinical response and inhibiting radiographic damage. METHODS: Pts in this multicenter double-blind randomized study had RA <1 year since diagnosis at baseline (BL) fulfilling the 2010 ACR/EULAR criteria; ≥4 swollen and ≥4 tender joints; DAS28(ESR)≥3.2; CRP≥10 mg/L and/or ESR≥28 mm/hr, rheumatoid factor or ACPA positive. 879 pts were randomized 3:1 to CZP (400 mg at Weeks [Wks] 0,2,4, 200 mg every 2 wks to Wk52)+MTX or PBO+MTX Q2W. MTX was initiated at 10 mg/wk and increased to 25 mg/wk by Wk8; the maximum tolerated dose per pt (optimized dose) was maintained to Wk52 in both treatment arms. Pts who could not tolerate ≥15 mg/wk MTX by Wk8 were withdrawn. Sustained DAS28(ESR) remission (sREM), defined as DAS28[ESR]≤2.6 at both Wk40 and Wk52, was the primary endpoint; sustained low disease activity (sLDA), defined as DAS28[ESR]≤3.2 at both Wk40 and Wk52, was a key secondary endpoint. Secondary efficacy variables included in the hierarchical testing were ACR50 response at Wk52, change from BL in HAQ-DI at Wk52 and change from BL at Wk52 in van der Heijde modified total Sharp score (mTSS). Pts with and without rapid radiographic progression at Wk52 (defined as change from BL mTSS>3 or >5 based on linearly extrapolated scores)2 were assessed post hoc. RESULTS: BL characteristics were balanced between arms (Table A). 96.5% pts had high disease activity (DAS28[ESR]>5.1), median diagnosis time was 2.6 months.3 All hierarchical endpoints were statistically significant (Table B); 28.9% of CZP+MTX vs 15% of PBO+MTX in sREM (p<0.001); 43.8% of CZP+MTX vs 28.6% of PBO+MTX in sLDA (p<0.001). Approximately 3 times more pts progressed rapidly by >3 and >5 mTSS points in PBO+MTX vs CZP+MTX (23.3% vs 7.4% and 15.3% vs 4.2%). AE incidence rates were similar for both arms. Infections were higher with CZP+MTX vs PBO+MTX (71.8 vs 52.7/100 pt-yrs), but similar for serious infections (3.3 vs 3.7/100 pt-yrs). 2 deaths were reported with CZP+MTX (1 stroke, considered not related to study drug; 1 systemic tuberculosis, considered related to study drug); 1 with PBO+MTX (respiratory failure, considered not related to study drug). No new safety signals for CZP were reported. CONCLUSION: CZP+MTX treatment of DMARD-naïve pts with active, severe, progressive RA resulted in a greater proportion of pts in sREM and sLDA; greater improvements in RA signs and symptoms; and inhibition of structural damage vs PBO+MTX. Safety profile of CZP+MTX was similar to PBO+MTX.
Background: C-EARLY is a phase 3 study in DMARD-naïve patients (pts) with early active RA. Objectives: To assess efficacy and safety of certolizumab pegol (CZP)+MTX vs placebo (PBO)+MTX treatment in inducing and maintaining sustained clinical response and inhibiting radiographic damage in DMARD-naïve pts with early active RA. Methods: Eligible pts in this multicenter, double-blind, randomized study (NCT01519791) were DMARD-naïve and had early, active RA:<1 year since diagnosis at baseline (BL) fulfilling 2010 ACR/EULAR criteria; ≥4 swollen and ≥4 tender joints; DAS28(ESR)≥3.2; CRP≥10mg/L and/or ESR≥28mm/hr, rheumatoid factor or ACPA positive. Pts were randomized 3:1 to CZP (400mg Wks 0,2,4 then 200mg every 2 wks to Wk52)+MTX or PBO+MTX. MTX was initiated at 10mg/wk and up to 25mg/wk by Wk8, maximum tolerated dose was maintained to Wk52. Primary endpoint was sustained DAS28(ESR) remission (sREM, DAS28[ESR]≤2.6 at Wk40 and Wk52) and key secondary endpoint was sustained low disease activity (sLDA) (DAS28[ESR]≤3.2 at Wk40 and Wk52). Other secondary endpoints (included in hierarchical testing) were Wk52 ACR50 response, change from BL in HAQ-DI and change from BL in van der Heijde modified total Sharp score (mTSS). Results: 660 (CZP+MTX) and 219 (PBO+MTX) pts were randomized. 655 vs 213 were included in full analysis set (FAS; pts with BL and post-BL DAS28[ESR]) and 528 vs 163 in radiographic analysis set (FAS pts with valid BL and post-BL radiographs), respectively. BL characteristics were balanced between arms. 96.5% pts had high disease activity (DAS28[ESR]>5.1), 77.8% had erosions; mean TJC and SJC 15.8 and 12.5, respectively. Mean MTX dose after Wk8 was 21.1 (CZP+MTX) and 22.3 (PBO+MTX) mg/wk. Primary (sREM) and secondary endpoints in hierarchical testing (sLDA, ACR50, HAQ-DI change from BL, mTSS change from BL) were statistically significant (Figure shows all except HAQ-DI LS mean change from BL, -1.00 vs -0.82, p<0.001). Lower Erosion Score, Joint Space Narrowing (Figure) and higher proportion of pts with mTSS non-progression (70.3% vs 49.7%) were seen with CZP+MTX vs PBO+MTX. AE incidence rates were similar for both arms. Infections were higher with CZP+MTX (71.8 [CZP+MTX] vs 52.7 [PBO+MTX]/100 pt-yrs), but similar for serious infections (3.3 vs 3.7/100 pt-yrs). 2 deaths were reported with CZP+MTX (1 stroke; 1 systemic tuberculosis); 1 with PBO+MTX (respiratory failure). No new safety signals for CZP were reported. Conclusions: This first report of efficacy and safety of CZP+MTX in DMARDnaïve early RA showed CZP+MTX resulted in more pts in sREM and sLDA; greater improvements in RA signs and symptoms including physical function; and inhibition of structural damage compared with PBO+MTX. Safety profile of CZP+MTX was similar to PBO+MTX. (Figure Presented).
BACKGROUND: Rheumatoid arthritis (RA) leads to high burden on patient (pt) physical function, quality of life (QoL) and work disability. Improvements in pt-reported outcomes (PROs)1 and workplace and household productivity2 with certolizumab pegol (CZP)+MTX were reported in established RA. Here we report results from C-EARLY, a phase 3 study of CZP+MTX in DMARD-naïve pts with early active RA. OBJECTIVES: To assess the effect of CZP+MTX vs placebo (PBO)+MTX on PROs, workplace and household productivity, and need for help with daily activities in DMARD-naïve pts with early active RA. Methods: Pts in this multicenter, double-blind, randomized study (NCT01519791) were DMARD-naïve, had early, active RA: <1yr diagnosis at baseline (BL), fulfilling 2010 ACR/EULAR criteria; ≥4 swollen and ≥4 tender joints; DAS28[ESR]≥3.2; CRP≥10mg/L and/or ESR≥28mm/hr, rheumatoid factor or ACPA positive. Pts were randomized 3:1 to CZP (400mg Wks 0, 2, 4 then 200mg Q2W to Wk52)+MTX or PBO+MTX. MTX was initiated at 10mg/wk and increased up to 25mg/wk by Wk8, maximum tolerated dose was maintained to Wk52. Changes from BL in HAQ-DI, PtGADA, Pain VAS, % pts achieving normative physical function (HAQ-DI≤0.5), health-related QoL (SF-36, EQ-5D-3L) and workplace and household productivity (Work Productivity Survey [WPS]3) were assessed. At Wk52 changes from BL were analyzed using ANCOVA (LOCF imputation); categorical variables were analyzed using logistic regression (non-responder imputation); WPS responses (LOCF imputation) were compared using a nonparametric bootstrap-t method. Need for regular assistance in usual activities was summarized descriptively. RESULTS: 660 (CZP+MTX) and 219 (PBO+MTX) pts were randomized; 655 vs 213 in the full analysis set (pts with BL and post-BL DAS28[ESR]). BL characteristics were balanced between study arms. BL disease severity was high: mean (SD) HAQ-DI 1.6 (0.6), Pain VAS 66.1 (22.4), PtGADA 65.3 (22.0) (Table A), DAS28[ESR] 6.7 (0.9), months since diagnosis 2.9 (4.3). 52% of pts were employed at BL (Table B). At Wk52, greater PRO improvements were observed with CZP+MTX vs PBO+MTX (Table A). CZP+MTX pts reported greater improvements vs PBO+MTX in household productivity, and lower need for assistance in usual activities. Employed CZP+MTX pts reported reductions in absenteeism and presenteeism vs PBO+MTX (Table B). CONCLUSIONS: In DMARD-naïve early RA pts, CZP+MTX showed greater improvements at 1yr in physical function, pain, disease activity, fatigue and health-related QoL, improved workplace and household productivity, and reduced need for assistance with regular activities compared to PBO+MTX. (Table Presented).
BACKGROUND/PURPOSE: In established rheumatoid arthritis (RA), a lack of response to treatment with certolizumab pegol (CZP) at early timepoints is associated with a low probability of achieving future target responses.1 The phase 3 C-EARLY study (NCT01519791) assessed efficacy and safety of CZP in inducing and maintaining a sustained clinical response and inhibiting radiographic damage in DMARD-naïve patients (pts) with active, severe, progressive RA with poor prognostic factors in comparison to MTX alone. Here, we examine the association between response to CZP+MTX in this pt population at an early visit (improvement/lack of improvement from baseline [BL] in DAS28[ESR] at Week [Wk] 12) and remission at Wk52. METHODS: This multicenter, double-blind, randomized study enrolled pts who were DMARD-naïve with active, severe, progressive RA (<1 year since diagnosis at BL, fulfilling 2010 ACR/EULAR criteria: ≥4 swollen and ≥4 tender joints; DAS28[ESR]≥3.2; CRP≥10 mg/L and/or ESR≥ 28 mm/hr, rheumatoid factor/ACPA positive). 879 pts were randomized 3:1 to CZP (400 mg at Wks 0, 2 and 4, then 200 mg every 2 wks to Wk52+MTX; n=660) or PBO+MTX Q2W (n=219). MTX was initiated at 10 mg/wk and increased to 25 mg/wk by Wk8, maximum tolerated dose per patient (optimized dose) was maintained to Wk52. Predictability analyses consisted of positive predictive value (PPV; probability of achieving Wk52 remission after achieving a Wk12 response) and negative predictive value (NPV; probability of failing to achieve Wk52 remission after failing to achieve a Wk12 response). Remission was defined as DAS28(ESR)<2.6; Wk12 responses analyzed were change from BL in DAS28(ESR) ≥0.6 and ≥1.2. Observed data were utilized for Wk12 responses; missing Wk52 values were imputed using non-responder imputation. RESULTS: At Wk52, 42.6% CZP+MTX pts vs 26.8% PBO+MTX pts achieved remission (DAS28[ESR] <2.6) (Table A). NPV of early responses was high (Table B): CZP+MTX-treated pts who did not achieve DAS28(ESR) improvements from BL ≥0.6 or ≥1.2 points at Wk12 had a high probability of not being in remission at Wk52; 92% and 93% respectively. Pts who did achieve an improvement from BL in DAS28(ESR) of ≥0.6 and ≥1.2 at Wk12 had 45% and 49% chance of Wk52 remission (Table B), respectively. CONCLUSION: DMARD-naïve pts with active, severe and progressive RA who failed to achieve DAS28(ESR) improvements at Wk12 after treatment with CZP+MTX were unlikely to be in remission at Wk52. These findings in DMARD-naïve pts are consistent with earlier reports in pts with established disease.
.OBJETIVES: To assess associations between certolizumab pegol (CZP)-mediated stringent clinical targets and workplace/household productivity improvements in DMARD-naïve, severe, progressive, early rheumatoid arthritis (RA) patients. METHODS: C-EARLY (NCT01519791), a double-blind RCT, enrolled DMARD-naïve patients with active, moderate-to-severe, progressive, early RA (<1year from diagnosis). Patients were randomized 3 CZP+MTX1 placebo (PBO)+MTX MTX was titrated to 15–25mg/wk by Week (Wk)8; maximum tolerated (optimized) dose was maintained to Wk52. Associations between clinical responses and workplace/household productivity outcomes were evaluated at Wk52 in CZP patients. Clinical response criteria included sustained remission (sREM.DAS28[ESR ]<2.6,Wks40&52), sustained low disease activity (sLDA.DAS28[ESR]≤3.2,Wks40&52 ), radiographic non-progression (mean change from baseline [CFB] mTSS≤0.5), and normative physical function (NF:HAQ-DI≤0.5). CFB at Wk52 in workplace/household productivity (Work Productivity Survey [WPS]) were compared in responders/nonresponders (non-parametric bootstrap-t method). Missing data were imputed using LOCF (WPS) and non-responder imputation (clinical). RESULTS: 655 CZP patients were included. At baseline, burden was similar between groups; 52.3% employed. Responders achieving sREM, sLDA or NF reported greater productivity improvements versus non-responders (workplace days missed month:-4.2 vs -2.5[p<0.05], -4.1 vs -1.9[p<0.01], -3.7 vs -2.3; workplace days with productivity reduced by ≥50%/ month:-6.2 vs -4.3,-6.5 vs -3.3[p<0.01], -5.8 vs -4.0; level of RA interference with work productivity: -4.6 vs -3.6[p<0.01], -4.6 vs -3.2[p<0.001], -4.4 vs -3.4[p<0.01]; household days missed/month:-8.3 vs -6.1[p<0.01], -8.0 vs -5.8[p<0.01], -7.7 vs -5.8[p<0.05]; household days with productivity reduced by ≥50%/month:-8.8 vs -6.3[p<0.01], -9.0 vs -5.5[p<0.001], -8.9 vs -5.3[p<0.001]; level of RA interference with household productivity: -5.1 vs -3.7[p<0.001], -4.9 vs -3.4[p<0.001], -4.9 vs -3.3[p<0.001]; nominal p-values). There were no associations with radiographic non-progression (data not shown). CONCLUSIONS: Achieving stringent clinical targets (sREM/sLDA) and NF was associated with numerically greater improvements in workplace/household productivity after 1year in CZP-treated DMARDnaïve patients with early, moderate-to-severe, progressive RA. The ability to return to maximum participation levels, early in the disease course, is an important goal for RA patients
Background: RA leads to high burden on patient (pt) work, functioning and quality of life. Certolizumab pegol (CZP)+MTX improves physical function,1 and workplace and household productivity,2,3 in established and early active RA. Here we report impact of maintaining, reducing frequency or stopping CZP from Week (Wk) 52 to 104 in pts who achieved sustained low disease activity (sLDA) following 1 year (yr) of CZP+optimized MTX. Objectives: To assess effect of 2 dosing frequencies of CZP+MTX vs stopping CZP on physical function and workplace/household productivity in Period 2 of C-EARLY, a phase 3 study in early RA pts with severe progressive disease. Methods: CZP+MTX-treated pts achieving sLDA (DAS28[ESR]≤3.2 at Wks40 and 52) in C-EARLY Period 1 (NCT01519791)4 entered Period 2 (NCT01521923), a randomized, double-blind study. Pts were randomized 2:3:2 to CZP standard dose (200mg Q2W+MTX), CZP reduced-frequency dose (200mg Q4W+MTX) or CZP stopped (PBO+MTX). Physical function (HAQ-DI) and %pts achieving normative physical function (HAQ-DI≤0.5) from Wk52 to 104 are reported (ANCOVA model with factors treatment, region, time since diagnosis at BL [≤4 vs >4 months], and BL/Wk52 values as covariate and logistic regression models [treatment, region and time since diagnosis at BL as factors] respectively; CZP stopped as comparator; LOCF). Workplace/household productivity (Work Productivity Survey, WPS)5 at Wk52 and 104 are reported (LOCF); non-parametric bootstrap-t method (CZP stopped as comparator). Results: In Period 2, 289 pts were included in the full analysis set: CZP Q2W+MTX (n=84), CZP Q4W+MTX (n=126) or PBO+MTX (n=79). Improvements in physical function were maintained from Wk52 to 104 in CZP Q2W+MTX (HAQ-DI mean [SD] 0.32 [0.42] to 0.37 [0.48], respectively) and CZP Q4W+MTX (0.33 [0.49] to 0.41 [0.57]), whereas deterioration was seen in PBO+MTX (0.33 [0.47] to 0.57 [0.65]). %pts with normative function was generally maintained between Wk52 to 104 in CZP Q2W+MTX (80.7% to 71.4%) and CZP Q4W+MTX (80.2% to 70.6%), but decreased in PBO+MTX pts (75.9% to 57.0%). At Wk104, employed CZP Q2W+MTX and CZP Q4W+MTX pts maintained on average the improvements in workplace productivity, whereas worsening was seen in pts stopping CZP (Table). Similar trends were observed in household productivity and need for regular assistance (Table). Conclusions: Pts continuing CZP treatment (both dose frequencies) after 1yr further maintained improvements at 2yrs in physical function and workplace/ household productivity, compared with pts who stopped CZP. (Table presented).
Background: C-EARLY (NCT01519791) assessed the efficacy and safety of certolizumab pegol (CZP)+optimized MTX vs placebo (PBO)+optimized MTX in inducing and maintaining a sustained clinical response, and inhibiting radiographic damage, in DMARD-naïve patients (pts) with active, severe, progressive RA.1 Here, we examine the association between an inadequate response to PBO+MTX or CZP+MTX treatments at Week (Wk) 12 (lack of improvement from baseline [BL] in DAS28[ESR], DAS28[CRP] or CDAI) and corresponding response at Wk 52. Objectives: To examine the association between Wk12 response and Wk52 clinical response (remission [REM]/low disease activity [LDA]) in recently diagnosed DMARD-naïve pts with active, severe, progressive RA, treated with CZP+optimized MTX vs PBO+optimized MTX. Methods: This multicenter, double-blind, randomized controlled trial enrolled pts who were DMARD-naïve with active, severe, progressive RA (<1yr since diagnosis, fulfilling 2010 ACR/EULAR criteria). 879 pts were randomized 3:1 to CZP (200mg Q2W+MTX; n=660) or PBO Q2W+MTX (n=219). MTX was initiated at 10mg/wk and increased to 25mg/wk by Wk8; maximum tolerated dose per pt (mean optimized dose, CZP: 21mg/wk, PBO: 22mg/wk) was maintained to Wk52. Negative predictive values (NPV) were defined as probability of failing to achieve Wk52 REM (DAS28[ESR]/[CRP]<2.6 or CDAI≤2.8) or LDA (DAS28[ESR]/[CRP]≤3.2 or CDAI≤10) after failing to achieve a corresponding defined response at Wk12; change from BL in DAS28(ESR)/(CRP)≥0.6 or ≥1.2/CDAI≥6 and ≥12. DAS28(CRP) LDA/REM definitions are not validated. Observed data were utilized for Wk12 responses; missing Wk52 values were imputed using non-responder imputation. Results: The NPV of Wk12 responses were high (Table): PBO+MTX pts who did not achieve DAS28(ESR) improvements from BL ≥0.6 had 94% probability of not being in REM or LDA at Wk52. CZP+MTX pts who did not achieve DAS28(ESR) improvements from BL ≥1.2 had 93% probability of not being in REM at Wk52. NPV of changes in DAS28(CRP) and CDAI at Wk12 were less informative for predicting remission at 1yr (Table). Conclusions: In early RA pts treated with optimized-dose MTX, failure to achieve a ≥0.6 DAS28(ESR) reduction from BL at Wk12 was associated with a low probability (6%) of DAS28(ESR) REM/LDA at Wk52, supporting treatment step-up at 3 months. For pts with active, severe RA with poor prognostic factors where CZP has been initiated as first-line treatment, failure to achieve a rapid decrease of 1.2 points was associated with a reduced likelihood of achieving REM (7%). These findings in DMARD-naïve pts are consistent with the negative predictability outcomes for CZP in established RA.2. (Table Presented).
<b>OBJECTIVES: </b>To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks.<b>METHODS: </b>DMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints.<b>RESULTS: </b>Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100 PY); the rate of serious infection was similar between CZP+MTX (3.3/100 PY) and PBO+MTX (3.7/100 PY).<b>CONCLUSIONS: </b>CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX.<b>Trial Registration Number: </b>NCT01519791.
