Certolizumab pegol plus methotrexate 5-year results from the rheumatoid arthritis prevention of structural damage (RAPID) 2 randomized controlled trial and long-term extension in rheumatoid arthritis patients

Abstract

Introduction: As patients with rheumatoid arthritis (RA) receive treatment with anti-tumour necrosis factors over several years, it is important to evaluate their long-term safety and efficacy. The objective of this study was to examine the safety and benefits of certolizumab pegol (CZP)+methotrexate (MTX) treatment for almost 5 years in patients with RA.

Methods: Patients who completed the 24-week Rheumatoid Arthritis Prevention of Structural Damage (RAPID) 2 randomized controlled trial (RCT; NCT00160602), or who were American College of Rheumatology (ACR) 20 non-responders at Week 16, entered the open-label extension (OLE; NCT00160641). After ≥6 months treatment with CZP 400 mg every two weeks (Q2W), dose was reduced to 200 mg Q2W, the approved maintenance dose. Safety data are presented from all patients who received ≥1 dose CZP (Safety population, n=612). Efficacy data are presented to Week 232 for the intent-to-treat (ITT, n=492) and Week 24 CZP RCT Completer (n=342) populations, and through 192 weeks of dose-reduction for the Dose-reduction population (patients whose CZP dose was reduced to 200 mg, n=369). Radiographic progression (modified total Sharp score change from RCT baseline >0.5) to Week 128 is reported for the Week 24 CZP Completers.

Results: In the RCT, 619 patients were randomized to CZP+MTX (n=492) or placebo+MTX (n=127). Overall, 567 patients (91.6%) entered the OLE: 447 CZP and 120 placebo patients. Of all randomized patients, 358 (57.8%) were ongoing at Week 232. Annual drop-out rates during the first four years ranged from 8.4-15.0%. Event rates per 100 patient-years were 163.0 for adverse events (AEs) and 15.7 for serious AEs. Nineteen patients (3.1%) had fatal AEs (incidence rate=0.8). Clinical improvements in the RCT were maintained to Week 232 in the CZP Completers: mean Disease Activity Score 28 (Erythrocyte Sedimentation Rate) change from baseline was -3.4 and ACR20/50/70 responses 68.4%/47.1%/25.1% (non-responder imputation). Similar improvements observed in the ITT were maintained following dose-reduction. 73.2% of CZP Completers had no radiographic progression at Week 128.

Conclusions: In patients with active RA despite MTX therapy, CZP was well tolerated, with no new safety signals identified. CZP provided sustained improvements in clinical outcomes for almost 5 years.

Trial registration: ClinicalTrials.gov, NCT00160602 and NCT00160641 . Registered 8 September 2005.

Figures

Fig. 1

Patient disposition in the Rheumatoid arthritis prevention of structural damage (RAPID) 2 randomized controlled trial and open-label extension (OLE). Percentages were calculated by dividing number of patients by total number of patients in each treatment arm (n = 127 for placebo, n = 492 for certolizumab pegol (CZP)). aTwo patients randomized in the placebo group received CZP 200 mg in the double-blind phase, and were analyzed as part of the safety population; bpatients who withdrew due to lack of efficacy at week 16 were eligible to enter the OLE; cat OLE entry all patients received 400 mg CZP + methotrexate every 2 weeks (Q2W), reduced to CZP 200 mg Q2W after ≥6 months; dpatients completed 232 weeks of CZP treatment from the first dose; enumber of withdrawers who entered the OLE differs from the number of week-16 withdrawers due to a windowing rule that resulted in a narrower group being defined for the week-16 withdrawers than actually were eligible for the OLE; week-16 withdrawers were defined as those who withdrew due to lack of efficacy at week 16, whereas withdrawers entering the RAPID 2 OLE included all withdrawers who entered the OLE, as recorded in the subject status evaluation. AE adverse event, ITT intention-to-treat, MTX methotrexate, RCT randomized controlled trial

Fig. 2

Kaplan-Meier plot of time to withdrawal for any reason and due to lack of efficacy or adverse event from start of the randomized controlled trial (RCT) for the certolizumab pegol (CZP) intention-to-treat (ITT) population (n =492). AE adverse event, MTX methotrexate, OLE open-label extension

Fig. 3

Percentage of patients experiencing adverse events (AEs) and serious AEs over each 6-month period from the start of the randomized controlled trial (safety population, n = 612). SAE serious adverse event

Fig. 4

Efficacy variables in the certolizumab pegol (CZP) intention-to-treat (ITT) (n = 492) and week-24 CZP completer populations (n = 342). a Mean disease activity score in 28 joints (erythrocyte sedimentation rate) (DAS28(ESR)). b Mean health assessment questionnaire-disability index (HAQ-DI). c American College of Rheumatologists (ACR)20 response. d ACR50 and ACR70 responses. For patients who withdrew at week 16, observed data from the week-12 visit was also included in the week-24 data (start of open-label extension). MMRM mixed model repeated measures, NRI non-responder imputation

Fig. 5

Efficacy variables in patients following dose reduction from certolizumab pegol (CZP) 400 mg every 2 weeks (Q2W) to CZP 200 mg Q2W (n = 369). a Mean disease activity score in 8 joints (erythrocyte sedimentation rate) (DAS28(ESR)). bAmerican College of Rheumatology (ACR)20 response rates. c ACR50 and ACR70 response rates. This analysis is presented as weeks following dose-reduction visit (Week 0 is defined as the final efficacy assessment visit where a patient received the CZP 400 mg dose). The sharp decline in patient numbers from week 150 following dose reduction is due to the per-protocol site closures in countries where CZP became commercially available. MMRM mixed model repeated measures, NRI non-responder imputation

Fig. 6

Comparison of clinical efficacy variables between patients responding early or late to certolizumab pegol (CZP), and American College of Rheumatology (ACR)20 non-responders who re-consented to the open-label extension study. a Percentage of patients achieving clinical outcomes at week 232 for early or late responders and ACR20 non-responders. b Change from baseline in mean disease activity score in 28 joints (erythrocyte sedimentation rate) (DAS28(ESR)) score in ACR20 non-responders compared to CZP intention-to-treat (ITT). c Change from baseline in mean health-assessment questionnaire-disability index (HAQ-DI) score in ACR20 non-responders compared to CZP ITT (last observation carried forward). Response was defined by ACR20 response or decrease from baseline in DAS28(ESR) ≥1.2. Early responders were those who responded to CZP at week 12 and late responders were those who responded to CZP at week 24 but not at week 12. aRemission defined as DAS28(ESR) <2.6; blow disease activity (LDA) defined as DAS28(ESR) ≤3.2; cdefined as a decrease from baseline of ≥0.22 in HAQ-DI. MCID minimal clinically important difference

Fig. 7

Assessment of structural damage in week-24 certolizumab pegol (CZP) and placebo (PBO) completers. a Mean modified total Sharp score (mTSS) (Observed). b Mean change from baseline in mTSS. c Percentage of patients with no radiographic progression. No radiographic progression was defined as an mTSS change from the randomized controlled trial baseline ≤0.5

Fig. 8

Patient-reported outcomes for certolizumab pegol (CZP) intention-to-treat (ITT) and week-24 CZP completer populations. a Change from baseline in patient’s assessment of arthritic pain. b Change from baseline in patient’s global assessment of disease activity (PtGA). c Change from baseline in fatigue. d Change from baseline in short form-36 physical component summary (SF-36 PCS). For patients who withdrew at week 16, observed data from the week-12 visit was also included in the week-24 data (start of open-label extension). MMRM mixed model repeated measures

Fig. 9

Improvements reported in minimally clinically important difference (MCID) for health-assessment questionnaire-disability index (HAQ-DI), patient’s assessment of arthritic pain, patient’s global assessment of disease activity (PtGA), short form-36 physical component summary (SF-36 PCS) and fatigue in certolizumab pegol (CZP) intention-to-treat (a) and CZP completers (b). Data were assessed using mixed model repeated measures imputation. MCID was defined as a decrease of ≥0.22 points from baseline in HAQ-DI, improvements ≥2.5 in the SF-36 PCS score from baseline, and for fatigue, pain and PtGA ≥10-point decrease from baseline. Data are presented at week 36 and week 220 as timing of visits meant that data were not available for week 24 and week 232