A Phase III Study Evaluating Continuation, Tapering, and Withdrawal of Certolizumab Pegol After One Year of Therapy in Patients With Early Rheumatoid Arthritis

Abstract

Objective: In disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) who had achieved sustained low disease activity (a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate of ≤3.2 at both week 40 and week 52) after 1 year of treatment with certolizumab pegol (CZP) at a standard dose (200 mg every 2 weeks plus optimized methotrexate [MTX]), we evaluated whether continuation of CZP treatment at a standard dose or at a reduced frequency (200 mg every 4 weeks plus MTX) was superior to stopping CZP (placebo plus MTX) in maintaining low disease activity for 1 additional year.

Methods: A total of 293 patients from period 1 of our study were re-randomized 2:3:2 in period 2 to CZP at a standard dose (n = 84), CZP at a reduced frequency (n = 127), or placebo plus MTX (CZP stopped) (n = 82). The primary end point was the percentage of patients who maintained low disease activity throughout weeks 52-104 without flares. We used a hierarchical testing scheme, comparing CZP at a standard dose with CZP stopped. If P < 0.05 was achieved, then CZP at a reduced frequency was compared with CZP stopped (nonresponder imputation).

Results: The 293 patients from period 1 represented 36% fewer patients than projected, yielding a smaller number of patients eligible for period 2. Higher proportions of patients treated with the standard and reduced frequency regimens maintained low disease activity than those who had stopped CZP (48.8% and 53.2%, respectively, versus 39.2% [P = 0.112 and P = 0.041, respectively; nominal P value, first hierarchical test not significant]). Similar trends were observed for radiographic nonprogression (change from baseline of ≤0.5 in modified Sharp/van der Heijde score; 79.2% and 77.9% of patients, respectively, versus 70.3%) and normative physical function (Health Assessment Questionnaire disability index score of ≤0.5; 71.4% and 70.6% of patients, respectively, versus 57.0%). Safety profiles were similar between all groups, with no new safety signals identified for continuing CZP to week 104. No deaths were reported.

Conclusion: The study failed to meet its primary end point. However, there were no clinically meaningful differences between the standard and reduced frequency doses of CZP plus MTX; both controlled RA more effectively than stopping CZP.

Trial registration: ClinicalTrials.gov NCT01521923.

© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Figures

Figure 1

C‐EARLY study design, showing set of enrolled patients. a = optimized methotrexate (MTX), defined as dose titrated from 10 mg/week (week 0) and increasing by 5 mg every 2 weeks (Q2W) to a maximum dose of 25 mg/week by weeks 6–8. Patients unable to tolerate ≥15 mg/week by week 8 were withdrawn from the study. b = low disease activity (LDA), defined as a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) of ≤3.2. Low disease activity was considered to be maintained if continued throughout weeks 52–104 without disease flares. Patients reporting a flare had to meet the following 3 criteria at 2 consecutive visits 2 weeks apart: 1) an increase in the DAS28‐ESR of ≥0.6 above the DAS28‐ESR at week 52; 2) a DAS28‐ESR of >3.2; and 3) in the investigator's judgment, an increase in the patient's rheumatoid arthritis (RA) activity. Sustained remission was defined as a DAS28‐ESR of 4 months). d = randomization stratified by time since RA diagnosis at baseline and by sustained remission status at week 52. CZP = certolizumab pegol; LD = loading dose; DMARD = disease‐modifying antirheumatic drug; PBO = placebo; Q4W = every 4 weeks. See Patients and Methods for descriptions of groups.

Figure 2

Clinical response in period 2 of the C‐EARLY study, showing the full analysis set. A, Proportion of patients in whom low disease activity (LDA) was maintained, and proportion in whom remission (REM) was maintained, at week 104. Odds ratios (ORs) with 95% confidence intervals (95% CIs) and corresponding P values are from a logistic regression model with factors for treatment, region, time since rheumatoid arthritis (RA) diagnosis, and sustained remission status at week 52. Only patients with disease in sustained remission at week 52 were included in the analysis for maintained remission at week 104. Nonresponder imputation was used for missing data. B, Proportion of patients with low disease activity, defined as a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) of ≤3.2. C, Proportion of patients with disease in remission, defined as a DAS28‐ESR of <2.6. D, Proportion of patients with normative physical function, defined as a Health Assessment Questionnaire disability index score of ≤0.5. B–D show results of post hoc analyses. The last observation carried forward approach was used to impute missing data. CZP = certolizumab pegol. See Patients and Methods for descriptions of groups.

Figure 3

Radiographic progression in the C‐EARLY study. Shown is the radiographic data set with methotrexate (MTX) responder patients meeting the same criteria (those who had valid radiographs at baseline, week 52, and week 104/withdrawal visit). A, Radiographic progression and nonprogression rates. B, Cumulative probability of change in modified Sharp/van der Heijde score (SHS) from week 52 to week 104. C, Cumulative probability of change in SHS from baseline to week 104. Results for MTX responder patients were obtained using post hoc analyses. Radiographic nonprogression was defined as a change in the SHS of ≤0.5 from baseline or week 52. Radiographic progression was defined as a change in the SHS of >0.5 from baseline or week 52. One outlier in the certolizumab pegol (CZP) stopped group was excluded. Linear extrapolation was used for missing data. Symbols in B and C represent values for each patient. See Patients and Methods for descriptions of groups.

Figure 4

Kaplan‐Meier plot of time to rheumatoid arthritis (RA) disease flare, showing the full analysis set. Disease flares had to be self‐reported by the patient to the investigator at a study visit; solicitation by the study investigators was not mandated by the protocol. Patients reporting a flare had to meet the following 3 criteria at 2 consecutive visits 2 weeks apart: 1) an increase in the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) of ≥0.6 above the DAS28‐ESR at week 52; 2) a DAS28‐ESR of >3.2; and 3) in the investigator's judgment, an increase in the patient's RA activity. Time to flare was defined as the time from the date of the week 52 injection of study medication to the date of the first flare visit for a confirmed flare. Patients who did not have a flare were censored at the date of the latest assessment of the DAS28‐ESR. CZP = certolizumab pegol. See Patients and Methods for descriptions of groups.