The life-affirming sounds quieted. My mother stood at the foot ofthe bed, blanch-faced. My husband yelled for a doctor, any doctor. “Ohmy God, I killed my baby!” I first thought. The anesthesiologist chargedin and immediately started CPR on my baby boy—Kenny. I listened tothe murmurs that his eyes had opened and he looked around but hadshallow and ragged breath. Thank God. He was alive. Gr
43949-acr 2011 p2228 vf.inddInitial Combination Therapy With Adalimumab Plus Methotrexate Leads to Better Long-term Outcomes in Patients With Advanced Rheumatoid Arthritis:
Analysis of the Final 10-Year Results of an Open-label Extension of a Phase 3 Trial
Edward C Keystone1, Désirée van der Heijde2, Michael E Weinblatt3, Neelufar Mozaffarian4, Benoît Guérette4, Hartmut Kupper5, Shufang Liu4, Arthur Kavanaugh6
1University of Toronto, Toronto, Ontario, Canada; 2Leiden University Medical Center, Leiden, The Netherlands; 3Brigham and Women’s Hospital, Boston, Massachusetts, United States; 4Abbott, Abbott Park, Illinois, United States; 5Abbott GmbH & Co. KG, Ludwigshafen, Germany; 6University of California San Diego, La Jolla, California, United States
Background/Purpose: DE019 was a phase 3, randomized,
radiographic progression (49.4% vs. 61.1%). No new safety signals Figure 2. Patient Disposition
Table 1. Baseline Demographic and Disease
Figure 3. Clinical and Functional Responses Following Up to 10 Years of Treatment With ADA + MTX
Figure 4. Radiographic Outcomes Following Up to 10 Years of Treatment With ADA + MTX
controlled trial (RCT) in which patients with active, advanced arose following up to 10 years of ADA exposure, and there was Characteristics: 10-Year Radiographic Completers
Randomized and entered DE019
rheumatoid arthritis (RA) and an inadequate response to perhaps a trend towards fewer deaths than would be expected methotrexate (MTX) were randomized to 1 year of adalimumab from a matched population [SMR (95% CI) = 0.77 (0.52, 1.10)].
(ADA) 40 mg every other week (eow), ADA 20 mg weekly, or Conclusions: Following up to 10 years of treatment with ADA +
ADA 40 mg eow
placebo (PBO) injections; all received concomitant MTX. RCT MTX, patients with long-standing RA experienced safe and results demonstrated the clinical and radiographic superiority effective disease control. Initial treatment with ADA led to better Characteristics
of ADA + MTX over PBO + MTX1. All patients completing the RCT outcomes than initial treatment with PBO, but the disparities in Completed double-blind, placebo-controlled
were eligible to receive open-label (OL) ADA 40 mg eow + MTX for clinical and functional response rates observed during the RCT phase and entered open-label extension
an additional 9 years. This post hoc analysis evaluated observed were largely ameliorated after treatment with OL ADA + MTX. patient data to determine whether a 1 year delay in initiation of Notably, radiographic damage remained lower in patients initially ADA treatment results in differences in clinical, functional, or randomized to ADA, owing to the more extensive damage accrued radiographic efﬁ cacy after up to 10 years of treatment. during the RCT in PBO-treated patients.
Reasons for all discontinuations
through 10 years (N = 417)
Methods: Clinical and functional outcomes were assessed
Completed open-label extension (N = 202)
by the 28-joint disease activity score [DAS28(CRP)] and the disability index of the health assessment questionnaire (HAQ-DI), “initial ADA”
respectively. Radiographic damage was assessed using the modiﬁ ed total Sharp Score (mTSS) at baseline (BL) and Years 1, • Randomized, controlled, clinical trials in patients with RA have 8, and 10; progressors were deﬁ ned as patients with a change (Δ) established that adding tumor necrosis factor (TNF) inhibitors in mTSS from BL >0.5. Differences in mean ΔmTSS between initial A total of 6 patients from the original PBO + MTX treatment group discontinued without a to existing MTX therapy in patients with an inadequate corresponding reason following completion of the blinded study.
treatment arms were assessed using a constrained longitudinal response to MTX results in signiﬁ cant improvements in clinical, data analysis. Safety was assessed in terms of adverse events • Of the 457 patients who entered the OL extension, functional, and radiographic outcomes1−6; however, the effect 202 (44.2%) completed 10 years of therapy (Figure 2)
on long-term disease control in these patients remains unclear Results: Of the 619 patients initially randomized, 202 (32.6%; 80,
66, and 56 patients from the initial ADA 40 mg eow, ADA 20 mg • The DE019 trial demonstrated the clinical and radiographic • Baseline demographics and disease characteristics were weekly, and PBO arms, respectively) continued on OL ADA + MTX superiority of 1 year of adalimumab (ADA) + MTX combination generally similar between patients with x-rays available at Baseline and Year 10 and the overall intent-to-treat treatment through Year 10. Efﬁ cacy outcomes at Year 10 were treatment over placebo (PBO) + MTX in patients with not different between the 2 ADA arms; therefore, results for the long-standing RA and an inadequate response to MTX1 population, with the exception that the population completing 10 years of treatment was younger1 (Table 1)
ADA 40 mg eow arm are presented as representative of both (A.) ACR50/70/90 responses, (B.) mean tender (TJC) and swollen (SJC) joint counts, (C.) the percentages of patients achieving DAS28(CRP) <3.2 (LDA), DAS28(CRP) [DAS28(CRP) <2.6] and SDAI (SDAI ≤3.3) remission, and (D.) the percentages of patients achieving normal physical function (HAQ-DI <0.5). “Delayed ADA” patients received PBO + MTX during year 1; “initial ADA” patients received ADA arms. Following the switch to OL ADA + MTX, the signiﬁ cant • Demographics and disease characteristics at Baseline as well % Patients
differences in clinical and functional responses observed during as efﬁ cacy outcomes at Year 10 were not different between Objectives
Mean change from Baseline in (A.) mTSS, (B.) JE, and JSN at Years 1, 8, and 10. Cumulative probability plots of changes in mTSS (C.) from Baseline and (D.) from the beginning of the OL extension. Year 1 (DAS28 = 3.4 and 4.5; HAQ-DI = 0.8 and 1.1 for ADA Clinical and Functional Responses Over Time
• Fewer patients who received “delayed ADA” achieved the 2 ADA groups (20 mg weekly and 40 mg eow, data not
“Delayed ADA” patients received PBO + MTX during Year 1; “initial ADA” patients received ADA + MTX throughout the study.
and PBO arms, respectively) were largely resolved following an ACR50/70/90 responses over time compared with patients in • To describe the long-term safety and impact of ADA + MTX shown); therefore, data for the ADA 40 mg eow group are
• Differences in clinical and functional responses between additional 9 years of OL ADA + MTX treatment (DAS28 = 2.4 the “initial ADA” group (Figure 3A), a ﬁ nding consistent with
All values are mean ± standard deviation, unless otherwise indicated.
Radiographic Outcomes Over Time
– Radiographic progression, although numerically higher treatment on the improvement/maintenance of clinical, presented as representative of both groups the original treatment groups that were apparent at Year 1 aPatients enrolled in DE019 received ongoing MTX therapy.
and 2.7; HAQ-DI = 0.7 and 0.8 for initial ADA and PBO arms, the greater persistence of tender and swollen joints in the in the “delayed ADA” group, was comparable between functional, and radiographic outcomes in patients with [DAS28(CRP) = 4.5 and 3.4 and HAQ-DI = 1.1 and 0.8 for Abbreviations: PBO, placebo; MTX, methotrexate; ADA, adalimumab; mg, milligram; eow, every • Rates of radiographic nonprogression were superior for respectively). In addition, rates of radiographic progression “delayed ADA” group (Figure 3B)
the treatment groups once all patients were receiving OL other week; RA, rheumatoid arthritis; DMARD, disease-modifying antirheumatic drug; DAS28, long-standing RA who entered the DE019 trial and the PBO + MTX and ADA + MTX groups, respectively] were patients receiving ADA + MTX during Year 1 [83% (n = 67/81) became comparable between the treatment arms during OL 28-joint disease activity score; CRP, C-reactive protein; dL, deciliter; TJC, tender joint count; largely resolved following 9 years of OL ADA + MTX treatment • The percentages of patients who achieved DAS28(CRP) ADA + MTX (mean ΔmTSS at Year 10 = 4.3 vs. 2.0 for the subsequently received up to 10 years of ADA + MTX therapy SJC, swollen joint count; HAQ-DI, disability index of the health assessment questionnaire; PGA, vs. 46% (n = 25/54) for the PBO + MTX group, P <.001], ADA + MTX treatment (P = .22). However, patients initially physician’s global assessment; VAS, visual analog scale; PaGA, patient’s global assessment; [DAS28(CRP) = 2.7 and 2.4; HAQ-DI = 0.8 and 0.7 at LDA, DAS28(CRP) remission, SDAI remission, and normal but after 9 years of OL ADA, the differences were no longer randomized to ADA had signiﬁ cantly lower mean ΔmTSS • To describe the impact of a 1-year delay in the addition mTSS, modiﬁ ed total Sharp score; JE, joint erosion score; JSN, joint space narrowing score.
Year 10, respectively]; however, cumulative disease activity physical function were maintained through 10 years in both statistically signiﬁ cant [51% (n = 40/79) vs. 39% (n = 21/54) • The JSN component of the mTSS appeared to drive compared with patients initially randomized to PBO (0.7 vs. 6.2; of ADA to existing MTX monotherapy in patients with was signiﬁ cantly greater in patients receiving “delayed groups; however, patients in whom ADA treatment was radiographic progression, irrespective of original treatment P = .002), as well as a lower percentage of patients with for the “initial ADA” and “delayed ADA” groups, respectively, ADA” treatment [AUC for DAS28(CRP) over the 10-year delayed for 1 year generally did not achieve the same level P = .18]; similar results were observed for the proportion of (Figure 4B)
period = 1648 and 1439, for the “delayed ADA” and “initial of response as patients who initially received ADA + MTX patients having minimal radiographic progression (ΔmTSS ≤5 • Among the patients who experienced radiographic ADA” groups, respectively; P = .007] (Figures 3C and 3D)
over 10 years, data not shown)
progression, those who received “delayed ADA” treatment • During the 9-year OL period, approximately 50% of patients experienced more severe progression than those initially in both groups did not progress radiographically; still, patients receiving ADA + MTX, even after 10 years of treatment Study Design and Patients
– Radiographic progression was assessed in patients whose who received “delayed ADA” treatment had signiﬁ cantly (Figure 4C); this difference persisted even when only the
time-averaged disease activity was in remission during the • DE019 was a 1-year, phase 3, randomized, double-blind, Adults ≥18 years with a diagnosis of RA as deﬁ ned by the higher mean ΔmTSS at Year 10 compared with patients who OL extension period was considered (Figure 4D)
PBO-controlled trial of ADA in patients with moderate to 1987-revised criteria and moderately to severely active Table 2. Radiographic Progression From Baseline
Figure 5. Percentages of Patients Achieving
Table 3. Overview of Adverse Events: All Patients
received ADA + MTX from the start of the study (6.2 vs 0.7; severe RA who demonstrated an inadequate response to disease despite a minimum of 3 months of treatment with To obtain time-averaged disease activity, areas under to Year 10 in Patients Whose Disease Activity Was
Comprehensive Disease Control (Clinical +
With at Least 1 ADA Injectiona
P = .002) (Figure 4A)
MTX1 (Figure 1)
MTX at weekly doses of 12.5–25 mg, plus: the curve (AUC) were determined for all time intervals of in Remission During the Open-label Extension
Functional + Radiographic) Following Up to 10
PY = 3089.2
available DAS28(CRP) or SDAI values from Year 1 through – Patients continuing weekly MTX were randomized 1:1:1 to – Tender joint count ≥9 out of 68 assessed joints Years of Treatment With ADA + MTX
Events (Events/100 PY)
Year 10 for individual patients. Values were summed and P valuea
receive weekly PBO, weekly ADA 20 mg, or ADA 40 mg – Swollen joint count ≥6 out of 66 assessed joints – C-reactive protein (CRP) ≥1.0 mg/dL Conclusions
– Patients completing the 1-year blinded study were Comprehensive Disease Control
– Rheumatoid factor positive, or at least 1 joint erosion TA-DAS28(CRP) <2.6, but not TA-SDAI ≤3.3 eligible to receive OL ADA 40 mg eow + MTX for up to • Comprehensive disease control was deﬁ ned as DAS28(CRP) AE leading to discontinuation of study drug Clinical and Functional Assessments
• Following up to 10 years of treatment Abbott sponsored the study (NCT00195702). The authors wish <3.2 or DAS28(CRP) <2.6 PLUS HAQ-DI <0.5 PLUS to acknowledge Benjamin Wolfe, Ph.D., of Abbott, for his “Delayed ADA” – patients who received PBO + MTX • Clinical assessments included 50%, 70%, and 90% assistance with the preparation of this poster.
during the blinded study before entering the OL extension responses in the American College of Rheumatology criteria – The percentages of patients achieving comprehensive TA-DAS28(CRP) <2.6, but not TA-SDAI ≤3.3 (ACR50, ACR70, and ACR90), the 28-joint disease activity “Initial ADA” – patients who received ADA + MTX disease control at Year 10 were determined Opportunistic infection (excluding tuberculosis) score with CRP [DAS28(CRP)], and the simpliﬁ ed disease Disclosures
P value for differences in ΔmTSS between TA-DAS28(CRP) <2.6 and TA-SDAI ≤3.3.
Figure 1. DE019 Trial Design
– Low disease activity (LDA) was deﬁ ned as • Adverse events (AEs) were assessed throughout the study ΔmTSS, change in modiﬁ ed total Sharp score; TA, time-averaged; DAS28, 28-joint disease Malignant AE (excluding NMSC and lymphoma) activity score; CRP, C-reactive protein; SDAI, simpliﬁ ed disease activity index.
ECK has received consulting fees or other remuneration from Randomization
and were summarized for all patients exposed to ADA as both Abbott, Amgen, AstraZeneca, BMS, Centocor, Genzyme, the number and percentage of patients affected as well as the • Regardless of original treatment group, patients whose – Remission was deﬁ ned as DAS28(CRP) <2.6 or SDAI ≤3.3 Merck, Novartis, Pﬁ zer, and UCB, and research grants from number of events per 100 patient-years of exposure time-averaged disease activity during the OL extension met • Physical function was assessed through the disability index Abbott, AstraZeneca, Biotest, BMS, Centocor, Genentech, DAS28(CRP), but not SDAI, remission criteria or met SDAI of the health assessment questionnaire (HAQ-DI) Statistical Analyses
Merck, Nycomed, Pﬁ zer, Roche, and UCB. DvdH has received remission criteria had similar levels of radiographic progression “Delayed ADA” patients received PBO + MTX during year 1; “initial ADA” patients received ADA – Normal physical function was deﬁ ned as HAQ-DI <0.5 • Clinical and functional outcomes were summarized as at Year 10 (Table 2)
aAny AE with an onset date on or after the day of the ﬁ rst ADA injection through 70 days after the consulting fees or other remuneration from Abbott, Amgen, Open-label
AstraZeneca, BMS, Centocor, Chugai, Merck, Novartis, Otsuka, ADA 40 mg eow
Comprehensive Disease Control at Year 10
ADA, adalimumab; PY, patient-years; AE, adverse event; NMSC, nonmelanoma skin cancer.
Pﬁ zer, Roche, Sanoﬁ -Aventis, Schering-Plough, UCB, and – AUC analysis was used to assess cumulative differences • Two radiologists, blinded to patient and sequence, scored Wyeth. MEW has received research grants and consulting fees • Signiﬁ cantly more patients from the “initial ADA” group ﬁ lms of the hands and feet using the modiﬁ ed total Sharp Long-Term Safety
or other remuneration from Abbott. AK has received research achieved comprehensive disease control at Year 10 compared • Radiographic assessments were analyzed according to score (mTSS, range 0−398) to assess joint erosion (JE, range with patients in the “delayed ADA” group (Figure 5)
• A total of 553 patients received at least 1 injection of ADA, grants from Abbott. NM, BG, HK, and SL are all full-time original treatment group for all patients with x-rays available 0−230) and joint space narrowing (JSN, range 0−168) with a mean exposure of 5.6 years, totaling 3089-patient- employees of Abbott and may hold stock or stock options.
years of exposure; no new safety signals were identiﬁ ed – Mean changes (Δ) in mTSS, JE, and JSN from Baseline to – Differences in mean ΔmTSS between original treatment following up to 10 years of ADA exposure (Table 3)
groups were assessed using a constrained longitudinal 12.5–25 mg weekly; patients must have been on a stable dose for at least 4 weeks prior – Radiographic nonprogression was deﬁ ned as ΔmTSS ≤0.5 • The SMR (95% conﬁ dence interval) was 0.77 (0.52, 1.10), References
data analysis (cLDA), following adjustment for the observed indicating an observed number of deaths (n = 24) that – Minimal radiographic progression was deﬁ ned as ΔmTSS was numerically lower than that expected in an age-, 1. Keystone, E., et al. Arthritis Rheum. 2004;50(5):1400−11.
• A standardized mortality ratio (SMR), deﬁ ned as the ratio of ≤5 at Year 10 (average of 0.5 per year over 10 years) observed to expected deaths was calculated based on the 2. Keystone, E., et al. Ann Rheum Dis. 2010;69(6):1129−35.
– Observed changes in mTSS from Baseline and from Year 1 Work Health Organization age-, sex-, and country-speciﬁ c through Year 10 were plotted as cumulative probabilities 3. Keystone, E., et al. Arthritis Rheum. 2008;58(11):3319−29.
4. Lipsky, P.E., et al. N Eng J Med. 2000;343(22):1594−602.
5. Weinblatt, M.E., et al. Arthritis Rheum. 2003;48(1):35−45.
Presented at 2011 ACR/ARHP Annual Scientiﬁ c Meeting in Chicago, Illinois, United States, November 5–9, 2011
6. Weinblatt, M.E., et al. N Eng J Med. 1999;340(4):253−9.
Pension application of John Hall S30451 [Methodology: Spelling, punctuation and/or grammar have been corrected in some instances for ease of reading and to facilitate searches of the database. Also, the handwriting of the original scribes often lends itself to varying interpretations. Users of this database are urged to view the original and to make their own decision as to how to decipher what