Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate

Abstract

Objective: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept.

Methods: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed.

Results: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients.

Conclusion: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

Trial registration: ClinicalTrials.gov NCT00559585.

Copyright © 2011 by the American College of Rheumatology.

Figures

Figure 1

Patient disposition over 6 months (intent-to-treat population). SC = subcutaneous; IV = intravenous.

Figure 2

Proportions of SC or IV abatacept–treated patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) over 6 months, as well as proportions of patients achieving ACR50 or ACR70 responses during the same time period. A, ACR20 (top), ACR50 (middle), and ACR70 (bottom) responses over 6 months for the per-protocol (PP) population (n = 693 in the SC abatacept–treated group, n = 678 in the IV abatacept–treated group). B, ACR20 (top), ACR50 (middle), and ACR70 (bottom) responses over 6 months for the intent-to-treat (ITT) population (n = 733 in the SC abatacept–treated group, n = 716 in the IV abatacept–treated group). C, ACR20 responses at month 6 by weight category for the ITT population (n = 733 in the SC abatacept–treated group, n = 716 in the IV abatacept–treated group). Not included are data on 8 patients who were excluded from all efficacy analyses owing to site noncompliance with study procedures. Asterisks indicate dosages corresponding to ∼10 mg/kg, according to weight range. Error bars represent 95% confidence intervals. See Figure 1 for other definitions.

Figure 3

Functional disability and disease activity over 6 months in SC or IV abatacept–treated patients (intent-to-treat [ITT] population). A, Health Assessment Questionnaire (HAQ) disability index response (improvement of ≥0.3 units from baseline) over 6 months. B, Low disease activity state (LDAS) (Disease Activity Score in 28 joints using the C-reactive protein level [DAS28-CRP] of ≤3.2) (top) and DAS28-defined remission (DAS28-CRP of <2.6) (bottom) over 6 months (as-observed analysis). Not included are data on 8 patients who were excluded from all efficacy analyses owing to site noncompliance with study procedures. Error bars represent 95% confidence intervals. See Figure 1 for other definitions.