Summary

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• A phase 3 study evaluated the efficacy and safety of SIMPONI ARIA, with and without MTX, in patients with active RA despite treatment with MTX.¹
• From a real-world evidence study, the utilization of methotrexate was evaluated in RA patients treated with SIMPONI ARIA.^2,3

CLINICAL DATA

Controlled Phase 3 Trial - GO-LIVE

Kremer et al (2010)¹ assessed the efficacy and safety of SIMPONI ARIA in patients with active RA despite treatment with MTX in a phase 3, randomized, double-blind, multicenter, placebo-controlled study. Active RA was defined as ≥4 tender and ≥4 swollen joints, plus at least 2 of the following: 1) C-reactive protein (CRP) ≥1.5 mg/dL or erythrocyte sedimentation rate (ESR) ≥28 mm/hour, 2) morning stiffness ≥30 minutes, 3) bone erosions, or 4) rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) positivity. Further, patients had to be treated with MTX for ≥3 months before screening, including treatment at a stable dose (15-25 mg/week) for ≥4 weeks.

Study Design/Methods

• A total of 643 adult RA patients were randomized to SIMPONI ARIA 2 mg/kg + MTX (n=129), SIMPONI ARIA 2 mg/kg (n=128), SIMPONI ARIA 4 mg/kg + MTX (n=128), SIMPONI ARIA 4 mg/kg (n=129), or intravenous (IV) infusions of placebo + MTX (n=129) every 12 weeks through week 48. IV infusions were administered over a period of 30 minutes (acceptable window for infusion of 25-35 minutes) at weeks 0, 12, 24, 36, and 48.
• Patients were permitted to continue stable doses of oral corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs). Previous but not current anti-tumor necrosis factor (TNF) therapy was also permitted (limited to 20% of the study population) with appropriate washout (infliximab washout period ≥3 months; etanercept or adalimumab washout period ≥2 months).
• Patients who had <20% improvement from baseline in both swollen and tender joint counts were eligible to enter early escape at week 16 or have a dose regimen adjustment at week 24 in a blinded manner.
• Patients who completed the week 48 infusion were eligible to continue in an open-label long-term extension with golimumab 50 mg subcutaneously every 4 weeks for an additional 24 weeks (extension weeks 0-24) and an additional 16 weeks of safety follow-up (extension weeks 24-40).
• The primary endpoint was the proportion of patients achieving 50% improvement according to the American College of Rheumatology criteria (ACR50) at week 14.
• Secondary endpoints included a 20% improvement according to the American College of Rheumatology criteria (ACR20) response at week 14, ACR50 response at week 24, Disease Activity Score in 28 joints using CRP (DAS28 [CRP]) moderate/good response at week 14, and the change in the Short Form-36 Physical Component Summary (SF-36 PCS) score at week 14.

Results

Patient Characteristics

• At baseline, the groups were well matched regarding demographics and clinical characteristics.
• The mean ages ranged from 48.4-50.2 years with mean disease duration ranging from 7.4-9.4 years.
• The mean swollen and tender joint counts ranged from 15.2-16.1 and 26.5-28.2, respectively.
• Prior to study participation, approximately 5% of patients had received infliximab (n=36), etanercept (n=29), and/or adalimumab (n=36).

Efficacy

• Results for primary and major secondary clinical outcomes at weeks 14, 24, and 48 are provided in Table: Summary of Efficacy Results at Weeks 14, 24, and 48.

Safety

• A summary of the safety results through week 48 is provided in Table: Summary of Safety Results through Week 16 (Placebo-Controlled Phase) and Week 48 (Including Early Escape and Dose Regimen Adjustments).
• Tuberculosis (TB) was reported in 2 SIMPONI ARIA treated patients (SIMPONI ARIA 4 mg/kg, n=1; SIMPONI ARIA 4 mg/kg + MTX, n=1); both patients tested negative for TB at screening.
• A total of 3 patients died through week 48: 1 each in the SIMPONI ARIA 2 mg/kg group, SIMPONI ARIA 4 mg/kg group, and the SIMPONI ARIA 4 mg/kg + MTX group. Two additional deaths (1 in the SIMPONI ARIA 2 mg/kg group and 1 in the SIMPONI ARIA 2 mg/kg + MTX group) were reported after week 48.
• A total of 8 malignancies reported in patients receiving SIMPONI ARIA. One occurred in the SIMPONI ARIA 2 mg/kg group (basal cell carcinoma), 2 occurred in the SIMPONI ARIA 4 mg/kg group (benign lipoma and colon cancer), 1 occurred in the SIMPONI ARIA 2 mg/kg + MTX group (fibrous histiocytoma), and 4 occurred in the SIMPONI ARIA 4 mg/kg + MTX group (benign breast neoplasm, bladder cancer, lung cancer, and ovarian tumor).
• Among patients for whom appropriate samples were available, a higher proportion of patients receiving SIMPONI ARIA monotherapy developed antibodies to golimumab compared with those receiving SIMPONI ARIA + MTX (9% [17/194] vs 3% [10/299]). Similarly, concomitant use of MTX was associated with a lower incidence of antibodies to golimumab at week 48.

Real World Evidence

Broadwell et al (2019)² evaluated MTX utilization among patients with RA treated with SIMPONI ARIA from the AWARE study. AWARE (Comparative and Pragmatic Study of intravenous [IV] Golimumab [SIMPONI ARIA] versus infliximab [REMICADE] in rheumatoid arthritis [RA]) is an on-going, phase 4, prospective, noninterventional, observational, multicenter, real world evidence study of SIMPONI ARIA compared to infliximab in rheumatoid arthritis (RA) patients.

Study Design/Methods

• A total of 1270 adult RA patients were enrolled in the AWARE study at the time of treatment initiation with SIMPONI ARIA (n=685) or infliximab (n=585).
• The primary endpoint of the AWARE study was the proportion of patients who had an infusion reaction during the first 52 weeks of treatment.
• Treatment decisions, including prescribed dose, dosing frequency, and MTX utilization were made at the discretion of the rheumatologist.  
• Concomitant MTX use was defined as patients who were administered at least 1 MTX dose on or after the first SIMPONI ARIA infusion.
• Change in Clinical Disease Activity Index (CDAI) from baseline was measured at months 3, 6, and 12.
• Change from baseline CDAI was based on imputed data using LOCF for missing data and/or treatment failure rule.

Patient Characteristics

• A summary of baseline and disease characteristics of patients treated with SIMPONI ARIA with or without MTX is presented in Table: Baseline Demographics and Disease Characteristics.

Efficacy

• The mean change from baseline in CDAI among bionaive patients treated with SIMPONI ARIA with or without MTX is reported in Table: Mean Changes from Baseline in CDAI Scores among Bionaïve Patients Treated with SIMPONI ARIA with or without Concomitant MTX.

Safety

• A summary of the safety results through week 52 is provided in Table: Summary of Safety Results through Week 52.

Summary of Safety Results through Week 52²

Schwartzman et al (2019)³ analyzed the effect of concomitant methotrexate utilization on the incidence and management of infusion reactions in adult RA patients treated with SIMPONI ARIA or infliximab from a prospective, noninterventional, observational, multicenter, real world evidence, phase 4 AWARE study conducted in the US.

Study Design/Methods

• A total of 1270 adult RA patients were enrolled in the AWARE study at the time of initiating treatment with SIMPONI ARIA (n=685) or infliximab (n=585).
• In the AWARE study, the primary endpoint was the proportion of patients with an infusion reaction at week 52 in the SIMPONI ARIA group compared to the infliximab group.
  • An infusion reaction was defined as any adverse event (AE) occurring during an infusion or within 1 hour after completion of an infusion.
  • At the planned interim analysis, when 833 patients reached 52 weeks of treatment, the primary endpoint was met (P<0.001).
• Prior biologic medication use and concomitant MTX use were recorded. Concomitant MTX use was defined as any dose of MTX on or after the baseline infusion of SIMPONI ARIA.
• The protocol did not restrict or introduce any medical interventions or medications.
• All treatment decisions including dose and dosing frequency were made at the discretion of the treating rheumatologist and patient visits occurred per usual clinical practice.
• Imputations were not performed in this analysis of the AWARE data.

Results

Patient Characteristics

• The baseline demographics were generally comparable between the 2 treatment groups. However, mean age and disease duration was greater in the SIMPONI ARIA treated patients compared to the infliximab treated patients by approximately 2 years. Also, the proportion of patients with ≥3 prior biologic use was approximately 2 fold greater in the SIMPONI ARIA treated patients vs infliximab treated patients.
• The proportion of patients who received concomitant MTX was similar between the SIMPONI ARIA group (n=420 [61.3%]) and the infliximab group (n=356 [60.9%]).

Safety

• A summary of infusion reactions in the SIMPONI ARIA and infliximab groups (overall and by concomitant MTX use) at week 52 is presented in Table: Summary of Infusion Reactions at Week 52.

• A summary of medications used in association with infusion reactions is provided in Table: Summary of Preinfusion Medications and Medications Used for Infusion Reactions.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 26 November 2024.