Efficacy and safety of intravenous golimumab plus methotrexate in patients with rheumatoid arthritis aged < 65 years and those ≥ 65 years of age

The details of the GO-FURTHER patient population and study design have been previously published [18]. The GO-FURTHER trial was a phase 3, randomized, placebo-controlled trial. Adults with active RA (≥ 6 swollen and ≥ 6 tender joints) for ≥ 3 months despite MTX therapy were eligible for enrollment. Patients also had to have a screening C-reactive protein level ≥ 1.0 mg/dL and a positive status for either anti-cyclic citrullinated peptide antibodies or rheumatoid factor. Patients who were receiving MTX had to have been receiving a stable dose (≥ 15 mg/week) for ≥ 3 months at screening and a stable dose (15–25 mg/week) for ≥ 4 weeks prior to enrollment. Concomitant use of oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) and nonsteroidal anti-inflammatory drugs (NSAIDs) (or other analgesics for RA, at usual approved doses) was permitted at stable doses [18]. Prior biologic therapy was not permitted, but patients could have received prior treatment with disease-modifying anti-rheumatic drugs (DMARDs) (other than MTX) and systemic immunosuppressives (e.g., d-penicillamine, hydroxychloroquine, chloroquine, oral or parenteral gold, sulfasalazine, leflunomide, azathioprine, cyclosporine, mycophenolate mofetil), but these medications were not permitted within 4 weeks of the first study drug administration.

Patients could not have a history of latent or active tuberculosis (TB) prior to screening and were screened using the QuantiFERON-TB Gold test or tuberculin skin test (if the former was not approved in that country) within 6 months before the first study agent administration and chest radiograph within 3 months before the first study agent administration. In addition, patients were excluded if they had received, or were expected to receive, any live virus or bacterial vaccination within 3 months prior to the first administration of study agent, during the study, or within 6 months after the last administration of study agent.

Eligible patients were randomized (2:1) to receive IV infusions of golimumab 2 mg/kg at weeks 0, 4, and every 8 weeks thereafter or placebo at weeks 0, 4, and 12, with crossover to golimumab 2 mg/kg at weeks 24, 28, and every 8 weeks thereafter through week 100. Patients in the placebo plus MTX group with < 10% improvement in swollen and tender joint counts from baseline to week 16 entered early escape and received golimumab at weeks 16, 20, and every 8 weeks. All patients continued to receive a stable dose of MTX (15-25 mg/week).

This analysis included only patients who received ≥ 1 IV golimumab administration, and patients were grouped according to age: < 65 years or ≥ 65 years, < 70 years or ≥ 70 years, and < 75 years or ≥ 75 years. Efficacy was determined using the American College of Rheumatology (ACR) criteria. The proportion of patients who achieved ≥ 20%, 50%, or 70% improvement in the ACR criteria (ACR20/ACR50/ACR70 response) was determined for patients < 65 years or ≥ 65 years; nominal p values (chi-square test) were generated for comparisons between treatment groups in each age group separately without adjustment for multiplicity. Nonresponder imputation was used for patients who met the treatment failure or early escape criteria. For patients with missing data, last observation carried forward was used for ACR components. Physical function was evaluated using the Health Assessment Questionnaire-Disability Index (HAQ-DI) [19] and general health-related quality of life (HRQoL) and 36-item Short-Form Health Survey Physical and Mental Component Summary (SF-36 PCS/MCS) scores [20]. ACR response and change in HAQ-DI were determined for weeks 14, 24, 52, and 100; change in SF-36 PCS and MCS scores was determined for weeks 12, 24, 52, and 112. Efficacy analyses were not performed for the higher age cutoffs (70 year and 75 years) due to the small numbers of patients in these groups. Safety events through 2 years were summarized for patients < 65 years or ≥ 65 years, patients < 70 years or ≥ 70 years, and patients < 75 or ≥ 75 years.

The GO-FURTHER study was conducted at 92 sites in 13 countries (Argentina, Australia, Columbia, Hungary, Korea, Lithuania, Malaysia, Mexico, New Zealand, Poland, Russia, Ukraine, and the USA). Patients were randomized to receive placebo plus MTX (n = 197) or golimumab plus MTX (n = 395) at baseline. Demographic and disease characteristics were well-balanced between the treatment groups [18]. In this analysis, there were 515 patients aged < 65 years and 77 patients ≥ 65 years. Baseline demographics and disease characteristics for these patients are reported in Table 1. As expected, the mean ages differed between patients < 65 years and those ≥ 65 years. The proportions of patients receiving oral corticosteroids, NSAIDs, and DMARDs were lower among those aged ≥ 65 years. Patients ≥ 65 years had a longer mean RA disease duration and a slightly lower mean dose of oral corticosteroids at baseline compared with patients < 65 years. MTX use was categorized by time periods of (< 1 year, 1 to < 3 years, ≥ 3 years), and a greater proportion of younger patients seemed to be receiving MTX for longer than 3 years compared with patients ≥ 65 years. Other demographic and disease characteristics, including the ACR core assessments, were similar between these patient age groups.

At weeks 14 and 24, greater proportions of golimumab-treated patients achieved an ACR20 and ACR50 response compared with placebo among patients aged < 65 years and those ≥ 65 years. In addition, greater proportions of golimumab-treated patients achieved an ACR70 response compared with placebo in both age groups; however, the difference between treatment groups did not reach statistical significance among patients ≥ 65 years (Fig. 1). At weeks 52 and 100, when all patients had been receiving golimumab plus MTX since week 24, the proportions of patients achieving ACR20, ACR50, and ACR70 responses were similar for patients < 65 years and those ≥ 65 years within each treatment group (Fig. 1).

Mean improvements in HAQ-DI scores were also greater in the golimumab group compared with placebo in patients < 65 years and patients ≥ 65 years at weeks 14 and 24 (Table 2). Mean improvements in SF-36 PCS and MCS scores were greater in the golimumab-treated patients compared with placebo at weeks 12 and 24; however, differences between the treatment groups did not always reach significance among patients ≥ 65 years (Table 2). Among patients < 65 years, mean improvements in HAQ-DI and SF-36 PCS and MCS scores were sustained in the golimumab group through weeks 52 and 100/112, and improvements in the placebo crossover group approached those of the golimumab group at weeks 52 and 100/112. Among patients ≥ 65 years, improvements in HAQ-DI and SF-36 PCS and MCS scores were maintained through week 100/112 in the golimumab group. Patients who crossed over from placebo to golimumab also demonstrated improvements at weeks 52 and 100/112, although these improvements were smaller than those in the golimumab group; however, the small number of patients ≥ 65 years in the placebo crossover group limits the interpretation of these results.

Through week 24, nine patients (2.2%) in the golimumab plus MTX group discontinued study treatment due to an AE. Of these, six patients (1.8%) were < 65 years at baseline, and three (5.1%) were ≥ 65 years of age. Through week 52 in the golimumab plus MTX group, 11 patients (3.3%) < 65 years and four patients (6.8%) ≥ 65 years discontinued study treatment due to AEs; through week 112, 23 patients (6.8%) < 65 years and 9 patients (15.3%) ≥ 65 years discontinued study treatment due to AEs. Overall, 86 (16.7%) patients < 65 years and 20 (26.0%) patients ≥ 65 years discontinued study agent through week 112. The two most common reasons for discontinuation were AEs (n = 44; 6.2% of patients < 65 years, 15.6% of patients ≥ 65 years) and withdrawal of consent (n = 31; 5.2% of patients < 65 years, 5.2% of patients ≥ 65 years). Among patients < 70 years, 6.5% discontinued study agent due to an AE, and 5.4% withdrew consent; among patients ≥ 70 years, 21.1% discontinued due to an AE, 2.6% withdrew consent, and 2.6% discontinued due to lack of efficacy. Among patients < 75 years, 6.9% discontinued study agent due to an AE, and 5.3% withdrew consent; among patients ≥ 75 years, 40.0% discontinued due to an AE, and all other discontinuations were for reasons other than AEs, withdrawal of consent or lack of efficacy.

Infections were the most common type of AE through week 52. The incidence of infections was similar between patients < 65 years (214/508, 42.1%) and those ≥ 65 years (30/76, 39.5%) and between patients < 70 years (227/547, 41.5%) and ≥ 70 years (17/37, 45.9%). Patients ≥ 75 years had a higher incidence of infections through week 52 than did patients < 75 years (5/10, 50.0%, and 239/574, 41.6%, respectively); however, the number of patients ≥ 75 years was small. Similar results were observed for the incidence of infections through week 112 (Table 3). Through week 112, upper respiratory infections were the most common infection in patients < 65 years (n = 67/508; 13.2%) and those ≥ 65 years (n = 9/76; 11.8%). The incidence of cellulitis was slightly higher among patients ≥ 65 years (n = 4/76, 5.3%) compared with those < 65 years (n = 10/508, 2.0%). Among patients ≥ 65 years, other infections included fungal urinary tract infection (n = 1) and septic arthritis (n = 2). There were four cases of herpes zoster; three occurred in patients < 65 years and one in a patient ≥ 70 years, and none were classified as serious or severe. Among patients who received golimumab plus MTX, 16/508 (3.1%) patients < 65 years and 7/76 (9.2%) ≥ 65 years had an infusion reaction through week 112. Skin reactions were the most common type of reaction among patients < 65 years (n = 5); vascular disorders (hypertension and flushing) were the most common reaction among patients ≥ 65 years (n = 3). Two patients in each age group experienced an infusion reaction of headache. None were considered serious or severe. No patient aged ≥ 65 years discontinued golimumab therapy due to an infusion reaction; one golimumab-treated patient, aged 39 years, discontinued due to a nonserious infusion reaction (mild skin reaction).

The proportion of patients with at least one SAE through week 52 was numerically higher in patients ≥ 65 years (9/76, 11.8%) than in those aged < 65 years (45/508, 8.9%). Through week 52, the proportion of patients with at least one SAE was numerically higher for patients ≥ 70 years (5/37, 13.5%) compared with patients < 70 years (49/547, 9.0%) and for patients ≥ 75 years (4/10, 40.0%; cholecystitis and electrolyte imbalance [both in one patient], hemorrhoids, cerebral infarction, interstitial lung disease) compared with patients < 75 years (50/574, 8.7%). However, it should be noted that the numbers of patients ≥ 70 years and ≥ 75 years were relatively small. A similar trend was also observed for the proportions of patients with at least one AE through week 52.

Through week 112, 19 (25.0%) patients ≥ 65 years had an SAE, including cellulitis and bacterial arthritis. Among patients ≥ 75 years (n = 10), 7 (70.0%) had an SAE, including intervertebral discitis and diverticulosis. Ninety patients (17.7%) < 65 years had an SAE through week 112, including one patient with acute pancreatitis. Other SAEs through week 112 included fractures in eight golimumab plus MTX-treated patients: five who were < 65 years, one who was ≥ 65 and < 70 years (femoral neck fracture), one who was ≥ 70 and < 75 years (upper limb fracture), and one who was ≥ 75 years (spinal compression fracture; same patient with the intervertebral discitis). Additionally, among patients treated with golimumab plus MTX, six malignancies were reported through week 112; all occurred in patients < 65 years (breast cancer, cervical carcinoma stage 0, basal cell carcinoma (n = 2), Bowen’s disease, and chronic lymphocytic leukemia).

In the overall GO-FURTHER population, 36 golimumab plus MTX-treated patients (6.2%) experienced a serious infection through week 112 [7]. In this post hoc analysis by age, there was a higher incidence of serious infections among patients ≥ 65 years, ≥ 70 years, and ≥ 75 years when compared with patients < 65 years, < 70 years, and < 75 years, respectively, through weeks 52 and 112; however, the numbers of patients ≥ 70 years and ≥ 75 years were small. Serious infections included sepsis (n = 2), septic arthritis (n = 1), and cellulitis (n = 1) among patients ≥ 65 years and rectal abscess (n = 1), sepsis (n = 1), and urosepsis (n = 1) among patients < 65 years. Two serious opportunistic infections were reported: infective spondylitis (Candida albicans) in a patient ≥ 75 years and a serious infection of cryptococcal pneumonia in a patient ≥ 65 years from South Korea. Three cases of active tuberculosis were reported through week 112, all in patients younger than 65 years. Through week 112, seven patients experienced an SAE of pneumonia; all were younger than 65 years, with the exception of the patient with cryptococcal pneumonia. There was no predominant type of serious infection, including opportunistic infections, among patients ≥ 65 years. Among patients who did not use corticosteroids at baseline, the incidence of serious infections through week 112 was similar for patients < 65 years and ≥ 65 years (13/170, 7.6%, and 3/33, 9.1%, respectively), while among patients who received oral corticosteroids at baseline, the incidence of serious infections was numerically higher for patients ≥ 65 years (6/43, 14.0%) compared with those < 65 years (14/338, 4.1%).

A total of five deaths occurred through 2 years in patients who received golimumab plus MTX [7, 18]: four occurred in patients who were younger than 65 years (myocardial infarction complicated by presumed pneumonia, abdominal tuberculosis, septic shock, and unknown causes) and one occurred in a patient older than 65 years (Clostridium difficile). One death occurred in a patient receiving placebo plus MTX (< 65 years; presumed stroke secondary to hypertensive crisis) as previously reported [18].