Golimumab

Patients were eligible for enrolment if they were ≥18 years of age and were diagnosed with active PsA. The institutional review boards at each participating medical centre approved the protocol and all patients provided written informed consent before study entry. Patients were required to meet the Classification Criteria for Psoriatic Arthritis (CASPAR)8 (link) at screening and have a minimum of both three swollen and three tender joints, despite prior treatment with traditional DMARDs and/or biologic treatment or concurrent treatment with traditional DMARDs. Prior tumour necrosis factor blocker efficacy failures were limited to ≤10% of enrolled patients. Patients taking methotrexate, leflunomide or sulfasalazine must have been treated for at least 16 weeks and on a stable dose (oral or parenteral methotrexate ≤25 mg/week; leflunomide ≤20 mg/day; sulfasalazine ≤2 g/day; or a combination) for at least 4 weeks before the screening visit. Stable doses of oral corticosteroids (prednisone ≤10 mg/day or equivalent for at least 1 month) and non-steroidal anti-inflammatory drugs (≥2 weeks) were permitted.
Key exclusion criteria were failure of more than three agents for PsA (DMARDs or biologics) or more than one tumour necrosis factor blocker. Patients were also excluded if they had a history of or current (1) inflammatory, rheumatic or autoimmune joint disease other than PsA; (2) erythrodermic, guttate or generalised pustular psoriasis; (3) were functional class IV, defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis; (4) had used phototherapy or DMARDs other than methotrexate, leflunomide or sulfasalazine within 4 weeks of randomisation; (5) had used adalimumab, etanercept, golimumab, infliximab, certolizumab pegol or tocilizumab within 12 weeks of randomisation or alefacept or ustekinumab within 24 weeks of randomisation; or (6) had prior treatment with apremilast. Topical therapy for psoriasis within 2 weeks of randomisation was not permitted. Patients with active tuberculosis or a history of incompletely treated tuberculosis could not participate.

Patients. Patients age ≥18 years were eligible for inclusion in the GO‐VIBRANT study if they were diagnosed as having PsA for ≥6 months and met Classification Criteria for Psoriatic Arthritis 9 at screening. Patients had to have active PsA (defined as ≥5 of 66 swollen joints and ≥5 of 68 tender joints at screening and baseline and a high‐sensitivity C‐reactive protein [CRP] level of ≥0.6 mg/dl at screening) despite current or previous DMARD therapy (≥3 months) and/or NSAID therapy (≥4 weeks) or demonstrate intolerance to these agents.
Previous biologic therapy for PsA was not permitted. Concomitant use of methotrexate (MTX) (≤25 mg/week) was permitted for patients who had been receiving MTX for ≥3 months before the first golimumab administration; MTX doses had to have remained stable for ≥4 weeks. Patients could receive concomitant oral corticosteroids if they had been receiving a stable dose (≤10 mg prednisone/day) for ≥2 weeks prior to the first golimumab administration. Patients were also permitted to receive concomitant NSAIDs at the usual approved marketed doses if they had received stable doses for ≥2 weeks prior to the first golimumab administration.
Patients were randomly assigned to treatment groups by stratified block randomization using an interactive web response system. Randomization was stratified by geographic region and baseline MTX use (yes or no). Patients and investigators were blinded with regard to treatment group assignment for the duration of the study.
Study design. GO‐VIBRANT is a phase III, multicenter, randomized, placebo‐controlled trial. Eligible patients were randomized to receive IV infusions of placebo or golimumab at 2 mg/kg at weeks 0 and 4 and every 8 weeks. Infusions were administered during a period of 30 ± 10 minutes. At week 16, patients in both treatment groups with <5% improvement in swollen and tender joint counts entered early escape and were allowed one of the following changes in treatment at the investigator's discretion: an increase in corticosteroid dose (total dose ≤10 mg/day prednisone or equivalent), MTX dose (total dose ≤25 mg/week), or NSAID dose; or initiation of NSAIDs, corticosteroids (≤10 mg/day prednisone or equivalent), MTX (≤25 mg/week), sulfasalazine (≤3 gm/day), hydroxychloroquine (≤400 mg/day), or leflunomide (≤20 mg/day).
Assessments. The activity of peripheral arthritis was primarily evaluated using the American College of Rheumatology (ACR) criteria for improvement in RA 10. Physical function was evaluated using the Health Assessment Questionnaire disability index (HAQ DI) 11. Enthesitis was assessed with the Leeds Enthesitis Index 12, which was developed for patients with PsA and evaluates the presence or absence of tenderness in the following entheses (left and right): lateral elbow epicondyle, medial femoral condyle, and Achilles tendon insertion. The presence and severity of dactylitis was assessed in both hands and feet using a scoring system from 0 to 3 (0 = no dactylitis, 1 = mild dactylitis, 2 = moderate dactylitis, and 3 = severe dactylitis). For patients with investigator‐assessed spondylitis with peripheral arthritis of PsA (n = 118), spondylitis was also assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 13. Skin response was evaluated using the Psoriasis Area and Severity Index (PASI), which ranges from 0 to 72 with higher scores indicating more severe disease, among patients with ≥3% body surface area involvement at baseline 14.
Health‐related quality of life (HRQoL) was evaluated using the Short Form 36 health survey (SF‐36) physical component summary (PCS) and mental component summary (MCS) scores 15. Minimal disease activity (MDA) was also evaluated as a composite measure with patients classified as achieving MDA if they met 5 of the following 7 criteria: tender joint count ≤1; swollen joint count ≤1; PASI ≤1 or body surface area involvement ≤3%; visual analog scale (VAS) score of ≤15 on patient's assessment of pain; VAS score of ≤20 on patient's global assessment of disease activity; HAQ DI score of ≤0.5; and ≤1 tender entheseal point 16.
Radiographs were obtained at weeks 0 and 24 and were read by 2 independent assessors who were blinded with regard to treatment group and time point. Patients who entered early escape also had radiographs at week 16. Changes in radiographic damage were measured using the modified Sharp/van der Heijde score (SHS) with modifications for patients with PsA (i.e., inclusion of distal interphalangeal joints in the hands and pencil‐in‐cup/gross osteolysis deformities) 17.
Patients were monitored throughout the study, including routine laboratory assessments, for adverse events (AEs). Serum golimumab concentrations were recorded at prespecified time points through week 20. The presence of antibodies to golimumab was assessed through week 20 using a recently developed, highly sensitive, drug‐tolerant enzyme immunoassay method in patients who received at least 1 administration of golimumab and had at least 1 postadministration sample available.
Statistical analysis. The primary end point was the proportion of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) 10 at week 14. Major secondary end points were the change from baseline in HAQ DI score at week 14, the proportion of patients with an ACR50 response at week 14, the proportion of patients with a ≥75% reduction in PASI scores (a PASI75 response) at week 14, and the change from baseline in total PsA‐modified SHS at week 24. To control for multiplicity, the major secondary end points were tested sequentially (according to the order listed above) only if the primary end point achieved statistical significance. Other controlled end points were change from baseline in enthesitis score at week 14, change from baseline in dactylitis score at week 14, change from baseline in SF‐36 PCS score at week 14, proportion of patients with an ACR50 response at week 24, proportion of patients with an ACR70 response at week 14, and change from baseline in SF‐36 MCS score at week 14. Changes in enthesitis and dactylitis were evaluated among patients with these findings at baseline. These end points were tested sequentially in the order listed only if the primary and major secondary end points achieved statistical significance. For other efficacy analyses, nominal P values were provided for selected end points.
Efficacy data were analyzed by randomized treatment group (intent‐to‐treat analysis). For the primary end point analysis (proportion of patients achieving an ACR20 response) and all other composite end points, missing data for components were imputed using last observation carried forward methodology, and patients with missing data for all components at week 14 were classified as nonresponders. For signs and symptoms end points, patients were classified as nonresponders (treatment failure) if they discontinued study treatment due to lack of efficacy, initiated prohibited therapies or had an increase in dose of MTX or oral corticosteroids (other than early escape treatment), or met the early escape criteria and initiated or increased concomitant medications.
The change in total PsA‐modified SHS was evaluated for randomized patients who had a baseline total PsA‐modified SHS. Multiple imputations 18, using data from patients who had data at both week 0 and week 24, were used to impute week 24 radiograph scores for missing data and/or early escape. A linear regression model with baseline score, ln(CRP + 1), and MTX usage as covariates was used to generate missing data. Comparisons were made using a t‐test from the aggregated data.
All statistical tests were performed at an alpha level of 0.05 (2‐sided). Differences between treatment groups were tested using the Cochran‐Mantel‐Haenszel test for dichotomous end points and mixed‐effects model repeated‐measures methodology using observed data for continuous variables. For the primary end point, it was estimated that 220 patients in each treatment group would ensure 99% power to detect a significant difference between the groups, assuming a 20% ACR20 response rate in the placebo group and a 40% ACR20 response rate in the golimumab group at a 2‐sided significance level of 0.05 (using a chi‐square test). In addition, for the radiographic end point, it was estimated that 220 patients in each group would provide 90.7% power to detect a significant difference in the mean change in total PsA‐modified SHS between treatment groups.