INTERVENTION: Product Name: Guselkumab Product Code: CNTO1959 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: Guselkumab Current Sponsor code: CNTO1959 Other descriptive name: GUSELKUMAB Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Trade Name: Stelara Product Name: Ustekinumab Product Code: CNTO1275 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: Ustekinumab CAS Number: 815610‐63‐0 Current Sponsor code: CNTO1275 Other descriptive name: USTEKINUMAB Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 90‐ Trade Name: Stelara Product Name: Ustekinumab Product Code: CNTO1275 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: Ustekinumab CAS Number: 815610‐63‐0 Current Sponsor code: CNTO1275 Other descriptive name: USTEKINUMAB Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 90‐ CONDITION: Active Psoriatic Arthritis ; MedDRA version: 18.0 Level: LLT Classification code 10037160 Term: Psoriatic arthritis System Organ Class: 100000004859 Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: ‐ To evaluate the efficacy of guselkumab in subjects with active PsA by assessing the reduction in signs and symptoms of PsA.; ‐ To assess the safety and tolerability of guselkumab in subjects with active PsA. Primary end point(s): Percentage of Participants who Achieve an American College of Rheumatology (ACR) 20 Response at Week 24 Secondary Objective: The secondary objectives are:; ‐ To evaluate the efficacy of guselkumab in improving physical function.; ‐ To evaluate the impact of guselkumab on quality of life.; ‐ To evaluate the efficacy of guselkumab on psoriatic skin lesions.; ‐ To evaluate the PK and immunogenicity of guselkumab in subjects with active PsA.; ‐ To evaluate the PD characteristics of guselkumab with and without MTX in subjects with active PsA.; ‐ To evaluate the efficacy and safety of guselkumab following 1 year of exposure.; ; The exploratory objectives are:; ‐ To evaluate the correlation between PK and PD characteristics of guselkumab in subjects with PsA.; ‐ To use ultrasound to evaluate the changes in musculoskeletal abnormalities (enthesitis, tenosynovitis, and synovitis) from baseline in patients with active PsA treated with guselkumab as compared to placebo) Timepoint(s) of evaluation of this end point: Week 24 SECONDARY OUTCOME: Secondary end point(s): 1. Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ‐DI) Score at Week 24 ; 2. Percentage of Participants who Achieve an American College of Rheumatology (ACR) 20 Response at Week 16 ; 3. Percentage of Participants who Achieve an ACR 50 Response at Week 24 ; 4. Percent Improvement in Enthesitis Scores at Week 24 Among Participants with Enthesitis at Baseline ; 5. Percent Improvement in Dactylitis Scores at Week 24 Among Participants with Dactylitis at Baseline ; ‐ secundairy end point 2 at week 16 ; ‐ secundairy end point 3 & 6 at week 24 ‐ Has plaque psoriasis with body surface area (BSA) involvement greater than or equal to (>=) 3% at Screening and baseline ‐ Has active PsA despite current or previous non‐biologic diseasemodifying antirheumatic drugs (DMARD), oral corticosteroid, and/or nonsteroidal anti‐inflammatory drug ( ; 6. Percentage of Participants who Achieve a Psoriatic Area and Severity Index (PASI) 75 Response at Week 24 Timepoint(s) of evaluation of this end point: ‐ secundairy end point 1, 4 & 5 at baseline & week 24 INCLUSION CRITERIA: ‐ Has had Psoriatic Arthritis (PsA) for at least 6 months before the first administration of study drug and meet classification criteria for Psoriatic Arthritis (CASPAR) at Screening ‐ Had active PsA as defined by: a. At least 3 swollen joints and at least 3 tender joints at Screening and at baseline b. C‐reactive protein (CRP) greater than or equal to (>=) 0.3 milligram (mg)/deciliter (dL) at Screening from the central laboratory ‐ Has at least 1 of the PsA subsets: distal interphalangeal joint involvement, polyarticular arthritis with absence of rheumatoid nodules, arthritis mutilans, asymmetric peripheral arthritis, or spondylitis with peripheral arthritis
BACKGROUND: Guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, has been approved for the treatment of moderate-to-severe psoriasis. Psoriatic arthritis is a common comorbidity of psoriasis with an umet need for novel treatments. We assessed the efficacy and safety of guselkumab in patients with active psoriatic arthritis.
METHODS: We did a randomised, double-blind, placebo-controlled, phase 2a trial at 34 rheumatology and dermatology practices in Canada, Germany, Poland, Romania, Russia, Spain, and the USA. Eligible participants were aged 18 years or older with active psoriatic arthritis and plaque psoriasis affecting at least 3% of their body surface area, with three or more of 66 tender joints and three or more of 68 swollen joints, who had an inadequate response or intolerance to standard treatments. We randomly assigned patients (2:1) via a central interactive web-response system using computer-generated permuted blocks with a block size of six, stratified by previous anti-tumour necrosis factor-α use, to receive subcutaneous guselkumab 100 mg or placebo at week 0, week 4, and every 8 weeks thereafter for 24 weeks. Patients, investigators, and site staff were masked to treatment assignment until final database lock at week 56. At week 16, patients with less than 5% improvement in swollen and tender joint counts were eligible for early escape to ustekinumab. At week 24, the remaining placebo-treated patients crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 and guselkumab-treated patients received a placebo injection at week 24, followed by guselkumab injections at weeks 28, 36, and 44. The primary endpoint was the proportion of patients with at least 20% improvement at week 24 in signs and symptoms of psoriatic arthritis according to American College of Rheumatology criteria (ACR20) in the modified intention-to-treat population (ie, all randomly assigned patients who received at least one dose of study treatment). Safety analyses included patients according to the study drug received. This study is registered with ClinicalTrials.gov, number NCT02319759.
FINDINGS: Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39·7% [95% CI 25·3-54·1]; p<0·0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred.
INTERPRETATION: Guselkumab, a novel anti-interleukin 23p19 antibody, significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 44 weeks of treatment. The results of this study support further development of guselkumab as a novel and comprehensive treatment in psoriatic arthritis.
FUNDING: Janssen Research & Development.
OBJECTIVE: To assess performance of psoriatic arthritis (PsA) composite indices and evaluate guselkumab's effect on achieving low disease activity or remission. METHODS: In this phase II trial, patients with active PsA (≥3 tender and ≥3 swollen joints, C‐reactive protein level ≥0.3 mg/dl, ≥3% body surface‐area with psoriasis involvement) were randomized 2:1 to subcutaneous guselkumab 100 mg (n = 100) or placebo (n = 49) at week 0, week 4, and every 8 weeks through week 44. At week 16, patients with <5% improvement in swollen and tender joints could early escape to open‐label ustekinumab. Patients continuing placebo crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 (placebo to guselkumab). PsA composite indices (Psoriatic Arthritis Disease Activity Score [PASDAS], Group for Research and Assessment of Psoriasis and Psoriatic Arthritis composite score [GRACE], modified Composite Psoriatic Disease Activity Index [mCPDAI], and Disease Activity in Psoriatic Arthritis [DAPSA]) were analyzed as secondary outcomes (last observation carried forward for missing/post‐early escape data through week 24; observed data post‐week 24). Instrument performance was assessed. RESULTS: Baseline PASDAS, GRACE, mCPDAI, and DAPSA scores indicated moderate‐to‐high disease activity. At week 24, mean changes in each of these composite indices showed significant improvement with guselkumab (‐2.50, ‐2.73, ‐3.8, and ‐23.08, respectively) versus placebo (‐0.49, 0.35, ‐0.8, and ‐4.98, respectively; P < 0.001 for all). Significantly more guselkumab‐treated patients achieved low/very low/remitted disease activity states according to PASDAS (very low + low 35% versus 4%; P < 0.001), GRACE (30% versus 2%; P < 0.001), mCPDAI (46% versus 10%; P < 0.001), and DAPSA (remission + low 40% versus 12%; P < 0.001). A total of 12% of guselkumab‐treated versus no placebo‐treated patients achieved DAPSA remission (P < 0.01). The PASDAS and GRACE instruments were more sensitive than the mCPDAI and DAPSA tools in detecting treatment effect. Residual skin disease and enthesitis were marginally more prominent in patients achieving DAPSA low disease activity versus other indices. CONCLUSION: Guselkumab demonstrated efficacy in achieving low disease activity/remission based on all PsA composite indices assessed. Composite index use in PsA trials and the clinic requires careful consideration to optimize feasibility and instrument performance.
