Journal Article

Guselkumab demonstrated an independent treatment effect in reducing fatigue after adjustment for clinical response—results from two phase 3 clinical trials of 1120 patients with active psoriatic arthritis

Helliwell, Philip S., Zhou, Bei, Hsia, Elizabeth C., Han, Chenglong, Mease, Philip J., Rahman, Proton, Gossec, Laure, Kavanaugh, Arthur, Karyekar, Chetan S., Lin, Xiwu, Shawi, May, Kollmeier, Alexa P., Deodhar, Atul

2021

Overview

Background The interleukin-23p19-subunit inhibitor guselkumab effectively treats signs and symptoms of psoriatic arthritis (PsA). We evaluated the effect of guselkumab on fatigue. Methods Across two phase 3 trials of guselkumab (DISCOVER-1, DISCOVER-2), patients with active PsA despite standard therapy were randomized to subcutaneous injections of guselkumab 100 mg every 4 weeks (Q4W, N = 373); guselkumab 100 mg at week 0, week 4, and then Q8W ( N = 375); or placebo ( N = 372) through week 24, after which patients in the placebo group crossed over to guselkumab Q4W. Fatigue was measured as a secondary endpoint using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue instrument (range 0–52, higher scores indicate less fatigue). Least-squares mean changes in FACIT-Fatigue scores were compared between treatments using a mixed-effect model for repeated measures. Mediation analysis was used to adjust for indirect effects on fatigue deriving from improvement in other outcomes, including ≥20% improvement in American College of Rheumatology criteria (ACR20; prespecified), minimal disease activity (MDA; post hoc), or C-reactive protein (CRP; post hoc). Results Baseline mean (SD) FACIT-Fatigue scores in DISCOVER-1 ( N = 381) and DISCOVER-2 ( N = 739), ranging from 29.1 (9.5) to 31.4 (10.1), indicated substantial levels of fatigue relative to the United States general population (43.6 [9.4]). Across studies, mean improvements, and proportions of patients with ≥4-point improvements, in FACIT-Fatigue scores at week 24 with guselkumab Q4W and Q8W (5.6–7.6 and 54–63%, respectively) were larger vs placebo (2.2–3.6 and 35–46%). Improvement in FACIT-Fatigue scores with guselkumab was sustained from week 24 to week 52, with moderate-to-large effect sizes (Cohen’s d = 0.52–0.81 at week 24; 0.66–0.91 at week 52). Mediation analyses demonstrated that substantial proportions of the effects of guselkumab vs placebo on fatigue were direct effect, after adjusting for achievement of ACR20 (Q4W 69–70%, Q8W 12–36% direct effect) or MDA (72–92% across dosing regimens) response or for change in serum CRP concentrations (82–88% across dosing regimens). Conclusions In patients with active PsA, guselkumab 100 mg Q4W or Q8W led to clinically meaningful and sustained improvements in fatigue through 1 year. A substantial portion of the improvement in FACIT-Fatigue scores induced by guselkumab was independent of effects on the achievement of other select outcomes. Trial registration Name of the registry: ClinicalTrials.gov Trial registrations: DISCOVER-1, NCT03162796; DISCOVER-2, NCT03158285 Date of registration: DISCOVER-1, May 22, 2017; DISCOVER-2, May 18, 2017 URLs of the trial registry record: DISCOVER-1, https://clinicaltrials.gov/ct2/show/NCT03162796?term=NCT03162796&draw=1&rank=1 DISCOVER-2, https://clinicaltrials.gov/ct2/show/NCT03158285?term=NCT03158285&draw=2&rank=1

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Antibodies, Monoclonal, Humanized / Antirheumatic Agents - therapeutic use / Arthritis / Arthritis, Psoriatic - drug therapy / Biologic / C-reactive protein / Care and treatment / Chronic illnesses / Clinical outcomes / Clinical trials / Diagnosis / Disease / Double-Blind Method / Fatigue / Fatigue - drug therapy / Human health and pathology / Humans / Immunology / Immunotherapy / Interleukin-23 / Life Sciences / Measurement / Medicine / Medicine & Public Health / Monoclonal antibodies / Orthopedics / p19 subunit / Patient outcomes / Patient-reported outcome / Patients / Psoriasis / Psoriatic arthritis / Research Article / Rheumatology / Rhumatology and musculoskeletal system / Severity of Illness Index / Treatment Outcome