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

Arthritis Research & Therapy

Chetan S. Karyekar¹  May Shawi¹  Bei Zhou²  Xiwu Lin²  Chenglong Han²  Elizabeth C. Hsia³  Alexa P. Kollmeier⁴  Proton Rahman⁵  Atul Deodhar⁶  Laure Gossec⁷  Philip J. Mease⁸  Arthur Kavanaugh⁹  Philip S. Helliwell^1,10 

[1] Janssen Global Services, LLC, Horsham, PA, USA;Janssen Research & Development, LLC, 19436, Spring House, PA, USA;Janssen Research & Development, LLC, 19436, Spring House, PA, USA;Univerisity of Pennsylvania School of Medicine, Philadelphia, PA, USA;Janssen Research & Development, LLC, San Diego, CA, USA;Memorial University of Newfoundland, St. Johns, Newfoundland, Canada;Oregon Health & Science University, Portland, OR, USA;Sorbonne Université, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris, France;AP-HP Pitié-Salpêtrière Hospital, Paris, France;Swedish Medical Center/Providence St. Joseph Health and University of Washington School of Medicine, Seattle, WA, USA;University of California San Diego, La Jolla, CA, USA;University of Leeds, Leeds, UK;

关键词: Interleukin-23;    p19 subunit;    Biologic;    Fatigue;    Psoriatic arthritis;    Patient-reported outcome;    Mediation analysis;   

DOI  :  10.1186/s13075-021-02554-3

来源: Springer

【 摘 要 】

BackgroundThe interleukin-23p19-subunit inhibitor guselkumab effectively treats signs and symptoms of psoriatic arthritis (PsA). We evaluated the effect of guselkumab on fatigue.MethodsAcross 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).ResultsBaseline 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).ConclusionsIn 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 registrationName of the registry: ClinicalTrials.govTrial registrations: DISCOVER-1, NCT03162796; DISCOVER-2, NCT03158285Date of registration: DISCOVER-1, May 22, 2017; DISCOVER-2, May 18, 2017URLs of the trial registry record:DISCOVER-1, https://clinicaltrials.gov/ct2/show/NCT03162796?term=NCT03162796&draw=1&rank=1DISCOVER-2, https://clinicaltrials.gov/ct2/show/NCT03158285?term=NCT03158285&draw=2&rank=1

【 授权许可】

CC BY