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

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

Abstract

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://ichgcp.net/clinical-trials-registry/NCT03162796?term=NCT03162796&draw=1&rank=1 DISCOVER-2, https://ichgcp.net/clinical-trials-registry/NCT03158285?term=NCT03158285&draw=2&rank=1.

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

Conflict of interest statement

PR has received research support (Janssen, Novartis), consulting fees (AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB), and speakers bureau support (AbbVie, Janssen, Eli Lilly, Novartis, Pfizer, and UCB). PJM has received research support, consulting fees (AbbVie, Amgen, Bristol Myers Squibb, Galapagos, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, SUN, and UCB) and consulting fees (Boehringer Ingelheim and GlaxoSmithKline). PSH has received research support and non-financial support (AbbVie), research support (Janssen, Pfizer), and consulting fees (Janssen, Galapagos, and Novartis). AD has received research support (AbbVie, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and UCB), consulting fees (AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB), and speakers bureau support (AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB). LG has received research grants (Amgen, Galapagos, Janssen, Eli Lilly, Pfizer, Sandoz, and Sanofi) and consulting fees (AbbVie, Amgen, Bristol Myers Squibb, Biogen, Celgene, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, and UCB). AK has received research support and/or consulting fees (AbbVie, Amgen, Bristol Myers Squibb, Genentech, Janssen, Eli Lilly, Merck, Novartis, Pfizer, and UCB). APK, ECH, BZ, XL, MS, CSK, and CH are employed by subsidiaries of, and own stock in, Johnson & Johnson.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Mediation analysis. Direct effect = treatment effect on outcome independent of the effect on the mediator; indirect effect = treatment effect on outcome that is attributed to its effect on the mediator. ACR20, ≥20% improvement in American College of Rheumatology criteria
Fig. 2
Fig. 2
Changes from baseline in FACIT-Fatigue score through week 52 in a DISCOVER-1 and b DISCOVER-2
Fig. 3
Fig. 3
Proportion of patients achieving clinically meaningful improvement in FACIT-Fatigue score (≥4-point increase [21]) through week 52 in a DISCOVER-1 and b DISCOVER-2
Fig. 4
Fig. 4
Modified cumulative distribution curves of changes in FACIT-Fatigue score at week 24 in a DISCOVER-1 and b DISCOVER-2

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