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.

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://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.

• Authors: 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
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 23 Issue 1 Pg. 190 (07 14 2021) ISSN: 1478-6362 [Electronic] England
• PMID: 34261541 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents
• guselkumab

Topics

• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents (therapeutic use)
• Arthritis, Psoriatic (drug therapy)
• Double-Blind Method
• Fatigue (drug therapy)
• Humans
• Severity of Illness Index
• Treatment Outcome