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Table 3 Mediation analysis of the effects of clinical responses on changes in FACIT-Fatigue scores through week 24

From: 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

Clinical response   Effect Guselkumab 100 mg Q4W vs placebo
Estimate (95% CI)
Guselkumab 100 mg Q8W vs placebo
Estimate (95% CI)
ACR20 DISCOVER-1 NDE 2.60 (0.58, 4.46)* 0.36 (−1.72, 2.40)
   NIE 1.20 (0.27, 2.31)* 2.75 (1.38, 4.32)*
   Total effect 3.79 (1.94, 5.44)* 3.12 (1.05, 5.15)*
   % Indirect (mediated) effect 31.5% 88.3%
   % Direct effect 68.5% 11.7%
  DISCOVER-2 NDE 2.49 (0.96, 4.14)* 1.44 (−0.11, 2.97)
   NIE 1.09 (0.42, 1.95)* 2.53 (1.62, 3.64)*
   Total effect 3.58 (2.10, 5.05)* 3.97 (2.41, 5.53)*
   % Indirect (mediated) effect 30.3% 63.7%
   % Direct effect 69.7% 36.3%
MDA DISCOVER-1 NDE 2.84 (0.97, 4.71)* 2.34 (0.24, 4.45)*
   NIE 0.78 (0.16, 1.40)* 0.74 (0.09, 1.39)*
   Total effect 3.62 (1.76, 5.49)* 3.08 (0.99, 5.18)*
   % Indirect (mediated) effect 21.6% 24.0%
   % Direct effect 78.4% 76.0%
  DISCOVER-2 NDE 3.13 (1.63, 4.63)* 2.67 (1.09, 4.26)*
   NIE 0.28 (0.07, 0.50)* 1.06 (0.49, 1.64)*
   Total effect 3.41 (1.96, 4.86)* 3.74 (2.13, 5.34)*
   % Indirect (mediated) effect 8.3% 28.5%
   % Direct effect 91.7% 71.5%
Change in CRP DISCOVER-1 NDE 3.19 (1.37, 5.02)* 2.51 (0.52, 4.50)*
   NIE 0.42 (−0.03, 0.86) 0.56 (−0.10, 1.22)
   Total effect 3.61 (1.74, 5.47)* 3.06 (0.95, 5.17)*
   % Indirect (mediated) effect 11.6% 18.2%
   % Direct effect 88.4% 81.8%
  DISCOVER-2 NDE 2.88 (1.36, 4.41)* 3.20 (1.62, 4.79)*
   NIE 0.49 (−0.07, 1.05) 0.60 (0.05, 1.14)*
   Total effect 3.37 (1.93, 4.81)* 3.80 (2.24, 5.36)*
   % Indirect (mediated) effect 14.5% 15.7%
   % Direct effect 85.5% 84.3%
  1. ACR20 and MDA were dichotomous mediators; change in CRP was a continuous mediator
  2. ACR20 ≥20% improvement in American College of Rheumatology criteria, CRP C-reactive protein, FACIT Functional Assessment of Chronic Illness Therapy, MDA minimal disease activity, NDE natural direct effect (effect on FACIT-F beyond the effect on the clinical response), NIE natural indirect effect (effect on FACIT-F mediated by clinical response), Q4W every 4 weeks, Q8W every 8 weeks
  3. *P vs placebo < 0.05