Introduction
Fatigue is a debilitating multifactorial symptom experienced by many patients with Crohn's disease (CD).1 Topline efficacy data of mirikizumab (MIRI), an anti-interleukin-23p19 antibody, vs. placebo (PBO) and ustekinumab (UST) in patients with moderately to severely active Crohn’s disease in the Phase 3 VIVID-1 study were previously reported.2-4
Aims & Methods
This analysis assesses the impact of MIRI vs. PBO in improving fatigue and the correlation of patient variables with fatigue severity at baseline (BL) in the VIVID-1 study. Participants were randomized 6:3:2 to MIRI (900 mg intravenous at Week [W]0, W4, and W8, then 300 mg subcutaneous every 4W from W12-W52), UST or PBO. Fatigue was assessed via the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire (scale 0-52, higher scores indicating less fatigue,5 meaningful within-patient change identified as a 6–9 point [pt] increase). At W12 we report the proportion of PBO (N=199) and MIRI (N=579) patients achieving FACIT-F ≥6- or ≥9-pt increase from BL. Comparisons with PBO at W52 used composite (C) endpoints: clinical response by Patient-Reported Outcome at W12 (≥30% decrease in stool frequency [SF] or abdominal pain [AP], and neither worse than BL), and FACIT-F increase of either ≥6-pts (C≥6) or ≥9-pts (C≥9) by W52. p-Values were calculated via Cochran-Mantel-Haenszel test adjusted by biologic-failed status (yes/no); BL Simple Endoscopic Score for CD (SES-CD) total score (<12, ≥12); either BL SF ≥7 and/or AP ≥2.5 (yes or unknown/no). The pooled population of patients randomized to PBO or MIRI at BL, excluding those with missing data, with a range of patient variables was analyzed by the random forest method to assess the correlation with fatigue severity. Variables were ranked by importance by the random forest method and Pearson correlation coefficients (r) calculated for continuous variables.
Results
At W12, 31.2% (PBO) and 43.0% (MIRI) patients achieved FACIT-F ≥6-pt increase (p<0.005) and 22.1% (PBO) and 32.6% (MIRI) patients achieved FACIT-F ≥9-pt increase (p<0.01). At W52, 20.1% (PBO) and 34.9% (MIRI) patients met C≥6 (p<0.0005) and 15.6% (PBO) and 28.5% (MIRI) patients met C≥9 (p<0.0005). A strong association (r>0.5) was found between fatigue severity and Inflammatory Bowel Disease Questionnaire (IBDQ), and with the emotional functioning domain of IBDQ and Mental Component Summary (MCS) of Short Form (SF)-36 (Table). There was a weak association (r=0.1–0.3) with AP score, SF score, and Urgency Numeric Rating Scale, and insubstantial association (r<0.1) with objective markers of inflammation, including SES-CD, C-reactive protein, and fecal calprotectin.
Table: Correlation of highest ranked BL variables with FACIT-F
Variable
| Importance value based on random forest
| Pearson correlation coefficient
| Association based on Pearson correlation
|
IBDQ-systemic symptoms score
| 56.756
| 0.784
| Strong
|
SF-36 Mental Component Summary
| 18.816
| 0.654
| Strong
|
IBDQ-emotional functioning score
| 12.299
| 0.686
| Strong
|
SF-36 Physical Component Summary
| 10.423
| 0.577
| Strong
|
Inflammatory Bowel Disease-Disability Index score
| 5.951
| -0.567
| Strong
|
IBDQ-social functioning score
| 3.529
| 0.602
| Strong
|
IBDQ-bowel symptoms score
| 1.510
| 0.538
| Strong
|
Patient Global Rating of Severity score
| 0.472
| -0.307
| Moderate |
Urgency Numeric Rating Scale
| 0.342
| -0.136
| Weak |
Conclusion
MIRI showed a nominally clinically significant improvement in fatigue vs. PBO at W12 and a nominally statistically higher improvement in composite endpoints vs. PBO at W52. At BL, fatigue was not associated with objective inflammatory markers of disease severity or with typical CD symptoms. The observed strong association between fatigue and MCS of SF-36 and the emotional functioning domain of IBDQ implies bidirectional effects of brain-gut interactions that are not well understood.
References
- D’Silva A, et al. Clin Gastroenterol Hepatol. 2022;20:995-1009.
- Ferrante M, et al. J Crohn's Colitis. 2024;18:i7–i9.
- Jairath V, et al. J Crohn's Colitis. 2024;18:i62–i64.
- Travis S, et al. J Crohn's Colitis.2024;18:i21-i23.
- Tinsley A, et al. Aliment Pharmacol Ther. 2011;34:1328-1336.
Disclosure
P. Bossuyt has received financial support for research from: AbbVie, Amgen, Janssen, Pfizer, and Viatris; lecture fees from: AbbVie, Bristol Myers Squibb, CAG, Celltrion, Eli Lilly and Company, EPGS, Galapagos NV, Globalport, Janssen, Materia Prima, Pentax, Scope, and Takeda; and advisory board fees from: AbbVie, Bristol Myers Squibb, Celltrion, CIRC, Dr. Falk Pharma Benelux, Eli Lilly and Company, Galapagos NV, Janssen, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros; M. Regueiro has served as an advisor and/or consultant for: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Genentech, Gilead Sciences, Janssen, Organon, Pfizer, Prometheus Therapeutics and Diagnostics, Salix Pharmaceuticals, Takeda, and UCB Pharma; M. Fischer has received consulting fees from: AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Ferring Pharmaceuticals, Janssen, Pfizer, Rebiotix, Scioto Biosciences, and Seres Therapeutics; K. Traxler, G. Yu, M. N. Protic, K. Tsilkos, and A. Vadhariya are employees and shareholders of: Eli Lilly and Company; T. Hisamatsu has received lecture fees from: AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda; has received honoraria as an advisory board member or consultant for: AbbVie, Bristol Myers Squibb, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Pfizer, and Takeda; and has received pharmaceutical/research grants from: AbbVie, Boston Scientific, Daiichi Sankyo, EA Pharma, Kissei Pharmaceutical, JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nichi-lko Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; P. Juillerat has received fees for lectures and consulting/advisory board from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Ferring Pharmaceuticals, Gilead Sciences, Janssen, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Sandoz, Takeda, Tillotts Pharma AG, and UCB Pharma.
