Introduction

In Crohn's disease (CD), fatigue is a common symptom that affects ~40% of patients [1] and often has a major impact on their quality of life. The Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) is a 13-item patient-reported outcome assessing fatigue over the previous week on a 5-point scale. In the FACIT-Fatigue, scores for all items are summed to give a total score between 0 and 52, with a higher score indicating less fatigue. The psychometric properties of the FACIT-Fatigue have been assessed in multiple chronic illnesses, including CD.

Aims & Methods

The objective of this study was to provide further evidence on the measurement properties of the FACIT-Fatigue and to determine thresholds for meaningful improvement in fatigue for patients with moderately to severely active CD. Pooled data from VIVID-1 (NCT03926130), a Phase 3, multicentre, randomised, placebo- and active-controlled study of mirikizumab in adults with moderately to severely active CD were analysed. The measurement properties (reliability, validity, and responsiveness) of the FACIT-Fatigue were evaluated at Weeks 0 (Baseline), 12, and 52. Other assessments completed in the trial were used for these analyses, including the Patient Global Rating of Severity (PGRS), Patient Global Impression of Change (PGIC), Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn’s Disease Activity Index (CDAI), and 36-Item Short Form Health Survey (SF-36). PGRS and PGIC were used as primary anchors to estimate the FACIT-Fatigue total score change that would constitute meaningful improvement.

Results

Analyses included 1065 adults (mean age 36.2 years [standard deviation: 13.0], 55% males, 71% White). The mean FACIT-Fatigue total score improved during the study (Baseline: 31.5; Week 12: 37.1; Week 52: 40.0). The measure demonstrated internal consistency across visits (Cronbach’s alpha: 0.92–0.94); correlations between individual items and the total score were moderate (0.30≤ r <0.70) to large (r ≥0.70). Across visits, the FACIT-Fatigue total score showed moderate to large correlations with the PGRS; IBDQ Bowel Function domain, item 2 (fatigue), and total score; CDAI score; and SF-36 Vitality domain score. However, correlations with clinical measures were weak (r <0.30), demonstrating discriminant validity. The FACIT-Fatigue could differentiate between groups of participants known to be distinct based on the PGRS, IBDQ total score, and IBDQ item 2. The FACIT-Fatigue was able to detect change, as FACIT-Fatigue total score improvements from Baseline to Weeks 12 and 52 were statistically significantly different between most PGRS change groups and PGIC groups, as well as between groups based on IBDQ response/remission, IBDQ item 2, SF-36 Vitality domain, and clinical response/remission by CDAI. Anchor-based analyses suggested that a 6–9-point increase in the FACIT-Fatigue total score could represent meaningful improvement.

Conclusion

These findings expand on previous research supporting the internal consistency, reliability, construct validity, and responsiveness of the FACIT-Fatigue. Analyses suggest an improvement range of 6–9 points for FACIT-Fatigue as clinically meaningful in the VIVID-1 trial population of adults with moderately to severely active CD.

References

[1] D'Silva A, Fox DE, Nasser Y, Vallance JK, Quinn RR, Ronksley PE, Raman M. Prevalence and risk factors for fatigue in adults with inflammatory bowel disease: A systematic review with meta-analysis. Clin Gastroenterol Hepatol. 2022 May;20(5):995-1009.e7. doi: 10.1016/j.cgh.2021.06.034. Epub 2021 Jun 30. PMID: 34216824.

Disclosure

VJ has received fees or grant and/or research support and/or served as a consultant and/or speaker for AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Flagship Pioneering, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Metacrine, Mylan, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist Therapeutics, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx Biosciences, and Vividion Therapeutics. SS, AV, and FD are employees and shareholders of Eli Lilly and Company. XZ is an employee of Syneos Health, which received funding from Eli Lilly and Company in connection with this study. LS, AK, and CC are employees of Evidera, which received funding from Eli Lilly and Company in connection with this study. MR serves on advisory boards for AbbVie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Eli Lilly and Company, TARGET Pharma Solutions, and Trellus.

Introduction

Bowel urgency is one of the symptoms that patients with Crohn’s disease (CD) frequently experience and consider most important to control. Bowel urgency often has a substantial negative impact on quality of life. The Urgency Numeric Rating Scale (NRS) is a single-item patient-reported outcome assessing severity of bowel urgency in the previous 24 hours on an 11-point scale (0–10), with higher scores indicating more severe bowel urgency. The Urgency NRS was initially developed to assess the urgency to have a bowel movement in ulcerative colitis due to lack of appropriate existing instruments.

Aims & Methods

This work aimed to evaluate the psychometric properties of the Urgency NRS in CD and to estimate thresholds for meaningful change and remission for bowel urgency. Pooled data from VIVID-1 (NCT03926130), a Phase 3, multicentre, randomised, placebo- and active-controlled study of mirikizumab in adults with moderately to severely active CD were analyzed. The measurement properties (reliability, validity, and responsiveness) of the Urgency NRS were evaluated using weekly average scores at Weeks 0 (Baseline), 4, 12, and 52, which were calculated by averaging the most recent 7 days in the 12 days prior to the visit. These analyses used other measures administered in VIVID-1, including the Patient Global Rating of Severity (PGRS), Patient Global Impression of Change (PGIC), Inflammatory Bowel Disease Questionnaire (IBDQ), and Crohn’s Disease Activity Index (CDAI). PGRS and PGIC were used as primary anchors to establish the Urgency NRS score thresholds for meaningful change and remission of bowel urgency. Data from VIVID-1 treatment arms were pooled for these analyses.

Results

The analysis population comprised 1065 adults (mean age 36.2 years [standard deviation: 13.0]; 55% male, 71% White). The Urgency NRS weekly average score decreased during the trial (from 6.6 at Baseline to 2.9 at Week 52), indicating a reduction in bowel urgency severity. Test-retest reliability was good for patients who were stable between Baseline and Week 4 based on the PGRS (intraclass correlation coefficient [ICC] 0.86) and the PGIC (ICC 0.78). At Weeks 12 and 52, the Urgency NRS showed moderate correlations (0.30≤ r <0.70) with the PGRS, IBDQ Bowel Symptom domain, IBDQ total score, and CDAI score; as expected, correlations with clinical and laboratory assessments were weak (r <0.30), demonstrating discriminant validity. The Urgency NRS could differentiate between groups of participants known to be distinct based on PGRS and IBDQ Bowel Symptom domain scores. Improvement in the Urgency NRS average score from Baseline to Weeks 12 and 52 was statistically significantly different between most PGRS change groups and PGIC groups, as well as groups based on IBDQ Bowel Symptom domain, IBDQ response and remission, and clinical response/remission by CDAI, indicating that the Urgency NRS was able to detect change. Anchor-based analysis indicated that clinically meaningful improvement could be represented by a 3–5-point reduction in the Urgency NRS score and that an Urgency NRS score of ≤2 could represent bowel urgency remission.

Conclusion

These results support the reliability, validity, responsiveness of the Urgency NRS and provide definitions of clinically meaningful improvement (reduction of 3–5 points in the Urgency NRS score) and remission of bowel urgency (Urgency NRS score of ≤2) in adults with moderately to severely active CD. These findings confirm the Urgency NRS as suitable for assessing treatment benefits in patients with CD during clinical trials.

Disclosure

MD reports being a consultant for AbbVie, Arena, BMS, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Gilead, Janssen, Merck, Pfizer, Prometheus Laboratories, Takeda, and UCB; and received research grants from Janssen, AbbVie, and Prometheus Laboratories. AV, SS, and FD are employees and shareholders of Eli Lilly and Company. XZ is an employee of Syneos Health, which received funding from Eli Lilly and Company in connection with this study. CC, LS, and AK are employees of Evidera, which received funding from Eli Lilly and Company in connection with this study. ST has received grants from AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Norman Collison Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott; and reports other disclosures from Abacus Pharma, AbbVie, Actial Farmaceutica, ai4gi, Alcimed, Allergan, Amgen, Aptel, Arena Pharmaceuticals, Asahi Kasei Pharma, Aspen Pharmacare, Astellas, AstraZeneca, Atlantic Pharmaceuticals, Barco, Biocare Medical, Biogen, BL Pharma, Boehringer Ingelheim, Bristol Myers Squibb, BUHLMANN Diagnostics, Calcico Therapeutics, Celgene, Cellerix, Cerimon Pharmaceuticals, ChemoCentryx, Chiesi, Cisbio, Comcast, Coronado Biosciences, Cosmo Pharmaceuticals, Dr. Falk Pharma, Ducentis BioTherapeutics, Dynavax Technologies, Elan Pharma, Eli Lilly and Company, Enterome, Equillium, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Genzyme, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Grünenthal, GW Pharmaceuticals, Immunocore, Indigo Biosciences, Janssen, Lexicon Pharmaceuticals, Medarex, MedTrix, Merck, Merrimack Pharmaceuticals, Mestag Therapeutics, Millennium Pharmaceuticals, Neovacs, Novartis, Novo Nordisk, NPS Pharmaceuticals/Nycomed, Ocera Therapeutics, OPTIMA Pharma, Origin Pharma, Otsuka, Palau Pharma, Pentax Medical, Pfizer, PharmaVentures, Phesi, Phillips Pharma Group, Procter & Gamble, Pronota, Proximagen, Resolute Pharma, Robarts Clinical Trials, Sandoz, Santarus, Satisfai Health, Sensyne Health, Shire, Sigmoid Pharma, Sorriso Pharmaceuticals, Souffinez, SynDermix, Synthon, Takeda, Theravance Biopharma, TiGenix, Tillotts Pharma AG, Topivert, Trino Therapeutics with Wellcome Trust, TxCell SA, UCB Pharma, Vertex Pharma, VHsquared, Vifor Pharma, Warner Chilcott, and Zeria Pharmaceutical.

Introduction

The Crohn’s Disease Activity Index (CDAI) is an 8-item disease activity measure with three patient-reported items that cover stool frequency, presence of abdominal pain, and patient’s general well-being. Absolute scores of the Stool Frequency (SF) and Abdominal Pain (AP) items, together referred to as the Patient Reported Outcome (PRO), have been used separately in the VIVID-1 study. Both PRO items have recall periods of 24 hours; the SF item measures the number of liquid or very soft stools per day and the AP item measures abdominal pain severity on a 4-point scale (0=none, 1=mild, 2=moderate, and 3=severe).

Aims & Methods

This study aimed to evaluate the measurement properties of the SF and AP items and estimate thresholds for remission. Pooled data from VIVID-1 (NCT03926130), a Phase 3, multicentre, randomized, placebo- and active-controlled study of mirikizumab in adults with moderately to severely active Crohn’s Disease (CD) were analysed. The measurement properties (reliability, validity, and responsiveness) of the PRO items were evaluated separately using average weekly scores of the SF and AP items at Weeks 0 (Baseline), 4, 12, and 52. Patient Global Rating of Severity (PGRS) and Patient Global Impression of Change (PGIC) were used as primary anchors to estimate the remission thresholds. Exit interviews were conducted in a subgroup of participants to support the remission thresholds.

Results

Data from 1065 participants (mean age: 36.2 years [standard deviation: 13.0], 55% males, 71% White) were analysed. During the trial, average weekly scores decreased for both items: SF from 5.7 (Baseline) to 1.9 (Week 52) and AP from 2.1 (Baseline) to 0.8 (Week 52). Both PRO items demonstrated moderate to good test-retest reliability for participants who were stable between Baseline and Week 4 based on PGRS (intraclass correlation coefficient [ICC] 0.85 for SF and 0.82 for AP) and PGIC (ICC 0.79 for SF and 0.69 for AP). SF had moderate (0.30≤ r <0.70) correlations with Inflammatory Bowel Disease Questionnaire (IBDQ) item 1–stool frequency (Baseline and Weeks 12 and 52) as well as with IBDQ total score, IBDQ Bowel Symptoms domain score, and PGRS (Weeks 12 and 52 only). AP had moderate to large correlations (0.30≤ r ≤0.90) with PGRS, IBDQ total score, IBDQ item 13–abdominal pain, 36-item Short Form Health Survey (SF-36) Bodily Pain domain, and EQ-5D-5L Pain/Discomfort (Baseline and Weeks 12 and 52). As anticipated, both PRO items had weak correlations (r <0.30) with the Simple Endoscopic Score for Crohn’s Disease (SES-CD), demonstrating discriminant validity. The PRO items could differentiate between groups of participants known to be distinct based on PGRS (for SF and AP), IBDQ Bowel Symptom domain score (for SF), and EQ-5D-5L Pain/Discomfort (for AP). The PRO items were able to detect change, as score changes in both items between Baseline and Weeks 12 and 52 were statistically significantly different between most PGRS change groups and PGIC groups. Anchor-based analyses combined with results from the exit interviews suggested that an SF score of ≤3 and an AP score of ≤1 could represent remission.

Conclusion

These psychometric evaluation results support the reliability, construct-validity, and responsiveness of the PRO items when administered to adults with moderately to severely active CD. A combination of an SF score of ≤3 and an AP score of ≤1 could represent clinical remission by PRO.

Disclosure

SS has been a consultant for AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, GSK, Gilead, I-MAB Biopharma, Janssen, Eli Lilly and Company, Merck, Novartis-Sandoz, Pfizer, Protagonist, Takeda, and Theravance. AV, SS, and FD are employees and shareholders of Eli Lilly and Company. XZ is an employee of Syneos Health, which received funding from Eli Lilly and Company in connection with this study. AK, LS, and CC are employees of Evidera, which received funding from Eli Lilly and Company in connection with this study. JL has received personal fees from Johnson & Johnson Consumer Inc; grants, personal fees, and other from Takeda Pharmaceuticals and Pfizer; personal fees and nonfinancial support from AbbVie; grants and personal fees from Janssen Pharmaceuticals, Nestle Health Science; personal fees from Eli Lilly and Company, Samsung Bioepis, UCB, Bristol-Myers Squibb, Bridge Biotherapeutics, Celgene, Merck, Gilead, Arena Parmaceuticals, and Protagonist Therapeutics.

Introduction

Accurate and timely endoscopic evaluation is critical for the management of postoperative Crohn’s disease (CD). Although numerous established and novel indices exist, their relative operating properties and the optimal instrument for routine use in clinical and research settings are unknown.

Aims & Methods

We characterised the reliability and responsiveness of both historical and novel endoscopic indices using centrally assessed ileocolonoscopy videos from a randomised controlled trial comparing infliximab versus placebo for preventing postoperative CD (PREVENT; NCT01190839). Three blinded central readers independently assessed 70 videos from the PREVENT trial using the Rutgeerts and modified Rutgeerts scores, POCER index, REMIND score, Simple Endoscopic Score for CD (SES-CD), and the CD Endoscopic Index of Severity (CDEIS). Indices were scored separately for the neoterminal ileum, the anastomosis (including the blind loop of a side-to-side anastomosis), and the distal colonic segment. Intra- and inter-rater reliability was quantified using the intraclass correlation coefficient (ICC) and was interpreted using the Landis and Koch benchmarks.¹ Responsiveness was quantified using the win probability (WinP), defined as the probability of a patient receiving infliximab having a better endoscopic score than a patient receiving placebo, and interpreted using Cohen’s benchmarks.²

Results

Inter-rater reliability was substantial for the Rutgeerts (ICC 0.74 [95% CI: 0.62-0.83]) and modified Rutgeerts scores (0.79 [0.68-0.86]), ileal REMIND score (0.79 [0.67-0.87]), SES‑CD (0.79 [0.70-0.86]), and CDEIS (0.80 [0.72-0.86]). Inter-rater reliability was moderate for the POCER index (ICC 0.49 [0.26-0.64]) and fair for the anastomotic REMIND score (0.30 [0.14-0.47]). Intra-rater reliability was almost perfect for all indices (ICC≥0.81) (Table 1). The Rutgeerts (WinP 0.77 [95% CI: 0.65-0.86]) and modified Rutgeerts scores (WinP 0.81 [0.69-0.89]), ileal REMIND score (WinP 0.83 [0.72-0.91]), SES-CD (WinP 0.80 [0.66-0.89]), and CDEIS (WinP 0.75 [0.61-0.86]) demonstrated a large degree of responsiveness when treatment assignment was the criterion for change. The POCER index (WinP 0.54 [0.43-0.65]) and the anastomotic REMIND score (WinP 0.53 [0.42-0.64]) had a small degree of responsiveness. The reliability and responsiveness of all indices were consistently lower when assessed at the anastomosis or distal colon compared to the neoterminal ileum.

Table 1. Reliability and responsiveness of endoscopic scores

Index	Inter-rater ICC (95% CI)a	Intra-rater ICC (95% CI)a	WinP (95% CI)b,c	WinP (95% CI)b,d
Rutgeerts score	0.74 (0.62, 0.83)	0.90 (0.85, 0.94)	0.77 (0.65, 0.86)	0.72 (0.57, 0.83)
Modified Rutgeerts score	0.79 (0.68, 0.86)	0.92 (0.88, 0.96)	0.81 (0.69, 0.89)	0.68 (0.52, 0.81)
POCER index	0.49 (0.26, 0.64)	0.89 (0.78, 0.95)	0.54 (0.43, 0.65)	0.61 (0.46, 0.74)
REMIND - Ileal	0.79 (0.67, 0.87)	0.91 (0.85, 0.96)	0.83 (0.72, 0.91)	0.71 (0.55, 0.83)
REMIND - Anastomotic	0.30 (0.14, 0.47)	0.81 (0.71, 0.89)	0.53 (0.42, 0.64)	0.62 (0.47, 0.75)
SES-CD	0.79 (0.70, 0.86)	0.93 (0.87, 0.96)	0.80 (0.66, 0.89)	0.70 (0.54, 0.82)
CDEIS	0.80 (0.72, 0.86)	0.91 (0.86, 0.95)	0.75 (0.61, 0.86)	0.70 (0.56, 0.81)
Overall VAS	0.81 (0.72, 0.87)	0.90 (0.84, 0.94)	0.80 (0.67, 0.88)	0.71 (0.55, 0.83)
a Interpreted according to the Landis and Koch benchmarks1: poor = <0; slight = 0.0–0.20; fair = 0.21–0.40; moderate = 0.41–0.60; substantial = 0.61–0.80; and almost perfect = 0.81–1.00. b WinPs of 0.56, 0.64, and 0.71 correspond to Cohen’s effect sizes of 0.2, 0.5, and 0.8, which are the benchmarks for “small”, “moderate”, and “large” effects, respectively.2 c Using treatment assignment as the criterion for change. d Using clinical recurrence as the criterion for change. Abbreviations: WinP, Win probability; CDEIS, Crohn’s Disease Endoscopic Index of Severity; CI, confidence interval; ICC, intraclass correlation coefficient; POCER, Postoperative Crohn's endoscopic recurrence; SES-CD, Simple Endoscopic Score for Crohn’s Disease; VAS, visual analogue scale.

Conclusion

Existing endoscopic indices are reliable and responsive for assessing postoperative CD activity in the neoterminal ileum but are suboptimal for assessing the anastomosis or distal colon.

References

1. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33 (1):159-174.
2. Zou G, Zou L, Qiu SF. Parametric and nonparametric methods for confidence intervals and sample size planning for win probability in parallel-group randomized trials with Likert item and Likert scale data. Pharm Stat 2023; 22 (3):418-439.

Disclosure

JH reports consulting fees from Abbvie,Alimentiv Inc,Eli Lilly,Janssen,and Takeda.
SKV,GZ,LMS report consulting fees from Alimentiv Inc.
BB reports advisory/speaker fees from: Ferring,Janssen,Abbvie,Takeda,Pfizer,BMS,Merck,Sandoz,Organon,Lifelabs,Celltrion,Alimentiv,Gilead,Iterative Health,Celgene,Merck,Amgen,Pendopharm,Eli Lilly,Fresenius Kabi,Mylan,Viatris,Bausch Health,BioJamp Pharma,Eupraxia; research support: Janssen,Abbvie,GSK,BMS,Amgen,Genentech,Merck.
MAS reports advisory fees from: Janssen,Takeda,Sandoz,Samsung Bioepis,Galapagos,AbbVie,Bristol-Myers Squibb,Tillotts,Pfizer,STADA,Sanofi,MSD; and lecture fees from: Bristol-Myers Squibb,Janssen,Takeda,MSD,Falk,AbbVie,Galapagos,Lilly.
MH is a former employee of Alimentiv Inc.
JR is an employee of Alimentiv Inc.
PDC reports advisory/speaker/consulting fees from AbbVie,Baxter,Ferring,Janssen,Celltrion,Emerge Health,Shire,and Takeda. PDC is sup­ported by an NHMRC Emerging Leader 2 Fellowship and reports research support from AbbVie,Ferring,Shire,Janssen,Pfizer,and Takeda.
MR reports advisory/consulting fees from Abbvie,Janssen,UCB,Takeda,Pfizer,BMS,Organon,Amgen,Genentech,Gilead,Salix,Prometheus,Lilly,Celgene,Boehringer Ingelheim Pharmaceuticals Inc. (BIPI),Celltrion,Roche,Merck,Sanofi,Biocon,Abavax.
SS reports research grants from Pfizer
RWS reports advisory/consulting fees from AbbVie,Bristol Myers Squibb,CorEvitas,Eli Lilly,Exact Sciences,Gilead,Johnson and Johnson,Merck,Okura Theraeutics,Pfizer,and Takeda; received investigator initiated research funding from Abbvie,Bristol Myers Squibb,Johnson and Johnson,and Merck; holds intellectual property and equity on medical imaging and endoscopic analysis technologies licensed by the University of Michigan to PreNovo,LLC,AMI,LLC and PathwaysGI,Inc.
MD reports speaking fees from Bristol Meyers Squibb,Takeda,Galapagos,Janssen,Dr. Falk; advisory board fees from Abbvie,Bristol Meyers Squibb,Celltrion,Galapagos/Alfasigma,Janssen,Takeda; grant/research support: Pfizer,Bristol Meyers Squibb,Galapagos/Alfasigma,Janssen.
GDH reports advisory/speaker fees from Abbvie,Agomab Therapeutics,Alimentiv,AstraZeneca,Bristol Meiers Squibb,Cytoki,Celltrion,Eli Lilly,Exeliom Biosciences,Ferring,Galapagos,Glaxo Smith Kline,Pfizer,Polpharm,Immunic,Index Pharmacueticals,Johnson and Johnson,Merck,ProciseDx,Roivant,Seres Health,Takeda,Tillotts and Ventyx.
LPB reports consulting fees from Abbvie,Abivax,Adacyte,Alimentiv,Amgen,Applied Molecular Transport,Arena,Banook,Biogen,BMS,Celltrion,Connect Biopharm,Cytoki Pharma,Enthera,Ferring,Fresenius Kabi,Galapagos,Genentech,Gilead,Gossamer Bio,GSK,IAC Image Analysis,Index Pharmaceuticals,Inotrem,Janssen,Lilly,Medac,Mopac,Morphic,MSD,Nordic Pharma,Novartis,Oncodesign Precision Medicine,ONO Pharma,OSE Immunotherapeuthics,Pandion Therapeuthics,Par' Immune,Pfizer,Prometheus,Protagonist,Roche,Samsung,Sandoz,Sanofi,Satisfay,Takeda,Telavant,Theravance,Thermo Fischer,Tigenix,Tillots,Viatris,Vectivbio,Ventyx,Ysopia; grants support from Celltrion,Fresenius Kabi,Medac,MSD,Takeda; lecture fees from Abbvie,Alfasigma,Amgen,Arena,Biogen,Celltrion,Ferring,Galapagos,Genentech,Gilead,Janssen,Kern Pharma,Lilly,Medac,MSD,Nordic Pharma,Pfizer,Sandoz,Takeda,Tillots,Viatris; and support for travel from Abbvie,Alfasigma,Amgen,Celltrion,Connect Biopharm,Ferring,Galapagos,Genentech,Gilead,Gossamer Bio,Janssen,Lilly,Medac,Morphic,MSD,Pfizer,Sandoz,Takeda,Thermo Fischer,Tillots.
SD reports consulting fees from AbbVie,Alimentiv Inc,Allergan,Amgen,AstraZeneca,Athos Therapeutics,Biogen,Boehringer Ingelheim,Bristol Myers Squibb,Celgene,Celltrion,Dr Falk Pharma,Eli Lilly,Enthera,Ferring Pharmaceuticals Inc.,Gilead,Hospira,Inotrem,Janssen,Johnson & Johnson,Morphic,MSD,Mundipharma,Mylan,Pfizer,Roche,Sandoz,Sublimity Therapeutics,Takeda,Teladoc Health,TiGenix,UCB Inc.,Vial,and Vifor; lecture fees from AbbVie,Amgen,Ferring Pharmaceuticals Inc.,Gilead,Janssen,Mylan,Pfizer,and Takeda.
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Introduction

Crohn’s disease (CD) is a chronic progressive inflammatory bowel disease (IBD) that can substantially impact one’s health-related quality of life (HRQoL). The treatment effect of risankizumab (RZB) vs ustekinumab (UST) on achieving clinically meaningful within-person changes (MWPCs) in patient (pt) reported outcomes (PROs) as measured by Inflammatory Bowel Disease Questionnaire (IBDQ) and 36-item Short-Form Health Survey (SF-36 v.2) scores, as well as on select individual items (symptoms) of the IBDQ, were evaluated using data from the phase 3 SEQUENCE (NCT04524611) study.

Aims & Methods

The SEQUENCE open-label, multicenter, randomized, efficacy assessor-blinded study directly compared the efficacy and safety of RZB vs UST in pts with moderate to severe CD with prior anti-TNF failure. Pts were randomized 1:1 to receive recommended induction and maintenance doses of RZB (N=255) or UST (N=265)¹. The proportion of pts who achieved MWPCs as measured by IBDQ response (≥ 16 point increase in total score), IBDQ remission (total score ≥ 170 points), and improvement in the SF-36 physical (PCS) and mental (MCS) component scores (≥ 4.1 and ≥ 3.9 points, respectively) between baseline (BL) and weeks 24 and 48 of maintenance were compared between pts who received RZB vs UST. In addition, the proportion of pts who reported all/most/a good bit/some of the time (“all–some of the time”) for the fatigue, depression, anxiety, and bowel urgency items on the IBDQ were compared for RZB vs UST. Chi-square P values are reported.

Results

IBDQ, inflammatory bowel disease questionnaire; MWPC, meaningful within-person change; SF-36, 36-item Short-Form Health Survey. aMWPC is the point at which an individual patient experiences clinically meaningful within-person benefit/improvement in quality of life. bThe IBDQ includes 32 items that represent 4 domains (physical, social, emotional, and systemic). Items are rated on a 7-point scale (1 = all of the time; 2 = most of the time; 3 = a good bit of the time; 4 = some of the time; 5 = a little bit of the time; 6 = hardly any of the time; 7 = none of the time), providing a total score ranging from 32 to 224; higher scores indicate better HRQoL. For IBDQ items assessed, the proportion of patients providing scores of 1 to 4 were combined, and the proportion of patients providing scores of 5 to 7 were combined; categories 1 to 4 are displayed here. cThe SF-36 includes 36 items are summarized in two components, the physical component summary (PCS) and mental component summary (MCS). The PCS comprises four subscales: physical function (PF), role limitations owing to physical health (RP), bodily pain (BP), and general health perceptions (GH). The MCS also comprises four subscales: vitality (VT), social functioning (SF), role limitations owing to emotional problems (RE), and mental health (MH). Scores range from 0 to 100 for each subscale in both components, with higher scores indicating better health. dThe amount of time one feels fatigued, tired, and worn out. eThe amount of time one felt depressed or discouraged. fThe amount of time one felt worried and anxious about never feeling any better and having a relapse. gThe amount of time one felt troubled by a feeling of having to go to the bathroom even with empty bowels. Patients with missing observations at any time point were considered as reporting the symptoms “all/most/a good bit/some of the time".
	Proportion of Patients Who Achieved Meaningful Within-Person Change (MWPCa)
	From Baseline to Week 24			From Baseline to Week 48
	Risankizumab N=255 n (%)	Ustekinumab N=265 n (%)	Chi-square P-value	Risankizumab N=255 n (%)	Ustekinumab N=265 n (%)	Chi-square P-value
Outcomes IBDQb total score (≥ 16-point increase) IBDQb remission (IBDQ ≥ 170 points) SF-36c Physical Component Score (PCS) (≥ 4.1-point increase) SF-36c Mental Component Score (MCS) (≥ 3.9-point increase)	192 (75.3%) 134 (52.5%) 168 (65.9%) 141 (55.3%)	170 (64.2%) 82 (30.9%) 141 (53.2%) 133 (50.2%)	<.01 <.0001 <.01 .2	175 (68.6%) 127 (49.8%) 163 (63.9%) 138 (54.1%)	135 (50.9%) 88 (33.2%) 122 (46.0%) 106 (40.0%)	<.0001 .0001 <.0001 <.01
	Proportion of Patients Who Reported IBDQ Items/Symptoms “All/Most/A Good Bit/Some of the Timeb
	Week 24			Week 48
	Risankizumab N=255 n (%)	Ustekinumab N=265 n (%)	Chi-square P-value	Risankizumab N=255 n (%)	Ustekinumab N=265 n (%)	Chi-square P-value
IBDQ Items (Symptoms) ​ Fatigued ​ Depressione ​ Anxietyf ​ Bowel urgencyg	131 (51.4%) 87 (34.1%) 87 (34.1%) 69 (27.1%)	183 (69.1%) 113 (42.6%) 132 (49.8%) 106 (40.0%)	<.0001 .05 <.001 <.01	140 (54.9%) 91 (35.7%) 90 (35.3%) 69 (27.1%)	191 (72.1%) 154 (58.1%) 155 (58.5%) 134 (50.6%)	<.0001 <.0001 <.0001 <.0001

A significantly greater proportion of RZB- vs UST-treated pts demonstrated clinically meaningful improvements in IBDQ response (week 24, 75.3% vs 64.2%; week 48, 68.6% vs 50.9%), IBDQ remission (week 24, 52.5% vs 30.9%; week 48, 49.8% vs 33.2%), and improvement from BL in SF-36v2 PCS (week 24, 65.9% vs 53.2%; week 48, 63.9% vs 46.0%) (all comparisons P< 0.01), In addition, a significantly greater proportion of RZB-treated pts vs UST demonstrated a MWPC from BL at week 48 in SF-36 MCS (54.1% vs 40.0%; P<.01) (Table). At BL, a similar proportion of pts with RZB vs UST, reported fatigue (92.2% vs 92.8%), depression (66.7% vs 70.9%), anxiety (71.4% vs 75.5%), or bowel urgency (69.8% vs 73.2%) “all–some of the time” on the IBDQ (Table). At both weeks 24 and 48, a significantly lower proportion of pts with RZB vs UST reported experiencing fatigue (week 24, 51.4% vs 69.1% [P<.0001]; week 48, 54.9% vs 72.1% [P<.0001]), depression (week 24, 34.1% vs 42.6% [P=.05]; week 48, 35.7% vs 58.1% [P<.0001]), anxiety (week 24, 34.1% vs 49.8% [P<.001]; week 48, 35.3% vs 58.5% [P<.0001]) or bowel urgency (week 24, 27.1% vs 40.0% [P<.01]; week 48, 27.1% vs 50.6% [P<.0001]) “all–some of the time” (Table).

Conclusion

RZB was more effective than UST in delivering clinically meaningful improvements in PROs in pts with moderate to severe CD who failed anti-TNF therapy. A significantly lower proportion of patients who received RZB vs UST reported symptoms of fatigue, depression, anxiety, and bowel urgency at weeks 24 and 48.

References

1 Peyrin-Biroulet, L. et al. UEG Journal. 2023; 11, 919–940.

Disclosure

Edward V. Loftus, Jr. has received consulting fees from AbbVie, Alvotech, Amgen, Arena, Avalo Therapeutics, BMS, Boehringer Ingelheim, Calibr, Celgene, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota Biosciences, Iterative Scopes, Janssen, KLS Diagnostics, Morphic Therapeutics, Ono Pharma, Pfizer, Protagonist, Scipher Medicine, Sun Pharma, Surrozen, Takeda, and UCB; has served as an advisory board participant for Eli Lilly and Morphic; has received research support from AbbVie, BMS, Celgene/Receptos, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Takeda, Theravance, and UCB; and holds stock in Exact Sciences.

Bruce Sands has received consulting fees from Abbvie, Adiso Therapeutics, Agomab, Alimentiv , Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Envied Biosciences, Evommune, Ferring, Fresenius Kabi, Fiat, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock/stock options from Ventyx Biopharma.

Vipul Jairath has received has received consulting/advisory board fees from AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi

Irina Blumenstein has no competing interests to declare.

Edouard Louis received educational and research grants from Takeda, Pfizer, Janssen, AbbVie, and Fresenius-Kabi; speaker fees from AbbVie, Ferring, Falk, Takeda, Janssen, Pfizer, Celgene, Galapagos, and BMS; and consultancy fees from AbbVie, Ferring, MSD, Takeda, Celgene, Janssen, Gilead-Galapagos, Arena, Pfizer, Eli Lilly, and BMS.

Namita Joshi, Nidhi Shukla, Kristina Kligys, Toni Anschutz, Jenny Griffith, and Javier Zambrano are full-time employees/contractor of AbbVie and may own AbbVie stock or options.

Funding and Acknowledgments
AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial.

Medical writing support was provided by Stephanie Parsons, PhD, and copy editing support was provided by Angela Hadsell, BS, both employees of AbbVie.