Abstract
Introduction
Ulcerative colitis is a chronic inflammatory condition of the colon that significantly impairs quality-of-life. While filgotinib (FIL) has shown long-term efficacy in improving disease-specific quality-of-life via Inflammatory Bowel Disease Questionnaire (IBDQ) total scores, its impact on individual bowel/systemic symptoms remains unclear. This post hoc analysis assessed FIL’s long-term effects on these symptoms and explored factors associated with sustained remission.
Methods
This analysis included 148 patients from SELECTION trial patients who completed induction and maintenance phases, enrolled in SELECTIONLTE, and continued 200-mg FIL (FIL200) without treatment change. Changes from induction baseline in IBDQ total and subscores (bowel/systemic symptoms) were assessed at Week 10, 58, and long-term extension (LTE) Week 96. Remission was defined as IBDQ ≥170 and partial Mayo Clinic Score (pMCS) ≤1 at each timepoint.
Results
At Week 10, for patients with vs. without pMCS remission, the mean ± standard deviation change in IBDQ total score was 72.98 ± 39.37 vs. 53.46 ± 31.75, respectively. At Week 58, it was 80.42 ± 34.44 vs. 49.97 ± 38.24 and at LTE Week 96, it was 84.14 ± 35.22 vs. 49.10 ± 28.00, respectively. Overall, bowel and systemic symptom scores were numerically higher in patients with vs. without pMCS remission at Week 10, slightly increased at Week 58, and remained consistent at LTE Week 96. Symptomatic remission at Week 10 and IBDQ remission at LTE Week 96 were associated significantly (odds ratio [95% confidence interval]: 2.288 [1.003–5.216]; p = 0.049).
Conclusions
FIL200 improved bowel and systemic symptoms beyond rectal bleeding and stool frequency, enhancing disease-specific quality-of-life. Week 10 symptomatic remission was marginally associated with higher odds of long-term IBDQ remission, suggesting that early symptomatic remission provides clinically relevant information on sustained quality-of-life improvement.
Keywords: Bowel and systemic symptoms, Clinical remission, Filgotinib, Quality-of-life, Ulcerative colitis
Introduction
Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disorder of the colon, associated with a burden of bowel and systemic symptoms that negatively impact patients’ quality-of-life (QoL) [1, 2]. The Adelphi survey showed that patients, regardless of clinical remission status, experienced significant symptomatic burden and impaired QoL [2]. The main goal of treatment is to induce and maintain clinical remission, prevent disease-related complications, and improve patients’ QoL [3].
Filgotinib (FIL) is an oral, once-daily, Janus kinase–preferential inhibitor approved in the European Union, United Kingdom, Japan, South Korea, Singapore, and Taiwan for the treatment of moderate-to-severe UC [4]. The efficacy and safety of FIL have been demonstrated in the SELECTION and SELECTION long-term extension (SELECTIONLTE) studies [5, 6]. An interim analysis of SELECTIONLTE showed prolonged benefits of FIL, with long-term improvement in health-related QoL (HRQoL), indicating the sustained effect of FIL, with stable or increasing proportions of patients achieving partial Mayo Clinic Score (pMCS) remission, Inflammatory Bowel Disease Questionnaire (IBDQ) remission, and fecal calprotectin remission [6]. Although the long-term efficacy of FIL with regard to disease-specific HRQoL has been shown through the IBDQ total score [6], its efficacy in terms of individual bowel and systemic symptoms has not been evaluated. Hence, this post hoc analysis of SELECTION and SELECTIONLTE aimed to evaluate the long-term effects of FIL on individual bowel and systemic symptom improvement and to identify potential factors associated with remission with FIL over the long term.
Methods
The SELECTION program included two induction studies, a maintenance study (NCT02914522), and an LTE study (NCT02914535). The study design and participants of SELECTION and SELECTIONLTE have been reported previously [5, 6]. This analysis included patients from SELECTION who completed the double-blind phases (induction and maintenance), enrolled in SELECTIONLTE, and continued to receive 200-mg FIL (FIL200) without any change in treatment at rerandomization in the maintenance phase. Completers, clinical remission, and Mayo Clinic Score (MCS) response were defined previously [5].
In this post hoc analysis, changes from induction baseline in bowel and systemic symptoms total score and subscores of the IBDQ were assessed at Week 10, Week 58, and LTE Week 96 (corresponding to Week 154 from baseline) [7]. Remission endpoints included IBDQ score ≥170 as IBDQ remission and pMCS ≤1 as pMCS remission at each mentioned timepoints.
Analyses were performed in the predefined population using descriptive statistics. Continuous variables were summarized as mean ± standard deviation (SD) and categorical variables as frequencies and percentages. IBDQ total and domain scores, and change from baseline at Week 10, Week 58, and LTE Week 96 were summarized by pMCS remission status at each mentioned timepoints. Associations between early factors (sex, baseline endoscopic score, biologic-naïve status, corticosteroid use at baseline, and symptomatic remission [defined as a Mayo rectal bleeding subscore of 0 and stool frequency subscore ≤1] at Day 7 and Week 10) and long-term remission (IBDQ ≥170 or pMCS ≤1) through LTE Week 96 were explored using univariate logistic regression, with odds ratios (ORs) and 95% confidence intervals (CIs). These factors were selected based on their reported associations with efficacy at later timepoints [8]. Analyses were exploratory, with statistical significance defined as p < 0.05. All analyses were conducted using R version 4.3.3.
This was a post hoc analysis of SELECTION and SELECTIONLTE. Both studies were conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki. Written informed consent was obtained from all patients.
Results
This post hoc analysis included 148 patients. Baseline characteristics are shown in Table 1. The proportion of concomitant use of systemic steroid was numerically different between with and without pMCS remission at LTE Week 96, and the distribution of endoscopic subscore was numerically different between patients with and without IBDQ remission at LTE Week 96.
Table 1.
Patient baseline characteristics for treatment with FIL200 (completers included in this analysis by pMCS status)
| Characteristics | Total at Week 10/Week 58 (N = 148) | pMCS remission at LTE Week 96 | IBDQ remission at LTE Week 96 | ||||
|---|---|---|---|---|---|---|---|
| with remission (N = 94) | without remission (N = 34) | total (N = 128) | with remission (N = 97) | without remission (N = 32) | total (N = 129) | ||
| Age | |||||||
| Mean (SD) | 43.2 (13.5) | 43.1 (12.7) | 43.6 (14.5) | 43.3 (13.2) | 43.3 (13.4) | 43.5 (12.7) | 43.4 (13.2) |
| Sex, n (%) | |||||||
| Female | 83 (56.1) | 55 (58.5) | 19 (55.9) | 74 (57.8) | 54 (55.7) | 20 (62.5) | 74 (57.4) |
| Male | 65 (43.9) | 39 (41.5) | 15 (44.1) | 54 (42.2) | 43 (44.3) | 12 (37.5) | 55 (42.6) |
| Duration of UC | |||||||
| Mean (SD) | 8.7 (7.7) | 8.8 (7.3) | 8.1 (7.6) | 8.6 (7.3) | 8.6 (7.5) | 8.5 (6.7) | 8.6 (7.3) |
| Total MCS | |||||||
| Mean (SD) | 8.8 (1.3) | 8.8 (1.4) | 8.6 (1.2) | 8.8 (1.3) | 8.7 (1.3) | 8.9 (1.4) | 8.8 (1.3) |
| pMCS | |||||||
| Mean (SD) | 6.2 (1.2) | 6.3 (1.2) | 6.0 (1.2) | 6.2 (1.2) | 6.2 (1.2) | 6.1 (1.1) | 6.2 (1.2) |
| Baseline endoscopic subscore, n (%) | |||||||
| 2 | 60 (40.5) | 38 (40.4) | 13 (38.2) | 51 (39.8) | 42 (43.3) | 10 (31.2) | 52 (40.3) |
| 3 | 88 (59.5) | 56 (59.6) | 21 (61.8) | 77 (60.2) | 55 (56.7) | 22 (68.8) | 77 (59.7) |
| C-reactive protein levels | |||||||
| Mean (SD) | 8.7 (18.6) | 10.8 (22.7) | 4.7 (4.1) | 9.2 (19.7) | 9.9 (22.2) | 6.9 (8.0) | 9.1 (19.7) |
| Fecal calprotectin levels | |||||||
| Mean (SD) | 2,712.7 (3,447.4) | 3,005.1 (3,784.6) | 1,868.1 (2,684.2) | 2,693.3 (3,543.4) | 3,016.2 (3,819.7) | 1,632.4 (2,230.4) | 2,673.0 (3,536.4) |
| Biologic-naïve status | |||||||
| n (%) | 87 (58.8) | 54 (57.4) | 20 (58.8) | 74 (57.8) | 58 (59.8) | 17 (53.1) | 75 (58.1) |
| Concomitant use of oral, systemically absorbed corticosteroids at baseline | |||||||
| n (%) | 54 (36.5) | 31 (33.0) | 16 (47.1) | 47 (36.7) | 35 (36.1) | 12 (37.5) | 47 (36.4) |
FIL200, 200-mg filgotinib; IBDQ, Inflammatory Bowel Disease Questionnaire; LTE, long-term extension; MCS, Mayo Clinic Score; pMCS, partial Mayo Clinic Score; SD, standard deviation; UC, ulcerative colitis.
IBDQ scores over time, stratified by pMCS remission, are shown in Figure 1a. Overall, 67, 105, and 94 patients had pMCS remission, while 81, 43, and 34 were without pMCS remission at Week 10, Week 58, and LTE Week 96, respectively. For patients with vs. without pMCS remission at Week 10, the mean ± SD IBDQ total score was 113.20 ± 31.96 vs. 118.11 ± 30.81 at baseline and 184.88 ± 26.23 vs. 171.39 ± 29.97 at Week 10, with a mean ± SD change of 72.98 ± 39.37 vs. 53.46 ± 31.75. For patients with vs. without pMCS remission at Week 58, it was 113.88 ± 31.74 vs. 120.72 ± 30.11 at baseline and 193.58 ± 24.18 vs. 172.82 ± 33.14 at Week 58, with a mean ± SD change of 80.42 ± 34.44 vs. 49.97 ± 38.24. For patients with vs. without pMCS remission at LTE Week 96, it was 113.43 ± 29.29 vs. 123.15 ± 32.46 at baseline and 197.11 ± 20.82 vs. 173.93 ± 28.49 at LTE Week 96, with a mean ± SD change of 84.14 ± 35.22 vs. 49.10 ± 28.00. There was a trend toward an increase in all bowel and systemic symptom scores with FIL200, with or without pMCS remission, at Week 10 (Fig. 1a). Overall, the increase in bowel and systemic symptom scores was numerically larger in patients with pMCS remission than in those without pMCS remission. The change in scores for all bowel and systemic symptoms remained consistent at LTE Week 96, with a slight increase in the symptom scores at Week 58, regardless of pMCS remission status (Fig. 1a).
Fig. 1.
a Mean changes from baseline in IBDQ bowel and systemic symptom scores by pMCS remission status at Week 10, Week 58, and LTE Week 96. b Association of factors with IBDQ remission at LTE Week 96. c Association of factors with pMCS remission at LTE Week 96. Higher IBDQ scores indicate better health-related quality-of-life. Error bars represent standard deviation. Only positive error bars are presented; however, standard deviations for each value apply to the negative sides as well. LTE Week 96 represents a duration of 154 weeks from the SELECTION baseline. Patients with and without pMCS remission are presented as n (%). a Nonresponder imputation was applied to participants who remained in the study through LTE Week 96 but did not provide IBDQ data at that visit. b Missing data were imputed as indicating no remission. CI, confidence interval; IBDQ, Inflammatory Bowel Disease Questionnaire; LTE, long-term extension; OR, odds ratio; pMCS, partial Mayo Clinic Score; ref, reference.
The association of factors with IBDQ remission or pMCS remission is shown in Figure 1b, c. The association between the presence of symptomatic remission at Week 10 and IBDQ remission at LTE Week 96 was significant, with an OR (95% CI) of 2.288 (1.003–5.216; p = 0.049); however, the association with pMCS remission was nonsignificant (OR [95% CI]: 2.065 [0.915–4.660]; p = 0.081). The association of other factors, such as sex, baseline endoscopic subscore, baseline biologic-naïve status, concomitant oral corticosteroid used at baseline, and symptomatic remission at Day 7, was nonsignificant with IBDQ remission (all p > 0.05) or pMCS remission (all p > 0.05) at LTE Week 96 (Fig. 1b, c).
Discussion
This post hoc analysis is the first to report the long-term effects of FIL on individual UC bowel and systemic symptoms and to identify potential association between early symptomatic improvement and long-term improvement in QoL with FIL200. Clinically, the treatment goal for UC is to improve the QoL of patients by managing bowel and systemic symptoms in addition to achieving clinical remission [3]. Previously, Feagan et al. [6] reported rapid and sustained efficacy of FIL with regard to HRQoL using the IBDQ total score, while the effect of FIL on individual bowel and systemic symptoms has not been evaluated before the current study. In this post hoc analysis, we utilized IBDQ individual items to assess bowel and systemic symptoms for disease-specific QoL [7] and showed long-term improvement in symptoms and, thus, disease-specific QoL, regardless of achieving pMCS remission. The clinical significance of the effect of FIL on individual symptoms could be supported by findings from the Adelphi Real World Disease Specific Programme for inflammatory bowel disease, which has shown that managing bowel symptoms beyond stool frequency and rectal bleeding, as well as systemic symptoms, is crucial to enhance disease-specific QoL [2]. Cross et al. [9] reported that patients with UC across the spectrum of disease activity, even in pMCS remission, had impaired functions, including fatigue and sleep disturbance assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) self-reported questionnaire. In contrast, this post hoc analysis demonstrated that FIL showed efficacy with regard to fatigue and sleep disturbance, regardless of achieving pMCS remission.
For the associations between early and long-term efficacy of FIL, Laharie et al. [10] showed an association between efficacy (clinical remission or MCS response) at Week 10 and at Week 58. Feagan et al. [6] reported an association between the efficacy of FIL at Week 58 and at LTE Week 96. Our findings demonstrated a significant association between symptomatic remission at Week 10 and IBDQ remission at LTE Week 96, which links the efficacy of FIL at earlier and later timepoints. Early prediction of IBDQ remission, rather than pMCS remission, may have clinical significance from the perspective of improving patients’ QoL. To clarify whether early symptom improvement simply leads to long-term sustained benefits, or intentional treatment intensification in the induction phase contributes to long-term benefits, a different approach is needed to compare long-term outcomes with or without the intensified induction therapy by prospective data collection.
This study has some limitations, as it included only completers-responders of the induction study and completers of the maintenance study in SELECTION who enrolled in SELECTIONLTE without change in FIL treatment. This may introduce selection bias, as these patients may represent a subset with better outcomes with FIL. Associations between early factors and remission outcomes were assessed by univariate analyses. Multivariate analyses could provide more robust insights by adjusting for potential confounders. However, implementing this approach was not practical, as by LTE Week 96, only a few patients had not achieved IBDQ or pMCS remission (32 and 34, respectively). With six predictors, the events-per-variable ratio was too low for reliable logistic regression analysis, increasing the risk of overfitting. Therefore, univariate analyses were used for exploratory purposes. Some data were missing at various timepoints, which could affect the robustness of the results.
Treatment with FIL200 improved a range of bowel and systemic symptoms beyond rectal bleeding and stool frequency, as assessed using the IBDQ subscores, and thus improved disease-specific QoL at Week 10, which was maintained through Week 58 and up to LTE Week 96. Symptomatic remission at Week 10 was marginally associated with higher odds of subsequent IBDQ remission, suggesting that it provides clinically relevant information on long-term QoL improvement with FIL200.
Acknowledgments
Medical writing assistance was provided by Niraj Vyas, PhD, and Sonali Dalwadi, PhD, CMPP™, of MedPro Clinical Research, which was funded by Gilead Sciences K.K., Eisai Co., Ltd., and EA Pharma Co., Ltd.
Statement of Ethics
This is a post hoc analysis using the data from SELECTION and SELECTIONLTE. Both studies (SELECTION: NCT02914522 and SELECTIONLTE: NCT02914535) were conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice Guidelines and the Declaration of Helsinki. The study protocol and amendments were reviewed and approved by Ethics Committees or institutional review boards at each of the participating sites. This full list of participating site and Ethics Committees can be found at https://clinicaltrials.gov/study/NCT02914522 for SELECTION and https://clinicaltrials.gov/study/NCT02914535 for SELECTIONLTE. Written informed consent was obtained from all patients.
Conflict of Interest Statement
Fumihito Hirai has served as a speaker for AbbVie, EA Pharma, Janssen, Mochida, Mitsubishi Tanabe, and Takeda, and has received research funding from AbbVie, Janssen, Eli Lilly, and MSD. Toshihiko Kaise is an employee of Gilead Sciences K.K., and a shareholder of Gilead Sciences, Inc. Christine Rudolph is a past employee of Galapagos Biopharma, Germany, and a current employee of Alfasigma GmbH. Toshifumi Hibi has served as a speaker for AbbVie, EA Pharma, JIMRO, Zeria, Mitsubishi Tanabe, Takeda, Janssen, Pfizer, and Mochida, is a consultant for Celltrion, JIMRO, AbbVie, Eli Lilly, Mitsubishi Tanabe, Mochida, Takeda, EA Pharma, and Janssen, and has received research funding from Alfresa Pharma, Kyorin, JIMRO, Zeria, Mochida, and Miyarisan. Toshifumi Hibi was a member of the journal’s Editorial Board at the time of submission.
Funding Sources
This post hoc analysis was funded by Gilead Sciences K.K., Eisai Co., Ltd., and EA Pharma Co., Ltd. The SELECTION trial was sponsored by Gilead Sciences, Inc. (Foster City, CA, USA). Galapagos NV (Mechelen, Belgium) was a collaborator for the SELECTION trial. The SELECTIONLTE trial was sponsored by Galapagos NV (Mechelen, Belgium). The author Toshihiko Kaise was involved in study conceptualization, study design, analysis, writing and reviewing the manuscript, and decision to publish as an employee of Gilead Sciences K.K. The author Christine Rudolph was involved in study conceptualization as an employee of Alfasigma, to which marketing authorization of filgotinib had been transferred from Galapagos NV (Mechelen, Belgium).
Author Contributions
F.H., C.R., and T.K.: conceptualization; F.H. and T.K.: formal analysis and investigation; T.K.: methodology and project administration. All authors were involved in writing, reviewing, editing, and approval of the final version of the manuscript.
Funding Statement
This post hoc analysis was funded by Gilead Sciences K.K., Eisai Co., Ltd., and EA Pharma Co., Ltd. The SELECTION trial was sponsored by Gilead Sciences, Inc. (Foster City, CA, USA). Galapagos NV (Mechelen, Belgium) was a collaborator for the SELECTION trial. The SELECTIONLTE trial was sponsored by Galapagos NV (Mechelen, Belgium). The author Toshihiko Kaise was involved in study conceptualization, study design, analysis, writing and reviewing the manuscript, and decision to publish as an employee of Gilead Sciences K.K. The author Christine Rudolph was involved in study conceptualization as an employee of Alfasigma, to which marketing authorization of filgotinib had been transferred from Galapagos NV (Mechelen, Belgium).
Data Availability Statement
Gilead Sciences shares anonymized individual patient data upon request or as required by law or regulation, with qualified external researchers based on submitted curricula vitae and confirmation of non-conflict of interest. The request proposal must also include a statistician. Approval of such requests is at Gilead Sciences’ discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to datarequest@gilead.com. Further enquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Gilead Sciences shares anonymized individual patient data upon request or as required by law or regulation, with qualified external researchers based on submitted curricula vitae and confirmation of non-conflict of interest. The request proposal must also include a statistician. Approval of such requests is at Gilead Sciences’ discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to datarequest@gilead.com. Further enquiries can be directed to the corresponding author.