Week 2 remission with vedolizumab as a predictor of long-term remission in patients with ulcerative colitis: a multicenter, retrospective, observational study
Article information
, Tadakazu Hisamatsu2, Satoshi Motoya3, Toshimitsu Fujii4, Reiko Kunisaki5, Tomoyoshi Shibuya6, Minoru Matsuura2, Ken Takeuchi7, Sakiko Hiraoka8, Hiroshi Yasuda9, Kaoru Yokoyama10, Noritaka Takatsu11, Atsuo Maemoto12, Toshiyuki Tahara13, Keiichi Tominaga14, Masaaki Shimada15, Nobuaki Kuno16, Mary Cavaliere17, Kaori Ishiguro17, Jovelle L Fernandez17, Toshifumi Hibi,1
Abstract
Background/Aims
Vedolizumab (VDZ), a gut-selective monoclonal antibody for ulcerative colitis (UC) treatment, has no established biomarkers or clinical features that predict long-term remission. Week 2 remission, a potential predictor of long-term remission, could inform maintenance treatment strategy.
Methods
This retrospective, observational chart review included patients with UC in Japan who initiated VDZ between December 2018 and February 2020. Outcome measures included 14- and 54-week remission rates in patients with week 2 and non-week 2 remission (remission by week 14), 54-week remission rates in patients with week 14 remission and primary nonresponse, and predictive factors of week 2 and week 54 remission (logistic regression).
Results
Overall, 332 patients with UC (176 biologic-naïve and 156 biologic-non-naïve) were included. Significantly more biologic-naïve than biologic-non-naïve patients achieved week 2 remission (36.9% vs. 28.2%; odds ratio [OR], 1.43; 95% confidence interval [CI], 1.05–1.94; P=0.0224). Week 54 remission rates were significantly different between week 14 remission and primary nonresponse (both groups: P<0.0001), and between week 2 and non-week 2 remission (all patients: OR, 2.41; 95% CI, 1.30–4.48; P=0.0052; biologic-naïve patients: OR, 2.40; 95% CI, 1.10–5.24; P=0.0280). Week 2 remission predictors were male sex, no anti-tumor necrosis factor alpha exposure, and normal/mild endoscopic findings. Week 54 remission was significantly associated with week 2 remission and no tacrolimus use.
Conclusions
Week 2 remission with VDZ is a predictor of week 54 remission in patients with UC. Week 2 may be used as an evaluation point for UC treatment decisions. (Japanese Registry of Clinical Trials: jRCT-1080225363)
INTRODUCTION
Ulcerative colitis (UC), a chronic inflammatory disease of the colon, has a major impact on disease burden worldwide [1] and is estimated to affect approximately 900,000 people in the United States [2] and more than 220,000 people in Japan [3]. Treatment targets entail both rapid relief of symptoms and endoscopic and histological healing, which are associated with longer-term outcomes, including improvements in quality of life [1,4,5]. Pharmacological treatment of moderately to severely active UC typically includes use of 5-aminosalicylates, corticosteroids, and immunomodulators followed by a step-up to biologic therapies such as tumor necrosis factor alpha inhibitors (anti-TNFα), ustekinumab, and vedolizumab (VDZ), or a Janus kinase inhibitor [5]. Remarkable progress has been made in the treatment of UC, with the approval of various therapeutic agents with different mechanisms. However, to date, biomarkers and clinical features that can predict long-term prognosis and clinical remission have not been established. Identification of early predictors of long-term remission would help inform patient selection and timely treatment escalation, and contribute to a more personalized approach to treatment. In addition, it is also important to identify clinical features that predict rapid improvement (e.g., remission at week 2) in clinical symptoms, which can be used to determine the appropriateness of continuing maintenance therapy and may also contribute to a more individualized treatment.
VDZ, a gut-selective monoclonal antibody, reduces inflammation by binding to α4β7 integrin, which is expressed on the surface of lymphocytes, and blocking the binding of the α4β7 integrin to its ligand, MAdCAM-1, thereby preventing T lymphocytes from entering gut tissue [6,7]. Approval of VDZ for treatment of patients with moderately to severely active UC was based on the findings from the global phase 3 GEMINI 1 trial [8], which showed that VDZ was more effective than placebo as induction therapy and as maintenance therapy in patients who responded to VDZ in the induction phase. Several studies have also been conducted to identify predictors of response to VDZ, with most being focused on long-term prognosis and remission [9-11]. However, studies focusing on week 2 remission and its effect as a predictor of long-term remission at week 54 are limited.
We conducted a multicenter, retrospective chart review of patients with UC to evaluate factors that contribute to responsiveness to treatment with VDZ. The objective of the current analysis of this chart review was to examine week 2 remission as a predictor of long-term remission at week 54, and the rate and predictors of week 2 remission.
METHODS
1. Study Design
This was a retrospective, observational chart review using data from hospital medical records, including case notes, prescribing records, and laboratory and investigation reports (Japanese Registry of Clinical Trials: jRCT-1080225363). Patients with UC from 16 tertiary hospitals in Japan were eligible if they received at least one dose of intravenous VDZ between December 1, 2018, and February 29, 2020. The index date was the date a patient received their first dose of VDZ, and the observation period was 54 weeks. This study was conducted in accordance with the Declaration of Helsinki, the Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, December 22, 2014), and all applicable laws and regulations, including, without limitation, data privacy laws and conflict of interest guidelines. The study protocol and the participant information sheet/opt-out form were submitted to the relevant independent ethics committees (IECs) and/or institutional review boards (IRBs) according to local requirements, and were approved by each participating study site (Supplementary Table 1). Informed consent was not required as personal identifiable data were not collected; however, informed consent was obtained if requested by an IEC/IRB, and all study sites were required to provide patients with the right to refuse collection of their data. Patients could also use an IEC-approved form to opt out at any time, from study site approval to the end of data collection at that site, in which case their data had to be deleted.
2. Study Population
1) Inclusion Criteria
Patients with a confirmed diagnosis of UC were included if they were aged ≥ 20 years at VDZ initiation and initiated VDZ in Japan during the eligibility period. Patients were also required to have medical information available from the date of their UC diagnosis. As this was an observational study, disease severity was determined by the attending physician. It was assumed that VDZ was used at the physician’s discretion in accordance with the package insert for VDZ in Japan; VDZ was administered at a dose of 300 mg via intravenous drip at weeks 0, 2, and 6, and every 8 weeks thereafter.
2) Exclusion Criteria
Patients were excluded from the study if they received VDZ as part of a clinical trial or interventional clinical study at another institution, initiated VDZ in combination with another biologic, or were enrolled in another clinical trial or interventional clinical study for inflammatory bowel disease when they initiated VDZ. Patients with missing partial Mayo scores at baseline and patients who opted out were also excluded.
3. Outcome Measures
Clinical remission was defined as a partial Mayo score ≤2 points, with no individual subscore >1, or a complete Mayo score ≤ 2 points, with no individual subscore >1. Response to VDZ was classified into the following 3 categories: week 2 remission, defined as clinical remission at the second administration of VDZ (week 2 ±1 week allowance); non-week 2 remission, defined as no clinical remission at the second administration of VDZ, but clinical remission by week 14 (±4 weeks allowance); and primary nonresponse, defined as no clinical remission by week 14. All patients were classified into only one of the 3 response categories. Outcome measures included the percentage of patients with week 2 remission, non-week 2 remission, and primary nonresponse among biologic-naïve and biologic-non-naïve patients; rates of clinical remission at week 14 (±4 weeks’ allowance) and week 54 (±4 weeks’ allowance) in patients with week 2 remission and in patients with non-week 2 remission; and rates of clinical remission at week 54 (±4 weeks’ allowance) in patients with week 14 remission (all patients in clinical remission by week 14 [i.e., all patients with week 2 and non-week 2 remission]) and in patients with primary nonresponse.
4. Statistical Analysis
Approximately 400 patients were planned for inclusion, which were anticipated to comprise 35% to 50% biologic-naïve patients and 50% to 65% biologic-non-naïve patients. Analyses were conducted on the full analysis set (FAS), which comprised all patients who received at least one dose of VDZ during the eligibility period and met all eligibility criteria. To verify that patients with week 2 remission had achieved remission at week 2 with VDZ administration, any patients who were in remission at baseline were further excluded from the FAS before analyses were performed. Rates of week 2 remission, non-week 2 remission, and primary nonresponse were compared between biologic-naïve and biologic-non-naïve patients. Clinical remission rates were compared between patients with week 2 remission and non-week 2 remission, and between patients with week 14 remission and primary nonresponse. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for each group. The models included clinical remission (as proportion) as objective variable, and groups (biologic-naïve vs. biologic-non-naïve, or week 2 remission vs. non-week 2 remission) and covariates (partial Mayo score and hemoglobin) as explanatory variables. Factors influencing week 2 remission were analyzed using univariate and multivariate logistic regression in cases with at least one confirmed clinical remission, selected through propensity score matching with a caliper width of 0.2 times the standard deviation of the logit of the propensity score. Similarly, factors affecting clinical remission at week 54 were examined using univariate and multivariate logistic regression models. Predictors were reported using ORs and 95% CIs, with P-value calculated using chi-square test. Variables in the univariate analysis included sex, age at first VDZ administration, disease duration, prior use of anti-TNFα therapy, concomitant use of tacrolimus, corticosteroids or immunomodulators, partial Mayo score, endoscopic findings, and serum levels of hemoglobin, albumin, or C-reactive protein; week 2 remission was also included in the analysis of predictors of week 54 remission. Those variables that were statistically significant in the univariate analyses were further explored in the multivariate analyses. Missing values were handled by multiple imputation for baseline variables used in the multivariate analyses (handled as sensitivity analysis for non-imputed results). Descriptive statistics included the number of observations (n), mean and standard deviation for continuous variables, and frequency (n and percent) for categorical variables. Categorical variables were evaluated using the Student t-test, and continuous variables were evaluated by Fisher exact test; significance was set at 5% using a two-tailed test. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
RESULTS
1. Demographic and Baseline Clinical Characteristics
A total of 374 patients with UC were identified for inclusion. Of these, 332 met the eligibility criteria and were included in the FAS: 176 in the biologic-naïve group and 156 in the biologic-non-naïve group. Excluded patients received VDZ outside the study period (n=2), had familial Mediterranean fever that could not be ruled out (n=1), had a missing partial Mayo score at VDZ initiation (n=1), or were in clinical remission at baseline (n=38).
Most patient demographics were similar between the biologic-naïve and biologic-non-naïve groups (Table 1). However, patients in the biologic-naïve group were older at UC diagnosis (mean age 40.5 years vs. 35.7 years, P=0.0067) and when they received their first dose of VDZ (mean age 49.1 years vs. 45.4 years, P=0.0417). In both groups, disease duration was approximately 9–10 years and most patients had pancolitis. Disease severity at baseline was the same in the biologic-naïve and biologic-non-naïve groups based on mean partial and complete Mayo scores (5.0 vs. 5.0 and 7.1 vs. 7.1, respectively). However, the incidence of bloody stool and mean modified Charlson Comorbidity Index scores at baseline were higher in the biologic-naïve group than in the biologic-non-naïve group (73.9% vs. 59.0%, P=0.0050, and 0.6 vs. 0.3, P=0.0461, respectively). Although the use of immunomodulators was similar between the 2 groups (25.6% vs. 32.1%, respectively), the use of oral corticosteroids was higher (58.0% vs. 44.9%, P=0.0208) and steroid resistance was lower (16.5% vs. 26.9%, grouped P=0.0251) in the biologic-naïve group than in the biologic-non-naïve group.
Patient Baseline Demographic and Clinical Characteristics
2. Clinical Remission and VDZ Response
In the biologic-naïve group, 36.9% (n=65), 41.5% (n=73), and 21.6% (n=38) of patients had week 2 remission, non-week 2 remission, and primary nonresponse, respectively (Fig. 1). In the biologic-non-naïve group, 28.2% (n=44), 39.7% (n=62), and 32.1% (n=50) of patients had week 2 remission, non-week 2 remission, and primary nonresponse, respectively. Overall, there was a significantly greater proportion of patients with week 2 remission (OR, 1.43; 95% CI, 1.05–1.94; P=0.0224) and a significantly smaller proportion of patients with primary nonresponse (OR, 0.61; 95% CI, 0.45–0.83; P=0.0015) in the biologic-naïve group than in the biologic-non-naïve group (Fig. 1). The difference in the percentage of patients with non-week 2 remission between the biologic-naïve and biologic-non-naïve groups was not statistically significant.
Percentage of patients achieving week 2 remission, non-week 2 remission, and primary nonresponse among biologic-naïve and biologic-non-naïve patients receiving vedolizumab therapy for ulcerative colitis. ORs were calculated using logistic regression model with clinical remission (as proportion) as the objective variable and the groups (biologic-naïve vs. biologic-non-naïve) and covariates as explanatory variables. OR, odds ratio; CI, confidence interval.
In general, numerically higher percentages of patients with week 2 remission than with non-week 2 remission went on to achieve clinical remission at week 14 and week 54 (Fig. 2). However, the rates of clinical remission at week 54 were only statistically different between the week 2 and non-week 2 remission groups for all patients (OR, 2.41; 95% CI, 1.30–4.48; P=0.0052) and for biologic-naïve patients (OR, 2.40; 95% CI, 1.10–5.24; P=0.0280).
Rates of clinical remission at week 14 and week 54 among patients with week 2 remission and patients with non-week 2 remission, and rates of clinical remission at week 54 among patients with week 14 remission and patients with primary nonresponse. ORs were calculated using logistic regression model with clinical remission (as proportion) as the objective variable and the groups (week 2 remission vs. non-week 2 remission) and covariates (confounding factors) as explanatory variables. OR, odds ratio; CI, confidence interval; CR, clinical remission.
As is to be expected, rates of clinical remission at week 54 were significantly different between the week 14 remission and primary nonresponse groups for all patients (OR, 9.32; 95% CI, 5.12–16.95; P<0.0001), for biologic-naïve patients (OR, 8.34; 95% CI, 3.54–19.65; P<0.0001), and for biologic-non-naïve patients (OR, 12.77; 95% CI, 5.17–31.57; P<0.0001) (Fig. 2).
3. Predictive Factors for Week 2 Remission with VDZ
The factors significantly associated with week 2 remission in the univariate analysis were male sex, no prior anti-TNFα exposure, and normal or mild endoscopic findings (Table 2). Similarly, the multivariate analysis further revealed that male sex (OR, 2.5220; 95% CI, 1.1548–5.5082; P=0.0203), no prior exposure to anti-TNFα agents (OR for prior exposure vs. no prior exposure, 0.3468; 95% CI, 0.1562–0.7701; P=0.0093), and normal or mild endoscopic findings (OR for moderate vs. normal or mild, 0.2196; 95% CI, 0.0640–0.7534; and severe vs. normal or mild: OR, 0.4231; 95% CI, 0.1153–1.5523; grouped P=0.0368) were significantly associated with week 2 remission.
Logistic Regression Analysis of Predictive Factors for Week 2 Remission with VDZ Treatment in Patients with UC (FAS with Propensity Score Matching) (n=158)
4. Predictive Factors for Week 54 Remission with VDZ
The factors significantly associated with week 54 remission in the univariate analysis were clinical remission at week 2, no concomitant use of tacrolimus, and albumin ≥3.0 g/dL (Table 3). Similarly, multivariate analysis revealed that clinical remission at week 2 (OR, 4.3767; 95% CI, 2.6278–7.2898; P<0.0001) and no concomitant use of tacrolimus (OR for use vs. no use, 0.3292; 95% CI, 0.1216–0.8915; P=0.0288) were significantly associated with week 54 remission.
Logistic Regression Analysis of Predictive Factors for Week 54 Remission with VDZ Treatment in Patients with UC (n=332)
DISCUSSION
This retrospective observational study is the first to examine the effect of week 2 remission during VDZ treatment as a predictor for long-term remission, and to identify predictive factors for achieving week 2 remission, in patients with UC. These results contribute to a better understanding of the outcomes of week 2 remission with VDZ. It has been suggested that VDZ has not only short-term effects in inducing remission, but also long-term effects in maintaining remission [12]. Prediction of the subsequent course of therapy at a very early stage after treatment initiation is an important factor in determining whether treatment should be changed or continued. However, in current medical practice, biomarkers that can predict long-term prognosis and long-term clinical remission have not been established.
In this study, clinical remission was reported as early as week 2, which predicted long-term remission at week 54 in all patients and in biologic-naïve patients. These findings were similar to the results from a post hoc analysis of a VDZ clinical study, which showed that improvement in patient-reported symptoms can occur as early as week 2 in anti-TNFα-naïve patients, and suggested that a symptom response to VDZ at week 2 can predict response to treatment at week 10 [13]. Remission at week 2 did not influence the likelihood of remission at week 14, but its impact on long-term remission at week 54 was evident. Conversely, the absence of remission by week 14 (i.e., primary nonresponse) was strongly associated with a minimal chance of achieving long-term remission at week 54. Predicting long-term treatment outcomes in UC can be challenging. However, the results from this study suggest that patients who achieve week 2 remission with VDZ are more likely than patients with non-week 2 remission to have successful treatment outcomes up to week 54. Early identification of such patients may help avoid unnecessary treatment changes or treatment intensification, reduce healthcare costs, and provide long-term treatment stability for the chronic disease of UC. Importantly, the results of this study should not be considered as evidence that VDZ treatment should stop if remission is not achieved by week 2. Instead, the results suggest that patients who achieve week 2 remission are less likely to relapse, allowing for less intensive monitoring and greater patient reassurance. For patients who do not achieve remission by week 2 but improve by week 14, careful monitoring is still crucial for managing relapse risk. Overall, analyzing patient progress during treatment helps improve remission predictions and management of UC in the long term.
Several other studies have examined the effects of early clinical remission in response to VDZ, particularly at week 6, on long-term remission [11,14,15]. In a single-center, retrospective observational study, clinical response to VDZ at week 6 was significantly associated with endoscopic remission at week 24 [14]. Moreover, a post hoc analysis of the VARSITY study reported that patients with UC who achieved early remission (at 4–6 weeks) with VDZ had a higher probability of remission at week 52 compared with those with delayed remission (at week 14) [15]. These findings indicated that patients who achieve early clinical remission with VDZ are more likely to achieve clinical remission in the long term, and suggested that week 6 of VDZ treatment may be considered as a possible evaluation point for treatment decisions [14]. In contrast to these findings, results of the current study suggest that the evaluation point for predicting long-term remission at week 54 could be moved to as early as week 2, especially in biologic-naïve patients. Nonetheless, given that approximately half of patients with non-week 2 remission achieved remission at week 54, with similar results observed among biologic-naïve (49.2%) and biologic-non-naïve patients (57.8%), predicting long-term remission based solely on week 2 remission may be premature, and careful monitoring is essential for patients who do not achieve remission by week 2.
In the GEMINI 1 trial, the clinical response rate at week 6 increased with increasing trough concentrations of VDZ [8], and findings from a prospective cohort study also showed that higher trough concentrations of VDZ may be related to efficacy [16]. However, in addition to differences in pharmacokinetics, the disease course and the response to treatment vary considerably among individual patients, even with the same apparent clinical phenotype, possibly because of differences in underlying immune pathways and gene expression [17-23]. Because of this complexity, it is currently still not possible in clinical practice to predict VDZ response, especially prior to initiation of therapy.
VDZ suppresses intestinal lymphocyte infiltration without directly inhibiting cytokine activity; it blocks the α4β7 integrin from binding to the MAdCAM-1 but does not inhibit the adhesion of α4β1 to the vascular cell adhesion molecule-1, expressed on systemic vascular endothelial cells [6,7]. Owing to this mechanism of action, VDZ is known to have a favorable safety profile, but a slow onset of action, compared with anti-TNFα therapies [7]. In a study by Buisson et al. [24], corticosteroid-free remission rates increased from 32.4% at week 2 to 41.6% at week 6 and 52.2% at week 14, and 35.5% of patients who did not achieve remission at week 6 did achieve remission at week 16, which indicated that the onset of action of VDZ may be slow. Therefore, the observation that patients treated with VDZ can achieve week 2 remission could challenge this conventional concept. In this study, 36.9% and 28.2% of biologic-naïve and biologic-non-naïve patients, respectively, achieved remission by week 2. This was higher than expected and could potentially refute the established notion that VDZ has a slow onset of therapeutic effects. Additionally, the rate of week 2 remission was higher in the biologic-naïve patients than in the biologic-non-naïve patients, supporting the potential use of VDZ as a first-line biologic with rapid effectiveness in many patients. VDZ may show symptomatic improvement before showing efficacy in objective measures of disease activity [25]. Therefore, objective measures, such as endoscopic mucosal remission and biomarker remission, will be investigated in the future among patients with week 2 remission.
In this study, male sex, absence of anti-TNFα exposure, and milder endoscopic findings were significantly associated with week 2 remission. The finding that male sex may influence week 2 remission was unexpected given that previous research has shown that women are more likely to experience endoscopic remission at week 6 [26], whereas other studies report no significant sex differences in endoscopic improvement in inflammatory bowel disease [27]. Further large-scale analyses are needed to better understand the relationship between sex and early remission. Concomitant use of immunomodulators, steroids, or tacrolimus was not associated with week 2 remission; this finding was consistent with results from a meta-analysis, which concluded that there is no clinical benefit of combination therapy of VDZ with immunomodulators during either induction or maintenance [28]. However, the effectiveness of combination therapy of VDZ with corticosteroids during maintenance therapy needs to be examined separately.
To better understand the relationship between week 2 remission and week 54 remission, we included week 2 remission as a variable and analyzed its role as a predictor of week 54 remission. The results demonstrated that achieving remission at week 2 was a significant predictor of remission at week 54 in the multivariate analysis, further supporting the finding of a significantly higher week 54 remission rate in the week 2 remission group than in the non-week 2 remission group. Conversely, the concomitant use of tacrolimus was associated with a negative impact on week 54 remission. We speculate that this may reflect the inclusion of patients with initially severe UC requiring tacrolimus, who represent a population more prone to relapse.
Baseline characteristics in this study may have reflected the real-world selection of therapy. For example, it cannot be ruled out that the older age of the biologic-naïve patients was driven by the fact that VDZ may have been preferred by these patients, who were more concerned about safety of treatment. The use of oral corticosteroids was higher in biologic-naïve patients than in biologic-non-naïve patients. This was not surprising, as many biologic-naïve patients would have used corticosteroids prior to the initiation of VDZ treatment. In addition, steroid resistance was higher in biologic-non-naïve than in biologic-naïve patients, suggesting that the lower corticosteroid use in biologic-non-naïve patients may also have been due to patients developing resistance during previous use of corticosteroids. Despite these observed differences between biologic-naïve and biologic-non-naïve patients, the overall disease severity was similar between the 2 cohorts. Therefore, these differences would not have affected the rate of week 2 remission or long-term remission at week 54. However, a comparative study in a propensity score–matched population may be required to further identify patients who are suitable for VDZ treatment during the induction phase.
There are a few limitations of this study. Clinical remission was defined as a partial or complete Mayo score of ≤ 2 with no subscore >1. However, because this was a multicenter, retrospective chart review, the possibility of inter-institutional or inter-observer bias cannot be ruled out. Moreover, data on endoscopic findings were limited, and endoscopic remission could not be assessed. Therefore, mucosal evaluation should be considered in the future.
In conclusion, this study showed that week 2 remission with VDZ is predictive of long-term clinical remission at week 54 in patients with UC. Furthermore, male sex, absence of anti-TNFα exposure, and normal or mild endoscopic findings were identified as predictors of week 2 remission. Predictors of week 54 remission were week 2 remission and no concomitant use of tacrolimus. From these results it can be inferred that physicians may use week 2 of VDZ treatment as an evaluation point for treatment decisions in UC.
Notes
Funding Source
This study was funded by Takeda Pharmaceutical Company Limited, manufacturer/licensee of vedolizumab. Takeda Pharmaceutical Company Limited was involved in the study design, data collection, data analysis, and preparation of the manuscript.
Conflict of Interest
Kobayashi T reports grants/contracts from AbbVie GK, Activaid, Alfresa Pharma Corporation, Bristol-Myers Squibb, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Inc., Google Asia Pacific Pte. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., JMDC Inc., Kyorin Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Otsuka Holdings, Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd.; payments/honoraria from AbbVie GK, Activaid, Alfresa Pharma Corporation, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Pfizer Japan Inc., Thermo Fisher Diagnostics K.K., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd.; and payment for expert testimony from AbbVie GK, Activaid, Alfresa Pharma Corporation, EA Pharma Co., Ltd., Galapagos, Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd. Hisamatsu T reports grants/contracts from AbbVie GK, Daiichi Sankyo, EA Pharma Co., Ltd., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd.; advisory fees from AbbVie GK, Bristol-Myers Squibb, EA Pharma Co., Ltd., Eli Lilly and Company, Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Nichi-lko Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co., Ltd.; and payments/honoraria from AbbVie GK, Daiichi Sankyo, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K, JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co,. Ltd. Motoya S reports grants/contracts from Janssen Pharmaceutical K.K.; and payments/honoraria from AbbVie GK, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Mochida Pharmaceutical Co., Ltd. Fujii T reports grants/contracts from AbbVie GK, Alfresa Corporation, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Celltrion Healthcare, EA Pharma Co., Ltd., Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical, Kissei Pharmaceutical Co., Mebix Inc, Sanofi, and Takeda Pharmaceutical Co., Ltd; and payment for lectures/presentations and speaker bureaus from AbbVie GK, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, EA Pharma Co., Ltd., Janssen Pharmaceutical, Kissei Pharmaceutical, Kyorin Pharma, Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma, Mochida Pharma, Nichi-lko Pharmaceutical, Nippon Kayaku, Pfizer, Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical, and Zeria Pharma. Kunisaki R reports support from Takeda Pharmaceutical Co., Ltd for the present manuscript; grants/ contracts from AbbVie and Janssen Pharmaceutical; consulting fees from Nippon Kayaku; payments/honoraria from AbbVie, Kyorin Pharmaceutical, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Pfizer, and Takeda Pharmaceutical Co., Ltd. Shibuya T reports support from Takeda Pharmaceutical Co., Ltd. for the present manuscript. Matsuura M reports consulting fees from AbbVie GK, Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd; and payments/honoraria from AbbVie GK, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Viatris Inc. and Zeria Pharmaceutical Co., Ltd. Takeuchi K reports grants/contracts from AbbVie GK, Amgen K.K., AstraZeneca K.K., Bristol-Myers Squibb K.K., EA Pharma Co., Ltd., Eli Lilly Japan K.K., Ferring Pharmaceutical Co., Ltd., IQVIA Inc, Nippon Shinyaku Co., Ltd., and Takeda Pharmaceutical Company Limited; consulting fees from Thermo Fisher Diagnostics K.K.; payments/honoraria from AbbVie GK, Ayumi Pharmaceutical Corporation, Celltrion Healthcare, EA Pharma Co., Ltd., Gilead Sciences, Inc, Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Otsuka Holdings Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, Viatris Inc. and Zeria Pharmaceutical Co., Ltd. Hiraoka S reports payments/honoraria (lecture fees) from AbbVie GK, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Yasuda H reports grants/contracts from Nippon Kayaku and support from Takeda Pharmaceutical Co., Ltd. for the present manuscript. Yokoyama K reports payments/honoraria from AbbVie GK, EA Pharma Co Ltd., Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co Ltd., and Takeda Pharmaceutical Co., Ltd. Maemoto A reports support from Takeda Pharmaceutical Co., Ltd. for the present manuscript; grants/contracts from AbbVie GK, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gil ead Sciences Inc, Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co Ltd., Pfizer R&D Japan K.K. and Takeda Pharmaceutical Co., Ltd., and payments/ honoraria from AbbVie GK, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Nippon Kayaku Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Cavaliere M was an employee of Takeda Pharmaceutical Co., Ltd. at the time of the study. Ishiguro K was an employee of Takeda Pharmaceutical Co., Ltd at the time of the study. Fernandez JL was an employee of Takeda Pharmaceutical Co., Ltd. at the time of the study and reports stock or share ownership in Cococell Nanotech, Inc., GlaxoSmithKline, Immunorock Co., Ltd., Mirai Biotech Inc., and Takeda Pharmaceutical Company Limited; and other financial interests in Jovelle Fernandez LLC. Hibi T reports grants/contracts from AbbVie GK, Activaid, Alfresa Pharma Corp., Celltrion, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Janssen Pharmaceutical K.K., JMDC Inc., Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical; payments/honoraria from AbbVie, EA Pharma, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Pfizer, Sandoz K.K., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical; and payment for expert testimony from AbbVie, Celltrion, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. He is an editorial board member of the journal but was not involved in the selection of peer reviewers, evaluation, or decision process for this article. No other potential conflicts of interest relevant to this article were reported.
Data Availability Statement
The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article, will be made available within 3 months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.
Author Contributions
Conceptualization: Kobayashi T, Hisamatsu T, Motoya S, Fujii T, Kunisaki R, Shibuya T, Matsuura M, Takeuchi K, Hiraoka S, Yasuda H, Yokoyama K, Takatsu N, Maemoto A, Tahara T, Tominaga K, Shimada M, Kuno N, Cavaliere M, Fernandez JL, Hibi T. Data curation: Kobayashi T, Hisamatsu T, Motoya S, Fujii T, Kunisaki R, Shibuya T, Matsuura M, Takeuchi K, Hiraoka S, Yasuda H, Yokoyama K, Takatsu N, Maemoto A, Tahara T, Tominaga K, Shimada M, Kuno N, Hibi T. Investigation: Ishiguro K. Supervision: Fernandez JL, Hibi T. Writing – original draft: Kobayashi T, Hisamatsu T, Ishiguro K. Writing – review & editing: all authors. Approval of final manuscript: all authors.
Additional Contributions
The authors would like to thank all study participants. Medical writing assistance was provided by Serina Stretton, PhD, CMPP, of ProScribe–Envision Pharma Group, and was funded by Takeda Pharmaceutical Company Limited. ProScribe’s services complied with international guidelines for Good Publication Practice.
Supplementary Material
Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).
Supplementary Table 1.
Institutional Review Board Approval Numbers