Factors affecting 1-year persistence with vedolizumab for ulcerative colitis: a multicenter, retrospective real-world 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, Jovelle L. Fernandez17, Kaori Ishiguro17, Mary Cavaliere17, Hisato Deguchi17, Toshifumi Hibi,1
Abstract
Background/Aims
The objectives of this real-world study were to determine 1-year persistence with vedolizumab in patients with ulcerative colitis and to evaluate factors contributing to loss of response.
Methods
In this multicenter, retrospective, observational chart review, patients with moderately to severely active ulcerative colitis who received ≥ 1 dose of vedolizumab in clinical practice at 16 tertiary hospitals in Japan (from December 2018 through February 2020) were enrolled.
Results
Persistence with vedolizumab was 64.5% (n = 370); the median follow-up time was 53.2 weeks. Discontinuation due to loss of response among initial clinical remitters was reported in 12.5% (35/281) of patients. Multivariate analysis showed that concomitant use of tacrolimus (odds ratio [OR], 2.76; 95% confidence interval [CI], 1.00–7.62; P= 0.050) and shorter disease duration (OR for median duration ≥ 7.8 years vs. < 7.8 years, 0.33; 95% CI, 0.13–0.82; P= 0.017) were associated with discontinuation due to loss of response. Loss of response was not associated with prior use of anti-tumor necrosis factor alpha therapy, age at the time of treatment, disease severity, or concomitant corticosteroids or immunomodulators. Of the 25 patients with disease duration < 1 year, 32.0% discontinued due to loss of response.
Conclusions
Persistence with vedolizumab was consistent with previous reports. Use of tacrolimus and shorter disease duration were the main predictors of decreased persistence.
INTRODUCTION
Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa that is characterized by repeated bouts of relapsing and remitting disease [1]. Patients with moderate to severe UC are typically treated with conventional therapeutics before escalating to biologic therapies [2]. The key goals of pharmacologic treatment are induction and maintenance of remission and, ultimately, improved health-related quality of life [2]. Because patients who are treated with biologics often experience a loss of response over time that requires dose escalation or a switch in therapy [3], it is important to understand the factors that may contribute to continuation with biologic therapy in real-world clinical practice.
Vedolizumab (VDZ) is a humanized monoclonal antibody that blocks lymphocyte infiltration to the gut tissue by selectively binding to α4β7 integrin without inducing systemic immunosuppression [4]. The efficacy and safety of VDZ for treatment of UC were established in the global GEMINI 1 trial [5], and several studies conducted in real-world clinical practice have shown high levels of persistence with VDZ in patients with UC [6-11]. In Japan, VDZ was approved for maintenance therapy based on findings from a randomized placebo-controlled trial in patients with UC [12], but few studies have assessed the use of VDZ in real-world clinical practice in this clinical setting [13].
The objective of this multicenter, retrospective chart review is to evaluate the real-world efficacy and safety of VDZ during induction and maintenance treatment of patients with UC. Here, this post hoc analysis reports persistence with VDZ and evaluates the factors that contribute to treatment discontinuation due to loss of response in patients who have previously achieved clinical remission.
METHODS
1. Study Design
This multicenter, retrospective, observational study, by chart review, enrolled patients who received ≥ 1 dose of intravenous (IV) infusion of VDZ during the eligibility period (December 1, 2018, through February 29, 2020) in clinical practice at 16 tertiary hospitals in Japan (Institutional Review Board Approvals are listed in Supplementary Table 1). Data were collected retrospectively from hospital medical records, including case notes, prescribing records, laboratory reports, and investigation reports. The observation period was 54 weeks and the index date was the date a patient received their first dose of VDZ. This study was registered with the Japanese Registry of Clinical Trials (registration number: jRCT-1080225363).
2. Study Population
Patients were included if they initiated VDZ IV therapy ( ≥ 1 infusion) in accordance with the Japanese label during the eligibility period and were assumed to have had a confirmed diagnosis of moderately to severely active UC. Disease severity determined by attending physicians and treatment was based on the assumption that VDZ was used in accordance with the package insert, including that dose escalation, which is not approved for VDZ in Japan, was not used. Patients had to be aged 20 years or older at initiation of VDZ and have medical information available from the date of UC diagnosis.
Patients were excluded for the following reasons: they were receiving VDZ IV as part of a clinical trial or interventional clinical study, or were enrolled in another inflammatory bowel disease clinical trial or interventional clinical study at initiation of VDZ; they did not have a partial Mayo score at baseline; they had initiated VDZ in combination with another biologic or initiated VDZ at another institution (patient’s medical information was not accessible); or they had requested to opt out their medical information.
3. Outcome Measures
Outcome measures for this study include persistence with VDZ up to 54 weeks, time to discontinuation due to loss of response, the percentage of patients experiencing loss of response, and the factors associated with discontinuation due to loss of response.
Persistence with VDZ was defined as the percentage of patients who continued treatment without discontinuation for any reason. Clinical remission was defined as complete or partial Mayo score ≤ 2 points, with no individual subscore > 1. Primary nonresponse was defined as patients who did not achieve clinical remission within the first 3 months of treatment (12 weeks), before the fourth dose of VDZ. Loss of response was based on the clinician’s evaluation and was defined as patients who achieved clinical remission at least once within the first 3 months of treatment (12 weeks) and who, in the opinion of the clinician, had a sustained nonresponse, disease worsening, or need for rescue medication while being treated with VDZ. Analyses of discontinuation due to loss of response were conducted on patients who entered maintenance treatment with VDZ (i.e., excluded patients who discontinued treatment because of primary nonresponse during the induction phase, from the first IV dose of VDZ up to the fourth VDZ IV dose). Time to loss of response was analyzed in patients from the first documentation of clinical remission to VDZ discontinuation. Mayo scores were calculated from data available in each medical record.
Adverse events (AEs) were collected from medical records and defined as any event that occurred between the start date of VDZ treatment and the last date of VDZ treatment and were categorized using the Medical Dictionary for Regulatory Activities–Japan version 24.0. AEs that resulted in treatment discontinuation are reported here. The safety analysis set excluded patients with AEs related to exacerbation of UC.
4. Statistical Analysis
The planned target sample size was approximately 400 patients with an anticipated ratio of 35% to 50% of biologic-naïve patients and 50% to 65% of biologic-non-naïve patients. The full analysis set comprised all patients who received ≥ 1 IV dose of VDZ from December 1, 2018, through February 29, 2020, and fulfilled all inclusion and exclusion criteria.
Time-to-event outcomes were analyzed using Kaplan-Meier curves with 95% confidence intervals (CIs). Univariate and multivariate logistic regression analyses were used to identify potential factors that were predictive of discontinuation due to loss of response; any associations were reported using odds ratios (OR) and 95% CI. Variables in the univariate analysis included sex; median age at first administration of VDZ; median disease duration; presence of extraintestinal manifestations; prior use of anti-tumor necrosis factor (TNF)-α therapy; concomitant use of tacrolimus; concomitant use of corticosteroid; concomitant use of immunomodulators; partial Mayo score; endoscopic findings (none or mild vs. moderate, severe); and serum levels of hemoglobin, albumin, and C-reactive protein. 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 and no adjustment for multiplicity was performed.
Descriptive statistics include the number of observations (n), mean, standard deviation (SD), median, and interquartile range for continuous variables, and frequency (n and percent) for categorical variables; inferential statistics included P-values or CIs. Statistical analyses were performed using the SAS software (SAS Institute, Cary, NC, USA), version 9.4.
RESULTS
1. Demographic and Baseline Clinical Characteristics
A total of 374 patients with UC were enrolled and, of these, 370 (197 who were biologic-naïve, and 173 who were biologicnon-naïve) met the eligibility criteria and were included in the study. Of the patients who were not eligible, 2 received VDZ outside the study period, 1 had familial Mediterranean fever that could not be ruled out, and 1 had a missing partial Mayo score at the start of VDZ treatment.
The mean ± SD age at diagnosis was 37.6 ± 16.3 years, duration of disease was 9.29 ± 8.21 years, and age at first dose of VDZ was 46.7 ± 16.5 years (Table 1). Mean ± SD partial Mayo score was 4.5 ± 2.2 and most patients had pancolitis (72.2%). Before starting VDZ, 46.2% of patients had received anti-TNF-α therapy and 4.1% had received tofacitinib (98.8% and 8.7% of biologic-non-naïve patients, respectively). At initiation of VDZ, no patients were receiving infliximab, adalimumab, golimumab, ustekinumab, or tofacitinib.
Patient Baseline Demographic and Clinical Characteristics
2. Persistence with VDZ
At the last follow-up (58 weeks), 64.5% of patients had persisted with treatment with VDZ (Fig. 1). The median and mean follow-up times were 53.2 weeks (interquartile range, 22.0–54.9 weeks) and 41.0 weeks (SD, ± 20.1), respectively.
Persistence with vedolizumab (VDZ) treatment in patients with ulcerative colitis (n=370).
The main reasons for treatment discontinuation among the 131 patients who discontinued treatment with VDZ after the fourth IV dose of VDZ were primary nonresponse (55 patients, 42.0%) and loss of response after the first remission (36 patients, 27.5%), AEs (15 patients, 11.5%) (Table 2), lost to follow-up (10 patients, 7.6%), and patient request (9 patients, 6.9%) (Fig. 2). Other reasons for treatment discontinuation were death due to aspiration pneumonia that was unrelated to VDZ treatment (1 patient), surgery at a non-participating institution (1 patient), total colectomy and, therefore, treatment no longer required (2 patients), in quarantine due to COVID-19 (1 patient), and terminal lung cancer (1 patient).
Reasons for discontinuation of treatment with vedolizumab in patients with ulcerative colitis during the observation period (n=370). Adverse events (AEs) related to exacerbation of ulcerative colitis were reported as lack of efficacy (either primary nonresponse or loss of response).
Loss of response leading to drug discontinuation during maintenance therapy was reported in 12.5% (35/281) of patients who achieved clinical remission at least once, from the first documentation of clinical remission to VDZ discontinuation at week 54 (Fig. 3). At week 54, 61.2% (172/281) of initial clinical remitters remained in clinical remission.
Loss of response from clinical remission in patients with ulcerative colitis treated with vedolizumab (VDZ) (n=281). (A) Time to loss of response from remission and (B) percentage of patients maintaining remission at week 54.
3. Predictors of Discontinuation due to Loss of Response during Maintenance Therapy with VDZ
Logistic regression analyses were conducted to identify factors associated with loss of response among initial clinical remitters. Of the factors analyzed, concomitant use of tacrolimus and disease duration (median duration cutoff: ≥ 7.8 years vs. < 7.8 years) were statistically significant in the univariate and multivariate analyses (Table 3). In the multivariate analyses, use of tacrolimus (OR, 2.76; 95% CI, 1.00–7.62; P= 0.050) and shorter disease duration (OR for ≥ 7.8 years vs. < 7.8 years, 0.33; 95% CI, 0.13–0.82; P= 0.017) remained associated with loss of response. No associations between loss of response and prior use of anti-TNF-α therapy, age at the time of treatment, disease severity, or concomitant corticosteroids or concomitant immunomodulators were observed.
Discontinuation due to loss of response occurred in 32% of the 25 patients with disease duration of < 1 year, 14.3% of patients with disease duration of ≥ 1 year and < 7 years, and 4.6% of patients with disease duration ≥ 7 years (Table 4).
DISCUSSION
This is a large-scale, multicenter, retrospective, observational study to evaluate persistence with VDZ treatment and the reasons for discontinuation due to loss of response in patients with UC. Persistence with VDZ was 64.5% at a median of 53.2 weeks of follow-up. Concomitant use of tacrolimus with VDZ and shorter disease duration were significantly associated with loss of response.
Assessment of long-term persistence in real-world clinical settings provides a clinically relevant indicator of treatment effectiveness and tolerability [14]. Findings from the GEMINI long-term safety study showed that 88% and 96% of patients who initially responded to VDZ maintained remission after approximately 104 and 152 weeks of treatment, respectively [15]. These findings are reflected in clinical practice where findings from 2 systematic reviews of the literature have shown that 46% of all patients and 61% to 64% of patients who are biologic-naïve achieve clinical remission after 1 year of treatment with VDZ [16,17]. More recently, a study conducted in the United States has shown that 41.8% and 45.5% of patients achieve corticosteroid-free clinical remission and mucosal healing after 2 and 4 years of treatment with VDZ, respectively [6]. In general, persistence with VDZ in this study, comprising almost equal proportions of biologic-naïve and non-naïve patients, was slightly lower than or similar to long-term (1–2 years) studies conducted in real-world clinical practice [7-11,18,19].
The long-term safety of VDZ for patients with UC has been established in the 8-year GEMINI long-term safety study [20] and an integrated summary of safety data from 6 clinical trials [21]. In addition, expert opinion based on an analysis of data from clinical trials and real-world evidence considers the safety of VDZ to be similar to that of the currently available advanced therapies for inflammatory bowel disease [22]. Consistent with the GEMINI long-term safety study [20] and previous reports in real-world clinical practice, the most common reasons for treatment discontinuation with VDZ in this study were a lack of efficacy and AEs [6,19]. In addition, consistent with the GEMINI study [20], which assessed patients over a median cumulative exposure of 42.4 months, the rate of discontinuation due to AEs during maintenance therapy was low (long-term safety study 15% and current study 11.5%), confirming the safety of VDZ in this study population [20].
In this study, 12.5% of patients experienced a loss of response during the 54-week observation period, which is slightly lower than has been reported (26–46 per 100 person-years) for patients who mostly had prior anti-TNF-α experience [23]. Some of the key reasons for a primary nonresponse or loss of response with biologics are low serum drug levels and immunogenicity, which may suggest high drug clearance and neutralizing drug activity. However, immunogenicity with long-term VDZ treatment is low [24], with anti-VDZ antibodies occurring infrequently and diminishing over time [5,25]. Moreover, although additional doses of VDZ may be of therapeutic benefit in patients with low trough levels [26], it is not clear to what extent trough concentration affects loss of response with VDZ [27]. In general, it is difficult to compare loss of response rates across studies because of the heterogeneity in definitions for clinical remission and because it is not always possible to determine whether or not patients with a partial response were included. In this cohort, prior anti-TNF-α exposure, disease severity, elevated C-reactive protein, and concomitant use of immunomodulators were significantly associated neither with a loss of response nor with persistence in this study.
To the authors’ knowledge, this is the first report to show an association between shorter disease duration and loss of response with VDZ in patients with UC. A previous study has shown that longer disease duration ( ≥ 2 years) contributes to a higher probability of corticosteroid-free remission at week 26 with VDZ in UC [28], but it is not clear why shorter disease duration was an independent predictor for the loss of treatment responsiveness to VDZ in this study. In addition, although 1 study has shown that patients with shorter Crohn’s disease duration are more likely to benefit from treatment with VDZ than those with longer disease duration, no such association has been found for UC [29]. In this study, patients with short disease duration ( < 1 year) had slightly worse disease severity than those with longer disease duration, which suggests that these patients had higher disease activity that could not be adequately controlled with VDZ and/or were refractory to early treatment. However, it is not clear why patients with longer disease duration ( ≥ 7 years) had the lowest rate of loss of response despite similar partial Mayo scores to those with disease durations ≥ 1 and < 7 years. It is possible that changes in the immune response with age [30,31] and/or gut microbiota that occur with increasing duration of UC may play a role [32]. Although the gut microbiota of patients with UC appears to be relatively stable from diagnosis onward [32], findings from a longitudinal analysis has shown that patients who experience a relapse or are nonresponsive or refractory to treatment have lower microbial diversity before treatment initiation than those who do not relapse or who are responsive to treatment [33]. Moreover, as disease duration increases, patients’ cytokine profiles become more complex and may play a role in treatment effectiveness and/or loss of response [34].
A clinically relevant finding in this analysis was the association between concomitant use of tacrolimus and VDZ discontinuation due to loss of response. Tacrolimus is recommended for use in patients with severe UC who are nonresponsive to corticosteroids [35]. However, long-term use of tacrolimus is not recommended due to an increased risk of AEs, including renal complications and opportunistic infection [36]. In this study, patients who used tacrolimus concomitantly included those with primary failure to VDZ. Therefore, it is possible that the switch to maintenance with VDZ was not as effective as maintenance with VDZ after initial success with VDZ induction therapy. However, it can be inferred that caution should be exercised when switching between drugs with different mechanisms of action.
The key strength of this study is that it provides real-world insights into management of UC with VDZ. Despite this, it may be difficult to generalize our results to other countries where dose escalation is approved, because dose escalation from once every 8 weeks to once every 4 weeks is not approved in Japan. In other words, the persistence shown in this study may be purely a reflection of loss of response and, therefore, enables an assessment of the risk factors for loss of response in this retrospective setting. It is conceivable that unrestricted access to dose escalation may have underestimated loss of response rates [15], but this would need to be confirmed in a prospective clinical trial. Despite the observational nature of the study design, selection bias was minimized because almost all potential patients from 16 tertiary care centers who were eligible were included in the analysis. In addition, by using a chart review, we were able to provide a more accurate assessment of disease status compared with administrative claims analyses. Mayo and partial Mayo scores were estimated from objective data collected in the medical records, but objective clinical criteria for loss of response were not used, and each clinician made their assessments based on worsening of symptoms, which may have introduced variability into the assessment of loss of response between physicians and study sites. In addition, identification of predictive factors may have been limited by the small numbers of patients for some of the subgroups included in the logistic regression analysis. Lastly, the observation was up to 54 weeks, and additional long-term observation persistence data are needed.
In conclusion, findings from this retrospective, real-world study have shown that almost two-thirds of patients who commence maintenance therapy with VDZ persist with their treatment for a median duration of 53.2 weeks. Of clinical relevance, the multivariate regression analyses showed that use of concomitant tacrolimus and shorter disease duration were the main factors that predicted decreased persistence.
Notes
Funding Source
This study was funded by Takeda Pharmaceutical Company Limited, manufacturer/licensee of vedolizumab. Medical writing assistance was provided by Serina Stretton, PhD, CMPP, and Koa Webster, 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. 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 Company Limited, 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 Company Limited, 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 Company Limited. Hisamatsu T reports grants/contracts from AbbVie GK, Daiichi Sankyo Company, Limited, 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 Company Limited, 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-Iko Pharmaceutical Co. Ltd., Pfizer Inc., and Takeda Pharmaceutical Company Limited; and payments/honoraria from AbbVie GK, Daiichi Sankyo Company, Limited, 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 Company Limited, 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 Pharma Corporation, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Celltrion Healthcare, EA Pharma Co., Ltd., Eli Lilly and Company, Gilead Sciences, Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd, Mebix, Inc., Sanofi, and Takeda Pharmaceutical Company Limited; payment for lectures/presentations and speaker bureaus from AbbVie GK, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Company, Limited, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd, Kyorin Pharmaceutical Co., Ltd., Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nichi-Iko Pharmaceutical Co. Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Company Limited, Taiho Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co., Ltd.; and is a councillor for the Japanese Society of Gastroenterology. Kunisaki R reports support from Takeda Pharmaceutical Company Limited for the present manuscript; grants/contracts from AbbVie GK and Janssen Pharmaceutical K.K.; consulting fees from Nippon Kayaku Co., Ltd.; payments/honoraria from AbbVie GK, Kyorin Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., and Takeda Pharmaceutical Company Limited; and participation on a data safety monitoring board/advisory board for Nippon Kayaku Co., Ltd. Shibuya T reports support from Takeda Pharmaceutical Company Limited for the present manuscript. Matsuura M reports consulting fees from AbbVie GK, Pfizer Japan Inc., and Takeda Pharmaceutical Company Limited; 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 Company Limited, 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 Pharmaceuticals, 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, 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 Corporation, Mochida Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited. Yasuda H reports grants/contracts from Nippon Kayaku Co., Ltd. and support from Takeda Pharmaceutical Company Limited for the present manuscript. Yokoyama K reports payments/honoraria from AbbVie GK, EA Pharma Co., Ltd., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited. Maemoto A reports support from Takeda Pharmaceutical Company Limited for the present manuscript; grants/contracts from AbbVie GK, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gilead 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 Company Limited; 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 Company Limited. Fernandez JL was an employee of Takeda Pharmaceutical Company Limited at the time of the study and reports stock or share ownership in GlaxoSmithKline, Immunorock Co., Ltd., Mirai Biotech Inc., and Takeda Pharmaceutical Company Limited; and other financial interests in Jovelle Fernandez LLC. Ishiguro K is an employee of Takeda Pharmaceutical Company Limited. Cavaliere M was an employee of Takeda Pharmaceutical Company Limited at the time of the study. Deguchi H is an employee of Takeda Pharmaceutical Company Limited. Hibi T reports grants/contracts from AbbVie GK, Activaid, Alfresa Pharma Corporation, Celltrion Healthcare, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., JMDC Inc., Mitsubishi Tanabe Pharma Corporation, Nichi-Iko Pharmaceutical Co. Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Company Limited, and Zeria Pharmaceutical Co., Ltd.; payments/honoraria from AbbVie GK, EA Pharma Co., Ltd., JIMRO Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., Sandoz K.K., Takeda Pharmaceutical Company Limited, and Zeria Pharmaceutical Co., Ltd.; and payment for expert testimony from AbbVie GK, Celltrion Healthcare, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited. Takatsu N, Tahara T, Tominaga K, Shimada M, and Kuno N have no conflicts of interest to declare.
Hibi T is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of 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
Conception: Fernandez JL, Ishiguro K, Cavaliere M, Deguchi H. Investigation: 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. Formal analysis: Fernandez JL, Kobayashi T, Hisamatsu T, Motoya S, Ishiguro K, Hibi T. Writing - original draft: Kobayashi T. Writing - review & editing: all authors. Approval of final manuscript: all authors.
Supplementary Material
Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).
Supplementary Table 1.
Institutional Review Board Approval Numbers