Efficacy and safety of a new vedolizumab subcutaneous formulation in Japanese patients with moderately to severely active ulcerative colitis

( Taku Kobayashi ),( Hiroaki Ito ),( Toshifumi Ashida ),( Tadashi Yokoyama ),( Masakazu Nagahori ),( Tomoki Inaba ),( Mitsuhiro Shikamura ),( Takayoshi Yamaguchi ),( Tetsuharu Hori ),( Philippe Pinton 대한장연구학회 2021 Intestinal Research Vol.19 No.4

Background/Aims: A subgroup analysis was conducted in Japanese patients with moderate to severe ulcerative colitis (UC) enrolled in the phase 3 VISIBLE 1 study, which evaluated the safety and efficacy of a new vedolizumab subcutaneous (SC) for-mulation. Methods: Eligible patients received open-label infusions of vedolizumab 300 mg intravenous (IV) at weeks 0 and 2 in the induction phase. Patients with clinical response by complete Mayo score at week 6 entered the double-blind maintenance phase and were randomized to vedolizumab 108 mg SC every 2 weeks, placebo, or vedolizumab 300 mg IV every 8 weeks. The primary endpoint was clinical remission (complete Mayo score ≤2 points; no individual subscore >1 point) at week 52. Results: Of 49 patients who entered the induction phase, 22 out of 49 patients (45%) had clinical response at week 6 and were randomized to vedolizumab 108 mg SC (n=10), placebo (n=10), or vedolizumab 300 mg IV (n=2). At week 52, 4 out of 10 pa-tients (40%) who received vedolizumab SC had clinical remission versus 2 out of 10 patients (20%) who received placebo (dif-ference: 20% [95% confidence interval, ±27.9 to 61.8]). Two patients (2/10, 20%) who received vedolizumab SC experienced an injection-site reaction versus none who received placebo. Conclusions: Our results indicate that the efficacy of vedolizumab SC in a subgroup of Japanese patients with UC are similar with those in the overall VISIBLE 1 study population, and with those established with vedolizumab IV. The safety and tolerability of vedolizumab SC were generally similar to that established for vedolizumab IV. (ClinicalTrials.gov ID NCT02611830; EudraCT 2015-000480-14) (Intest Res 2021;19:448-460)

Predicting outcomes to optimize disease management in inflammatory bowel disease in Japan: their differences and similarities to Western countries

( Taku Kobayashi ),( Tadakazu Hisamatsu ),( Yasuo Suzuki ),( Haruhiko Ogata ),( Akira Andoh ),( Toshimitsu Araki ),( Ryota Hokari ),( Hideki Iijima ),( Hiroki Ikeuchi ),( Yoh Ishiguro ),( Shingo Kato 대한장연구학회 2018 Intestinal Research Vol.16 No.2

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract, with increasing prevalence worldwide. IBD Ahead is an international educational program that aims to explore questions commonly raised by clinicians about various areas of IBD care and to consolidate available published evidence and expert opinion into a consensus for the optimization of IBD management. Given differences in the epidemiology, clinical and genetic characteristics, management, and prognosis of IBD between patients in Japan and the rest of the world, this statement was formulated as the result of literature reviews and discussions among Japanese experts as part of the IBD Ahead program to consolidate statements of factors for disease prognosis in IBD. Evidence levels were assigned to summary statements in the following categories: disease progression in CD and UC; surgery, hospitalization, intestinal failure, and permanent stoma in CD; acute severe UC; colectomy in UC; and colorectal carcinoma and dysplasia in IBD. The goal is that this statement can aid in the optimization of the treatment strategy for Japanese patients with IBD and help identify high-risk patients that require early intervention, to provide a better long-term prognosis in these patients. (Intest Res 2018;16:168-177)

Performing colonoscopy before steroid induction is associated with shorter steroid use in patients with ulcerative colitis

Taku Kobayashi,Eri Udagawa,Lisa Hirose,Toshifumi Hibi 대한장연구학회 2023 Intestinal Research Vol.21 No.2

Background/Aims: Risks of long-term steroid use in patients with ulcerative colitis (UC) outweigh the benefits, thus dosing should be tapered once a response is achieved. Colonoscopy is a key technique for assessing disease severity and optimizing treatment involving steroids. This retrospective longitudinal cohort study of patients with UC explored factors associated with the duration of systemic steroid use. Methods: The Japan Medical Data Center database, an employer-based insurance claims database, was used to select individuals initiating prednisolone, with a prescription issued between January 1, 2010, and January 31, 2018. The study included adults with a confirmed diagnosis of UC, who had received ≥1 year of continuous treatment with 5-aminosalicylic acid, biologics, or thiopurine. Factors associated with prednisolone duration were assessed using a multivariate regression model. Results: Median duration of prednisolone treatment was 98 days, and colonoscopy was performed ≤1 month before or at the first prescription of prednisolone (index date) in 32.8% of patients (607/1,853). Shorter durations of prednisolone treatment were associated with colonoscopy ≤1 month before or at the index date and higher prednisolone dose at index date, with incidence rate ratios (IRRs) of 0.776 (95% confidence interval [CI], 0.682–0.884; P<0.001) and 0.998 (95% CI, 0.996–1.000; P=0.018), respectively. Charlson Comorbidity Index scores of 1 and ≥2 predicted longer prednisolone treatment (IRR, 1.332; 95% CI, 1.174–1.511; P<0.001 and IRR, 1.599; 95% CI, 1.357–1.885; P<0.001, respectively). Conclusions: Performing colonoscopy before or at the time of initiating steroid was associated with a shorter duration of steroid use in patients with UC.

Individualized treatment based on CYP3A5 single-nucleotide polymorphisms with tacrolimus in ulcerative colitis

Shinji Okabayashi,Taku Kobayashi,Eiko Saito,Takahiko Toyonaga,Ryo Ozaki,Shintaro Sagami,Masaru Nakano,Junichi Tanaka,Keiji Yagisawa,Satoshi Kuronuma,Osamu Takeuchi,Toshifumi Hibi 대한장연구학회 2019 Intestinal Research Vol.17 No.2

Background/Aims: The pharmacokinetics of tacrolimus (TAC) is known to be largely influenced by single-nucleotide polymorphisms (SNPs) in CYP3A5. Patients starting TAC require careful dose adjustment, owing to the wide range of optimal dosages, depending on their CYP3A5 expression status. Here, we evaluated whether individualization of TAC dosages based on CYP3A5 SNPs would improve its therapeutic efficacy in ulcerative colitis. Methods: Twenty-one patients were prospectively treated, with their initial dosage adjusted according to their CYP3A5 status (0.1, 0.15, and 0.2 mg/kg/day for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively). Their clinical outcomes were compared with those of patients treated with a fixed dose (0.1 mg/kg/day). Results: The first blood trough level of CYP3A5 expressors, CYP3A5*1/*3 or CYP3A5*1/*1, and the overall rate in achieving the target blood trough level within a week in the individualized-dose group were significantly higher than those in the fixed-dose group (5.15±2.33 ng/mL vs. 9.63±0.79 ng/mL, P=0.035 and 12.5% vs. 66.7%, P=0.01). The remission rate at 2 weeks in the expressors was as high as that in the nonexpressors, CYP3A5*3/*3, in the individualized-dose group. Conclusions: Individualized TAC treatment is effective against ulcerative colitis regardless of the CYP3A5 genotype. (Intest Res 2019;17:218-226)

Randomized, crossover questionnaire survey of acceptabilities of controlled-release mesalazine tablets and granules in ulcerative colitis patients

Keiji Yagisawa,Taku Kobayashi,Ryo Ozaki,Shinji Okabayashi,Takahiko Toyonaga,Miki Miura,Mari Hayashida,Eiko Saito,Masaru Nakano,Hajime Matsubara,Tadakazu Hisamatsu,Toshifumi Hibi 대한장연구학회 2019 Intestinal Research Vol.17 No.1

Background/Aims: Oral mesalazine is an important treatment for ulcerative colitis (UC), and non-adherence to mesalazineincreases the risk of relapse. Controlled-release (CR) mesalazine has 2 formulations: tablets and granules. The relative acceptabilitiesof these formulations may influence patient adherence; however, they have not been compared to date. This studyaimed to evaluate the acceptabilities of the 2 formulations of CR mesalazine in relation to patient adherence using a crossoverquestionnaire survey. Methods: UC patients were randomly assigned to 2 groups in a 1:1 ratio. Patients in each group tookeither 4 g of CR mesalazine tablets or granules for 6 to 9 weeks, and then switched to 4 g of the other formulation for a further 6to 9 weeks. The acceptability and efficacy were evaluated by questionnaires, and adherence was assessed using a visual analogscale. The difference in acceptabilities between the 2 formulations and its impact on adherence were assessed. Results: A totalof 49 patients were prospectively enrolled and 33 patients were included in the analysis. Significantly more patients found thetablets to be less acceptable than the granules (76% vs. 33%, P=0.0005). The granules were preferable to the tablets when the 2formulations were compared directly (73% vs. 21%, P=0.004), for their portability, size, and numbers of pills. The adherence ratewas slightly better among patients taking the granules (94% vs. 91%) during the observation period, but the difference was notsignificant (P=0.139). Conclusion: CR mesalazine granules are more acceptable than tablets, and may therefore be a better optionfor long-term medication. (Intest Res 2019;17:87-93)

Steroid-refractory extensive enteritis complicated by ulcerative colitis successfully treated with adalimumab

( Shinji Okabayashi ),( Taku Kobayashi ),( Tomohisa Sujino ),( Ryo Ozaki ),( Satoko Umeda ),( Takahiko Toyonaga ),( Eiko Saito ),( Masaru Nakano ),( Maria Carla Tablante ),( Shojiroh Morinaga ),( Tosh 대한장연구학회 2017 Intestinal Research Vol.15 No.4

Extracolonic involvement of the gastrointestinal tract is extremely uncommon in ulcerative colitis (UC) and rarely found in the upper gastrointestinal tract or in postoperative cases since it typically responds to steroids. Here we report a case of UC complicated by extensive ileal inflammation that was refractory to steroids. A 20-year-old man was diagnosed with UC of typical pancolitis without ileal involvement and started treatment with pH-dependent mesalazine and oral prednisolone. Although his symptoms transiently resolved, the condition flared when the steroid dose was tapered down. Computed tomography revealed marked thickening of the ileal wall, and capsule endoscopy and balloon-assisted enteroscopy found diffuse mucosal inflammation with ulcers in the ileum. On the contrary, the inflammation in the colon and rectum was improving. Since the response to the second steroid course was inadequate, treatment with adalimumab and 6-mercaptopurine was initiated and finally achieved clinical and endoscopic remission. The investigation of small intestinal lesions is necessary in patients with UC whose clinical deterioration cannot be explained by colonic lesions. (Intest Res 2017;15:535-539)

Infliximab biosimilar CT-P13 is interchangeable with its originator for patients with inflammatory bowel disease in real world practice

Tomoo Nakagawa,Taku Kobayashi,Kiyohiro Nishikawa,Fumika Yamada,Satoshi Asai,Yukinori Sameshima,Yasuo Suzuki,Mamoru Watanabe,Toshifumi Hibi 대한장연구학회 2019 Intestinal Research Vol.17 No.4

Background/Aims: An interim analysis of post-marketing surveillance of CT-P13, an infliximab biosimilar, was performed to evaluate its safety and efficacy in Japanese patients with inflammatory bowel disease. Methods: Patients were prospectively enrolled between November 2014 and March 2017, after the launch of CT-P13 in Japan, and case report forms of patients followed for at least 4 months were analyzed as of July 2018. Results: Of 523 patients in the analysis set, 372 remained on CT-P13 therapy, while 54 (20.2%) of 267 patients with Crohn’s disease, and 97 (37.9%) of 256 patients with ulcerative colitis were withdrawn during follow-up. A total of 144 adverse drug reactions (ADRs) were reported in 106 patients (20.3%). Infusion reaction was the most frequent ADR observed in 49 patients (9.4%). Efficacy parameters decreased immediately after the start of treatment in naïve patients to anti-tumor necrosis factor-α antibody. In the patients switched from originator infliximab for nonmedical reasons, the decreased parameters due to proceeded treatment with the originator were maintained in low ranges, and the treatment continuation rate was high with low ADR incidence. In contrast, in patients switched for medical reasons such as adverse event or loss of response, the incidence of ADRs was high. However, the efficacy parameters were improved, and the treatment continuation rate was not significantly different from that of the naïve patient group. Conclusions: In this interim analysis, CT-P13 was comparable to the originator infliximab with respect to ADRs and efficacy, and is therefore considered to be a cost-efficient interchangeable biosimilar for Japanese patients with inflammatory bowel disease.

Capsule endoscopy in inflammatory bowel disease: when and how

( Ida Hilmi ),( Taku Kobayashi ) 대한장연구학회 2020 Intestinal Research Vol.18 No.3

Capsule endoscopy (CE) is emerging as an important investigation in inflammatory bowel disease (IBD); common types include the standard small bowel CE and colon CE. More recently, the pan-enteric CE was developed to assess the large and small bowel in patients with Crohn’s disease (CD). Emerging indications include noninvasive assessment for mucosal healing (both in the small bowel and the colon) and detection of postoperative recurrence in patients with CD. Given the increasing adoption, several CE scoring systems have been specifically developed for IBD. The greatest concern with performing CE, particularly in CD, is capsule retention, but this can be overcome by performing cross-sectional imaging such as magnetic resonance enterography and using patency capsules before performing the procedure. The development of software for automated detection of mucosal abnormalities typically seen in IBD may further increase its adoption. (Intest Res 2020;18:265-274)

De-escalation of Therapy in Patients with Quiescent Inflammatory Bowel Disease

Miyatani Yusuke,Kobayashi Taku 거트앤리버 소화기연관학회협의회 2023 Gut and Liver Vol.17 No.2

Inflammatory bowel disease is a chronic disease of unknown origin that requires long-term treatment. The optical duration of maintenance treatment once remission has been achieved remains unclear. When discussing a de-escalation strategy, not only the likelihood of relapse but also, the outcome of retreatment for relapse after de-escalation should be considered. Previous evidence has demonstrated controversial results for risk factors for relapse after de-escalation due to the various definitions of remission and relapse. In fact, endoscopic or histologic remission has been suggested as a treatment target; however, it might not always be indicative of a successful drug withdrawal. For better risk stratification of relapse after de-escalation, it may be necessary to evaluate both the current and previous treatments. Following de-escalation, biomarkers should be closely monitored. In addition to the risk of relapse, a comprehensive understanding of the overall outcome, such as the long-term safety, patient quality of life, and impact on healthcare costs, is necessary. Therefore, a shared decision-making with patients on a case-by-case basis is imperative.

A simple technique for repositioning of the mandible by a surgical guide prepared using a three-dimensional model after segmental mandibulectomy

Funayama, Akinori,Kojima, Taku,Yoshizawa, Michiko,Mikami, Toshihiko,Kanemaru, Shohei,Niimi, Kanae,Oda, Yohei,Kato, Yusuke,Kobayashi, Tadaharu Korean Association of Maxillofacial Plastic and Re 2017 Maxillofacial Plastic Reconstructive Surgery Vol.39 No.-

Background: Mandibular reconstruction is performed after segmental mandibulectomy, and precise repositioning of the condylar head in the temporomandibular fossa is essential for maintaining preoperative occlusion. Methods: In cases without involvement of soft tissue around the mandibular bone, the autopolymer resin in a soft state is pressed against the lower border of the mandible and buccal and lingual sides of the 3D model on the excised side. After hardening, it is shaved with a carbide bar to make the proximal and distal parts parallel to the resected surface in order to determine the direction of mandibular resection. On the other hand, in cases that require resection of soft tissue around the mandible such as cases of a malignant tumor, right and left mandibular rami of the 3D model are connected with the autopolymer resin to keep the preoperative position between proximal and distal segments before surgical simulation. The device is made to fit the lower border of the anterior mandible and the posterior border of the mandibular ramus. The device has a U-shaped handle so that adaptation of the device will not interfere with the soft tissue to be removed and has holes to be fixed on the mandible with screws. Results: We successfully performed the planned accurate segmental mandibulectomy and the precise repositioning of the condylar head by the device. Conclusions: The present technique and device that we developed proved to be simple and useful for restoring the preoperative condylar head positioning in the temporomandibular fossa and the precise resection of the mandible.