Conflict of Interest T. HISAMATSU. Honoraria: EA pharma Co. Ltd., AbbVie GK, Celgene K.K., Janssen Pharmaceutical K.K., Pfizer Inc., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Mochida Pharmaceutical Co., Ltd., Nichi-lko Pharmaceutical Co., Ltd. Commercial research funding: EA pharma Co. Ltd., AbbVie GK, Daiichi-Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co., Ltd, Nippon Kayaku Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Mochida Pharmaceutical Co., Ltd., Astellas Pharma Inc., Asahi Kasei Medical Co., Ltd., ZERIA Pharmaceutical Co. Ltd. S. KATO. Honoraria: Mistubishi Tanabe Pharma Corporation , Janssenn Pharma K,K. R. KUNISAKI. Honoraria: AbbVie GK, EA pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Nioppon Kayaku Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd., ZERIA Pharmaceutical Co. Ltd. Commercial research funding: AbbVie GK, EA pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Corporation, RPM Co. Ltd, Takeda A-Pharmaceutical1256 Co. Ltd. M. MATSUURA. Honoraria: AbbVie GK, Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Nioppon Kayaku Co. Ltd., Kissei Pharmaceutical Co. Ltd. Commercial research funding: AbbVie GK, Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., Mochida Pharmaceutical Co., Ltd., Nioppon Kayaku Co. Ltd., JIMRO Co. M. NAGAHORI. Honoraria: Kissei Pharmaceutical Co. Ltd., WithdrawalTakeda Pharmaceutical Co. Ltd., Kyorin ofPharmaceutical thiopurines Co. Ltd., Mochida Pharmaceutical Co.,in Ltd., AbbVieCrohn’s GK, Mitsubishi Tanabe Pharmadisease Corporation, Nioppon Kayaku Co. Ltd., Asahi Kasei Medical Co., Ltd., ZERIA Pharmaceutical Co. Ltd., Astellas Pharma Inc., Nichi-lko Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. S. MOTOYA. Honoraria: Eisai Corporation, AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Corporation, Mochida Pharma Corporation, Janssen Pharmaceutical K.K. M. treatedESAKI. Honoraria: AbbVie, with Mitsubishi Tanabe scheduled Pharma Corporation. Commercial adalimumab research funding: EA pharma Co. Ltd., AbbVie maintenance GK, Mitsubishi Tanabe Pharma Corporation. N. FUKATA. NO Conflict of Interest. S. INOUE. NO Conflict of Interest. T. SUGAYA. Conflict of Interest. H. SAKURABA. Commercial research funding: Bristol-Myers Squibb, AbbVie GK, MSD Inc., Daiichi-Sankyo Co. Ltd., ZERIA Pharmaceutical Co. Ltd. F. HIRAI. Honoraria: EA Pharma CO. Ltd, AbbVie GK, Mitsugishi Tanabe Pharma, Eisai CO.,Ltd. A Kprospective. WATANABE. Honoraria: EA Pharma Co.randomized Ltd., AbbVie, Mitsubishi Tanabe Pharma clinical Corporation, Kyorin trialPharmaceutical (DIAMOND2) Co. Ltd., JIMRO Co. Ltd., Mochida Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K, Takeda Pharmaceutical Co. Ltd. Commercial research funding: EA Pharma Co. Ltd., AbbVie, Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Astellas Pharma Inc. T. KANAI. Honoraria: EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., Yakult Honsha Co., Ltd., ZERIA Pharmaceutical Co. Ltd., Miyarisan Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co. Ltd. Commercial research funding: Eisai Corporation, JIMRO Co. Ltd., Nippon Kayaku Co. Ltd., Daiichi-Sankyo Co. Ltd., Tsumura & Co., Taiho Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., EN Otsuka Pharmaceutical Co. Ltd., Ezaki Glico Co. Ltd., RPM Co. Ltd., Yakult Bio-Science Foundation.Hisamatsu M. NAGANUMA. HonorariaT, Kato: EA Pharma Co.S, Ltd. Kunisaki Commercial research funding:R, MatsuuraEA Pharma Co. Ltd., ZERIA, M, Mochida Nagahori Pharmaceutical CO. Ltd.M, H. NAKASE. Honoraria: Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical CO. Ltd., Janssen Pharmaceutical K.K, Abbvie GK. Commercial research funding: Hoya group PentaxMotoya Medical. BoehringerS,Ingelheim EsakiGmbH, DatichoM, -SankyoFukata Co. Ltd. Y. SUZUKI.N, Inoue Honoraria: AbbVieS ,GK, Sugaya Mitsubishi Tanabe PharmaT, SakurabaCorporation, ZERIA PharmaceuticalH, Co. Ltd., Mochida Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., EA pharma Co. Ltd., Janssen Pharmaceutical K.K. Commercial research funding: AbbVie GK, Mitsubishi TanabeHirai Pharma Corporation, F, Watanabe EA pharma Co. Ltd., JIMRO K, Co. Kanai Ltd., Mochida PharmaceuticalT, Naganuma Co. Ltd., Nippon KayakuM, Co. Ltd.,Nakase KISSEI. M. WATANABE. H, Suzuki Honoraria: Mitsubishi Tanabe Pharma Corp., Eisai Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., AbbVie GK, Takeda Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., ZERIA PharmaceuticalY, Watanabe Co. Ltd., Asahi Kasei MedicalM, Co.Hibi Ltd., EA PharmaT, Nojima Co. Ltd., Astellas PharmaM, Inc., Matsumoto Mochida Pharmaceutical Co. T, Ltd., Janssen Pharmaceutical Co. Ltd., Gilead Sciences, Inc., Celgene Corp., Kissei Pharmaceutical Co. Ltd. Commercial research funding: Asahi Kasei Medical Co. Ltd., AbbVie GK, EA Pharma Co. Ltd., Eisai Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., ZERIA Pharmaceutical Co. Ltd., JIMRO Co. Ltd., TakedaDIAMOND2study Pharmaceutical Co. Ltd., Nippon Kayaku Co.group Ltd., Mochida Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Astellas Pharma Inc., MSD K.K., Dainippon Sumitomo Dainippon Pharma Co. Ltd., Bristol-Myers, K.K, Chugai Pharmaceutical Co. Ltd., Gilead Sciences Inc., Pfizer Inc., Miyarisan Pharmaceutical Co. Ltd., Kissei Pharmaceutical Co. Ltd.,Bella Taiho Pharmaceutical Center Co. Ltd., T.Center HIBI. HonorariaBlvd.: Mitsubishi Tanabe5, 2300 Pharma CO., Copenhagen, AbbVie GK, EA Pharma Co., Ltd. Denmark, M. NOJIMA. NO Conflict of Interest. T. MATSUMOTO. Honoraria: Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Janssen Pharmaceutical K.K., Commercial research funding: Mitsubishi TanabeMarch Pharma Corporation, 07 2019 EA pharma Co. Ltd., Nippon Kayaku Co. Ltd. Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance A prospective randomized clinical trial (DIAMOND2) Aims: We aimed to study the influence of withdrawal of thiopurines in CD patients in corticosteroid free clinical remission with adalimumab scheduled maintenance combined with thiopurines in an open label, randomized, controlled trial (DIAMOND2; UMIN000009596). Study design • A prospective, randomized, multicenter, open-labeled clinical trial • Superiority study to reveal a clear benefit of continuation of thiopurines >6 months over scheduled ADA monotherapy Primary endpoint: corticosteroid free clinical remission at 52W. Randomization 0 W 52 W CD Patients in steroid free ＋ clinical remission for at least Continue group (ADA thiopurines) 6 months with ADA scheduled maintenance combined with Discontinue group (ADA) thiopurines Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance A prospective randomized clinical trial (DIAMOND2) Demographic and clinical Continue Discontinue P value [n=22] [n=28] characteristics of the patients Demographics Woman 4[18.2%] 6[21.4%] 1.000 Age [years]average ±SD) 35±11 35±14 0.947 Patients with CD who were in corticosteroid-free Disease duration [month] 97.6±67.8 87.9±75.5 0.635 Disease location 0.758 clinical remission (CFCR)(CDAI<150) with Ileitis 4 [18.2%] 4 [14.3%] concomitant use of thiopurines with scheduled Ileocolitis 14 [63.6%] 20 [71.4%] maintenance of ADA for ≥6 months were Colitis 4 [18.2%] 4 [14.3%] Internal fistula 1 [4.5%] 1 {[3.6%] 1.000 enrolled. Perianal lesion 3 [13.6%] 3 [11.1%] 1.000 Previous surgical resection 0.048 Patients contraindicated for ADA or thiopurines, 0 13 [59.1%] 20 [71.4%] 1 or more 9 [40.9%] 8 [28.6%] those with pregnant or breast feeding, those Current smoking 5 [22.7%] 5 [19.2%] 0.647 with a malignant neoplasm, those with an Previous IFX use 8 [36.4%] 3 [10.7%] 0.042 ileostomy or colostomy, or those inappropriate Medication at entry 5-ASA 8[36.4%] 5[17.9%] 0.197 for clinical trials were excluded. Elemental diet 13[59.1%] 18[64.3%] 0.774 Duration of ADA [month] 36.6±29.3 23.7±9.7 0.048 C-reactive protein [mg/dl] 0.12±0.29 0.15±0.26 0.694 6-TGN 306.1±190.8 327.5±218.6 0.728 Data are n [%] or mean ± standard deviation. Positive of AAA 1 [4.5%] 3[10.7%] 0.621 IFX, infliximab; 5-ASA, 5-aminosalicylic acid; ADA, CDAI 49.43±33.06 50.92±29.01 0,866 adalimumab; 6-TGN, 6-thioguanine nucleotide; AAA, anti- SES-CD 5.46±5.66 4.39±4.04 0.450 adalimumab antibody; CDAI, Crohn’s disease activity index; 0.771 SES-CD, Simple Endoscopic Score for Crohn’s disease Mucosal healing (SES-CD≤2) 14 [63.6%] 15 [57.7%] Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance A prospective randomized clinical trial (DIAMOND2) Primary endpoint Corticosteroid Free Clinical Remission (CFCR) at 52W

100 P=1.000 B. 割付 90 1.0 A ConB 80 A-censored B-censored 70 0.8 Dis 60 log-rank P=0.704 0.6 50

40 95.5 % 92.3 % 0.4 Cum Survival 30

20 0.2 10 remission rate remissionrate

0 clinicalCumulative 0.0

Clinical remission at week 52 (%) rate Con Dis Con Dis 0 10 20 30 40 50 60 time (N=22) (N=28) Time (Week) Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance A prospective randomized clinical trial (DIAMOND2) Endoscopic remission Negative CRP Triple remission (SES-CD≤2) (CRP<0.10 mg/dl) (CFCR, ER, N-CRP) 50 100 P=0.711 50 40 80 P=1.000 40 P=0.750 30 60 30

20 40 20 76.2 84.6 10 30 32 20 10 22.7 28.6

patients(%) 0 0 0 Proportion of Proportion Con Dis Con Dis Con Dis Con Dis Con Dis Con Dis (n=20) (n=25) (n=21) (n=26) (n=22) (n=28) ADA trough level AAA positivity 12 50

10 40 8 P=0.515 30 6 P=0.437 20 4 2 7.08 6.48 10 10.0 20.0 0 0 g/mL) Con Dis Con Dis µ ADA trough ADA trough level Proportion patients Proportion of with AAA positive (%) ( Con Dis Con Dis (n=20) (n=25) (n=20) (n=25) Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance A prospective randomized clinical trial (DIAMOND2) SummaryAcknowledgements of results • Continuation of thiopurines >6 months offers no clear benefit over scheduled ADA monotherapy in Thepatients authors who were are in grateful corticosteroid to members-free clinical remissionof DIAMOND2 with concomitant study groupuse of thiopurines; with scheduledKatsuya Endo maintenance (Tohoku University), of ADA Motohiro for ≥6 Esaki months. (Kyushu University), Hiroyuki Hanai (Hamamatsu South Hospital), Taku Kobayashi and Toshifumi Hibi (Kitasato University Kitasato Institute Hospital), Sakiko Hiraoka (Okayama University), Tadakazu Hisamatsu (Kyorin University), Yutaka Honda (Niigata University), Satoko Inoue (Kobe City Medical Center General Hospital), • CFCR,Takuya ER,Inoue and (Osaka ADA Medical trough College), level Shuji at week Inoue 52(Kochi were National not Hospital),significantly Tetsuya different Ishida (Ishida between Clinic ofContinue IBD and and DiscontinueGastroenterology), groups. Hiroaki Ito (Kinshukai Infusion Clinic), Ryuichi Iwakiri (Saga University), Motoyoshi Izumi (Machida Municipal Hospital), Takashi Kagaya (Kanazawa University), Noriko Kamata (Osaka City University), Makoto Naganuma and Takanori Kanai (Keio University), Yumiko Naganawa, Hiroyuki Kaneto (Muroran City General Hospital), Kazuhito Kani and LimitationsShingo Kato (Saitama Medical University), Fukunori Kinjyo (Ryukyu University), Reiko Kunisaki (Yokohama City University Medical Center), Hiroki Yasaka and Koichi Kurahara (Matsuyama Red Cross Hospital), Lee Kyouwon (Moriguchikeijinkai • TheHospital), actual Yutaka number Yano, ofFumihito registered Hirai and cases Toshiyuki in the Matsui DIAMOND2 (Fukuoka University was lower Chikushi than Hospital), that in Takayuki the schedule, Matsumoto so our (Iwate Medical University), Hiroki Tanaka and Satoshi Motoya (Sapporo Kosei General Hospital), Yoshinori Munemoto (Fukui- studyken Saiseikai was under Hospital),-powered Yuji Naito statistically. (Kyoto Prefectural University of Medicine), Tomoo Nakagawa (Chiba University), Yoko Yokoyama, Kenji Watanabe and Shiro Nakamura (Hyogo College of Medicine), Hiroshi Nakase (Sapporo Medical University, • WeSchool assumed of Medicine), the superiorityMasanori Nojima of (Thecontinuation University of of Tokyo), thiopurines. Norimasa The Fukata DIAMOND2 and Kazuichi wasOkazaki not (Kansai powered Medical to demonstrateUniversity), Sachiko subtle Ouchi differences (Steel Memorial in clinical Hirohata benefit Hospital), between Hirotake Sakuraba the two (Hirosaki groups. University), Masayuki Saruta (The Jikei University School of Medicine), Makoto Sasaki (Aichi Medical University), Takeshi Sugaya (Japan Red Cross Ashikaga Hospital), Yasuo Suzuki (Toho University Sakura Medical Center), Fuminao Takeshima (Nagasaki University), Hiroyuki Tamaki • The(Takamatsu observation Red Cross period Hospital), of the Shinji DIAMOND2 Tanaka (Hiroshima was 52University), weeks. Satoshi We may Tanida have and missedTsutomu Mizoshitathe disadvantage (Nagoya City of withdrawalUniversity), Keiichiof thiopurines Tominaga (Dokkyo in this Medical observation University), period Masakazu if it Nagahori had a gradualand Mamoru influence. Watanabe Long(Tokyo- term,Medical and extensiveDental University), observation Masaki Yamashitaof patients (St. enrolledMarianna University in the DIAMOND2 School of Medicine), should Atsushi provide Yoshida the (Ofuna risk ofCentral withdrawal Hospital), of and Naoki Yoshimura (Tokyo Yamate Medical Center). thiopurines in ADA maintenance in CD.