Circulation Reports Supplementary File Circ Rep 2019; 1: 347 – 351 doi: 10.1253/circrep.CR-19-0049

Rationale and Design of the CANONICAL Study ― Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Canagliflozin for Heart Failure With Preserved Ejection Fraction With Type 2 Diabetes Mellitus ―

Shu Kasama, MD, PhD; Tohru Masuyama, MD, PhD; Shiro Uemura, MD, PhD; Yukihito Sato, MD, PhD; Shinya Hiramitsu, MD, PhD; Izuru Masuda, MD, PhD; Kazuhiro Yamamoto, MD, PhD; Sei Komatsu, MD, PhD; Toshihisa Anzai, MD, PhD; Kunihiro Nishimura, MD, PhD; Tomoya Ueda, MD; Masato Kasahara, MD, PhD; Hiroyuki Tanaka, BSc; Yutaka Susuta, PhD; Yoshihiko Saito, MD, PhD Study Organization

Principal investigator Yoshihiko Saito: Nara Medical University

1. Steering committee Toshihisa Anzai (chairperson): Hokkaido University Graduate School of Medicine, Koichiro Kuwahara: Shinshu University School of Medicine, and Kenichi Tsujita: Kumamoto University Graduate School of Medical Sciences

2. Protocol committee Tohru Masuyama (chairperson): Hyogo College of Medicine, Shiro Uemura: Kawasaki Medical University, Sei Komatsu: Osaka Gyoumeikan Hospital, Yukihito Sato: Hyogo Prefectural Amagasaki General Medical Center, Shinya Hiramitsu: Hiramitsu Heart Clinic, Izuru Masuda: Takeda Hospital, and Kazuhiro Yamamoto: Tottori University

3. Study secretariat Masato Kasahara (person in charge): Nara Medical University Hospital

4. Independent monitoring committee Michihiro Yoshimura (chairperson): The Jikei Medical University School of Medicine, Masayuki Iwano: University of Fukui Hospital, Takeshi Kimura: Kyoto University Hospital, and Issei Komuro: The University of Hospital

5. Data management Masato Kasahara (person in charge): Nara Medical University Hospital

6. Statistical analysis Kunihiro Nishimura: National Cerebral and Cardiovascular Center, Masato Kasahara: Nara Medical University Hospital, CMIC Co., Ltd

7. Monitoring Miyoko Hasebe: Nara Medical University Hospital

8. Auditing Noriaki : CMIC Co., Ltd

9. Study sites and investigators Investigator Study site Department Nippon Medical School Musashi-Kosugi Department of Internal Medicine, 1 Naoki Sato Hospital Cardiology 2 Hiroshi Asano Tosei General Hospital Department of Cardiology 3 Koichiro Kuwahara Shinshu University School of Medicine Department of Cardiovascular Medicine Kumamoto University Graduate School of 4 Kenichi Tsujita Department of Cardiovascular Medicine Medical Sciences 5 Satoshi Yasuda National Cerebral and Cardiovascular Center Department of Cardiovascular Medicine 6 Yoshihiko Saito Nara Medical University Department of cardiovascular medicine Division of Cardiovascular Medicine, Endocrinology and Metabolism, 7 Kazuhiro Yamamoto Tottori University Department of Molecular Medicine and Therapeutics, Faculty of Medicine Cardiovascular Division, Department of 8 Masanori Asakura Hyogo College of Medicine Internal Medicine 9 Yasuchika Takeishi Fukushima Medical University Department of Cardiovascular Medicine 10 Shinya Hiramitsu Hiramitsu Heart Clinic 11 Katsuya Onishi Onishi Heart Clinic 12 Yasushi Sakata Osaka University Graduate School of Medicine Department of Cardiovascular Medicine 13 Ichiro Hamanaka Rakuwakai Marutamachi Hospital Department of Cardiology 14 Naofumi Doi Nara Prefecture Seiwa Medical Center Department of Cardiology 15 Manabu Horii Nara City Hospital Department of Cardiovascular Medicine 16 Yoshinobu Morikawa Minami-nara General Medical Center Division of Cardiovascular Medicine 17 Atsuyuki Wada Kusatsu General Hospital Cardiovascular Medicine 18 Tsutomu Yoshikawa Sakakibara Heart Institute Department of Cardiology 19 Yasuhiro Sakaguchi Sakaguchi Clinic 20 Takeshi Takami Clinic Jingu-mae 21 Akira Nakatani Nakatani Clinic 22 Yoshihiro Fujii Fujii Clinic 23 Toshio Sutani Sutani Clinic 24 Hiroyuki Sugimoto Sugimoto Clinic 25 Kuninori Kiriyama Kiriyama Clinic Hokkaido University Graduate School of 26 Toshihisa Anzai Department of Cardiovascular Medicine Medicine Gunma University Graduate School of 27 Noriaki Takama Department of Cardiovascular Medicine Medicine 28 Sei Komatsu Osaka Gyoumeikan Hospital Cardiovascular Center 29 Kenji Nagae Takanohara Central Hospital Department of Cardiology 30 Masafumi Nakayama Nakayama Cardiovascular Clinic 31 Fumitaka Inoue Yamato Kashihara Hospital Department of Cardiovascular Medicine 32 Kazuhiro Ueshima Yamato Takada Municipal Hospital Department of Cardiovascular Medicine 33 Hiroyuki Kawata Nara Prefecture General Medical Centar Department of Cardiovascular Medicine 34 Hirokazu Sakan Shirakashi Clinic

Testing Items and Measurements

The following data will be collected according to the schedule in Table 1 in the text; patient characteristics, treatment compliance, use of prohibited or restricted concomitant medications, height, body weight, BMI, blood pressure, heart rate, chest X-ray images, echocardiography, blood tests, urinalysis, cardiovascular events, electrocardiogram results, and AEs.

Patient characteristics Patient characteristics includes sex, age, duration of diabetes and heart failure, complication, height, body weight, BMI and severity of heart failure (NYHA classification).

Echocardiography LV ejection fraction, E/e’, LV mass index, and LA volume index will be measured using echocardiography.

Blood test Blood tests will be performed as a centralized laboratory using blood samples collected before breakfast in the morning. Blood tests 1 includes plasma aldosterone level, plasma renin activity, osteocalcin, and ICTP. Blood tests 2 includes plasma BNP, plasma NT-proBNP, HbA1c, fasting blood glucose, WBC, RBC, hemoglobin, hematoclit, MCV, MCH, MCHC, platelet, differential WBC, total protein, albumine, BUN, serum creatinine, serum uric acid, eGFR, AST, ALT, ALP, gamma-GTP, triglyceride, HDL-C, LDL-C, creatine kinase, Na, K, Mg, Cl, Ca, P, ketone bodies fractionation, FT3, FT4, and TSH. eGFR will be calculated using following formula proposed by Japanese Society of Nephrology: Male: eGFR = 194 x Cr-1.094 x age-0.287 (mL/min/1.73m2) Female: eGFR = 194 x Cr-1.094 x age-0.287 x 0.739 (mL/min/1.73m2)

Urine tests Urine sampling will be performed before breakfast (drug can be taken) in the morning at the study institution. Urine tests includes qualitative test (protein, glucose, urobilinogen, bilirubin, ketones, and occult blood) and specific gravity

Adverse events An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, or disease, including any abnormal laboratory value that occurs during the treatment period. AEs will be identified by investigators based on laboratory values and patient-reported events at each visit. The date of onset, severity, treatment for the AE, the causal relationship with canagliflozin or other drugs, the outcome, and classification using the Medical Dictionary for Regulatory Activities/Japanese edition (MedDRA/J) will be recorded for each AE．If a patient is discontinued during the treatment period, a follow-up AE assessment should be performed at the end of the treatment period.

Potential Conflicts of Interest

SK has received research funding from Mitsubishi Tanabe Pharma Corporation. TM has received consulting fees and/or honoraria for lectures from Mitsubishi Tanabe Pharma Corporation and Co., Ltd. and research funding from Amgen Astellas BioPharma K.K., AstraZeneca K.K., Cook Inc., Daiichi Sankyo Co., Ltd., Japan Lifeline Co., Ltd., Johnson & Johnson K.K., Medtronic Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Shinyaku Co., Ltd., St. Jude Medical Japan Co., Ltd., Corporation, and W. L. Gore & Associates, Inc. and scholarship grants from Actelion Pharmaceuticals Japan Ltd., Inc., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Fukuda Denshi Co., Ltd., Kowa Pharmaceutical Co., Ltd., Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Nippon Shinyaku Co., Ltd., Novartis Pharma K.K., Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanwa Kagaku Kenkyusho Co., Ltd., & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd. and Pharma Ltd. and belongs to endowed departments by Abbott Medical Japan Co., Ltd., Boston Scientific Japan K.K., Cardinal Health Japan, Medicon, Inc., Medtronic Japan Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., St. Jude Medical Japan Co., Ltd., Takeda Pharmaceutical Co., Ltd. and Zeon Medical Inc. SU has received consulting fees and/or honoraria for lectures from Abbott Vascular Japan Co., Ltd., Astellas Pharma Inc., Bayer Yakuhin, Ltd., and Daiichi Sankyo Co., Ltd., and research funding from Daiichi sankyo Co.,Ltd. and Mitsubishi Tanabe Pharma Corporation and scholarship grants from Abbott Vascular Japan Co., Ltd., Daiichi Sankyo Co., Ltd., KAKEN PHARMACEUTICAL CO., LTD., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., Shionogi&Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharma Co., Ltd., and Takeda Pharmaceutical Co., Ltd. YS has received consulting fees and/or honoraria for lectures from Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. and research funding from Mitsubishi Tanabe Pharma Corporation and Otsuka Pharmaceutical Co., Ltd. SH has received consulting fees and/or honoraria for lectures from Bayer Yakuhin, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K. and Takeda Pharmaceutical Co., Ltd. and research funding from Mitsubishi Tanabe Pharma Corporation. IM has received consulting fees and/or honoraria for lectures from Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo Co., Ltd., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Ono Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. and research funding from Mitsubishi Tanabe Pharma Corporation. KY has received consulting fees and/or honoraria for lectures from Boehringer Ingerlheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Pfizer Inc. and research funding from Mitsubishi Tanabe Pharma Corporation and scholarship grants from Abbott Japan Co., Ltd., Biotronik Japan, Inc., Boston Scientific Corporation, Daiichi Sankyo Co., Ltd., Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., Kowa Pharmaceutical Co. Ltd., LifeScan Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd. SK is a consultant for Nemoto Kyorindo Co., Ltd. and has received research funding from Mitsubishi Tanabe Pharma Corporation. TA has received consulting fees and/or honoraria for lectures from Bayer Yakuhin, Ltd., Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Co., Ltd., Sanofi Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Toa Eiyo Ltd., and research funding from Mitsubishi Tanabe Pharma Corporation and belongs to endowed departments by Biotronik Japan, Inc., Hokuyaku Takeyama Holdings, Inc., Medical System Network Co., Ltd., Medtronic Japan Co., Ltd., and Win International Co., Ltd. KN has received research funding from Daiichi Sankyo Co., Ltd., Miraca Holdings Inc., Mitsubishi Tanabe Pharma Corporation, and Philips Japan Corporation. TU has received research funding from Mitsubishi Tanabe Pharma Corporation. MK is an advisor for Reason Why Inc. and has received consulting fees and/or honoraria for lectures from Baxter Ltd., Daiichi Sankyo Co., Ltd., Fujifilm Corporation, Fuji Yakuhin Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., and Teijin Pharma Ltd., and research funding from Daiichi Sankyo Co., Ltd., Fuji Yakuhin Co., Ltd. and Mitsubishi Tanabe Pharma Corporation, and scholarship grants from Daiichi Sankyo Co., Ltd. and belongs to endowed departments by Co., Ltd. HT and YS are employees of Mitsubishi Tanabe Pharma Corporation. YS is a consultant for Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., and Ono Pharmatical Co., Ltd., and has received consulting fees and/or honoraria for lectures from Amgen Astellas BioPharma K.K., AstraZeneca K.K., Bayer Holding Ltd., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co., Ltd., Medtronic, Inc., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., MSD K.K., Nippon Shinyaku Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Otsuka Pharmaceutical Co., Ltd., Siemens Healthcare Diagnostics K.K., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., and research funding from Mitsubishi Tanabe Pharma Corporation and scholarship grants from Astellas Pharma Inc., Bayer Holding Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Fuji Yakuhin Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Nihon Medi-Physics Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Prizer Japan Inc., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., The Japan Agency for Medical Research and Development, The Japan Society for the Promotion of Science, and The Ministry of Health, Labour and Walfare Scientific Research.