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Title Long-Term Safety and Efficacy of a Novel Once-Weekly Oral Trelagliptin As Monotherapy Or in Combination with an Existing O

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Title Long-Term Safety and Efficacy of a Novel Once-Weekly Oral Trelagliptin As Monotherapy Or in Combination with an Existing O Long-term safety and efficacy of a novel once-weekly oral trelagliptin as monotherapy or in combination with an existing Title oral antidiabetic drug in patients with type 2 diabetes mellitus: A 52-week open-label, phase 3 study Inagaki, Nobuya; Sano, Hiroki; Seki, Yoshifumi; Kuroda, Author(s) Shingo; Kaku, Kohei Citation Journal of Diabetes Investigation (2016), 7(5): 718-726 Issue Date 2016-09 URL http://hdl.handle.net/2433/215204 © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd; This is an open access article under the terms of the Creative Commons Right Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Type Journal Article Textversion publisher Kyoto University CLINICAL TRIAL Long-term safety and efficacy of a novel once- weekly oral trelagliptin as monotherapy or in combination with an existing oral antidiabetic drug in patients with type 2 diabetes mellitus: A 52-week open-label, phase 3 study Nobuya Inagaki1*, Hiroki Sano2,YoshifumiSeki2, Shingo Kuroda2, Kohei Kaku3 1Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, 2Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, and 3Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan Keywords ABSTRACT Long-term safety and efficacy, Aims/Introduction: Trelagliptin is a novel once-weekly oral dipeptidyl peptidase-4 inhi- Trelagliptin, Type 2 diabetes mellitus bitor for type 2 diabetes mellitus that was first approved in Japan. We evaluated long- term safety and efficacy of trelagliptin in Japanese patients with type 2 diabetes mellitus. *Correspondence Materials and Methods: This was a phase 3, multicenter, open-label study to evaluate Nobuya Inagaki long-term safety and efficacy of trelagliptin. Patients with type 2 diabetes mellitus inade- Tel.: +81-75-751-3562 quately controlled despite diet/exercise or treatment with one of the existing oral antidia- Fax: +81-75-771-6601 betic drugs along with diet/exercise received trelagliptin 100 mg orally once weekly for E-mail address: [email protected]. 52 weeks as monotherapy or combination therapies. The primary end-points were the kyoto-u.ac.jp safety variables, and the secondary end-points were glycosylated hemoglobin and fasting J Diabetes Investig 2016 plasma glucose. Results: A total of 680 patients received the following antidiabetic therapies: trelagliptin doi: 10.1111/jdi.12499 monotherapy (n = 248), combination with a sulfonylurea (n = 158), a glinide (n = 67), an a-glucosidase inhibitor (n = 65), a biguanide (n = 70), or a thiazolidinedione (n = 72). Dur- Clinical Trials Registry ing the study, 79.8% of the patients experienced at least one adverse event for monother- ClinicalTrials.gov apy, 87.3% for combination with a sulfonylurea, 77.6% for a glinide, 81.5% for an a- NCT01431807 glucosidase inhibitor, 64.3% for a biguanide, and 84.7% for a thiazolidinedione, respectively. Most of the adverse events were mild or moderate. The change in glycosylated hemoglo- bin from baseline at the end of the treatment period was -0.74 to -0.25% for each ther- apy. Conclusions: Once-weekly oral trelagliptin provides well-tolerated long-term safety and efficacy in both monotherapy and combination therapies in Japanese patients with type 2 diabetes mellitus. – INTRODUCTION mellitus4 7. Drug regimens with reduced dosing frequency are As hyperglycemia is the key determinant factor in micro- and often preferred by patients, and could result in improved treat- – macrovascular complications of type 2 diabetes mellitus, it is ment compliance5 9. Dipeptidyl peptidase-4 (DPP-4) inhibitors important to maintain long-term glycemic control to prevent are prescribed to patients with type 2 diabetes mellitus, with – and delay the onset and development of complications1 3. administration once or twice a day. Adherence to treatment is often poor in patients with chronic, Trelagliptin succinate (trelagliptin) is a novel long-acting, potentially asymptomatic diseases, such as type 2 diabetes highly selective DPP-4 inhibitor that is available as a once- – weekly oral dosing regimen10 12. In a phase 1 study, the pro- fi Received 1 November 2015; revised 28 January 2016; accepted 9 February 2016 le of single doses of trelagliptin supported once-weekly ª 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. No. 2016 1 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. CLINICAL TRIAL Inagaki et al. http://onlinelibrary.wiley.com/journal/jdi dosing, and showed sustained inhibition of DPP-4 for Procedures 7days10. The results of a phase 2 placebo-controlled study After a 2-week screening period, eligible patients received showed that trelagliptin once a week for 12 weeks produced a 100 mg of oral trelagliptin once a week. For the combination dose-dependent improvement in glycemic control11.Ina therapygroup,patientswhohadbeenusinganexistingoral phase 3 study, 24-week treatment with once-weekly oral tre- antidiabetic drug according to the package insert of the drug at lagliptin at a dose of 100 mg showed non-inferiority of tre- a stable dose and regimen for at least 10 weeks (14 weeks for lagliptin to once-daily DPP-4 inhibitor alogliptin with thiozolidinedione) before the start of the screening period were favorable safety and tolerability profiles, which were also com- enrolled and continued to receive the same antidiabetic drug in parable with those of alogliptin12. addition to trelagliptin until the end of the study. We moni- The present study was designed to evaluate the long-term tored the patients’ compliance with diet and exercise through- safety and efficacy of once-weekly oral trelagliptin when adminis- out the study by assigning all patients to one of the following tered alone or in combination with an existing oral antidiabetic categories of compliance with diet and exercise sessions: fully drug for 52 weeks in patients with type 2 diabetes mellitus. complied (≥90% for diet and exercise sessions); almost com- plied (≥70%); occasionally complied (≥50%); and rarely com- MATERIALS AND METHODS plied (<50%). We assessed drug compliance through analysis of Study design and patients the records of the administration date of trelagliptin, and the This was a long-term, multicenter, open-label phase 3 study to number of drugs prescribed and collected for each basal oral evaluate the safety and efficacy of once-weekly oral trelagliptin antidiabetic drug. No rescue therapy was planned. as monotherapy or in combination with an existing oral antidi- Patients were assessed for safety and efficacy parameters at abetic drug in Japanese patients with type 2 diabetes mellitus 2-week intervals from the end of screening (i.e., baseline, with inadequate glycemic control despite diet and exercise ther- week 0) to week 4, and then every 4 weeks until the end of apies or treatment with one of the existing oral antidiabetic treatment (week 52), with a final follow-up visit 1 week later. drugs along with diet and exercise therapies. Patients consid- At each assessment, we measured the following: safety variables, ered eligible according to the inclusion and exclusion criteria including adverse events (AEs); vital signs; 12-lead ECG find- during the 2-week screening period received one tablet of tre- ings; clinical laboratory test data and self-measured blood glu- lagliptin 100 mg orally once weekly before breakfast for cose (only for patients who received combination therapy with 52 weeks during the treatment period. asulfonylurea);HbA1c, fasting plasma glucose (FPG); fasting We enrolled patients aged 20 years and older who had been insulin; fasting glucagon; glycoalbumin; weight; homeostasis given a diagnosis of type 2 diabetes mellitus; who had glycosy- model assessments of insulin resistance (HOMA-IR) and b-cell lated hemoglobin (HbA1c) values between 6.9% and 10.5% at function (HOMA-b); and DPP-4 activity. All samples for clini- the beginning of the screening period; who had been on speci- cal laboratory tests were obtained before drug dosage. fic diet and exercise therapies for at least 10 weeks before the All clinical laboratory tests were carried out at an indepen- start of screening. The inclusion criteria for the patients who dent central laboratory (LSI Medience Corporation, Tokyo, only received long-term combination therapy included the fol- Japan). HbA1c was converted from Japan Diabetes Society val- lowing: use of an existing oral antidiabetic drug at a stable dose ues (%) into National Glycohemoglobin Standardization Pro- and a regimen from at least 10 weeks (14 weeks for thiazo- gram values (%) using the following calculation: National lidinedione) before the start of screening. In the present study, Glycohemoglobin Standardization Program HbA1c fi = 9 + the basal antidiabetic drug was de ned as an existing oral (%) 1.02 Japan Diabetes Society HbA1c (%) 0.25%. antidiabetic drug that the patient was receiving at the beginning DPP-4 activity was measured
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