title: SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  In patients with type 2 diabetes, improving adherence to medication is important in order to maintain favourable glycaemic control during long-term treatment and, thus, prevent the onset or aggravation of complications. SYR-472 is a novel once-weekly oral DPP-4 inhibitor for type 2 diabetes, which could be a treatment option when clinicians seek to improve medication adherence by reducing the number of required administrations. In this study, we assessed the efficacy and safety of SYR-472 in patients with type 2 diabetes.
  
  
  METHODS
  In this phase 2, multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging study, we included Japanese patients with inadequately controlled type 2 diabetes despite diet and exercise treatment. Patients were randomly assigned (allocation ratio 1:1:1:1:1:1) to receive either placebo or SYR-472 at five different doses (12·5 mg, 25 mg, 50 mg, 100 mg, or 200 mg). Randomisation was done with a permuted block schedule. All investigators and patients were unaware of the treatment assignment. Treatment drug was given orally once weekly for 12 weeks. The primary efficacy variable was the change in HbA1c concentration from baseline to the end of treatment. This study has been registered at the Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information: Japic CTI-090899.
  
  
  RESULTS
  322 patients were randomly assigned to receive placebo (55 patients) or SYR-472 at 12·5 mg (54 patients), 25 mg (52 patients), 50 mg (51 patients), 100 mg (55 patients) or 200 mg (55 patients). The least square (LS) mean change in HbA1c concentration from baseline was 0·35% (SE 0·068; -20 mmol/mol) for the placebo group, -0·37% (0·068; -28 mmol/mol) for the 12·5 mg group, -0·32% (0·070; -27 mmol/mol) for the 25 mg group, -0·42% (0·070; -28 mmol/mol) for the 50 mg group, -0·54% (0·068; -29 mmol/mol) for the 100 mg group, and -0·55% (0·069; -30 mmol/mol) for the 200 mg group. In general, HbA1c concentration decreased in a dose-dependent manner (trend test using contrast coefficients p<0·0001) and the reduction was significantly greater for all SYR-472 doses (p<0·0001 for each group) than for placebo. The incidence of treatment-emergent adverse events in each SYR-472 group was similar to that in the placebo group. The most common adverse event was nasopharyngitis in all groups. No episodes of hypoglycaemia defined by investigator occurred with any treatment during the study.
  
  
  CONCLUSIONS
  Once-weekly SYR-472 treatment produced clinically and statistically significant improvements in glycaemic control in patients with type 2 diabetes. It was well tolerated and might be a new treatment option for patients with this disease.
  
  
  BACKGROUND
  Takeda Pharmaceutical Company Limited.
authors.affiliation: Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: inagaki@metab.kuhp.kyoto-u.ac.jp.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Onouchi
authors.affiliation: Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sano
authors.affiliation: Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Funao
authors.affiliation: Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kuroda
authors.affiliation: Kawasaki Medical School, Okayama, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D006801:Humans; D008875:Middle Aged; D010919:Placebos; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010919:Placebos; D014498:Uracil; C000595449:trelagliptin