A Phase 4, Randomized, Double-blind, Parallel-group, Comparative Study and a Phase 4, Open-label, Long-term Study of SYR-472 (100 mg) in Combination With Insulin in Patients With Type 2 Diabetes

The purposes of this study is to evaluate the efficacy and safety of SYR-472 when administered at a dose of 100 mg once weekly as an add-on to insulin therapy compared with placebo in patients with type 2 diabetes mellitus and inadequate glycemic control despite treatment with insulin preparations in addition to diet and/or exercise therapy; and to evaluate the long-term efficacy and safety of SYR-472 when administered at a dose of 100 mg once weekly as an add-on to insulin therapy in patients with type 2 diabetes mellitus and inadequate glycemic control despite treatment with insulin preparations in addition to diet and/or exercise therapy.

This is a phase 4, multicenter, randomized, double-blind, parallel-group, comparative study using placebo (Treatment Period I) and a phase 4, multicenter, open-label, long-term study (Treatment Period II) to evaluate the efficacy and safety of SYR-472 when administered at a dose of 100 mg as an add-on to insulin therapy in patients with type 2 diabetes mellitus and inadequate glycemic control despite treatment with insulin preparations in addition to diet and/or exercise therapy.

Eligibility Criteria:
Inclusion Criteria:

Participant eligibility is determined according to the following criteria:

1. The participant has a diagnosis of type 2 diabetes mellitus.
2. The participant has a fasting C-peptide level of 0.6 ng/mL or higher at the start of the screening period (Week -6) and Week -2 of the screening period.
3. The participant has a Haemoglobin A1c (HbA1c) value of 7.5% or higher but less than 10.0% at Week -2 of the screening period.
4. The participant has an HbA1c value difference between the start of the screening period (Week -6) and Week -2 of the screening period within 10.0%\* (\* rounded to one decimal place) of the HbA1c value at the start of the screening period (Week -6).
5. The participant has been on a fixed diet and/or exercise therapy (if any) from at least 6 weeks prior to the start of the screening period (Week -6).
6. The participant is being treated with insulin preparations alone (≥8 units/day and ≤40 units/day) \*\* from at least 6 weeks prior to the start of the screening period (Week -6) at a fixed dose and regimen of the insulin preparation.

   * The participant on any one of the following insulin monotherapies: mixed (rapid-acting or short-acting insulin containing no more than 30% volume), intermediate-acting, or long-acting soluble insulin preparations
7. The participant is deemed appropriate for treatment with a combination of insulin and another antidiabetic drug at the start of the screening period (Week -6) by the investigator or subinvestigator.
8. The participants with controlled and stable blood pressure will not need any change in the dose of antihypertensive drugs (including discontinuation and suspension) or additional antihypertensive drugs during the study period as assessed by the investigator or subinvestigator.
9. The participant is male or female and aged 20 years or older at the time of informed consent.
10. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent until one month after the end of the study.
11. In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements.
12. The participant signs and dates a written, informed consent form prior to the initiation of any study procedures.

Exclusion Criteria:

Any participant who meets any of the following criteria will not qualify for entry into the study:

1. The participants has clinical manifestations of hepatic impairment \[e.g., Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥2.5 times the upper limit of normal or total bilirubin of ≥2.0 mg/dL at the start of the screening period (Week -6) or at Week -2 of the screening period\].
2. The participant has moderate or severe renal impairment or end-stage renal failure \[e.g., creatinine clearance (Ccr) \<50 mL/min at the start of the screening period (Week -6) or Week -2 of the screening period\].
3. The participant has any serious cardiac diseases, cerebrovascular disorders, or serious pancreatic or hematological diseases (e.g., participants who require inpatient treatment or are hospitalized for treatment within 24 weeks prior to the start of the screening period).
4. The participant has, in the judgment of the investigator or subinvestigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at the start of the screening period (Week - 6) or Week -2 of the screening period.
5. The participant has a systolic blood pressure of 180 mmHg or higher or a diastolic blood pressure of 110 mmHg or higher during the screening period.
6. The participant is on at least two antidiabetic therapies other than one insulin preparation one day before 6 weeks prior to the start of the screening period (Week -6) (43 days prior to the start of the screening period).
7. The participants altered the dose and regimen of their insulin preparation within 6 weeks prior to the start of the screening period or during the screening period.
8. The participant experienced hypoglycemia (participants with a blood glucose level of ≤70 mg/dL or hypoglycemic symptoms) within 6 weeks prior to the start of the screening period or during the screening period (at least twice per week).
9. The participant has a fasting blood glucose level of 240 mg/dL or higher at the start of the screening period (Week -6) or at Week -2 of the screening period.
10. The participant has malignancies.
11. The participant has a history of hypersensitivity or allergies to dipeptidyl peptidase 4 (DPP-4) inhibitors or insulin preparations.
12. The participant has a history of gastrectomy or small intestinal resection.
13. The participant is habitual drinker consuming a daily average of more than 100 mL of alcohol.
14. The participant has a history of drug abuse (defined as the use of an illegal drug) or alcohol dependence.
15. The participant is required to take excluded medications during the study period.
16. The participant has received SYR-472 in a previous clinical study.
17. The participant is deemed to be in a condition contraindicating treatment as specified in the package insert of insulin preparations by the investigator or subinvestigator.
18. The participant received any investigational products (including study drugs in a post-marketing clinical study) within 12 weeks prior to the start of the screening period.
19. The participant is participating in other clinical studies at the time of informed consent.
20. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.
21. The participant is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
22. The participant is hospitalized during the screening period or deemed as requiring hospitalization during the study period by the investigator or subinvestigator, unless the hospitalization is for short-term evaluations including complete health checkups.
23. The participant is deemed to be ineligible for the study for any other reason by the investigator or subinvestigator.