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
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: SYR-472; Placebo
Intervention description: SYR-472 tablets; Placebo tablets
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 240.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Pharmacological therapy

Summary:

      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.
    

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.