Clinical trial NCT02068443 (phase 3, status: completed)
Conditions: type 2 diabetes mellitus
ICD codes: E11.65, E11.9, E11.21, E11.36, E11.41, E11.42, E11.44
Drugs: alogliptin, metformin hydrochloride, metformin hydrochloride placebo
SMILES: CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C=CC=C2)C#N)C1=O, CN(C)C(=N)NC(N)=N, CSCC[C@H](N)C(O)=O
Eligibility criteria:

        Inclusion Criteria:

          1. Has a diagnosis of type 2 diabetes mellitus.

          2. Has a hemoglobin A1c (HbA1c) (National glycohemoglobin standardization program [NGSP])
             of ≥6.9% to <10.5% at 8 weeks after the start of the screening period (Week -4).

          3. Has an HbA1c (NGSP) difference between 4 weeks after the start of the screening period
             (Week -8) and 8 weeks after the start of the screening period (Week -4) being within
             10.0% (rounded off to the first decimal place) of the value at 4 weeks after the start
             of the screening period (Week -8).

          4. Has been on a certain diet therapy and exercise therapy (if any) during the screening
             period.

          5. Has been receiving alogliptin on a stable dose and regimen (after breakfast, 25
             mg/day) during the screening period.

          6. In the opinion of investigator or subinvestigator, the participant is considered
             appropriate to receive a biguanide as an add-on to alogliptin, at the end of the
             screening period (Week 0).

          7. In the opinion of investigator or subinvestigator, the participant is unlikely to
             require changes in the dose of antihypertensive agents (including discontinuation and
             suspension) or an additional antihypertensive agent during the study.

          8. Is a male and female aged ≥20 years to <75 years. Participants aged ≥65 years to <75
             years need to be considered eligible for the enrollment by the investigator or
             subinvestigator at the end of the screening period (Week 0) taking into consideration
             the cardiovascular disorders pulmonary function disorders, renal function, hepatic
             function, etc.

          9. A female participant of childbearing potential who is sexually active with a
             nonsterilized male partner agrees to routinely use adequate contraception from signing
             of informed consent throughout the duration of the study.

         10. Is treated in outpatient settings during the screening period.

         11. In the opinion of the investigator or subinvestigator, the participant is capable of
             understanding and complying with protocol requirements.

         12. Signs and dates a written, informed consent form prior to the initiation of any study
             procedures.

        Exclusion Criteria:

          1. Has received other antidiabetic drugs than alogliptin (including insulin preparations
             and glucagon-like peptidase-1 [GLP-1] analog preparations) during the screening
             period.

          2. Has clinical manifestations of hepatic impairment.

          3. Has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 ×
             upper limit of normal during the screening period.

          4. Has clinical manifestations of renal impairment, including mild impairment.

          5. Has a history of lactic acidosis.

          6. Has any cardiovascular disease including shock, heart failure, myocardial infarction
             and pulmonary embolism, any serious pulmonary function disorder, or any other
             condition predisposing him/her to hypoxemia.

          7. Has dehydration or gastrointestinal dysfunction such as diarrhea or vomiting, which
             may cause dehydrated state.

          8. Has malnutrition, starved state, hyposthenia, pituitary gland dysfunction or adrenal
             insufficiency.

          9. Has any serious cardiac disease, any serious cerebrovascular disorder, or any serious
             pancreatic or hematological disease (eg, the participant requiring inpatient treatment
             or having been hospitalized for treatment within 24 weeks prior to the start of the
             screening period).

         10. In the opinion of the investigator or subinvestigator, the participant has clinically
             significant abnormal hematological parameters of hemoglobin, hematocrit, or
             erythrocytes during the screening period.

         11. Has a systolic blood pressure ≥ 180 mmHg or a diastolic blood pressure ≥ 110 mmHg
             during the screening period.

         12. Has a condition requiring insulin for blood glucose control (eg, severe ketosis,
             diabetic coma or precoma, type 1 diabetes, severe infection, pre- or post-operative
             condition, or serious trauma).

         13. Has any malignancy.

         14. Has a history of hypersensitivity or allergies to dipeptidyl-peptidase-4 (DPP-4)
             inhibitors or biguanides.

         15. Is a habitual drinker consuming more than 100 mL of alcohol on average daily.

         16. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
             dependence.

         17. Requires an excluded medication or a prohibited matter during the study.

         18. Has received combination therapy of alogliptin benzoate and metformin hydrochloride in
             a previous clinical study or as a therapeutic agent.

         19. Has received any investigational compound within 12 weeks prior to the start of the
             screening period (Week -12).

         20. Is a participant in another clinical study at the time of signing informed consent.

         21. If female, the participant is pregnant or lactating; intending to become pregnant
             between the time of signing informed consent and the end of the study; or intending to
             donate ova during such period.

         22. Is a study site employee, is its immediate family member, is in a dependent
             relationship with a study site employee who is involved in conduct of this study (eg,
             spouse, parent, child, sibling), or may consent under duress.

         23. Is considered ineligible for the study for any other reason by the investigator or
             subinvestigator.