Comparative Study to Evaluate Efficacy and Safety When Metformin Hydrochloride 500 mg Once Daily is Added on to SYR-322 25 mg in Type 2 Diabetic Patients With Inadequate Glycemic Control Despite Treatment With SYR-322 25 mg in Addition to Diet and Exercise Therapy

The drugs being tested in this study are called alogliptin and metformin hydrochloride. Alogliptin in combination with metformin hydrochloride was being tested to treat people who have Type 2 diabetes mellitus (T2DM) with inadequate glycemic control despite treatment with alogliptin in addition to diet and exercise. This study looked at the efficacy and safety of alogliptin 25 mg once daily (QD) + metformin hydrochloride 500 mg QD compared to alogliptin 25 mg QD + metformin hydrochloride 250 mg twice daily (BID) and alogliptin 25 mg QD administered alone.

The study enrolled 374 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need):

• Alogliptin 25 mg QD + metformin hydrochloride 500 mg QD
• Alogliptin 25 mg QD + metformin hydrochloride 250 mg BID
• Alogliptin 25 mg QD

This multi-center trial was conducted in Japan. The overall time to participate in this study was 36 weeks (12-week screening period and 24-week treatment period). Participants made multiple visits to the clinic including a final visit 24 weeks after the start of study medication.

Inclusion criteria

• Has a diagnosis of type 2 diabetes mellitus.
• 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).
• 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).
• Has been on a certain diet therapy and exercise therapy (if any) during the screening period.
• Has been receiving alogliptin on a stable dose and regimen (after breakfast, 25 mg/day) during the screening period.
• 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).
• 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.
• 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.
• 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.
• Is treated in outpatient settings during the screening period.
• In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements.
• Signs and dates a written, informed consent form prior to the initiation of any study procedures.

Exclusion criteria

• Has received other antidiabetic drugs than alogliptin (including insulin preparations and glucagon-like peptidase-1 [GLP-1] analog preparations) during the screening period.
• Has clinical manifestations of hepatic impairment.
• Has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 × upper limit of normal during the screening period.
• Has clinical manifestations of renal impairment, including mild impairment.
• Has a history of lactic acidosis.
• 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.
• Has dehydration or gastrointestinal dysfunction such as diarrhea or vomiting, which may cause dehydrated state.
• Has malnutrition, starved state, hyposthenia, pituitary gland dysfunction or adrenal insufficiency.
• 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).
• 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.
• Has a systolic blood pressure ≥ 180 mmHg or a diastolic blood pressure ≥ 110 mmHg during the screening period.
• 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).
• Has any malignancy.
• Has a history of hypersensitivity or allergies to dipeptidyl-peptidase-4 (DPP-4) inhibitors or biguanides.
• Is a habitual drinker consuming more than 100 mL of alcohol on average daily.
• Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol dependence.
• Requires an excluded medication or a prohibited matter during the study.
• Has received combination therapy of alogliptin benzoate and metformin hydrochloride in a previous clinical study or as a therapeutic agent.
• Has received any investigational compound within 12 weeks prior to the start of the screening period (Week -12).
• Is a participant in another clinical study at the time of signing informed consent.
• 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.
• 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.
• Is considered ineligible for the study for any other reason by the investigator or subinvestigator.