Safety and Efficacy of Once-Daily KRP-104 in Type 2 Diabetic Patients That Cannot Control Their Diabetes on Metformin Alone (Synergy 104)

Inclusion Criteria:

Patients meeting the following criteria at the screening visit (Visit 1) will be eligible to participate in the trial:

1. Signed written informed consent;
2. Males and females 18 to 75 years of age, inclusive;
3. Females of childbearing potential must agree to use 2 adequate forms of barrier method contraception (eg, latex condom AND intrauterine device or a diaphragm) to avoid pregnancy while in the study;

4. On a stable dose (Greater than or equal to 10 weeks at the same dose) of metformin monotherapy (Less than or equal to 1500 mg/day or maximum tolerated dose), have an HbA1c greater than or equal to 7.0% and less than or equal to 10.5%; or

   • On metformin (less than or equal to 1500 mg/day) and 1 other antidiabetic agent (excluding TZD, insulin, or incretin therapies [DPP-4 inhibitors and GLP-1 analogues]) and have an HbA1c greater than or equal to 6.8% and less than or equal to 10.0%; or
   • Not on antidiabetic therapy (for at least 3 months prior to Visit 1) or have not been on a stable dose of metformin monotherapy for 10 weeks and have an HbA1c greater than or equal to 8.0% and less than or equal to 11.0%.

Exclusion Criteria:

1. History of type 1 diabetes mellitus or history of diabetic ketoacidosis or persistent hypoglycemia;
2. History or presence of alcoholism or drug abuse within the 2 years prior to dosing;
3. Typical consumption of greater than or equal to 10 drinks of alcohol weekly;

4. Presence of any of the following conditions:

   • Significant renal impairment (glomerular filtration rate less than 60 mL/min);
   • Diabetic gastroparesis;
   • Active liver disease (other than asymptomatic nonalcoholic fatty liver disease), cirrhosis, or symptomatic gallbladder disease;
5. Fasting plasma glucose/blood glucose greater than 240 mg/dL (13.3 mmol/L) at Visit 3 (Week -2) (1 laboratory retest permitted);
6. Body mass index less than or equal to 20 kg/m2 and greater than or equal to 48 kg/m2;
7. Systolic blood pressure <100 mmHg or >160 mmHg and diastolic blood pressure <50 mmHg or >100 mmHg at Visit 3 (Note: medication to control blood pressure is allowed and should be optimized and stabilized prior to Visit 3);
8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 X the upper limit of normal (ULN) (1 laboratory retest permitted);
9. Creatine phosphokinase (CPK) greater than 2 X the ULN (if not explained by muscular trauma or exercise) (1 laboratory retest permitted);
10. Serum creatinine >1.5 mg/dL for males (132.6 μmol/L) and 1.4 mg/dL for females (123.8 μmol/L);
11. Fasting triglycerides (TG) >600 mg/dL (6.78 mmol/L) at Visit 3 (Week -2) (Note: diet/exercise and lipid-lowering medication to control elevated TG is allowed; medications should be optimized and stabilized prior to Visit 3);
12. Treatment with pioglitazone or rosiglitazone within the previous 10 weeks (Visit 1); treatment with incretin therapy (DPP-4 inhibitors or GLP-1 analogues) within the previous 4 weeks (Visit 1);
13. Treatment with any type of insulin (ie, injected or inhaled) within the previous 3 months;
14. Must meet other laboratory and Medical History clinical criteria. Please contact recruitment center for referrals