ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3-6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes. This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18-80 years with glycated hemoglobin (HbA ) 7.5-10% 58-86 mmol/mol 1:1:1 to placebo, ITCA 650 40 μg/day, or ITCA 650 60 μg/day. Primary end point was change in HbA at 39 weeks. Least squares (LS) mean change from baseline HbA was -1.1% -12.2 mmol/mol and -1.2% -13.2 mmol/mol for ITCA 650 40 and 60 μg/day, respectively ( < 0.001 vs. placebo -0.1% -1.3 mmol/mol). In a prespecified analysis, greater HbA reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (-1.7% vs. -1.2% -18.6 and -13.1 mmol/mol). At week 39, HbA <7% 53 mmol/mol was attained in 37%, 44%, and 9% of ITCA 650 40 μg/day, ITCA 650 60 μg/day, and placebo groups, respectively ( < 0.001 each dose vs. placebo). LS mean change from baseline body weight was -2.3 kg and -3.0 kg for ITCA 650 40 and 60 μg/day, respectively ( ≤ 0.015 vs. placebo -1.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient. ITCA 650 significantly reduced HbA and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications.