The SimpliciT1 Study: A Randomized,Double-Blind,Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator,for Adjunctive Treatment of Type 1 Diabetes

OBJECTIVEDespite advances in exogenous insulin therapy, many patients with type 1 diabetes do not achieve acceptable glycemic control and remain at risk for ketosis and insulin-induced hypoglycemia. We conducted a randomized controlled trial to determine whether TTP399, a novel hepatoselective glucokinase activator, improved glycemic control in people with type 1 diabetes without increasing hypoglycemia or ketosis.RESEARCH DESIGN AND METHODSSimpliciT1 was a phase 1b/2 adaptive study. Phase 2 activities were conducted in two parts. Part 1 randomly assigned 20 participants using continuous glucose monitors and continuous subcutaneous insulin infusion (CSII). Part 2 randomly assigned 85 participants receiving multiple daily injections of insulin or CSII. In both parts 1 and 2, participants were randomly assigned to 800 mg TTP399 or matched placebo (fully blinded) and treated for 12 weeks. The primary end point was change in HbA_1c from baseline to week 12.RESULTSThe difference in change in HbA_1c from baseline to week 12 between TTP399 and placebo was −0.7% (95% CI −1.3, −0.07) in part 1 and −0.21% (95% CI −0.39, −0.04) in part 2. Despite a greater decrease in HbA_1c with TTP399, the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo in part 2. In both parts 1 and 2, plasma β-hydroxybutyrate and urinary ketones were lower during treatment with TTP399 than placebo.CONCLUSIONSTTP399 lowers HbA_1c and reduces hypoglycemia without increasing the risk of ketosis and should be further evaluated as an adjunctive therapy for the treatment of type 1 diabetes.