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

Despite 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 methods

SimpliciT1 was a Phase 1b/2 adaptive study. Phase 2 activities were conducted in 2 parts. Part 1 randomized 20 participants using continuous glucose monitors (CGM) and continuous subcutaneous insulin infusion (CSII). Part 2 randomized 85 participants on multiple daily injections of insulin or CSII. In both Part 1 and 2, participants were randomized to TTP399 800 mg or matched placebo (fully blinded) and treated for 12-weeks. The primary endpoint was the change in HbA1c from baseline to week 12.

Results

The difference in the change in HbA1c 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 HbA1c with TTP399, the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo in Part 2. In both Part 1 and Part 2, plasma beta-hydroxybutrate and urinary ketones were lower during treatment with TTP399 than placebo.

Conclusions

TTP399 lowers HbA1c 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.