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

Abstract

Objective: 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 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.

Results: The 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.

Conclusions: TTP399 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.

Trial registration: ClinicalTrials.gov NCT03335371.

Figure 1

The effect of TTP399 on HbA_1c, insulin dosing, and safety in parts 1 and 2 of the SimpliciT1 study. A and B: Mean change in HbA_1c from baseline to week 12 in parts 1 (A) and 2 (B). C: Percentages of responders in parts 1 and 2 are shown. Part 1 data were analyzed by the responder criteria outlined in the statistical analysis plan from parts 1 and 2. D: Change in HbA_1c is plotted against change in total insulin. The positive correlation between reduction in HbA_1c and reduction in total insulin was significant (P = 0.008). Data analyzed comprise the full analysis set. E: Cumulative number of episodes of severe or symptomatic hypoglycemia in part 2. Post hoc analysis demonstrated nominal P < 0.05. F: Cumulative incidence of β-hydroxybutyrate >0.4 mmol/L. Data in F represent the pooled cohort from parts 1 and 2 of the study. BOHB, β-hydroxybutyrate.