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

Klara R Klein, Jennifer L R Freeman, Imogene Dunn, Chris Dvergsten, M Sue Kirkman, John B Buse, Carmen Valcarce, SimpliciT1 research group, John B Buse, Klara R Klein, M Sue Kirkman, Katherine A Bergamo, Elizabeth H Harris, Jean M Dostou, Laura A Young, Sriram Machineni, Alex M Kass, Jamie C Diner, Milana Dezube, Virginia C Purrington, Julie M Uehling, Rachael M Fraser, Katherine R Schuch, Jennifer V Rowell, Ali Qamar, K Jean Lucas, Luke Snedaker, Stephanie Hoover, Justin Smith, Paul Becton, Jeffrey Hainsworth, Timothy S Bailey, Juan Pablo Garcia-Naranjo, Niki Nguyen, Bruce W Bode, Jennifer M Boyd, Betsy Childs, Pablo Mora, Allison Camacho, Carl D Vance, Karen Lugo, Anuj Bhargava, Kirstie Stifel, Lisa B Connery, Birjis Khan, Simone D Smith, John Parker, Kathryn Zweier, Emily Kronenfeld, Brittany Savoca, Viral N Shah, Prakriti Joshee, Shivani Dixit, Hal Joseph, Halis Kaan Akturk, Subbulaxami Trikudanathan, Dori Khakpour, Julia Chang, Anne Peters, Pejman Cohan, Mark Harmel, Wendy S Lane, Klara R Klein, Jennifer L R Freeman, Imogene Dunn, Chris Dvergsten, M Sue Kirkman, John B Buse, Carmen Valcarce, SimpliciT1 research group, John B Buse, Klara R Klein, M Sue Kirkman, Katherine A Bergamo, Elizabeth H Harris, Jean M Dostou, Laura A Young, Sriram Machineni, Alex M Kass, Jamie C Diner, Milana Dezube, Virginia C Purrington, Julie M Uehling, Rachael M Fraser, Katherine R Schuch, Jennifer V Rowell, Ali Qamar, K Jean Lucas, Luke Snedaker, Stephanie Hoover, Justin Smith, Paul Becton, Jeffrey Hainsworth, Timothy S Bailey, Juan Pablo Garcia-Naranjo, Niki Nguyen, Bruce W Bode, Jennifer M Boyd, Betsy Childs, Pablo Mora, Allison Camacho, Carl D Vance, Karen Lugo, Anuj Bhargava, Kirstie Stifel, Lisa B Connery, Birjis Khan, Simone D Smith, John Parker, Kathryn Zweier, Emily Kronenfeld, Brittany Savoca, Viral N Shah, Prakriti Joshee, Shivani Dixit, Hal Joseph, Halis Kaan Akturk, Subbulaxami Trikudanathan, Dori Khakpour, Julia Chang, Anne Peters, Pejman Cohan, Mark Harmel, Wendy S Lane

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 HbA1c from baseline to week 12.

Results: The difference in 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 parts 1 and 2, plasma β-hydroxybutyrate 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.

Trial registration: ClinicalTrials.gov NCT03335371.

© 2021 by the American Diabetes Association.

Figures

Figure 1
Figure 1
The effect of TTP399 on HbA1c, insulin dosing, and safety in parts 1 and 2 of the SimpliciT1 study. A and B: Mean change in HbA1c 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 HbA1c is plotted against change in total insulin. The positive correlation between reduction in HbA1c 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.

References

    1. Foster NC, Beck RW, Miller KM, et al. . State of type 1 diabetes management and outcomes from the T1D exchange in 2016-2018. Diabetes Technol Ther 2019;21:66–72
    1. American Diabetes Association . 6. Glycemic targets: Standards of Medical Care in Diabetes—2020. Diabetes Care 2020;43(Suppl. 1):S66–S76
    1. Vellanki P, Umpierrez GE. Increasing hospitalizations for DKA: a need for prevention programs. Diabetes Care 2018;41:1839–1841
    1. Iynedjian PB. Molecular physiology of mammalian glucokinase. Cell Mol Life Sci 2009;66:27–42
    1. Froguel P, Vaxillaire M, Sun F, et al. . Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992;356:162–164
    1. Hattersley AT, Turner RC, Permutt MA, et al. . Linkage of type 2 diabetes to the glucokinase gene. Lancet 1992;339:1307–1310
    1. Njølstad PR, Sagen JV, Bjørkhaug L, et al. . Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 2003;52:2854–2860
    1. Glaser B, Kesavan P, Heyman M, et al. . Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998;338:226–230
    1. Matschinsky FM, Glaser B, Magnuson MA. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 1998;47:307–315
    1. Matschinsky FM, Wilson DF. The central role of glucokinase in glucose homeostasis: a perspective 50 Years after demonstrating the presence of the enzyme in islets of langerhans. Front Physiol 2019;10:148.
    1. Vandercammen A, Van Schaftingen E. The mechanism by which rat liver glucokinase is inhibited by the regulatory protein. Eur J Biochem 1990;191:483–489
    1. Vandercammen A, Van Schaftingen E. Competitive inhibition of liver glucokinase by its regulatory protein. Eur J Biochem 1991;200:545–551
    1. Vandercammen A, Van Schaftingen E. Species and tissue distribution of the regulatory protein of glucokinase. Biochem J 1993;294:551–556
    1. de la Iglesia N, Veiga-da-Cunha M, Van Schaftingen E, Guinovart JJ, Ferrer JC. Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase. FEBS Lett 1999;456:332–338
    1. Brown KS, Kalinowski SS, Megill JR, Durham SK, Mookhtiar KA. Glucokinase regulatory protein may interact with glucokinase in the hepatocyte nucleus. Diabetes 1997;46:179–186
    1. Hale C, Lloyd DJ, Pellacani A, Véniant MM. Molecular targeting of the GK-GKRP pathway in diabetes. Expert Opin Ther Targets 2015;19:129–139
    1. McCarty MF. In type 1 diabetics, high-dose biotin may compensate for low hepatic insulin exposure, promoting a more normal expression of glycolytic and gluconeogenic enyzymes and thereby aiding glycemic control. Med Hypotheses 2016;95:45–48
    1. Morral N, McEvoy R, Dong H, et al. . Adenovirus-mediated expression of glucokinase in the liver as an adjuvant treatment for type 1 diabetes. Hum Gene Ther 2002;13:1561–1570
    1. Vella A, Freeman JLR, Dunn I, Keller K, Buse JB, Valcarce C. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Sci Transl Med 2019;11:eaau3441.
    1. European Medicines Agency Committee for Medicinal Products for Human Use . Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design. Accessed 22 December 2020. Available from
    1. Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research , Eds. Adaptive design for clinical trials of drugs and biologics: guidance for industry. Accessed 22 December 2020. Available from
    1. Cryer PE. Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes 2014;63:2188–2195
    1. Ferre T, Pujol A, Riu E, Bosch F, Valera A. Correction of diabetic alterations by glucokinase. Proc Natl Acad Sci U S A 1996;93:7225–7230
    1. Valcarce C. Selective activation of glucokinase (GK) in the liver: improves glycemic control and reduces insulin need as well as risk of ketoacidosis in type 1 diabetic minipigs. Accessed 19 August 2020. Available from
    1. Karras SN, Koufakis T, Zebekakis P, Kotsa K. Pharmacologic adjunctive to insulin therapies in type 1 diabetes: the journey has just begun. World J Diabetes 2019;10:234–240
    1. Ahrén B, Hirsch IB, Pieber TR, et al. .; ADJUNCT TWO Investigators . Efficacy and safety of liraglutide added to capped insulin treatment in subjects with type 1 diabetes: the ADJUNCT TWO randomized trial. Diabetes Care 2016;39:1693–1701
    1. Taylor SI, Blau JE, Rother KI, Beitelshees AL. SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks. Lancet Diabetes Endocrinol 2019;7:949–958
    1. Mathieu C, Zinman B, Hemmingsson JU, et al. .; ADJUNCT ONE Investigators . Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: the ADJUNCT ONE treat-to-target randomized trial. Diabetes Care 2016;39:1702–1710
    1. Wang W, Liu H, Xiao S, Liu S, Li X, Yu P. Effects of insulin plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in treating type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Ther 2017;8:727–738
    1. Peters AL, McGuire DK, Danne T, et al. . Diabetic ketoacidosis and related events with sotagliflozin added to insulin in adults with type 1 diabetes: a pooled analysis of the inTandem 1 and 2 studies. Diabetes Care 2020;43:2713–2720

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe