Doms № 1 -2022

Doms № 2 -2022 (11-21 p)

Inrange: comparison of the second-generation basal insulin analogues glargine 300 u/ml and degludec 100 u/ml in persons with type 1 diabetes using continuous glucose monitoring— study design
Tadej Battelino, Zsolt Bosnyak, Thomas Danne, Bhaswati Mukherjee, Steve Edelman, Valerie Pilorget, Pratik Choudhary, Eric Renard, Richard Bergenstal

Abstract Aims: Suboptimal glycaemic control among people with type 1 diabetes (T1D) is known to lead to long-term micro- and macrovascular complications and, unfortunately, it is still prevalent even in the most affluent societies. Although glycated haemoglobin monitoring is considered to be the gold standard for assessing glycaemic control, such monitoring is unable to reliably measure acute glycaemic excursions. Continuous glucose monitoring (CGM) has been shown to improve glucose control and reduce the incidence of hypoglycaemia, and also allow a more complete assessment of overall glycaemic control and hyper- and hypoglycaemic excursions. The use of CGM has led to time-in-range, which is the time that a patient is within the glycaemic range of 70 to 180 mg/dL, to be adopted as a treatment target. To date, only limited data comparing the second-generation insulins glargine 300 U/mL (Gla-300) and degludec 100 U/mL (IDeg-100) in people with T1D are available, and there is no CGM literature on comparisons of the use of CGM results to assess primary, secondary and tertiary endpoints. The aim of the InRange study was to address this unmet need.

Methods: InRange is a multicentre, randomised, active-controlled, parallel-group, 12-week, open-label, phase 4, comparative study. Adults with T1D will be randomised to receive once-daily Gla-300 or IDeg-100 by subcutaneous injection in the morning. Following an 8-week titration period, CGM data will be collected over 20 consecutive days.

Planned outcomes: The primary objective is to demonstrate that Gla-300 is noninferior to IDeg-100 in terms of glycaemic control [timein-range C 70 to B 180 mg/dL (C 3.9 to B 10 mmol/L)] and variability, as assessed using CGM, in adults with T1D. The results are expected to help confirm the utility of CGM in clinical practice in this population and provide insight into its application as an outcome measure in clinical practice.

Keywords: Continuous glucose monitoring; Fasting plasma glucose; Glucose variability; Glycated haemoglobin; Insulin; Insulin degludec; Insulin glargine; Self-monitoring of plasma glucose; Time-in-range; Type 1 diabetes.

  1. Nathan DM, DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37(1):9-16.
  2. Leiter LA, YaleJ-F, Chiasson J-L, Harris S, Kleinstiver P, Sauriol L. Assessment of the impact of fear of hypoglycemic episodes on glycemic and hypoglycemia management. Can J Diabetes. 2005;29(3): 186-92.
  3. Martyn-Nemeth P, Schwarz Farabi S, Mihailescu D, Nemeth J, Quinn L. Fear of hypoglycemia in adults with type 1 diabetes: impact of therapeutic advances and strategies for prevention—a review. J Diabetes Complic. 2016;30(1):167-77.
  4. 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(2):66-72.
  5. Pettus JH, Zhou FL, Shepherd L, et al. Incidences of severe hypoglycemia and diabetic ketoacidosis and prevalence of microvascular complications stratified by age and glycemic control in U.S. adult patients with type 1 diabetes: a real- world study. Diabetes Care. 2019;42(12):2220-7.
  6. Ferrari MTM, Neto AM. Efficacy, safety and clinical use of newer basal insulins analogs. Endocrinol Metab Int J. 2018;6(3):215-21.
  7. Klonoff DC, Ahn D, Drincic A. Continuous glucose monitoring: a review of the technology and clinical use. Diabetes Res Clin Pract. 2017;133:178-92.
  8. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, Kroger J, Weitgasser R. Novel glucose-sensing technology and hypo-glycaemia in type 1 diabetes: a multicentre, non-masked, ran- domised controlled trial. Lancet. 2016;388(10057):2254-63.
  9. Battelino T, Danne T, Bergenstal RM, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care. 2019;42(8):1593-603.
  10. Sanofi S.A. TOUJEO: prescribing information. https://www. label/2015/206538lbl. pdf. Accessed 23 Sep 2019.
  11. Novo Nordisk A/S. TRESIBA: prescribing information. docs/ label/2015/203314lbl.pdf2015. Accessed 23 Sep 2019.
  12. White JR Jr. Advances in insulin therapy: a review of new insulin glargine 300 units/mL in the management of diabetes. Clin Diabetes. 2016;34(2): 86-91.
  13. Bailey TS, Pettus J, Roussel R, et al. Morning administration of 0.4 U/kg/day insulin glargine 300 U/mL provides less fluctuating 24-hour pharmacodynamics and more even pharmacokinetic profiles compared with insulin degludec 100 U/mL in type 1 diabetes. Diabetes Metab. 2018;44(1):15-21.
  14. Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet. 2014;53(9):787-800.
  15. Rosenstock J, Cheng A, Ritzel R, et al. More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: the randomized head- to-head BRIGHT trial. Diabetes Care. 2018;41(10): 2147-54.
  16. Philis-Tsimikas A, Klonoff DC, Khunti K, et al. Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial. Diabetologia. 2020. https://doi. org/10.1007/s00125-019-05080-9.
  17. Kawaguchi Y, Sawa J, Sakuma N, Kumeda Y. Efficacy and safety of insulin glargine 300 U/mL vs insulin degludec in patients with type 2 diabetes: a randomized, open-label, cross-over study using continuous glucose monitoring pro- files. J Diabetes Investig. 2019;10(2):343-51.
  18. Yamabe M, Kuroda M, Hirosawa Y, Kamino H, Ohno H, Yoneda M. Comparison of insulin glargine 300 U/mL and insulin degludec using flash glucose monitoring: a randomized cross-over study. J Diabetes Investig. 2019;10(2):352-7.
  19. Monnier L, Colette C, Wojtusciszyn A, et al. Toward defining the threshold between low and high glucose variability in diabetes. Diabetes Care. 2017;40(7):832-8.
  20. Heise T, Norskov M, Nosek L, Kaplan K, Famulla S, Haahr HL. Insulin degludec: lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes. Diabetes Obes Metab. 2017;19(7): 1032-9.
  21. International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2017;40(1):155-7.
  22. Danne T, Nimri R, Battelino T, et al. International consensus on use of continuous glucose monitoring. Diabetes Care. 2017;40(12):1631-40.
  23. American Diabetes Association. Standards of medical care in diabetes-2019. Diabetes Care. 2019; 42(Supplement):1.
  24. Hochberg Y, Tamhane AC. Multiple comparison procedures. Hoboken: Wiley. 1987.
  25. Wojciechowski P, Rys P, Lipowska A, Gaweska M, Malecki MT. Efficacy and safety comparison of continuous glucose monitoring and self-monitoring of blood glucose in type 1 diabetes: systematic review and meta-analysis. Pol Arch Med Wewn. 2011;121(10):333-43.
  26. Klonoff DC. Improving the safety of blood glucose monitoring. J Diabetes Sci Technol. 2011;5(6): 1307-11.
  27. Johnson T, Zhang X, Balo A. Assessing glucose trend accuracy with a novel continuous glucose monitoring system. Diabetes. 2018;67[Suppl 1]:950-P.
  28. Wright LA, Hirsch IB. Metrics beyond hemoglobin A1C in diabetes management: time in range, hypoglycemia, and other parameters. Diabetes Technol Ther. 2017;19(S2):S16-26.
  29. Burd JF, Melero FAA, Noetzel V. Hemoglobin A1c (HbAlc) shows improvement in glycemic control in as little as two weeks following the addition of lysulinTM, to the treatment of diabetes. Diabetes Manag. 2018;8(3):82-4.
  30. Biagi L, Bertachi A, Quiros C, et al. Accuracy of continuous glucose monitoring before, during, and after aerobic and anaerobic exercise in patients with type 1 diabetes mellitus. Biosensors (Basel). 2018;8(1). doi: bios8010022.
  31. Originally published: Battelino T., Bosnyak Z., Danne T. et al. InRange: Comparison of the Second-Generation Basal Insulin Analogues Glargine 300 U/mL and Degludec 100 U/mL in Persons with Type 1 Diabetes Using Continuous Glucose Monitoring—Study Design. Diabetes Th er. 2020;11, 1017–1027. https://doi. org/10.1007/s13300-020-00781-6
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