Controlled Insulin Delivery: Combining Technology With Treatment

NCT01484457 | Completed Early Phase 1 DMC

• 1 other identifier: JDRF 22-2009-796
• Study Type: interventional
• Target: 19
• Locations: 2 countries
• Sites: 2

Brief Summary

Hypothesis: Closed-loop control systems for an artificial pancreas using multi-parametric model predictive control can be developed and evaluated safely in patients with Type 1 Diabetes Mellitus (T1DM) to control blood glucose concentrations. This study seeks to combine real-time continuous glucose sensing with automated insulin delivery in a closed-loop system that will achieve euglycemia in patients with T1DM. The end result of this line of research will be an artificial pancreas that will provide around-the-clock glucose regulation through controlled insulin delivery in response to detected patterns of change in glucose levels.

Conditions

Diabetes Mellitus, Type 1

Keywords

Diabetes Mellitus; Closed Loop; Artificial Pancreas

Outcome Measures

Primary Outcomes (1)

• Restoration of Euglycemia

  The primary endpoint of this pilot study is successful restoration of euglycemia from the two perturbed conditions using closed loop control with minimal hypo- and hyperglycemia exposure. The first condition involves restoration of euglycemia when the subject is in a hyperglycemic state. The second condition involves restoration of euglycemia following consumption of a meal containing 25g CHO with no insulin bolus. The patients will be followed for the duration of the 12 hour study.

  12 hours

Secondary Outcomes (1)

• Average percent-of-time-in-range (80 - 180 mg/dL)

  12 hours

Study Arms (1)

Closed-loop control system

EXPERIMENTAL

The objective of this study is to automate glucose control in subjects with type 1 diabetes using a computer control algorithm in a controlled in-clinic research setting. The controller will be evaluated under two conditions: 1. restoring euglycemia (80-140 mg/dL) when the controller is initiated during a period when the subject's glucose is above the euglycemic range; 2. restoring euglycemia (80-140 mg/dL) when the controller is challenged with a small unannounced meal (\~25 g CHO).

Device: Closed-loop session

Interventions

Closed-loop session DEVICE

Subjects will arrive fasting at 7am unless needed for hypoglycemia (glucose \< 70 mg/dL) and no extra bolus insulin after 3am. An IV catheter will be inserted for blood samples and for IV administration of glucose if necessary. Blood samples will be analyzed for glucose by YSI 2300Stat every 30 minutes. Breakfast consisting of 25g of CHO will be eaten at 7:30 am and the subject will bolus for this amount of CHO. The controller is switched "on" on the down slope of the meal response, and the subject is brought to a basal steady-state by the controller. Target blood glucose is 110 ± 30-mg/dL. After approximately 3 hours a small lunch will be eaten consisting of 25g of CHO (unannounced meal challenge). The subject will be monitored until blood glucose returns to euglycemia.

Also known as: Closed-loop Artificial Pancreas Device

Closed-loop control system

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing to sign the consent form
• Type 1 diabetes for at least 1 year prior to the study
• Using continuous subcutaneous insulin infusion pump
• Above 21 years of age
• Willing to follow the study requirements

You may not qualify if:

• Allergy to the sensor or to one of its components
• Psychiatric disorders
• Reported diabetic ketoacidosis within last 3 months
• Abnormal liver function (Transaminase \> 2 times the upper limit of normal)
• Heart failure
• Any carcinogenic disease
• Any other chronic abnormality
• Unwilling to perform or to follow the research protocol
• Participation in any other study concurrent with the proposed study
• Creatinine concentration above the upper limit of normal for age and sex
• Active coronary artery disease
• Active gastroparesis
• History of uncontrolled seizures
• Pregnancy
• Untreated adrenal insufficiency

Sponsors & Collaborators

• Sansum Diabetes Research Institute: lead
• Juvenile Diabetes Research Foundation: collaborator
• Schneider Children's Medical Center, Israel: collaborator

Study Sites (2)

Sansum Diabetes Research Institute

Santa Barbara, California, 93105, United States

Location

Schneider Children's Medical Center of Israel

Petah Tikva, Israel

Location

Related Publications (50)

• Basu R, Di Camillo B, Toffolo G, Basu A, Shah P, Vella A, Rizza R, Cobelli C. Use of a novel triple-tracer approach to assess postprandial glucose metabolism. Am J Physiol Endocrinol Metab. 2003 Jan;284(1):E55-69. doi: 10.1152/ajpendo.00190.2001.

  PMID: 12485809 BACKGROUND

• Bellazzi R, Arcelloni M, Bensa G, Blankenfeld H, Brugues E, Carson E, Cobelli C, Cramp D, D'Annunzio G, De Cata P, De Leiva A, Deutsch T, Fratino P, Gazzaruso C, Garcia A, Gergely T, Gomez E, Harvey F, Ferrari P, Hernando E, Boulos MK, Larizza C, Ludekke H, Maran A, Nucci G, Pennati C, Ramat S, Roudsari A, Rigla M, Stefanelli M. Design, methods, and evaluation directions of a multi-access service for the management of diabetes mellitus patients. Diabetes Technol Ther. 2003;5(4):621-9. doi: 10.1089/152091503322250640.

  PMID: 14511417 BACKGROUND

• Bellazzi R, Nucci G, Cobelli C. The subcutaneous route to insulin-dependent diabetes therapy. IEEE Eng Med Biol Mag. 2001 Jan-Feb;20(1):54-64. doi: 10.1109/51.897828. No abstract available.

  PMID: 11211661 BACKGROUND

• Bequette BW. A critical assessment of algorithms and challenges in the development of a closed-loop artificial pancreas. Diabetes Technol Ther. 2005 Feb;7(1):28-47. doi: 10.1089/dia.2005.7.28.

  PMID: 15738702 BACKGROUND

• Bevier WC, Zisser H, Palerm CC, Finan DA, Seborg DE, Doyle FJ, Wollitzer AO, Jovanovic L. Calculating the insulin to carbohydrate ratio using the hyperinsulinaemic-euglycaemic clamp-a novel use for a proven technique. Diabetes Metab Res Rev. 2007 Sep;23(6):472-8. doi: 10.1002/dmrr.727.

  PMID: 17315240 BACKGROUND

• Bode BW. Clinical utility of the continuous glucose monitoring system. Diabetes Technol Ther. 2000;2 Suppl 1:S35-41. doi: 10.1089/15209150050214104. No abstract available.

  PMID: 11469630 BACKGROUND

• Bode BW, Gross TM, Thornton KR, Mastrototaro JJ. Continuous glucose monitoring used to adjust diabetes therapy improves glycosylated hemoglobin: a pilot study. Diabetes Res Clin Pract. 1999 Dec;46(3):183-90. doi: 10.1016/s0168-8227(99)00113-8.

  PMID: 10624783 BACKGROUND

• Bode BW, Hirsch IB. Using the continuous glucose monitoring system to improve the management of type 1 diabetes. Diabetes Technol Ther. 2000;2 Suppl 1:S43-8. doi: 10.1089/15209150050214113. No abstract available.

  PMID: 11469631 BACKGROUND

• Broekhuyse HM, Nelson JD, Zinman B, Albisser AM. Comparison of algorithms for the closed-loop control of blood glucose using the artificial beta cell. IEEE Trans Biomed Eng. 1981 Oct;28(10):678-87. doi: 10.1109/tbme.1981.324661. No abstract available.

  PMID: 7033107 BACKGROUND

• Chanoch LH, Jovanovic L, Peterson CM. The evaluation of a pocket computer as an aid to insulin dose determination by patients. Diabetes Care. 1985 Mar-Apr;8(2):172-6. doi: 10.2337/diacare.8.2.172.

  PMID: 3838930 BACKGROUND

• Dalla Man C, Caumo A, Basu R, Rizza R, Toffolo G, Cobelli C. Measurement of selective effect of insulin on glucose disposal from labeled glucose oral test minimal model. Am J Physiol Endocrinol Metab. 2005 Nov;289(5):E909-14. doi: 10.1152/ajpendo.00299.2004. Epub 2005 Jun 21.

  PMID: 15972269 BACKGROUND

• Dassau E, Palerm CC, Zisser H, Buckingham BA, Jovanovic L, Doyle FJ. In silico evaluation platform for artificial pancreatic beta-cell development--a dynamic simulator for closed-loop control with hardware-in-the-loop. Diabetes Technol Ther. 2009 Mar;11(3):187-94. doi: 10.1089/dia.2008.0055.

  PMID: 19191486 BACKGROUND

• Dassau E, Zisser H, C Palerm C, A Buckingham B, Jovanovic L, J Doyle F 3rd. Modular artificial beta-cell system: a prototype for clinical research. J Diabetes Sci Technol. 2008 Sep;2(5):863-72. doi: 10.1177/193229680800200518.

  PMID: 19885271 BACKGROUND

• Diabetes Research in Children Network (DirecNet) Study Group; Buckingham B, Beck RW, Tamborlane WV, Xing D, Kollman C, Fiallo-Scharer R, Mauras N, Ruedy KJ, Tansey M, Weinzimer SA, Wysocki T. Continuous glucose monitoring in children with type 1 diabetes. J Pediatr. 2007 Oct;151(4):388-93, 393.e1-2. doi: 10.1016/j.jpeds.2007.03.047. Epub 2007 Aug 24.

  PMID: 17889075 BACKGROUND

• Dua P, Doyle FJ 3rd, Pistikopoulos EN. Model-based blood glucose control for Type 1 diabetes via parametric programming. IEEE Trans Biomed Eng. 2006 Aug;53(8):1478-91. doi: 10.1109/TBME.2006.878075.

  PMID: 16916082 BACKGROUND

• Garg S, Zisser H, Schwartz S, Bailey T, Kaplan R, Ellis S, Jovanovic L. Improvement in glycemic excursions with a transcutaneous, real-time continuous glucose sensor: a randomized controlled trial. Diabetes Care. 2006 Jan;29(1):44-50. doi: 10.2337/diacare.29.01.06.dc05-1686.

  PMID: 16373894 BACKGROUND

• Hovorka R, Chassin LJ, Wilinska ME, Canonico V, Akwi JA, Federici MO, Massi-Benedetti M, Hutzli I, Zaugg C, Kaufmann H, Both M, Vering T, Schaller HC, Schaupp L, Bodenlenz M, Pieber TR. Closing the loop: the adicol experience. Diabetes Technol Ther. 2004 Jun;6(3):307-18. doi: 10.1089/152091504774197990.

  PMID: 15198833 BACKGROUND

• Hovorka R, Shojaee-Moradie F, Carroll PV, Chassin LJ, Gowrie IJ, Jackson NC, Tudor RS, Umpleby AM, Jones RH. Partitioning glucose distribution/transport, disposal, and endogenous production during IVGTT. Am J Physiol Endocrinol Metab. 2002 May;282(5):E992-1007. doi: 10.1152/ajpendo.00304.2001.

  PMID: 11934663 BACKGROUND

• Jeha GS, Karaviti LP, Anderson B, Smith EO, Donaldson S, McGirk TS, Haymond MW. Insulin pump therapy in preschool children with type 1 diabetes mellitus improves glycemic control and decreases glucose excursions and the risk of hypoglycemia. Diabetes Technol Ther. 2005 Dec;7(6):876-84. doi: 10.1089/dia.2005.7.876.

  PMID: 16386093 BACKGROUND

• Jones SM, Quarry JL, Caldwell-McMillan M, Mauger DT, Gabbay RA. Optimal insulin pump dosing and postprandial glycemia following a pizza meal using the continuous glucose monitoring system. Diabetes Technol Ther. 2005 Apr;7(2):233-40. doi: 10.1089/dia.2005.7.233.

  PMID: 15857224 BACKGROUND

• Jovanovic L. Role of diet and insulin treatment of diabetes in pregnancy. Clin Obstet Gynecol. 2000 Mar;43(1):46-55. doi: 10.1097/00003081-200003000-00005. No abstract available.

  PMID: 10694987 BACKGROUND

• Kan S, Onodera H, Furutani E, Aung T, Araki M, Nishimura H, Maetani S, Imamura M. Novel control system for blood glucose using a model predictive method. ASAIO J. 2000 Nov-Dec;46(6):657-62. doi: 10.1097/00002480-200011000-00004.

  PMID: 11110261 BACKGROUND

• Kaufman FR. Searching for glycemic control in pediatric type 1 diabetes: A long way to go. J Pediatr. 2001 Aug;139(2):174-6. doi: 10.1067/mpd.2001.117573. No abstract available.

  PMID: 11487739 BACKGROUND

• Klonoff DC. Continuous glucose monitoring: roadmap for 21st century diabetes therapy. Diabetes Care. 2005 May;28(5):1231-9. doi: 10.2337/diacare.28.5.1231. No abstract available.

  PMID: 15855600 BACKGROUND

• Klonoff DC. A review of continuous glucose monitoring technology. Diabetes Technol Ther. 2005 Oct;7(5):770-5. doi: 10.1089/dia.2005.7.770. No abstract available.

  PMID: 16241880 BACKGROUND

• Kovatchev BP, Cox DJ, Gonder-Frederick LA, Young-Hyman D, Schlundt D, Clarke W. Assessment of risk for severe hypoglycemia among adults with IDDM: validation of the low blood glucose index. Diabetes Care. 1998 Nov;21(11):1870-5. doi: 10.2337/diacare.21.11.1870.

  PMID: 9802735 BACKGROUND

• Lehmann ED, Deutsch T. A physiological model of glucose-insulin interaction in type 1 diabetes mellitus. J Biomed Eng. 1992 May;14(3):235-42. doi: 10.1016/0141-5425(92)90058-s.

  PMID: 1588781 BACKGROUND

• Lehmann ED, Deutsch T. Compartmental models for glycaemic prediction and decision-support in clinical diabetes care: promise and reality. Comput Methods Programs Biomed. 1998 May;56(2):193-204. doi: 10.1016/s0169-2607(98)00025-x.

  PMID: 9700433 BACKGROUND

• Livesey G, Wilson PD, Dainty JR, Brown JC, Faulks RM, Roe MA, Newman TA, Eagles J, Mellon FA, Greenwood RH. Simultaneous time-varying systemic appearance of oral and hepatic glucose in adults monitored with stable isotopes. Am J Physiol. 1998 Oct;275(4):E717-28. doi: 10.1152/ajpendo.1998.275.4.E717.

  PMID: 9755093 BACKGROUND

• Ludvigsson J, Hanas R. Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: a controlled crossover study. Pediatrics. 2003 May;111(5 Pt 1):933-8. doi: 10.1542/peds.111.5.933.

  PMID: 12728068 BACKGROUND

• Magni L, Raimondo DM, Man CD, Breton M, Patek S, Nicolao GD, Cobelli C, Kovatchev BP. Evaluating the efficacy of closed-loop glucose regulation via control-variability grid analysis. J Diabetes Sci Technol. 2008 Jul;2(4):630-5. doi: 10.1177/193229680800200414.

  PMID: 19885239 BACKGROUND

• Matsuo Y, Shimoda S, Sakakida M, Nishida K, Sekigami T, Ichimori S, Ichinose K, Shichiri M, Araki E. Strict glycemic control in diabetic dogs with closed-loop intraperitoneal insulin infusion algorithm designed for an artificial endocrine pancreas. J Artif Organs. 2003;6(1):55-63. doi: 10.1007/s100470300009.

  PMID: 14598126 BACKGROUND

• Mauras N, Beck RW, Ruedy KJ, Kollman C, Tamborlane WV, Chase HP, Buckingham BA, Tsalikian E, Weinzimer S, Booth AD, Xing D; Diabetes Research in Children Network (DirecNet) Accuracy Study. Lack of accuracy of continuous glucose sensors in healthy, nondiabetic children: results of the Diabetes Research in Children Network (DirecNet) accuracy study. J Pediatr. 2004 Jun;144(6):770-5. doi: 10.1016/j.jpeds.2004.03.042.

  PMID: 15192625 BACKGROUND

• Owens C, Zisser H, Jovanovic L, Srinivasan B, Bonvin D, Doyle FJ 3rd. Run-to-run control of blood glucose concentrations for people with Type 1 diabetes mellitus. IEEE Trans Biomed Eng. 2006 Jun;53(6):996-1005. doi: 10.1109/TBME.2006.872818.

  PMID: 16761826 BACKGROUND

• Palerm CC, Zisser H, Bevier WC, Jovanovic L, Doyle FJ 3rd. Prandial insulin dosing using run-to-run control: application of clinical data and medical expertise to define a suitable performance metric. Diabetes Care. 2007 May;30(5):1131-6. doi: 10.2337/dc06-2115. Epub 2007 Feb 15.

  PMID: 17303792 BACKGROUND

• Palerm CC, Zisser H, Jovanovic L, Doyle FJ 3rd. A Run-to-Run Control Strategy to Adjust Basal Insulin Infusion Rates in Type 1 Diabetes. J Process Control. 2008;18(3-4):258-265. doi: 10.1016/j.jprocont.2007.07.010.

  PMID: 18709180 BACKGROUND

• Parker RS, Doyle FJ 3rd, Peppas NA. A model-based algorithm for blood glucose control in type I diabetic patients. IEEE Trans Biomed Eng. 1999 Feb;46(2):148-57. doi: 10.1109/10.740877.

  PMID: 9932336 BACKGROUND

• Parker RS, Doyle FJ 3rd, Peppas NA. The intravenous route to blood glucose control. IEEE Eng Med Biol Mag. 2001 Jan-Feb;20(1):65-73. doi: 10.1109/51.897829. No abstract available.

  PMID: 11211662 BACKGROUND

• Peterson CM, Jones RL, Drexler AJ, Jovanovic LB. A randomized comparative crossover evaluation of glucose monitoring technologies. Diabetes Res. 1984 Nov;1(4):195-9.

  PMID: 6529891 BACKGROUND

• Peterson CM, Jovanovic L, Chanoch LH. Randomized trial of computer-assisted insulin delivery in patients with type I diabetes beginning pump therapy. Am J Med. 1986 Jul;81(1):69-72. doi: 10.1016/0002-9343(86)90184-1.

  PMID: 3524226 BACKGROUND

• Palerm CC, Rodriguez-Fernandez M, Bevier WC, Zisser H, Banga JR, Jovanovic L, Doyle FJ 3rd. Robust parameter estimation in a model for glucose kinetics in type 1 diabetes subjects. Conf Proc IEEE Eng Med Biol Soc. 2006;2006:319-22. doi: 10.1109/IEMBS.2006.260045.

  PMID: 17946395 BACKGROUND

• Shimoda S, Nishida K, Sakakida M, Konno Y, Ichinose K, Uehara M, Nowak T, Shichiri M. Closed-loop subcutaneous insulin infusion algorithm with a short-acting insulin analog for long-term clinical application of a wearable artificial endocrine pancreas. Front Med Biol Eng. 1997;8(3):197-211.

  PMID: 9444512 BACKGROUND

• Steil GM, Clark B, Kanderian S, Rebrin K. Modeling insulin action for development of a closed-loop artificial pancreas. Diabetes Technol Ther. 2005 Feb;7(1):94-108. doi: 10.1089/dia.2005.7.94.

  PMID: 15738707 BACKGROUND

• Steil GM, Panteleon AE, Rebrin K. Closed-loop insulin delivery-the path to physiological glucose control. Adv Drug Deliv Rev. 2004 Feb 10;56(2):125-44. doi: 10.1016/j.addr.2003.08.011.

  PMID: 14741112 BACKGROUND

• Tanenberg R, Bode B, Lane W, Levetan C, Mestman J, Harmel AP, Tobian J, Gross T, Mastrototaro J. Use of the Continuous Glucose Monitoring System to guide therapy in patients with insulin-treated diabetes: a randomized controlled trial. Mayo Clin Proc. 2004 Dec;79(12):1521-6. doi: 10.4065/79.12.1521.

  PMID: 15595336 BACKGROUND

• Trajanoski Z, Wach P. Neural predictive controller for insulin delivery using the subcutaneous route. IEEE Trans Biomed Eng. 1998 Sep;45(9):1122-34. doi: 10.1109/10.709556.

  PMID: 9735562 BACKGROUND

• Wilinska ME, Chassin LJ, Schaller HC, Schaupp L, Pieber TR, Hovorka R. Insulin kinetics in type-I diabetes: continuous and bolus delivery of rapid acting insulin. IEEE Trans Biomed Eng. 2005 Jan;52(1):3-12. doi: 10.1109/TBME.2004.839639.

  PMID: 15651559 BACKGROUND

• Zisser H, Jovanovic L, Doyle F 3rd, Ospina P, Owens C. Run-to-run control of meal-related insulin dosing. Diabetes Technol Ther. 2005 Feb;7(1):48-57. doi: 10.1089/dia.2005.7.48.

  PMID: 15738703 BACKGROUND

• Zisser H, Robinson L, Bevier W, Dassau E, Ellingsen C, Doyle FJ, Jovanovic L. Bolus calculator: a review of four "smart" insulin pumps. Diabetes Technol Ther. 2008 Dec;10(6):441-4. doi: 10.1089/dia.2007.0284.

  PMID: 19049372 BACKGROUND

• Zisser HC, Bevier WC, Jovanovic L. Restoring euglycemia in the basal state using continuous glucose monitoring in subjects with type 1 diabetes mellitus. Diabetes Technol Ther. 2007 Dec;9(6):509-15. doi: 10.1089/dia.2007.0220.

  PMID: 18034605 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetes Mellitus

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Lois Jovanovic, M.D.

  Sansum Diabetes Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2011
• First Posted: December 2, 2011
• Study Start: July 1, 2008
• Primary Completion: January 1, 2010
• Study Completion: January 1, 2010
• Last Updated: March 23, 2021

Record last verified: 2021-03

Locations

US (1); IL (1)