Glucose Counterregulation in Long Standing Type 1 Diabetes

NCT01474889 | Completed Results DMC

• 2 other identifiers: 814114R01DK091331-01
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 3

Brief Summary

Enrollment for this study is complete. This study is designed to determine if use of a real-time continuous glucose monitor (RT-CGM) can reverse defective Glucose counter regulation and hypoglycemia unawareness in long standing type 1 diabetes.

Conditions

Hypoglycemia Unawareness; Type 1 Diabetes; Healthy

Keywords

Hypoglycemia, Unawareness, RT-CGM, Type 1 Diabetes

Outcome Measures

Primary Outcomes (1)

• Endogenous Glucose Production

  Measure of hepatic glucose output during final hour of hypoglycemic clamp. Outcome Measures are not assigned to the control groups in ct.gov as they were only used as a baseline for clinical significance. Neither group wore a CGM nor were they analyzed at 6-month and 18-month time-points.

  6 months

Secondary Outcomes (3)

• Endogenous Glucose Production

  18 months

• Autonomic Symptom Response to Hypoglycemia

  6 months

• Autonomic Symptom Response to Hypoglycemia

  18 months

Study Arms (1)

Hypoglycemia Unaware T1 Diabetes RT-CGM

EXPERIMENTAL

This arm is the intervention group. It consists of participants with type 1 diabetes complicated by hypoglycemia unawareness. Patients wore an RT-CGM for 18 months. We studied glucose production and symptom generation during insulin-induced hypoglycemia (metabolic testing) by subjecting this intervention group to a pair of metabolic clamps (hypoglycemic and euglycemic) at baseline, at 6 months and at 18 months to determine if hypoglycemia avoidance can reverse unawareness. Please note: Arms are not assigned to the two control groups (non-diabetics and T1Ds with intact awareness) in ct.gov as they are only used as a baseline for clinical significance. Neither group wore a CGM nor are they analyzed at 6-month and 18-month time-points.

Device: RT-CGM

Interventions

RT-CGM DEVICE

Each device is approximately the size of a pager and transmits with a subcutaneously placed sensor consisting of a 21 - 26 gauge needle 5 - 12 mm in length. Sensors are placed using sterile precautions and changed every 3 - 7 days depending on the manufacturers' instructions. All devices are approved as adjunctive tools to blood glucose monitoring that will be continued at least 4 times daily, before each meal and at bedtime.

Also known as: DexCom SEVEN PLUS, Guardian R-T, or FreeStyle Navigator.

Hypoglycemia Unaware T1 Diabetes RT-CGM

Eligibility Criteria

• Age: 25 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female subjects aged 25 to 70 years
• Able to provide written informed consent and to comply with the protocol procedures
• Clinical history compatible with type 1 diabetes with disease onset \< 40 years of age OR onset ≥ 40 years and documented islet autoimmunity
• Insulin-dependent for \> 10 years
• Absent C-peptide (\< 0.3 ng/mL).
• Involvement in intensive diabetes management defined as self-monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the previous 12 months.)
• Hypoglycemia unawareness manifested by a Clarke score of 4 or more AND at least one of the following:
• HYPO score greater than or equal to the 90th percentile (1047); OR marked glycemic lability defined by a glycemic lability index (LI) score greater than or equal to the 90th percentile (433 mmol/l2/h·wk-1); OR
• A composite of a HYPO score greater than or equal to the 75th percentile (423) and a LI greater than or equal to the 75th percentile (329).
• At least one episode of severe hypoglycemia in the past 12 months defined as an event with symptoms or signs compatible with hypoglycemia in which the subject was unable to treat him/herself and which was associated with either a blood glucose level \< 54 mg/dl \[3.0 mmol/L\] or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration; OR documented \> 5% time spent in the hypoglycemic range (glucose \< 60 mg/dl) by 72-hour blinded CGM.
• Male and female subjects aged 25 to 70 years.
• Able to provide written informed consent and to comply with the procedures of the study protocol.
• Clinical history compatible with type 1 diabetes with disease onset \< 40 years of age
• Insulin-dependent for \> 10 years
• Absent C-peptide (\< 0.3 ng/mL).

You may not qualify if:

• Body mass index (BMI) greater than 38 kg/m2.
• Insulin requirement of more than 1.0 IU/kg/day.
• HbA1c greater than 10%.
• Untreated proliferative diabetic retinopathy.
• SBP greater than 160 mmHg or DBP greater than 100 mmHg.
• Glomerular filtration rate (GFR) less than 55 ml/min/1.73 m-squared
• Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study.
• Baseline hemoglobin less than 11 g/dl in women and less than12 g/dl in men.
• Severe co-existing cardiac disease
• Persistent elevation of liver function tests greater than 1.5 upper normal limits
• Hyperlipidemia despite medical therapy
• Receiving treatment for a medical condition requiring chronic use of systemic steroids
• Presence of a seizure disorder not attributable to hypoglycemia.
• Untreated hypothyroidism, Addisons disease, or Celiac disease.
• Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (3)

Clinical and Translational Research Center, Hospital of University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Rodebaugh Diabetes Center, University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (11)

• Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes. 1997 Feb;46(2):271-86.

  PMID: 9000705 BACKGROUND

• Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005 Dec;54(12):3592-601. doi: 10.2337/diabetes.54.12.3592.

  PMID: 16306382 BACKGROUND

• Pedersen-Bjergaard U, Pramming S, Heller SR, Wallace TM, Rasmussen AK, Jorgensen HV, Matthews DR, Hougaard P, Thorsteinsson B. Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev. 2004 Nov-Dec;20(6):479-86. doi: 10.1002/dmrr.482.

  PMID: 15386817 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

• Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group; Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, Clemons R, Fiallo-Scharer R, Fox LA, Gilliam LK, Hirsch IB, Huang ES, Kollman C, Kowalski AJ, Laffel L, Lawrence JM, Lee J, Mauras N, O'Grady M, Ruedy KJ, Tansey M, Tsalikian E, Weinzimer S, Wilson DM, Wolpert H, Wysocki T, Xing D. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008 Oct 2;359(14):1464-76. doi: 10.1056/NEJMoa0805017. Epub 2008 Sep 8.

  PMID: 18779236 BACKGROUND

• Hirsch IB, Abelseth J, Bode BW, Fischer JS, Kaufman FR, Mastrototaro J, Parkin CG, Wolpert HA, Buckingham BA. Sensor-augmented insulin pump therapy: results of the first randomized treat-to-target study. Diabetes Technol Ther. 2008 Oct;10(5):377-83. doi: 10.1089/dia.2008.0068.

  PMID: 18715214 BACKGROUND

• Hermanides J, Norgaard K, Bruttomesso D, Mathieu C, Frid A, Dayan CM, Diem P, Fermon C, Wentholt IM, Hoekstra JB, DeVries JH. Sensor-augmented pump therapy lowers HbA(1c) in suboptimally controlled Type 1 diabetes; a randomized controlled trial. Diabet Med. 2011 Oct;28(10):1158-67. doi: 10.1111/j.1464-5491.2011.03256.x.

  PMID: 21294770 BACKGROUND

• JDRF CGM Study Group. JDRF randomized clinical trial to assess the efficacy of real-time continuous glucose monitoring in the management of type 1 diabetes: research design and methods. Diabetes Technol Ther. 2008 Aug;10(4):310-21. doi: 10.1089/dia.2007.0302.

  PMID: 18828243 BACKGROUND

• Rickels MR, Schutta MH, Mueller R, Markmann JF, Barker CF, Naji A, Teff KL. Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes. Diabetes. 2005 Nov;54(11):3205-11. doi: 10.2337/diabetes.54.11.3205.

  PMID: 16249446 BACKGROUND

• Rickels MR, Schutta MH, Mueller R, Kapoor S, Markmann JF, Naji A, Teff KL. Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients. J Clin Endocrinol Metab. 2007 Mar;92(3):873-9. doi: 10.1210/jc.2006-2426. Epub 2006 Dec 27.

  PMID: 17192287 BACKGROUND

• Rickels MR, Peleckis AJ, Dalton-Bakes C, Naji JR, Ran NA, Nguyen HL, O'Brien S, Chen S, Lee I, Schutta MH. Continuous Glucose Monitoring for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes. J Clin Endocrinol Metab. 2018 Jan 1;103(1):105-114. doi: 10.1210/jc.2017-01516.

  PMID: 29190340 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia; Unconsciousness

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Consciousness Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Cornelia V. Dalton Bakes
• Organization: UPenn

corneliv@pennmedicine.upenn.edu

215-746-2085

Study Officials

• Michael R Rickels, M.D., M.S.

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Hypoglycemia Unaware T1 Diabetics \& 2 Control Groups. Non-Diabetics \& T1Ds With Intact Awareness.

Study Record Dates

• First Submitted: November 15, 2011
• First Posted: November 18, 2011
• Study Start: October 1, 2011
• Primary Completion: May 1, 2016
• Study Completion: March 5, 2021
• Last Updated: August 31, 2023
• Results First Posted: August 31, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)