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Glucose Counterregulation in Long Standing Type 1 Diabetes

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by University of Pennsylvania
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT01474889
First received: November 15, 2011
Last updated: April 12, 2013
Last verified: April 2013
  Purpose

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


Condition Intervention
Hypoglycemia Unawareness
Type 1 Diabetes
Healthy
Device: RT-CGM

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: Effect of Real-Time Continuous Glucose Monitoring on Glucose Counterregulation in Long Standing Type 1 Diabetes

Resource links provided by NLM:


Further study details as provided by University of Pennsylvania:

Primary Outcome Measures:
  • Endogenous glucose production [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Endogenous Glucose Production [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Magnitude and Glycemic thresholds for counter-regulatory Hormonal and Symptom Responses [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Magnitude and Glycemic thresholds for counter-regulatory Hormonal and Symptom Responses [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 36
Study Start Date: October 2011
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Hypoglycemia Unaware T1 Diabetes RT-CGM
Type 1 Diabetes with Hypoglycemia Unawareness. Patients wear an RT-CGM for 18 months. We are comparing type 1 diabetic patients who experience severe hypoglycemia unawareness to two other (control) groups: Type 1 diabetic patients without hypoglycemia unawareness and patients who are not diabetic at all. The control groups will only have 3 visits. We plan to study glucose production and symptom generation during insulin-induced hypoglycemia (metabolic testing) by subjecting each group to a pair of metabolic clamps (hypoglycemic and euglycemic) at baseline. This group of Hypoglycemia unaware diabetics will have an additional two sets of clamps at 6 months and 18 months after wearing the RT-CGM to determine if hypoglycemia avoidance can reverse unawareness.
Device: RT-CGM
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.
Other Name: DexCom SEVEN PLUS, Guardian R-T, or FreeStyle Navigator.

Detailed Description:

The present protocol is designed to determine whether strict hypoglycemia avoidance by real-time continuous glucose monitoring (RT-CGM), can restore endogenous glucose production in response to hypoglycemia in patients with long standing disease. Twelve subjects with long standing type 1 diabetes complicated by hypoglycemia unawareness will undergo assessment of the endogenous glucose production response to insulin-induced hypoglycemia using paired hyperinsulinemic eu- and hypoglycemic clamps with stable glucose isotope infusions before and at 6 and 18 months following initiation of RT-CGM. The primary analysis will be change in the endogenous glucose production response from before to 6 months following initiation of RT-CGM, and a secondary analysis will consider the persistence of any change at 18 months. The clinical significance of any determined changes in the endogenous glucose production response to insulin-induced hypoglycemia will be determined by comparison to responses obtained using paired hyperinsulinemic eu- and hypoglycemic clamps on one occasion in a matched control group of 12 subjects with long-standing type 1 diabetes but no hypoglycemia unawareness, and in a matched control group of 12 nondiabetic subjects.

Hypoglycemia is a major barrier to the achievement of adequate glycemic control for most patients with insulin-dependent diabetes. Type 1 diabetic patients with absolute insulin deficiency (C-peptide negative) are at greatest risk for experiencing severe hypoglycemic events because the near total destruction of insulin producing islet β-cells produces an associated defect in glucagon secretion from neighboring α-cells. Such patients then depend on the sympathoadrenal system as a final defense against hypoglycemia, but unfortunately, recurrent episodes of hypoglycemia blunt sympathoadrenal activation and produce a syndrome of hypoglycemia unawareness that is associated with a twenty-fold increased risk of life-threatening hypoglycemia. Without intact islet or sympathoadrenal (especially epinephrine) responses to hypoglycemia, these patients cannot increase endogenous (primarily hepatic) glucose production to prevent or correct low blood glucose.

  Eligibility

Ages Eligible for Study:   25 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Key Inclusion Criteria

  1. Male and female subjects age 25 to 70 years.
  2. T1D with disease onset 40 years of age OR onset 40 years and documented islet autoimmunity.
  3. Insulin-dependent for more than 10 years.
  4. Absent C-peptide ( less than 0.3 ng/mL).
  5. Involvement in intensive diabetes management
  6. Hypoglycemia unawareness manifested by a Clarke score of 4 or more AND at least 1 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/hwk-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).
  7. At least one episode of severe 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.

Key Exclusion Criteria for all 3 groups

  1. (BMI) greater than 30 kg/m2.
  2. Insulin requirement of more than 1.0 IU/kg/day.
  3. HbA1c greater than 10%.
  4. Untreated proliferative diabetic retinopathy.
  5. SBP greater than 160 mmHg or DBP greater than 100 mmHg.
  6. GFR less than 55 ml/min/1.73 m-squared
  7. Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study.
  8. Baseline hemoglobin less than 11 g/dl in women and less than12 g/dl in men.
  9. Severe co-existing cardiac disease
  10. Persistent elevation of liver function tests greater than 1.5 upper normal limits
  11. Hyperlipidemia despite medical therapy
  12. Receiving treatment for a medical condition requiring chronic use of systemic steroids
  13. Presence of a seizure disorder not attributable to hypoglycemia.
  14. Untreated hypothyroidism, Addisons disease, or Celiac disease.
  15. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
  16. Use of RT-CGM within 4 weeks of enrollment.

    • Non diabetic patients do not need to meet any of the glucose criteria.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01474889

Contacts
Contact: (Ginger) Cornelia V. Dalton- Bakes, CRC 215 746 2085 cornelia.dalton-bakes@uphs.upenn.edu
Contact: Amy Peleckis, NP 215 746 2084 amy.peleckis@uphs.upenn.edu

Locations
United States, Pennsylvania
Clinical and Translational Research Center, Hospital of University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Ginger (Cornelia V) Dalton-Bakes    215-746-2085    cornelia.dalton-bakes@uphs.upenn.edu   
Contact: Amy Peleckis    215-746-2084    amy.peleckis@uphs.upenn.edu   
Principal Investigator: Michael R Rickels, M.D., M.S.         
Rodebaugh Diabetes Center, University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Ginger (Cornelia V) Bakes    215-746-2085    cornelia.dalton-bakes@uphs.upenn.edu   
Contact: Amy Peleckis    215-746-2084    amy.peleckis@uphs.upenn.edu   
Principal Investigator: Michael R. Rickels, M.D., M.S.         
Sub-Investigator: Mark H. Schutta, M.D.         
University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Ginger (Cornelia V) Bakes, CRC    215-746-2085    cornelia.dalton-bakes@uphs.upenn.edu   
Contact: Amy Peleckis, NP    215 746-2084    amy.peleckis@uphs.upenn.edu   
Principal Investigator: Michael R Rickels, MD., MS         
Sponsors and Collaborators
University of Pennsylvania
Investigators
Principal Investigator: Michael R Rickels, M.D., M.S. University of Pennsylvania
  More Information

Publications:
Hermanides J, Norgaard K, Bruttomesso D, Mathieu C, Frid A, Dayan CM, Diem P, Fermon C, Wentholt IME, Hoekstra JBL, DeVries JH: Sensor augmented pump therapy substantially lowers HbA(1c); a randomized controlled trial. Diabetologia 52:S43, 2009

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT01474889     History of Changes
Other Study ID Numbers: 814114, R01DK091331-01
Study First Received: November 15, 2011
Last Updated: April 12, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pennsylvania:
Hypoglycemia, Unawareness, RT-CGM, Type 1 Diabetes

Additional relevant MeSH terms:
Diabetes Mellitus, Type 1
Diabetes Mellitus
Hypoglycemia
Unconsciousness
Autoimmune Diseases
Consciousness Disorders
Endocrine System Diseases
Glucose Metabolism Disorders
Immune System Diseases
Metabolic Diseases
Nervous System Diseases
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms

ClinicalTrials.gov processed this record on November 20, 2014