Conditions hypoglycemia unawareness, type 1 diabetes, healthy
Treatment rt-cgm
Sponsor University of Pennsylvania
Collaborator National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Start date October 2011
End date December 2018
Trial size 36 participants
Trial identifier NCT01474889, 814114, R01DK091331-01


The Investigator is in the final phase of this study and is searching for a Hypo-AWARE Type 1 diabetic control group (Group 2). The primary goal for Group 2 in this study; is to demonstrate how hormones of Type 1 diabetics should react during hypoglycemic and non-hypoglycemic events.

Enrollment for Group 1 (Hypo-Unaware) and Group 3 (Non-diabetic) is complete.

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.

Recruiting in the following locations…

United States Pennsylvania
Other countries No locations recruiting

Study Design

Intervention model single group assignment
Primary purpose other
Masking no masking
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.
rt-cgm DexCom SEVEN PLUS, Guardian R-T, or FreeStyle Navigator.
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.

Primary Outcomes

Endogenous glucose production
time frame: 6 months

Secondary Outcomes

Endogenous Glucose Production
time frame: 18 months
Magnitude and Glycemic thresholds for counter-regulatory Hormonal and Symptom Responses
time frame: 6 months
Magnitude and Glycemic thresholds for counter-regulatory Hormonal and Symptom Responses
time frame: 18 months

Eligibility Criteria

All participants from 25 years up to 70 years old.

Key Inclusion Criteria for GROUP 2 only (Group 1 and Group 3 are complete) 1. Male and female subjects age 25 to 70 years. 2. Able to provide written informed consent and to comply with the procedures of the study protocol. 3. Clinical history compatible with type 1 diabetes with disease onset < 40 years of age 4. Insulin-dependent for > 10 years 5. Absent C-peptide (< 0.3 ng/mL). 6. Involvement in intensive diabetes management defined as the use of basal-bolus insulin analog delivery by multi-dose injection (MDI) or continuous subcutaneous insulin infusion (CSII) together with self-monitoring of blood glucose values four or more times daily, without continuous glucose monitoring (CGM), under the direction of an endocrinologist, diabetologist, or diabetes nurse practitioner with at least 3 clinical evaluations during the previous 12 months. 7. Intact hypoglycemia awareness indicated by a Clarke score of 3 or less. 8. No episodes of severe hypoglycemia in the past 3 years. Key Exclusion Criteria for all 3 groups 1. Body mass index (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. Glomerular filtration rate (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 (continuous glucose monitor) within last 4 weeks. - Non-diabetic patients do not need to meet any of the glucose criteria.

Additional Information

Official title Effect of Real-Time Continuous Glucose Monitoring on Glucose Counterregulation in Long Standing Type 1 Diabetes
Principal investigator Michael R Rickels, M.D., M.S.
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 underwent 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 (GROUP 2) and in a matched control group of 12 nondiabetic subjects (GROUP 3). The Investigator is now ONLY recruiting for GROUP 2. Enrollment for Group 1 (Hypo-Unaware) and Group 3 (Non-diabetic) is complete. 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.
Trial information was received from ClinicalTrials.gov and was last updated in February 2017.
Information provided to ClinicalTrials.gov by University of Pennsylvania.