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


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

Endpoint classification efficacy study
Intervention model single group assignment
Masking open label
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

Male or female participants from 25 years up to 70 years old.

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.

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 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.
Trial information was received from ClinicalTrials.gov and was last updated in January 2017.
Information provided to ClinicalTrials.gov by University of Pennsylvania.