Healthy, Hypoglycemia Unawareness, Type 1 Diabetes
Conditions
Keywords
Hypoglycemia, Unawareness, RT-CGM, Type 1 Diabetes
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.
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 underwent assessment of the endogenous glucose production response to insulin-induced hypoglycemia using paired hyperinsulinemic euglycemic 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 euglycemic 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). Arms are not assigned to these two control groups in ct.gov as they were 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. This said, for control group clarification, inclusion and exclusion criteria for each group is included in ct.gov 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.
Interventions
DEVICERT-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.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
Hypoglycemia Unaware T1 Diabetics & 2 Control Groups. Non-Diabetics & T1Ds With Intact Awareness.
Eligibility
Sex/Gender
ALL
Age
25 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria for intervention GROUP 1 (Long-standing T1D complicated by hypoglycemia unawareness) 1. Male and female subjects aged 25 to 70 years 2. Able to provide written informed consent and to comply with the protocol procedures 3. Clinical history compatible with type 1 diabetes with disease onset \< 40 years of age OR onset ≥ 40 years and documented islet autoimmunity 4. Insulin-dependent for \> 10 years 5. Absent C-peptide (\< 0.3 ng/mL). 6. 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.) 7. 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). 8. 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. Key Inclusion Criteria for control GROUP 2 (Long-standing T1D with intact hypoglycemia awareness) 1. Male and female subjects aged 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 Inclusion Criteria for control GROUP 3 (Non-diabetic controls) 1. Male and female subjects aged 25 to 70 years. 2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol. 3. No history of diabetes. Key
Exclusion criteria
for ALL 3 groups 1. Body mass index (BMI) greater than 38 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endogenous Glucose Production | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endogenous Glucose Production | 18 months | Measure of hepatic glucose output during final hour of hypoglycemic clamp |
| Autonomic Symptom Response to Hypoglycemia | 6 months | Response measure during hypoglycemic clamp using an Autonomic Symptom Questionnaire. The autonomic symptom response is calculated during the final hour of the Hypoglycemic clamp as the sum of scores ranging from 0 (none) to 5 (severe) for each of the following symptoms: anxiety, palpitations, sweating, tremor, hunger, and tingling. This results in a minimum of 0 or a maximum of 30 score with the higher score a better outcome. The scale title is Autonomic Symptom Response to hypoglycemia. |
Countries
United States
Participant flow
Pre-assignment details
The Intervention Group (Group 1) consists of participants with Type 1 Diabetes complicated by Hypoglycemia Unawareness. There were two Control Groups: (Group 2) T1Ds With Intact Awareness and (Group 3) Non-diabetics are used as a baseline for clinical significance. Neither of these two Control Groups wore a CGM nor were they analyzed at 6-month and 18-month time-points.
Participants by arm
| Arm | Count |
|---|---|
| Hypoglycemia Unaware T1 Diabetics This main 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.
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. | 13 |
| Control Group 2 - T1Ds With Intact Awareness Control Group 2 consists of 12 type one diabetics with intact awareness. Participants in control group 2 are enrolled as a baseline for clinical significance and not assessed for outcome measures. Control group 2 did not wear a CGM. They attended 3 visits (screening, HypoGlycemic clamp and EuGlycemic clamp) and they were not analyzed at 6-month and 18-month time-points. | 12 |
| Control Group 3 - Non-diabetics Control Group 3 consists of 12 non-diabetics. Participants in control group 3 are enrolled as a baseline for clinical significance and not assessed for outcome measures. Control group 3 did not wear a CGM. They attended 3 visits (screening, HypoGlycemic clamp and EuGlycemic clamp) and they were not analyzed at 6-month and 18-month time-points. | 12 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Did not meet inclusion | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Control Group 2 - T1Ds With Intact Awareness | Control Group 3 - Non-diabetics | Hypoglycemia Unaware T1 Diabetics | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 13 Participants | 37 Participants |
| Age, Continuous | 35.416 years STANDARD_DEVIATION 12.442 | 46.166 years STANDARD_DEVIATION 7.309 | 46.307 years STANDARD_DEVIATION 14.343 | 42.729 years STANDARD_DEVIATION 12.593 |
| Region of Enrollment United States | 12 participants | 12 participants | 13 participants | 37 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 5 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 0 / 13 | 0 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 | 0 / 12 |
Outcome results
Primary
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.
Time frame: 6 months
Population: Type 1 Diabetes with Hypoglycemia Unawareness. Patients wear an RT-CGM for 18 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hypoglycemia Unaware T1 Diabetes RT-CGM | Endogenous Glucose Production | 0.54 mg/kg/min | Standard Error 0.07 |
Secondary
Autonomic Symptom Response to Hypoglycemia
Response measure during hypoglycemic clamp using an Autonomic Symptom Questionnaire. The autonomic symptom response is calculated during the final hour of the Hypoglycemic clamp as the sum of scores ranging from 0 (none) to 5 (severe) for each of the following symptoms: anxiety, palpitations, sweating, tremor, hunger, and tingling. This results in a minimum of 0 or a maximum of 30 score with the higher score a better outcome. The scale title is Autonomic Symptom Response to hypoglycemia.
Time frame: 6 months
Population: Type 1 Diabetes with Hypoglycemia Unawareness. Patients wear an RT-CGM for 18 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hypoglycemia Unaware T1 Diabetes RT-CGM | Autonomic Symptom Response to Hypoglycemia | 5.1 score on a scale | Standard Error 1 |
Secondary
Autonomic Symptom Response to Hypoglycemia
Response measure during hypoglycemic clamp using an Autonomic Symptom Questionnaire. The autonomic symptom response is calculated during the final hour of the Hypoglycemic clamp as the sum of scores ranging from 0 (none) to 5 (severe) for each of the following symptoms: anxiety, palpitations, sweating, tremor, hunger, and tingling. This results in a minimum of 0 or a maximum of 30 score with the higher score a better outcome. The scale title is Autonomic Symptom Response to hypoglycemia.
Time frame: 18 months
Population: Type 1 Diabetes with Hypoglycemia Unawareness. Patients wear an RT-CGM for 18 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hypoglycemia Unaware T1 Diabetes RT-CGM | Autonomic Symptom Response to Hypoglycemia | 5.6 score on a scale | Standard Error 1.2 |
Secondary
Endogenous Glucose Production
Measure of hepatic glucose output during final hour of hypoglycemic clamp
Time frame: 18 months
Population: Type 1 Diabetes with Hypoglycemia Unawareness. Patients wear an RT-CGM for 18 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hypoglycemia Unaware T1 Diabetes RT-CGM | Endogenous Glucose Production | 0.84 mg/kg/min | Standard Error 0.15 |