Diabetes Mellitus, Type 1, Hypoglycemia, Hypoglycemia Unawareness
Conditions
Keywords
diabetes, hypoglycemia, naloxone, healthy subjects, low blood sugar
Brief summary
The overall goal of this study is to develop a new and practical way to prevent the development of Hypoglycemia Associated Autonomic Failure (HAAF), which is unawareness of hypoglycemia (low blood sugar) in individuals with diabetes. Previous studies suggest that two medications, naloxone and diazoxide, may increase the body's ability to respond to episodes of low blood sugar and prevent the development of HAAF (or hypoglycemia unawareness). Only healthy subjects are being recruited for this study. The study has three distinct phases. In the first phase, healthy, non-diabetic individuals who are susceptible to developing HAAF are identified. Only these individuals will be studied in the second and third phases. The second phase of this study evaluates the effect of using a naloxone nasal spray versus a placebo nasal spray in improving the body's response to episodes of low blood sugar and in preventing the development of HAAF. The third phase of this study evaluates the effect of using naloxone nasal spray and diazoxide in combination, compared to naloxone nasal spray plus a placebo (for diazoxide) or diazoxide plus a placebo (for naloxone) in improving the body's response to episodes of low blood sugar and in preventing the development of HAAF.
Detailed description
Type I diabetes affects the body's ability to respond to low blood sugar (hypoglycemia). Repeated episodes of hypoglycemia may affect an individual's autonomic system, and leads to Hypoglycemia Associated Autonomic Failure (HAAF) in around two-thirds of individuals. This study is looking at healthy, non-diabetic individuals who are susceptible to developing HAAF and their response to either naloxone nasal spray alone or in combination with diazoxide in improving their body's ability to respond to episodes of low blood sugar, and in preventing the development of HAAF. The body's response to episodes of hypoglycemia is measured using a procedure called a hypoglycemic clamp. Each phase of this study involves three clamp procedures over a period of 2 days. During the clamp procedures, glucose (a sugar) and insulin (a hormone produced in the pancreas that regulates the amount of glucose in the blood) are infused with an intravenous catheter, and blood samples are collected periodically throughout the procedure to measure blood sugar levels and the levels of several hormones, including epinephrine, that are found in the body and are related to glucose metabolism. The rates of endogenous glucose production (a measure of the body's production of sugar) will be measured. Additionally, the level of awareness of hypoglycemia symptoms will be monitored using a standardized questionnaire. Both hypoglycemia and stress activate the body's opioid system. Recently published data has shown that blocking opioid receptors with naloxone may increase the body's ability to respond to hypoglycemia.The body's response to hypoglycemia affects many systems, and acting on several of these systems may help the body to respond more effectively to episodes of low blood sugar, and to prevent the development of HAAF. Studies have shown that potassium channels in the hypothalamus, a part of the brain, have an important role in detecting hypoglycemia. Diazoxide activates potassium channels in the cells of the brain that respond to changes in sugar (glucose) that occur in the body, and may also reduce the development of hypoglycemia associated autonomic failure. Additionally, certain glucose-responsive cells in the brain have opioid receptors that are combined with potassium channels which may respond to both diazoxide and naloxone which may work together to more effectively increase the body's ability to respond to episodes of low blood sugar and prevent HAAF. UPDATE: This study was terminated early and only the second phase (Aim 2) of the study above was conducted. This phase was designed to assess the effect of opioid receptor antagonist - intranasal naloxone - as compared to matched placebo on experimentally induced HAAF in healthy, nondiabetic volunteers.
Interventions
DRUGNaloxone
Naloxone Nasal Spray
DRUGDiazoxide
Diazoxide (oral)
DRUGPlacebo (for Naloxone)
Sterile water nasal spray
Taste matched oral placebo for diazoxide
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Albert Einstein College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Masking description
The subject and investigator will be blinded as to which intervention(s) participant is receiving first (Drug, Drug and Placebo combination, or Placebo).
Intervention model description
This study is a combination of model types. In phase 1 of the study, non-diabetic participants who are susceptible to hypoglycemia-associated autonomic failure (HAAF) are identified. Only participants who are susceptible to HAAF are studied in the second and third phases. Thus, continuation of subjects identified in phase one into phase two and/or three studies follows a sequential model. The second phase follows a crossover design in which subjects receive naloxone or placebo nasal sprays in a randomized, double blinded fashion. In the third phase, subjects will receive either oral diazoxide or oral placebo (for diazoxide), in combination with naloxone nasal spray or placebo (for naloxone) nasal spray in a randomized, double blinded crossover design.
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
-Healthy, non-diabetic subjects 21-55 years old
Exclusion criteria
* Body Mass Index (BMI) \>35kg/m2 * If Blood Pressure (BP) \>150/90 or \<90/60 on repeated measurements and on more than one occasion * Uncontrolled hyperlipidemia defined as Triglycerides \>400 mg/dL and/or total cholesterol \>300 mg/dL * Clinically significant liver dysfunction: including thrombocytopenia (platelets \<100,000/uL), anemia (as below), hypoalbuminemia (\<3.5 g/dL), coagulopathy (INR \> 1.5), and/or liver enzymes more than 3 times the upper limit of normal * Clinically significant kidney dysfunction: Glomerular Filtration Rate (GFR): \<60 mg/dL * Clinically significant anemia: Prospective subjects with hemoglobin below the lower limit of 12 g/dL for for men and 11 g/dL for women will be assessed with history and physical exam to rule out clinically significant anemia, defined as an individual with symptoms (e.g. fatigue, weakness, shortness of breath, palpitations), signs (pallor, brittle nails etc.), or currently under treatment for anemia. In the absence of a documented hemoglobin decrease or iron deficiency, subjects will not be excluded. * Clinically significant leukocytosis or leukopenia * Clinically significant thrombocytopenia or thrombocytosis * Coagulopathy * Positive drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, oxycodone, Phencyclidine (PCP). Occasional use of cannabis (not more than twice per week) is not an exclusion. If the test is read as indeterminate it will be repeated at the bedside and an additional sample will be sent to the lab. * Use of medications such as beta-blockers or medications that affect counterregulatory response to hypoglycemia * Urinalysis: clinically significant abnormalities * Clinically significant electrolyte abnormalities * Smoking \>10 cigarettes/day * Heavy alcohol use defined as: Men \>14 drinks/week or \> 4 drinks/day, Women \> 7 drinks/week or \> 3 drinks/day * History of chronic liver disease, active hepatitis infection, HIV/AIDS, chronic kidney disease (stage 3 or greater), active cancer, cardiovascular disease or other heart disease, systemic rheumatologic conditions, seizures, bleeding disorders, muscle disease * Surgeries that involve removal of endocrine glands except for thyroidectomy (if euthyroid on thyroid hormone replacement - if such history Free Thyroxine (fT4) and Thyroid Stimulating Hormone (TSH) will be checked) * Pregnancy * Subject enrolled in another medication intervention study less than one month prior to their anticipated start date in this study besides those done by our group * Family history of diabetes or premature cardiac death in first degree relatives * Allergies to medications administered during study * Uncontrolled psychiatric disorders * Any condition which in the opinion of the PI makes the subject ill-suited for participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes | Obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to approximately 6 months apart | Peak epinephrine levels during the first (during Day 1) and third (During Day 2) hypoglycemic clamp episodes were compared. Blood samples were taken every 15 minutes throughout clamp procedures and analyzed using high performance liquid chromatography to measure epinephrine levels. Peak epinephrine levels during the course of the three clamp procedures over the two days were identified for each participant. Results are summarized and reported by study arm using basic descriptive statistics. A reduction of \>20% in the average peak epinephrine levels between first and third hypoglycemic clamp episodes will be considered to define HAAF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endogenous Glucose Production (EGP) | Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~6 months apart. Data from the five timepoints over the final hour of the 1st and 3rd clamp episodes were averaged/reported. | EGP, a measure of the body's production of sugar, was assessed by determining the Glucose Infusion Rate (GIR), an indirect measure of endogenous glucose production, during the first and third hypoglycemic clamp episodes. GIR is reported in cubic centimeters/minute (cc/min) and results are summarized and reported by study arm using basic descriptive statistics. |
| Symptoms of Low Blood Sugar | Obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to approximately 6 months apart | Symptoms of low blood sugar were assessed during steady state (the last 30 minutes) using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS questionnaire is comprised 11 key symptoms (sweating, palpitations, shaking, hunger, confusion, drowsiness, odd behavior, speech difficulty, incoordination, nausea, and headache) and asked participants to evaluate these symptoms using an 8-point Likert scale ranging from 0 (Not at all) to 7 (Very severe), for an overall possible range of 0-77 for each patient, such that higher scores are associated with more intense hypoglycemic symptoms. EHSS scores were summed and averaged and reported by study arm using basic descriptive statistics. |
Countries
United States
Participant flow
Pre-assignment details
4 patients were consented and enrolled into Aim 2 of the study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Naloxone evaluation: Intranasal naloxone (4 mg NARCAN Nasal Spray) via a nostril twice during the first hypoglycemia episode; once at the start of insulin administration and again after one hour. Intranasal naloxone (4 mg NARCAN Nasal Spray) will again be given via a nostril twice during the second period of hypoglycemia; once at the start of insulin administration and again after one hour.
Naloxone evaluation: Placebo (for naloxone) nasal spray via a nostril twice during the first hypoglycemia episode; once at the start of insulin administration and again after one hour. Placebo (for naloxone) nasal spray will again be given via a nostril twice during the second period of hypoglycemia; once at the start of insulin administration and again after one hour.
Naloxone: Naloxone Nasal Spray
Placebo (for Naloxone): Sterile water nasal spray | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 2nd Intervention (2 Days) | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | All Participants | — |
|---|---|---|
| Age, Continuous | 46.5 years STANDARD_DEVIATION 10.9 | — |
| Body Mass Index (BMI) | 24.9 kg/m^2 STANDARD_DEVIATION 0.7 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 4 participants | — |
| Sex: Female, Male Female | 0 Participants | — |
| Sex: Female, Male Male | 4 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 0 / 3 | 0 / 4 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 |
Outcome results
Primary
Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes
Peak epinephrine levels during the first (during Day 1) and third (During Day 2) hypoglycemic clamp episodes were compared. Blood samples were taken every 15 minutes throughout clamp procedures and analyzed using high performance liquid chromatography to measure epinephrine levels. Peak epinephrine levels during the course of the three clamp procedures over the two days were identified for each participant. Results are summarized and reported by study arm using basic descriptive statistics. A reduction of \>20% in the average peak epinephrine levels between first and third hypoglycemic clamp episodes will be considered to define HAAF.
Time frame: Obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to approximately 6 months apart
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naloxone | Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes | 1st hypoglycemic clamp episode (Day 1) | 372 pg/mL | Standard Error 134 |
| Naloxone | Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes | 3rd hypoglycemic clamp episode (Day 2) | 397 pg/mL | Standard Error 168 |
| Placebo (for Naloxone) | Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes | 1st hypoglycemic clamp episode (Day 1) | 707 pg/mL | Standard Error 195 |
| Placebo (for Naloxone) | Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes | 3rd hypoglycemic clamp episode (Day 2) | 601 pg/mL | Standard Error 55 |
Secondary
Endogenous Glucose Production (EGP)
EGP, a measure of the body's production of sugar, was assessed by determining the Glucose Infusion Rate (GIR), an indirect measure of endogenous glucose production, during the first and third hypoglycemic clamp episodes. GIR is reported in cubic centimeters/minute (cc/min) and results are summarized and reported by study arm using basic descriptive statistics.
Time frame: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~6 months apart. Data from the five timepoints over the final hour of the 1st and 3rd clamp episodes were averaged/reported.
Population: GIR data was obtained from 1 participant following Naloxone administration and 3 participants following Placebo administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naloxone | Endogenous Glucose Production (EGP) | 1st hypoglycemic clamp episode (Day 1) | 1.6 cc/min | — |
| Naloxone | Endogenous Glucose Production (EGP) | 3rd hypoglycemic clamp episode (Day 2) | 0.9 cc/min | — |
| Placebo (for Naloxone) | Endogenous Glucose Production (EGP) | 1st hypoglycemic clamp episode (Day 1) | 0.7 cc/min | Standard Error 0.2 |
| Placebo (for Naloxone) | Endogenous Glucose Production (EGP) | 3rd hypoglycemic clamp episode (Day 2) | 1.1 cc/min | Standard Error 0.3 |
Secondary
Symptoms of Low Blood Sugar
Symptoms of low blood sugar were assessed during steady state (the last 30 minutes) using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS questionnaire is comprised 11 key symptoms (sweating, palpitations, shaking, hunger, confusion, drowsiness, odd behavior, speech difficulty, incoordination, nausea, and headache) and asked participants to evaluate these symptoms using an 8-point Likert scale ranging from 0 (Not at all) to 7 (Very severe), for an overall possible range of 0-77 for each patient, such that higher scores are associated with more intense hypoglycemic symptoms. EHSS scores were summed and averaged and reported by study arm using basic descriptive statistics.
Time frame: Obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to approximately 6 months apart
Population: Symptoms of low blood sugar scores were able to be collected from 1 participant following Naloxone administration and 3 participants following Placebo administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naloxone | Symptoms of Low Blood Sugar | 1st hypoglycemic clamp episode (Day 1) | 2.0 score on a scale | — |
| Naloxone | Symptoms of Low Blood Sugar | 3rd hypoglycemic clamp episode (Day 2) | 1.2 score on a scale | — |
| Placebo (for Naloxone) | Symptoms of Low Blood Sugar | 1st hypoglycemic clamp episode (Day 1) | 4.5 score on a scale | Standard Error 2.1 |
| Placebo (for Naloxone) | Symptoms of Low Blood Sugar | 3rd hypoglycemic clamp episode (Day 2) | 4.2 score on a scale | Standard Error 2.4 |