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.
Brief Title
Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Diabetes Mellitus, Type 1
Hypoglycemia
Hypoglycemia Unawareness
Eligibility Criteria
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
-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
Inclusion Criteria
Inclusion Criteria:
-Healthy, non-diabetic subjects 21-55 years old
-Healthy, non-diabetic subjects 21-55 years old
Gender
All
Gender Based
false
Keywords
diabetes
hypoglycemia
naloxone
healthy subjects
low blood sugar
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Estimated
Last Update Submit Date
Maximum Age
55 Years
Minimum Age
21 Years
NCT Id
NCT03608163
Org Class
Other
Org Full Name
Albert Einstein College of Medicine
Org Study Id
2018-9208
Overall Status
Terminated
Phases
Phase 4
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)
Primary Outcomes
Outcome Description
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.
Outcome Measure
Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes
Outcome 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
Secondary Ids
Secondary Id
R01DK079974
Secondary Outcomes
Outcome Description
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.
Outcome 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.
Outcome Measure
Endogenous Glucose Production (EGP)
Outcome Description
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.
Outcome 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
Outcome Measure
Symptoms of Low Blood Sugar
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Maximum Age Number (converted to Years and rounded down)
55
Minimum Age Number (converted to Years and rounded down)
21
Investigators
Investigator Type
Principal Investigator
Investigator Name
Meredith Hawkins
Investigator Email
meredith.hawkins@einsteinmed.org
Investigator Phone
718-430-3186
Categories Mesh Debug
Diabetes --- DIABETES MELLITUS
Diabetes & Endocrine System --- DIABETES MELLITUS
Diabetes --- GLUCOSE METABOLISM DISORDERS
Diabetes & Endocrine System --- GLUCOSE METABOLISM DISORDERS
Diabetes --- METABOLIC DISEASES
Diabetes & Endocrine System --- METABOLIC DISEASES
Endocrine System Cancers --- ENDOCRINE SYSTEM DISEASES
Diabetes --- ENDOCRINE SYSTEM DISEASES
Diabetes & Endocrine System --- ENDOCRINE SYSTEM DISEASES
Infectious Disease --- IMMUNE SYSTEM DISEASES
Lung --- IMMUNE SYSTEM DISEASES
MeSH Terms
DIABETES MELLITUS, TYPE 1
HYPOGLYCEMIA
DIABETES MELLITUS
GLUCOSE METABOLISM DISORDERS
METABOLIC DISEASES
NUTRITIONAL AND METABOLIC DISEASES
ENDOCRINE SYSTEM DISEASES
AUTOIMMUNE DISEASES
IMMUNE SYSTEM DISEASES
NALOXONE
DIAZOXIDE
COUNTERFEIT DRUGS
MORPHINANS
OPIATE ALKALOIDS
ALKALOIDS
HETEROCYCLIC COMPOUNDS
HETEROCYCLIC COMPOUNDS, BRIDGED-RING
HETEROCYCLIC COMPOUNDS, 4 OR MORE RINGS
HETEROCYCLIC COMPOUNDS, FUSED-RING
PHENANTHRENES
POLYCYCLIC AROMATIC HYDROCARBONS
POLYCYCLIC COMPOUNDS
BENZOTHIADIAZINES
SULFONAMIDES
SULFONES
SULFUR COMPOUNDS
ORGANIC CHEMICALS
THIAZIDES
HETEROCYCLIC COMPOUNDS, 2-RING
SUBSTANDARD DRUGS
PHARMACEUTICAL PREPARATIONS