Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)

Conditions
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Diabetes Mellitus, Type 1, Hypoglycemia, Hypoglycemia Unawareness

Intervention / Treatment
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* Drug: Naloxone
* Drug: Diazoxide
* Drug: Placebo (for Naloxone)
* Drug: Placebo (for Diazoxide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Healthy, non-diabetic subjects 21-55 years old Exclusion Criteria: BMI >35kg/m2 BP >150/90 or <90/60 on repeated measurements and on more than one occasion Triglycerides >400 mg/dL and/or total cholesterol >300 mg/dL Clinically significant liver dysfunction Clinically significant kidney dysfunction Clinically significant anemia Clinically significant leukocytosis or leukopenia Clinically significant thrombocytopenia or thrombocytosis Positive drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, oxycodone, PCP Currently taking 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 History of chronic conditions (eg, chronic liver disease, cardiovascular disease, bleeding disorders, cancer, HIV/AIDS, seizures, systemic rheumatologic conditions) Surgeries involving endocrine glands Pregnancy Enrollment in another medication intervention study less than one month prior, besides those done by our group Family history of diabetes or premature cardiac death in first degree relatives Allergies to medications given during study Uncontrolled psychiatric disorders

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No intervention (Susceptibility to HAAF evaluation)<br>Susceptibility to HAAF evaluation: No intervention medication will be given during episodes of hypoglycemia. | |
| Experimental: Naloxone<br>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. | Drug: Naloxone<br>* Naloxone Nasal Spray<br>* Other names: NARCAN Nasal Spray;|
| Placebo Comparator: Placebo (for Naloxone)<br>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. | Drug: Placebo (for Naloxone)<br>* Sterile water nasal spray<br>|
| Experimental: Naloxone + diazoxide<br>Naloxone/Diazoxide evaluation: Up to 7 mg/kg oral diazoxide 3 hours before the first hypoglycemic episode. 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. | Drug: Naloxone<br>* Naloxone Nasal Spray<br>* Other names: NARCAN Nasal Spray;Drug: Diazoxide<br>* Diazoxide (oral)<br>|
| Active Comparator: Diazoxide + placebo (for naloxone)<br>Naloxone/Diazoxide evaluation: Up to 7 mg/kg oral diazoxide 3 hours before the first hypoglycemic episode. 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. | Drug: Diazoxide<br>* Diazoxide (oral)<br>Drug: Placebo (for Naloxone)<br>* Sterile water nasal spray<br>|
| Active Comparator: Naloxone + placebo (for diazoxide)<br>Naloxone/Diazoxide evaluation: Oral placebo (for diazoxide) 3 hours before the first hypoglycemic episode. 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. | Drug: Naloxone<br>* Naloxone Nasal Spray<br>* Other names: NARCAN Nasal Spray;Drug: Placebo (for Diazoxide)<br>* Taste matched oral placebo for diazoxide<br>|
| Placebo Comparator: Placebo (for naloxone) + placebo (for diazoxide)<br>Naloxone/Diazoxide evaluation: Oral placebo (for diazoxide) 3 hours before the first hypoglycemic episode. 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. | Drug: Placebo (for Naloxone)<br>* Sterile water nasal spray<br>Drug: Placebo (for Diazoxide)<br>* Taste matched oral placebo for diazoxide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in peak epinephrine levels between first and third hypoglycemic episodes | Small blood samples will be taken every 15 minutes throughout clamp procedures and analyzed using high performance liquid chromatography to measure epinephrine levels. The difference in peak epinephrine levels between the first and third episodes of hypoglycemia under various treatment conditions (eg, no medication, naloxone, diazoxide, naloxone/diazoxide and matched placebos) will be reported. | Every 15 minutes during first and third hypoglycemic clamp procedures (on Day 1 and Day 2 of two day study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endogenous glucose production (EGP) | Rates of EGP (a measure of the body's production of sugar) will be measured during the third hypoglycemic clamp procedure on the second day of clamp studies under various treatment conditions (eg, no medication, naloxone, diazoxide, naloxone/diazoxide and matched placebos), by monitoring changes in the level of a non-radioactive, naturally occurring form of glucose (sugar). | Every 15 minutes during the third 2-hour hypoglycemic clamp procedure (on Day 2 of the two day study) | 
| Symptoms of low blood sugar (hypoglycemia) | Determined using the Edinburgh Hypoglycemia Symptom Scale Score which determines the participant's awareness of eleven specific symptoms of hypoglycemia. Each symptom is scored 0-1 (0=not present or 1=present), which are then added together to yield a total between 0-11. Higher values mean participant has greater awareness of hypoglycemia, lower values mean participant has impaired awareness of hypoglycemia. | Every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, hypoglycemia, diazoxide, naloxone, healthy subjects, low blood sugar