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

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.

Study Overview

• Status: Terminated
• Conditions: Hypoglycemia; Diabetes Mellitus, Type 1; Hypoglycemia Unawareness
• Intervention / Treatment: Drug: Naloxone; Drug: Placebo (for Naloxone); Drug: Diazoxide; Drug: Placebo (for Diazoxide)

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • The Bronx, New York, United States, 10461
      • Albert Einstein College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No intervention (Susceptibility to HAAF evaluation); Susceptibility to HAAF evaluation: No intervention medication will be given during episodes of hypoglycemia.
Experimental: Naloxone; 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; Naloxone Nasal Spray; Other Names: NARCAN Nasal Spray
Placebo Comparator: Placebo (for Naloxone); 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); Sterile water nasal spray
Experimental: Naloxone + diazoxide; 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; Naloxone Nasal Spray; Other Names: NARCAN Nasal Spray; Drug: Diazoxide; Diazoxide (oral)
Active Comparator: Diazoxide + placebo (for naloxone); 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: Placebo (for Naloxone); Sterile water nasal spray; Drug: Diazoxide; Diazoxide (oral)
Active Comparator: Naloxone + placebo (for diazoxide); 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; Naloxone Nasal Spray; Other Names: NARCAN Nasal Spray; Drug: Placebo (for Diazoxide); Taste matched oral placebo for diazoxide
Placebo Comparator: Placebo (for naloxone) + placebo (for diazoxide); 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); Sterile water nasal spray; Drug: Placebo (for Diazoxide); Taste matched oral placebo for diazoxide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.
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.	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

Collaborators and Investigators

• Sponsor: Albert Einstein College of Medicine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Meredith Hawkins, MD, MS, Albert Einstein College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2019
• Primary Completion (Actual): August 22, 2019
• Study Completion (Actual): August 22, 2019

Study Registration Dates

• First Submitted: July 24, 2018
• First Submitted That Met QC Criteria: July 24, 2018
• First Posted (Actual): July 31, 2018

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: diabetes; hypoglycemia; healthy subjects; naloxone; low blood sugar
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Nutritional and Metabolic Diseases; Hypoglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 1; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Substandard Drugs; Pharmaceutical Preparations; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Sulfonamides; Sulfones; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Benzothiadiazines; Thiazides; Diazoxide; Naloxone; Counterfeit Drugs
• Other Study ID Numbers: 2018-9208; R01DK079974 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No