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

NCT03608163 | Terminated Phase 4 Results DMC FDA Drug

• 2 other identifiers: 2018-9208R01DK079974
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

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.

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia; Hypoglycemia Unawareness

Keywords

diabetes; hypoglycemia; naloxone; healthy subjects; low blood sugar

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• 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.

• 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

Study Arms (7)

No intervention (Susceptibility to HAAF evaluation)

NO INTERVENTION

Susceptibility to HAAF evaluation: No intervention medication will be given during episodes of hypoglycemia.

Naloxone

EXPERIMENTAL

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

Placebo (for Naloxone)

PLACEBO COMPARATOR

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)

Naloxone + diazoxide

EXPERIMENTAL

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; Drug: Diazoxide

Diazoxide + placebo (for naloxone)

ACTIVE COMPARATOR

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; Drug: Placebo (for Naloxone)

Naloxone + placebo (for diazoxide)

ACTIVE COMPARATOR

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; Drug: Placebo (for Diazoxide)

Placebo (for naloxone) + placebo (for diazoxide)

PLACEBO COMPARATOR

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); Drug: Placebo (for Diazoxide)

Interventions

Naloxone DRUG

Naloxone Nasal Spray

Also known as: NARCAN Nasal Spray

Naloxone; Naloxone + diazoxide; Naloxone + placebo (for diazoxide)

Diazoxide DRUG

Diazoxide (oral)

Diazoxide + placebo (for naloxone); Naloxone + diazoxide

Placebo (for Naloxone) DRUG

Sterile water nasal spray

Diazoxide + placebo (for naloxone); Placebo (for Naloxone); Placebo (for naloxone) + placebo (for diazoxide)

Placebo (for Diazoxide) DRUG

Taste matched oral placebo for diazoxide

Naloxone + placebo (for diazoxide); Placebo (for naloxone) + placebo (for diazoxide)

Eligibility Criteria

• Age: 21 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy, non-diabetic subjects 21-55 years old

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Albert Einstein College of Medicine: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia; Diabetes Mellitus

Interventions

Naloxone; Diazoxide

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Dr. Meredith Hawkins
• Organization: Albert Einstein College of Medicine

meredith.hawkins@einsteinmed.edu

718-430-2903

Study Officials

• Meredith Hawkins, MD, MS

  Albert Einstein College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The subject and investigator will be blinded as to which intervention(s) participant is receiving first (Drug, Drug and Placebo combination, or Placebo).
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: 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.

Study Record Dates

• First Submitted: July 24, 2018
• First Posted: July 31, 2018
• Study Start: January 8, 2019
• Primary Completion: August 22, 2019
• Study Completion: August 22, 2019
• Last Updated: September 11, 2025
• Results First Posted: September 11, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)