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

NCT ID: NCT03608163

Last Updated: 2025-09-11

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 4 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-08
• Study Completion Date: 2019-08-22

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.

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia; Hypoglycemia Unawareness

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

No intervention (Susceptibility to HAAF evaluation)

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

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.

Group Type: EXPERIMENTAL

Naloxone

Intervention Type: DRUG

Naloxone Nasal Spray

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.

Group Type: PLACEBO_COMPARATOR

Placebo (for Naloxone)

Intervention Type: DRUG

Sterile water nasal spray

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.

Group Type: EXPERIMENTAL

Naloxone

Intervention Type: DRUG

Naloxone Nasal Spray

Diazoxide

Intervention Type: DRUG

Diazoxide (oral)

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.

Group Type: ACTIVE_COMPARATOR

Diazoxide

Intervention Type: DRUG

Diazoxide (oral)

Placebo (for Naloxone)

Intervention Type: DRUG

Sterile water nasal spray

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.

Group Type: ACTIVE_COMPARATOR

Naloxone

Intervention Type: DRUG

Naloxone Nasal Spray

Placebo (for Diazoxide)

Intervention Type: DRUG

Taste matched oral placebo for diazoxide

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.

Group Type: PLACEBO_COMPARATOR

Placebo (for Naloxone)

Intervention Type: DRUG

Sterile water nasal spray

Placebo (for Diazoxide)

Intervention Type: DRUG

Taste matched oral placebo for diazoxide

Interventions

Naloxone

Naloxone Nasal Spray

Intervention Type: DRUG

Diazoxide

Diazoxide (oral)

Intervention Type: DRUG

Placebo (for Naloxone)

Sterile water nasal spray

Intervention Type: DRUG

Placebo (for Diazoxide)

Taste matched oral placebo for diazoxide

Intervention Type: DRUG

Other Intervention Names

NARCAN Nasal Spray

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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Albert Einstein College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Meredith Hawkins

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Meredith Hawkins, MD, MS

Role: PRINCIPAL_INVESTIGATOR

Albert Einstein College of Medicine

Locations

Albert Einstein College of Medicine

The Bronx, New York, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

R01DK079974

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2018-9208

Identifier Type: -

Identifier Source: org_study_id