Purpose

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 both 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

Eligibility

Eligible Ages
Between 21 Years and 55 Years
Eligible Genders
All
Accepts Healthy Volunteers
Yes

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

Study Design

Phase
Phase 4
Study Type
Interventional
Allocation
Randomized
Intervention Model
Crossover Assignment
Intervention 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.
Primary Purpose
Prevention
Masking
Double (Participant, Investigator)
Masking Description
The subject and investigator will be blinded as to which study drug(s) participant is receiving first (Drug, Drug and Placebo combination, or Placebo).

Arm Groups

ArmDescriptionAssigned Intervention
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) in one 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 in one 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 in one 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 in one 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) in one 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 in one 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 in one 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 in one nostril twice during the second period of hypoglycemia; once at the start of insulin administration and again after one hour.
  • Drug: Diazoxide
    Diazoxide (oral)
  • Drug: Placebo (for Naloxone)
    Sterile water nasal spray
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) in one 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 in one 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 in one 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 in one 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

Recruiting Locations

Albert Einstein College of Medicine
Bronx, New York 10461

More Details

NCT ID
NCT03608163
Status
Recruiting
Sponsor
Albert Einstein College of Medicine

Study Contact

Tulsi Patel
718-430-2903
tulsi.patel@einsteinmed.org

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 2/3 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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.