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

Sponsor
Albert Einstein College of Medicine (Other)
Overall Status
Suspended
CT.gov ID
NCT03608163
Collaborator
National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
45
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Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 4

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
45 participants
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.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 (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).
Primary Purpose:
Prevention
Official Title:
Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)
Actual Study Start Date :
Aug 10, 2018
Anticipated Primary Completion Date :
Dec 1, 2022
Anticipated Study Completion Date :
Dec 1, 2022

Arms and Interventions

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: 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) 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

    Outcome Measures

    Primary Outcome Measures

    1. Difference in peak epinephrine levels between first and third hypoglycemic episodes [Every 15 minutes during first and third hypoglycemic clamp procedures (on Day 1 and Day 2 of two day study)]

      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.

    Secondary Outcome Measures

    1. Endogenous glucose production (EGP) [Every 15 minutes during the third 2-hour hypoglycemic clamp procedure (on Day 2 of the two day study)]

      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).

    2. Symptoms of low blood sugar (hypoglycemia) [Every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2)]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    21 Years to 55 Years
    Sexes Eligible for Study:
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Albert Einstein College of Medicine Bronx New York United States 10461

    Sponsors and Collaborators

    • Albert Einstein College of Medicine
    • National Institutes of Health (NIH)
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    Investigators

    • Principal Investigator: Meredith Hawkins, MD, MS, Albert Einstein College of Medicine

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Meredith Hawkins, Professor of Medicine, Albert Einstein College of Medicine
    ClinicalTrials.gov Identifier:
    NCT03608163
    Other Study ID Numbers:
    • 2018-9208
    • R01DK079974
    First Posted:
    Jul 31, 2018
    Last Update Posted:
    Feb 7, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Meredith Hawkins, Professor of Medicine, Albert Einstein College of Medicine
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Feb 7, 2022