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

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ClinicalTrials.gov Identifier: NCT03608163
Recruitment Status : Recruiting
First Posted : July 31, 2018
Last Update Posted : September 17, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Meredith Hawkins, Albert Einstein College of Medicine

Tracking Information
First Submitted Date  ICMJE July 24, 2018
First Posted Date  ICMJE July 31, 2018
Last Update Posted Date September 17, 2018
Actual Study Start Date  ICMJE August 10, 2018
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 31, 2018)
Difference in peak epinephrine levels between first and third hypoglycemic episodes [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 24, 2018)
Difference in peak epinephrine levels between first and third hypoglycemic episodes [ Time Frame: Every 15 minutes during first and third hypoglycemic clamp procedures (on Day 1 and Day 2 of two day study) ]
All subjects will undergo three 2-hour hypoglycemic studies over the course of two days. When subjects develop HAAF, they show a significant reduction in plasma epinephrine levels during the third vs. the first hypoglycemic episode. Thus, the difference in peak epinephrine levels between the first and third episodes of hypoglycemia will be measured under various treatment conditions (eg, no medication, naloxone, diazoxide, naloxone/diazoxide and matched placebos). Very small blood samples are taken every 15 minutes during the clamp procedures and later analyzed using high performance liquid chromatography to determine epinephrine levels. Investigators will compare the difference in peak epinephrine levels between first and third hypoglycemic episode under each treatment condition to determine whether naloxone alone, or in combination with diazoxide is effective in increasing the body's ability to respond to episodes of low blood sugar and in preventing HAAF.
Change History Complete list of historical versions of study NCT03608163 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 31, 2018)
  • Endogenous glucose production (EGP) [ Time Frame: 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).
  • Symptoms of low blood sugar (hypoglycemia) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2018)
  • Endogenous glucose production (EGP) [ Time Frame: 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).
  • Symptoms of low blood sugar (hypoglycemia) [ Time Frame: Every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2) ]
    Determined using a standardized questionnaire measuring the presence (0=not present, 1=present) of eleven specific symptoms of hypoglycemia. The questionnaire is administered every 15 minutes during the first and third 2-hour hypoglycemic episode.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)
Official Title  ICMJE Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)
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 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE 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.
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
Condition  ICMJE
  • Diabetes Mellitus, Type 1
  • Hypoglycemia
  • Hypoglycemia Unawareness
Intervention  ICMJE
  • Drug: Naloxone
    Naloxone Nasal Spray
    Other Name: NARCAN Nasal Spray
  • Drug: Diazoxide
    Diazoxide (oral)
  • Drug: Placebo (for Naloxone)
    Saline nasal spray
  • Drug: Placebo (for Diazoxide)
    Taste matched oral placebo for diazoxide
Study Arms  ICMJE
  • No Intervention: No intervention (Susceptibility to HAAF evaluation)
    Susceptibility to HAAF evaluation: No medication will be given during the first or second 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.
    Intervention: Drug: Naloxone
  • 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.
    Intervention: Drug: Placebo (for Naloxone)
  • 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 each hypoglycemia episode; once at the start of insulin administration and again after one hour.
    Interventions:
    • Drug: Naloxone
    • Drug: Diazoxide
  • 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 each hypoglycemia episode; once at the start of insulin administration and again after one hour.
    Interventions:
    • Drug: Diazoxide
    • Drug: Placebo (for Naloxone)
  • 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 each hypoglycemia episode; once at the start of insulin administration and again after one hour.
    Interventions:
    • Drug: Naloxone
    • Drug: 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 each hypoglycemia episode; once at the start of insulin administration and again after one hour.
    Interventions:
    • Drug: Placebo (for Naloxone)
    • Drug: Placebo (for Diazoxide)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 24, 2018)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2020
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

Exclusion Criteria:

  • BMI >30kg/m2
  • BP >140/90 or <90/60 on more than one occasion (unless determined to be white coat hypertension)
  • Triglycerides >400 mg/dL and/or total cholesterol >300 mg/dL
  • Clinically significant liver dysfunction
  • Clinically significant kidney dysfunction
  • Anemia
  • Leukocytosis or leukopenia
  • Thrombocytopenia or thrombocytosis
  • Positive drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, PCP
  • Currently taking beta-blockers or medications that affect counterregulatory response to hypoglycemia
  • Urinalysis: clinically significant abnormalities
  • Clinically significant electrolyte abnormalities
  • Smoking >7 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
  • Family history of diabetes or premature cardiac death in first degree relatives
  • Allergies to medications given during study
  • Uncontrolled psychiatric disorders
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Matthew Zhao, BS 718-430-2903 matthew.zhao@einstein.yu.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03608163
Other Study ID Numbers  ICMJE 2018-9208
R01DK079974 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Meredith Hawkins, Albert Einstein College of Medicine
Study Sponsor  ICMJE Albert Einstein College of Medicine
Collaborators  ICMJE
  • National Institutes of Health (NIH)
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators  ICMJE
Principal Investigator: Meredith Hawkins, MD, MS Albert Einstein College of Medicine
PRS Account Albert Einstein College of Medicine
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP