Clinical trial NCT03608163: Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)
Official title: Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 1
Hypoglycemia
Hypoglycemia Unawareness
Keywords: diabetes
hypoglycemia
diazoxide
naloxone
healthy subjects
low blood sugar
Lead sponsor: Albert Einstein College of Medicine
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2018-07-31
Enrollment: 17
Sex: ALL
Minimum age (years): 21
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Difference in peak epinephrine levels between first and third hypoglycemic episodes
timeFrame: Every 15 minutes during first and third hypoglycemic clamp procedures (on Day 1 and Day 2 of two day study)
Secondary outcomes:
measure: Endogenous glucose production (EGP)
timeFrame: Every 15 minutes during the third 2-hour hypoglycemic clamp procedure (on Day 2 of the two day study)
measure: Symptoms of low blood sugar (hypoglycemia)
timeFrame: Every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2)
Other outcomes:
Locations:
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
Study officials:
affiliation: Albert Einstein College of Medicine
name: Meredith Hawkins, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: