AzTrials
AzTrials

Diabetes Mellitus, Type 1Phase 4NCT03608163

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

A Phase 4 study testing Naloxone and Diazoxide in people with Diabetes Mellitus, Type 1 and Hypoglycemia, run by Albert Einstein College of Medicine at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 21 to 55 yearsHealthy volunteers can take part
What is being tested?
Naloxone and Diazoxide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
4 participants
Where
1 siteUnited States
Study dates
8 Jan 2019to 22 Aug 2019
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 to 55 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

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

Who cannot join

  • 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.
Show all 23Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Albert Einstein College of Medicine

    The Bronx, New York, 10461

Other trials in United States

About this study

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.

Read the 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.

Being tested
Naloxone, Diazoxide, Placebo (for Naloxone), Placebo (for Diazoxide)
Keywords
diabetes, hypoglycemia, naloxone, healthy subjects, low blood sugar
Medical subject headings
Diabetes Mellitus, Type 1, Hypoglycemia, Diabetes Mellitus

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NaloxoneDrug

    Also called NARCAN Nasal Spray

    Naloxone Nasal Spray

  • DiazoxideDrug

    Diazoxide (oral)

  • Placebo (for Naloxone)Drug

    Sterile water nasal spray

  • Placebo (for Diazoxide)Drug

    Taste matched oral placebo for diazoxide

Study groups in NCT03608163
Study groupRoleWhat they receive
No intervention (Susceptibility to HAAF evaluation)No interventionSusceptibility to HAAF evaluation: No intervention medication will be given during episodes of hypoglycemia.
NaloxoneExperimentalNaloxone 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.
Receives: Drug: Naloxone
Placebo (for Naloxone)Placebo comparatorNaloxone 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.
Receives: Drug: Placebo (for Naloxone)
Naloxone + diazoxideExperimentalNaloxone/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.
Receives: Drug: Naloxone; Drug: Diazoxide
Diazoxide + placebo (for naloxone)Active comparatorNaloxone/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.
Receives: Drug: Diazoxide; Drug: Placebo (for Naloxone)
Naloxone + placebo (for diazoxide)Active comparatorNaloxone/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.
Receives: Drug: Naloxone; Drug: Placebo (for Diazoxide)
Placebo (for naloxone) + placebo (for diazoxide)Placebo comparatorNaloxone/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.
Receives: Drug: Placebo (for Naloxone); Drug: Placebo (for Diazoxide)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes

    Peak epinephrine levels during the first (during Day 1) and third (During Day 2) hypoglycemic clamp episodes were compared. Blood samples were taken every 15 minutes throughout clamp procedures and analyzed using high performance liquid chromatography to measure epinephrine levels. Peak epinephrine levels during the course of the three clamp procedures over the two days were identified for each participant. Results are summarized and reported by study arm using basic descriptive statistics. A reduction of >20% in the average peak epinephrine levels between first and third hypoglycemic clamp episodes will be considered to define HAAF.

    Measured: Obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to approximately 6 months apart

Secondary outcomes (2)

  1. Endogenous Glucose Production (EGP)

    EGP, a measure of the body's production of sugar, was assessed by determining the Glucose Infusion Rate (GIR), an indirect measure of endogenous glucose production, during the first and third hypoglycemic clamp episodes. GIR is reported in cubic centimeters/minute (cc/min) and results are summarized and reported by study arm using basic descriptive statistics.

    Measured: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~6 months apart. Data from the five timepoints over the final hour of the 1st and 3rd clamp episodes were averaged/reported.

  2. Symptoms of Low Blood Sugar

    Symptoms of low blood sugar were assessed during steady state (the last 30 minutes) using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS questionnaire is comprised 11 key symptoms (sweating, palpitations, shaking, hunger, confusion, drowsiness, odd behavior, speech difficulty, incoordination, nausea, and headache) and asked participants to evaluate these symptoms using an 8-point Likert scale ranging from 0 ("Not at all") to 7 ("Very severe"), for an overall possible range of 0-77 for each patient, such that higher scores are associated with more intense hypoglycemic symptoms. EHSS scores were summed and averaged and reported by study arm using basic descriptive statistics.

    Measured: Obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to approximately 6 months apart

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jul 2018
  2. Study start8 Jan 2019
  3. Primary completion22 Aug 2019
  4. Study completion22 Aug 2019

Why it stopped: Study suspended for a prolonged duration due to the Pandemic. Once research resumed project was streamlined due to insufficient resources. Study was sufficiently powered to conduct analysis for 2 of the arms. Remaining Aims were never initiated.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Crossover
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 blind
Who is masked
Participant, Investigator
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03608163
Sponsor's protocol ID
2018-9208
Other IDs
R01DK079974
Status last verified
Aug 2025
First submitted
24 Jul 2018
Last updated
11 Sep 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Naloxone and Diazoxide in people with Diabetes Mellitus, Type 1 and Hypoglycemia, run by Albert Einstein College of Medicine at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 11 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Sep 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes (time frame: Obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to approximately 6 months apart). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03608163.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2025.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in