Diabetes MellitusPhase 2NCT00678145
Mechanisms of Hypoglycemia Associated Autonomic Failure
A Phase 2 study testing naloxone, fructose and exercise in people with Diabetes Mellitus and Hypoglycemia, run by Albert Einstein College of Medicine at 1 site in United States.
Trial summary
Intensive glucose control in type 1 diabetes mellitus (T1DM) is associated with clear health benefits. However, despite development of insulin analogs, pump/multi-dose treatment and continuous glucose monitoring, maintaining near-normal glycemia remains an elusive goal for most patients, in large part owing to the… Read more about this study
- Who is it for?
- Ages 21 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Hypoglycemia, Autonomic Failure
- What is being tested?
- naloxone, fructose and exercise
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 39 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2008to Aug 2018
- Phase
- Phase 2
- 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 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Non-diabetic individuals
Who cannot join
- Hypertension
- Hyperlipidemia
- Heart disease
- Cerebrovascular disease
- Seizures
- Bleeding disorders
Trial locations and contacts
1 site in 1 country.
United States1 site
Albert Einstein College of Medicine / General Clinical Research Center
The Bronx, New York, 10461
About this study
Intensive glucose control in type 1 diabetes mellitus (T1DM) is associated with clear health benefits. However, despite development of insulin analogs, pump/multi-dose treatment and continuous glucose monitoring, maintaining near-normal glycemia remains an elusive goal for most patients, in large part owing to the risk of hypoglycemia. T1DM patients are susceptible to hypoglycemia due to defective counterregulatory responses (CR) characterized by: 1) deficient glucagon release during impending/early hypoglycemia; 2) additional hypoglycemia-associated autonomic failure (HAAF) and exercise-associated autonomic failure (EAAF) that blunt the sympathoadrenal responses to hypoglycemia following repeated episodes of hypoglycemia or exercise as well as degrading other CR; and 3) hypoglycemia unawareness (HU), lowering the threshold for symptoms that trigger behavioral responses (e.g. eating). Thus, the risk of hypoglycemia in T1DM impedes ideal insulin treatment and leads to defaulting to suboptimal glycemic control. There are two approaches that could resolve this important clinical problem: 1) perfection of glucose sensing and insulin and glucagon delivery approaches (bioengineered or cell-based) that mimic normal islet function and precisely regulate glucose continuously, or 2) a drug to enhance or normalize the pattern of CR to hypoglycemia. Despite much research and important advances in the field, neither islet transplantation nor biosensor devices have emerged as viable long-term solutions for the majority of patients. Over the past several years, the Diabetes Research Center laboratory at Albert Einstein College of Medicine has explored the approach of enhancing CR by examining mechanisms responsible for HAAF/EAAF and searching for potential pharmacological methods to modulate the CR to hypoglycemia. The work by the laboratory has led to a paradigm shift in the field of hypoglycemia, exemplified by the novel hypothesis and published experimental data supporting a role for opioid signaling that resulted in the initiation of exploratory clinical trials by other research groups.
Read the detailed description
In the prior project period of R01DK079974, the study team elucidated the central role played by the opioid signaling system as a mechanism for the development of HAAF/EAAF. The study team has previously demonstrated that opioid receptor blockade by acute infusion of naloxone during antecedent hypoglycemia can prevent experimentally induced HAAF in nondiabetic and T1DM subjects (JCEM 94:3372-80, 2009; JCEM 96:3424-31, 2011). The study team has also shown that opioid receptor blockade also abolishes EAAF, and that both effects are regulated by the stress response (hypoglycemia and exercise, respectively). Furthermore, activation of μ-opioid receptors with IV infusion of morphine reproduces some of the key biochemical and clinical features of HAAF in nondiabetic humans. Taken together, these studies demonstrate that the opioid system plays a central role in hypoglycemia counterregulation and in HAAF.
NOTE: This ClinicalTrials.gov registration does not include the proposed fructose and exercise interventions described within the Arms/Interventions section. These interventions predate the change in PI and official notice of transfer of the NIH-NIDDK grant on February 06, 2014 and were not conducted. Interventions conducted as part of this study include the independent assessments of Epinephrine and Morphine as part of Aim 1 and assessment of intranasal Naloxone as part of Aim 3: Aim 2 of this protocol was not conducted prior to early termination of the study.
It should be noted that information, including summarized Results data for four of the participants associated with the intranasal naloxone intervention were reported as part of a separate study approved by the IRB under a different study number. For these results, please reference NCT03608163 (ID: 2018-9208).
- Conditions
- Diabetes Mellitus, Hypoglycemia, Autonomic Failure
- Being tested
- naloxone, fructose, exercise, Morphine sulfate, Epinephrine
- Keywords
- Diabetes, Hypoglycemia, HAAF, Counterregulation
- Medical subject headings
- Diabetes Mellitus, Hypoglycemia, Pure Autonomic Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
naloxoneDrug
Also called Narcan
Administering naloxone on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
fructoseDietary supplement
Also called Insulin
Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
exerciseBehavioural
Administering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Morphine sulfateDrug
Also called Morphine
Administering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
EpinephrineDrug
Also called Adrenaline
Administering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
| Study group | Role | What they receive |
|---|---|---|
| Healthy | Experimental | Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator. Receives: Drug: naloxone; Dietary Supplement: fructose; Behavioral: exercise; Drug: Morphine sulfate; Drug: Epinephrine |
| Type 1 Diabetes | Experimental | T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator. Receives: Drug: naloxone; Dietary Supplement: fructose; Behavioral: exercise; Drug: Morphine sulfate; Drug: Epinephrine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Endogenous Glucose Production (EGP) Response Rate - Morphine Sulfate Study
EGP response after antecedent morphine administration was assessed in the Morphine Sulfate vs Matched Placebo study. EGP response is a measure of how the body produces glucose from substrates to maintain blood sugar levels, particularly during fasting. Morphine was administered on Day 1 followed by a stepped hypoglycemia clamp (i.e., euglycemia → 90 mg/dl → 80 mg/dl → 70 mg/dl → 60 mg/dl) on Day 2. EGP response rate is reported in milligrams/kilograms/minute (mg/kg/min) and results are summarized and reported by study arm using basic descriptive statistics. Data from the final hour of the 3rd clamp episode were averaged/reported.
Measured: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~7 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
Endogenous Glucose Production (EGP) Via Glucose Infusion Rate - Naloxone Study
For the Naloxone vs Matched Placebo study, 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 ~5 months apart. Data from the five timepoints over the final hour of the 1st and 3rd clamp episodes were averaged/reported.
Endogenous Glucose Production (EGP) Response Rate - Epinephrine Study
EGP response after antecedent epinephrine administration was assessed in the Epinephrine vs Matched Epinephrine study. EGP response, a measure of how the body produces glucose from substrates to maintain blood sugar levels, was assessed during the final hypoglycemic clamp episode. EGP at the major nadir at the 60 mg/dL, during the last 10 minutes of the 3rd clamp episode, is reported in milligrams per kilogram per minute (mg/kg/min) and results are summarized and reported by study arm using basic descriptive statistics. Data from the final hour of the 3rd clamp episode were averaged/reported
Measured: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~19 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
Counterregulatory Response to Hypoglycemia - Morphine Sulfate Study
Counterregulatory response to hypoglycemia was assessed for the Morphine Sulfate study by quantifying peak plasma responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 54 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. Group mean results are summarized for the Morphine Sulfate arm and Matched Placebo arm.
Measured: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~7 months apart.
Counterregulatory Response to Hypoglycemia - Naloxone Study
Counterregulatory response to hypoglycemia was assessed for the Naloxone study by quantifying peak plasma responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 54 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. The second challenge on Day 1 was conducted to assess the impact of the third episode for informational purposes only but was not reported. Group mean results are summarized for the 1st and 3rd episodes in the Naloxone arm and Matched Placebo arm.
Measured: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~5 months apart.
Counterregulatory Response to Hypoglycemia - Epinephrine Study
Counterregulatory response to hypoglycemia was assessed for the Epinephrine study by quantifying peak plasma epinephrine level responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 60 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. Group mean results are summarized for the Epinephrine arm and Matched Placebo arm.
Measured: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~19 months apart.
Hypoglycemic Symptom Scores - Morphine Sulfate Study
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 8-point Likert scale ranging from 0 = "Not at all" to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Measured: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores - Naloxone Study
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 8-point Likert scale ranging from 0 = "Not at all", to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Measured: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores - Epinephrine Study
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 7-point Likert scale ranging from 1 = "Not at all", to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Measured: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 May 2008 (estimated)
- Study startMar 2008
- Primary completionAug 2018
- Study completionAug 2018
Why it stopped: Protocol was terminated due to enrollment + feasibility issues. Aim 2 not conducted. Aims 1 + 3 were conducted in part. During Aim 3 the IRB requested that the study be transitioned under a new protocol (2018-9208) in order to simplify reporting.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diabetes MellitusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 39 participants (actual)
Sponsor and investigators
- Lead sponsor
- Albert Einstein College of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Responsible party
- Principal investigator, Meredith Hawkins, Albert Einstein College of Medicine
- Investigators
- Meredith Hawkins, M.D., M.S., Principal investigator, Albert Einstein College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00678145
- Sponsor's protocol ID
- 2012-665
- Other IDs
- R01DK079974
- Status last verified
- Apr 2026
- First submitted
- 14 May 2008
- Last updated
- 19 May 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Carey M, Gospin R, Goyal A, Tomuta N, Sandu O, Mbanya A, Lontchi-Yimagou E, Hulkower R, Shamoon H, Gabriely I, Hawkins M. Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans. Diabetes. 2017 Nov;66(11):2764-2773. doi: 10.2337/db16-1478. Epub 2017 Aug 31.
PubMed 28860128Milman S, Leu J, Shamoon H, Vele S, Gabriely I. Opioid receptor blockade prevents exercise-associated autonomic failure in humans. Diabetes. 2012 Jun;61(6):1609-15. doi: 10.2337/db11-1622. Epub 2012 Apr 20.
PubMed 22522612
Study at a glance
From the registry record, last updated by the sponsor on 19 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanisms of Hypoglycemia Associated Autonomic Failure
- ClinicalTrials.gov ID
- NCT00678145
- Acronym / sponsor ID
- 2012-665
- Conditions
- Diabetes Mellitus, Hypoglycemia, Autonomic Failure
- Keywords
- Diabetes, Hypoglycemia, HAAF, Counterregulation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Protocol was terminated due to enrollment + feasibility issues. Aim 2 not conducted. Aims 1 + 3 were conducted in part. During Aim 3 the IRB requested that the study be transitioned under a new protocol (2018-9208) in order to simplify reporting.
- Enrolment
- 39 participants (actual)
- Lead sponsor
- Albert Einstein College of MedicineUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Mar 2008 (actual)
- Primary completion
- Aug 2018 (actual)
- Study completion
- Aug 2018 (actual)
- First posted
- 15 May 2008 (estimated)
- Results
- Posted 19 May 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Intensive glucose control in type 1 diabetes mellitus (T1DM) is associated with clear health benefits. However, despite development of insulin analogs, pump/multi-dose treatment and continuous glucose monitoring, maintaining near-normal glycemia remains an elusive goal for most patients, in large part owing to the risk of hypoglycemia. T1DM patients are susceptible to hypoglycemia due to defective counterregulatory responses (CR) characterized by: 1) deficient glucagon release during impending/early hypoglycemia; 2) additional hypoglycemia-associated autonomic failure (HAAF) and exercise-associated autonomic failure (EAAF) that blunt the sympathoadrenal responses to hypoglycemia following repeated episodes of hypoglycemia or exercise as well as degrading other CR; and 3) hypoglycemia unawareness (HU), lowering the threshold for symptoms that trigger behavioral responses (e.g. eating). Thus, the risk of hypoglycemia in T1DM impedes ideal insulin treatment and leads to defaulting to suboptimal glycemic control. There are two approaches that could resolve this important clinical problem: 1) perfection of glucose sensing and insulin and glucagon delivery approaches (bioengineered or cell-based) that mimic normal islet function and precisely regulate glucose continuously, or 2) a drug to enhance or normalize the pattern of CR to hypoglycemia. Despite much research and important advances in the field, neither islet transplantation nor biosensor devices have emerged as viable long-term solutions for the majority of patients. Over the past several years, the Diabetes Research Center laboratory at Albert Einstein College of Medicine has explored the approach of enhancing CR by examining mechanisms responsible for HAAF/EAAF and searching for potential pharmacological methods to modulate the CR to hypoglycemia. The work by the laboratory has led to a paradigm shift in the field of hypoglycemia, exemplified by the novel hypothesis and published experimental data supporting a role for opioid signaling that resulted in the initiation of exploratory clinical trials by other research groups.
Detailed description
In the prior project period of R01DK079974, the study team elucidated the central role played by the opioid signaling system as a mechanism for the development of HAAF/EAAF. The study team has previously demonstrated that opioid receptor blockade by acute infusion of naloxone during antecedent hypoglycemia can prevent experimentally induced HAAF in nondiabetic and T1DM subjects (JCEM 94:3372-80, 2009; JCEM 96:3424-31, 2011). The study team has also shown that opioid receptor blockade also abolishes EAAF, and that both effects are regulated by the stress response (hypoglycemia and exercise, respectively). Furthermore, activation of μ-opioid receptors with IV infusion of morphine reproduces some of the key biochemical and clinical features of HAAF in nondiabetic humans. Taken together, these studies demonstrate that the opioid system plays a central role in hypoglycemia counterregulation and in HAAF.
NOTE: This ClinicalTrials.gov registration does not include the proposed fructose and exercise interventions described within the Arms/Interventions section. These interventions predate the change in PI and official notice of transfer of the NIH-NIDDK grant on February 06, 2014 and were not conducted. Interventions conducted as part of this study include the independent assessments of Epinephrine and Morphine as part of Aim 1 and assessment of intranasal Naloxone as part of Aim 3: Aim 2 of this protocol was not conducted prior to early termination of the study.
It should be noted that information, including summarized Results data for four of the participants associated with the intranasal naloxone intervention were reported as part of a separate study approved by the IRB under a different study number. For these results, please reference NCT03608163 (ID: 2018-9208).
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Healthy | Experimental | Drug: naloxone, Dietary Supplement: fructose, Behavioral: exercise, Drug: Morphine sulfate, Drug: EpinephrineHealthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator. |
| Type 1 Diabetes | Experimental | Drug: naloxone, Dietary Supplement: fructose, Behavioral: exercise, Drug: Morphine sulfate, Drug: EpinephrineT1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator. |
Who may qualify
- Ages
- 21 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Non-diabetic individuals
Key exclusion criteria (6 listed)
- Hypertension
- Hyperlipidemia
- Heart disease
- Cerebrovascular disease
- Seizures
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| naloxoneAlso: NarcanAdministering naloxone on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. | Drug | Healthy, Type 1 Diabetes |
| fructoseAlso: InsulinAdministering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. | Dietary supplement | Healthy, Type 1 Diabetes |
| exerciseAdministering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. | Behavioural | Healthy, Type 1 Diabetes |
| Morphine sulfateAlso: MorphineAdministering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. | Drug | Healthy, Type 1 Diabetes |
| EpinephrineAlso: AdrenalineAdministering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. | Drug | Healthy, Type 1 Diabetes |
Primary outcome
Endogenous Glucose Production (EGP) Response Rate - Morphine Sulfate Study
Time frame: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~7 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
EGP response after antecedent morphine administration was assessed in the Morphine Sulfate vs Matched Placebo study. EGP response is a measure of how the body produces glucose from substrates to maintain blood sugar levels, particularly during fasting. Morphine was administered on Day 1 followed by a stepped hypoglycemia clamp (i.e., euglycemia → 90 mg/dl → 80 mg/dl → 70 mg/dl → 60 mg/dl) on Day 2. EGP response rate is reported in milligrams/kilograms/minute (mg/kg/min) and results are summarized and reported by study arm using basic descriptive statistics. Data from the final hour of the 3rd clamp episode were averaged/reported.
Endogenous Glucose Production (EGP) Via Glucose Infusion Rate - Naloxone Study
Time frame: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~5 months apart. Data from the five timepoints over the final hour of the 1st and 3rd clamp episodes were averaged/reported.
For the Naloxone vs Matched Placebo study, 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.
Endogenous Glucose Production (EGP) Response Rate - Epinephrine Study
Time frame: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~19 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
EGP response after antecedent epinephrine administration was assessed in the Epinephrine vs Matched Epinephrine study. EGP response, a measure of how the body produces glucose from substrates to maintain blood sugar levels, was assessed during the final hypoglycemic clamp episode. EGP at the major nadir at the 60 mg/dL, during the last 10 minutes of the 3rd clamp episode, is reported in milligrams per kilogram per minute (mg/kg/min) and results are summarized and reported by study arm using basic descriptive statistics. Data from the final hour of the 3rd clamp episode were averaged/reported
Counterregulatory Response to Hypoglycemia - Morphine Sulfate Study
Time frame: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~7 months apart.
Counterregulatory response to hypoglycemia was assessed for the Morphine Sulfate study by quantifying peak plasma responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 54 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. Group mean results are summarized for the Morphine Sulfate arm and Matched Placebo arm.
Counterregulatory Response to Hypoglycemia - Naloxone Study
Time frame: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~5 months apart.
Counterregulatory response to hypoglycemia was assessed for the Naloxone study by quantifying peak plasma responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 54 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. The second challenge on Day 1 was conducted to assess the impact of the third episode for informational purposes only but was not reported. Group mean results are summarized for the 1st and 3rd episodes in the Naloxone arm and Matched Placebo arm.
Counterregulatory Response to Hypoglycemia - Epinephrine Study
Time frame: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~19 months apart.
Counterregulatory response to hypoglycemia was assessed for the Epinephrine study by quantifying peak plasma epinephrine level responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 60 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. Group mean results are summarized for the Epinephrine arm and Matched Placebo arm.
Hypoglycemic Symptom Scores - Morphine Sulfate Study
Time frame: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 8-point Likert scale ranging from 0 = "Not at all" to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Hypoglycemic Symptom Scores - Naloxone Study
Time frame: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 8-point Likert scale ranging from 0 = "Not at all", to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Hypoglycemic Symptom Scores - Epinephrine Study
Time frame: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 7-point Likert scale ranging from 1 = "Not at all", to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 May 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 28860128Carey M, Gospin R, Goyal A, Tomuta N, Sandu O, Mbanya A, Lontchi-Yimagou E, Hulkower R, Shamoon H, Gabriely I, Hawkins M. Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans. Diabetes. 2017 Nov;66(11):2764-2773. doi: 10.2337/db16-1478. Epub 2017 Aug 31.
- Derived from this study: PubMed 22522612Milman S, Leu J, Shamoon H, Vele S, Gabriely I. Opioid receptor blockade prevents exercise-associated autonomic failure in humans. Diabetes. 2012 Jun;61(6):1609-15. doi: 10.2337/db11-1622. Epub 2012 Apr 20.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Meredith Hawkins, M.D., M.S. principal investigator
Albert Einstein College of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing naloxone, fructose and exercise in people with Diabetes Mellitus 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 6 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 19 May 2026. 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. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 19 May 2026). 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?
Endogenous Glucose Production (EGP) Response Rate - Morphine Sulfate Study (time frame: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~7 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.). The study lists 9 primary outcomes in all. 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 NCT00678145, which also lists 2 linked publications.
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 19 May 2026.