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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK079974 | U.S. NIH Grant/Contract | View source |
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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.
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Healthy | Experimental | Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator. |
|
| Type 1 Diabetes | Experimental | T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| naloxone | Drug | Administering naloxone on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Meredith Hawkins, M.D., M.S. | Albert Einstein College of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Albert Einstein College of Medicine / General Clinical Research Center | The Bronx | New York | 10461 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28860128 | Derived | 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. | |
| 22522612 | Derived | Milman 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. |
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Zero (0) Type 1 Diabetes (T1D) patients were enrolled into the study. All study participants were healthy individuals without diabetes who were not on medication and had no history of hypoglycemia or family history of diabetes. One participant in the Naloxone vs Placebo comparator crossover study consented but was not enrolled. As such, 17 participants were enrolled into that study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Healthy (Non-Type 1 Diabetes) Participants. Morphine Sulfate First, Then Placebo | Healthy participants received Morphine Sulfate first, and then Placebo comparator. Morphine Sulfate: Administered Morphine on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. |
| FG001 | Healthy (Non-Type 1 Diabetes) Participants. Placebo First, Then Morphine Sulfate | Healthy participants received Placebo comparator first, then Morphine Sulfate. Placebo (for Morphine Sulfate): Placebo saline nasal spray administered in one nostril at the start of insulin infusion and again after 60 minutes. Day 2 will include a single two-hour hypoglycemic clamp. |
| FG002 | Healthy (Non-Type 1 Diabetes) Participants. Epinephrine First, Then Placebo | Healthy participants received Epinephrine first, then Placebo comparator. Epinephrine: Administered Epinephrine on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. |
| FG003 | Healthy (Non-Type 1 Diabetes) Participants. Placebo First, Then Epinephrine | Healthy participants received Placebo comparator first, then Epinephrine. Placebo (for Epinephrine): Placebo saline nasal spray administered in one nostril at the start of insulin infusion and again after 60 minutes. Day 2 will include a single two-hour hypoglycemic clamp. |
| FG004 | Healthy (Non-Type 1 Diabetes) Participants. Naloxone First, Then Placebo | Healthy participants received Naloxone first, then Placebo comparator. Naloxone: Intranasal naloxone (4 mg NARCAN® Nasal Spray) administered twice during each hypoglycemia episode on Day 1, at the start of insulin administration and after one hour. Day 2 will include a single two-hour hypoglycemic clamp. Naloxone: Naloxone Nasal Spray (NARCAN®) |
| FG005 | Healthy (Non-Type 1 Diabetes) Participants. Placebo First, Then Naloxone | Healthy participants received Placebo comparator first, then Naloxone. Placebo (for Naloxone): Sterile water nasal spray administered twice during each hypoglycemia episode on Day 1, at the start of insulin administration and after one hour. Day 2 will include a single two-hour hypoglycemic clamp. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1st Intervention (2 Days) |
| |||||||||||||
| Washout (~5-19 months) |
| |||||||||||||
| 2nd Intervention (2 Days) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Naloxone and Placebo Participants | XXXXX healthy individuals without diabetes. All were in good health, taking no medications and no history of hypoglycemia or family history of diabetes. |
| BG001 | All Morphine Sulfate and Saline Participants |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Age data was not documented from three (3) participants at baseline for the Naloxone vs Placebo comparator crossover study. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | EGP response rate was only assessed following antecedent morphine administration. EGP response was not assessed following other treatment combinations and parameters due to early study termination. | Posted | Mean | Standard Deviation | mg/kg/min | 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. |
Adverse events were assessed on two consecutive days over two series of visits. For the morphine/placebo crossover study, visits were scheduled up to a maximum of 7 months apart. For the naloxone/placebo crossover study, visits were scheduled up to a maximum of 5 months apart. For the epinephrine/placebo crossover study, visits were scheduled up to a maximum of 19 months apart.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Morphine Sulfate | Healthy participants received Morphine Sulfate and placebo comparator. Morphine Sulfate: Administered Morphine on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. Matched Placebo: Administered matched placebo on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. |
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Early termination of study led to small cohorts being enrolled. No T1D patients were consented/enrolled into any of the studies.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Meredith Hawkins | Diabetes Research and Training Center, Albert Einstein College of Medicine | 718 430 2903 | meredith.hawkins@einsteinmed.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 8, 2018 | Feb 21, 2026 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Mar 8, 2018 | Nov 4, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D007003 | Hypoglycemia |
| D054970 | Pure Autonomic Failure |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D009270 | Naloxone |
| D005632 | Fructose |
| D007328 | Insulin |
| D015444 | Exercise |
| D009020 | Morphine |
| D004837 | Epinephrine |
| ID | Term |
|---|---|
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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| fructose | Dietary Supplement | Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. |
|
|
| exercise | Behavioral | Administering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. |
|
| Morphine sulfate | Drug | Administering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. |
|
|
| Epinephrine | Drug | Administering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2. |
|
|
| 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. | 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. | 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. | 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. | 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. | 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. | 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 |
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
|
12 healthy individuals without diabetes. All were in good health, taking no medications and no history of hypoglycemia or family history of diabetes. |
| BG002 | All Epinephrine and Placebo Participants | 10 healthy individuals without diabetes. All were in good health, taking no medications and no history of hypoglycemia or family history of diabetes. |
| BG003 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Race data was not collected from any participants in the Naloxone vs Placebo comparator crossover study. | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index (BMI) | BMI measurements were obtained at baseline and reported in kg/m^2. Generally accepted ranges for BMI are < 18.5 = underweight; 18.5-5 = healthy; 25-30 = overweight; 30-40 = obese | Height and weight data was not collected from three participants in the Naloxone vs Placebo crossover study and from one participant in the Epinephrine vs Placebo crossover study. As such, BMI baseline data is not available for these participants. | Mean | Standard Deviation | kg/m^2 |
|
| Hemoglobin-A1C (HbA1c) | HbA1c concentrations were obtained at baseline and summarized and reported in percentages. Normal ranges can vary but for a range of < 5.7% is considered normal. | Blood samples for HbA1c analysis were not collected from any of the 18 participants in the Naloxone vs Placebo comparator crossover study. Blood samples for HbA1c analysis were also not collected from three participants in the Epinephrine vs Placebo comparator crossover study. | Mean | Full Range | percentage |
|
| Fasting Glucose | Blood samples were collected for Fasting Glucose at baseline. Samples were analyzed and baseline results were summarized in mg/dL. Fasting glucose test results measure levels of sugar (glucose) in the blood and is a convenient and common way to screen for prediabetes and diabetes. | Blood samples for Fasting Glucose analysis were not collected from any participants in the Naloxone vs Placebo comparator crossover study. | Mean | Standard Deviation | mg/dL |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | Morphine Sulfate | Morphine Sulfate: Administered Morphine on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. |
| OG001 | Matched Placebo (Saline for Morphine Sulfate) | Healthy participants received Placebo comparator. Placebo (for Morphine Sulfate): Placebo saline nasal spray administered in one nostril at the start of insulin infusion and again after 60 minutes. Day 2 will include a single two-hour hypoglycemic clamp. |
|
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| Primary | 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. | Data from 1 study participant is missing. Two study participants did not receive either the Naloxone or Matched Placebo infusion prior to study termination. | Posted | Mean | Standard Deviation | cc/min | 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. |
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| Primary | 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 | EGP results data were derived from visual estimates of the bar graphs. EGP response rate was only assessed following antecedent epinephrine administration. EGP response was not assessed following other treatment combinations and parameters due to early study termination. | Posted | Median | Full Range | mg/kg/min | 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. |
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| Primary | 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. | Data was not collected from all participants across all timepoints. | Posted | Mean | Standard Error | pg/mL | Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~7 months apart. |
|
|
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| Primary | 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. | Data was not available for 2 participants in the matched placebo arm. | Posted | Mean | Standard Error | pg/mL | Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~5 months apart. |
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| Primary | 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. | Posted | Mean | Standard Error | pg/mL | Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~19 months apart. |
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| Primary | 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. | Posted | Mean | Full Range | score on a scale | 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 |
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| Primary | 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. | Data was unable to be collected from all study participants prior to termination. | Posted | Mean | Full Range | score on a scale | 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 |
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| Primary | 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. | No Type 1 Diabetes participants were enrolled into the study prior to termination. | Posted | Mean | Full Range | score on a scale | 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 |
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| 0 |
| 12 |
| 0 |
| 12 |
| 0 |
| 12 |
| EG001 | Matched Placebo (for Morphine Sulfate) | Matched placebo | 0 | 12 | 0 | 12 | 0 | 12 |
| EG002 | Epinephrine | Healthy participants received Epinephrine and placebo comparator. Epinephrine: Administered Epinephrine on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. Matched Placebo: Administered matched placebo on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. | 0 | 10 | 0 | 10 | 0 | 10 |
| EG003 | Matched Placebo (for Epinephrine) | Matched placebo | 0 | 10 | 0 | 10 | 0 | 10 |
| EG004 | Naloxone | Healthy participants received Naloxone and placebo comparator. Naloxone: Administered Naloxone on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. Matched Placebo: Administered matched placebo on Day 1 and quantified the counterregulatory responses to hypoglycemia on Day 2. | 0 | 17 | 0 | 17 | 0 | 17 |
| EG005 | Matched Placebo (for Naloxone) | Matched placebo | 0 | 17 | 0 | 17 | 0 | 17 |
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| D054969 | Primary Dysautonomias |
| D001342 | Autonomic Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D006572 |
| Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| D002241 | Carbohydrates |
| D007661 | Ketoses |
| D011384 | Proinsulin |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
| D009022 | Morphine Derivatives |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D000588 | Amines |
| D015306 | Biogenic Monoamines |
| D001679 | Biogenic Amines |
| D002395 | Catecholamines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Peak epinephrine for second clamp episode (Day 1) |
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| Peak epinephrine for third clamp episode (Day 2) |
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| Peak epinephrine for third clamp episode (Day 2) |
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