Naloxone, Hypoglycemia and Exercise

Hypoglycemia After Exercise in Type 1 Diabetes: Intranasal Naloxone as a Novel Therapy to Preserve Hypoglycemia Counterregulation

The overall objective of this project is to determine if the intranasal administration of naloxone during exercise will be a novel approach to preserve the counterregulatory response to hypoglycemia experienced the next day in patients with type 1 diabetes. Exercise induced autonomic failure contributes to the development of impaired awareness of hypoglycemia. Treatments that blunt the consequences of exercise induced autonomic failure, such as preserving the post-exercise counterregulatory response to hypoglycemia, may improve awareness of hypoglycemia. Naloxone, an opioid antagonist, is an extremely promising agent. In healthy volunteers, intravenous administration of naloxone during exercise preserved the counterregulatory response to hypoglycemia the following day (1). In this study, investigators will extend the clinical applicability by administering intranasal naloxone to individuals with type 1 diabetes. Specifically, the investigators will use a randomized, placebo controlled, crossover design to administer drug or placebo to patients with type 1 diabetes during acute exercise and assess the counterregulatory response to hypoglycemia the following day. The use of intranasal naloxone is a highly innovative aspect of this proposal. Intranasal naloxone translates readily to clinical use and, as demonstrated by the investigators preliminary data, achieves similar plasma drug concentrations as after IV administration.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Naloxone then placebo; Drug: Placebo then Naloxone

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Type 1 diabetes diagnosed on clinical grounds (history of DKA, use of insulin within 6 months of diagnosis)
• Diabetes duration < 30 years (impaired awareness of hypoglycemia increases with duration so it will be more likely that shorter duration participants will have hypoglycemia awareness) but > 2 years (to ensure that they have lost hypoglycemia induced glucagon secretion as is typical in patients who develop impaired awareness of hypoglycemia)
• Age 18 - 65 years
• Baseline hemoglobin A1C 6.8 - 9.0% (range selected to reduce the risk of hypoglycemia and uncontrolled diabetes in the weeks before the study, both of which may affect the responses to hypoglycemia)
• Awareness of hypoglycemia as verified by Cox questionnaire

Exclusion Criteria:

• History of stroke, seizures (other than those related to hypoglycemia), arrhythmias, active cardiac disease
• History of hypertension or blood pressure > 140/95 mm Hg at screening visit
• Pregnancy or plan to become pregnant during the study period
• Health related limitations in exercise (including but not limited to: angina, uncontrolled asthma, peripheral arterial disease)
• Unwillingness to avoid exercise during the 7 days before each part of the study
• Concomitant medical problems that may prevent the participant from successfully completing the protocol
• Smoking as defined by 2 or more tobacco cigarettes a week
• Daily use of opioids or an opioid antagonist or use in the past two weeks
• Unwillingness to wear a continuous glucose monitor for one week before and one week after each part of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Naloxone, then placebo	Drug: Naloxone then placebo; naloxone intranasal 4mg, then placebo
Placebo Comparator: 2; Placebo, then Naloxone	Drug: Placebo then Naloxone; placebo then naloxone intranasal 4mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Epinephrine Levels	The primary outcome variable for Aim 2 will be the difference, naloxone vs. saline, in peak epinephrine levels measured during the hypoglycemic clamp on Day 2, after administration of treatment during exercise on Day 1.	Day 2
Change in Symptom Score	The primary outcome variable for Aim 1 will be the difference, naloxone vs. saline, in symptom scores collected using a standard questionnaire during the hypoglycemic clamp on Day 2, after administration of intranasal treatment during exercise on Day 1. the scale for symptoms score is 0-72. A higher score represents a better outcome.	Day 2

Collaborators and Investigators

• Sponsor: University of Minnesota
• Investigators: Principal Investigator: Elizabeth Seaquist, MD, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2017
• Primary Completion (Actual): May 1, 2022
• Study Completion (Actual): April 1, 2023

Study Registration Dates

• First Submitted: May 9, 2017
• First Submitted That Met QC Criteria: May 9, 2017
• First Posted (Actual): May 11, 2017

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Naloxone
• Other Study ID Numbers: MED-2017-25555

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No