Trial Outcomes & Findings for Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF) (NCT NCT03608163)

Last Updated: 2025-09-11

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

4 participants

Primary outcome timeframe

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

Results posted on

2025-09-11

Participant Flow

4 patients were consented and enrolled into Aim 2 of the study.

Participant milestones

Participant milestones
Measure	Naloxone First, Then Placebo Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray	Placebo (for Naloxone), Then Naloxone Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray
1st Intervention (2 Days) STARTED	2	2
1st Intervention (2 Days) COMPLETED	2	2
1st Intervention (2 Days) NOT COMPLETED	0	0
Washout (~6 Months) STARTED	2	2
Washout (~6 Months) COMPLETED	2	2
Washout (~6 Months) NOT COMPLETED	0	0
2nd Intervention (2 Days) STARTED	2	2
2nd Intervention (2 Days) COMPLETED	2	1
2nd Intervention (2 Days) NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Naloxone First, Then Placebo Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray	Placebo (for Naloxone), Then Naloxone Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray
2nd Intervention (2 Days) Physician Decision	0	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=4 Participants Naloxone 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. Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray
Age, Continuous	46.5 years STANDARD_DEVIATION 10.9 • n=4 Participants
Sex: Female, Male Female	0 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=4 Participants
Region of Enrollment United States	4 participants n=4 Participants
Body Mass Index (BMI)	24.9 kg/m^2 STANDARD_DEVIATION 0.7 • n=4 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Naloxone n=3 Participants Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray	Placebo (for Naloxone) n=4 Participants Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray
Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes 1st hypoglycemic clamp episode (Day 1)	372 pg/mL Standard Error 134	707 pg/mL Standard Error 195
Comparison of Peak Epinephrine Levels Between First and Third Hypoglycemic Clamp Episodes 3rd hypoglycemic clamp episode (Day 2)	397 pg/mL Standard Error 168	601 pg/mL Standard Error 55

SECONDARY outcome

Timeframe: 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.

Population: GIR data was obtained from 1 participant following Naloxone administration and 3 participants following Placebo administration.

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.

Outcome measures

Outcome measures
Measure	Naloxone n=1 Participants Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray	Placebo (for Naloxone) n=3 Participants Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray
Endogenous Glucose Production (EGP) 1st hypoglycemic clamp episode (Day 1)	1.6 cc/min Standard Error NA Standard error is not able to be determined for the Naloxone participant due to sample size of 1.	0.7 cc/min Standard Error 0.2
Endogenous Glucose Production (EGP) 3rd hypoglycemic clamp episode (Day 2)	0.9 cc/min Standard Error NA Standard error is not able to be determined for the Naloxone participant due to sample size of 1.	1.1 cc/min Standard Error 0.3

SECONDARY outcome

Timeframe: 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

Population: Symptoms of low blood sugar scores were able to be collected from 1 participant following Naloxone administration and 3 participants following Placebo administration.

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.

Outcome measures

Outcome measures
Measure	Naloxone n=1 Participants Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray	Placebo (for Naloxone) n=3 Participants Naloxone 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. Naloxone: Naloxone Nasal Spray Placebo (for Naloxone): Sterile water nasal spray
Symptoms of Low Blood Sugar 1st hypoglycemic clamp episode (Day 1)	2.0 score on a scale Standard Error NA Standard error is not able to be determined for the Naloxone participant due to sample size of 1.	4.5 score on a scale Standard Error 2.1
Symptoms of Low Blood Sugar 3rd hypoglycemic clamp episode (Day 2)	1.2 score on a scale Standard Error NA Standard error is not able to be determined for the Naloxone participant due to sample size of 1.	4.2 score on a scale Standard Error 2.4

Adverse Events

Naloxone

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo (for Naloxone)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr. Meredith Hawkins

Albert Einstein College of Medicine

Phone: 718-430-2903

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place