Trial Outcomes & Findings for Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone (NCT NCT04764630)
NCT ID: NCT04764630
Last Updated: 2024-04-19
Results Overview
Naloxone plasma concentrations will be determined at specified timepoints. The four naloxone nasal spray dose arm (1 dose every 2.5 min) will be compared separately to the two naloxone nasal spray dose arm (1 dose every 2.5 min).
COMPLETED
PHASE1
21 participants
10, 12.5, and 15 minutes, 10 minutes reported
2024-04-19
Participant Flow
Participant milestones
| Measure |
Treatment Sequence ABC
Participants first received treatment A and then crossed over to the sequential treatments with two days of washout in between treatments. Treatments are as follows:
Treatment A: Four 4 mg IN naloxone doses (1 dose every 2.5 min; Left nostril at 0 min, Right nostril at 2.5 min, Left nostril at 5 min, Right nostril at 7.5 min) Treatment B: Four 4 mg IN naloxone doses (2 doses every 2.5 min; Left and Right nostril at 0 min, Left and Right nostril at 2.5 min) Treatment C: Two 4 mg IN naloxone doses (Left nostril at 0 min, Right nostril at 2.5 min)
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Treatment Sequence ACB
Participants first received treatment A and then crossed over to the sequential treatments with two days of washout in between treatments. Treatments are as follows:
Treatment A: Four 4 mg IN naloxone doses (1 dose every 2.5 min; Left nostril at 0 min, Right nostril at 2.5 min, Left nostril at 5 min, Right nostril at 7.5 min) Treatment C: Two 4 mg IN naloxone doses (Left nostril at 0 min, Right nostril at 2.5 min) Treatment B: Four 4 mg IN naloxone doses (2 doses every 2.5 min; Left and Right nostril at 0 min, Left and Right nostril at 2.5 min)
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Treatment Sequence BAC
Participants first received treatment B and then crossed over to the sequential treatments with two days of washout in between treatments. Treatments are as follows:
Treatment B: Four 4 mg IN naloxone doses (2 doses every 2.5 min; Left and Right nostril at 0 min, Left and Right nostril at 2.5 min) Treatment A: Four 4 mg IN naloxone doses (1 dose every 2.5 min; Left nostril at 0 min, Right nostril at 2.5 min, Left nostril at 5 min, Right nostril at 7.5 min) Treatment C: Two 4 mg IN naloxone doses (Left nostril at 0 min, Right nostril at 2.5 min)
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Treatment Sequence BCA
Participants first received treatment B and then crossed over to the sequential treatments with two days of washout in between treatments. Treatments are as follows:
Treatment B: Four 4 mg IN naloxone doses (2 doses every 2.5 min; Left and Right nostril at 0 min, Left and Right nostril at 2.5 min) Treatment C: Two 4 mg IN naloxone doses (Left nostril at 0 min, Right nostril at 2.5 min) Treatment A: Four 4 mg IN naloxone doses (1 dose every 2.5 min; Left nostril at 0 min, Right nostril at 2.5 min, Left nostril at 5 min, Right nostril at 7.5 min)
|
Treatment Sequence CAB
Participants first received treatment C and then crossed over to the sequential treatments with two days of washout in between treatments. Treatments are as follows:
Treatment C: Two 4 mg IN naloxone doses (Left nostril at 0 min, Right nostril at 2.5 min) Treatment A: Four 4 mg IN naloxone doses (1 dose every 2.5 min; Left nostril at 0 min, Right nostril at 2.5 min, Left nostril at 5 min, Right nostril at 7.5 min) Treatment B: Four 4 mg IN naloxone doses (2 doses every 2.5 min; Left and Right nostril at 0 min, Left and Right nostril at 2.5 min)
|
Treatment Sequence CBA
Participants first received treatment C and then crossed over to the sequential treatments with two days of washout in between treatments. Treatments are as follows:
Treatment C: Two 4 mg IN naloxone doses (Left nostril at 0 min, Right nostril at 2.5 min) Treatment B: Four 4 mg IN naloxone doses (2 doses every 2.5 min; Left and Right nostril at 0 min, Left and Right nostril at 2.5 min) Treatment A: Four 4 mg IN naloxone doses (1 dose every 2.5 min; Left nostril at 0 min, Right nostril at 2.5 min, Left nostril at 5 min, Right nostril at 7.5 min)
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|---|---|---|---|---|---|---|
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Overall Study
STARTED
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3
|
4
|
3
|
4
|
3
|
4
|
|
Overall Study
COMPLETED
|
3
|
3
|
3
|
3
|
3
|
3
|
|
Overall Study
NOT COMPLETED
|
0
|
1
|
0
|
1
|
0
|
1
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone
Baseline characteristics by cohort
| Measure |
All Participants
n=21 Participants
Participants were randomized to 1 of 6 treatment sequences (i.e., ABC, ACB, BAC, BCA, CAB, CBA) and over 3 treatment periods received received 3 treatments as follows:
Treatment A: Four 4 mg IN naloxone doses (1 dose every 2.5 min; Left nostril at 0 min, Right nostril at 2.5 min, Left nostril at 5 min, Right nostril at 7.5 min) Treatment B: Four 4 mg IN naloxone doses (2 doses every 2.5 min; Left and Right nostril at 0 min, Left and Right nostril at 2.5 min) Treatment C: Two 4 mg IN naloxone doses (Left nostril at 0 min, Right nostril at 2.5 min)
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|---|---|
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Age, Continuous
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34 Years
n=5 Participants
|
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Sex: Female, Male
Female
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10 Participants
n=5 Participants
|
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Sex: Female, Male
Male
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11 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
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4 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
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17 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
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0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
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0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
9 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
11 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
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0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
1 Participants
n=5 Participants
|
|
Region of Enrollment
United States
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21 participants
n=5 Participants
|
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Body weight
|
79.6 kg
n=5 Participants
|
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Body mass index
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28.4 kg/m^2
n=5 Participants
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PRIMARY outcome
Timeframe: 10, 12.5, and 15 minutes, 10 minutes reportedPopulation: Includes any participant who had naloxone plasma concentration samples available within the specified PK sampling window and who did not miss one of the assigned doses. Prespecified timepoints for comparison were 10, 12.5, and 15 minutes. Only the data for the first timepoint when there is a higher naloxone plasma concentration in the 4 naloxone dose arm was prespecified for reporting. 10-minute data is shown. below
Naloxone plasma concentrations will be determined at specified timepoints. The four naloxone nasal spray dose arm (1 dose every 2.5 min) will be compared separately to the two naloxone nasal spray dose arm (1 dose every 2.5 min).
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=17 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=17 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
First Timepoint When There is a Higher Naloxone Plasma Concentration in the 4 Naloxone Dose Arm (1 Every 2.5 Min) Compared to the 2 Naloxone Dose Arm (1 Every 2.5 Min)
|
8.49 ng/mL
Geometric Coefficient of Variation 70
|
4.42 ng/mL
Geometric Coefficient of Variation 159
|
—
|
PRIMARY outcome
Timeframe: 4.5, 7, and 10 minutesPopulation: Includes any participant who had naloxone plasma concentration samples available within the specified PK sampling window and who did not miss one of the assigned doses. Prespecified timepoints for comparison were 4.5, 7, and 10 minutes. Only the data for the first timepoint when there is a higher naloxone plasma concentration in the 4 naloxone dose arm (2 doses every 2.5 min) was prespecified for reporting. 4.5-minute data is shown. below
Naloxone plasma concentrations will be determined at specified timepoints. The four naloxone nasal spray dose arm (2 doses every 2.5 min) will be compared separately to the two naloxone nasal spray dose arm (1 dose every 2.5 min).
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=16 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=16 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
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|---|---|---|---|
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First Timepoint When There is a Higher Naloxone Plasma Concentration in the 4 Naloxone Dose Arm (2 Doses Every 2.5 Min) Compared to the 2 Naloxone Dose Arm (1 Every 2.5 Min)
|
2.24 ng/mL
Geometric Coefficient of Variation 134
|
1.23 ng/mL
Geometric Coefficient of Variation 250
|
—
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SECONDARY outcome
Timeframe: 4.5, 7, and 10 minutesPopulation: Includes any participant who had naloxone plasma concentration samples available within the specified PK sampling window and who did not miss one of the assigned doses. Prespecified timepoints for comparison were 4.5, 7, and 10 minutes. Only the data for the first timepoint when there is a higher naloxone plasma concentration in the 4 naloxone dose arm (2 every 2.5 min) was prespecified for reporting. 4.5-minute data is shown. below
Naloxone plasma concentrations will be determined at specified timepoints. The 4 naloxone dose arm B (2 doses every 2.5 min) will be compared to the 4 naloxone dose arm A (1 dose every 2.5 min)
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
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First Timepoint When There is a Higher Naloxone Plasma Concentration in the 4 Naloxone Dose Arm B (2 Doses Every 2.5 Min) Compared to the 4 Naloxone Dose Arm A (1 Dose Every 2.5 Minutes)
|
2.24 ng/mL
Geometric Coefficient of Variation 134
|
1.33 ng/mL
Geometric Coefficient of Variation 124
|
—
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SECONDARY outcome
Timeframe: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutesPopulation: Includes any participant who receive study drug and have at least one post-dose sample collected.
Dose proportionality based on Cmax will be compared between each of the three IN naloxone treatments as a secondary endpoint. For the comparisons, the 4 naloxone dose arms will be considered as the test and the reference will be the 2 naloxone dose arm. An additional comparison will be performed between the 4 naloxone dose arm B (2 doses every 2.5 min) as test and the 4 naloxone dose arm A (1 dose every 2.5 min) as reference. Values are reported as dose-normalized Cmax.
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
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|---|---|---|---|
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Dose-proportionality of the 4 Naloxone Dose Arms in Reference to the 2 Naloxone Dose Arm Based on Maximum Concentration (Cmax).
|
1.10 ng/mL / mg (dose)
Geometric Coefficient of Variation 36
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0.96 ng/mL / mg (dose)
Geometric Coefficient of Variation 44
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1.25 ng/mL / mg (dose)
Geometric Coefficient of Variation 48
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SECONDARY outcome
Timeframe: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutesPopulation: Includes any participant who received study drug and had at least one post-dose sample collected.
Dose proportionality based on AUC0-inf will be compared between each of the three IN naloxone treatments as a secondary endpoint. For the comparisons, the 4 naloxone dose arms will be considered as the test and the reference will be the 2 naloxone dose arm. An additional comparison will be performed between the 4 naloxone dose arm B (2 doses every 2.5 min) as test and the 4 naloxone dose arm A (1 dose every 2.5 min) as reference. Values are reported as dose-normalized AUC0-inf.
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
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|---|---|---|---|
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Dose-proportionality of the 4 Naloxone Dose Arms in Reference to the 2 Naloxone Dose Arm Based on Area Under the Curve From Time 0 to Infinity (AUC0-inf)
|
4.18 ng/mL * hr / mg (dose)
Geometric Coefficient of Variation 25
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3.79 ng/mL * hr / mg (dose)
Geometric Coefficient of Variation 26
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5.05 ng/mL * hr / mg (dose)
Geometric Coefficient of Variation 21
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SECONDARY outcome
Timeframe: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutesPopulation: Includes any participant who received study drug and had at least one post-dose sample collected.
Dose proportionality based on AUC0-t will be compared between each of the three IN naloxone treatments as a secondary endpoint. For the comparisons, the 4 naloxone dose arms will be considered as the test and the reference will be the 2 naloxone dose arm. An additional comparison will be performed between the 4 naloxone dose arm B (2 doses every 2.5 min) as test and the 4 naloxone dose arm A (1 dose every 2.5 min) as reference. Values are reported as dose-normalized AUC0-t.
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Dose-proportionality of the 4 Naloxone Dose Arms in Reference to the 2 Naloxone Dose Arm Based on Area Under the Curve From Time 0 to Last Sample (AUC0-t)
|
4.13 ng/mL * hr / mg (dose)
Geometric Coefficient of Variation 25
|
3.74 ng/mL * hr / mg (dose)
Geometric Coefficient of Variation 26
|
5.05 ng/mL * hr / mg (dose)
Geometric Coefficient of Variation 21
|
SECONDARY outcome
Timeframe: 720 minutesPopulation: Simulated patient data are reported as median and interquartile range (IQR) based on 200 randomly selected simulated patients from a population of 2000 with different pharmacokinetic and binding parameters and repeating this 2500 times with replacement. Reported result is the median and interquartile range from 2500 simulated studies with 200 simulated patients each.
Data from this study will be combined with an existing pharmacokinetic/pharmacodynamic (PK/PD) model for opioid-induced respiratory depression to determine mean time to rescue. An intravenous fentanyl dose of 1.63 mg was selected as representative of a medium overdose scenario. The first naloxone dose in the simulations was administered 1 minute after ventilation decreased to 40% of baseline. Brain hypoxia (time to rescue a simulated patient) was defined as time brain oxygen partial pressure was less than 20 mm Hg and cardiac arrest was defined as the time cardiac output was less than 0.01 L/min. A value of 120 minutes means that simulated patients for that measure/dispersion metric were not predicted to recovered for the opioid dose and intervention.
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
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|---|---|---|---|
|
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Fentanyl for a Medium Overdose Scenario
|
2.2 min
Interval 0.0 to 4.5
|
1.6 min
Interval 0.0 to 3.7
|
2.2 min
Interval 0.0 to 4.5
|
SECONDARY outcome
Timeframe: 720 minutesPopulation: Simulated patient data are reported as median and interquartile range (IQR) based on 200 randomly selected simulated patients from a population of 2000 with different pharmacokinetic and binding parameters and repeating this 2500 times with replacement. Reported result is the median and interquartile range from 2500 simulated studies with 200 simulated patients each.
Data from this study will be combined with an existing pharmacokinetic/pharmacodynamic (PK/PD) model for opioid-induced respiratory depression to determine mean time to rescue. An intravenous fentanyl dose of 2.97 mg was selected as representative of a medium overdose scenario. The first naloxone dose in the simulations was administered 1 minute after ventilation decreased to 40% of baseline. Brain hypoxia (time to rescue a simulated patient) was defined as time brain oxygen partial pressure was less than 20 mm Hg and cardiac arrest was defined as the time cardiac output was less than 0.01 L/min. A value of 120 minutes means that simulated patients for that measure/dispersion metric were not predicted to recovered for the opioid dose and intervention.
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Fentanyl for a High Overdose Scenario
|
4.5 min
Interval 2.1 to 120.0
|
3.7 min
Interval 1.5 to 120.0
|
4.5 min
Interval 2.1 to 120.0
|
SECONDARY outcome
Timeframe: 720 minPopulation: Simulated patient data are reported as median and interquartile range (IQR) based on 200 randomly selected simulated patients from a population of 2000 with different pharmacokinetic and binding parameters and repeating this 2500 times with replacement. Reported result is the median and interquartile range from 2500 simulated studies with 200 simulated patients each.
Data from this study will be combined with an existing pharmacokinetic/pharmacodynamic (PK/PD) model for opioid-induced respiratory depression to determine mean time to rescue. An intravenous carfentanil dose of 0.012 mg was selected as representative of a medium overdose scenario. The first naloxone dose in the simulations was administered 1 minute after ventilation decreased to 40% of baseline. Brain hypoxia (time to rescue a simulated patient) was defined as time brain oxygen partial pressure was less than 20 mm Hg and cardiac arrest was defined as the time cardiac output was less than 0.01 L/min. A value of 120 minutes means that simulated patients for that measure/dispersion metric were not predicted to recovered for the opioid dose and intervention.
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Carfentanil for a Medium Overdose Scenario
|
2.3 min
Interval 0.0 to 120.0
|
1 min
Interval 0.0 to 4.4
|
2.3 min
Interval 0.0 to 120.0
|
SECONDARY outcome
Timeframe: 720 minPopulation: Simulated patient data are reported as median and interquartile range (IQR) based on 200 randomly selected simulated patients from a population of 2000 with different pharmacokinetic and binding parameters and repeating this 2500 times with replacement. Reported result is the median and interquartile range from 2500 simulated studies with 200 simulated patients each.
Data from this study will be combined with an existing pharmacokinetic/pharmacodynamic (PK/PD) model for opioid-induced respiratory depression to determine mean time to rescue. An intravenous carfentanil dose of 0.022 mg was selected as representative of a medium overdose scenario. The first naloxone dose in the simulations was administered 1 minute after ventilation decreased to 40% of baseline. Brain hypoxia (time to rescue a simulated patient) was defined as time brain oxygen partial pressure was less than 20 mm Hg and cardiac arrest was defined as the time cardiac output was less than 0.01 L/min. A value of 120 minutes means that simulated patients for that measure/dispersion metric were not predicted to recovered for the opioid dose and intervention.
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=2500 Number of Simulations
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Carfentanil for a High Overdose Scenario
|
120 min
Interval 4.1 to 120.0
|
120 min
Interval 3.3 to 120.0
|
120 min
Interval 4.1 to 120.0
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OTHER_PRE_SPECIFIED outcome
Timeframe: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutesPopulation: Includes any participant who received study drug and had at least one post-dose sample collected.
PK parameter for Cmax will be calculated
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Naloxone Cmax
|
17.6 ng/mL
Geometric Coefficient of Variation 36
|
15.4 ng/mL
Geometric Coefficient of Variation 44
|
10.0 ng/mL
Geometric Coefficient of Variation 48
|
OTHER_PRE_SPECIFIED outcome
Timeframe: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutesPopulation: Includes any participant who received study drug and had at least one post-dose sample collected.
PK parameter AUC0-inf for naloxone will be calculated
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Naloxone AUC0-inf
|
1606 ng/mL * hr
Geometric Coefficient of Variation 25
|
1455 ng/mL * hr
Geometric Coefficient of Variation 26
|
978 ng/mL * hr
Geometric Coefficient of Variation 20
|
OTHER_PRE_SPECIFIED outcome
Timeframe: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutesPopulation: Includes any participant who received study drug and had at least one post-dose sample collected.
PK parameter AUC0-t for naloxone will be calculated
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Naloxone AUC0-t
|
1587 ng/mL * hr
Geometric Coefficient of Variation 25
|
1437 ng/mL * hr
Geometric Coefficient of Variation 26
|
970 ng/mL * hr
Geometric Coefficient of Variation 21
|
OTHER_PRE_SPECIFIED outcome
Timeframe: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutesPopulation: Includes any participant who received study drug and had at least one post-dose sample collected.
PK parameter tmax for naloxone will be calculated
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Naloxone Time of Maximum Concentration (Tmax)
|
15 min
Interval 15.0 to 20.0
|
15 min
Interval 15.0 to 20.0
|
20 min
Interval 15.0 to 30.0
|
OTHER_PRE_SPECIFIED outcome
Timeframe: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, and 30 minutesPopulation: Includes any participant who received study drug and had at least one post-dose sample collected. Partial AUCs are reported for 0 minutes to 7 minutes, 0 minutes to 10 minutes, 0 minutes to 12.5 minutes, 0 minutes to 15 minutes, 0 minutes to 20 minutes, and 0 minutes to 30 minute.
PK parameter pAUC from time 0 to 30 minutes for naloxone will be calculated
Outcome measures
| Measure |
A. Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
Four naloxone nasal spray doses (1 every 2.5 min): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
C. Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=18 Participants
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min): Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Naloxone Partial Area Under the Curve (pAUC) From First Dose to 30 Minutes
Partial AUC 0 to 20 minutes
|
162.7 ng/mL * hr
Geometric Coefficient of Variation 54
|
161.4 ng/mL * hr
Geometric Coefficient of Variation 57
|
84.0 ng/mL * hr
Geometric Coefficient of Variation 97
|
|
Naloxone Partial Area Under the Curve (pAUC) From First Dose to 30 Minutes
Partial AUC 0 to 30 minutes
|
298.7 ng/mL * hr
Geometric Coefficient of Variation 40
|
279.5 ng/mL * hr
Geometric Coefficient of Variation 46
|
167.7 ng/mL * hr
Geometric Coefficient of Variation 37
|
|
Naloxone Partial Area Under the Curve (pAUC) From First Dose to 30 Minutes
Partial AUC 0 to 7.5 minutes
|
9.2 ng/mL * hr
Geometric Coefficient of Variation 108
|
12.9 ng/mL * hr
Geometric Coefficient of Variation 121
|
6.0 ng/mL * hr
Geometric Coefficient of Variation 275
|
|
Naloxone Partial Area Under the Curve (pAUC) From First Dose to 30 Minutes
Partial AUC 0 to 10 minutes
|
28.0 ng/mL * hr
Geometric Coefficient of Variation 87
|
34.6 ng/mL * hr
Geometric Coefficient of Variation 93
|
17.2 ng/mL * hr
Geometric Coefficient of Variation 176
|
|
Naloxone Partial Area Under the Curve (pAUC) From First Dose to 30 Minutes
Partial AUC 0 to 12.5 minutes
|
54.1 ng/mL * hr
Geometric Coefficient of Variation 74
|
58.6 ng/mL * hr
Geometric Coefficient of Variation 87
|
28.8 ng/mL * hr
Geometric Coefficient of Variation 176
|
|
Naloxone Partial Area Under the Curve (pAUC) From First Dose to 30 Minutes
Partial AUC 0 to 15 minutes
|
86.3 ng/mL * hr
Geometric Coefficient of Variation 68
|
93.9 ng/mL * hr
Geometric Coefficient of Variation 70
|
44.9 ng/mL * hr
Geometric Coefficient of Variation 137
|
Adverse Events
Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
Four Naloxone Nasal Spray Doses (2 Every 2.5 Min)
Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Four Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=21 participants at risk
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
|
Four Naloxone Nasal Spray Doses (2 Every 2.5 Min)
n=21 participants at risk
Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min)
|
Two Naloxone Nasal Spray Doses (1 Every 2.5 Min)
n=21 participants at risk
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
|---|---|---|---|
|
Gastrointestinal disorders
Abdominal pain
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
4.8%
1/21 • Number of events 1 • 7 Days
|
|
Gastrointestinal disorders
Nausea
|
4.8%
1/21 • Number of events 1 • 7 Days
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
|
Gastrointestinal disorders
Retching
|
4.8%
1/21 • Number of events 1 • 7 Days
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
|
Gastrointestinal disorders
Vomiting
|
4.8%
1/21 • Number of events 1 • 7 Days
|
0.00%
0/21 • 7 Days
|
4.8%
1/21 • Number of events 1 • 7 Days
|
|
General disorders
Asthenia
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
4.8%
1/21 • Number of events 1 • 7 Days
|
|
General disorders
Vessel Puncture Site Pain
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
9.5%
2/21 • Number of events 2 • 7 Days
|
|
Nervous system disorders
Dizziness
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
4.8%
1/21 • Number of events 1 • 7 Days
|
|
Nervous system disorders
Headache
|
4.8%
1/21 • Number of events 1 • 7 Days
|
0.00%
0/21 • 7 Days
|
4.8%
1/21 • Number of events 1 • 7 Days
|
|
Nervous system disorders
Restless Leg Syndrome
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
4.8%
1/21 • Number of events 1 • 7 Days
|
|
Nervous system disorders
Somnolence
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
4.8%
1/21 • Number of events 1 • 7 Days
|
|
Nervous system disorders
Syncope
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
4.8%
1/21 • Number of events 1 • 7 Days
|
|
Renal and urinary disorders
Pollakiuria
|
4.8%
1/21 • Number of events 1 • 7 Days
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
|
Respiratory, thoracic and mediastinal disorders
Nasal Discomfort
|
38.1%
8/21 • Number of events 9 • 7 Days
|
23.8%
5/21 • Number of events 6 • 7 Days
|
23.8%
5/21 • Number of events 8 • 7 Days
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Pain
|
4.8%
1/21 • Number of events 1 • 7 Days
|
0.00%
0/21 • 7 Days
|
0.00%
0/21 • 7 Days
|
Additional Information
David Strauss, MD, PhD
U.S. Food and Drug Administration
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place