Opioid Overdose
Conditions
Brief summary
The purpose of this study is to determine the pharmacodynamics (change in minute ventilation) of nalmefene when given as an autoinjector intramuscularly (IM; into the thigh) compared to naloxone when given intranasally (IN; into the nose) to healthy subjects with prior opioid exposure under steady state fentanyl concentrations (opioid agonism).
Interventions
Nalmefene Hydrochloride injection 1.5 mg for intramuscular (IM) administration
DRUGNaloxone HCl intranasal
Naloxone 4 mg for intranasal (IN) administration
Sponsors
Purdue Pharma LP
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria include: 1. Healthy and free of significant abnormal findings as determined by medical history, physical examination, clinical laboratory values, vital signs, and ECG. 2. Body weight ranging from 50 to 100 kg (110-220 lbs) and body mass index (BMI) within the range \[18-30\] kg/m2 (inclusive). 3. Willing to be compliant with the protocol, capable of subjective evaluation, if applicable, able to read and understand questionnaires, if applicable. Key
Exclusion criteria
include: 1. Females who are pregnant or lactating. 2. Any significant illness during the 30 days preceding the initial dose in this study. 3. History or any current conditions that might interfere with drug absorption, distribution, metabolism or excretion. 4. Refusal to abstain from caffeine or xanthine containing beverages entirely during confinement. 5. Refusal to abstain from consumption of alcoholic beverages 48 hours prior to initial study drug administration and through the end-of-study visit. 6. Difficulty with venous access or unsuitable for or unwilling to undergo catheter insertion. Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Minute Ventilation 5 Minutes From Opioid Induced Nadir | 5 minutes after opioid antagonist administration | To assess the change in minute ventilation at 5 minutes of intramuscular nalmefene and intranasal naloxone reversal from the opioid induced nadir. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC0-2.5) | 2.5 minutes post-dose | Area under the plasma concentration-time curve from time zero to 2.5 minutes |
| Area Under the Curve (AUC0-5) | 5 minutes post-dose | Area under the plasma concentration-time curve from time zero to 5 minutes |
| Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | Baseline, 2.5, 5, 10, 15, 20, 30, and 90 minutes after opioid antagonist administration | To assess the time course of changes in minute ventilation of intramuscular nalmefene and intranasal naloxone reversal from the opioid induced nadir. |
| Maximum Plasma Concentration (Cmax) | up to 24 hours post-dose | Maximum plasma concentration of nalmefene and naloxone. |
| Area Under the Curve (AUC0-15) | 15 minutes post-dose | Area under the plasma concentration-time curve from time zero to 15 minutes |
| Area Under the Curve (AUC0-10) | 10 minutes post-dose | Area under the plasma concentration-time curve from time zero to 10 minutes |
| Area Under the Curve (AUCt) | up to 24 hours post-dose | Area under the plasma concentration-time curve from time zero to the time of last measurable concentration. |
| Area Under the Curve (AUCinf) | up to 24 hours post-dose | Area under the plasma concentration-time curve from time zero to infinity. |
| Time to Maximum Plasma Concentration (Tmax) | up to 24 hours post-dose | Time to maximum plasma concentration of nalmefene and naloxone. |
| Time to First Measurable Plasma Concentration (Tlag) | up to 24 hours post-dose | Time to first measurable plasma concentration of nalmefene and naloxone. |
| Half-life (T1/2) | up to 24 hours post-dose | Half life of nalmefene and naloxone. |
| Area Under the Curve (AUC0-20) | 20 minutes post-dose | Area under the plasma concentration-time curve from time zero to 20 minutes |
Countries
United States
Participant flow
Recruitment details
The first subject was dosed 03-October-2022 and the last subject completed the study 23-December-2022. The study was conducted at 1 site in the US.
Pre-assignment details
The Qualification Phase (Part 1) was conducted prior to the Treatment Phase (Part 2) to identify subjects eligible for participation in Part 2. N=13 subjects who had not previously qualified in a similar study at the same site and N=11 subjects who had previously qualified in a similar study at the same site for a total of N=24 subjects who participated in the Treatment Phase (Part 2).
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Subjects received Nalmefene Hydrochloride injection 1.5 mg for intramuscular (IM) administration or Naloxone 4 mg for intranasal (IN) administration in a crossover fashion according to the randomization sequence. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Washout (up to 72 Hours) | Adverse Event | 0 | 0 | 1 |
| Washout (up to 72 Hours) | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 39.1 years STANDARD_DEVIATION 7.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 9 / 13 | 20 / 23 | 18 / 24 |
| serious Total, serious adverse events | 0 / 13 | 0 / 23 | 0 / 24 |
Outcome results
Primary
Change in Minute Ventilation 5 Minutes From Opioid Induced Nadir
To assess the change in minute ventilation at 5 minutes of intramuscular nalmefene and intranasal naloxone reversal from the opioid induced nadir.
Time frame: 5 minutes after opioid antagonist administration
Population: Eligible analysis set was defined as subjects/periods who were randomized, received study drug, had at least 1 valid pharmacodynamic (PD) measurement, and their opioid-induced respiratory depressions (OIRDs) were worse than baseline for minute ventilation (MV) and transcutaneous CO2 (TCO2). The data for the overall treatment period was calculated as the average of available data from individual periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation 5 Minutes From Opioid Induced Nadir | 4.42 L/min | Standard Deviation 2.033 |
| Narcan Intranasal | Change in Minute Ventilation 5 Minutes From Opioid Induced Nadir | 2.03 L/min | Standard Deviation 0.992 |
Secondary
Area Under the Curve (AUC0-10)
Area under the plasma concentration-time curve from time zero to 10 minutes
Time frame: 10 minutes post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Area Under the Curve (AUC0-10) | 0.7576 ng*hr/mL | Standard Deviation 0.38147 |
| Narcan Intranasal | Area Under the Curve (AUC0-10) | 0.3311 ng*hr/mL | Standard Deviation 0.27201 |
Secondary
Area Under the Curve (AUC0-15)
Area under the plasma concentration-time curve from time zero to 15 minutes
Time frame: 15 minutes post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Area Under the Curve (AUC0-15) | 1.2716 ng*hr/mL | Standard Deviation 0.52366 |
| Narcan Intranasal | Area Under the Curve (AUC0-15) | 0.6300 ng*hr/mL | Standard Deviation 0.43256 |
Secondary
Area Under the Curve (AUC0-20)
Area under the plasma concentration-time curve from time zero to 20 minutes
Time frame: 20 minutes post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Area Under the Curve (AUC0-20) | 1.7479 ng*hr/mL | Standard Deviation 0.61346 |
| Narcan Intranasal | Area Under the Curve (AUC0-20) | 0.9817 ng*hr/mL | Standard Deviation 0.6105 |
Secondary
Area Under the Curve (AUC0-2.5)
Area under the plasma concentration-time curve from time zero to 2.5 minutes
Time frame: 2.5 minutes post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Area Under the Curve (AUC0-2.5) | 0.0440 ng*hr/mL | Standard Deviation 0.03923 |
| Narcan Intranasal | Area Under the Curve (AUC0-2.5) | 0.256 ng*hr/mL | Standard Deviation 0.03663 |
Secondary
Area Under the Curve (AUC0-5)
Area under the plasma concentration-time curve from time zero to 5 minutes
Time frame: 5 minutes post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Area Under the Curve (AUC0-5) | 0.2225 ng*hr/mL | Standard Deviation 0.13565 |
| Narcan Intranasal | Area Under the Curve (AUC0-5) | 0.1002 ng*hr/mL | Standard Deviation 0.11542 |
Secondary
Area Under the Curve (AUCinf)
Area under the plasma concentration-time curve from time zero to infinity.
Time frame: up to 24 hours post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Area Under the Curve (AUCinf) | 25.7412 ng*hr/mL | Standard Deviation 4.65028 |
| Narcan Intranasal | Area Under the Curve (AUCinf) | 13.4938 ng*hr/mL | Standard Deviation 2.87023 |
Secondary
Area Under the Curve (AUCt)
Area under the plasma concentration-time curve from time zero to the time of last measurable concentration.
Time frame: up to 24 hours post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Area Under the Curve (AUCt) | 23.1620 ng*hr/mL | Standard Deviation 3.60968 |
| Narcan Intranasal | Area Under the Curve (AUCt) | 13.4803 ng*hr/mL | Standard Deviation 2.78735 |
Secondary
Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir
To assess the time course of changes in minute ventilation of intramuscular nalmefene and intranasal naloxone reversal from the opioid induced nadir.
Time frame: Baseline, 2.5, 5, 10, 15, 20, 30, and 90 minutes after opioid antagonist administration
Population: Eligible analysis set was defined as subjects/periods who were randomized, received study drug, had at least 1 valid pharmacodynamic (PD) measurement, and their opioid-induced respiratory depressions (OIRDs) were worse than baseline for minute ventilation (MV) and transcutaneous CO2 (TCO2). The data for overall treatment period was calculated as the average of available data from individual periods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | Baseline | 2.92 L/min | Standard Deviation 1.254 |
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 2.5 minutes | 2.00 L/min | Standard Deviation 1.284 |
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 5 minutes | 4.42 L/min | Standard Deviation 2.033 |
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 10 minutes | 3.97 L/min | Standard Deviation 1.755 |
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 15 minutes | 4.15 L/min | Standard Deviation 1.99 |
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 20 minutes | 4.00 L/min | Standard Deviation 2.176 |
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 30 minutes | 3.62 L/min | Standard Deviation 1.82 |
| Nalmefene Hydrochloride (HCl) Injection | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 90 minutes | 2.74 L/min | Standard Deviation 1.519 |
| Narcan Intranasal | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 90 minutes | 2.55 L/min | Standard Deviation 0.994 |
| Narcan Intranasal | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | Baseline | 3.02 L/min | Standard Deviation 1.022 |
| Narcan Intranasal | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 15 minutes | 2.79 L/min | Standard Deviation 1.328 |
| Narcan Intranasal | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 2.5 minutes | 1.67 L/min | Standard Deviation 1.046 |
| Narcan Intranasal | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 30 minutes | 2.92 L/min | Standard Deviation 1.357 |
| Narcan Intranasal | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 5 minutes | 2.03 L/min | Standard Deviation 0.992 |
| Narcan Intranasal | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 20 minutes | 3.11 L/min | Standard Deviation 1.16 |
| Narcan Intranasal | Change in Minute Ventilation at 2.5, 5, 10, 15, 20, 30, and 90 Minutes From Opioid Induced Nadir | 10 minutes | 2.57 L/min | Standard Deviation 1.364 |
Secondary
Half-life (T1/2)
Half life of nalmefene and naloxone.
Time frame: up to 24 hours post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Half-life (T1/2) | 7.9754 hour | Standard Deviation 2.1655 |
| Narcan Intranasal | Half-life (T1/2) | 1.6353 hour | Standard Deviation 0.050257 |
Secondary
Maximum Plasma Concentration (Cmax)
Maximum plasma concentration of nalmefene and naloxone.
Time frame: up to 24 hours post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Maximum Plasma Concentration (Cmax) | 8.3576 ng/mL | Standard Deviation 3.71139 |
| Narcan Intranasal | Maximum Plasma Concentration (Cmax) | 5.6015 ng/mL | Standard Deviation 2.30753 |
Secondary
Time to First Measurable Plasma Concentration (Tlag)
Time to first measurable plasma concentration of nalmefene and naloxone.
Time frame: up to 24 hours post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Time to First Measurable Plasma Concentration (Tlag) | 0.0527 hour | Standard Deviation 0.01912 |
| Narcan Intranasal | Time to First Measurable Plasma Concentration (Tlag) | 0.0464 hour | Standard Deviation 0.01023 |
Secondary
Time to Maximum Plasma Concentration (Tmax)
Time to maximum plasma concentration of nalmefene and naloxone.
Time frame: up to 24 hours post-dose
Population: Full analysis population was defined as all subjects who were randomized, received study drug and had at least 1 valid pharmacodynamics (PD) measurement. Pharmacokinetic analyses and summaries were based on the full analysis population. For the overall analysis, the values were averaged within each subject first, then the descriptive statistics were calculated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nalmefene Hydrochloride (HCl) Injection | Time to Maximum Plasma Concentration (Tmax) | 0.2083 hour |
| Narcan Intranasal | Time to Maximum Plasma Concentration (Tmax) | 0.6667 hour |