Pharmacodynamic Evaluation of Intranasal Nalmefene

A Two-part Open Label Study of the Pharmacodynamic Effects of Intranasal Nalmefene Compared to Intranasal Naloxone in Healthy Volunteers Under Steady State Opioid Agonism

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04828005

Enrollment

Registered

2021-04-01

Start date

2021-03-30

Completion date

2022-03-14

Last updated

2025-07-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pharmacodynamic

Brief summary

This study is to determine the pharmacodynamics (the effects of the drug and mechanisms of their action within the body) of Nalmefene when given intranasally (IN; into the nose) compared to intranasal naloxone when given to healthy volunteers under steady state opioid agonism.

Detailed description

Open-label, 2-part study. Part 1 is a pilot study to determine the relationship between opioid agonism and suppression of carbon dioxide induced increases in minute ventilation prior to opioid exposure. Part 2 will be a randomized, 2 period, 2 treatment, crossover study to evaluate the pharmacodynamic effects of intranasal (IN) nalmefene compared to IN naloxone to reverse opioid-induced suppression of carbon dioxide induced increases in minute ventilation, in healthy volunteers with prior opioid exposure. Both Part 1 and Part 2 of the study will consist of an outpatient Screening Visit taking place 28 days prior to admission, an in-clinic Treatment Phase consisting of a 6 or 7 day inpatient stay, and a Follow-Up Phone Call conducted 3 to 7 days after discharge.

Interventions

DRUGNalmefene hydrochloride

3mg Nasal spray

DRUGNaloxone hydrochloride

4mg Nasal Spray

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 55 Years

Healthy volunteers

Yes

Inclusion criteria

* Male or female aged 18 to 55 years inclusive * BMI ranging from 18 to 32 kg/m2, inclusive * Adequate venous access * Healthy subjects and non-dependent who are non dependent opioid experienced users, opioid experience defined as exposure to an opioid on at least 1 occasion prior to screening

Exclusion criteria

* History of clinically significant disease * Significant trauma injury, major surgery, open biopsy within 30 days prior to screening * Subject who has a difficult airway for intubation. * Following an abnormal diet 4 weeks prior to screening * Use of over-the-counter medications, dietary supplements, herbal products, vitamins or opioid analgesics 14 days before intervention * Use of enzyme altering drugs 30 days before intervention * Use of nasal products 28 days before intervention and throughout the study * Previous or current opioid, alcohol, or other drug dependence * Donated or received blood 30 days before intervention * Women who are pregnant or breastfeeding at screening * Women of childbearing potential unless surgically sterile or use effective contraception * Current or recent upper respiratory tract infection * Allergic to nalmefene or naloxone or known hypersensitivity reaction to plastics.

Design outcomes

Primary

Measure	Time frame	Description
Change in Minute Ventilation	5 minutes	Change in minute ventilation from opioid induced nadir

Secondary

Measure	Time frame	Description
Maximum Change in Minute Ventilation	Up to 2 hours	Maximum change in minute ventilation from opioid induced nadir
Time to Maximum Change in Minute Ventilation	Up to 2 hours	Time to maximum change in minute ventilation from opioid induced nadir
Change in Minute Ventilation	90 minutes	Change in minute ventilation from opioid induced nadir

Countries

United States

Participant flow

Pre-assignment details

Part 1 Setup and Part 1 Extension Setup were Ventilation Models only; outcome measures were not collected in Part 1. Part 2 participant flow was only reported as one group (i.e., it is not possible to show how many participants received each intervention).

Participants by arm

Arm	Count
Part 1: Intranasal Nalmefene Subjects received First Treatment (1 Day), followed by Washout (4 Days), followed by Second Treatment (1 Day). Treatment in Part 1 * Healthy volunteers with prior opioid exposure received pretreatment with ondansetron (8 mg, oral) and sodium citrate (30 mL, oral) 30 minutes to 1 hour prior to remifentanil infusion. * Subjects started receiving a hypercapnic gas mixture (50% O2, 43% N2, 7% CO2) using a ventilatory response to hypercapnia (VRH) face mask at Time 0 minutes, followed by a remifentanil hydrochloride infusion at Time 5 minutes. * Subjects received 4 mg IN naloxone hydrochloride at Time 25 minutes. * Remifentanil infusion continued up to Time 115 minutes.	7
Part 1 Extension: Intranasal Nalmefene Subjects received First Treatment (1 Day) only. Treatment in Part 1 Extension. * Healthy volunteers with prior opioid exposure received a naloxone challenge test on the day of clinical admission to ensure the subject was not physically dependent on opioids. * Subjects then received pretreatment with famotidine (20 mg IV), ondansetron (8 mg, oral), and sodium citrate (30 mL, oral) 30 minutes to 1 hour prior to remifentanil infusion. * Subjects started receiving a hypercapnic gas mixture (50% O2, 43% N2, 7% CO2) using a ventilatory response to hypercapnia (VRH) face mask at Time 0 minutes, followed by a remifentanil hydrochloride infusion at Time 10 minutes. * IN naloxone hydrochloride was administered at Time 25 minutes. * Remifentanil infusion continued up to Time 146 minutes.	8
Part 2: Intranasal Nalmefene Compared to Intranasal Naloxone Part 2 was a randomized, 2-treatment crossover study to compare Intranasal Nalmefene to Intranasal Naloxone. Subjects received First Treatment (1 Day), followed by Washout (4 Days), followed by Second Treatment (1 Day). Treatment in Part 2 * Healthy volunteers with prior opioid exposure received a naloxone challenge test on the day of clinical admission to ensure the subject was not physically dependent on opioids. * After the naloxone challenge test, eligibility review and completion of admission procedures, each subject was randomized to receive either IN nalmefene hydrochloride or IN naloxone hydrochloride in a 2-period crossover manner, with a 4-day washout period between doses. * All subjects received pretreatment with famotidine (20 mg IV), ondansetron (8 mg, oral), and sodium citrate (30 mL, oral) 30 minutes to 1 hour prior to remifentanil infusion. * All subjects started receiving a hypercapnic gas mixture (50% O2, 43% N2, 7% CO2) using a ventilatory response to hypercapnia (VRH) face mask at Time 0 minutes, followed by a remifentanil hydrochloride infusion at Time 10 minutes. * In accordance with the randomization schedule, IN nalmefene hydrochloride (3 mg) or IN naloxone hydrochloride (4 mg) was administered at Time 25 minutes. * Remifentanil infusion continued up to Time 146 minutes.	69
Total	84

Withdrawals & dropouts

Period	Reason	FG000	FG002	FG003
Part 1 Setup: Washout (4 Days)	Withdrawal by Subject	2	0	0
Part 2: 1st Treatment (1 Day)	Adverse Event	0	3	0
Part 2: 1st Treatment (1 Day)	Equipment failure	0	0	1
Part 2: 1st Treatment (1 Day)	Protocol Violation	0	2	1
Part 2: 1st Treatment (1 Day)	Withdrawal by Subject	0	2	1
Part 2: 2nd Treatment (1 Day)	Adverse Event	0	0	1
Part 2: 2nd Treatment (1 Day)	Protocol Violation	0	0	2
Part 2: Washout (4 Days)	Physician Decision	0	0	2
Part 2: Washout (4 Days)	Withdrawal by Subject	0	2	0

Baseline characteristics

Characteristic	Part 1 Extension: Intranasal Nalmefene	Total	Part 1: Intranasal Nalmefene	Part 2: Intranasal Nalmefene Compared to Intranasal Naloxone
Age, Customized	29.1 years STANDARD_DEVIATION 11.05	29.1 years STANDARD_DEVIATION 7.84	28.6 years STANDARD_DEVIATION 4.5	29.1 years STANDARD_DEVIATION 7.79
BMI	24.48 kg/m2 STANDARD_DEVIATION 3.665	25.17 kg/m2 STANDARD_DEVIATION 3.317	25.03 kg/m2 STANDARD_DEVIATION 3.338	25.27 kg/m2 STANDARD_DEVIATION 3.316
Height	179.8 cm STANDARD_DEVIATION 9.38	176.3 cm STANDARD_DEVIATION 10.08	178.7 cm STANDARD_DEVIATION 9.71	175.6 cm STANDARD_DEVIATION 10.21
Race/Ethnicity, Customized American Indian or Alaskan Native	0 Participants	3 Participants	0 Participants	3 Participants
Race/Ethnicity, Customized Asian	0 Participants	2 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Black or African American	2 Participants	9 Participants	1 Participants	6 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Unknown	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized White	6 Participants	69 Participants	6 Participants	57 Participants
Region of Enrollment United States	8 participants	84 participants	7 participants	69 participants
Sex: Female, Male Female	2 Participants	24 Participants	1 Participants	21 Participants
Sex: Female, Male Male	6 Participants	60 Participants	6 Participants	48 Participants
Weight	78.65 kg STANDARD_DEVIATION 9.735	78.40 kg STANDARD_DEVIATION 13.833	79.13 kg STANDARD_DEVIATION 16.616	78.30 kg STANDARD_DEVIATION 14.12

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 61	0 / 60
other Total, other adverse events	56 / 61	52 / 60
serious Total, serious adverse events	0 / 61	0 / 60