An Open-Label, Three-Period, Three-Treatment, Six-Sequence, Randomized Crossover Study of the Pharmacokinetics of Intranasal Nalmefene in Healthy Volunteers Using Three Dosing Regimens
Phase: PHASE1
Conditions: Opioid Overdose
Sponsor: Opiant Pharmaceuticals Inc

Opiant Pharmaceuticals  
Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
 4 of 15                                                                                                                                          CONFIDENTIAL 
 
 
1) STUDY SYNOPSIS 
 
 
Name of Sponsor 
Opiant Pharmaceuticals 
Name of 
Investigational 
Product: 
Nalmefene hydrochloride nasal spray 
Title of Study: 
An Open-Label, Three-Period, Three-Treatment, Six-Sequence, 
Randomized Crossover Study of the Pharmacokinetics of 
Intranasal Nalmefene in Healthy Volunteers using Three Dosing 
Regimens 
Clinical Phase: 
Phase I (Healthy Volunteers)  
Protocol Number: 
OPNT003-PK-002 
Study Design: 
Open-label, randomized, 3-period, 3-treatment, 6-sequence, 
randomized crossover study in 24 healthy volunteers. Subjects 
will be assigned to each of the 6 possible sequences.  
 
Each subject will receive 3 intranasal (IN) Nalmefene doses: 
· 3mg IN dose (one 0.1mL spray of a 30mg/mL solution in one nostril) 
· 6mg IN dose (one 0.1mL spray of a 30mg/mL solution in each nostril) 
· 6mg IN dose (two 0.1mL sprays of a 30mg/mL solution in one nostril) 
 
There will be a 6 day washout period between doses. Screening 
can occur up to 28 days before admission, subjects will then stay 
in the inpatient facility for 16 days to complete the treatment 
phase of the study and will be discharged following completion of 
the discharge procedures at the end of the last period. Subjects 
will be called 3 to 5 days after discharge to inquire concerning 
Adverse Events (AEs) and concomitant medications since 
discharge. 
All subjects who have given their written informed consent and 
who satisfy all of the relevant inclusion criteria and none of the 
exclusion criteria will be screened for eligibility to participate in the 
study including medical history, demographics, concomitant 
medications, physical examination, height, weight, body mass 
index (BMI), nasal passage examination, smell test, clinical 
chemistry, coagulation markers, hematology, serum Follicle 
Stimulating Hormone (FSH) levels (females postmenopausal 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.1 - Page 67

Opiant Pharmaceuticals  
Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
 5 of 15                                                                                                                                          CONFIDENTIAL 
 
 
only), infectious disease serology, urinalysis, urine drug, urine 
cotinine and urine alcohol toxicology screen, serum pregnancy 
test (females only), vital signs and electrocardiogram (ECG).  
 
On the day of clinic admission (Day -1) the following procedures 
will be performed to review eligibility, update on medical history, 
update on concomitant medications, physical examination, nasal 
passage examination, 12-lead ECG, vital signs, urine pregnancy 
test (females only), urine drug, urine cotinine and urine alcohol 
toxicology screen. 
 
After eligibility of established and admission procedures has been 
reviewed by an investigator, patients will be randomized.  
 
On the day after admission subjects, in a fully supine position, will 
be administered the IN dose randomized to a sequence order of 
receipt.  
 
Subjects should be instructed to hold their breath during 
administration of the nasal spray into the nose. Blood will then be 
collected prior to dosing (within 15 minutes) and approximately 
2.5, 5, 7.5, 10, 15, 20, 30, 45 minutes and 1, 2, 3, 4, 6, 8, 12, 18, 
24 and 48 hours after drug administration. Pre-dose blood sample 
will be collected within 15 minutes before dosing. 
 
Actual blood collection times can vary as follows: ±30 seconds for 
the 2.5, 5 & 7.5 samples, ±1 minute for the 10 to 30-minute 
samples, ±3 minutes for the 45 to 120-minute samples, and ±5 
minutes for the 180 minute or greater samples. Actual sampling 
times will be recorded. 
 
On days of study drug administration (days 1, 7 and 13): 
A numerical rating scale (NRS) to assess acute nasal pain will be 
completed pre-dose, and at approximately 15 (± 2) and 60 (± 10) 
minutes post-dose. 
Continuous cardiac monitoring (telemetry) will be performed from 
approximately one hour (± 30 minutes) pre-dose to 6 hours (± 30 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.1 - Page 68

Opiant Pharmaceuticals  
Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
 6 of 15                                                                                                                                          CONFIDENTIAL 
 
 
minutes) post-dose. ECG assessment will be conducted within ± 
5 minutes of the nominal blood collection at 20 minutes, and ± 15 
minutes of the nominal blood collections at 1 and 6 hours post-
dose.  
Vital signs will be measured pre-dose and at approximately 15 
and 30 minutes, and ± 15 minutes of the nominal blood collections 
at 1, 2, 4 and 8 hours post-dose. Vital signs will also be measured 
if the subject displays any change in condition including 
lightheadedness, dizziness, syncope, nausea, vomiting or 
tachy/bradyarrhythmia 
as 
noted 
on 
continuous 
cardiac 
monitoring. 
Nasal passage examination will be conducted in both nostrils pre-
dose, at approximately 5 minutes and ± 15 minutes of the nominal 
blood collections at 1 and 8 hours post-dose.  
Smell test will be conducted pre-dose and ± 15 minutes of the 
nominal blood collections at 1 and 4 hours post-dose. 
Tolerability assessed via AE query and concomitant medications 
will be reviewed.  
On the day after dosing (day 2,8 and 14) tolerability via AE query 
will be assessed, concomitant medications reviewed, vital signs 
measured, the smell test will be conducted and examination of 
the nasal passage performed in both nostrils at approximately 24 
hours post-dose.  
On the second day after dosing (day 3 and day 9) tolerability via 
AE query will be assessed, concomitant medications reviewed, 
vital signs measured and examination of the nasal passage 
performed in both nostrils at approximately 48 hours post-dose.  
On days 4, 5, 10 and 11 tolerability will be assessed, and 
concomitant medications reviewed. On the days before the next 
dosing (days 6 and 12) tolerability will be assessed, concomitant 
medications reviewed, a urine pregnancy test (females only) and 
12-lead ECG performed. On the day of clinic discharge (day 15) 
from the inpatient stay the following procedures will be performed: 
assess tolerability via AE query, update on concomitant 
medications, vital signs at approximately 48 hours post-dose, 
physical examination, weight, examination of the nasal passage 
in both nostrils at approximately 48 hours post-dose, smell test,, 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.1 - Page 69

Opiant Pharmaceuticals  
Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
 7 of 15                                                                                                                                          CONFIDENTIAL 
 
 
12-lead ECG, serum pregnancy test (females only), clinical 
chemistry, coagulation markers, hematology and urinalysis.  
AEs will be assessed by spontaneous reports by subjects, by 
examination of the nasal mucosa and by measuring vital signs, 
ECG and clinical laboratory parameters. 
Planned 
Sample 
Size: 
Twenty-four subjects  
Investigational 
medicinal product, 
route of 
administration and 
dosage: 
Nalmefene hydrochloride 3mg nasal spray  
Nasal (IN) 
 
Period 1: 3mg (one 0.1 mL spray of 30 mg/mL nalmefene 
hydrochloride in one nostril) 
Period 2: 6mg (one 0.1 mL sprays of 30 mg/mL nalmefene 
hydrochloride in each nostril) 
Period 3: 6mg (two 0.1 mL sprays of 30 mg/mL nalmefene 
hydrochloride in one nostril) 
Maximum Duration 
of Treatment 
Screening can occur up to 28 days before admission. The total 
subject inpatient stay is 16 days, during which the treatment will 
be administered.  
Subjects will be called 3 to 5 days after final discharge to inquire 
concerning adverse events and concomitant medications since 
discharge. Total subject duration is up to 48 days to complete the 
entire study. 
 
 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.1 - Page 70

Opiant Pharmaceuticals  
Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
 8 of 15                                                                                                                                          CONFIDENTIAL 
 
 
 
1) SCHEDULE OF EVENTS 
 
 
 
 
 
 
 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.1 - Page 71