Two-Period, Two-Treatment, Randomized Crossover Study of the Pharmacokinetics of Nalmefene by Intranasal and Intramuscular Administration in Healthy Volunteers
Phase: PHASE1
Conditions: Pharmacokinetics
Sponsor: Opiant Pharmaceuticals Inc

 
 
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Protocol No.: OPNT003-PK-001 
1.0  STUDY SYNOPSIS 
Name of Sponsor 
Opiant Pharmaceuticals 
Name of Investigational 
Product: 
Nalmefene hydrochloride nasal spray 
Title of Study: 
A Two-Period, Two-Treatment, Randomized Crossover Study of the 
Pharmacokinetics of Nalmefene by Intranasal and Intramuscular 
Administration in Healthy Volunteers 
Clinical Phase: 
Phase I (Healthy Volunteers)  
Protocol Number: 
OPNT003-PK-001  
Study Design: 
Open-label, randomized, 2-period, 2-treatment, 2-sequence, crossover 
study in 68 healthy volunteers. Subjects will be assigned to each of the 2 
possible sequences. Each subject will receive 2 treatments during the 2 
dosing periods: Intranasal (IN) dose of 3 mg nalmefene hydrochloride and 
intramuscular (IM) dose of 1.0 mg nalmefene, with a 4 day washout 
period between doses. Screening can occur up to 28 days before baseline 
admission, subjects will then stay in the inpatient facility for 7 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 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 complete,  
patients will be randomized.  
On the day after admission subjects, in a fully supine position, will be 
administered the IN or IM 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, 36 and 48 
hours after drug administration. Actual blood collection times can vary as 
follows: ± 1 minutes for the 1 to 30 minute samples, ± 2 minutes for the 
45 to 90 minute samples, and ± 5 minutes for the 120 minute or greater 
samples. Actual sampling times will be recorded. 
On days of study drug administration (days 1 and 5): 

 
 
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Protocol No.: OPNT003-PK-001 
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 (IN dose only). 
Continuous cardiac monitoring (telemetry) will be performed from 
approximately one hour (± 30 minutes) pre-dose to 10 hours (± 30 
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 10 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 (IN dose only) will be conducted pre-dose, at 
approximately 5 minutes and ± 15 minutes of the nominal blood 
collections at 1 and 8 hours post-dose.  
Smell test (IN dose only) 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 and 6) tolerability via AE querry will be 
assessed, concomitant medications reviewed, vital signs measured, the 
smell test (IN dose only) will be conductedand examination of the nasal 
passage performed (IN dose only) at approximately 24 hours post-dose.  
On the second day after dosing (day 3) tolerability via AE query will be 
assessed, concomitant medications reviewed, vital signs measured and 
examination of the nasal passage performed (IN dose only) at 
approximately 48 hours post-dose.  
On the day before the next dosing (day 4) 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 7) 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 
dose only) at approximately 48 hours post-dose, smell test, 12-lead ECG, 
serum pregnancy test (females only), urine cotinine, 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: 
Sixty eight subjects  
Trial Subjects  
Selection Criteria: 
Inclusion criteria: 
The subject must satisfy the following criteria for entry into the study: 
1. Male or female aged 18 to 55 years inclusive, having provided 
written, informed consent prior to any study specific procedure being 
conducted 
2. BMI ranging from 18 to 30 kg/m2, inclusive 
3. Adequate venous access, as determined by the investigator 
4. Subjects must be non-smokers 

 
 
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Protocol No.: OPNT003-PK-001 
5. On screening and admission, the following are the vital signs criteria 
that need to be met before dosing (with subject sitting at least 5 
minutes before obtaining measures): 
x 
Systolic blood pressure: 140 mmHg or less and equal to or 
greater than 90 mmHg 
x 
Diastolic blood pressure: 90 mmHg or less and equal to or 
greater than 55 mmHg 
x 
Heart rate: 100 bpm or less and equal to or greater than 40 
beats per minute (bpm) 
x 
Respiratory rate: 20 respirations per minute (rpm) or less and 
equal to or greater than 8 rpm 
Vital signs may be repeated once. 
Exclusion criteria: 
The subject will be excluded from the study if any of the following 
applies: 
1. A history of clinically significant gastrointestinal, renal, hepatic, 
neurologic, hematologic, endocrine, oncologic, pulmonary, 
immunologic, psychiatric, or cardiovascular disease, severe seasonal 
or non-seasonal allergies, nasal polyps or any nasal passage 
abnormality that could interfere with nasal spray administration, or 
any other condition which, in the opinion of the Principal 
Investigator, would jeopardize the safety of the subject or impact the 
validity of the study results 
2. Subject has had significant traumatic injury, major surgery or open 
biopsy within 30 days prior to study screening 
3. Subjects who (for whatever reason) have been on an abnormal diet 
(such as one that severely restricts specific basic food groups [e.g., 
ketogenic diet], limits calories [e.g., fast], and/or requires the use of 
daily supplements as a substitute for the foods typically eaten at 
mealtimes), during the four (4) weeks preceding screening 
4. Taking prescribed or over the counter medications, dietary 
supplements, herbal products, vitamins or recent use of opioid 
analgesics for pain relief within 14 days before initial dosing and 
throughout the duration of the study 
5. Treatment with any known enzyme altering drugs such as 
barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 
30 days prior to the first dose of study drug or during the study 
6. Use of over the counter or prescription nasal products within 28 days 
of initial dosing and throughout the duration of the study 
7. Experimental agents must have been discontinued at least 8 weeks 
prior to initial dosing for a period equivalent to 5 half-lives of the 
agent (whichever is longer) 
8. Positive urine drug test for alcohol, opioids, cocaine, 
methamphetamine, benzodiazepines, tetrahydrocannabinol (THC), 
barbiturates, or methadone at screening or admission/baseline 
9. Previous or current opioid, alcohol, or other drug dependence 
(excluding nicotine and caffeine), based on medical history 
10. Positive urine screen for cotinine (smoking and the use of tobacco 
products is not permitted for four (4) weeks prior to the first dose of 
Study Drug and throughout the duration of the study)  

 
 
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Protocol No.: OPNT003-PK-001 
11. On standard 12-lead ECG, a QTcF interval >450 msec for males and 
>470 msec for females 
12. Clinically significant concurrent medical conditions considered by the 
investigator, determined by medical history, physical examination, 
clinical laboratory examination, vital signs and 12 lead-ECG 
13. Donated or received blood or underwent plasma or platelet apheresis 
within the 30 days before initial dosing 
14. Women of childbearing potential, defined as all women 
physiologically capable of becoming pregnant; unless surgically sterile 
or use effective contraception (either combined estrogen and 
progestogen containing hormonal contraception associated with 
inhibition of ovulation [oral, intravaginal, transdermal], progestogen 
only hormonal contraception associated with inhibition of ovulation 
[oral, injectable, implantable], intrauterine device [IUD], intrauterine 
hormone-releasing system [IUS], vasectomised partner, sexual 
abstinence (only considered an acceptable method of contraception 
when it is in line with the subjects’ usual and preferred lifestyle), 
combination of male condom with either cap, diaphragm or sponge 
with spermicide [double barrier methods]), and willing and able to 
continue contraception for 1 month after the last administration of 
Investigational Medicinal Product (IMP).  Women using oral 
contraception must have started using it at least 2 months prior to 
screening. Women are not considered to be of childbearing potential 
if they have had 12 months of natural (spontaneous) amenorrhea 
with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or six months of spontaneous amenorrhea 
with serum follicle stimulating hormone (FSH) levels that have been 
confirmed to be in the “postmenopausal range”. Or have had a 
surgical bilateral oophorectomy (with or without hysterectomy) or 
bilateral tubal ligation at least six weeks before the screening visit. In 
case of oophorectomy alone, the reproductive status of the woman 
should have been confirmed by follow-up hormone level assessment 
15. Women who are pregnant or breastfeeding at screening and prior to 
each administration of study drug 
16. Positive test for HBsAg, HCVAb, or HIVAb at screening 
17. Current or recent (within 7 days prior to screening) upper respiratory 
tract infection 
18. Current or recent (within 14 days prior to first dose) use of any 
decongestants 
19. Allergic to nalmefene or any of the excipients 
20. Subjects who will not abstain from engaging in strenuous exercise 
during the inpatient stay of the study 
21. Subjects who will not abstain from consuming poppy seed or similar 
opium derived food stuff during the study 
22. Subjects who will not abstain from ingesting alcohol, drinks 
containing xanthine >500mg/day (eg. Coca Cola®, coffee, tea, etc.), or 
grapefruit/grapefruit juice 72 hours before initial dosing and 
throughout the duration of the study 
23. Subject is deemed unlikely to be able to comply with the 
requirements of the protocol 
24. Subjects with any laboratory tests from samples taken at screening 
considered clinically significant 

 
 
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Protocol No.: OPNT003-PK-001 
25. Subjects with a known intolerance to continuous ECG lead adhesive 
exposure considered clinically significant by the investigator 
26. Brief Smell identification Test (BSIT) < 9 
27. Subjects with a known hypersensitivity reaction to plastics 
Study Objectives: 
The primary objective is to determine the pharmacokinetics (PK) of 3mg 
nalmefene hydrochloride IN compared to a 1.0 mg dose of nalmefene 
administered IM, to demonstrate systemic exposure comparable to an 
approved IM dose.  
A secondary objective of this study is to evaluate the safety and 
tolerability of IN nalmefene. 
Investigational medicinal 
product, route of 
administration and dosage: 
Nalmefene hydrochloride 3mg nasal spray  
Nasal (IN) 
1 spray in 1 nostril delivers 0.1 millilitres (mL) of 30mg/mL nalmefene 
hydrochloride 
Reference product, route 
of administraction and 
dosage: 
Nalmefene hydrochloride 1.108 mg/mL solution given intramuscularly 
(IM) 
1.0 mL IM delivers 1.0 mg nalmefene 
Maximum Duration of 
Treatment 
Screening can occur up to 28 days before baseline admission. 
The total subject inpatient stay is 7 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 40 days to complete the entire study.  
Blood and urine sampling 
Blood for PK assessments will be obtained via direct venipuncture or 
through an Intravenous (IV) catheter in the forearm. Four mL of blood will 
be collected in a K2EDTA-containing vacutainer tube for each time point 
for determination of nalmefene. 
Blood samples will be taken at Screening and after last blood draw prior 
to Final Discharge (or early termination) after the second dosing for 
clinical chemistry, coagulation markers and hematology. 
Urine samples will also be taken at screening and clinic admission for 
urinalysis, urine drug, urine cotinine and urine alcohol toxicology screen. 
Urine sample will also be taken at discharge for urine cotinine.  
Female subjects of child-bearing potential will be asked to provide a 
blood sample at screening, a urine sample prior to each dose and a blood 
sample prior to study discharge (or early termination) after the second 
dosing for a pregnancy test. 
Pharmacokinetic 
Endpoints: 
The following plasma pharmacokinetic parameters for nalmefene will be 
calculated using non-compartmental analysis: maximum plasma 
concentration (Cmax), time to maximum plasma concentration (Tmax), area 
under the curve to the final time with a concentration equal to or greater 
than the lower limit of quantitation [AUC(0-t)], to infinity [AUC(inf)], and 
during the first 30 minutes [AUC0-2.5 mins, AUC0-5 mins, AUC0-10 mins, AUC0-15 
mins, AUC0-20 mins and AUC0-30 mins], terminal ĞůŝŵŝŶĂƚŝŽŶƌĂƚĞĐŽŶƐƚĂŶƚ;ʄǌͿ, 
half-life (t½), clearance (CL/F) and volume of distribution (Vz/F) 
uncorrected for bioavailability (F). 
Safety Endpoints: 
Adverse events will be elicited by a verbal probe. Any events 
spontaneously reported by the subject or observed by investigator staff 
(physical examinations and nasal cavity examinations) will be recorded. 

 
 
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Protocol No.: OPNT003-PK-001 
Vital signs, clinical laboratory results and ECG abnormalities will be 
reported as an adverse event if considered clinically significant. 
Objective evaluations of nasal irritation will be assessed after each 
administration of study drug using a 6-point (0 to 5) score. A NRS will also 
be used to assess acute nasal pain following each administration of study 
drug. 
Statistical Analyses: 
Individual subject plasma concentrations, actual sampling times, and 
pharmacokinetic parameters will be listed by analyte and treatment.  
Descriptive statistics will be calculated by analyte and treatment for 
plasma concentrations and pharmacokinetic parameters.  Individual 
subject and mean plasma concentrations will be displayed on linear and 
semi-logarithmic axes. 
The pharmacokinetic parameters Cmax and AUC(inf), AUC0-2.5 mins, AUC0-5 mins, 
AUC0-10 mins, AUC0-15 mins, AUC0-20 mins and AUC0-30 mins for nalmefene will be 
compared between the treatments using an analysis of variance (ANOVA) 
model with treatment, period, sequence, and subject within sequence as 
the factors using the natural logarithms (ln) of the data.  Confidence 
intervals (CI) (90%) will be constructed for the geometric mean ratios, 
nalmefene intranasal (test formulations) to intramuscular on a dose 
adjusted basis, using the log-transformed data and the two one-sided 
t-tests procedure.  The point estimates and confidence limits will be 
exponentiated back to the original scale.  Comparability between the 
nalmefene intranasal (test formulation) and nalmefene intramuscular 
(reference formulation) will be assessed from the geometric mean ratios 
and 90% confidence intervals. 
Adverse events will be coded using the most recent version of the 
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms 
and will be grouped by system, organ, class (SOC) designation. Adverse 
events will be presented as a listing including the start date, stop date, 
severity, relationship, outcome, and duration. Vital signs, ECG, and clinical 
laboratory parameters will be presented as summary statistics. 

 
 
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Protocol No.: OPNT003-PK-001 
1.1 Schedule of Events  

 
 
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Protocol No.: OPNT003-PK-001 
 
Screening 
Admission 
/Baseline 
Period 1 
Washout  
Period 
2 
Washout 
Discharge or  
Early term 
Follow-Up  
Phone call 
Study Day(s) 
 -28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
+3 to 5 days after 
discharge 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History (includes smoking history) 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Eligibility (Inclusion/Exclusion) 
X 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
X 
 
Nasal Passage Examination 
X 
X 
Xa 
Xb 
Xc 
 
Xa 
Xb 
Xc 
 
NRS 
 
 
Xr 
 
 
 
Xr 
 
 
 
Smell test 
X 
 
Xt 
Xu 
 
 
Xt 
Xu 
X 
 
12-lead ECG s 
X 
X 
 
 
 
X 
 
 
X 
 
Continuous cardiac monitoring (telemetry) 
 
 
Xv 
 
 
 
Xv 
 
 
 
ECG assessment 
 
 
Xd 
 
 
 
Xd 
 
 
 
Vital Signs 
Xe 
Xe 
Xf 
Xg 
Xh 
 
Xf 
Xg 
Xe 
 
Weight 
X 
 
 
 
 
 
 
 
X 
 
Height, BMI 
X 
 
 
 
 
 
 
 
 
 
Clinical Chemistries & Coagulation parameters i 
X 
 
 
 
 
 
 
 
X 
 
Hematology j 
X 
 
 
 
 
 
 
 
X 
 
Urinalysis k 
X 
 
 
 
 
 
 
 
X 
 
Serum FSH levels (females postmenopausal) 
X 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test (females) 
X 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy test (females) 
 
X 
 
 
 
X 
 
 
 
 
Urine drug and alcohol toxicology screen l 
X 
X 
 
 
 
 
 
 
 
 
Urine cotinine screen 
X 
X 
 
 
 
 
 
 
X 
 
HIV, Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
PK blood sampling  
 
 
Xm 
Xn 
Xo 
 
Xm 
Xn 
Xo 
 
AEs  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization  
 
X 
 
 
 
 
 
 
 
 
Study drug administration p 
 
 
X 
 
 
 
X 
 
 
 

 
 
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Protocol No.: OPNT003-PK-001 
Meals q 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
a Nasal passage examination pre-dose, and at approximately 5 minutes and ± 15 minutes of the nominal blood collections at 1 and 8 hours post-dose (IN Period).  
b Nasal passage examination at approximately 24 hours post dose (IN Period). 
c Nasal passage examination at approximately 48 hours post dose (IN Period). 
d 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 10 hours 
post-dose. 
e Sitting (5 mintues) blood pressure, heart rate, respiration rate, and temperature. 
f Blood pressure, heart rate, respiration rate, pre-dose (sitting, 5 minutes) and at approximately 15 and 30 minutes (supine), and ± 15 minutes of the nominal blood 
collections at 1, 2, 4 and 8 hours (sitting, 5 minutes) post-dose.  
g Sitting (5 minutes) blood pressure, heart rate, respiration rate, at approximately 24 hours post-dose.  
h Sitting (5 minutes) blood pressure, heart rate, respiration rate, at approximately 48 hours post-dose.  
i Chemistry parameters include: total protein, albumin, blood urea nitrogen, creatinine, alkaline phosphatase, ALT, AST, total bilirubin, glucose, sodium, potassium, 
chloride, CO2, total cholesterol, and calcium. Coagulation parameters include PT and aPTT. 
j CBC with differentials and platelet count will be performed.  
k Urinalysis includes: pH, specific gravity, blood, ketones, nitrites, glucose, bilirubin, leukocyte esterase, protein. 
l Urine toxicology screen for alcohol, opioids, cocaine, amphetamine/methamphetamine, benzodiazepines, barbiturates, THC, or methadone. 
m Pre-dose (within 15 mins), 2.5, 5, 7.5, 10, 15, 20, 30, 45 minutes and 1, 2, 3, 4, 6, 8, 12, 18 hours post-dose. Actual blood collection times windows can vary as follows: ± 1 
minutes for the 1 to 30 minute samples, ± 2 minutes for the 45 to 90 minute samples, and ± 5 minutes for the 120 minute or greater samples. 
n 24 and 36 hours post dose. 
o 48 hours post dose. At discharge, collect sample after last blood draw prior to Final Discharge (or early termination) after the second dosing for clinical chemistry, 
coagulation markers and hematology. 
p Subjects will receive either a 3 mg nalmefene hydrochloride (one 0.1 mL spray of 30 mg/mL nalmefene hydrochloride) IN dose or a 1.0 mg nalmefene (1.0 mL injection of 
1.108 mg/mL nalmefene hydrochloride) IM dose . Subjects must be in a fully supine position at dosing and for 1 hour post-dose. Subjects should be instructed to hold their 
breath during administration of the nasal spray into the nose. 
q Subjects will fast from midnight the day before nalmefene dosing until one hour after dosing. Water will be provided ad libitum. 
r Pre-dose, 15 (± 2) and 60 (± 10) minutes post-dose (IN Period). 
s Subjects will be supine for at least 5 minutes prior to obtaining ECGs 
t Smell test will be conducted pre-dose and ± 15 minutes of the nominal blood collections at 1 and 4 (IN period) 
u Smell test wil be conducted at approximately 24 hours post-dose (IN Period) 
v Continuous cardiac monitoring will be performed from approximately one hour (± 30 minutes) pre-dose to 10 hours (± 30 minutes) post-dose