Clinical trial NCT04759768
Conditions: Pharmacokinetics
Sponsor: Opiant Pharmaceuticals Inc
Start date: 2021-02-08; Completion date: 2021-05-24
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is to determine the pharmacokinetics (how the body absorbs, breaks down and eliminates drug from your body) of nalmefene when given intranasally (IN;into the nose) compared to a dose of nalmefene when given intramuscularly (IM; into the muscle); to compare the blood levels of nalmefene when given IN to nalmefene when given IM; and to evaluate the safety and tolerability of nalmefene IN.

Detailed description:
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.

Arms: arm 1: Nalmefene hydrochloride nasal spray, 3mg, 1 spray arm 2: Nalmefene injection, 1mg, 1 injection
Interventions: intervention 1: Nalmefene Hydrochloride intervention 2: Nalmefene
Intervention descriptions: intervention 1: 3mg nasal spray intervention 2: 1mg intramuscular injection

Protocol documents:
Prot_000.pdf: 
 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020 
Page 10 of 56 
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): 


 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020 
Page 11 of 56 
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 


 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020 
Page 12 of 56 
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)  


 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020 
Page 13 of 56 
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 


 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020 
Page 14 of 56 
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. 


 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020 
Page 15 of 56 
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. 


 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020  
Page 16 of 56 
Protocol No.: OPNT003-PK-001 
1.1 Schedule of Events  


 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020 
Page 17 of 56 
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 
 
 
 


 
 
Pharmacokinetic evaluation of intranasal nalmefene  
Version: 5.0 11th November 2020 
Page 18 of 56 
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 
 

SAP_001.pdf: 
Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 1 of 26
Statistical Analysis Plan 
Title: A Two-Period, Two-Treatment, Randomized Crossover Study of the 
Pharmacokinetics of Nalmefene by Intranasal and Intramuscular 
Administration in Healthy Volunteers 
Protocol Number: OPNT003-PK-001 
Protocol Version: 5.0 / 11-Nov-2020 
SAP Version 1.0 
SAP Issue Date: 09-Feb-2021 
Previous SAP Versions 
NA 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 2 of 26
SAP Amendments before database lock 
Version 
Issue Date
Section
Revision / Addition
Rationale


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 3 of 26
Table of Contents 
1
INTRODUCTION ............................................................................................... 5
2
STUDY OBJECTIVES ....................................................................................... 5
3
ENDPOINTS ....................................................................................................... 5
3.1 
Pharmacokinetic Endpoints ............................................................................................ 5 
3.2 
Safety Endpoints ............................................................................................................. 6 
4
SAMPLE SIZE .................................................................................................... 6
5
RANDOMIZATION ........................................................................................... 7
6
PLANNED ANALYSES ..................................................................................... 7
6.1 
Analysis Populations ....................................................................................................... 7 
6.1.1 
Safety Population ...................................................................................................... 7 
6.1.2 
Pharmacokinetic Evaluation Population ................................................................... 7 
6.2 
Derived Data ................................................................................................................... 8 
6.2.1 
Race........................................................................................................................... 8 
6.2.2 
Baseline ..................................................................................................................... 8 
6.2.3 
Early Terminations Assessments .............................................................................. 8 
6.2.4 
Duration / Study Day / Time ..................................................................................... 8 
6.2.5 
Conventions for Missing and Partial Dates .............................................................. 8 
6.2.6 
Inexact Values ........................................................................................................... 9 
6.2.7 
Unscheduled Visits ................................................................................................... 9 
6.2.8 
PK Parameters ........................................................................................................... 9 
6.3 
Conventions .................................................................................................................. 11 
6.3.1 
Decimal Places ........................................................................................................ 12 
6.4 
Subject Disposition ....................................................................................................... 12 
6.5 
Protocol Deviations ....................................................................................................... 12 
6.6 
Baseline Comparability ................................................................................................. 13 
6.6.1 
Demographic Data .................................................................................................. 13 
6.7 
Medical History ............................................................................................................ 13 
6.8 
Substance Use ............................................................................................................... 13 
6.9 
Prior and Concomitant Medications ............................................................................. 13 
6.10 
Exposure to Study Drug ................................................................................................ 14 
6.11 
PK Analyses .................................................................................................................. 14 
6.12 
Safety Analyses ............................................................................................................. 15 
6.12.1 
Adverse Events ....................................................................................................... 15 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 4 of 26
6.12.2 
Laboratory Data ...................................................................................................... 16 
6.12.3 
Vital Signs ............................................................................................................... 17 
6.12.4 
Electrocardiogram Data .......................................................................................... 17 
6.12.5 
Physical Examination.............................................................................................. 17 
6.12.6 
Nasal Passage Examination .................................................................................... 18 
6.12.7 
Numerical Rating Scale  ......................................................................................... 18 
6.12.8 
Smell Test ............................................................................................................... 18 
7 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................19
8 
REFERENCES ..................................................................................................20
9 
LIST OF TABLES, FIGURES AND LISTINGS .............................................21


Worldwide Clinical Trials Controlled Quality Management Document 
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Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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1 INTRODUCTION 
This document details the planned statistical analyses for Opiant Pharmaceuticals, protocol 
“OPNT003-PK-001” study titled “A Two-Period, Two-Treatment, Randomized Crossover Study 
of the Pharmacokinetics of Nalmefene by Intranasal and Intramuscular Administration in Healthy 
Volunteers”. 
The proposed analyses are based on the contents of the final version of the protocol (dated 11-
NOV-2020) and the protocol clarification letter (dated 04-JAN-2021). 
This will be an inpatient, open-label, randomized, 2-period, 2-treatment, 2 sequence, crossover 
study in healthy volunteers. Each subject will receive 2 treatments during the 2 dosing periods (1 
treatment per dosing period): 
Treatment A (Test) 
3 mg nalmefene hydrochloride IN dose (one 
0.1 mL spray of a 30 mg/mL solution in one 
nostril)
Treatment B (Reference) 
1.0 mg nalmefene IM dose (1.0 mL of 1.108 
mg/mL nalmefene hydrochloride solution as a 
single dose in the gluteal muscle)
2 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
The secondary objective is to 
-
Evaluate the safety and tolerability of IN nalmefene
3 ENDPOINTS 
3.1 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)


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-
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 elimination rate constant (λz)
-
Half-life (t½)
-
Clearance (CL/F)
-
Volume of distribution (Vz/F) uncorrected for bioavailability (F)
3.2 Safety Endpoints 
Safety endpoints will include: 
-
Adverse events (AEs)
-
Vital signs (heart rate, sitting blood pressure, and respiration rate)
-
Electrocardiogram (ECG)
-
Clinical laboratory changes
-
Numerical rating scale (NRS) measuring acute nasal pain and nasal irritation (erythema,
edema, and erosion) determined from the nasal passage examination following each nasal
administration of study drug
4 SAMPLE SIZE 
This study is designed to obtain information regarding the PK of IN nalmefene under the 
conditions of this study. The number of subjects has been determined based on the data from the 
pilot study.  
The sample size was based on Geometric Means Ratio (GMR) and Intrasubject Variability 
(ISCV) results obtained for partial AUC in the pilot study, covering the initial 30 minutes. 
Sample size calculations are based on the non-inferiority t-test for log-normal distributed data 
and were performed for study designs: 2x2x2 (2 treatments x 2 sequences x 2 periods), using a 
target power of 80% and alpha level of 5%. 
Parameter
Total ISCV %
GMR % 
Sample size estimation
Expected power
AUC0-5 mins/Dose
178.15
149.40
48
81.0
AUC0-10 mins/Dose
129.21
127.06
60
81.1
AUC0-15 mins/Dose
159.69
108.76
168
80.1
AUC0-20 mins/Dose
127.97
125.68
60
81.0
AUC0-30 mins/Dose
74.40
123.57
32
81.5


Worldwide Clinical Trials Controlled Quality Management Document 
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Based on these findings a sample size of 60 subjects has been selected. For this study 68 subjects 
will be enrolled. 
5 RANDOMIZATION 
Subjects will be randomized to a sequence order of receipt of IN or IM doses after establishing 
eligibility and completing admission procedures. Subjects will be assigned to each of the 2 
possible sequences. 
The 2 sequences will be assigned as follows: 
Sequence
Period 1 
Period 2
I
Treatment A 
Treatment B
II
Treatment B 
Treatment A
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final Clinical Study Report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained. The justification for any such additional analyses will be fully documented 
in the final CSR. 
6.1 Analysis Populations 
Subjects excluded from the Populations and the reason for their exclusion will be listed 
in Appendix 16.2 of the CSR. 
6.1.1 
Safety Population 
The safety population will include all subjects who receive at least one administration of the 
study drugs. 
6.1.2 
Pharmacokinetic Evaluation Population 
The evaluable population will include all subjects who complete at least one treatment with all 
sampling time points taken to derive meaningful PK parameters.  The PK population will be used 
for PK analysis. PK data for subjects who experience AEs (e.g. emesis) that may impact the PK 
results will be reviewed to assess the potential effect. 


Worldwide Clinical Trials Controlled Quality Management Document 
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6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 
Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories.  
6.2.2 
Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the subject receives the first dose of study drug.  
For variables that will be summarized by treatment, the Baseline for each period is defined as the 
last non-missing value (either scheduled, unscheduled or repeat) that is collected before dosing, 
but after check-in for the relevant period.  
6.2.3 
Early Terminations Assessments 
Data collected during Early Termination assessments will be summarized alongside EOS 
procedures.  All Early Termination data will be displayed as “Early Termination” in the listings, 
along with relevant Study Day.     
6.2.4 
Duration / Study Day / Time 
Study day will be calculated as the number of days from first dose of study drug. 

date of event – date of first dose of study drug + 1, for events on or after first dose

date of event – date of first dose of study drug, for events before first dose
6.2.5 
Conventions for Missing and Partial Dates 
It is not expected that there will be any missing dates, however in the rare case that an Adverse 
Event (AE) start date or time is missing and it is unclear whether the AE is treatment emergent or 
not then a conservative approach will be taken and it will be assumed that the AE occurred after 
first dosing.  
All dates presented in the individual subject listings will be as recorded on the Electronic Case 
Report Form (eCRF).  


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6.2.6 
Inexact Values 
In the case where a safety laboratory variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value 
of x will be taken for analysis purposes. 
6.2.7 
Unscheduled Visits 
Only scheduled post-baseline laboratory and vital signs values will be tabulated. Post-baseline 
repeat / unscheduled assessments will be disregarded, although these post-baseline assessments 
will be listed in the relevant appendices to the CSR.  
6.2.8 
PK Parameters 
Concentration-time data will be analyzed using noncompartmental methods in Phoenix™ 
WinNonlin® (Version 8.1 or higher, Certara, L.P.)2 in conjunction with the internet-accessible 
implementation of Pharsight® Knowledgebase ServerTM (PKSO; Version 4.0.4 or comparable 
product, Certara, L.P.). PKSO provides protected and structured storage, audit trails, and version 
control for study data, analyses, and related files, supporting 21 CFR Part 11 compliance. 
During the PK analysis, concentrations below the limit of quantitation (BLQ) up to the time of the 
first quantifiable concentration will be treated as zero. Embedded (values between 2 quantifiable 
concentrations) and terminal BLQ concentrations will be treated as missing. PK analysis will be 
based on actual elapsed sample times, relative to time of dose.  
The following PK parameters will be calculated: 
Cmax 
Maximum concentration, determined directly from individual concentration-
time data
Cmax/Dose
Cmax adjusted for the nominal administered dose
Tmax
Time to reach maximum concentration
AUC0-2.5min 
Area under the concentration–time curve from time-zero to 2.5 min; 
calculated using the linear trapezoidal rule allowing for 
extrapolation/interpolation to 2.5 min
AUC0-5min 
Area under the concentration–time curve from time-zero to 5 min; calculated 
using the linear trapezoidal rule allowing for extrapolation/interpolation to 
5min
AUC0-10min 
Area under the concentration–time curve from time-zero to 10 min; calculated 
using the linear trapezoidal rule allowing for extrapolation/interpolation to 
10min
AUC0-20 min 
Area under the concentration–time curve from time-zero to 20 min; calculated 
using the linear trapezoidal rule allowing for extrapolation/interpolation to 
20min


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AUC0-30min 
Area under the concentration–time curve from time-zero to 30 min; calculated 
using the linear trapezoidal rule allowing for extrapolation/interpolation to 
30min
AUClast 
(AUC0-t)
Area under the concentration–time curve from time-zero to the time of the 
last quantifiable concentration; calculated using the linear trapezoidal rule
AUClast/Dose
AUClast adjusted for the nominal administered dose
AUCinf 
Area under the concentration–time curve extrapolated to infinity, calculated 
as: 
AUCinf = AUClast + Clast/λz, 
where Clast is the last quantifiable concentration and λz is the terminal 
elimination rate constant. The percentage of AUCinf based on extrapolation 
should be <30.0%
AUCinf/Dose
AUCinf adjusted for the nominal administered dose
AUC%Extrap 
The percentage of AUCinf based on extrapolation, calculated as: 
%AUCExtrap = (AUCinf – AUClast)/AUCinf*100
λz 
The observed elimination rate constant (λz); estimated by linear regression in 
the terminal phase of the log concentration-time profile; 
see additional criteria below 
T1/2 
The observed terminal elimination half-life calculated as: 
T½ = ln(2)/λz
Clast 
The last quantifiable concentration, determined directly from individual 
concentration-time data
Tlast
Time of the last quantifiable concentration
CL/F 
Apparent total body clearance after extravascular administration, calculated 
as: 
CL/F = Dose/AUCinf
Vz/F 
Apparent volume of distribution following extravascular administration based 
on the terminal phase, calculated as: 
Vz/F = Dose/(AUCinf*λz)
Frel 
Ratio of dose-adjusted AUCinf following IN administration of the test product 
relative to dose-adjusted AUCinf following IM administration of the reference 
product
λz and AUCinf Criteria 
The following criteria will be used to report λz: 

At least three quantifiable concentrations will be used in the regression

Cmax or data prior to Cmax will not be included in the regression.


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
The adjusted regression coefficient (R2 adj) should be ≥ 0.80.
If these acceptance criteria are not met, λz and descriptive parameters (λz time range, Adj R2, etc.) 
will be retained in a parameter listing for informational purposes; λz will be excluded from 
summary statistics. Parameters calculated using λz (AUCinf, T1/2, CL/F, etc.) will be reported as 
ND (not determinable). 
If λz acceptance criteria are met and AUCinf is estimable, the following criteria are used to report 
AUCinf: 

The percentage of AUCinf based on extrapolation should be <30.0%.
If the percentage of AUCinf based on extrapolation is 30.0% or greater, AUCinf and AUCextrap will 
be excluded from summary statistics, subsequent pharmacokinetic parameter calculations (e.g. 
CL/F, Vz/F), and statistical analysis (e.g. ANOVA). 
6.3 Conventions 
All clinical data listings, summaries, figures and statistical analyses will be generated using SAS 
(Version 9.4 or higher)1. 
Summaries of the clinical data will be presented by treatment and/or overall unless otherwise 
stated.  
PK data listings, summaries, figures, and statistical analyses will be generated using Phoenix™ 
WinNonlin® (Version 8.1 or higher)2 or SAS (Version 9.4 or higher)1. PK concentration data will 
be summarized by analyte and treatment at each nominal sample time. PK parameter data will be 
summarized by analyte and treatment.   
Treatment labels will be displayed as follows: 
Treatment A 
Treatment B 
Footnotes describing each treatment will be provided in each output. 
Treatment sequence labels will be displayed as follows:  
Sequence AB 
Sequence BA 
Overall 
Listings will be sorted in the following order treatment sequence, subject, visit and parameter 
unless otherwise stated. All data will be listed. 
For clinical data, continuous variables will be summarized by the number of non-missing 
observations, mean (Gmean and Amean), median, standard deviation, and minimum and 
maximum.  


Worldwide Clinical Trials Controlled Quality Management Document 
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PK data (concentration-time data and PK parameters) will be summarized by the number of 
non-missing observations (n), mean, standard deviation (SD), median, minimum (min), maximum 
(max), and coefficient of variation (CV%), calculated as (SD/Mean)*100.  In addition, the 
geometric mean and geometric CV%, calculated as SQRT[exp(SD2 of log transformed 
data)-1]*100, will be reported for Cmax and AUCs.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
6.3.1 
Decimal Places 
Derived data where it is known in advance the result will be an integer for example, day will be 
presented with zero decimal places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place.  
For PK data, individual concentrations will be reported to 3 significant figures and individual PK 
parameters will be reported to 3 significant figures. For summary statistics, n will be reported as a 
whole number; mean, standard deviation, median, minimum, maximum, and geometric mean will 
be reported to the same precision as for individual data.  CV% and geometric CV% will be reported 
to 3 significant figures; p-values will be reported to 3 significant figures.  Percent ratios of the 
geometric least squares means and associated 90% confidence intervals will be reported to 2 
decimal places.  
6.4 Subject Disposition 
Subject disposition will be summarized for all randomized subjects as follows: 

The number of subjects who were randomized and who are in each analysis population will
be summarized by treatment sequence and overall.

The number of early withdrawals and the reasons for withdrawals will be tabulated by
treatment sequence and overall.
6.5 Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2 of the CSR. 


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6.6 Baseline Comparability 
The comparability of treatment sequences with respect to subject demographics and Baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed. 
Standard continuous or categorical variable summaries will be presented by treatment sequences 
and overall for the following variables based on the Safety Population. 
6.6.1 
Demographic Data 
Standard continuous or categorical variable summaries will be presented by treatment sequence 
and overall for the following variables based on the Safety Population. 

Age at Informed Consent (years)

Gender

Ethnicity

Race, where more than one race is selected the subject will be presented under the ‘Multiple
Races’ category in the summary but each selected race will be identified in the listing.

Weight at Screening (kg)

Height at Screening (cm)

BMI at Screening (kg/m2)
6.7 Medical History 
Listings of previous and ongoing conditions at screening will be presented for the Safety 
Population. Conditions will be coded using the Medical Dictionary of Regulated Activities 
(MedDRA) version 23.1 or higher. 
Prior conditions are defined as all conditions starting and stopping before the date of first dose of 
study drug.  Ongoing conditions are defined as conditions present on or after the date of first dose 
of study drug.   
6.8 Substance Use 
All substance use data will be listed for the Safety Population. 
6.9 Prior and Concomitant Medications 
Prior and concomitant medications will be listed for the Safety Population. 


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Prior medications are defined as all medications starting and stopping before the date of first dose 
of study drug. Concomitant medications are defined as medications taken on or after the date of 
first dose of study drug. 
Medications will be coded using World Health Organization Drug Dictionary (WHODD) Version 
September 2020.  
6.10 Exposure to Study Drug 
All dosing information will be listed. 
6.11 PK Analyses 
Blood samples for determination of plasma concentrations of nalmefene will be collected at: 
Predose (0 h), and at 2.5, 5, 7.5, 10, 15, 20, 30, and 45 minutes and 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 
and 48 hours post dose.  
Concentration-time data will be tabulated by nominal time, analyte, and treatment using 
descriptive statistics. For presentation of the individual data and summary statistics, concentrations 
below the limit of quantitation (BLQ) will be set to zero. 
Individual subject and mean plasma concentration-time data will be presented graphically on linear 
and semi-logarithmic scales. Mean data will be plotted using nominal sample times, and individual 
data will be plotted using actual times. 
PK parameters for nalmefene will be calculated as described in section 5.2.13. 
PK parameters will be summarized by analyte and treatment using descriptive statistics. 
Comparison of the log-transformed PK parameters Cmax, AUC0-2.5min, AUC0-5min, AUC0-10min, 
AUC0-15min, AUC0-20min, and AUC0-30min, AUClast, and AUCinf across treatments will be performed 
using an analysis of variance (ANOVA) model and the two one-sided t-tests procedure at the 
α =0.05 level of significance. The model will include sequence, treatment, and period as fixed 
effects and subject nested within sequence as the random effect. The following comparison(s) 
will be made: 

Test Product (Treatment A) vs. Reference Product (Treatment B)
The ratios of the geometric means (Test / Reference) and 90% confidence intervals will be 
reported.  The analysis will be performed in SAS using PROC GLM. 
Conclusions regarding the results of the statistical analysis (ANOVA) of PK parameters across 
treatments will be based on the ratio of the geometric means (Test / Reference) and the 90% 
confidence interval about the ratio.  No significant difference will be demonstrated if the 90% 
confidence intervals are fully contained within the limits of 80.00% to 125.00%. 


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6.12 Safety Analyses 
The safety analyses will be presented by the treatment received for the Safety Population. 
6.12.1 
Adverse Events 
A treatment emergent adverse event (TEAE) is defined as: 
 Any AE that has an onset on or after the first dose of study drug.   
 Any pre-existing AE that has worsened in severity on or after the first dose of study drug.  
The following rules will be used to assign a TEAE to a treatment group: 
 A TEAE will be assigned to the treatment received immediately before onset. 
 Any TEAE reported within the washout period between doses will be attributed to the 
previous treatment.  
 If the severity of a TEAE increases in a later period the TEAE at the increased severity will 
be assigned to the treatment received immediately before the increase in severity. 
A treatment-related AE is defined as an AE as being possibly, probably or definitely related to 
the study drug. If an AE has missing relationship it is assumed to be related to the study drug for 
analysis purposes. 
Maximum severity will be assumed for an AE with missing severity.  
The following tables will be presented for AEs: 
 Overall incidence and the number of TEAEs, Related TEAEs, SAEs, Related SAEs, 
TEAEs leading to withdrawal. 
 TEAE by system organ class and preferred term, incidence and number of events. 
 Treatment related TEAE by system organ class and preferred term, incidence and number 
of events. 
 Serious TEAE by system organ class and preferred term, incidence and number of events. 
 TEAE by system organ class, preferred term and maximum severity, incidence. 
 Treatment related TEAE by system organ class, preferred term and maximum severity, 
incidence. 
 TEAE by system organ class, preferred term and relationship, incidence  
 TEAEs leading to early withdrawal by system organ class and preferred term, incidence. 
 Listing of Serious TEAEs (presented in the Table section of the appendices). 
 Listing of Deaths (presented in the Table section of the appendices). 


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In counting the number of AEs reported, a continuous event (i.e. reported more than once and 
which did not cease), will be counted only once; non-continuous AE reported several times by the 
same subject will be counted as multiple events. 
All AEs will be listed. 
6.12.2 
Laboratory Data 
The following laboratory tests will be performed at Screening and prior to discharge (or early 
termination). 
Hematology 
Urinalysis 
Serum Chemistry 
Coagulation 
Hemoglobin
Specific gravity
Total protein
Prothrombin time 
Hematocrit
Glucose
Albumin
Activated partial  
thromboplastin 
time 
Red blood cells
Bilirubin
Blood urea nitrogen
Total white blood cells
Ketones
Creatinine
Automated differential 
blood count 
Blood
Alkaline Phosphatase
pH
Alanine aminotransferase
Platelet count
Protein
Aspartate aminotransferase
Nitrite
Total bilirubin
Leukocyte esterase
Sodium
Potassium
Chloride
CO2
Calcium
Glucose
Total cholesterol
Descriptive statistics of the observed values for Baseline and end of study (EOS) visit and change 
from Baseline (continuous data) to EOS will be for each hematology, urinalysis, serum chemistry 
parameter and coagulation markers will be presented by treatment sequence and overall. Each 
measurement (continuous data) will be classed as below, within, or above normal range, based on 
ranges supplied by the laboratory used. Shift tables in relation to the normal range from Baseline 
to EOS visit will be presented. 
All hematology, urinalysis, serum chemistry and coagulation markers data will be listed. 
A separate listing of any clinically significant laboratory measurements recorded throughout the 
study will be presented. 
All other laboratory data, for example Viral Serology, Serum FSH, Pregnancy Test, and Urine 
Drug, Alcohol and Cotinine, will be listed only. 


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Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 17 of 26
6.12.3 
Vital Signs 
Vital signs will be tabulated for Baseline, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h and 48 h post-dose 
and the respective changes from Baseline, per treatment. In addition, vital signs values will be 
tabulated for Baseline, EOS, and change from Baseline to EOS by treatment sequence and overall. 
Descriptive statistics for the following vital signs will be presented: 

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Pulse rate (bpm)

Respiration rate (breath/min)

Body temperature (degrees Celsius)
Also, Shift tables in relation to investigator assessment i.e. Normal, Abnormal NCS (Not 
Clinically Significant), and Abnormal CS (Clinically Significant), from Baseline to each follow-
up visit will be presented. 
All vital sign data, including details of any clinical significant values will be listed. 
6.12.4 
Electrocardiogram Data 
12-lead ECGs will be tabulated for Baseline, 0.33 h, 1 h, and 10 h post-dose and the respective
changes from Baseline, per treatment. In addition, ECG values will be tabulated for Period 1
Baseline, day 4 and EOS, and change from Baseline to day 4 and change from Baseline to EOS
by treatment sequence and overall.
Shift tables in relation to the overall interpretation i.e. Normal, Abnormal NCS, and Abnormal CS, 
from Baseline to each follow-up visit will be presented. 
All ECG data, including details of any abnormalities, will be listed. 
6.12.5 
Physical Examination 
The body systems within the physical examination data at the EOS will be summarized by 
treatment sequence and overall (Normal, Abnormal NCS, Abnormal CS) as a shift from Baseline 
table.  
All data, including details of clinically significant findings will be listed. 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 18 of 26
6.12.6 
Nasal Passage Examination 
Nasal passage examination will be conducted at Screening, Admission/Baseline, pre-dose, and at 
approximately 5 minutes and ± 15 minutes of the nominal blood collections at 1 h and 8 h post-
dose, and at approximately 24 h and 48 h post-dose, after the IN dose. The nasal passage will be 
examined by a physician (or qualified medical professional) for evidence of irritation (erythema, 
edema, and erosion). 
The number and percentage of subjects reporting each nasal irritation scale at Baseline, 5 mins, 1 
h, 8 h, 24 h and 48 h post-dose will be provided for the Safety Population. 
Nasal irritation will be determined on the following scale: 
Nasal Irritation Scale 
0 - Normal appearing mucosa, no bleeding 
1 - Inflamed mucosa (erythema/edema), no bleeding 
2 - Minor bleeding which stops within 1 minute 
3 - Minor bleeding, taking 1-5 minutes to stop 
4 - Substantial bleeding for 4-60 minutes, does not require medical intervention 
5 - Ulcerated lesions, bleeding which requires medical intervention 
A shift table for nasal irritation scale from Baseline to post-baseline time points will be 
presented. 
All nasal passage examination data will be listed for the Safety Population. 
6.12.7 
Numerical Rating Scale 
Numerical rating scale (NRS) assessments will be conducted pre-dose and at 15 (± 2 min) and 60 
(± 10 min) minutes post-dose (IN period). 
Descriptive statistics of NRS data at Baseline, 15 minutes and 60 minutes post-dose will be 
presented by overall and a listing of all NRS data will be provided for the Safety Population. 
6.12.8 
Smell Test 
Smell test will be conducted at Screening, pre-dose and ± 15 minutes of the nominal blood 
collections at 1 h and 4 h, and at approximately 24 h post-dose after the IN dose, and final 
discharge. 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 19 of 26
Descriptive statistics of smell test score for Baseline and post-baseline time points will be 
presented by overall. Additionally, all smell test data will be listed for the Safety Population. 
7 CHANGES TO PLANNED PROTOCOL ANALYSIS 
During the analysis and reporting process, any deviations from the statistical analysis plan will be 
described and justified in writing in the CSR.  


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 20 of 26
8 REFERENCES 
1. SAS Institute Inc., Cary, NC, 27513, USA
2. Phoenix™ WinNonlin® (Version 8.1, Certara, L.P.)


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 21 of 26
9 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the electronic common technical document (eCTD). The eCTD section is shown in bold. 
The following validation methods maybe used:  

Independent programming of numbers and manual review of format (IP)

Independent programming by statistician of numbers and manual review of format (Stat
IP)

Manual review (MR)

Code review (CR)
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat)
Items in bold are not table titles but references to the section headings within eCTD.
14.1 
Demographics Data
14.1.1 
Disposition
14.1.1 
Subject Disposition, Analysis Populations – All 
Randomized Subjects 
IP 
14.1.2 
Demographics 
14.1.2 
Summary of Demographics - Safety Population 
IP
14.1.3 
Baseline Characteristics 
Not Applicable
14.2 
Efficacy Data
Not Applicable
14.3 
Safety Data
14.3.1 
Displays of Adverse Events
14.3.1.1 
Overall Summary of Treatment Emergent Adverse 
Events (TEAEs) – Safety Population 
IP 
14.3.1.2 
TEAEs By Primary System Organ Class and Preferred 
Term – Safety Population
IP 
14.3.1.3 
Treatment Related TEAEs By Primary System Organ 
Class and Preferred Term – Safety Population
IP 
14.3.1.4 
Serious TEAEs By Primary System Organ Class and 
Preferred Term – Safety Population
IP 
14.3.1.5 
TEAEs By Primary System Organ Class Preferred Term 
and Maximum Severity – Safety Population
IP 
14.3.1.6 
Treatment Related TEAEs By Primary System Organ 
Class Preferred Term and Maximum Severity – Safety 
Population
IP 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 22 of 26
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat)
14.3.1.7 
TEAEs By Primary System Organ Class Preferred Term 
and Relationship – Safety Population
IP 
14.3.1.8 
TEAEs Leading to Early Withdrawal by Primary System 
Organ Class and Preferred Term – Safety Population
IP 
14.3.2 
Listings of Deaths, Other Serious and Significant 
Adverse Events
14.3.2.1
Listing of SAEs – Safety Population
MR
14.3.2.2
Listing of Deaths – Safety Population
 MR
14.3.3 
Narratives of Deaths, Other Serious and Certain 
Other Significant Adverse Events 
14.3.4 
Abnormal Laboratory Values
14.3.4 
Listing of Clinically Significant Abnormal Laboratory 
Values – Safety Population  
MR 
14.3.5 
Extent of Exposure, Dosage Information, And 
Compliance
14.3.6 
Vital Signs and Physical Examination
14.3.6.1
Vital Signs, Change from Baseline – Safety Population
IP
14.3.6.2
Vital Signs, Normal Range Shift – Safety Population
IP
14.3.6.3 
Physical Examination, Shift from Baseline – Safety 
Population
IP 
14.3.6.4.1
Summary of Nasal Irritation Scale – Safety Population
IP
14.3.6.4.2 
Nasal Irritation Scale, Shift from Baseline – Safety 
Population
IP 
14.3.6.5 
NRS Assessment, Descriptive Statistics – Safety 
Population
IP 
14.3.6.6 
Smell Test Score, Descriptive Statistics – Safety 
Population
IP 
14.3.7 
Other Safety
14.3.7.1 
Hematology Data, Change from Baseline – Safety 
Population
IP 
14.3.7.2 
Hematology Data, Normal Range Shift – Safety 
Population
IP 
14.3.7.3 
Serum Chemistry Data, Change from Baseline – Safety 
Population
IP 
14.3.7.4 
Serum Chemistry Data, Normal Range Shift – Safety 
Population
IP 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 23 of 26
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat)
14.3.7.5 
Coagulation Data, Change from Baseline – Safety 
Population
IP 
14.3.7.6 
Coagulation Data, Normal Range Shift – Safety 
Population
IP 
14.3.7.7 
Urinalysis Data, Change from Baseline – Safety 
Population
IP 
14.3.7.8
Urinalysis Data, Normal Range Shift – Safety Population
IP
14.3.7.9
ECG Data, Change from Baseline – Safety Population
IP
14.3.7.10
ECG Data, Shift from Baseline in Overall Interpretation
IP
14.3.8 
Concomitant Medication
Not Applicable
14.4 
PK Tables
14.4.1 
Descriptive Statistics for Concentration-Time Data of 
Nalmefene after Intranasal (IN) Administration of 3.0 mg 
Nalmefene Hydrochloride (Treatment A) and 
Intramuscular (IM) Administration of 1.0 mg of 
Nalmefene Hydrochloride (Treatment B) – PK Polulation
IP 
14.4.2 
PK Parameters of Nalmefene after Intranasal (IN) 
Administration of 3.0 mg Nalmefene Hydrochloride 
(Treatment A) and Intramuscular (IM) Administration of 
1.0 mg of Nalmefene Hydrochloride (Treatment B) – PK 
Polulation
IP 
14.4.3 
Statistical Analysis of the Natural Log-Transformed 
Systemic Exposure of Nalmefene Comparing 3.0 mg 
Nalmefene hydrochloride (IN) (Treatment A, Test) to 1.0 
mg of Nalmefene Hydrochloride (IM) (Treatment B, 
Reference) – PK Polulation
IP 
14.5 
PD Tables
14.6 
Other Data


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 24 of 26 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat)
14.4.1 
Nalmefene Concentration-Time Data, Mean Profiles on 
Linear and Semi-Logarithmic Scales after Intranasal 
(IN) Administration of 3.0 mg Nalmefene 
Hydrochloride (Treatment A) and Intramuscular (IM) 
Administration of 1.0 mg of Nalmefene Hydrochloride 
(Treatment B) – PK Population
MR 
 
14.4.2 
Nalmefene Concentration-Time Data, All Subject 
Profiles on Linear and Semi-Logarithmic Scales after 
Intranasal (IN) Administration of 3.0 mg Nalmefene 
Hydrochloride (Treatment A) and Intramuscular (IM) 
Administration of 1.0 mg of Nalmefene Hydrochloride 
(Treatment B) – PK Population
MR 
 
14.4.3 
Nalmefene Concentration-Time Data, Individual 
Profiles on Linear and Semi-Logarithmic Scales after 
Intranasal (IN) Administration of 3.0 mg Nalmefene 
Hydrochloride (Treatment A) and Intramuscular (IM) 
Administration of 1.0 mg of Nalmefene Hydrochloride 
(Treatment B) – PK Population
MR 
 
14.4.4 
Concentration-Time Profiles for Nalmefene with Linear 
Regression for Estimating the Terminal Elimination – 
Rate PK Population
MR 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 25 of 26
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat)
16.2 
Subject Data Listings
16.2.1 
Discontinued Subjects 
16.2.1.1 
Subject Disposition – All Randomized Subjects 
MR
16.2.2 
Protocol Deviations 
16.2.2.1
Protocol Deviations – Safety Population
MR
16.2.3
Subjects Excluded from the Efficacy Analyses
16.2.3.1 
Analysis Populations – All Randomized Subjects 
MR
16.2.4 
Demographic Data
16.2.4.1 
Demographic Data – Safety Population
MR
16.2.4.2
Previous Medical History – Safety Population
MR
16.2.4.3
Ongoing Medical History – Safety Population
MR
16.2.4.4
Substance Use – Safety Population
MR
16.2.4.5
Prior and Concomitant Medications – Safety Population
MR
16.2.5 
Compliance and / or Drug Concentration Data
16.2.5.1 
Dosing Information – Safety Population 
MR
16.2.5.2
PK Sampling Information – Safety Population
MR
16.2.6 
Individual Efficacy Response Data 
16.2.6.1 
Nalmefene Concentration-Time Data Listing – Safety 
Population 
MR 
16.2.6.2 
Terminal Elimination Rate of Nalmefene in Plasma for 
Individual Subjects – PK Population 
MR 
16.2.6.3 
PK Output Text 
MR
16.2.6.4 
SAS Output Text (ANOVA) 
MR
16.2.7 
Adverse Event Listings 
16.2.7.1
Adverse Event Data – Safety Population
MR
16.2.8 
Individual Laboratory Measurements and Other 
Safety 
16.2.8.1
Hematology Data – Safety Population
MR
16.2.8.2
Serum Chemistry Data – Safety Population
MR
16.2.8.3
Urinalysis Data – Safety Population
MR
16.2.8.4
Drug and Alcohol Screen – Safety Population
MR
16.2.8.5
Serology Data – Safety Population
MR
16.2.8.6
Pregnancy Test Data – Safety Population
MR
16.2.8.7
Physical Examination Data – Safety Population
MR
16.2.8.8
Vital Signs Data – Safety Population
MR
16.2.8.9
ECG Data – Safety Population
MR


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Opiant Pharmaceuticals 
Protocol Number: 
OPNT003-PK-001 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 26 of 26
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat)
16.2.8.10
Nasal Passage Examination Data – Safety Population
MR
16.2.8.11
NRS Assessment Data – Safety Population
MR
16.2.8.12
Smell Test Data – Safety Population
MR