Clinical trial NCT05219669
Conditions: Opioid Overdose
Keywords: Pharmacokinetics
Sponsor: Opiant Pharmaceuticals Inc
Start date: 2021-09-01; Completion date: 2021-11-22
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is to compare the pharmacokinetics (how the body absorbs, breaks down and eliminates drug from your body) of nalmefene when given as a single dose intranasally (IN;into the nose), as a single dose in each nostril and as two doses in one nostrils; and to evaluate the safety and tolerability of nalmefene IN.

Detailed description:
Open-label, randomized, 3-period, 3-treatment, 6-sequence, ranodmised crossover study in 24 healthy volunteers. Subjects will be assigned to each of the 6 possible sequences. Each subject will receive 3 intranasal (IN) nalmefene doses:

* 3mg IN dose (one 0.1mL spray of a 30mg/mL solution in one nostril)
* 6mg IN dose (one 0.1mL spray of a 30mg/mL solution in each nostril)
* 6mg IN dose (two 0.1mL sprays of a 30mg/mL solution in one nostril)

There will be a 6 day washout period between doses. Screening can occur up to 28 days before admission, subjects will then stay in the inpatient facility for 16 days to complete the treatment phase of the study and will be discharged following completion of the discharge procedures at the end of the last period. Subjects will be called 3 to 5 days after discharge to inquire concerning Adverse Events (AEs) and concomitant medications since discharge.

Arms: arm 1: 3 mg IN Nalmefene Hydrochloride dose (one 0.1 mL spray of a 30 mg/mL solution in one nostril) arm 2: 6 mg IN Nalmefene Hydrochloride dose (two 0.1 mL sprays of a 30 mg/mL solution in one nostril) arm 3: 6 mg IN Nalmefene Hydrochloride dose (one 0.1 mL spray of a 30 mg/mL solution in each nostril)
Interventions: intervention 1: Nalmefene Hydrochloride
Intervention descriptions: intervention 1: 30 mg/mL solution

Protocol documents:
Prot_000.pdf: 
Opiant Pharmaceuticals  
Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
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1) STUDY SYNOPSIS 
 
 
Name of Sponsor 
Opiant Pharmaceuticals 
Name of 
Investigational 
Product: 
Nalmefene hydrochloride nasal spray 
Title of Study: 
An Open-Label, Three-Period, Three-Treatment, Six-Sequence, 
Randomized Crossover Study of the Pharmacokinetics of 
Intranasal Nalmefene in Healthy Volunteers using Three Dosing 
Regimens 
Clinical Phase: 
Phase I (Healthy Volunteers)  
Protocol Number: 
OPNT003-PK-002 
Study Design: 
Open-label, randomized, 3-period, 3-treatment, 6-sequence, 
randomized crossover study in 24 healthy volunteers. Subjects 
will be assigned to each of the 6 possible sequences.  
 
Each subject will receive 3 intranasal (IN) Nalmefene doses: 
· 3mg IN dose (one 0.1mL spray of a 30mg/mL solution in one nostril) 
· 6mg IN dose (one 0.1mL spray of a 30mg/mL solution in each nostril) 
· 6mg IN dose (two 0.1mL sprays of a 30mg/mL solution in one nostril) 
 
There will be a 6 day washout period between doses. Screening 
can occur up to 28 days before admission, subjects will then stay 
in the inpatient facility for 16 days to complete the treatment 
phase of the study and will be discharged following completion of 
the discharge procedures at the end of the last period. Subjects 
will be called 3 to 5 days after discharge to inquire concerning 
Adverse Events (AEs) and concomitant medications since 
discharge. 
All subjects who have given their written informed consent and 
who satisfy all of the relevant inclusion criteria and none of the 
exclusion criteria will be screened for eligibility to participate in the 
study including medical history, demographics, concomitant 
medications, physical examination, height, weight, body mass 
index (BMI), nasal passage examination, smell test, clinical 
chemistry, coagulation markers, hematology, serum Follicle 
Stimulating Hormone (FSH) levels (females postmenopausal 
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Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
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only), infectious disease serology, urinalysis, urine drug, urine 
cotinine and urine alcohol toxicology screen, serum pregnancy 
test (females only), vital signs and electrocardiogram (ECG).  
 
On the day of clinic admission (Day -1) the following procedures 
will be performed to review eligibility, update on medical history, 
update on concomitant medications, physical examination, nasal 
passage examination, 12-lead ECG, vital signs, urine pregnancy 
test (females only), urine drug, urine cotinine and urine alcohol 
toxicology screen. 
 
After eligibility of established and admission procedures has been 
reviewed by an investigator, patients will be randomized.  
 
On the day after admission subjects, in a fully supine position, will 
be administered the IN dose randomized to a sequence order of 
receipt.  
 
Subjects should be instructed to hold their breath during 
administration of the nasal spray into the nose. Blood will then be 
collected prior to dosing (within 15 minutes) and approximately 
2.5, 5, 7.5, 10, 15, 20, 30, 45 minutes and 1, 2, 3, 4, 6, 8, 12, 18, 
24 and 48 hours after drug administration. Pre-dose blood sample 
will be collected within 15 minutes before dosing. 
 
Actual blood collection times can vary as follows: ±30 seconds for 
the 2.5, 5 & 7.5 samples, ±1 minute for the 10 to 30-minute 
samples, ±3 minutes for the 45 to 120-minute samples, and ±5 
minutes for the 180 minute or greater samples. Actual sampling 
times will be recorded. 
 
On days of study drug administration (days 1, 7 and 13): 
A numerical rating scale (NRS) to assess acute nasal pain will be 
completed pre-dose, and at approximately 15 (± 2) and 60 (± 10) 
minutes post-dose. 
Continuous cardiac monitoring (telemetry) will be performed from 
approximately one hour (± 30 minutes) pre-dose to 6 hours (± 30 
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Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
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minutes) post-dose. ECG assessment will be conducted within ± 
5 minutes of the nominal blood collection at 20 minutes, and ± 15 
minutes of the nominal blood collections at 1 and 6 hours post-
dose.  
Vital signs will be measured pre-dose and at approximately 15 
and 30 minutes, and ± 15 minutes of the nominal blood collections 
at 1, 2, 4 and 8 hours post-dose. Vital signs will also be measured 
if the subject displays any change in condition including 
lightheadedness, dizziness, syncope, nausea, vomiting or 
tachy/bradyarrhythmia 
as 
noted 
on 
continuous 
cardiac 
monitoring. 
Nasal passage examination will be conducted in both nostrils pre-
dose, at approximately 5 minutes and ± 15 minutes of the nominal 
blood collections at 1 and 8 hours post-dose.  
Smell test will be conducted pre-dose and ± 15 minutes of the 
nominal blood collections at 1 and 4 hours post-dose. 
Tolerability assessed via AE query and concomitant medications 
will be reviewed.  
On the day after dosing (day 2,8 and 14) tolerability via AE query 
will be assessed, concomitant medications reviewed, vital signs 
measured, the smell test will be conducted and examination of 
the nasal passage performed in both nostrils at approximately 24 
hours post-dose.  
On the second day after dosing (day 3 and day 9) tolerability via 
AE query will be assessed, concomitant medications reviewed, 
vital signs measured and examination of the nasal passage 
performed in both nostrils at approximately 48 hours post-dose.  
On days 4, 5, 10 and 11 tolerability will be assessed, and 
concomitant medications reviewed. On the days before the next 
dosing (days 6 and 12) tolerability will be assessed, concomitant 
medications reviewed, a urine pregnancy test (females only) and 
12-lead ECG performed. On the day of clinic discharge (day 15) 
from the inpatient stay the following procedures will be performed: 
assess tolerability via AE query, update on concomitant 
medications, vital signs at approximately 48 hours post-dose, 
physical examination, weight, examination of the nasal passage 
in both nostrils at approximately 48 hours post-dose, smell test,, 
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Pharmacy Manual - Version 1.0 
Protocol Number OPNT003-PK-002 
29Sep2021 
 
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12-lead ECG, serum pregnancy test (females only), clinical 
chemistry, coagulation markers, hematology and urinalysis.  
AEs will be assessed by spontaneous reports by subjects, by 
examination of the nasal mucosa and by measuring vital signs, 
ECG and clinical laboratory parameters. 
Planned 
Sample 
Size: 
Twenty-four subjects  
Investigational 
medicinal product, 
route of 
administration and 
dosage: 
Nalmefene hydrochloride 3mg nasal spray  
Nasal (IN) 
 
Period 1: 3mg (one 0.1 mL spray of 30 mg/mL nalmefene 
hydrochloride in one nostril) 
Period 2: 6mg (one 0.1 mL sprays of 30 mg/mL nalmefene 
hydrochloride in each nostril) 
Period 3: 6mg (two 0.1 mL sprays of 30 mg/mL nalmefene 
hydrochloride in one nostril) 
Maximum Duration 
of Treatment 
Screening can occur up to 28 days before admission. The total 
subject inpatient stay is 16 days, during which the treatment will 
be administered.  
Subjects will be called 3 to 5 days after final discharge to inquire 
concerning adverse events and concomitant medications since 
discharge. Total subject duration is up to 48 days to complete the 
entire study. 
 
 
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Appendix 16.1.1 - Page 70


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

SAP_001.pdf: 
Worldwide Clinical Trials Controlled Quality Management Document 
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I Protocol Number: 
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Statistical Analysis Plan 
Title: An Open-Label, Three-Period, Three-Treatment, Six-Sequence, Randomized 
Crossover Study of the Pharmacokinetics of Intranasal Nalmefene in Healthy 
Volunteers using Three Dosing Regimens 
Protocol Number: OPNT003-PK-002 
Protocol Version: 1.0 I 06-AUG-2021 
SAP Version 1.0 
SAP Issue Date: 16-NOV-2021 
SAP Authors: Sangli Therasanathan, MSc, 
Kathryn Roupe, PhD 
Previous SAP Versions 
NA 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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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-001 f-1.3 
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WORLDWIDE 
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SAP Amendments before database lock 
Version 
Issue Date 
Section 
Revision I Addition 
Rationale 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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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-001 f-1.3 
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6.11.2 
Laboratory Data ...................................................................................................... 18 
6.11.3 
VitalSigns ............................................................................................................... 19 
6.11.4 
Electrocardiogram Data .......................................................................................... 20 
6.11.5 
Physical Examination .............................................................................................. 20 
6.11.6 
Nasal Passage Examination .................................................................................... 21 
6.11. 7 
Numerical Rating Scale .......................................................................................... 21 
6.11.8 
Smell Test ............................................................................................................... 21 
7 
CHANGES TO PLANNED PROTOCOL ANALYSIS ................................... 22 
8 
REFERENCES .................................................................................................. 23 
9 
LIST OF TABLES, FIGURES AND LISTINGS ............................................. 24 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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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-001 f-1.3 
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Where, 
• 
Treatment A: 3 mg, one 0.1 mL spray in one nostril. 
• 
Treatment B: 6 mg, one 0.1 mL spray in each nostril. 
• 
Treatment C: 6 mg, two 0.1 mL sprays in one nostril. 
6 
PLANNEDANALYSES 
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 
Pharmacokinetic Analysis Population for Test 2 versus Test 1 Comparison (B vs. A) 
The pharmacokinetic analysis population for Test 2 versus Test 1 comparison will include all 
subjects who have evaluable pharmacokinetic data on the Test 2 period and on the Test 1 period 
and did not deviate from the protocol in a way that might affect the evaluation of the 
pharmacokinetic endpoints. 
Pharmacokinetic Analysis Population for Test 3 versus Test 1 Comparison (C vs. A) 
The pharmacokinetic analysis population for Test 3 versus Test 1 comparison will include all 
subjects who have evaluable pharmacokinetic data on the Test 3 period and on the Test 1 period 
and did not deviate from the protocol in a way that might affect the evaluation of the 
pharmacokinetic endpoints. 
Pharmacokinetic Analysis Population for Test 2 versus Test 3 Comparison (B vs. C) 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
I 
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-001 f-1.3 
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Worldwide Clinical Trials Controlled Quality Management Document 
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The pharmacokinetic analysis population for Test 2 versus Test 3 comparison will include all 
subjects who have evaluable pharmacokinetic data on the Test 2 period and on the Test 3 period 
and did not deviate from the protocol in a way that might affect the evaluation of the 
pharmacokinetic endpoints. 
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 
Study Period / Visits 
Each visit as per study schedule will be mapped to treatment period and analysis visit for summary 
tables as given below. Listings will reflect actual period and visit as defined in protocol. 
Collected Visit 
Analysis Visit 
Analysis Period 
Screening 
Screening 
-
Day-1 
Day-1 
-
Day 1 
Day 1 
Period 1 
Day2 
Day2 
Period 1 
Day3 
Day3 
Period 1 
Day4 
Day4 
Period 1 
Day5 
Day 5 
Period 1 
Day6 
Day6 
Period 1 
Day7 
Day7 
Period 2 
Day 8 
Day8 
Period 2 
Day9 
Day9 
Period 2 
Day 10 
Day 10 
Period 2 
Day 11 
Day 11 
Period 2 
Day 12 
Day 12 
Period 2 
Day 13 
Day 13 
Period 3 
Day 14 
Day 14 
Period 3 
Day 15 (Discharge) 
EOS/ET 
-
Early Termination 
EOS/ET 
-
Follow-Up Phone Call 
FUP 
-
Any Discharge assessments taken more than once will be mapped as "DIS - Unscheduled" in 
listings. 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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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-001 f-1.3 
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Appendix 16.1.9 - Page 11


 
 
 
 
6.2.10.1 Concentration-Time Data 
 
 
 
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Appendix 16.1.9 - Page 12


6.2.10.2 PK Parameters 
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Worldwide Clinical Trials Controlled Quality Management Document 
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• 
Cmax or data prior to Cmax will not be included in the regression. 
• 
The adjusted regression coefficient (R2 adj) should be 2'.: 0.80. 
If these acceptance criteria are not met, Ke1 and descriptive parameters (Ke1 time range, Adj R2, 
etc.) will be retained in a parameter listing for informational purposes; Ke1 will be excluded from 
summary statistics. Parameters calculated using Ke1 (t½, CL/F, VJF) will be reported as ND (not 
determinable). 
If Ke1 acceptance criteria are met and AUCm is estimable, the following criteria are used to report 
AUCnr: 
• The percentage of AUCnr based on extrapolation should be <30.0%. 
If the percentage of AUCinf based on extrapolation is 30.0% or greater, AUCnr and AUC%extrap will 
be excluded from summary statistics, subsequent PK calculations ( e.g. CL/F, V JF), and statistical 
analysis ( e.g. ANOV A). 
Individual PK parameters will be listed by treatment and summarized by descriptive statistics: n, 
mean, SD, median, min, max, CV%, geometric mean, and geometric CV%. 
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 treatment sequence 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)'. PK concentration data will 
be summarized by treatment at each nominal sample time. PK parameter data will be summarized 
by treatment. 
Treatment labels will be displayed as follows: 
Treatment A 
Treatment B 
Treatment C 
Footnotes describing each treatment will be provided in each output. 
Treatment sequence labels will be displayed as follows: 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Sequence 5 
Sequence 6 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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Governing QMD: Worldwide-S0P-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-001 f-1.3 
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Worldwide Clinical Trials Controlled Quality Management Document 
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data. p-values will be reported to 4 decimal places. Percent ratios of the geometric least squares 
means and associated 90% confidence intervals will be reported to 2 decimal places. Time will be 
presented to 3 significant figures. 
6.4 Subject Disposition 
Subject disposition will be summarized for all randomized subjects as follows: 
• 
The number of subjects who were randomized; number and percentage of subjects in each 
analysis population will be summarized by treatment sequence and overall. 
• 
The number and percentage of subjects who completed the study and who terminated 
early, along reason for early termination, will be summarized based on the Safety 
Population. 
The Safety and PK Evaluation Population will be based on actual treatment received. Percentage 
for safety population will be based on randomized subjects. Percentages for all other categories 
will be based on Safety Population. Percentage for "Reason for withdrawal" is based on number 
of non-completers. 
A listing of population flags, disposition details and reason for exclusion from population will be 
provided. 
In Mock Shells: Table 14.1.1.1, Listing 16.2.1.1, Listing 16.2.3.1. 
6.5 Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2 of the CSR. 
In Mock Shells: Listing 16.2.2.1. 
6.6 Demographics and Baseline Comparability 
Subject demographics will be summarized by treatment sequence and overall. Categorical and 
continuous variables will be provided in the same table. The following variables will be presented: 
age at Informed Consent (years), sex, ethnicity, race, baseline height (cm), baseline weight (kg), 
baseline BMI (kg/m2). Percentages will be based on the respective population. 
The summaries will be repeated for Safety and PK Evaluation Populations (as per ICH E3 
Guidelines). If the populations are the same, then demographic summary for PK Evaluable 
Population will be removed. 
A listing of subject demographics, baseline characteristics and contraception details will be 
provided. 
In Mock Shells: Table 14.1.2.1 to 14.1.2.2, Listing 16.2.4.1. 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
j 
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-001 f-1.3 
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Worldwide Clinical Trials Controlled Quality Management Document 
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• 
Treatment related serious TEAE by system organ class and preferred term, incidence, and 
number of events. 
• 
TEAE leading to early withdrawal by system organ class and preferred term, incidence 
• 
TEAE by system organ class, preferred term and maximum severity, incidence. If a subject 
had multiple occurrences of the same PT within a treatment period, it is counted once with 
maximum severity under the PT; if a subject had multiple PTs within the SOC with 
different grades of maximum severity, it is counted once within each applicable severity 
grade within the SOC and Any TEAE categories. 
• 
TEAE by system organ class, preferred term and closest relationship, incidence. If a subject 
had multiple occurrences of the same PT within a treatment period, it is counted once with 
closest relationship under the PT; if a subject had multiple PTs within the SOC with 
different grades of closest relationship, it is counted once within each applicable 
relationship category within the SOC and Any TEAE categories. Listing of Serious TEAEs 
(presented in the Table section of the appendices). 
• 
Listing of Deaths (presented in the Table section of the appendices). 
• 
Listing of Adverse events leading to Early Withdrawal (presented in the Table section of 
the appendices). 
All AEs will be separately listed. 
In Mock Shells: Tables 14.3.1.1 to 14.3.1.8, Tables 14.3.2.1 to 14.3.2.3, Listing 16.2.7.1 
6.11.2 
Laboratory Data 
The following laboratory tests will be performed at Screening and during discharge ( or early 
termination). 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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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-001 f-1.3 
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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 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if repeat) 
Items in bold are not table titles but references to the section headings within eCTD. 
14.1 
Demo2raphics Data 
14.1.1 
Disposition 
14.1.1 
Subject Disposition, Analysis Populations - All 
IP 
-
Randomized Subjects 
14.1.2 
Demo2raphics 
14.1.2.1 
Summary of Demographics - Safety Population 
IP 
-
14.1.2.2 
Summary of Demographics -PK Population 
IP 
14.1.2.2 
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 
IP 
-
Events (TEAEs)- Safety Population 
14.3.1.2 
TEAEs By Primary System Organ Class and Preferred 
IP 
-
Term - Safety Population 
14.3.1.3 
Treatment Related TEAEs By Primary System Organ 
IP 
14.3.1.2 
Class and Preferred Term - Safety Population 
14.3.1.4 
Serious TEAEs By Primary System Organ Class and 
IP 
14.3.1.2 
Preferred Term - Safety Population 
14.3.1.5 
Related Serious TEAEs by Primary System Organ Class 
IP 
14.3.1.2 
and Preferred Term- Safety Population 
14.3.1.6 
Treatment Emergent Adverse Events leading to Early 
IP 
14.3.1.2 
Withdrawal by SOC and PT - Safety Population 
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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-001 f-1.3 
Page 24 of30 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 26


Worldwide Clinical Trials Controlled Quality Management Document 
1!r WORLDWIDE 
I Sponsor: 
I OpiantPharmaceuticals 
f 
I Protocol Number: 
I OPNT003-PK-002 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if repeat) 
14.3.1.7 
Treatment Emergent Adverse Events by SOC, PT and 
IP 
-
Maximum Severity - Safety Population 
14.3.1.8 
Treatment Emergent Adverse Events by SOC, PT and 
IP 
-
Closest Relationship - Safety Population 
14.3.2 
Listings of Deaths, Other Serious and Significant 
Adverse Events 
14.3.2.1 
Listing of SAEs - Safety Population 
IP 
16.2.7.1 
14.3.2.2 
Listing of Deaths - Safety Population 
IP 
16.2.7.1 
14.3.2.3 
Listing of TEAEs Leading to Early Withdrawal - Safety 
IP 
16.2.7.1 
Population 
14.3.3 
Narratives of Deaths, Other Serious and Certain 
Other Si2nificant Adverse Events 
14.3.4 
Abnormal Laboratory Values 
14.3.4.1 
Hematology Data, Descriptive Statistics - Safety 
IP 
-
Population 
14.3.4.2 
Clinical Chemistry Data, Descriptive Statistics - Safety 
IP 
14.3.4.1 
Population 
14.3.4.3 
Coagulation Data, Descriptive Statistics - Safety 
IP 
14.3.4.1 
Population 
14.3.4.4 
Urinalysis Data, Descriptive Statistics - Safety 
IP 
14.3.4.1 
Population 
14.3.4.5 
Hematology Data, Shift Summary - Safety Population 
IP 
-
14.3.4.6 
Clinical Chemistry Data, Shift Summary - Safety 
IP 
14.3.4.5 
Population 
14.3.4.7 
Clinical Chemistry Data, Shift Summary - Safety 
IP 
14.3.4.5 
Population 
14.3.4.8 
Urinalysis Data, Shift Summary - Safety Population 
IP 
16.2.8.1 
14.3.4.9 
Listing of Out of Range Laboratory Data - Safety 
IP 
-
Population 
14.3.5 
Vital Si2ns and Physical Examination 
14.3.5.1 
Vital Signs, Change from Baseline - Safety Population 
IP 
-
14.3.5.2 
Vital Signs, Shift Summary - Safety Population 
IP 
-
14.3.6 
Other Safety 
14.3.6.1 
12 Lead ECG, Descriptive Statistics - Safety Population 
IP 
-
14.3.6.2 
12 Lead ECG, Shift Summary - Safety Population 
IP 
-
14.3.6.3 
Physical Examination Data, Shift from Baseline - Safety 
IP 
-
Population 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001 f-1.3 
Page 25 of30 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 27


Worldwide Clinical Trials Controlled Quality Management Document 
1!r WORLDWIDE 
I Sponsor: 
I OpiantPharmaceuticals 
f 
I Protocol Number: 
I OPNT003-PK-002 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if repeat) 
14.3.6.4.1 
Nasal Cavity Examination Data, Descriptive Statistics -
IP 
-
Safety Population 
14.3.6.4.2 
Nasal Cavity Examination Data, Shift from Baseline -
IP 
-
Safety Population 
14.3.6.5 
Numerical Rating Scale Data, Descriptive Statistics -
IP 
-
Safety Population 
14.3.6.6 
Brief Smell Identification Score Data, Descriptive 
IP 
-
Statistics - Safety Population 
14.3.7 
Concomitant Medication 
Not Applicable 
14.4 
PK Tables 
14.4.1 
Descriptive Statistics for Concentration-Time Data of 
IP 
-
Nalmefene after IN Administration of 3 mg Nalmefene 
HCl in One Nostril (Tl, Treatment A), 3 mg (6 mg Total 
Dose) Nalmefene HCl in Each Nostril (Treatment B, T2), 
and 6 mg Nalmefene HCl in One Nostril (Treatment C, 
T3) - PK Evaluation Population 
14.4.2 
Plasma PK Parameters ofNalmefene after IN 
IP 
-
Administration of 3 mg Nalmefene HCl in One Nostril 
(Tl, Treatment A), 3 mg (6 mg Total Dose) Nalmefene 
HCl in Each Nostril (Treatment B, T2), and 6 mg 
Nalmefene HCl in One Nostril (Treatment C, T3)-PK 
Evaluation Population 
14.4.3 
Plasma PK Partial AUCs ofNalmefene after IN 
IP 
-
Administration of 3 mg Nalmefene HCl in One Nostril 
(Tl, Treatment A), 3 mg (6 mg Total Dose) Nalmefene 
HCl in Each Nostril (Treatment B, T2), and 6 mg 
Nalmefene HCl in One Nostril (Treatment C, T3) - PK 
Population 
14.4.4 
Plasma Dose-Normalized Parameters ofNalmefene after 
IP 
-
IN Administration of 3 mg Nalmefene HCl in One 
Nostril (Tl, Treatment A), 3 mg (6 mg Total Dose) 
Nalmefene HCl in Each Nostril (Treatment B, T2), and 
6 mg Nalmefene HCl in One Nostril (Treatment C, T3)-
PK Population 
14.4.5 
Dose-Normalized Plasma PK Partial AUCs of 
IP 
-
Nalmefene after IN Administration of 3 mg Nalmefene 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001 f-1.3 
Page 26 of30 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 28


Worldwide Clinical Trials Controlled Quality Management Document 
1!r WORLDWIDE 
I Sponsor: 
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f 
I Protocol Number: 
I OPNT003-PK-002 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if repeat) 
HCl in One Nostril (Tl, Treatment A), 3 mg (6 mg Total 
Dose) Nalmefene HCl in Each Nostril (Treatment B, T2), 
and 6 mg Nalmefene HCl in One Nostril (Treatment C, 
T3)-PK Population 
14.4.6 
Statistical Analysis of the Natural Log-Transformed, 
IP 
-
Dose-Normalized Exposure Parameters ofNalmefene 
Comparing 6 mg Nalmefene Hydrochloride in One 
Nostril (Treatment C, T3, Test) and 3 mg Nalmefene 
Hydrochloride in One Nostril (Treatment A, Tl, 
Reference) - PK Evaluation Population 
14.4.7 
Statistical Analysis of the Natural Log-Transformed, 
IP 
-
Dose-Normalized Exposure Parameters of Nalmefene 
Comparing 3 mg Nalmefene Hydrochloride in Each 
Nostril (6 mg Total Dose, Treatment B, T2, Test) and 
3 mg Nalmefene Hydrochloride in One Nostril 
(Treatment A, Tl, Reference) -PK Evaluation 
Population 
14.4.8 
Statistical Analysis of the Natural Log-Transformed, 
IP 
-
Dose-Normalized Exposure Parameters ofNalmefene 
Comparing 3 mg Nalmefene Hydrochloride in Each 
Nostril (6 mg Total Dose, Treatment B, T2, Test) and 
6 mg Nalmefene Hydrochloride in One Nostril 
(Treatment C, T3, Reference) -PK Evaluation 
Population 
14.5 
PD Tables 
14.6 
Other Data 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
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Page 27 of30 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 29


Worldwide Clinical Trials Controlled Quality Management Document 
1!r WORLDWIDE 
I Sponsor: 
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f 
I Protocol Number: 
I OPNT003-PK-002 
Figure 
Figure Title 
Validation 
Shell 
Number 
Method 
Number (if 
repeat) 
14.4.1 
Nalmefene Concentration-Time Data, Mean Profiles on 
IP 
-
Linear and Semi-Logarithmic Scales after Intranasal 
(IN) Administrations of 3 mg Nalmefene 
Hydrochloride in One Nostril (Tl), 2 x 3 mg 
Nalmefene Hydrochloride in Each Nostril (6 mg Total 
Dose, T2), and 6 mg Nalmefene Hydrochloride in One 
Nostril (T3) - PK Evaluation Population 
14.4.2 
Nalmefene Concentration-Time Data, All Subject 
IP 
-
Profiles on Linear and Semi-Logarithmic Scales after 
Intranasal (IN) Administrations of 3 mg Nalmefene 
Hydrochloride in One Nostril (Tl), 2 x 3 mg 
Nalmefene Hydrochloride in Each Nostril (6 mg Total 
Dose, T2), and 6 mg Nalmefene Hydrochloride in One 
Nostril (T3) -PK Evaluation Population 
14.4.3 
Nalmefene Concentration-Time Data, Individual 
IP 
-
Profiles on Linear and Semi-Logarithmic Scales after 
Intranasal (IN) Administrations of 3 mg N almefene 
Hydrochloride in One Nostril (Tl), 2 x 3 mg 
Nalmefene Hydrochloride in Each Nostril (6 mg Total 
Dose, T2), and 6 mg Nalmefene Hydrochloride in One 
Nostril (T3) -PK Evaluation Population 
14.4.4 
Concentration-Time Profiles for Nalmefene with Linear 
IP 
-
Regression for Estimating the Terminal Elimination 
Rate - PK Evaluation Population 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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Page 28 of30 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 30


 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 31


Worldwide Clinical Trials Controlled Quality Management Document 
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I Protocol Number: 
I OPNT003-PK-002 
Listing 
Listing Title 
Validation 
Shell Number (if 
Number 
Method 
repeat) 
16.2.8.9 
COVID-19 PCT Test Data- Safety Population 
IP 
-
16.2.8.10 
Vital Signs Data - Safety Population 
IP 
-
16.2.8.11 
ECG Data - Safety Population 
IP 
-
16.2.8.12 
Physical Examination Data - Safety Population 
IP 
-
16.2.8.13 
Nasal Cavity Examination Data - Safety 
IP 
-
Population 
16.2.8.14 
Nasal Numerical Rating Scale (NRS) Data -
IP 
-
Safety Population 
16.2.8.15 
Brief Smell Identification Score Data - Safety 
IP 
-
Population 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
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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-001 f-1.3 
Page 30 of30 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 32


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Statistical Analysis Plan 
Post Database Lock Addendum 
An Open-Label, Three-Period, Three-Treatment, Six-Sequence, Randomized 
Crossover Study of the Pharmacokinetics of Intranasal N almefene in Healthy 
Volunteers using Three Dosing Regimens 
Protocol Number: OPNT003-PK-002 
Protocol Version: 1.0 / 06-AUG-2021 
SAP Version 1.0 I 16-NOV-2021 
Addendum Version: 1.0 
Addendum issue Date: 29-MAR-2022 
Previous Addenda 
Not Applicable 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
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Confidentiality Statement 
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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 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 35


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
1. 
BACKGROUND 
This document details changes and / or additions to the planned statistical analyses for 
Opiant Pharmaceuticals, protocol "OPNT003-PK-002" study previously described in Vl .0 
of the Statistical Analysis Plan (SAP) dated 16-NOV-2021. 
These amendments were made post database lock. 
Rationale for Addendum: 
1) In electrocardiogram assessments, results were summarized only by sequence. Since 
the data is collected during treatment periods, tables is updated to presented results by 
both treatment and sequence. 
2) 
Truncated mean, all subject, and individual subject plots through 4 hours postdose 
were added to illustrate early nalmefene exposure. 
2. 
CHANGES TO EXISTING SAP 
2.1 
Change 1 
2.1.1 
Original text 
6.11.4 Electrocardiogram Data 
ECG values will be tabulated for Baseline, day 6, day 12 and EOS/ET, and change from 
Baseline to day 6 and 12, and change from Baseline to EOS by treatment sequence and 
overall. Parameters will be listed in the order given below and in units collected. 
2.1.2 New text 
6.11.4 Electrocardiogram Data 
ECG values will be tabulated for Baseline, 20 mins, lh and 6h, and change from baseline 
to 20 mins, 1 h and 6h by treatment periods. In addition, ECG results will be tabulated for 
Baseline, EOS/ET, and change from Baseline to EOS/ET by treatment sequence and 
overall. 
2.2 
Change 2 
2.2.1 
Original text 
6.3 Conventions 
"Sequence l" represents subjects taking Treatment A in period 1, Treatment B in period 2 
and Treatment C in period 3; "Sequence 2" represents subjects taking Treatment B in 
period 1, Treatment C in period 2 and Treatment A in period 3; "Sequence 3" represents 
subjects taking Treatment C in period 1, Treatment A in period 2 and Treatment B in period 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
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without prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
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Page 2 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 36


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
3; "Sequence 4" represents subjects taking Treatment A in period 1, Treatment C in period 
2 and Treatment B in period 3; "Sequence 5" represents subjects taking Treatment B in 
period 1, Treatment A in period 2 and Treatment C in period 3; "Sequence 6" represents 
subjects taking Treatment C in period 1, Treatment A in period 2 and Treatment B 
in period 3. 
2.2.2 New text 
6.3 Conventions 
"Sequence l" represents subjects taking Treatment A in period 1, Treatment B in period 2 
and Treatment C in period 3; "Sequence 2" represents subjects taking Treatment B in 
period 1, Treatment C in period 2 and Treatment A in period 3; "Sequence 3" represents 
subjects taking Treatment C in period 1, Treatment A in period 2 and Treatment B in period 
3; "Sequence 4" represents subjects taking Treatment A in period 1, Treatment C in period 
2 and Treatment B in period 3; "Sequence 5" represents subjects taking Treatment B in 
period 1, Treatment A in period 2 and Treatment C in period 3; "Sequence 6" represents 
subjects taking Treatment C in period 1, Treatment B in period 2 and Treatment A 
in period 3. 
2.3 
Change3 
Titles of few outputs were not matching with SAP section 9 List of Tables, Figures and 
Listings. SAP is updated to have the same names of TFLs as in TFL Mock Shells. 
3. 
ADDITIONS TO EXISTING SAP 
3.1 
Addition 1 
Truncated mean, all subject, and individual subject concentration-time profiles through 
4 hours postdose were added to illustrate early nalmefene exposure. 
4. 
CHANGES TO TABLES, FIGURES AND LISTINGS (TFL) SHELL 
TABLE OF CONTENT (TOC) WITHIN SAP 
New TOC attached: 
s. 
CHANGES TO TFL SHELL 
Previous version of TFL Shells: 
New version ofTFL shells: 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
~yes 
Ono 
1.0 I 16-Nov-2021 
1. 1 / 29-Mar-2022 
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Page 3 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 37


Worldwide Clinical Trials Controlled Quality Management Document 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
T 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
• 
Safety population definition was incorrect in few tables. It is corrected to "Safety 
Population includes subjects who took at least one dose of study drug". 
• 
All TFLs - In footnote, treatment sequence 6 definition was incorrect. It has been updated 
as "Sequence 6" represents subjects taking Treatment C in period 1, Treatment B in period 
2 and Treatment A in period 3. 
• 
Tables 14.3.1.1 and Table 14.3.1.8 - "Unknown" row is removed from relationship 
category. 
• 
Table 14.3.1.2, Table 14.3.1.7, Table 14.3.1.8 and Listing 16.2.7.1 - MedDRA version is 
updated to 24 .1. 
• 
Table 14.3.4.7 -Title was incorrect. It has been updated to "Coagulation Data". 
• 
Table 14.3.5.1 and Table 14.3.5.2 - Reference listing number was incorrect. It has been 
corrected as 'Listing 16.2.8.1 O'. 
• 
Table 14.3.6.1 and Table 14.3.6.2 - Table is revamped to present ECG results by both 
treatment and treatment sequence. 
• 
Table 14.3.6.1 and Table 14.3.6.2 - Reference listing number was incorrect. It has been 
corrected as 'Listing 16.2.8.11 '. 
• 
Table 14.3.6.3 - Reference listing number was incorrect. It has been corrected as 'Listing 
16.2.8.12'. 
• 
Table 14.3.6.4.1 - "Not Done I Missing" column has been added. 
• 
Table 14.3.6.4.2- "Not Done/ Missing" row and column has been added. 
• 
Table 14.3.6.4.1 and Table 14.3.6.4.2 - Reference listing number was incorrect. It has been 
corrected as 'Listing 16.2.8.13'. 
• 
Table 14.3.6.4.2- "Not Done/ Missing" row and column has been added. 
• 
Table 14.3.6.5 - Reference listing number was incorrect. It has been corrected as 'Listing 
16.2.8.14'. 
• 
Table 14.3.6.6 - Reference listing number was incorrect. It has been corrected as 'Listing 
16.2.8.15'. 
• 
Figures 14.4.1.1, 14.4.2.1, and 14.4.3.1 for truncated mean, all subject, and individual 
subject concentration-time profiles were added. 
• 
Listing 16.2.4.1 - there was a spelling mistake in title. It has been updated to "Demographic 
Data". 
• 
Listing 16.2.4.3 - WHODD version updated as "Sep 2021". 
• 
Listing 16.2.8.8 - "Occurrence" column has been added. "Category" column moved prior 
to that. 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
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REF: Worldwide-TMP-QA-001f-1 .3 
Page 4 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 38


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
• 
14.3.6.3 - Title was incorrect. It has been updated to "Physical Examination Data, Shift 
Summary". 
• 
14.3.6.4.2 - Title was incorrect. It has been updated to "Nasal Cavity Examination Data, 
Shift Summary". 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
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 
14.1.1.1 
Subject Disposition, Analysis Populations - All Subjects 
IP 
-
14.1.2 
Demographics 
14.1.2.1 
Subject Demographics - Safety Population 
IP 
-
14.1.2.2 
Subject Demographics - PK Evaluation Population 
IP 
14.1.2.2 
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 
Adverse Events, Overall Summary - Safety Population 
IP 
-
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
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without prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
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Page 5 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 39


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if 
repeat) 
14.3.1.2 
Adverse Events, Treatment Emergent Adverse Events by 
IP 
-
SOC and PT - Safety Population 
14.3.1.3 
Adverse Events, Related Treatment Emergent Adverse 
IP 
14.3.1.2 
Events by SOC and PT - Safety Population 
14.3.1.4 
Adverse Events, Serious Treatment Emergent Adverse 
IP 
14.3.1.2 
Events by SOC and PT - Safety Population 
14.3.1.5 
Adverse Events, Related Serious Treatment Emergent 
IP 
14.3.1.2 
Adverse Events by SOC and PT - Safety Population 
14.3.1.6 
Adverse Events, Treatment Emergent Adverse Events 
IP 
14.3.1.2 
leading to Early Withdrawal by SOC and PT - Safety 
Population 
14.3.1.7 
Adverse Events, Treatment Emergent Adverse Events by 
IP 
-
SOC, PT and Maximum Severity - Safety Population 
14.3.1.8 
Adverse Events, Treatment Emergent Adverse Events by 
IP 
-
SOC, PT and Closest Relationship - Safety Population 
14.3.2 
Listings of Deaths, Other Serious and Significant 
Adverse Events 
14.3.2.1 
Serious Adverse Event Data - Safety Population 
IP 
16.2.7.1 
14.3.2.2 
Adverse Event Leading to Death - Safety Population 
IP 
16.2.7.1 
14.3.2.3 
Adverse Event Leading to Early Withdrawal - Safety 
IP 
16.2.7.1 
Population 
14.3.3 
Narratives of Deaths, Other Serious and Certain 
Other Significant Adverse Events 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
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without prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
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Page 6 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 40


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if 
repeat) 
14.3.4 
Abnormal Laboratory Values 
14.3.4.1 
Hematology Data, Descriptive Statistics - Safety 
IP 
-
Population 
14.3.4.2 
Clinical Chemistry Data, Descriptive Statistics - Safety 
IP 
14.3.4.1 
Population 
14.3.4.3 
Coagulation Data, Descriptive Statistics - Safety 
IP 
14.3.4.1 
Population 
14.3.4.4 
Urinalysis Data, Descriptive Statistics - Safety 
IP 
14.3.4.1 
Population 
14.3.4.5 
Hematology Data, Shift Summary - Safety Population 
IP 
-
14.3.4.6 
Clinical Chemistry Data, Shift Summary - Safety 
IP 
14.3.4.5 
Population 
14.3.4.7 
Coagulation Data, Shift Summary - Safety Population 
IP 
14.3.4.5 
14.3.4.8 
Urinalysis Data, Shift Summary - Safety Population 
IP 
16.2.8.1 
14.3.4.9 
Out of Range Laboratory Data - Safety Population 
IP 
-
14.3.5 
Vital Signs and Physical Examination 
14.3.5.1 
Vital Signs, Descriptive Statistics - Safety Population 
IP 
-
14.3.5.2 
Vital Signs, Shift Summary - Safety Population 
IP 
-
14.3.6 
Other Safety 
14.3.6.1 
12 Lead ECG, Descriptive Statistics - Safety Population 
IP 
-
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
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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 7 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 41


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if 
repeat) 
14.3.6.2 
12 Lead ECG, Shift Summary- Safety Population 
IP 
-
14.3.6.3 
Physical Examination Data, Shift Summary - Safety 
IP 
-
Population 
14.3.6.4.1 
Nasal Cavity Examination Data, Descriptive Statistics -
IP 
-
Safety Population 
14.3.6.4.2 
Nasal Cavity Examination Data, Shift Summary - Safety 
IP 
-
Population 
14.3.6.5 
Numerical Rating Scale Data, Descriptive Statistics -
IP 
-
Safety Population 
14.3.6.6 
Brief Smell Identification Score Data, Descriptive 
IP 
-
Statistics - Safety Population 
14.3.7 
Concomitant Medication 
Not Applicable 
14.4 
PK Tables 
14.4.1 
Descriptive Statistics for Concentration-Time Data of 
IP 
-
Nalmefene after IN Administration of 3 mg Nalmefene 
HCl in One Nostril (Tl, Treatment A), 3 mg (6 mg Total 
Dose) Nalmefene HCl in Each Nostril (Treatment B, T2), 
and 6 mg Nalmefene HCl in One Nostril (Treatment C, 
T3) - PK Evaluation Population 
14.4.2 
Plasma PK Parameters ofNalmefene after IN 
IP 
-
Administration of 3 mg Nalmefene HCl in One Nostril 
(Tl, Treatment A), 3 mg (6 mg Total Dose) Nalmefene 
HCl in Each Nostril (Treatment B, T2), and 6 mg 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
I 
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 8 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 42


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if 
repeat) 
Nalmefene HCl in One Nostril (Treatment C, T3)-PK 
Evaluation Population 
14.4.3 
Plasma PK Partial AUCs ofNalmefene after IN 
IP 
-
Administration of 3 mg Nalmefene HCl in One Nostril 
(Tl, Treatment A), 3 mg (6 mg Total Dose) Nalmefene 
HCl in Each Nostril (Treatment B, T2), and 6 mg 
Nalmefene HCl in One Nostril (Treatment C, T3)-PK 
Population 
14.4.4 
Plasma Dose-Normalized Parameters ofNalmefene after 
IP 
-
IN Administration of3 mg Nalmefene HCl in One 
Nostril (Tl, Treatment A), 3 mg (6 mg Total Dose) 
Nalmefene HCl in Each Nostril (Treatment B, T2), and 
6 mg Nalmefene HCl in One Nostril (Treatment C, T3)-
PK Population 
14.4.5 
Dose-Normalized Plasma PK Partial AUCs of 
IP 
-
N almefene after IN Administration of 3 mg N almefene 
HCl in One Nostril (Tl, Treatment A), 3 mg (6 mg Total 
Dose) Nalmefene HCl in Each Nostril (Treatment B, T2), 
and 6 mg Nalmefene HCl in One Nostril (Treatment C, 
T3)-PK Population 
14.4.6 
Statistical Analysis of the Natural Log-Transformed, 
IP 
-
Dose-Normalized Exposure Parameters ofNalmefene 
Comparing 6 mg Nalmefene Hydrochloride in One 
Nostril (Treatment C, T3, Test) and 3 mg Nalmefene 
Hydrochloride in One Nostril (Treatment A, Tl, 
Reference) - PK Evaluation Population 
14.4.7 
Statistical Analysis of the Natural Log-Transformed, 
IP 
-
Dose-Normalized Exposure Parameters ofNalmefene 
Comparing 3 mg Nalmefene Hydrochloride in Each 
Nostril (6 mg Total Dose, Treatment B, T2, Test) and 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
I 
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 9 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 43


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Table 
Table Title 
Validation 
Shell 
Number 
Method 
Number 
(if 
repeat) 
3 mg Nalmefene Hydrochloride in One Nostril 
(Treatment A, T 1, Reference) - PK Evaluation 
Population 
14.4.8 
Statistical Analysis of the Natural Log-Transformed, 
IP 
-
Dose-Normalized Exposure Parameters ofNalmefene 
Comparing 3 mg Nalmefene Hydrochloride in Each 
Nostril (6 mg Total Dose, Treatment B, T2, Test) and 
6 mg Nalmefene Hydrochloride in One Nostril 
(Treatment C, T3, Reference) -PK Evaluation 
Population 
14.5 
PD Tables 
14.6 
Other Data 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
I 
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 10 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 44


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Figure 
Figure Title 
Validation 
Shell 
Number 
Method 
Number 
(if repeat) 
14.4.1 
Nalmefene Concentration-Time Data, Mean Profiles on 
IP 
-
Linear and Semi-Logarithmic Scales after Intranasal 
(IN) Administrations of 3 mg Nalmefene 
Hydrochloride in One Nostril (Tl), 2 x 3 mg 
Nalmefene Hydrochloride in Each Nostril (6 mg Total 
Dose, T2), and 6 mg Nalmefene Hydrochloride in One 
Nostril (T3) - PK Evaluation Population 
14.4.1.1 
Nalmefene Concentration-Time Data, Mean Profiles on 
IP 
Linear and Semi-Logarithmic Scales after Intranasal 
(IN) Administrations of 3 mg Nalmefene 
Hydrochloride in One Nostril (Tl), 3 mg Nalmefene 
Hydrochloride in Each Nostril (6 mg Total Dose, T2), 
and 6 mg Nalmefene Hydrochloride in One Nostril 
(T3) (X-Axis Truncated to 4 h Post Dose)-PK 
Evaluation Population 
14.4.2 
Nalmefene Concentration-Time Data, All Subject 
IP 
-
Profiles on Linear and Semi-Logarithmic Scales after 
Intranasal (IN) Administrations of 3 mg Nalmefene 
Hydrochloride in One Nostril (Tl), 2 x 3 mg 
Nalmefene Hydrochloride in Each Nostril (6 mg Total 
Dose, T2), and 6 mg Nalmefene Hydrochloride in One 
Nostril (T3) -PK Evaluation Population 
14.4.2.1 
Nalmefene Concentration-Time Data, All Subject 
IP 
Profiles on Linear and Semi-Logarithmic Scales after 
Intranasal (IN) Administrations of 3 mg Nalmefene 
Hydrochloride in One Nostril (Tl), 3 mg Nalmefene 
Hydrochloride in Each Nostril (6 mg Total Dose, T2), 
and 6 mg Nalmefene Hydrochloride in One Nostril 
(T3) (X-Axis Truncated to 4 h Post Dose)-PK 
Evaluation Population 
14.4.3 
Nalmefene Concentration-Time Data, Individual 
IP 
-
Profiles on Linear and Semi-Logarithmic Scales after 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
I 
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 11 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 45


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Figure 
Figure Title 
Validation 
Shell 
Number 
Method 
Number 
(if repeat) 
Intranasal (IN) Administrations of 3 mg Nalmefene 
Hydrochloride in One Nostril (Tl), 2 x 3 mg 
Nalmefene Hydrochloride in Each Nostril (6 mg Total 
Dose, T2), and 6 mg Nalmefene Hydrochloride in One 
Nostril (T3) - PK Evaluation Population 
14.4.3.1 
Nalmefene Concentration-Time Data, Individual 
IP 
Profiles on Linear and Semi-Logarithmic Scales after 
Intranasal (IN) Administrations of 3 mg Nalmefene 
Hydrochloride in One Nostril (Tl), 3 mg Nalmefene 
Hydrochloride in Each Nostril (6 mg Total Dose, T2), 
and 6 mg Nalmefene Hydrochloride in One Nostril 
(T3) (X-Axis Truncated to 4 h Post Dose)-PK 
Evaluation Population 
14.4.4 
Concentration-Time Profiles for Nalmefene with Linear IP 
-
Regression for Estimating the Terminal Elimination 
Rate - PK Evaluation Population 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
I 
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 12 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 46


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Listing 
Listing Title 
Validation 
Shell Number (if 
Number 
Method 
repeat) 
16.2 
Subject Data Listings 
16.2.1 
Discontinued Subjects 
16.2.1.1 
Subject Disposition - All Subjects 
IP 
-
16.2.2 
Protocol Deviations 
16.2.2.1 
Protocol Deviations - Safety Population 
IP 
-
16.2.3 
Subjects Excluded from the Efficacy Analyses 
16.2.3.1 
Analysis Populations - All Subjects 
IP 
-
16.2.4 
Demographic Data 
16.2.4.1 
Demographic Data - Safety Population 
IP 
-
16.2.4.2 
Medical History - Safety Population 
IP 
-
16.2.4.3 
Prior and Concomitant Medications - Safety 
IP 
-
Population 
16.2.5 
Compliance and / or Drug Concentration 
Data 
16.2.5.1 
Exposure Data - Safety Population 
IP 
-
16.2.6 
Individual Efficacy Response Data 
16.2.6.1 
Nalmefene Concentration-Time Data Listing-
IP 
-
Safety Population 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
I 
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 13 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 47


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Listing 
Listing Title 
Validation 
Shell Number (if 
Number 
Method 
repeat) 
16.2.6.2 
Terminal Elimination Rate of Nalmefene in 
IP 
-
Plasma for Individual Subjects - PK Evaluation 
Population 
16.2.6.3 
PK Output Text-PK Evaluation Population 
IP 
-
16.2.6.4 
SAS Output Text (ANOV A) - PK Evaluation 
IP 
-
Population 
16.2.7 
Adverse Event Listings 
16.2.7.1 
Adverse Event Data - Safety Population 
IP 
-
16.2.8 
Individual Laboratory Measurements and 
Other Safety 
16.2.8.1 
Hematology Data - Safety Population 
IP 
-
16.2.8.2 
Serum Chemistry Data - Safety Population 
IP 
16.2.8.1 
16.2.8.3 
Coagulation Data - Safety Population 
IP 
16.2.8.1 
16.2.8.4 
Urinalysis Data - Safety Population 
IP 
16.2.8.1 
16.2.8.5 
Drug, Alcohol and Cotinine Screen - Safety 
IP 
-
Population 
16.2.8.6 
Serology Data - Safety Population 
IP 
16.2.8.5 
16.2.8.7 
Pregnancy Test Data - Safety Population 
IP 
-
16.2.8.8 
Substance Use Data - Safety Population 
IP 
-
16.2.8.9 
COVID-19 PCR Test Data- Safety Population 
IP 
-
16.2.8.10 
Vital Signs Data - Safety Population 
IP 
-
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
I 
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 14 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 48


Worldwide Clinical Trials Controlled Quality Management Document 
T 
WORLDWIDE 
I Sponsor: 
I Opiant Pharmaceuticals 
I Protocol Number: I OPNT003-PK-002 
POST DATABASE LOCK STATISTICAL ANALYSIS PLAN ADDENDUM 
Listing 
Listing Title 
Validation 
Shell Number (if 
Number 
Method 
repeat) 
16.2.8.11 
ECG Data - Safety Population 
IP 
-
16.2.8.12 
Physical Examination Data - Safety Population 
IP 
-
16.2.8.13 
Nasal Cavity Examination Data - Safety 
IP 
-
Population 
16.2.8.14 
Nasal Numerical Rating Scale (NRS) Data -
IP 
-
Safety Population 
16.2.8.15 
Brief Smell Identification Score Data - Safety 
IP 
-
Population 
QMD Ref: Worldwide-TMP-ST-008-2.0 Effective: 12Aug2019 
I 
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 15 of 17 
Opiant Pharmaceuticals Protocol OPNT003-PK-002 
Appendix 16.1.9 - Page 49