A Study to Evaluate the Relative Bioavailability of a Test Formulation of Lofexidine Granules for Reconstitution and the Effect of Food on the Bioavailability of the Test Formulation in Healthy Adult Subjects
Phase: PHASE1
Conditions: Normal Healthy Volunteers
Sponsor: USWM, LLC (dba US WorldMeds)

PRODUCT: Lofexidine granules for reconstitution (oral) 
PROTOCOL NUMBER / AMENDMENT: USWM-LX2-1001 / 4 
 
SPONSOR: 
USWM, LLC 
4441 Springdale Rd. 
Louisville, KY 40241 
United States of America (USA) 
 
TITLE: 
A Study to Evaluate the Relative Bioavailability of a Test Formulation of Lofexidine 
Granules for Reconstitution and the Effect on Food on the Bioavailability of the Test Formula in   
Healthy Adult Subjects  
 
DOCUMENT DATE: January 25, 2021 
IND NUMBER: 47857 
NCT NUMBER: NCT04188730 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 1 of 45 
 
1.0 
TITLE PAGE 
DRUG PRODUCTS: 
Lofexidine granules for reconstitution (oral), 
, final strength 
lofexidine 90 μg/mL 
LUCEMYRA® (lofexidine) tablets, 
EQ 0.18 mg base  
DESIGN: 
Open-Label, Single-Dose, Randomized, 
Three-Treatment, Three-Period, Four-
Sequence, Crossover Study Evaluating Tablet 
(Fasted) versus Granules (Fasted) and the 
Effect of Food on the Granules (Fed versus 
Fasted) 
POPULATION: 
16 Healthy Adult Male and Female Subjects 
SPONSOR: 
USWM, LLC 
4441 Springdale Rd. 
Louisville, KY 40241 
United States of America (USA) 
SPONSOR PROTOCOL NO.: 
USWM-LX2-1001 
 
 
ORIGINAL PROTOCOL DATE: 
10/16/19 
AMENDMENT 1 PROTOCOL DATE: 
12/05/19 
AMENDMENT 2 PROTOCOL DATE: 
12/19/19 
AMENDMENT 3 PROTOCOL DATE: 
05 Oct 2020 
AMENDMENT 4 PROTOCOL DATE: 
25 Jan 2021 
IND NO: 
47857 
CONTRACT RESEARCH  
ORGANIZATION: 
  
 
 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 2 of 45 
 
SPONSOR REPRESENTATIVE: 
 
 
 
  
 
  
 
 
 
 
 
 
 
Signature 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document is a confidential communication of 
.  
Receipt of this document constitutes an agreement by the recipient that no unpublished 
information contained herein will be disclosed without 
 written approval. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 3 of 45 
 
Principal Investigator’s Signature 
I have received and read the Investigator’s Brochure for lofexidine including the Package 
Insert. I  agree to conduct Protocol No. USWM-LX2-1001 
 
) “A study to evaluate the relative bioavailability of a test formulation of 
lofexidine granules for reconstitution  and the effect of food on the bioavailability of the test 
formulation in healthy adult subjects” in accordance with Good Clinical Practice (GCP), 
and all applicable regulations, including the Federal Food, Drug and Cosmetics Act., U.S. 
applicable Code of Federal Regulations (Title 21), and ICH Guidelines. 
 
 
 
  
 
 
 
 
 
Date 
 
 
 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 4 of 45 
 
AMENDMENTS TO THE PROTOCOL 
Amendments to the protocol after initial IRB approval are summarized below. 
Amendment  
Date 
 
4 
25 Jan 2021 
 
The following update was made to the protocol dated 05 Oct 2020: 
Throughout the protocol: 
• 
At the request of the Sponsor, a third study period has been added to also evaluate the 
effect of food on the relative bioavailability of the test product. Updates to the study 
title, design, objectives, study conduct, study treatments, randomization, subject 
removal criteria, total blood volume collected during the study, pharmacokinetic and 
statistical analyses, and references have been made, as appropriate. 
• 
At the request of the Sponsor, the volume of granules for reconstitution and dose 
volume administered to subjects has been removed from the protocol. A Pharmacy 
Manual will be provided by the Sponsor, which will include this information. 
Section 1.0: 
• 
Included IND number, for reference. 
Section 5.3.3: 
• 
For additional subject safety during the ongoing COVID-19 pandemic, “diabetes” and 
“respiratory conditions” have been added to Exclusion #3. 
Section 5.7: 
• 
Updated and rearranged based in accordance with current 
 protocol template. 
Section 7.0: 
• 
Updated reference for the FDA Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health Emergency. 
Amendment  
Date 
 
3 
05 Oct 2020 
 
The following update was made to the protocol dated 12/19/19: 
Section 1.0: 
• 
Updated the Principal Investigator from 
 to 
 
  In addition, Sponsor Representative and Key Study Personnel has been 
updated to current information. 
•
 
 
 
. 
• 
Updated List of Abbreviations. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 5 of 45 
 
Sections 1.0, 5.7.1 and 6.5.5: 
• 
In accordance with Sponsor request, updated to reflect that 
 and not 
 will conduct pharmacokinetic and statistical analyses. 
Sections 5.1 and 5.3.4: 
• 
Included 
 standard language for study conduct during the ongoing COVID-
19 pandemic. 
Section 5.4.1 and Synopsis: 
• 
Updated dosing procedures after discussions between 
 and Sponsor. 
Section 5.5.1: 
• 
Updated the MedDRA version to the current version utilized by 
. 
Section 5.5.2.2 
• 
Updated SAE contact information, at Sponsor request. 
Section 7.0: 
• 
Added references for FDA Guidances on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health Emergency and Compliance Policy for the 
Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 
320.38(c). These documents are cited within the protocol, where appropriate and 
subsequent references have been updated accordingly. 
Appendix 8.2: 
• 
In accordance with the Note to File generated on 17 Jan 2020, the taste questionnaire 
has been updated to remove “flavor” from the Taste Assessment evaluation. 
Amendment  
Date 
 
2 
12/19/19 
 
The following update was made to the protocol dated 12/05/19: 
Section 1.0: 
• 
Updated the Principal Investigator from 
 to Carmelo
 
 
Amendment  
Date 
 
1 
12/05/19 
 
Based on feedback on the protocol from NIDA for subject safety, the following updates 
were made to the protocol dated 10/16/19: 
Sections 5.3.1.1 and 5.3.3: 
• 
Screening blood pressure limit requirements were updated and an orthostatic blood 
pressure assessment/requirements at screening were added. 
Sections 5.3.4 and 5.5.5: 
• 
Added pre-dose blood pressure requirements for subject dosing eligibility as well as 
safety instructions for if a subject experiences clinically significant hypotension during 
the study. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 6 of 45 
 
KEY STUDY PERSONNEL 
PRINCIPAL INVESTIGATOR: 
 
 
MEDICAL MONITOR: 
 
CLINICAL MANAGER: 
 
 
 
QUALITY ASSURANCE: 
 
SCIENTIFIC AFFAIRS: 
 
 
BIOANALYTICAL: 
 
 
 
 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 7 of 45 
 
STUDY FACILITIES 
CLINICAL FACILITY: 
  
 
 
PHARMACOKINETICS/STATISTICS: 
 
 
 
 
 
 
INSTITUTIONAL REVIEW BOARD: 
 
 
 
 
 
 
BIOANALYTICAL LABORATORY: 
 
 
GENOTYPING FOR CLINICAL 
SAMPLES: 
 
 
 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 8 of 45 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ANOVA 
Analyses of Variance 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero to 
infinity 
AUC0-t 
Area under the plasma concentration-time curve from time zero 
to the time of last measurable concentration 
BLQ 
Below Limit of Quantitation 
BMI 
Body Mass Index 
°C 
Degrees Celsius 
CDER 
Center for Drug Evaluation and Research 
Cmax 
Maximum observed plasma concentration 
CL/F 
Apparent total clearance of the drug from plasma 
COVID-19 
Coronavirus Disease of 2019 
CNS 
Central Nervous System 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
Ct 
Last measurable plasma concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EQ 
Equivalent to 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GLM 
General Linear Model 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
λz 
Apparent first-order terminal rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
ng 
Nanogram 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 9 of 45 
 
Abbreviation 
Definition 
IRB 
 Institutional Review Board 
OTC 
Over-the-counter 
PK 
Pharmacokinetic 
QA 
Quality Assurance 
RLD 
Reference Listed Drug 
RS 
Reference Standard 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
t½ or T½ 
Apparent first-order terminal half-life 
THC 
Tetrahydrocannabinol 
Tmax 
Time of maximum observed plasma concentration 
USA 
United States of America 
VZ/F 
Apparent volume of distribution during the terminal phase 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 10 of 45 
 
STUDY SYNOPSIS 
Drug Products: 
Lofexidine granules for reconstitution (oral), 
 
, final strength lofexidine 90 μg/mL 
LUCEMYRA® (lofexidine) tablets, EQ 0.18 mg base 
Study Phase: 
Comparative Bioavailability, Phase I Study 
Agency of 
Submission: 
United States (U.S.) Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER) 
Study Objectives: 
The primary objectives of this study are to evaluate the relative 
bioavailability of a test formulation of lofexidine granules for 
reconstitution (oral), final concentration 90 μg/mL (
 
) compared to the Orange Book RS/RLD product, 
LUCEMYRA tablets, EQ 0.18 mg base (US WorldMeds, LLC) 
under fasted conditions and to evaluate the effect of food on the 
relative bioavailability of lofexidine granules for reconstitution 
(oral) when administered under fed compared to fasted conditions, 
following a single 0.36 mg dose to healthy adult male and female 
subjects. 
The secondary objective is to assess the safety and tolerability of a 
single 0.36 mg oral dose of lofexidine granules for reconstitution 
formulation when administered to healthy subjects under fasted 
and fed conditions. 
Study Design: 
Open-label, single-dose, randomized, three-treatment, three-
period, four-sequence, crossover study evaluating tablet (fasted) 
versus granules (fasted) and the effect of food on the granules (fed 
versus fasted). 
Subject Population:  
The subject population will include 16 healthy, non-tobacco-, non-
nicotine-using adult male and female subjects who satisfy all entry 
criteria. 
Study Treatments: 
Treatment A: Lofexidine oral solution (90 μg/mL) reconstituted 
from Lofexidine Granules for Reconstitution 
(Oral)(Manufactured by 
) – 
0.36 mg total dose  
Administered following an overnight fast of at 
least 10 hours. 
Treatment B: 2 × LUCEMYRA Tablets, EQ 0.18 mg base 
(US WorldMeds, LLC) – 0.36 mg total dose 
Administered following an overnight fast of at 
least 10 hours. 
Treatment C: Lofexidine oral solution (90 μg/mL) reconstituted 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 11 of 45 
 
from Lofexidine Granules for Reconstitution 
(Oral)(Manufactured by 
) – 
0.36 mg total dose 
Administered 30 minutes after the start of an 
FDA-recommended standardized high-fat, high-
calorie breakfast preceded by an overnight fast of 
at least 10 hours. 
The volume of lofexidine granules for reconstitution and dose 
volume to be administered to subjects (Treatments A and C) will 
be included in the Pharmacy Manual, to be provided by the 
Sponsor prior to study start.  
Treatment 
Administration: 
Eligible subjects will receive a 0.36 mg oral dose of the test 
(Treatment A and C) or reference (Treatment B) treatment 
according to a three-treatment, four-sequence randomization 
schedule under direct observation. 
Treatments A and C 
Treatment A will be administered following an overnight fast of at 
least 10 hours. Treatment C will be administered at 30 minutes 
after the start of an FDA-recommended standardized high-fat, 
high-calorie breakfast preceded by an overnight fast of at least 10 
hours. 
Lofexidine will be supplied as granules for reconstitution (oral), 
. The granules will be reconstituted no 
more than 2 hours prior to dosing according to the instructions 
outlined in Section 5.4.1. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Following this, the 
subjects will be provided with a volume of room temperature 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 12 of 45 
 
distilled water to drink such that the total volume of the oral 
suspension administered, the volume of rinse, and the water 
provided after the dose equals 240 mL (i.e., volume of dose + 
volume of rinse + volume of additional water = 240 mL). 
Immediately after, a mouth check will be performed to confirm that 
the oral solution, mouth rinse and additional water have been 
swallowed. 
Treatment B 
Subjects will be administered one dose of 2 × 0.18 mg 
LUCEMYRA tablets following an overnight fast of at least 
10 hours. The dose will be administered with 240 mL of room 
temperature distilled water. Subjects will be instructed to swallow 
the two tablets whole without chewing or biting. Any subject who 
bites or chews the tablets will be discontinued from the study. 
Immediately after dosing a mouth check will be performed to 
confirm that the tablets were swallowed whole without chewing or 
biting. 
The volume of lofexidine granules for reconstitution will be 
administered to subjects in accordance to the instructions included 
in the Pharmacy Manual, to be provided by the Sponsor prior to 
study start. Additionally, dose preparation and administration 
procedures will be generated by 
Pharmacy department 
and approved by the Sponsor before initial dosing in Period I. 
Taste Assessment for 
Treatments A or C: 
Within 10 minutes after completion of the dosing procedure for the 
subject’s first dose of lofexidine granules (Treatment A or C), each 
subject will be required to complete a Taste Assessment 
Questionnaire (see Appendix 8.2). The taste assessment will be 
completed once by each subject, after the subject’s first dose of 
lofexidine granules, whether administered in the fed or fasted state.  
Plasma Sample 
Collection: 
Blood samples will be collected pre-dose (0-hour, within 
45 minutes prior to dosing and before breakfast, if applicable 
[relative to the dosing minute]) and at 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 
4.0, 5.0, 7.0, 10.0, 16.0, 24.0, 30.0, 36.0, 48.0 and 54.0 hours post-
dose; 17 samples/period in 6 mL K2EDTA vacutainers. 
The total maximum volume of blood collected for pharmacokinetic 
sampling may be up to 306 mL. 
 
 
 
 
 
 
 
 The total 
volume of blood collected during this study is anticipated to be 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 13 of 45 
 
 
approximately 352.5 mL for male subjects and approximately 
367.5 mL for female subjects. 
Bioanalytical: 
Concentrations of lofexidine in plasma will be measured by 
 using a fully validated analytical 
method. 
Safety monitoring: 
Safety will be assessed by qualified study staff by evaluating the 
following: reported adverse events, clinical laboratory test results, 
vital sign measurements, ECG findings, Columbia-Suicide 
Severity 
Rating 
Scale 
(C-SSRS) 
assessments, 
physical 
examination (including height and body weight measurements at 
screening) and concomitant medication usage. 
Confinement: 
Subjects will enter the clinical facility on Day -1 at least 
10.5 hours before dosing and will remain confined until at least 54 
hours after dosing in each study period. 
Returns: 
None 
Washout Period: 
The interval between doses will be at least 7 days. 
Study Duration: 
Approximately 45 days from the start of screening to the last 
clinical event. 
Pharmacokinetic 
Parameters: 
AUC0-t, AUC0-∞, Cmax, Tmax, λz T½, CL/F and Vd/F 
Statistical Analyses: 
Confidence intervals (90%) on the geometric mean ratios 
(obtained from logarithmic transformed data) for AUC0-t, AUC0-∞ 
and Cmax for the comparison of Treatment A to Treatment B (to 
compare the test formulation and reference product under fasted 
conditions) and the comparison of Treatment C to Treatment A (to 
compare the granules for reconstitution [test formulation] under fed 
and fasted conditions) will be constructed to test two-one-sided 
hypotheses at the α = 0.05 level of significance. 
Descriptive statistics (n, mean, SD, % coefficient of variation 
(%CV), minimum, median, maximum) will be reported for 
lofexidine concentrations at each time point by treatment. 
Descriptive statistics (n, mean, SD, % coefficient of variation 
(%CV), geometric mean, minimum, median, maximum) will be 
reported for all PK parameters. 
A description of all of the statistical analyses will be provided in the 
Statistical Analysis Plan (SAP). 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 14 of 45 
 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE ............................................................................................................... 1 
2.0 
TABLE OF CONTENTS ........................................................................................... 14 
3.0 
INTRODUCTION ..................................................................................................... 16 
4.0 
STUDY OBJECTIVES .............................................................................................. 17 
5.0 
INVESTIGATIONAL PLAN .................................................................................... 17 
5.1 
Study Design and Plan Description .............................................................. 17 
5.2 
Selection of Study Design ............................................................................. 18 
5.3 
Selection of Study Population ....................................................................... 18 
5.3.1 
Screening ......................................................................................... 18 
5.3.2 
Inclusion Criteria ............................................................................. 19 
5.3.3 
Exclusion Criteria ............................................................................ 19 
5.3.4 
Removal of Subjects from the Study ............................................... 21 
5.4 
Treatments .................................................................................................... 23 
5.4.1 
Treatment Administration ................................................................ 23 
5.4.2 
Identity of Investigational Products ................................................. 24 
5.4.3 
Method of Assigning Subjects to Treatment Groups ....................... 25 
5.4.4 
Study Conduct ................................................................................. 25 
5.5 
Safety Evaluation .......................................................................................... 27 
5.5.1 
Adverse Events (AEs) ...................................................................... 27 
5.5.2 
Expedited Reporting of Events ........................................................ 30 
5.5.3 
Pregnancy ........................................................................................ 31 
5.5.4 
Clinical Laboratory Evaluations ...................................................... 31 
5.5.5 
Vital Signs and Other Safety Assessments ...................................... 32 
5.6 
Drug Concentration Measurements .............................................................. 34 
5.7 
Statistical Methods ........................................................................................ 35 
5.7.1 
Statistical and Analytical Plans ........................................................ 35 
5.7.2 
Safety Analysis ................................................................................ 37 
5.7.3 
C-SSRS Assessments ....................................................................... 38 
5.7.4 
Determination of Sample Size ......................................................... 38 
6.0 
REGULATORY OBLIGATIONS............................................................................. 38 
6.1 
Compliance ................................................................................................... 38 
6.2 
Quality Assurance ......................................................................................... 38 
6.3 
Institutional Review Board ........................................................................... 38 
6.4 
Audits, Inspections and Monitoring .............................................................. 38 
6.5 
Study Documentation ................................................................................... 39 
6.5.1 
Protocol ............................................................................................ 39 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 15 of 45 
 
6.5.2 
Informed Consent ............................................................................ 39 
6.5.3 
Protocol and Informed Consent Changes ........................................ 39 
6.5.4 
Source Documents and Case Report Forms..................................... 39 
6.5.5 
Final Report ..................................................................................... 39 
6.6 
Drug Accountability ..................................................................................... 40 
6.7 
Record Retention .......................................................................................... 40 
6.8 
Financing and Insurance ............................................................................... 40 
6.9 
Confidentiality .............................................................................................. 40 
7.0 
REFERENCES .......................................................................................................... 41 
8.0 
APPENDIX ................................................................................................................ 42 
8.1 
Clinical Laboratory Evaluations ................................................................... 42 
8.1.1 
Laboratory Determinations .............................................................. 42 
8.1.2 
Genetic Analysis .............................................................................. 42 
8.1.3 
Laboratory Drug of Abuse Testing .................................................. 42 
8.1.4 
Immediate Alcohol and Drug Screen ............................................... 42 
8.1.5 
Pregnancy Tests ............................................................................... 43 
8.1.6 
Follicle-Stimulating Hormone (FSH) .............................................. 43 
8.2 
Taste Assessment Questionnaire................................................................... 44 
8.3 
Study Schematic ........................................................................................... 45 
 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 16 of 45 
 
3.0 
INTRODUCTION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 17 of 45 
 
LUCEMYRA is well absorbed and pharmacokinetics are approximately dose-proportional 
 
 
 
 
 
 
 
 
 
 
 
4.0 
STUDY OBJECTIVES 
The primary objectives of this study are to evaluate the relative bioavailability of a test 
formulation of lofexidine granules for reconstitution (oral), final concentration 90 μg/mL 
(
 compared to the Orange Book RS/RLD product, LUCEMYRA tablets, EQ 
0.18 mg base (US WorldMeds, LLC) under fasted conditions and to evaluate the effect of food 
on the relative bioavailability of lofexidine granules for reconstitution (oral) when 
administered under fed compared to fasted conditions, to healthy adult male and female 
subjects. 
The secondary objective is to assess the safety and tolerability of a single 0.36 mg oral dose 
of lofexidine granules for reconstitution formulation when administered to healthy subjects 
under fasted and fed conditions. 
5.0 
INVESTIGATIONAL PLAN 
5.1 
Study Design and Plan Description 
This is an open-label, single-dose, randomized, three-treatment, three-period, four-
sequence, crossover study comparing equal doses of the test formulation and 
reference product under fasted conditions and comparing the bioavailability of the 
granules for reconstitution [test formulation] under fed and fasted conditions. In two 
of the study periods, a single 0.36 mg dose of lofexidine will be administered to 
subjects following an overnight fast of at least 10 hours. In a third study period, a 
single 0.36 mg dose of lofexidine will be administered 30 minutes after the start of an 
FDA-recommended standardized high-fat, high-calorie breakfast preceded by an 
overnight fast of at least 10 hours. The subjects will receive either lofexidine granules 
for reconstitution (oral)† (Treatment A or C) or two (2) LUCEMYRA tablets, EQ 
0.18 mg base (Treatment B). The subjects will receive the test formulation in two of 
the study periods and the reference product in a third study period according to a 
four-sequence randomization schedule. Serial blood samples will be collected at pre-
dose and at specified time points over 54 hours after dosing in each study period. 
Subjects will be confined at the clinical facility from at least 10.5 hours before dosing 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 18 of 45 
 
until after the 54-hour blood sample collection in each study period. The interval 
between doses will be at least 7 days.   
† The volume of lofexidine granules for reconstitution to be administered to subjects 
will be included in the Pharmacy Manual, to be provided by the Sponsor prior to 
study start. 
The plasma concentrations of lofexidine will be measured by fully validated analytical 
procedures. Statistical analysis using an average bioavailability approach will be 
performed to estimate the bioavailability of the test formulation relative to the reference 
product under fasted conditions. The bioavailability of the granules for reconstitution 
[test formulation] under fasted and fed conditions will also be compared.  
If study conduct is disrupted as a result of the COVID-19 pandemic, contingency 
measures implemented to manage study conduct will be discussed within the final 
report. 
5.2 
Selection of Study Design 
The study was designed based on the known pharmacokinetics of LUCEMYRA 
tablets and generally accepted standards for the conduct of bioavailability studies 
under fasted and fed conditions.1-7 
To minimize any possibility of a carry-over effect, a washout period of at least 7 days 
was selected for this study.  
5.3 
Selection of Study Population 
The subject population will include 16 healthy, non-tobacco-, non-nicotine-using 
adult male and female subjects who satisfy all entry criteria.  
5.3.1 
Screening 
5.3.1.1 Health Assessments 
The following health assessments will be performed within 28 days 
before initial study dosing (unless otherwise specified): 
1. Medical and social history, sitting/supine vital sign assessment 
(temperature, respiration rate, pulse, and blood pressure) and 
orthostatic blood pressure assessment (within 3 minutes of 
standing from a sitting/supine position), physical examination 
(including height and weight), and 12 lead ECG (conducted in 
triplicate). 
2. Clinical laboratory tests, including electrolytes (12.5 mL blood 
collection and urine sample) – see Appendix 8.1.1. 
3. Follicle stimulating hormone (FSH) test, if applicable – see 
Appendix 8.1.6. 
4. HIV, Hepatitis B surface antigen and Hepatitis C antibody screen 
(17 mL blood collection) – see Appendix 8.1.1.  

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 19 of 45 
 
5. Urine drug panel – see Appendix 8.1.3.  
6. Serum pregnancy test; females only (5 mL blood collection) – 
see Appendix 8.1.5. 
5.3.1.2 Demographics 
The name, birth date, sex, race, ethnicity, body weight, and height 
will be recorded for each subject.  
5.3.2 
Inclusion Criteria 
1. 
Males and females, 18-50 years of age, inclusive, with a Body Mass 
Index (BMI) of 20.0-35.0 kg/m², inclusive. BMI will be calculated 
using 
 Standard Operating 
Procedures (BMI [kg/m2] = 703 × weight (lbs) / [height (in)] 2). 
2. 
Female subjects must meet at least one of the following criterion: 
• 
Agree to abstain from sexual intercourse from screening and 
throughout the duration of the study. 
• 
Have used and agree to continue to use a reliable method of 
contraception (e.g., condom with spermicide, IUD, hormonal 
contraceptives) for at least 30 days before initial dosing and 
throughout the duration of the study. 
• 
Surgically sterile (bilateral oophorectomy or hysterectomy, 
bilateral tubal ligation or Essure® device placement at least 
3 months prior to initial dosing). 
• 
At least 1 year postmenopausal and have a documented FSH 
level ≥ 40 mIU/mL at screening. 
3. 
Good health as determined by lack of clinically significant 
abnormalities in health assessments performed at screening. 
4. 
Signed and dated informed consent form, which meets all criteria of 
current FDA regulations. 
5.3.3 
Exclusion Criteria 
1. 
Females who are pregnant, lactating, or likely to become pregnant 
during the study. 
2. 
History of allergy or sensitivity to lofexidine or any component of the 
study drug or history of any drug hypersensitivity or intolerance which, 
in the opinion of the Investigator, would compromise the safety of the 
subject or the study.  
3. 
Significant history or current evidence of chronic infectious disease, 
system disorders, or organ dysfunction, especially cardiovascular 
disorders (e.g., severe coronary insufficiency, recent myocardial 
infarction [within 1 year before initial dosing], cerebrovascular disease), 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 20 of 45 
 
respiratory disorders, congenital long QT syndrome, diabetes, hepatic or 
renal disorders (e.g., chronic renal failure).  
4. 
Pulse < 50 bpm or symptomatic bradycardia, as determined by the 
Investigator. 
5. 
Clinically significant history of hypotension, as determined by the 
Investigator, or has a sitting/supine systolic blood pressure < 90 mmHg 
and/or diastolic blood pressure < 60 mmHg, or hypertension, as 
determined by the Investigator, or has sitting/supine systolic blood 
pressure > 190 mmHg and/or diastolic > 95 mmHg; determined at 
screening. 
6. 
Experiences reduction of systolic blood pressure of at least 20 mmHg or 
diastolic blood pressure of at least 10 mmHg within 3 minutes of 
standing from a resting (sitting or supine) position; determined at 
screening. 
7. 
12-lead ECG, conducted in triplicate, considered by the Investigator to 
be clinically significant (e.g., second or third degree heart block, 
uncontrolled arrhythmia) or has a QTcF (Fridericia’s correction) 
interval > 440 msec in 2 of the 3 ECGs performed; determined at 
screening. 
8. 
Clinically significant history or presence of any gastrointestinal disease 
or history of malabsorption within the last year, as determined by the 
Investigator.  
9. 
History of any psychiatric disorders occurring within the last two years 
that required the subject to be hospitalized or treated with medication. 
10. Subject has history of suicidality based on responses provided on the 
Columbia-Suicide Severity Rating Scale (C-SSRS), or is at risk for self-
harm or harm to others based on clinical interview, at the discretion of 
the Investigator. 
11. Ingestion of grapefruit-containing food or beverages (e.g., Fresca®) 
within 7 days before dosing. 
12. Ingestion of alcohol- or caffeine/xanthine-containing food or beverages 
(e.g., chocolate, coffee, tea, cola) or energy drinks (e.g., Red Bull, 5-
Hour Energy®, Monster Energy®) within 72 hours before dosing. 
13. Use of any over-the-counter (OTC) medication, nutritional or dietary 
supplements, or vitamins within 7 days before dosing. 
14. Use of any prescription drugs (except hormonal contraceptives) within 
14 days before dosing.   
15. Use of pharmacologic agents known to significantly induce or inhibit 
drug-metabolizing enzymes (especially drugs that induce or inhibit 
CYP2D6 such as bupropion, fluoxetine, metoclopramide, paroxetine, 
quinidine or glutethimide) within 30 days before initial dosing.  

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 21 of 45 
 
16. Use of benzodiazepines, other CNS depressants (e.g., non-
benzodiazepine 
sedatives/hypnotics, 
barbiturates, 
anxiolytics, 
tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other 
opioids) or methadone within 14 days before initial dosing. 
17. Receipt of any drug as part of a research study within 30 days before 
initial dosing. 
18. Drug or alcohol addiction requiring treatment in the 12 months before 
initial dosing. 
19. History of excessive alcohol consumption (on average more than 
14 units of alcohol/week) during the past 12 months. 
20. Donation or significant loss of whole blood (480 mL or more) within 
30 days or plasma within 14 days before initial dosing.   
21. Positive test results for HIV, Hepatitis B surface antigen, or Hepatitis C 
antibody.   
22. Positive test results for drugs of abuse (benzodiazepines, cocaine, 
cannabinoids/THC, opiates and at screening only: amphetamines, 
barbiturates, methadone and phencyclidine).  
23. Positive test results for alcohol at check-in. 
24. If female, has a positive pregnancy test. 
25. Use of tobacco or nicotine-containing products within 30 days before 
initial dosing. 
Subjects who fail to meet eligibility criteria at Screening may be eligible to 
rescreen, at the Investigator’s discretion, during the 28-day screening period.  
Violations of the above restrictions may result in the Investigator excluding 
the subject from entering the study, or discontinuing the subject’s ongoing 
participation. Individual exceptions to the above restrictions, that the 
Investigator does not believe will affect subject safety or the integrity of the 
study data, may be allowed if approved by Sponsor’s Representative. 
5.3.4 
Removal of Subjects from the Study 
Subjects will be informed that they are free to withdraw from the study at 
any time and for any reason or, if necessary, the Investigator or Sponsor may 
withdraw a subject from the study to protect the health of a subject. A subject 
may also be withdrawn for not complying with study procedures. The final 
report will include reasons for withdrawals, adverse events and any necessary 
medical treatment.   
The Period I pre-dose safety ECG will be collected in triplicate and must show 
QTcF findings that remain ≤ 440 msec on two of the three recordings for the 
subject to be eligible to receive study drug in Period I. If two of the three QTcF 
intervals exceed 440 msec, the subject will not be eligible to receive the study 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 22 of 45 
 
drug in Period I and will be discontinued from further participation in the 
study. 
The Periods II and III check-in and pre-dose safety ECGs will be collected in 
triplicate and must show QTcF findings that are ≤ 440 msec on two of the 
three recordings for the subject to be eligible to receive study drug in the 
respective study period. If two of the three QTcF intervals exceed 440 msec, 
the subject will not be eligible to receive the study drug in the respective study 
period. The subject may participate in subsequent periods of the study, as 
applicable, at the discretion of the Investigator. 
Any subject with a QTcF interval exceeding 500 msec at any safety ECG 
reading (as applicable, see Section 5.5.5), will be discontinued from the study.  
The subject must have a pre-dose systolic blood pressure ≥ 90 mmHg to be 
eligible for dosing in the respective study period. If the subject’s pre-dose 
systolic blood pressure is < 90 mmHg, the assessment must be repeated 
2 additional times, 10 minutes apart. If two of the three systolic blood 
pressure measurements are < 90 mmHg, the subject will not be eligible to 
receive the study drug in the respective study period. The subject may 
participate in subsequent periods of the study, as applicable, at the discretion of 
the Investigator.  
Subjects who experience a serious AE due to hypotension or bradycardia in a 
specific study period will not be eligible to participate in subsequent periods of 
the study. In such a case, observations and sample collections should be 
completed for the subject following dosing in the respective study period and 
the subject will then be discontinued from the study (i.e., will not receive the 
dose in subsequent periods of the study). 
Any subject who experiences emesis within 10 hours of dosing (based on two 
times the anticipated maximum Tmax of about 5 hours for lofexidine) will be 
discontinued from the specific study period.5 The subject may participate in 
subsequent periods of the study, as applicable, at the discretion of the 
Investigator. 
In addition, in accordance with the FDA Guidance on the Conduct of Clinical 
Trials of Medical Products during COVID-19 Public Health Emergency, 
study discontinuations due to COVID-19 will be documented in the subject’s 
eCRF and summarized in the final report.8 
Subjects who are discontinued or withdraw from study participation should 
remain in the clinical facility until such time as the Investigator considers it 
safe for the subject to be discharged. Subjects who are discontinued or 
withdraw from the study will not be replaced. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 23 of 45 
 
5.4 
Treatments 
5.4.1 
Treatment Administration 
Eligible subjects will receive a 0.36 mg oral dose of the test formulation 
(Treatment A or C) or reference product (Treatment B) according to a 
three-treatment, four-sequence randomization schedule under direct 
observation. 
Treatments A and C 
Treatment A will be administered following an overnight fast of at least 
10 hours. Treatment C will be administered at 30 minutes after the start of an 
FDA-recommended standardized high-fat, high-calorie breakfast preceded by 
an overnight fast of at least 10 hours. 
Lofexidine will be supplied as granules for reconstitution (oral), 
 
. The granules will be reconstituted no more than 2 hours 
prior to dosing according to the instructions that follow:  
The volume of lofexidine granules for reconstitution will be administered to 
subjects in accordance to the instructions included in the Pharmacy Manual, 
to be provided by the Sponsor prior to study start. Additionally, dose 
preparation and administration procedures will be generated by 
 
Pharmacy department and approved by the Sponsor before initial dosing in 
Period I. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Following this, the subjects will be 
provided with a volume of room temperature distilled water to drink such that 
the total volume of the oral suspension administered, the volume of rinse, and 
the water provided after the dose equals 240 mL (i.e., volume of dose + 
volume of rinse + volume of additional water = 240 mL). Immediately after, a 
mouth check will be performed to confirm that the oral solution, mouth rinse 
and additional water have been swallowed. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 24 of 45 
 
Within 10 minutes after completion of the dosing procedure for the subject’s 
first dose of lofexidine granules (Treatment A or C), each subject will be 
required to complete a Taste Assessment Questionnaire (see Appendix 8.2). 
The taste assessment will be completed once by each subject, after the 
subject’s first dose of lofexidine granules, whether administered in the fed or 
fasted state. 
Treatment B 
Subjects will be administered one dose of 2 × 0.18 mg LUCEMYRA tablets 
following an overnight fast of at least 10 hours. The dose will be 
administered with 240 mL of room temperature distilled water. Subjects will 
be instructed to swallow the two tablets whole without chewing or biting. 
Any subject who bites or chews the tablets will be discontinued from the 
study. Immediately after dosing a mouth check will be performed to confirm 
that the tablets were swallowed whole without chewing or biting.  
5.4.2 
Identity of Investigational Products 
The following products will be used in this study: 
Test: 
Lofexidine Granules for Reconstitution (Oral), 
 
, final strength lofexidine 90 μg/mL 
(Manufactured by 
) 
Reference: 
LUCEMYRA Tablets, EQ 0.18 mg base (US WorldMeds, 
LLC) 
The following treatments will be used in this study: 
Treatment A: Lofexidine oral solution (90 μg/mL) reconstituted from 
Lofexidine Granules for Reconstitution (Oral) 
(Manufactured by 
) – 0.36 mg total dose  
Administered following an overnight fast of at least 
10 hours. 
Treatment B: 2 × LUCEMYRA Tablets, EQ 0.18 mg base 
(US WorldMeds, LLC) – 0.36 mg total dose 
Administered following an overnight fast of at least 10 
hours. 
Treatment C: Lofexidine oral solution (90 μg/mL) reconstituted from 
Lofexidine Granules for Reconstitution (Oral) 
(Manufactured by 
) – 0.36 mg total dose 
Administered 30 minutes after the start of an FDA-
recommended standardized high-fat, high-calorie breakfast 
preceded by an overnight fast of at least 10 hours. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 25 of 45 
 
The volume of lofexidine granules for reconstitution to be administered to 
subjects (Treatments A and C) will be included in the Pharmacy Manual, to 
be provided by the Sponsor prior to study start. 
The same lot of each product will be used during the entire study. 
As applicable, the Sponsor should notify 
 before shipment of study 
drug to the clinic. Drug should be shipped to the attention of the Pharmacy at 
the following address: 
Attn: Pharmacy  
  
 
 
5.4.3 
Method of Assigning Subjects to Treatment Groups 
Treatments will be administered according to a three-treatment, three-period, 
four-sequence design as outlined below. The randomization will be generated 
in blocks of four with each sequence occurring once in each block.   
Sequence 
Period I 
Period II 
Period III 
1 (N=4) 
Treatment B 
Treatment A 
Treatment C 
2 (N=4) 
Treatment B 
Treatment C 
Treatment A 
3 (N=4) 
Treatment A 
Treatment C 
Treatment B 
4 (N=4) 
Treatment C 
Treatment A 
Treatment B 
Treatment A = Lofexidine granules – fasted conditions 
Treatment B = LUCEMYRA tablets – fasted conditions 
Treatment C = Lofexidine granules – fed conditions 
The randomization schedule will be generated by the Biostatistics 
Department at 
 before the first 
dosing period using SAS®, Version 9.4 or higher. 
5.4.4 
Study Conduct  
Confinement: Subjects will enter the clinical facility on Day -1 at least 
10.5 hours before dosing and will remain confined until at least 54 hours 
after dosing in each study period. 
Returns: None 
Washout: The interval between doses will be at least 7 days.   
Fasting: During the fasted periods of the study (Treatments A and B) all 
subjects will fast (except water) for at least 10 hours before dosing. During 
the fed period of the study (Treatment C) all subjects will fast (except water) 
for at least 10 hours prior to receiving a standardized high-fat, high-calorie 
breakfast. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 26 of 45 
 
After dosing, subjects will fast until at least 4 hours post-dose. 
Meals: A meal will be served on the evening of Day -1 and consumed at 
least 10 hours before dosing or receiving a standardized high-fat, high-calorie 
breakfast (as applicable for each study period). During confinement, the 
subjects should consume only the food and beverages provided.  
In the fed period of the study (Treatment C), subjects should start a FDA-
recommended standardized high-fat, high-calorie breakfast 30 minutes prior 
to dosing and should consume this meal within the 30 minutes before dosing. 
 
 
   
 
 
 
 
 
 
 
 
A standard meal will be provided at 4 hours after dosing in each study 
period. Meals after 4 hours will be scheduled at appropriate times by the 
clinic. 
 
 
 
For all subjects, during confinement, the same 
meal plan will be used in each period of the study. When meals and blood 
sample collections coincide, samples will be collected before meals are 
served. 
Fluids: Fluids will be restricted from four (4) hours before dosing until eight 
(8) hours after dosing, with the exception of 240 mL water administered with 
the dose, scheduled water administrations and milk given with breakfast (fed 
study period only). At -4, -3, -2 and -1 hours (± 15 minutes) before dosing all 
subjects will be required to drink 300 mL of room temperature water and at 2, 
4, 6 and 8 hours (± 15 minutes) after dosing, all subjects will be required to 
drink 240 mL of room temperature water. Water will be encouraged ad lib at 
all other times. No fluids other than water and those served with meals will be 
permitted. 
Ambulatory: For safety purposes, subjects will be confined to bed for the 
first 8 hours post-dose and should remain sitting upright or supine during this 
time, except as required for study procedures. Subjects will be escorted by 
site staff when out of bed for the first 8 hours post-dose. If a subject is 
experiencing an Adverse Event or other medical conditions that prevents the 
subject from remaining sitting upright for safety reasons, the subject may be 
allowed to lie down, at the discretion of the Investigator. No strenuous 
activity will be permitted during confinement.  
Tobacco: The use of tobacco or nicotine-containing products is prohibited 
from 30 days before initial dosing and throughout the duration of the study. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 27 of 45 
 
5.5 
Safety Evaluation 
An Investigator will be present at the clinical facility for dosing and available by cell 
phone throughout the study. 
5.5.1 
Adverse Events (AEs) 
Adverse events (AEs) will be assessed and recorded daily after each dosing, 
as needed by study staff during clinic confinement, and end of study (or upon 
early termination, if applicable). If an AE requires medical attention, it will 
be reported to a study Investigator immediately. A study Investigator, or 
qualified designee, must meet with the subject, if possible, to assess all 
medical and psychiatric AEs reported by the subject, as well as those 
recorded by other study staff.  
AEs will be collected through both solicited and unsolicited means and 
subsequently coded in tabular form using the MedDRA Version 23.0 or 
higher adverse event dictionary. The subjects will be encouraged to report 
signs, symptoms, and any changes in health to the clinic staff. 
Adverse events will be assessed by asking the subject, “How have you been 
feeling since I saw you last?” After current AEs are assessed, the study 
Investigator must review with the subject and assess any AEs unresolved 
from the previous day. After each daily AE assessment, the Investigator (or 
designee) will record in the subject’s source document and AE eCRF, 
according to the procedures described in Section 5.5.1.3, the type of AE and 
whether serious or non-serious, severity of each AE, and the relationship to 
the study drug. These categories are asking for the Investigator’s best 
judgment of the severity and relatedness of each AE.  
Any study subject with a related AE will be followed by the Investigator 
until the event is resolved to the satisfaction of the Principal Investigator and 
Sponsor’s Medical Monitor. If the AE is unrelated, the subject will not be 
discharged until medically stable, and then will be referred, at the subject’s 
sole expense, for ongoing care and/or treatment, which may include 
psychological and lifestyle counseling, support groups, or pharmacological 
and medical treatment. 
5.5.1.1 Definitions 
Adverse Event 
Per 21 Code of Federal Regulations (CFR) 312.32, an AE is any untoward 
medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. Therefore, such an occurrence is considered an 
AE if it occurs after the Investigational Medicinal Product (IMP) has been 
administered. An AE includes any noxious, pathologic, or unintended change 
in anatomic, physiologic, or metabolic functions as indicated by physical 
signs, symptoms and/or laboratory changes. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 28 of 45 
 
 
 
 
. Study events occurring after signing informed consent 
but prior to IMP administration are to be documented in the subject’s 
medical history source and eCRF. 
Serious Adverse Event 
Per 21CFR.312.32, an SAE is an AE occurring after administration of the 
IMP at any dose, comparator or placebo, that fulfils one or more of the 
following: 
1. Results in death during the period of protocol-defined surveillance 
2. Is life-threatening (NOTE: The term "life-threatening" in the definition 
of "serious" refers to an event in which the subject, in the view of the 
Investigator, was at immediate risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused 
death if it were more severe) 
3. Requires inpatient hospitalization or prolongation of existing 
hospitalization 
4. Results in persistent or significant disability or incapacity or substantial 
disruption of the ability to conduct normal life functions 
5. Results in a congenital anomaly/birth defect 
6. Is an important medical event 
Hospitalization: Outpatient treatment in an emergency room is not in itself an 
SAE, although the reasons for it might be (e.g., bronchospasms, laryngeal 
edema). Hospital admission and/or surgical operations planned before or 
during a study are not considered SAEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. It should be noted that for this study, 
subjects with planned or anticipated surgery will not be enrolled into the 
study. 
Important Medical Events: Important medical events are events that may not 
be immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the definition above. Examples of 
important medical events include adverse events that suggest a significant 
hazard, contraindication or precaution, occurrence of malignancy or 
development of drug dependency or drug abuse. Medical and scientific 
judgment should be exercised in deciding whether events qualify as 
medically important. All SAEs will be assessed and recorded by the 
Investigator as detailed in Sections 5.5.1.2 and 5.5.1.3. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 29 of 45 
 
5.5.1.2 Relationship of Adverse Event to IMP 
For each AE, the Investigator must assess the attribution of the IMP to the 
AE and determine whether the AE is related or not related to the study or test 
drug as defined below. When in doubt, the AE will be considered “related” 
until further evidence becomes available to refute this assessment. 
• 
Unrelated: Clinical event with an incompatible time relationship to 
IMP administration, and that could be explained by underlying disease 
or other drugs or chemicals or is incontrovertibly not related to the 
IMP. 
• 
Related: Clinical event with a reasonable or plausible time 
relationship to IMP administration and that is unlikely to be attributed 
to or cannot be explained by concurrent disease or other drugs or 
chemicals. 
5.5.1.3 Recording Adverse Events 
All AEs and details for the events will be recorded in the subject’s source 
document and Adverse Event eCRF. An AE should be documented in terms 
of a medical diagnosis and reported in standard medical terminology when 
possible. When this is not possible, the AE will be documented in terms of 
signs and/or symptoms observed or reported. It is important for the 
Investigator to only record 1 AE per line on the eCRF. Combination events 
(e.g., nausea/vomiting), should not be entered as 1 event, but 2 events.  
AEs can be collected by either the Investigator and/or designee; however, the 
Investigator must determine the intensity of the AE as defined by:  
• 
Mild: no medical interventions required, short lasting discomfort, and 
does not interfere with subject’s daily activities 
• 
Moderate: activity may be limited and subject may require minimal 
medical therapy, intervention, or assistance 
• 
Severe: definitely limits subject’s daily activity that may require 
hospitalization and or intervention/therapy assess whether or not the 
IMP caused the AE 
The Investigator or designee will record whether the AE or AEs led to 
discontinuation of the subject from the study, record the outcome of the AE 
(unresolved, resolved, resolved with sequelae, death, or unknown), and 
determine if the AE is serious. 
For this study, AEs and SAEs will be collected beginning with the start of 
dosing on Day 1 and will end at study completion. All adverse events 
encountered during the study will be reported on the appropriate form and 
summarized in the final report. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 30 of 45 
 
5.5.1.4 Follow-up of Adverse Events 
The clinical course of each AE will be followed until resolution, 
stabilization, until it has been determined that the study treatment or 
participation is not the cause, or if subject is declared lost to follow-up. SAEs 
that are still ongoing at the end of the study period must be followed to 
determine the final outcome. The Investigator must provide the Sponsor with 
all relevant follow-up information necessary to facilitate a thorough 
understanding of the event and judgment regarding the relationship to the 
IMP. If a subject discontinues participation due to an AE/SAE that is at least 
possibly related to the IMP, the subject will be followed until the event has 
resolved, stabilized or otherwise explained, or if subject is declared lost to 
follow-up. This telephone contact will be documented in source.  
5.5.2 
Expedited Reporting of Events 
5.5.2.1 Events Requiring Expedited Reporting to 
 
The following events will be forwarded to the Sponsor’s pharmacovigilance 
group, 
, via the study Event Form within 24 hours of 
becoming aware of any of the following events: 
• All SAEs, regardless of causality 
• Overdose (with or without an AE) 
• Inadvertent or accidental exposure 
• Pregnancy  
• Unexpected therapeutic benefit 
5.5.2.2 Timeframe for Collecting and Reporting Serious Adverse Events 
and Other Immediately Reportable Events 
SAEs and other events requiring expedited reporting occurring after 
administration of the IMP and through study completion (or for discontinued 
subjects, within 7 days after his/her last dose of the IMP) must be reported to 
 within 24 hours of the time any study staff member is 
made aware of the event. The study SAE Form must be completed and 
emailed to 
 and to relevant study 
team members or faxed to 
 Additional eCRF and/or  
source documentation may need to be supplied to 
. 
SAEs should also be reported to the 
IRB within 24 hours (or 48 hours, if 
occurring on a weekend) of the time any study staff member is made aware 
of the event. 
5.5.2.3 Regulatory Notification 
USWM is responsible for notifying the relevant regulatory authorities of 
certain events. It is the Principal Investigator’s responsibility to notify the 
IRB or IEC of all SAEs that occur at his or her site. Investigators will also be 
notified of all unexpected, serious, drug-related events that occur during the 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 31 of 45 
 
clinical trial. Each site is responsible for notifying his or her IRB or IEC of 
these additional SAEs. 
Under 21 CFR 312.32(c)(l), the Sponsor must notify the FDA and all 
participating investigators in an IND safety report as soon as possible but no 
later than 15 calendar days after the Sponsor’s safety physician determines 
that the unexpected or suspected adverse reaction or other information 
qualifies for reporting. The Sponsor must report any suspected adverse event 
that is both serious and unexpected. Before submitting an IND safety report, 
the Sponsor must report an AE as a suspected adverse reaction only if there 
is evidence to suggest a causal relationship between the drug and the AE.9 
Under 21 CFR 312.32(c)(2), any unexpected fatal or life-threatening 
suspected adverse reactions represent especially important safety information 
and, therefore, must be reported more rapidly to FDA. The requirement for 
reporting any unexpected fatal or life-threatening suspected adverse reaction 
by Sponsor to FDA is no later than 7 calendar days after the sponsor’s safety 
physician initial receipt of the information. If the safety report submitted 
within 7 calendar days is complete, an additional submission within 15 days 
from day zero is not required (21 CFR 312.32(c)(1)(v)).9 
5.5.3 
Pregnancy 
Although pregnancy is not considered an AE, it is the responsibility of the 
Investigator to report any pregnancy in a female subject (spontaneously 
reported to them or discovered during a protocol-defined pregnancy test) that 
occurs during the study or within 7 days after the day during which the 
subject received her last dose of the IMP to 
 within 24 
hours (or 48 hours, if occurring on a weekend), using the contact information 
outlined in Section 5.5.2.2.  
All female subjects who become pregnant must be discontinued immediately 
and must be followed, at appropriate intervals, until completion/termination 
of the pregnancy. If the pregnancy continues to term, the outcome (health of 
infant) and status of mother and child must also be reported to 
 
. 
The 
IRB should be reported about any pregnancies that occur in the study. 
Hospitalization for normal delivery of a healthy newborn should not be 
considered an SAE. Any SAE that occurs during pregnancy must be recorded 
on the SAE report form (e.g., maternal serious complications, therapeutic 
abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, 
birth defect) and reported within 24 hours (or 48 hours, if occurring on a 
weekend) to the Sponsor in accordance with the procedure for reporting 
SAEs. 
5.5.4 
Clinical Laboratory Evaluations 
All subjects will be screened for alcohol, and marijuana (THC), cocaine, 
benzodiazepine, and opiate metabolites using immediate saliva/urine testing 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 32 of 45 
 
at check-in each study period (see Appendix 8.1.4). Subjects with positive 
results will be withdrawn from the study. 
All female subjects will have a urine pregnancy test performed at check-in 
each study period (see Appendix 8.1.5). Subjects with positive results will be 
withdrawn from the study. 
A 12.5 mL sample of blood will be collected after the last pharmacokinetic 
blood sample in Period III (or early termination) for a post-study hematology 
and clinical chemistry determination and a urine sample for urinalysis (see 
Appendix 8.1.1). Subjects will be instructed to not donate blood or plasma 
until at least 30 days after the last dose of study medication. 
In Period I, a blood sample for genotyping to determine CYP2D6 
genotype/lofexidine metabolizer status will be obtained at the time of the pre-
dose (Day 1, 0-hour) pharmacokinetic sample (see Appendix 8.1.2). This 
sample will only be analyzed, if needed, upon review of the PK results, as 
determined by the Sponsor.  
All female subjects will have a serum pregnancy test performed at the end of 
the study (or early termination) (see Appendix 8.1.5). 
5.5.5 
Vital Signs and Other Safety Assessments 
Additional vital sign assessments or safety evaluations may be performed at 
the discretion of the Investigator.  
Vital Sign Assessments 
Vital signs (temperature, pulse, and blood pressure) will be measured in the 
sitting position at check-in of each study period. 
Blood pressure and pulse (sitting) will be measured at pre-dose (between 
-1.5 and -0.5 hours before dosing), and 3.5 and 7.5 hours (± 30 minutes) after 
dosing in each study period and before release from the clinical facility in 
Periods I and II. 
The subject must have a pre-dose systolic blood pressure ≥ 90 mmHg to be 
eligible for dosing in the respective study period. If the subject’s pre-dose 
systolic blood pressure is < 90 mmHg, the assessment must be repeated 
2 additional times, 10 minutes apart. If two of the three systolic blood 
pressure measurements are < 90 mmHg, the subject will not be eligible to 
receive the study drug in the respective study period. The subject may 
participate in subsequent periods of the study, as applicable, at the discretion of 
the Investigator.  
At the end of the study (i.e., release from the clinic in Period III or early 
termination) all subjects will have vital signs (temperature, pulse, and blood 
pressure) performed. 
Any subject who experiences clinically significant hypotension (symptomatic 
orthostasis or as determined by the Investigator) will be required to remain 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 33 of 45 
 
supine, provided supportive care (e.g., hydration), and closely monitored until 
symptoms are resolved. Subjects who experience symptomatic hypotension in 
a specific study period will be permitted to remain in the study and enrolled in 
a subsequent study period, as applicable, if systolic blood pressure is ≥ 90 
mmHg at the pre-dose assessment in a subsequent study period and per the 
Investigator’s discretion.  
Subjects who experience a serious AE due to hypotension or bradycardia in a 
specific study period will not be eligible to participate in a subsequent study 
period, as applicable. In such a case, observations and sample collections 
should be completed for the subject following dosing in the respective study 
period and the subject will then be discontinued from the study (i.e., will not 
receive the dose in a subsequent study period). 
Physical Examinations 
A brief physical examination will be performed at check-in of each study 
period and before release from the clinical facility in Periods I and II. At the 
end of the study (or early termination), all subjects will have a complete 
physical examination (including weight [NOT height]) performed. 
12-lead ECG Assessments 
A 12-lead ECG will be performed at pre-dose in Periods I, II and III (Day 1, 
before vital sign assessments) and 3.5 hours post-dose (± 30 minutes), at 
release from the clinic (Periods I and II), at check-in (Day -1) for Periods II 
and III, and at the end of the study (i.e., release from the clinic in Period III or 
early termination). ECGs will be performed prior to vital sign assessments 
when time points coincide.  
The Period I pre-dose safety ECG will be collected in triplicate and must show 
QTcF findings that remain ≤ 440 msec on two of the three recordings for the 
subject to be eligible to receive study drug in Period I. If two of the three QTcF 
intervals exceed 440 msec, the subject will not be eligible to receive the study 
drug in Period I and will be discontinued from further participation in the 
study.   
In the event that a post-dose QTcF reading is > 450 msec, two additional ECGs 
should be taken at 10- to 15-minute intervals. If two of the three QTcF 
intervals exceed 450 msec, the subject will be monitored hourly until the QTcF 
has returned to below 450 msec. If a subject’s QTcF interval is > 500 msec at 
the post-dose ECG assessment or during hourly ECG monitoring, the subject 
will be discontinued from further participation in the study. Subjects with a 
post-dose QTcF interval > 450 msec in the respective study period that remains 
below 500 msec and resolves will be allowed to participate in  subsequent 
study periods if the subject’s respective check-in (Day -1) and pre-dose (Day 1, 
before vital sign assessments) ECGs are ≤ 440 msec (as outlined below). 
The Periods II and III check-in and pre-dose safety ECGs will be collected in 
triplicate and must show QTcF findings that are ≤ 440 msec on two of the 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 34 of 45 
 
three recordings for the subject to be eligible to receive study drug in the 
respective study period. If two of the three QTcF intervals exceed 440 msec, 
the subject will not be eligible to receive the study drug in the respective study 
period.. The subject may participate in subsequent periods of the study, as 
applicable, at the discretion of the Investigator. 
C-SSRS Assessments 
Subjects will complete the Columbia Suicidality Severity Rating Scale 
(C-SSRS) at check-in for each study period, at release from the clinical 
facility in Periods I and II, and at the end of study (i.e., release from the 
clinical facility in Period III or early termination). The C-SSRS: Baseline 
document should be used at check-in for Period I and the C-SSRS: Since 
Last Visit document should be used in all other instances. 
5.6 
Drug Concentration Measurements 
Sample Size: 6 mL collections (K2EDTA vacutainers) 
Collection Times: Pre-dose samples will be collected within 45 minutes  prior to 
dosing and before breakfast, if applicable. All times are relative to the dosing minute. 
Pre-dose (0-hour, within 45 minutes prior to dosing) and at 0.5, 0.75, 1.0, 1.5, 2.0, 
3.0, 4.0, 5.0, 7.0, 10.0, 16.0, 24.0, 30.0, 36.0, 48.0 and 54.0 hours post-dose 
Total Number of Collections per Period/per Subject: 17 
Total Blood Volume per Subject: The total maximum volume of blood collected for 
pharmacokinetic sampling may be up to 306 mL. 
 
 
 
 
 
 
The total volume of blood collected during this study is 
anticipated to be approximately 352.5 mL for male subjects and approximately 
367.5 mL for female subjects.  
Sample Processing: Samples will be collected in 6 mL K2EDTA vacutainers. 
 
 
 
 
 
 
 
 
After collection until placement in the 
freezer, blood/plasma samples will be kept cooled in an ice/water bath. 
Sample Shipment: Plasma samples will be sent to the bioanalytical laboratory for 
those subjects who were dosed with at least one of the study treatments (Treatment 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 35 of 45 
 
A, B or C). Plasma samples will be shipped only Monday through Wednesday via 
overnight courier to:   
 
 
 
   
 
 
 
 
 
 
 
   
5.7 
Statistical Methods 
5.7.1 
Statistical and Analytical Plans 
Concentrations of lofexidine in plasma will be measured by 
 
 using a fully validated analytical method. The analytical 
laboratory will be blinded to the randomization until after the analysis is 
completed. Samples will be analyzed by the bioanalytical laboratory for 
those subjects who were dosed with at least one of the study treatments 
(Treatment A, B or C), as indicated in Section 5.6. 
Pharmacokinetic and statistical services will be performed by 
 
. SAS®, Version 9.4 or higher will be used 
for all pharmacokinetic and statistical calculations. 
Data from subjects who have sufficient plasma concentrations to characterize 
Cmax and AUC0-t of at least one of the study treatments (A, B or C) will be 
included in the pharmacokinetic analysis. Data from any subject/period that 
does not provide sufficient plasma concentrations to characterize Cmax and 
AUC0-t will be excluded from the pharmacokinetic analysis. 
Data from subjects who have sufficient plasma concentrations to characterize 
Cmax and AUC0-t from at least two periods of the study, one of which includes 
Treatment A, will be included in the comparative statistical analysis.  
5.7.1.1 Pharmacokinetic Analysis: 
Linear and semi-logarithmic graphs of the concentration-time profiles for each 
subject will be provided, using the actual times of sample collections.  
Graphical presentations of mean results will use the scheduled times of sample 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 36 of 45 
 
collections. Actual sample collection time will be used for calculating the 
pharmacokinetic parameters. 
For the test and reference products, the peak exposure (Cmax) will be the 
observed maximum plasma concentration; the time to peak exposure (Tmax) 
will be the collection time at which Cmax is first observed. 
Areas under the plasma concentration-time curve from time zero to the time 
of last measurable concentration (AUC0-t) will be calculated by the linear 
trapezoidal method. Area under the plasma concentration-time curve from 
time zero to time infinity (AUC0-∞) will be calculated as follows:   
AUC0-∞ = AUC0-t + Ct/λz, where Ct is the last measurable plasma 
concentration and λz is the apparent first-order terminal rate constant. 
λz will be estimated, when possible, from the negative of the slope of the 
dataset with the best-fit least-squares linear regression analysis of the 
terminal ln-linear concentration-time data. The number of data points (3 or 
more) in the terminal phase (not including Cmax) to be included in the final 
regression analysis for an evaluable λz will be determined from the dataset 
that has the highest adjusted R-squared (R2) value of 0.7 or more. 
λz will be considered non-evaluable if (1) the last three terminal points are 
used to determine λz and either the middle or the last point is higher than the 
preceding point or (2) the resulting adjusted R2 value is less than 0.7. 
An evaluable λz will be considered not reliable and not reportable if the 
resulting apparent first-order terminal half-life (T½) value is longer than the 
time interval over which λz is estimated. If the resulting T½ value is longer 
than the time interval over which λz is determined, an interval that is longer 
than the estimated T½ will be explored. The interval with the next highest 
adjusted R2 value will be chosen and the decrease in the adjusted R2 value 
will be assessed to determine if a reliable estimation of the λz is possible. If λz 
is deemed not reliable then no T½ and AUC0-∞ values will be reported for that 
dataset. T½ will be calculated as ln(2)/λz. 
Apparent volume of distribution during the terminal phase (VZ/F) of the drug 
from plasma will be calculated as follows: Dose / [AUC0-∞·λz]). 
Apparent total clearance of the drug from plasma (CL/F) will be calculated 
as follows: Dose / AUC0-∞. 
No concentration estimates will be provided for missing sample values. Any 
sample with a missing value will be treated as if the sample had not been 
scheduled for collection. Data from subjects with missing concentration 
values (such as missing blood draws, lost samples, samples unable to be 
quantified) may be used if pharmacokinetic parameters can be estimated 
using the remaining data points, otherwise data from these subjects will be 
excluded from the final analysis.  

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 37 of 45 
 
5.7.1.2 Statistical Analyses 
Descriptive statistics (n, mean, SD, % coefficient of variation (%CV), 
minimum, median, maximum) will be reported for lofexidine concentrations 
at each time point by treatment. Descriptive statistics (n, mean, SD, % 
coefficient of variation (%CV), geometric mean, minimum, median, 
maximum) will be reported for all PK parameters. 
The statistical model will be conducted separately for Treatment A versus 
Treatment B analysis and for Treatment C versus Treatment A analysis using 
an incomplete block design. 
If a subject has immediate pre-dose (0-hour sample) concentrations that are 
greater than 5% of the measured Cmax value for that specific study period, the 
subject’s data will be excluded from the statistical analysis. If a subject has 
measurable pre-dose concentrations that are 5% or less of the measured Cmax 
value for that specific study period, the subject’s data will be included in the 
analysis without adjustment. 
Linear mixed effect model with treatment, sequence and period as fixed 
effects and random effects of subject nested within sequence will be used. 
Sequence effects will be tested against the Type III mean square term for 
subject-within sequence at the two-sided α = 10% level of significance. Least 
squares means for the treatments (LSMEANS statement), the differences 
between adjusted treatment means, and the standard errors associated with 
these differences (ESTIMATE statement) will be estimated. 
Confidence intervals (90%) on the geometric mean ratios (obtained from 
logarithmic transformed data) for AUC0-t, AUC0-∞ and Cmax for the 
comparison of Treatment A to Treatment B (to compare the test formulation 
and reference product under fasted conditions) and the comparison of 
Treatment C to Treatment A (to compare the granules for reconstitution [test 
formulation] under fed and fasted conditions) will be constructed to test two 
one-sided hypotheses at the α = 0.05 level of significance.5-7 
A description of all of the statistical analyses will be provided in the Statistical 
Analysis Plan (SAP). 
5.7.2 
Safety Analysis 
For safety, all AEs, ECGs, VS and safety laboratory values will be listed for 
each subject and tabulated by treatment. Physical examination data will also 
be listed. 
Safety (12-lead) ECG changes from baseline will be presented in a shift table 
(i.e., normal to abnormal) at each post-dose time point. For vital signs, 
descriptive statistics will be used to summarize the observed values at each 
time point and the change from baseline at each post-dose time point.  
No formal statistical testing will be performed on safety variables. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 38 of 45 
 
5.7.3 
C-SSRS Assessments  
Subjects will complete the Columbia Suicidality Severity Rating Scale 
(C-SSRS) at check-in for each study period, at release from the clinical 
facility in Periods I and II, and at the end of study (i.e., release from the 
clinical facility in Period III or early termination). 
Categorical variables for C-SSRS data, the number and percent of each 
category within a parameter, will be calculated for non-missing data and 
tabulated by time point. 
5.7.4 
Determination of Sample Size  
A sample size of 16 subjects enrolled to complete 12 subjects is considered, 
by the Sponsor, sufficient to meet the objectives of this study. The sample 
size for this study was determined based on clinical and practical 
considerations and not on a formal statistical power calculation. 
6.0 
REGULATORY OBLIGATIONS 
6.1 
Compliance 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), and all applicable regulations, including the Federal Food, Drug and 
Cosmetics Act., U.S. applicable Code of Federal Regulations (Title 21), ICH 
Guidelines, and IRB requirements relative to clinical studies. 
6.2 
Quality Assurance 
All aspects of the clinical and statistical phases of the study including all associated 
documentation will be reviewed by the quality assurance unit of 
 following 
their appropriate SOPs for QA methods and procedures. The final report will be 
audited to ensure that the methods described and the results reported accurately 
reflect the raw data generated during the study. 
6.3 
Institutional Review Board 
The study protocol, informed consent form, Investigator's brochure, or package insert 
(as applicable), and any specific advertising will be submitted to and approved by the 
 Institutional Review Board (
IRB) before the start of the 
study. 
 
 
6.4 
Audits, Inspections and Monitoring 
In accordance with the principles of GCP, 
 will ensure that it will permit trial 
related monitoring, audits, IRB/IEC review and regulatory inspection(s) by providing 
direct access to the clinical facility while the study is in progress and source data/ 
documents. Monitoring may occur virtually through electronic monitoring means. 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 39 of 45 
 
6.5 
Study Documentation 
6.5.1 
Protocol 
The Investigator indicated on Form FDA 1572 will act as the Principal 
Investigator.
 
 
 
 
  
6.5.2 
Informed Consent 
An Informed Consent Form (ICF) that includes all of the relevant elements 
currently required by FDA or state regulations will be provided to each 
prospective study subject at screening and before enrollment into the study.  
 
 
 
 
 
 
 
 
A copy of the ICF will be provided to the subject. 
 
   
6.5.3 
Protocol and Informed Consent Changes 
Changes to the protocol or the ICF will be implemented as amendments to the 
original document and approved by the 
IRB.
 
 
 
 Any addenda, amendment, or 
revision that substantially alters the study design or increases potential risk to 
the subject requires the subject's consent to continue in the study. 
6.5.4 
Source Documents and Case Report Forms 
All subjects will be identified by initials, date of birth, and the last four digits 
of his/her social security number, and will be assigned a study subject number.  
Source documents will be used to record all study-related data. Source 
document entries will be used to complete electronic Case Report Forms 
(eCRFs). 
 
 All data and eCRFs will be reviewed, evaluated, and signed by the 
Investigator, as required. 
6.5.5 
Final Report  
At the conclusion of the study, a final report will be issued to the Sponsor. 
Where applicable, it will contain a narrative description of the clinical 

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 40 of 45 
 
conduct of the study. Appropriate tables and graphs will be created to 
summarize the data.  
 
 
  
6.6 
Drug Accountability 
All drug receipt, inventory, dispensing, dosing and reconciliation records will be 
maintained in compliance with 
 Standard Operating Procedures. The study 
drugs will be used by the Investigator or by a qualified individual under the 
Investigator's direct supervision 
 
 
 
 
 
 At the end of the study, 
all study drug will be accounted for; any unused drug will be inventoried and retained 
on site. 
 
6.7 
Record Retention 
All drug accountability records, eCRFs, source data, and related regulatory 
documents must be retained for at least two years following marketing approval by 
the FDA. The Sponsor must notify the Investigator when approval of this formulation 
is received.   
6.8 
Financing and Insurance 
 
 
 
6.9 
Confidentiality 
This document contains trade secrets and commercial information that is confidential 
and may not be disclosed to third parties. Persons to whom this study protocol is 
disclosed must be informed that all the information herein is confidential and may not 
be further divulged. These restrictions will apply as well to all future communications 
if deemed privileged or confidential. Publication of the study results may only be 
allowed with written permission from the Sponsor.  
All subject information related to this study will remain confidential. Outside of 
, subjects will be identified, at all times, by a number and initials. Sponsor, 
study monitors, auditors, the IRB, FDA, and applicable regulatory authorities will be 
granted direct access to the subject’s original medical records for verification of 
clinical trial procedures and/or data, without violating the confidentiality of the 
subject, to the extent permitted by applicable laws and regulations.   

CONFIDENTIAL PROTOCOL 
A study to evaluate the relative bioavailability of a test formulation of lofexidine granules 
for reconstitution and the effect of food on the bioavailability of the test formulation in 
healthy adult subjects 
 
Protocol No. USWM-LX2-1001/
; 25 Jan 2021 
 
  Page 41 of 45 
 
7.0 
REFERENCES 
1. Product Label for LUCEMYRA™ (lofexidine hydrochloride) Tablets (US WorldMeds, 
LLC), May 2018. 
2. Summary of Product Characteristics for BritLofex™ tablets 0.2 mg (Britannia 
Pharmaceuticals Limited); 12 October 1990, Revised 02 January 2015. 
3. Electronic Orange Book. http://www.fda.gov/cder/ob/ (Retrieved on July 29, 2019) 
4. Approval for LUCEMYRA™ (lofexidine hydrochloride) Tablets. Multi-Discipline 
Review. US WorldMeds, LLC, NDA 209229, May 2018. 
5. Draft Guidance for Industry. Bioavailability Studies Submitted in NDAs or INDs — 
General Considerations. U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), February 2019. 
6. Guidance for Industry. Statistical Approaches to Establishing Bioequivalence. U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), January 2001. 
7. Guidance for Industry. Food Effect Bioavailability and Fed Bioequivalence Studies. U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), December 2002. 
8. Guidance for Industry, Investigators, and Institutional Review Boards. FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency. U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER) Center for Biologics 
Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) 
Oncology Center of Excellence (OCE) Office of Good Clinical Practice (OGCP); March 
2020, Updated December 4, 2020. 
9. Guidance for Industry and Investigators. Safety Reporting Requirement for INDs and 
BA/BE Studies. U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), December 2012. 
10. Guidance for Industry, Handling and Retention of BA and BE Testing Samples. U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Office of Generic Drugs (OGD), May 2004. 
11. Guidance for Industry. Compliance Policy for the Quantity of Bioavailability and 
Bioequivalence Samples Retained Under 21 CFR 320.38(c). U.S. Department of Health 
and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER), August 2020.