Clinical trial NCT04188730
Conditions: Normal Healthy Volunteers
Sponsor: USWM, LLC (dba US WorldMeds)
Start date: 2021-02-16; Completion date: 2021-03-26
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this open-label, single-dose, randomized, three-treatment, three-period, four-sequence, crossover study is to evaluate the relative bioavailability of a test formulation of lofexidine granules for reconstitution (oral) and LUCEMYRA tablets 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.

Detailed description:

Arms: arm 1: Participants will be administered lofexidine granules for reconstitution following an overnight fast of at least 10 hours. arm 2: Participants will first be administered LUCEMYRA (lofexidine) tablets following an overnight fast of at least 10 hours arm 3: Participants will first be administered lofexidine granules for reconstitution, 30 minutes following a standardized breakfast preceded by an overnight fast of at least 10 hours.
Interventions: intervention 1: Lofexidine (granules for reconstitution) intervention 2: LUCEMYRA (lofexidine) tablets
Intervention descriptions: intervention 1: All subjects will be administered one 0.36 mg dose of lofexidine granules for reconstitution. intervention 2: All subjects will be administered one 0.36 mg dose of LUCEMYRA (lofexidine) tablets.

Protocol documents:
ICF_000.pdf: 
PRODUCT: Lofexidine granules for reconstitution (oral) 
 
INFORMED CONSENT FORM 
 
PROTOCOL NUMBER: USWM-LX2-1001 
 
 
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd 
Louisville, KY 40241 
 
 
TITLE: 
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 
 
 
DOCUMENT DATE: February 2, 2021 
IND NUMBER: 47857 
NCT NUMBER: NCT04188730 
 


 
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 
Consent Form Revision 4 
  
 
 
 
 
Page 1 of 13 
 
 
 
Approved by the 
IRB on 02/02/2021   
The information being provided below is some of the most important information about this 
study. More details about the study are explained later in this consent form.  
Taking part in this research project is voluntary. You do not have to participate, and you can 
stop at any time. Please take time to read this entire form and ask questions before deciding 
whether to take part in this research project. 
Key Information 
  
Drugs being studied: Lofexidine in a liquid form and a tablet form are being compared. The 
liquid form is new and investigational (meaning not approved by the FDA). The tablet form 
(LUCEMYRA®) is already FDA-approved. Lofexidine is used in adults to help lessen symptoms 
of opioid withdrawal when opioid medications are stopped suddenly.   
 
Purpose: To see how quickly and to what extent the body absorbs and gets rid of the liquid 
form of lofexidine compared to the tablet form of lofexidine. 
 
Who is being asked to participate: About 16 healthy volunteers, ages 18 to 50. Females 
must not be pregnant or breastfeeding and must be using an effective birth control method 
before and during the study. 
 
Medical benefits to participating in this study: This is a healthy volunteer study. There are 
no direct medical benefits to you by participating in this study.  
 
Time commitment: 3 study periods lasting about 3½ days (3 overnights) each. Your total 
participation in this study will be about 2½ weeks. This does not include your screening visit.  
 
Restrictions: During confinement you will eat/drink only the food and beverages given to you. 
You won’t be allowed to eat/drink/use certain products before and during the study, such as 
caffeine, alcohol, grapefruit, and tobacco/nicotine. You will have to fast (not eat anything) for at 
least 10 hours before each dosing.  
 
Procedures: If you are eligible and decide to participate, you will receive one dose of the 
tablets in one period and one dose of the liquid form in the other two periods (either on an 
empty stomach or after eating a high-fat, high-calorie breakfast). You will be asked to remain 
lying down in bed for 8 hours after dosing. Study staff will monitor your health and perform 
various safety tests while you are in the clinic, such as taking your blood pressure, pulse, and 
ECG (measurement of the electrical activity of the heart). 
 
Blood draws each period: About 17 blood samples. Total of about 1½ cups of blood, 
including blood taken to check your health and 1 sample for a genetic test to see how your 
body metabolizes [breaks down] the study drug(s). 
 
Common Side Effects: Low blood pressure or symptoms of low blood pressure, slow 
heartbeat, dizziness, lightheadedness, and feeling faint at rest or when standing up. The 
complete list can be found later in the form. For your safety, you should be honest about your 
medical and social history. 
 
Risks associated with blood draws: Pain, bruising, swelling and/or numbness of the arm, 
fainting, and infections (rarely). 
 
Privacy Risks: Accidental breach of confidential information collected from you as part of this 
study.  


Consent Form Revision 4 
Lofexidine Oral Solution and Tablets (Study No. 11965001) 
Page 2 of 13 
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“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” 
STUDY DRUG(S):   Lofexidine granules for reconstitution (oral), 
, final strength 
lofexidine 90 μg/mL
LUCEMYRA® (lofexidine) tablets, EQ 0.18 
mg base (US WorldMeds, LLC) 
SPONSOR 
PROTOCOL NO.: 
USWM-LX2-1001 
SPONSOR: 
USWM, LLC 
4441 Springdale Rd. 
Louisville, KY 40241
INVESTIGATOR: 
SUBJECT’S RIGHTS ADVOCATE:
What is informed consent? 
You are being asked to take part in a clinical research study. It is important that you 
understand the potential risks and benefits of participating in the study to make an 
informed decision. This process is known as informed consent. 
This consent form describes the purpose, procedures, possible benefits, and risks of 
participating in the study. This form will also explain how your medical information will be 
used and who may see it. Once you have been informed about the study and had all 
questions answered to your satisfaction, you will be asked if you are willing to sign this 
form. By giving your consent, you are allowing your medical information to be collected, 
used, and shared with certain persons involved in the study. Signing this form will also 
show that this study has been sufficiently and appropriately explained to you and that you 
agree to participate in it.   
You cannot be in this study if you have participated in any other study, at 
 or any 
other research facility, within the last 30 days. The study investigator is interested both in 
your health and in the conduct of this study. 
 is paid by USWM, LLC (the study 
sponsor) to conduct this study. 
What drug will be used in this study? 
Lofexidine in the form of granules that will be dissolved into an oral solution (liquid) and 
as tablets, of the same strength, will be used in this research study. Lofexidine is a drug 
approved by the United States Food and Drug Administration (FDA) to be used in adults 
to help with the symptoms of opioid withdrawal that may happen when someone stops 
taking an opioid suddenly. Lofexidine tablets (LUCEMYRA®) have been approved by the 
FDA for use in the U.S. for approximately 3 years; however, lofexidine tablets have been 
approved and prescribed by doctors in the United Kingdom (U.K.) for over 25 years. 
The usual dose of lofexidine in adults is 0.54 mg (three tablets) taken by mouth 4 times 
a day, about 5 to 6 hours apart. The total daily dosage of LUCEMYRA® should not 


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exceed 2.88 mg (16 tablets) and no single dose should exceed 0.72 mg (4 tablets). A 
single 0.36 mg dose of lofexidine will be given in each period of this study.  
 
Why is this study being done? 
This study is being done to compare how the two forms (liquid and tablet) of the study 
drug are absorbed (passed from the gut into the blood stream) and eliminated (removed) 
from the body after taken on an empty stomach and taken after eating a high-fat, high-
calorie breakfast. A new, UNMARKETED “investigational” version of lofexidine (dissolved 
granules) will be compared to an approved, MARKETED version of lofexidine (tablets) 
called LUCEMYRA®. “Investigational” means the formulation being tested has not been 
approved yet by the FDA. 
 
Who is being asked to take part in this study? 
You are one of about 16 non-tobacco, non-nicotine using adults who have been asked to 
participate in this study. To be in this study, you must be 18 to 50 years of age and be in 
good health. Since we usually sign up more eligible participants for the first study check-in 
than we need, you may be released from the study before dosing. 
 
How will I know if I am eligible to take part in this study? 
Screening Visit (within 28 days of first dosing) 
The purpose of this visit is to obtain information about your current health status and to 
decide if you qualify for the study. The screening evaluation will include (but may not be 
limited to) the following:  
• 
Review of your medical (including allergies) and social (drug, alcohol, tobacco, and 
caffeine use, etc.) history. It is potentially dangerous to withhold information 
concerning your medical and social history. 
• 
Review of any medicines, vaccines, nutritional supplements, vitamins, and herbal 
products that you are taking or have taken recently.   
• 
A general physical examination. 
• 
Measurement of your vital signs in a sitting or supine (flat on your back) position 
(blood pressure, pulse, and body temperature), body weight, and height.  
• 
A blood pressure assessment for orthostatic hypotension. Orthostatic hypotension 
is a form of low blood pressure that happens when you stand up from sitting or 
lying down. 
• 
Measurement of heart rhythms (ECG or electrocardiogram). 
• 
Collection of a blood sample (about 2½ teaspoonfuls) to verify you can safely enter 
the clinical study. 
• 
Collection of a blood sample (about 3½ teaspoonfuls) to test for Hepatitis B, 
Hepatitis C, and HIV (the virus that causes AIDS).   
• 
Collection of a blood sample (about 1 teaspoonful) for pregnancy testing (females).  
• 
Females who are considered post-menopausal (meaning no menstrual period for 
at least 1 year) will have a sample of blood collected (about 1 teaspoonful) to 
confirm postmenopausal status. 
• 
Collection of a urine sample to test for selected diseases and drugs of abuse.  


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• 
You will be given a “Participant Handbook” to read or have read to you. This 
handbook contains the 
 Rules and Regulations. 
Some of these tests may be repeated for safety reasons before you begin the study, 
during the study, or at the end of the study.   
Study Restrictions: 
If you have taken any prescription medication (except hormonal contraceptives) within 
14 days of the study start or plan to take them during the study, you can NOT 
participate in this study. If you are taking any over-the-counter medications (including 
vitamins and herbal products) or dietary supplements (for example, Cellucor®, Muscle 
Tech®), you will be asked to stop taking them within 7 days before dosing with study 
drug and throughout the blood collection portion of the study. You will not be allowed to 
take any of the following products within the following timeframes before dosing with 
study drug and throughout the blood collection portion of the study: 
• Alcohol (beer, wine, liquor, etc.) – 3 days 
• Caffeine (coffee, tea, chocolate, soda, cola, etc.) – 3 days 
• Energy drinks (for example, Red Bull, 5-Hour Energy®, Monster Energy®) – 3 days 
• Grapefruit containing products (grapefruit or grapefruit juice, Ruby Red, Fresca®, etc.) 
– 7 days 
You will not be allowed to use tobacco or nicotine-containing products (patches, gum, 
etc.) for 30 days before the study start and throughout the entire study. 
Since there may be other medicines or products that are not allowed prior to or during 
the study, it is very important for your safety that you tell the study staff about all 
medications or products you have taken or used. You will be given an information sheet 
that lists the dates and times of your clinic visits and study restrictions. 
 
What are the procedures of this study? 
This study consists of 3 study periods. Each study period will involve about a 3½ day (3 
overnights) stay at the clinic. There will be about 3 days between study periods during 
which no procedures will be performed. Your total participation in this study will be about 
2½ weeks. This does not include your screening visit. 
At each check-in (the day before dosing), the following will occur: 
• 
Your personal belongings will be searched to make sure you did not bring any 
restricted items, as listed in the Participant Handbook.  
• 
A brief physical examination will be performed. 
• 
You will be asked to complete the Columbia Suicidality Severity Rating Scale (C-
SSRS), an assessment for your risk of suicide. 
• 
You will be asked about your health and any medication/drug use.  
• 
You will have a urine/saliva test for alcohol and drugs of abuse.   
• 
Females will have a urine pregnancy test. 
• 
Your blood pressure, temperature, and pulse rate will be measured.  
• 
Your heart rhythms (ECG or electrocardiogram) will be measured at check-in 
Periods 2 and 3 only. 


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At check-in of Groups A and B (fasted periods): 
• 
If you arrive before dinnertime, you will be provided a meal. You will not be able 
to eat anything past 10:00 pm (approved snacks may be allowed before this 
time) until lunch the next day. 
At check-in of Group C (fed period): 
• 
If you arrive before dinnertime, you will be provided a meal. You will not be able 
to eat anything past 10:00 pm (approved snacks may be allowed before this 
time) until breakfast the next day. You will be required to eat 100% of a high–fat, 
high-calorie breakfast within 30 minutes of dosing. The high-fat, high-calorie 
breakfast consists of 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast 
with butter, 4 ounces of hash brown potatoes, and 8 ounces of milk. 
Day of Dosing 
If you are still eligible to be in the study, you will be required to drink about a 1¼ cup of 
water in the morning at 4, 3, 2, and 1 hours before dosing. You will receive one of the 
following: 
Group A: 
A little less than 1 teaspoonful of lofexidine oral solution
 
0.36 mg total dose – Administered following an overnight fast of at least 10 
hours 
Group B:  
0.36 mg lofexidine (2 × 0.18 mg) tablets, LUCEMYRA® (US WorldMeds, 
LLC) – Administered following an overnight fast of at least 10 hours 
Group C: 
A little less than 1 teaspoonful of lofexidine oral solution 
 
 0.36 mg total dose – Administered 30 minutes after eating a 
high-fat, high-calorie breakfast 
Groups A and C:  
 
 
 
You will then 
be required to drink about one cup of room temperature, distilled water. Immediately 
after dosing, a mouth check will be performed to confirm that the solution, mouth rinse, 
and additional water have been swallowed. Within 10 minutes after completing the 
dosing procedure, you will complete a Taste Assessment Questionnaire. It should take 
you less than 10 minutes to complete it. 
Group B:  
When lofexidine is given in tablet form, you will be required to drink one cup of room 
temperature, distilled water with the two tablets provided to you by study staff. You will be 
instructed to swallow the tablets whole without chewing or biting. Immediately after 
dosing, the study staff will perform a mouth check to ensure that the study drug and 
water have been swallowed. If you bite or chew the tablets, you will be discontinued from 
the study.  
Over the course of the entire study, you will receive each of the study drugs listed above. 
The order that you receive the study drugs will be determined randomly (by chance). 
Tests and Procedures during Your Stay 
The following tests and procedures will also occur as follows: 


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• 
Blood samples (a little more than 1 teaspoonful each time) will be collected just 
before and frequently after dosing to measure the study drug. 
• 
In Period 1 only, a blood sample (about 1 teaspoonful) will be collected to see if 
your body has limited ability to make a certain enzyme called CYP2D6. This 
enzyme is responsible for breaking down certain drugs in the body. People who 
have limited ability to make this enzyme are sometimes known as “slow 
metabolizers” and it may take them longer to break down and eliminate certain 
drugs from the body than other people. Whether or not you are a “slow 
metabolizer” is determined by your genetic makeup and is pre-determined at birth. 
This sample will only be analyzed, if needed, after review of your blood sample 
results.  
• 
Your health will be monitored while you are in the clinic. You will be asked to report 
any side effects you are experiencing throughout the study. The study staff will 
monitor how well you follow study requirements throughout the study. 
• 
Your blood pressure and pulse rate will be measured at least 2 times before each 
dosing, at least 2 times after each dosing, and before release from the clinical 
facility in Periods 1 and 2. 
• 
Your heart rhythms (ECG or electrocardiogram) will be measured at least 1 time 
before each dosing, at least 1 time after dosing, and before release from the 
clinical facility in Periods 1 and 2. 
• 
You will be restricted in the times that you may drink water or stand up. You will be 
asked to lie down flat on your back or in a reclined position for about 8 hours after 
dosing, except as required for study procedures or at the discretion of the study 
investigator. You will not be allowed to drink water or any other fluids starting 4 
hours before dosing until 8 hours after dosing, with the exception of the scheduled 
water administrations and milk given with breakfast (fed study period only). At 
about 2, 4, 6, and 8 hours after dosing, you will be required to drink about 1 cup of 
room temperature water. 
• 
You will not be permitted to participate in strenuous activity while you are in the 
clinic. 
• 
You will be provided with food and drinks. You will be required to consume all food 
and drinks provided to you.  
• 
A brief physical examination will be performed before you leave the clinical facility 
in Periods 1 and 2.  
• 
You will be asked to complete the Columbia Suicidality Severity Rating Scale (C-
SSRS) before you leave the clinical facility in Periods 1 and 2. 
Additional procedures or laboratory tests may be performed to monitor your health. 
End of Study or Early Withdrawal from the Study 
• 
A blood sample (about 2 ½ teaspoonfuls) and a urine sample for laboratory testing 
will be collected. Your blood and urine will be tested to assess your general health. 
• 
A blood sample (about 1 teaspoonful) will be collected to test for pregnancy 
(females). 


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• 
A complete physical examination (including weight) will be performed. 
• 
Your heart rhythms (ECG or electrocardiogram) will be measured. 
• 
Your blood pressure, pulse rate, and temperature will be measured. 
• 
You will be asked to complete the Columbia Suicidality Severity Rating Scale (C-
SSRS). 
 
How much blood and urine will be collected during this study? 
Blood samples will be collected from you using a sterile needle about 17 times over 
approximately a 54-hour period in each study period. About 9 of these samples will be 
collected within the first 7 hours after dosing. There may be more than 1 tube of blood 
collected at each collection time. Over the course of the entire study, a total of about 52 
blood samples will be collected. This includes your screening visit. 
About 1½ cups of blood will be collected from you during this study. For your 
comparison, when people donate blood, they give about 2 cups at once. 
You should not give blood during this study and within 30 days prior to check-in. You 
should not donate plasma for 14 days prior to check-in. You should not donate blood until 
at least 30 days after dosing. 
A urine/saliva test will be collected at screening and at check-in of each study period. A 
urine test will also be collected at the end of the study or early withdrawal. 
 
What are the possible risks, side effects, and discomforts of this study? 
You may experience none, some, or all the side effects listed below. Some side effects 
may occur that may not be expected or predicted. The study drugs may have other risks 
that might include life-threatening reactions that are not yet known. Side effects should be 
reported to the study investigator or 
 medical staff as soon as possible. 
The following Side Effects have been reported by people taking the marketed version of 
lofexidine (LUCEMYRA®). However, because the test formulation of lofexidine (granules 
dissolved in liquid) is “investigational” and not currently approved by FDA or available in 
the commercial market, it is possible that more or different side effects could occur.  
The most common side effects of LUCEMYRA® (lofexidine tablets) include:
• Low blood pressure or symptoms of low blood pressure such as lightheadedness 
• Slow heart rate 
• Dizziness 
• Sleepiness 
• Dry mouth 
You should be careful not to stand up too suddenly from lying down or sitting. 
Taking LUCEMYRA® (lofexidine) with opioid medicines, benzodiazepines, alcohol, 
or other central nervous system depressants (including street drugs) can cause 
severe drowsiness, breathing problems (respiratory depression), coma, and 
death. 
 
 


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Since LUCEMYRA® (lofexidine) can cause dizziness or sleepiness, you should 
take caution while participating in activities that require mental alertness and 
potentially hazardous activities, such as operating machinery, DRIVING a motor 
vehicle, or riding a bicycle until you feel fully awake.  
 
Allergic Reaction Risks 
As with taking any drug, there is a risk of allergic reaction. If you have a very serious 
allergic reaction, you may be at risk of death. Some symptoms of allergic reactions are: 
• Rash/hives. 
• Difficulty breathing and wheezing.  
• A sudden drop in blood pressure. 
• Swelling around the mouth, tongue, throat, or eyes. 
• A fast pulse. 
• Sweating. 
Please seek treatment immediately and tell the study investigator and study staff if you 
have any of these symptoms, or any other side effects, during the study. 
 
Side effects of blood collections: 
Pain, bruising, swelling and/or numbness of the arm, fainting, and infections (rarely) may 
result from the multiple blood collections taken during this study.  
 
NEW INFORMATION 
You will be given any new information about the study drug that becomes known during 
the course of the study that the study investigator or the study sponsor believes might 
reasonably affect your willingness to continue to take part in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is not a complete list of side effects. Others may occur including serious or 
even life-threatening reactions. You should be aware that not being truthful about 
your medical history, the use of alcohol or any other drugs or medicines during 
the study (other than the study drugs), could lead to serious or even life-
threatening reactions. 


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CONTRACEPTION/PREGNANCY/BREASTFEEDING: 
There are no well-controlled studies in pregnant women with the drugs used in this study. 
There could be unknown, unforeseeable risks to an unborn child or breast-feeding 
infants. You cannot participate in this study if you are pregnant or become pregnant 
during the study or are breast-feeding a child. If you are a woman of child-bearing 
potential: 
 
• You must take precautions to prevent pregnancy during this study.   
 
• A pregnancy test will be done to confirm that you are not pregnant before you 
take part in this study. A pregnancy test will be done before the beginning of 
each study period. Even if the test result is negative, this does not guarantee that 
you are not pregnant.   
 
• You must agree to use a reliable form of birth control (e.g., condom with 
spermicide, IUD, hormonal contraceptives), if you are sexually active, to avoid 
becoming pregnant from at least 30 days before the first dose of study drug and 
throughout the study. 
The study investigator will decide if you are using an acceptable form of birth control. 
Please Note: Whichever method of birth control you choose, remember that aside from 
abstinence (not having sexual intercourse), all birth control methods sometimes fail, 
even if used properly and consistently. 
You must tell the study investigator right away if you become pregnant during this study 
or within 30 days of completion of the study. The study investigator will follow you to the 
completion or termination of your pregnancy to collect information about the pregnancy 
and the health of the baby. 
 
Will I benefit from taking part in this study? 
There is no intended medical benefit to you from taking part in this study. However, you 
may indirectly benefit by having a physical examination, an electrocardiogram (ECG), 
and blood and urine tests.  
 
Will anyone know that I am taking part in this study? 
Certain people and organizations will need to see and copy your research records so 
that they can do their part in the study. Only authorized users will be given access to 
and may make copies of your research records. Your research records may or may not 
include your name and they may be traced back to you even if it does not include your 
name.  Authorized users include: 
• 
Representatives of 
 
• 
Representatives of the 
 
• 
Representatives of USWM, LLC. 
• 
Representatives of the Food and Drug Administration (FDA) and other US 
 
governmental agencies.  
• 
Governmental agencies of other countries. 
• 
Labs working with the Sponsor and 
 on this study.   


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• 
State/Governmental agencies to whom certain diseases (like HIV, hepatitis) must 
 
be reported. 
We cannot promise complete confidentiality of your research records and personal 
health information. However, sharing your research records will be guided by 
professional standards and the law. Information from this study may be presented at 
meetings or published in medical journals but will not include your name or information 
that can be traced back to you. Your records shall not be used for any other purpose or 
shown to any other third party, except as required by law. 
For your safety, the study investigator should tell your regular health care provider that 
you are in this study. Please inform the study staff if you would like us to do so. If you 
would like us to send results from your physical examination and laboratory tests to your 
personal doctor, we will do so if you complete a release of information form. At your 
request, we can also supply those results to you. 
 
Will persons looking at my medical information be able to identify me? 
Records of your participation in this study will be held confidential except when sharing 
the information is required by law or as described in this form. Research records that 
are sent to the study sponsor do not identify you by name. The study investigator uses 
your initials and a code number on these records. However, authorized users may look 
at all of your research records at the study investigator’s site that will identify you. The 
reason these persons may look at your research records is to make sure the study has 
been done properly and that study data have been collected correctly, or for other 
reasons allowed by law.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time.  
 
Will my information be used for future research? 
There is no future research planned for your provided samples (e.g., blood, urine).  The 
research study results, including individual research results, will not be provided to you. 
  
Who will pay if I am injured during this study? 
If you have a medical emergency, illness or bodily injury that was caused by the 
administration of the research drug or any study procedures, medical care approved by 
the study investigator will be provided to you free of charge. The study investigator will 
arrange for medical treatment and any tests necessary to determine the cause of your 
illness or injury. Other than the payment for participation and free medical care for study-
related illness and injury, you can expect no other payment or care from 
 or the 
sponsor.  
To pay medical expenses, related to your participation in the study, 
 or the sponsor 
will need to know some information about you like your name, date of birth, and Medicare 
Beneficiary Identifier. This is because the sponsor has to check to see if you receive 
Medicare and if you do, report the payment it makes to Medicare. 


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If a research-related adverse effect or injury occurs after you have left our facility, call 
our duty nurse at: 
. If you are not in the 
 area, you may use our 
toll-free number: 
. 
 
How can I get more information about this study? 
For more information about this study you may contact the 
 medical staff at 
 or 
.   
 
Who do I call if I think my rights as a research subject have been violated? 
For information about your rights as a research subject call the subject’s research 
advocate at 
.  
 
Is my participation in this study voluntary? 
Your participation in this study is purely voluntary. You may refuse to take part in it, or you 
may stop participating at any time, even after signing this form. If you stop, it is in your 
best interest to tell the study staff and follow any instructions they may give you. You will 
not be penalized or lose any medical benefits to which you are otherwise entitled. When 
you stop taking part in the study, you will be asked to go through the termination 
procedures the study investigator thinks are necessary for your safety. You may be asked 
to remain at the clinic until the study investigator considers it safe for you to leave. Any 
data or samples that have already been collected from you may still be used as 
described in this consent form. 
The sponsor and the study investigator may stop the study or stop your participation at 
any time. This may be done for any of the reasons listed below and does not require your 
agreement.   
• 
If you do not follow the study investigator’s instructions 
• 
If we find out you should not be in the study 
• 
If the study is stopped 
• 
If you have difficulties with blood collection 
• 
If it becomes harmful to your health 
• 
If you are female and become pregnant 
• 
Adverse events/side effects 
 
What other treatments are available to me? 
This is not a study designed to provide treatment. Your alternative is to not take part in 
this study. 
 
 
 
 
 
 
 
 
 
 
 
 


Consent Form Revision 4 
Lofexidine Oral Solution and Tablets 
  
 
 
 
 
Page 12 of 13 
 
 
Approved by the 
IRB on 02/02/2021     
How much will I be paid if I complete this study? 
If you complete the entire study, you will be paid 
 
.   
You will be paid an appropriate amount based on your extent of participation if: 
• 
You are unable to complete the study.  
• 
You voluntarily leave the study.  
• 
The study is stopped early.  
• 
You are withdrawn because of side effects.  
• 
You screened and qualified for the study but you were not chosen to participate.  
 
 
 
 


Consent Form Revision 4 
Lofexidine Oral Solution and Tablets 
  
 
 
 
 
Page 13 of 13 
 
 
Approved by the 
IRB on 02/02/2021     
SIGNATURE PAGE 
 
SUBJECT 
 
• I have read or have had read to me the consent form for this study and the 
contents were explained to me. All of my questions were answered to my 
satisfaction. I understand that I have the right to be provided with answers to any 
questions that may come up during the study.   
 
• I understand that my participation in this study is voluntary and I may stop 
participating at any time. 
 
• I agree to be in this research study. 
 
• I will receive a copy of this consent form. 
 
 
 
 
 
 
Subject Name (Print)  
 
 
 
 
 
 
 
 
Subject Name (Sign)  
 
 
Dated by Subject 
 
 
 
 
 
INFORMED CONSENT OBTAINED BY: 
 
 
I have explained to the subject the nature and purpose of this study.  There has been an 
opportunity for the subject to ask questions about this research study.  I hereby verify the 
informed consent, the subject’s signature and acknowledge that a copy of the consent 
was provided to the subject.  
 
My signature verifies that the subject provided consent prior to participation in this 
research study. 
 
 
 
 
 
 
 
 
 
Investigator or Investigator's Designee (Sign) 
Title 
 
Date 
 
 
 

SAP_002.pdf: 
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: March 23, 2021 
IND NUMBER: 47857 
NCT NUMBER: NCT04188730 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 /
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 1 of 49 
 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE 
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 (Amendment 4) 
 
 
SPONSOR 
USWM, LLC 
4441 Springdale Rd. 
Louisville, KY 40241 
United States of America (USA) 
CLINICAL RESEARCH 
ORGANIZATION 
 
 
 
DATE AND VERSION 
23 Mar 2021 – Version 1.0 - Final 
 
 


STATISTICAL ANAL YSlS PLAN 
PROTOCOL No. USWM~LX2-1001 /
 
LOFEXJDINE GRANULES fOR RECONSTHUTION (ORAi.) FORMULATION, 90 p<i/ML 
SAP Final Venion Approvals 
A study to evaluate the relative bioavailability of a test fonnulation of lofexidine granules for 
reconstitution and the effect of food on the bioavailability of the test fonnulation in healthy 
, 
adult subjects 
Written B,·: 
 
Reviewed By: 
 
 
(\_,. f .. 
 
 
 
 
Approved By: 
Signature:------·--· _________________________ _ 
 
Date: 1-i Muv 2-02-l 
Date: 
2 '~ 
fl)ct 
20 2 I 
Date: ---------
USWM-LX2-IOOI: SAP Ver.LO• 
 
• Page 2 of49 
I 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 3 of 49 
 
Revision History 
VERSION 
DATE 
DESCRIPTION OF REVISIONS 
REVISED BY 
Draft 0.1 
19 Feb 2021 
New Document 
 
Draft 0.2 
05 Mar 2021 
Incorporated Sponsor Comments 
 
Draft 0.3 
18 Mar 2021 
Incorporated Sponsor Comments 
 
Final 1.0 
23 Mar 2021 
Finalized Document 
 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 4 of 49 
 
List of Abbreviations and Definition of Terms 
ADAE 
Analysis Dataset of Adverse Events 
ADPC 
Analysis Dataset of PK Concentrations 
ADPP 
Analysis Dataset of PK Parameters 
ADSL 
Subject Level Analysis Dataset 
AE 
Adverse Event 
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 (t) 
BMI 
Body Mass Index 
bpm 
Beats per minute 
CL/F 
Apparent total clearance of the drug from plasma 
Cmax 
Maximum observed plasma concentration  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
Ct 
Last measurable plasma concentration 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EQ 
Equivalent to 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
g 
Gram 
hr 
Hour 
ICH 
International Council for Harmonisation 
in 
Inch 
ISCV 
Intra-subject coefficient of variation 
kg 
Kilogram 
λz 
Apparent first-order terminal elimination rate constant 
m2 
Meters squared 
Max. 
Maximum 
Mean 
Arithmetic mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
µg 
Microgram 
min 
Minute 
Min. 
Minimum 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
msec 
Millisecond 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PR 
PR interval of the ECG 
QRS 
QRS interval of the ECG 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 5 of 49 
 
QT 
QT interval of the ECG 
QTc 
Corrected QT interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
T½ 
First-order terminal elimination half-life 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time of maximum observed plasma concentration 
VZ/F 
Apparent volume of distribution during the terminal phase 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 6 of 49 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
SAP Final Version Approvals ..........................................................................................................2 
Revision History ..............................................................................................................................3 
List of Abbreviations and Definition of Terms................................................................................4 
TABLE OF CONTENTS .................................................................................................................6 
1. INTRODUCTION .......................................................................................................................9 
2. STUDY OBJECTIVES ................................................................................................................9 
3. OVERALL STUDY DESIGN .....................................................................................................9 
STUDY SCHEMATIC .............................................................................................................11 
4. RANDOMIZATION..................................................................................................................12 
5. SAMPLE SIZE ..........................................................................................................................12 
6. ANALYSIS POPULATIONS ...................................................................................................12 
6.1 Pharmacokinetic Population ...............................................................................................12 
6.2 Safety Population ................................................................................................................12 
7. STATISTICAL ANALYSIS METHODS .................................................................................12 
7.1 Baseline Characteristics ......................................................................................................13 
7.1.1 Baseline Demographics ...............................................................................................13 
7.1.2 Medical History ...........................................................................................................13 
7.2 Pharmacokinetic and Statistical Analyses ...........................................................................13 
7.2.1 Pharmacokinetic Parameters .......................................................................................13 
7.2.2 Statistical Analyses .....................................................................................................14 
7.3 Safety Analysis ...................................................................................................................14 
7.3.1 Adverse Events ............................................................................................................15 
7.3.2 Vital Signs ...................................................................................................................15 
7.3.3 ECG .............................................................................................................................15 
7.3.4 Physical Examination ..................................................................................................16 
7.3.5 Concomitant Medications ...........................................................................................16 
7.3.6 Clinical Laboratory Tests ............................................................................................16 
7.3.7 C-SSRS Assessments ..................................................................................................16 
7.4 Taste Assessment ................................................................................................................16 
7.5 Multiple Comparisons .........................................................................................................16 
7.6 Interim Analyses .................................................................................................................16 
8. PK Reconciliation ......................................................................................................................16 
9. TABLE, LISTING AND FIGURE SHELLS ............................................................................17 
Table 10.1.1 Subject Disposition ..............................................................................................18 
Table 11.2.1 Summary of Demographic Data (Safety Population) ..........................................19 
Table 11.4.1.1 Summary of Pharmacokinetic Parameters of Untransformed Data: 
Lofexidine (N = XX subjects) ..............................................................................................20 
Table 11.4.1.2: Summary of Primary Endpoints Based on Plasma Lofexidine 
Concentrations (Ln-transformed): Treatment A vs. Treatment B (Fasted BE) ....................22 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 7 of 49 
 
Table 11.4.1.3: Summary of Primary Endpoints Based on Plasma Lofexidine 
Concentrations (Ln-transformed): Treatment C vs. Treatment A (Food Effect) .................23 
Table 12.2.2.1 Summary of Treatment-Emergent Adverse Events by System Organ 
Class and MedDRA Preferred Term ....................................................................................24 
Table 12.5.1 Summary of Vital Signs .......................................................................................25 
Table 12.5.2 Shift Table for Changes from Baseline in ECGs .................................................26 
Table 12.5.3 Columbia-Suicide Severity Rating Scale – Ideation and Behavior .....................27 
Table 12.5.4 Columbia-Suicide Severity Rating Scale – Most Severe Ideation .......................28 
Table 14.2.1 Summary of Plasma Lofexidine Concentrations (units/mL) – (Treatment 
A) ..........................................................................................................................................29 
Table 14.2.2 Summary of Plasma Lofexidine Concentrations (units/mL) – (Treatment 
B) ..........................................................................................................................................29 
Table 14.2.3 Summary of Plasma Lofexidine Concentrations (units/mL) – (Treatment 
C) ..........................................................................................................................................29 
Table 14.2.4 Summary of PK Parameters Based on Plasma Lofexidine Concentrations – 
(Treatment A) .......................................................................................................................30 
Table 14.2.5 Summary of PK Parameters Based on Plasma Lofexidine Concentrations – 
(Treatment B) .......................................................................................................................30 
Table 14.2.6 Summary of PK Parameters Based on Plasma Lofexidine Concentrations – 
(Treatment C) .......................................................................................................................30 
Table 14.2.7 Summary of Taste Assessment Questionnaire Results (Treatment A or C) ........31 
Listing 16.2.1 Discontinued Subjects........................................................................................34 
Listing 16.2.2 Protocol Deviations ...........................................................................................35 
Listing 16.2.3 Subjects Excluded from Statistical Analysis .....................................................36 
Listing 16.2.4.1 Subject Demographics ....................................................................................37 
Listing 16.2.4.2 Prior and Concomitant Medications ...............................................................38 
Listing 16.2.5.1 Dosing Date, Time, and Treatment Schedule .................................................39 
Listing 16.2.5.2 Deviations from Scheduled Collection Times ................................................40 
Listing 16.2.5.3 Taste Assessment Questionnaire (Treatment A or C) ....................................41 
Listing 16.2.7 Adverse Events ..................................................................................................42 
Listing 16.2.8.1 Serum Chemistry Laboratory Test Results .....................................................43 
Listing 16.2.8.2 Hematology Laboratory Test Results .............................................................43 
Listing 16.2.8.3 Urinalysis Laboratory Test Results ................................................................43 
Listing 16.2.8.4 Vital Signs ......................................................................................................44 
Listing 16.2.8.5 Electrocardiogram Results ..............................................................................45 
Listing 16.2.8.6 Physical Examination Results .........................................................................47 
Listing 16.2.8.7 Genotyping Results (If Applicable) ................................................................48 
Figure 11.4.1.1 Mean Plasma Lofexidine Concentrations ........................................................49 
Figure 11.4.1.2 Mean Plasma Lofexidine Concentrations – Semi-logarithmic Scale ..............49 
Figure 14.2.1 Mean Plasma Lofexidine Concentrations (Including Error-bars) – 
Treatment A ..........................................................................................................................49 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 8 of 49 
 
Figure 14.2.2 Mean Plasma Lofexidine Concentrations (Including Error-bars) – 
Treatment B ..........................................................................................................................49 
Figure 14.2.3 Mean Plasma Lofexidine Concentrations (Including Error-bars) – 
Treatment C ..........................................................................................................................49 
Appendix 16.1.9 Individual Plasma Lofexidine Concentrations by Subject ............................49 
Appendix 16.1.9 Individual Plasma Lofexidine Concentrations by Subject – Semi-
logarithmic Scale ..................................................................................................................49 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 9 of 49 
 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the final Clinical Study Protocol USWM-LX2-
1001 / Study No. 
(Amendment 4) dated 25 Jan 2021. The SAP provides details on the 
planned statistical methodology for the analysis of the study data. The SAP also outlines the 
statistical programming specifications for the tables, listings and figures. 
This SAP describes the study endpoints, derived variables, anticipated data transformations and 
manipulations, and other details of the analyses not provided in the study protocol. This SAP 
therefore outlines in detail all other aspects pertaining to the planned analyses and presentations 
for this study. 
The following documents were reviewed in preparation of this SAP: 
• Final Clinical Study Protocol USWM-LX2-1001 / Study No. 
 (Amendment 4) 
dated 25 Jan 2021 
• Note to File/Memo to File dated 08 Feb 2021 
• Electronic Case Report Form (eCRF) Spec Version 1.1 dated 04 Mar 2021 
This SAP has been developed and finalized prior to database lock of the clinical database for 
Protocol USWM-LX2-1001 / Study No.
 
2. 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. 
3. OVERALL STUDY DESIGN 
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 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 10 of 49 
 
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.  
† 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. 
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 until after the 54-hour blood sample collection in each study period. The interval 
between doses will be at least 7 days.   
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. 
For evaluation of the safety endpoint, the following assessments will be performed throughout the 
study: collection of medical history and Adverse Events (AEs), laboratory tests, vital signs, 
physical examination, 12-lead electrocardiograms (ECGs), and Columbia Suicidality Severity 
Rating Scale (C-SSRS) assessments. No formal statistical testing will be performed on safety 
variables. 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 11 of 49 
 
STUDY SCHEMATIC 
Study Phase 
Screening 
Periods I, II and III 
End of Study 
Day 3  
Period III 
Activity 
Within 28 days 
of Day 1 
Check-In 
Day -1 
Day  
1 
Day  
2 
Day  
3 
Informed Consent 
X 
 
 
 
 
 
Social, Medical History and 
Demographic Data 
X 
 
 
 
 
 
Physical Examination1 
X 
X 
 
 
X 
X 
C-SSRS2 
 
X 
 
 
X 
X 
Virology Testing 
X 
 
 
 
 
 
FSH testing (if applicable)3 
X 
 
 
 
 
 
12 Lead ECG4 
X 
X 
X 
 
X 
X 
Clinical Lab Tests5 
X 
 
 
 
 
X 
Inclusion/Exclusion 
X 
 
 
 
 
 
Eligibility 
 
X 
 
 
 
 
Vital Signs4 
X 
X 
X 
 
X 
X 
Drug and Alcohol Screen6 
X 
X 
 
 
 
 
Serum Pregnancy Test7  
X 
 
 
 
 
X 
Urine Pregnancy Test7  
 
X 
 
 
 
 
Prior and Concomitant Medication  
X 
X 
X 
X 
X 
X 
Confinement8 
 
X 
X 
X 
X 
 
Genotype sampling9 
 
 
X 
 
 
 
High-fat, high-calorie breakfast10 
 
 
X  
 
 
 
Dosing11 
 
 
X 
 
 
 
Taste Assessment12 
 
 
X 
 
 
 
PK sampling13 
 
 
X 
X 
X 
 
Adverse Events14 
 
X 
X 
X 
X 
X 
1. 
To be performed as specified in Sections 5.3.1.1 (screening) and 5.5.5 of the Clinical Study Protocol. 
2. 
C-SSRS to be obtained as specified in Section 5.5.5 of the Clinical Study Protocol. 
3. 
To be performed as specified in Appendix 8.1.6 of the Clinical Study Protocol, if applicable. 
4. 
ECGs and vital signs to be measured as specified in Sections 5.3.1.1 and 5.3.3 (screening) and 5.5.5 of the Clinical Study 
Protocol. Note: ECG to be conducted at check-in for Periods II and III only.  
5. 
Clinical laboratory tests (see Appendix 8.1.1 of the Clinical Study Protocol) to be performed as specified in Sections 5.3.1.1 
(screening) and 5.5.4 of the Clinical Study Protocol. 
6. 
For all subjects, test results must be negative before drug will be administered to the subject. Alcohol tested at check-in only. 
Drug and alcohol tests, as appropriate, to be performed as specified in Appendix 8.1.3 of the Clinical Study Protocol (at 
screening) and Appendix 8.1.4 of the Clinical Study Protocol (at check-in). 
7. 
Female subjects only. For all female subjects, test results must be negative before drug will be administered to the subject. 
Pregnancy tests to be performed as specified in Appendix 8.1.5 of the Clinical Study Protocol. 
8. 
Subjects should enter the clinical facility at least 10.5 hours before dosing and will remain confined until at least 54 hours 
after dosing in each study period. 
9. 
Blood sample to be collected in Period I as specified in Appendix 8.1.2 of the Clinical Study Protocol. 
10. The standardized high-fat, high-calorie breakfast will be provided as specified in Section 5.4.4 of the Clinical Study 
Protocol. 
11. Single dose to be administered as specified in Section 5.4.1 of the Clinical Study Protocol. 
12. Treatments A or C only. To be performed as outlined in Section 5.4.1 and Appendix 8.2 of the Clinical Study Protocol. 
13. Blood samples to be collected as specified in Section 5.6 of the Clinical Study Protocol. 
14. From dosing in Period I until the end of the study. 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 12 of 49 
 
4. RANDOMIZATION 
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. 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. ANALYSIS POPULATIONS 
6.1 Pharmacokinetic Population 
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. 
6.2 Safety Population 
The safety population will include all subjects who are administered at least one dose of a study 
treatment (A, B or C). 
7. STATISTICAL ANALYSIS METHODS 
Data will be summarized with respect to demographic, baseline characteristics, safety, and 
pharmacokinetic (PK) variables. 
For categorical variables, the number and percent of each category within a parameter will be 
calculated for non-missing data. For continuous variables, statistics will include number of 
observations, mean, standard deviation, median, minimum, and maximum values. 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 13 of 49 
 
7.1 Baseline Characteristics 
7.1.1 Baseline Demographics 
Demographic information collected at screening includes age, sex, ethnicity, race, body weight 
(lbs), height (in), BMI, and tobacco use. Body weight and height will be converted into kg and cm, 
respectively, for presentation in listings and tables. 
All data will be listed by subject. A summary table will be presented for the safety population. 
7.1.2 Medical History 
Only clinically significant medical history data, if they exist, will be presented and listed by 
subject. 
7.2 Pharmacokinetic and Statistical Analyses 
Pharmacokinetic and statistical services will be performed by 
 
. SAS®, Version 9.4 or higher will be used for all pharmacokinetic and statistical 
calculations. 
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.  
Descriptive statistics (n, mean, SD, % coefficient of variation [%CV], minimum, median, 
maximum, geometric mean, geometric CV) will be reported for lofexidine concentrations at each 
time point by treatment. 
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 collections. Actual sample collection time will be used for 
calculating the pharmacokinetic parameters, although data will be summarized referencing the 
scheduled sample collection times. 
7.2.1 Pharmacokinetic Parameters 
The pharmacokinetic parameters will be determined from the plasma concentration data using a 
non-compartmental model. 
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 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 14 of 49 
 
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-∞. 
Descriptive statistics (n, mean, SD, % coefficient of variation (%CV), geometric mean, minimum, 
median, maximum) will be reported for all PK parameters.  
7.2.2 Statistical Analyses 
A 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. 
Two-sided 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. 
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. 
7.3 Safety Analysis 
No formal statistical testing will be performed on safety variables. 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 15 of 49 
 
7.3.1 Adverse Events 
Adverse events (AEs) and Serious Adverse Events (SAEs) will be collected through both solicited 
and unsolicited means from dosing in Period I until the end of the study.  
All reported AEs will be coded and classified according to the MedDRA Version 23.0 or higher 
adverse event dictionary. Each adverse event is to be evaluated for date of start and end, 
seriousness, severity, causal relationship to study treatment, action taken and outcome. The 
severity is characterized as mild, moderate or severe. The relationship to the study treatment is 
characterized as unrelated or related. 
Adverse events will be listed by subject, treatment, system organ class, and preferred term. The 
incidence of AEs will be summarized by system organ class (SOC), preferred term (PT) and 
treatment. Subjects will be counted once per preferred term and once per system organ class, per 
treatment. The system organ classes will be ordered by decreasing total frequency then 
alphabetically. The preferred terms within each system organ class will be ordered by decreasing 
total frequency then alphabetically. 
The summary table for Adverse Events will be based upon the safety population. AEs and SAEs 
will be summarized by overall number of AEs in the final report text, per treatment. The number 
of AEs leading to withdrawal from the study or SAEs will also be summarized in text.   
7.3.2 Vital Signs 
Sitting/supine vital signs assessment (temperature, respiration rate, pulse, and blood pressure) and 
orthostatic blood pressure assessment (within 3 minutes of standing from a sitting/supine position) 
will be performed at the screening visit. 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. 
Descriptive statistics will be used to summarize the observed values by treatment at each time 
point and the change from baseline at each post-dose time point. Vital signs will be listed by 
subject. 
7.3.3 ECG 
A 12-lead ECG will be conducted in triplicate for all subjects at the screening visit. A 12-lead ECG 
will also be performed at pre-dose (in triplicate) 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). 
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. Safety 12-lead ECG parameters will be listed by subject 
with any out of normal range values flagged. 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 16 of 49 
 
7.3.4 Physical Examination 
A complete physical examination (including height and weight) will be performed at screening. 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. 
Physical examination results will be listed by subject.  
7.3.5 Concomitant Medications 
All prior and concomitant medications taken since screening until the end of the study will be 
listed by subject. 
7.3.6 Clinical Laboratory Tests 
All subjects will have chemistry, hematology, and urinalysis performed at screening and end of 
study.  
Clinical laboratory results will be listed by subject and any clinically significant out of range 
laboratory results will be flagged. 
7.3.7 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. 
For 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.  
7.4 Taste Assessment 
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. 
Taste Assessment Questionnaire results will be listed by treatment then by subject. 
7.5 Multiple Comparisons 
No multiple comparison adjustment will be made in this study. 
7.6 Interim Analyses 
There is no interim analysis planned in this study. 
8. PK Reconciliation 
Biostatistics team will reconcile the plasma concentration data sent by the bioanalytical laboratory 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 17 of 49 
 
and the PK sample collection times from the SDTM dataset (i.e., BE domain). This reconcile step 
will be verified and documented appropriately.  
9. TABLE, LISTING AND FIGURE SHELLS 
The following shells are presented in order to provide a framework for the display of data from 
this study. These shells may not be reflective of every aspect of this study but are intended to show 
the general layout of the Tables, Listings and Figures that will be included in the final clinical 
study report. Tables, Listings, and Figures are numbered following the ICH structure. Table 
headers, variables names and footnotes will be modified as needed following data analyses. In 
addition to the standard SDTM datasets; the ADaM datasets; ADSL, ADAE, ADPC and ADPP 
will be programmed and submitted. 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 18 of 49 
 
Table 10.1.1 Subject Disposition 
Subject Disposition 
Overall 
N = xx 
Subjects Randomized 
xx (xx.x%) 
Subjects included in Safety Population 
xx (xx.x%) 
Subjects included in Pharmacokinetic Population 
xx (xx.x%) 
Total Discontinued 
xx (xx.x%) 
 
 
Reason for Discontinuation 
xx (xx.x%) 
Adverse Event 
xx (xx.x%) 
Non-Compliance 
xx (xx.x%) 
Positive Substance Abuse Screen 
xx (xx.x%) 
Withdrawal by Subject 
xx (xx.x%) 
… 
xx (xx.x%) 
 
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Page 1 of N 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 19 of 49 
 
Table 11.2.1 Summary of Demographic Data (Safety Population) 
 
Overall 
N = xx 
Age (years) 
Mean ± SD 
xx.x ± xx.x 
Range (Min., Max.) 
xx, xx 
Median 
xx 
Age Groups 
< 18 
x (xx.x%) 
18 – 40 
x (xx.x%) 
41 – 64 
x (xx.x%) 
65 – 75 
x (xx.x%) 
> 75 
x (xx.x%) 
Sex 
Male 
x (xx.x%) 
Female 
x (xx.x%) 
Ethnicity* 
Hispanic or Latino 
x (xx.x%) 
Not Hispanic or Latino 
x (xx.x%) 
Race* 
American Indian or Alaska Native 
x (xx.x%) 
Asian 
x (xx.x%) 
Black or African American 
x (xx.x%) 
Native Hawaiian or Other Pacific Islander 
x (xx.x%) 
White 
x (xx.x%) 
Multiple 
x (xx.x%) 
BMI 
(kg/m2) 
Mean ± SD 
xx.x ± xx.x 
Range (Min., Max.) 
xx, xx 
Median 
xx 
Other Factors 
Height 
(cm) 
Mean ± SD 
xx.x ± xx.x 
Range (Min., Max.) 
xx, xx 
Median 
xx 
Weight 
(kg) 
Mean ± SD 
xx.x ± xx.x 
Range (Min., Max.) 
xx, xx 
Median 
xx 
Tobacco Users† 
Yes 
x (xx.x%) 
No 
x (xx.x%) 
* Categories based on FDA Guidance “Collection of Race and Ethnicity Data in Clinical Trials”, Issue 
Date: October 26, 2016. 
† Defined as current tobacco user (having used tobacco- or nicotine-containing products within 30 days 
before initial dosing). 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 20 of 49 
 
Table 11.4.1.1 Summary of Pharmacokinetic Parameters of Untransformed Data: 
Lofexidine (N = XX subjects) 
Pharmacokinetic 
Parameter 
Treatment 
N 
(# datasets) 
Arithmetic mean ± SD 
(%CV)* 
Min. 
Median 
Max. 
AUC0-t 
(units·hr/mL) 
A 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
B 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
AUC0-∞ 
(units·hr/mL) 
A 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
B 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
AUC0-t/ 
AUC0-∞ 
A 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
B 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
Cmax 
(units/mL) 
A 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
B 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
Tmax 
(hr) 
A 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
B 
x 
xxx.xxxx ± xx.xxxx 
(xx.xxxx) 
xxx.xxxx 
xxx.xxxx 
xxx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
λz 
(hr-1) 
A 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
B 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 21 of 49 
 
Pharmacokinetic 
Parameter 
Treatment 
N 
(# datasets) 
Arithmetic mean ± SD 
(%CV)* 
Min. 
Median 
Max. 
T1/2 
(hr) 
A 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
B 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
CL/F 
(units) 
A 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
B 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
Vz/F 
(units) 
A 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
B 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
C 
x 
xx.xxxx ± xx.xxxx 
(xx.xxxx) 
xx.xxxx 
xx.xxxx 
xx.xxxx 
* %CV is calculated as 100*SD/Mean 
 
Created on: DDMMMYYYY 
Page 1 of N 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 22 of 49 
Table 11.4.1.2: Summary of Primary Endpoints Based on Plasma Lofexidine Concentrations (Ln-transformed): Treatment A 
vs. Treatment B (Fasted BE) 
Parameter 
Trt. 
LS 
Geometric 
Mean  
Standard 
Error 
Geometric CV 
(%) 
Contrast 
(# subjects) 
LSGM 
Ratio 
(%) 
90% 
Confidence 
Interval (%) 
ISCV (%)* 
P-value 
Period 
P-value 
Sequence 
90% CI 
within 80-
125% 
AUC0-t 
(units·hr/mL) 
A 
xx 
xx 
xx.x 
A vs B 
(n = xx) 
xx. xx 
xx. xx - xx. xx 
xx.x 
x.xxxx 
x.xxxx 
Yes/No 
 
B 
xx 
xx 
xx.x 
 
 
 
 
 
 
 
AUC0-∞ 
(units·hr /mL) 
A 
xx 
xx 
xx.x 
A vs B 
(n = xx) 
xx. xx 
xx. xx - xx. xx 
xx.x 
x.xxxx 
x.xxxx 
Yes/No 
 
B 
xx 
xx 
xx.x 
 
 
 
 
 
 
 
Cmax 
(units/mL) 
A 
xx 
xx 
xx.x 
A vs B 
(n = xx) 
xx. xx 
xx. xx - xx. xx 
xx.x 
x.xxxx 
x.xxxx 
Yes/No 
 
B 
xx 
xx 
xx.x 
 
 
 
 
 
 
 
* ISCV (Intra-subject coefficient of variation) is calculated as sqrt[exp(MSE)-1] using the model mean square error. 
 
Created on: DDMMMYYYY 
Page 1 of N 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 23 of 49 
Table 11.4.1.3: Summary of Primary Endpoints Based on Plasma Lofexidine Concentrations (Ln-transformed): Treatment C 
vs. Treatment A (Food Effect) 
Parameter 
Trt. 
LS 
Geometric 
Mean 
Standard 
Error 
Geometric CV 
(%) 
Contrast 
(# subjects) 
LSGM 
Ratio 
(%) 
90% 
Confidence 
Interval (%) 
ISCV (%)* 
P-value 
Period 
P-value 
Sequence 
90% CI 
within 80-
125% 
AUC0-t 
(units·hr/mL) 
C 
xx 
xx 
xx.x 
C vs A 
(n = xx) 
xx. xx 
xx. xx - xx. xx 
xx.x 
x.xxxx 
x.xxxx 
Yes/No 
 
A 
xx 
xx 
xx.x 
 
 
 
 
 
 
 
AUC0-∞ 
(units·hr /mL) 
C 
xx 
xx 
xx.x 
C vs A 
(n = xx) 
xx. xx 
xx. xx - xx. xx 
xx.x 
x.xxxx 
x.xxxx 
Yes/No 
 
A 
xx 
xx 
xx.x 
 
 
 
 
 
 
 
Cmax 
(units/mL) 
C 
xx 
xx 
xx.x 
C vs A 
(n = xx) 
xx. xx 
xx. xx - xx. xx 
xx.x 
x.xxxx 
x.xxxx 
Yes/No 
 
A 
xx 
xx 
xx.x 
 
 
 
 
 
 
 
* ISCV is calculated as sqrt[exp(MSE)-1] using the model mean square error. 
 
Created on: DDMMMYYYY 
Page 1 of N 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 24 of 49 
Table 12.2.2.1 Summary of Treatment-Emergent Adverse Events by System Organ Class and MedDRA Preferred Term 
System Organ Class/MedDRA Preferred Term 
Treatment A 
n (%) 
Treatment B 
n (%) 
Treatment C 
n (%) 
Overall 
n (%) 
Subjects having at least one TEAE 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
System Organ Class 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Preferred Term 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Preferred Term 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Preferred Term 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Preferred Term 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
… 
 
 
 
 
n = Number of subjects reporting AE 
% = (Number of subjects reporting AE / number of subjects dosed with respective study drug) x 100 
Subjects counted once per preferred term and once per system organ class, per treatment. 
Treatment A = ## subjects dosed. 
Treatment B = ## subjects dosed. 
Treatment C = ## subjects dosed. 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
Programming Note 1: Subjects with more than one PT for the same SOC will be counted only once. Subjects with more than one incidence of same PT will be 
counted only once. 
Programming Note 2: The system organ classes will be ordered by decreasing overall frequency then alphabetically. The preferred terms within each system organ 
class will be ordered by decreasing overall frequency then alphabetically 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 25 of 49 
Table 12.5.1 Summary of Vital Signs 
 
 
 
Observed Data 
Change from Baseline 
Evaluation 
Treatment 
Time Point 
n 
Mean (SD) 
Median 
Min, Max 
n 
Mean (SD) 
Median 
Min, Max 
Diastolic 
Blood 
Pressure 
(mmHg) 
A 
Pre-dose 
(Baseline) 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
 
 
 
A 
3.5 hr 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
A 
7.5 hr 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
  
etc. 
 
 
 
 
 
 
 
 
 
B 
Pre-dose 
(Baseline) 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
 
 
 
 
B 
3.5 hr 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
B 
7.5 hr 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
 
etc. 
 
 
 
 
 
 
 
 
 
C 
Pre-dose 
(Baseline) 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
 
 
 
 
C 
3.5 hr 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
C 
7.5 hr 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
 
etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse 
(beats/min) 
A 
Pre-dose 
(Baseline) 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
 
 
 
A 
3.5 hr 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
A 
7.5 hr 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
xx 
xx.x (xx.x) 
xx.x 
xx.x, xx.x 
 
etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
Programming Note: If any pre-dose assessment data are missing, the nearest non-missing pre-dose value will be used as the baseline.  
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 26 of 49 
Table 12.5.2 Shift Table for Changes from Baseline in ECGs 
 
 
3.5 Hours Post-dose 
Release 
Treatment Pre-dose 
(Baseline) 
Normal 
n (%) 
Abnormal 
(NCS) 
n (%) 
Abnormal 
(CS) 
n (%) 
Normal 
n (%) 
Abnormal 
(NCS) 
n (%) 
Abnormal 
(CS) 
n (%) 
A 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal (NCS) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal (CS) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
B 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal (NCS) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Abnormal (CS) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
… 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 27 of 49 
Table 12.5.3 Columbia-Suicide Severity Rating Scale – Ideation and Behavior 
C-SSRS Question 
Period I 
Check-in –  
Lifetime 
n (%) 
Period I 
Release –  
Since Last Visit 
n (%) 
Period II 
Check-in – 
Since Last Visit 
n (%) 
Period II 
Release – 
Since Last Visit 
n (%) 
Period III 
Check-in – 
Since Last Visit 
n (%) 
Period III 
Release/Early 
Termination – 
Since Last Visit 
n (%) 
Suicidal Ideation 
 
 
 
 
 
 
Wish to be dead 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Non-specific active suicidal thoughts 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Active suicidal ideation with any methods (not plan) 
without intent to act 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Active suicidal ideation with some intent to act, 
without specific plan 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Active suicidal ideation with specific plan and intent 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Suicidal Behavior 
 
 
 
 
 
 
Engaged in non-suicidal self-injurious behavior 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Preparatory acts or behavior 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Suicidal behavior 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Actual attempt 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Interrupted attempt 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Aborted attempt 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Suicide 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
n = Number of subjects who experience the event (i.e., respond ‘Yes’) 
% = (Number of subjects who experience the event / number of subjects dosed) x 100 
 
Created on: DDMMMYYYY 
Page 1 of N 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 28 of 49 
Table 12.5.4 Columbia-Suicide Severity Rating Scale – Most Severe Ideation 
C-SSRS Question 
Visit 
1 
n (%) 
2 
n (%) 
3 
n (%) 
4 
n (%) 
5 
n (%) 
0 
n (%) 
Most severe ideation type no. 
Period I Check-in – Lifetime 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Frequency 
Period I Check-in – Lifetime 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Duration 
Period I Check-in – Lifetime 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Controllability 
Period I Check-in – Lifetime 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Deterrents 
Period I Check-in – Lifetime 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Reasons for ideation 
Period I Check-in – Lifetime 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Most severe ideation type no. 
Period I Release – Since Last Visit x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
Frequency 
Period I Release – Since Last Visit x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
… 
 
 
 
 
 
 
 
n = Number of subjects in category 
% = (Number of subjects in category / number of subjects dosed) × 100 
 
Created on: DDMMMYYYY 
Page 1 of N 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 29 of 49 
Table 14.2.1 Summary of Plasma Lofexidine Concentrations (units/mL) – (Treatment A) 
Sub. 
Per. Seq. 
Pre-
dose 
0.5 
hr 
0.75 
hr 
1.0 
hr 
1.5 
hr 
2.0 
hr 
3.0 
hr 
4.0 
hr 
5.0 
hr 
7.0 
hr 
10.0 
hr 
16.0 
hr 
24.0 
hr 
30.0 
hr 
… 
54.0 
hr 
3001 
x 
x 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
3002 
x 
x 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
3003 
x 
x 
x.xx 
x.xx 
x.xx 
etc. 
 
 
 
 
 
 
 
 
 
 
 
 
3004 
x 
x 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
3005 
x 
x 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St. Dev. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CV (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Min. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Geometric 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Geometric 
CV (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
Note: Similar listings will be produced for Treatment B and Treatment C. 
 
Table 14.2.2 Summary of Plasma Lofexidine Concentrations (units/mL) – (Treatment B) 
Table 14.2.3 Summary of Plasma Lofexidine Concentrations (units/mL) – (Treatment C) 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 30 of 49 
Table 14.2.4 Summary of PK Parameters Based on Plasma Lofexidine Concentrations – (Treatment A) 
Sub. 
Per. 
Seq. 
AUC 0-t 
(units·hr/mL) 
AUC 0-∞ 
(units·hr/mL) 
AUC 0-t/ 
AUC0-∞ 
Cmax 
(units/mL) 
Tmax 
(h) 
λz 
(hr-1) 
T1/2 
(hr) 
CL/F 
(units) 
Vz/F 
(units) 
3001 
x 
x 
x.xxx 
x.xxx 
x.xxx 
x.xxxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
3002 
x 
x 
x.xxx 
x.xxx 
x.xxx 
x.xxxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
3003 
x 
x 
x.xxx 
x.xxx 
x.xxx 
x.xxxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
3004 
x 
x 
x.xxx 
x.xxx 
x.xxx 
x.xxxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
3005 
x 
x 
x.xxx 
x.xxx 
x.xxx 
x.xxxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
… 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
St. Dev. 
 
 
 
 
 
 
 
 
 
 
 
CV (%) 
 
 
 
 
 
 
 
 
 
 
 
Min. 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
Max. 
 
 
 
 
 
 
 
 
 
 
 
Geometric Mean 
 
 
 
 
 
 
 
 
 
 
 
Geometric CV (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
Note: A similar table will be produced for Treatment B and Treatment C. 
Table 14.2.5 Summary of PK Parameters Based on Plasma Lofexidine Concentrations – (Treatment B) 
Table 14.2.6 Summary of PK Parameters Based on Plasma Lofexidine Concentrations – (Treatment C) 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 31 of 49 
Table 14.2.7 Summary of Taste Assessment Questionnaire Results (Treatment A or C) 
 
Treatment A 
N = xx 
n (%) 
Treatment C 
N = xx 
n (%) 
Overall Taste 
 
 
Like very much 
x (xx.x%) 
x (xx.x%) 
Like moderately 
x (xx.x%) 
x (xx.x%) 
Like slightly 
x (xx.x%) 
x (xx.x%) 
Neither like nor dislike 
x (xx.x%) 
x (xx.x%) 
Dislike slightly 
x (xx.x%) 
x (xx.x%) 
Dislike moderately 
x (xx.x%) 
x (xx.x%) 
Dislike very much 
x (xx.x%) 
x (xx.x%) 
Sourness 
 
 
Like very much 
x (xx.x%) 
x (xx.x%) 
Like moderately 
x (xx.x%) 
x (xx.x%) 
Like slightly 
x (xx.x%) 
x (xx.x%) 
Neither like nor dislike 
x (xx.x%) 
x (xx.x%) 
Dislike slightly 
x (xx.x%) 
x (xx.x%) 
Dislike moderately 
x (xx.x%) 
x (xx.x%) 
Dislike very much 
x (xx.x%) 
x (xx.x%) 
Bitterness 
 
 
Like very much 
x (xx.x%) 
x (xx.x%) 
Like moderately 
x (xx.x%) 
x (xx.x%) 
Like slightly 
x (xx.x%) 
x (xx.x%) 
Neither like nor dislike 
x (xx.x%) 
x (xx.x%) 
Dislike slightly 
x (xx.x%) 
x (xx.x%) 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 32 of 49 
 
Treatment A 
N = xx 
n (%) 
Treatment C 
N = xx 
n (%) 
Dislike moderately 
x (xx.x%) 
x (xx.x%) 
Dislike very much 
x (xx.x%) 
x (xx.x%) 
Mouthfeel/Texture 
 
 
Like very much 
x (xx.x%) 
x (xx.x%) 
Like moderately 
x (xx.x%) 
x (xx.x%) 
Like slightly 
x (xx.x%) 
x (xx.x%) 
Neither like nor dislike 
x (xx.x%) 
x (xx.x%) 
Dislike slightly 
x (xx.x%) 
x (xx.x%) 
Dislike moderately 
x (xx.x%) 
x (xx.x%) 
Dislike very much 
x (xx.x%) 
x (xx.x%) 
Grittiness 
 
 
Like very much 
x (xx.x%) 
x (xx.x%) 
Like moderately 
x (xx.x%) 
x (xx.x%) 
Like slightly 
x (xx.x%) 
x (xx.x%) 
Neither like nor dislike 
x (xx.x%) 
x (xx.x%) 
Dislike slightly 
x (xx.x%) 
x (xx.x%) 
Dislike moderately 
x (xx.x%) 
x (xx.x%) 
Dislike very much 
x (xx.x%) 
x (xx.x%) 
Aftertaste 
 
 
Like very much 
x (xx.x%) 
x (xx.x%) 
Like moderately 
x (xx.x%) 
x (xx.x%) 
Like slightly 
x (xx.x%) 
x (xx.x%) 
Neither like nor dislike 
x (xx.x%) 
x (xx.x%) 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 33 of 49 
 
Treatment A 
N = xx 
n (%) 
Treatment C 
N = xx 
n (%) 
Dislike slightly 
x (xx.x%) 
x (xx.x%) 
Dislike moderately 
x (xx.x%) 
x (xx.x%) 
Dislike very much 
x (xx.x%) 
x (xx.x%) 
 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 34 of 49 
Listing 16.2.1 Discontinued Subjects 
Subject 
No. 
Discontinuation Reason 
Date of 
Discontinuation 
Time of 
Discontinuation 
Discontinuation 
Related to COVID-19 
Pandemic 
xxxx 
Withdrawal By Subject 
dd/Mmm/yyyy 
hh:mm 
 
xxxx 
Withdrawal By Subject 
dd/Mmm/yyyy 
hh:mm 
 
… 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
Programming Notes: Listings will be presented by subject number. Secondary fields for AEs, PDs, and Other must be listed 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 35 of 49 
Listing 16.2.2 Protocol Deviations 
Subject No. 
Type of Protocol Deviation 
Deviation Date 
PD Related to 
COVID-19 Pandemic 
xxxx 
Consumption or use of a restricted item 
dd/Mmm/yyyy 
 
xxxx 
Assessment performed out of window: Vital signs 
dd/Mmm/yyyy 
 
… 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
Programming Note: Secondary fields for deviation categories of Assessment Not Performed and Assessment Performed Out of Window are required to be 
presented. 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 36 of 49 
Listing 16.2.3 Subjects Excluded from Statistical Analysis 
Sub.  
Excluded from Analysis 
Reason for Exclusion from Analysis 
Applicable 
Treatment(s) 
xxxx 
A vs B 
Subject did not have sufficient pharmacokinetic data for this analysis 
B 
xxxx 
A vs B , C vs A 
Pre-dose concentration > 5% of Cmax 
A 
xxxx 
C vs A 
Cmax observed at first post-dose sampling timepoint 
C 
xxxx 
A vs B, C vs A 
Data excluded because of protocol deviation 
B, C 
… 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 37 of 49 
Listing 16.2.4.1 Subject Demographics 
Subject 
No. 
Sex 
Age 
(yrs) 
Ethnicity 
Race 
Tobacco 
User 
Height 
(in) 
Weight 
(lbs) 
BMI 
(kg/m2) 
xxxx 
Male 
43 
Not Hispanic or Latino 
Black or African American 
No 
xx 
xx 
xx.x 
xxxx 
Male 
36 
Not Hispanic or Latino 
Black or African American 
No 
xx 
xx 
xx.x 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 38 of 49 
Listing 16.2.4.2 Prior and Concomitant Medications 
Subject 
No. 
Medication  
Indication 
Dose 
Route 
Frequency* Date Started 
Date Stopped 
Therapeutic 
Drug Class 
xxxx 
Vitamin D 
General health 
1000 IU 
Oral 
QD 
--/Mmm/yyyy 
Ongoing 
 
xxxx 
Multivitamin 
General health 
1 Tablet 
Oral 
QD 
dd/Mmm/yyyy 
dd/Mmm/yyyy 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*PRN - As needed; QD - Daily (once per day); Q4H - Every 4 hours; Q8H - Every 8 hours; Q12H - Every 12 hours; BID - Twice per day; 
TID - 3 times per day; QID - 4 times per day; QOD - Every other day; QS - Every week; QM - Every month; Q3M - Every 3 months 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
Programming Note: Only the applicable abbreviations need to be included in the footnote. 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 39 of 49 
Listing 16.2.5.1 Dosing Date, Time, and Treatment Schedule 
Subject No. 
Period 
Date 
Time 
Treatment 
xxxx 
I 
dd/Mmm/yyyy 
hh:mm 
A 
xxxx 
II 
dd/Mmm/yyyy 
hh:mm 
B 
xxxx 
III 
dd/Mmm/yyyy 
hh:mm 
C 
xxxx 
I 
dd/Mmm/yyyy 
hh:mm 
C 
xxxx 
II 
dd/Mmm/yyyy 
hh:mm 
A 
xxxx 
III 
dd/Mmm/yyyy 
hh:mm 
B 
xxxx 
I 
dd/Mmm/yyyy 
hh:mm 
B 
xxxx 
II 
dd/Mmm/yyyy 
hh:mm 
A 
xxxx 
III 
dd/Mmm/yyyy 
hh:mm 
C 
… 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 40 of 49 
Listing 16.2.5.2 Deviations from Scheduled Collection Times 
Subject No. 
Treatment 
Period 
Sample Time 
(hrs) 
Deviation* 
xxxx 
A 
I 
10.0 
+3 
xxxx 
B 
II 
0.5 – 54.0† 
DFP 
xxxx 
C 
III 
5.0 
+4 
xxxx 
B 
I 
16.0 
+3 
xxxx 
A 
II 
48.0 
NS 
… 
 
 
 
 
 
 
 
 
 
*  Minutes assessment was performed late (+) or early (-). 
   DFP: Dropped from Period 
   DFS: Dropped from Study 
   NS: No Sample Collected 
†Subject did not participate in this portion of the study 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 41 of 49 
Listing 16.2.5.3 Taste Assessment Questionnaire (Treatment A or C) 
Subject 
No. 
Treatment* Overall Taste 
Smell 
Sweetness 
Sourness 
Bitterness 
Mouthfeel/ 
Texture 
Grittiness 
Aftertaste 
xxxx 
A 
Like very much Like very much Like very much 
Like very much Like very much Like very much Like very much Like very much 
xxxx 
A 
Like 
moderately 
Like 
moderately 
Like 
moderately 
Like 
moderately 
Like 
moderately 
Like 
moderately 
Like 
moderately 
Like 
moderately 
xxxx 
A 
Like slightly 
Like slightly 
Like slightly 
Like slightly 
Like slightly 
Like slightly 
Like slightly 
Like slightly 
xxxx 
A 
Neither like nor 
dislike 
Neither like nor 
dislike 
Neither like nor 
dislike 
Neither like nor 
dislike 
Neither like nor 
dislike 
Neither like nor 
dislike 
Neither like nor 
dislike 
Neither like nor 
dislike 
xxxx 
C 
Dislike slightly Dislike slightly Dislike slightly Dislike slightly Dislike slightly Dislike slightly Dislike slightly Dislike slightly 
xxxx 
C 
Dislike 
moderately 
Dislike 
moderately 
Dislike 
moderately 
Dislike 
moderately 
Dislike 
moderately 
Dislike 
moderately 
Dislike 
moderately 
Dislike 
moderately 
xxxx 
C 
Dislike very 
much 
Dislike very 
much 
Dislike very 
much 
Dislike very 
much 
Dislike very 
much 
Dislike very 
much 
Dislike very 
much 
Dislike very 
much 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Taste Assessment Questionnaire completed once by each subject, only after the subject’s first dose of lofexidine granules (Treatment A or C). 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 42 of 49 
Listing 16.2.7 Adverse Events 
Subject 
No. 
System Organ Class/ 
MedDRA Preferred Term/ 
AE Term 
Treatment 
Onset 
Date 
Time 
Onset 
Date 
Time 
Severity 
Relationship Outcome 
Action 
Taken 
with Study 
Treatment 
Other 
Action 
Taken 
SAE 
xxxx 
Nervous system disorders / 
Headache / Headache 
A 
dd/Mmm/yyyy 
hh:mm  
dd/Mmm/yyyy 
hh:mm  
Mild 
Unrelated 
Recovered/ 
Resolved 
Dose Not 
Changed 
None 
No 
xxxx 
Investigations / Blood 
pressure increased / Blood 
pressure increased 
C 
dd/Mmm/yyyy 
hh:mm 
dd/Mmm/yyyy 
hh:mm 
Moderate Related 
Recovered/ 
Resolved  
Dose Not 
Changed 
None 
No 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
  
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 43 of 49 
Listing 16.2.8.1 Serum Chemistry Laboratory Test Results 
Subject 
No. 
Visit 
Date 
Time 
Test 
Result 
Units 
Clinically Significant 
(if out of range) 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Alanine Aminotransferase 
xx.x 
U/L 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Alkaline Phosphatase 
xx.x 
U/L 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Aspartate Aminotransferase 
xx.x 
U/L 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Bilirubin 
xx.x 
mg/dL 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Creatinine 
xx.x 
mg/dL 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Glucose 
xx.x 
mg/dL 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Potassium 
xx.x 
mmol/L 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Urea Nitrogen 
xx.x 
mg/dL 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Magnesium 
xx.x 
mg/dL 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Sodium 
xx.x 
mEq/L 
xxxx 
Screening 
dd/Mmm/yyyy 
hh:mm 
Chloride 
xx.x 
mEq/L 
xxxx 
End of Study/  
Early Termination 
dd/Mmm/yyyy 
hh:mm 
Alanine Aminotransferase 
xx.x 
U/L 
… 
… 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 
Note: Similar listings will be produced for hematology and urinalysis. 
 
Listing 16.2.8.2 Hematology Laboratory Test Results 
Listing 16.2.8.3 Urinalysis Laboratory Test Results 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 44 of 49 
Listing 16.2.8.4 Vital Signs 
Subject 
No. 
Treatment Visit 
Time Point Date 
Time 
Vital Sign 
Result Units 
Clinically 
Significant 
(if out of 
range) 
xxxx 
 
Screening 
 
dd/Mmm/yyyy hh:mm Diastolic Blood Pressure 
xx 
mmHg 
 
xxxx 
 
Screening 
 
dd/Mmm/yyyy hh:mm Pulse 
xx 
beats/min 
 
xxxx 
 
Screening 
 
dd/Mmm/yyyy hh:mm Respiration Rate 
xx 
breaths/min  
xxxx 
 
Screening 
 
dd/Mmm/yyyy hh:mm Systolic Blood Pressure 
xxx 
mmHg 
 
xxxx 
 
Screening 
 
dd/Mmm/yyyy hh:mm Temperature 
xx.x 
F 
 
xxxx 
 
Screening Repeat 1 
 
dd/Mmm/yyyy hh:mm Diastolic Blood Pressure 
xx 
mmHg 
 
xxxx 
 
Screening Repeat 1 
 
dd/Mmm/yyyy hh:mm Systolic Blood Pressure 
xxx 
mmHg 
 
xxxx 
A 
Period I 
Check-in 
dd/Mmm/yyyy hh:mm Diastolic Blood Pressure 
xx 
mmHg 
 
xxxx 
A 
Period I 
Check-in 
dd/Mmm/yyyy hh:mm Pulse 
xx 
beats/min 
 
xxxx 
A 
Period I 
Check-in 
dd/Mmm/yyyy hh:mm Systolic Blood Pressure 
xxx 
mmHg 
 
xxxx 
A 
Period I 
Check-in 
dd/Mmm/yyyy hh:mm Temperature 
xx.x 
F 
 
xxxx 
A 
Period I 
Pre-dose 
dd/Mmm/yyyy hh:mm Diastolic Blood Pressure 
xx 
mmHg 
 
xxxx 
A 
Period I 
Pre-dose 
dd/Mmm/yyyy hh:mm Pulse 
xx 
beats/min 
 
xxxx 
A 
Period I 
Pre-dose 
dd/Mmm/yyyy hh:mm Systolic Blood Pressure 
xxx 
mmHg 
 
xxxx 
A 
Period I 
3.5 hr 
dd/Mmm/yyyy hh:mm Diastolic Blood Pressure 
xx 
mmHg 
 
xxxx 
A 
Period I 
3.5 hr 
dd/Mmm/yyyy hh:mm Pulse 
xx 
beats/min 
 
xxxx 
A 
Period I 
3.5 hr 
dd/Mmm/yyyy hh:mm Systolic Blood Pressure 
xxx 
mmHg 
 
xxxx 
A 
Period I 
7.5 hr 
dd/Mmm/yyyy hh:mm Diastolic Blood Pressure 
xx 
mmHg 
 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 45 of 49 
Listing 16.2.8.5 Electrocardiogram Results  
 
Intervals (msec) 
 
Subject 
No. 
Treatment Visit 
Time Point 
Date 
Time 
Vent. 
Rate 
(bpm) 
PR 
QRS 
QT 
QTc 
Result 
Clinical 
Significance 
(if abnormal) 
xxxx 
 
Screening  
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
 
Screening  
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
 
Screening  
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
A 
Period I 
Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
A 
Period I 
Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
A 
Period I 
Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
A 
Period I 
3.5 hr 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
A 
Period I 
Release 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
 
Period II Check-in 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
 
Period II Check-in 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
Variant 
 
xxxx 
 
Period II Check-in 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
B 
Period II Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
B 
Period II Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
B 
Period II Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
B 
Period II 3.5 hr 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Abnormal Clinically 
Significant 
xxxx 
B 
Period II Release 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
 
Period III Check-in 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
 
Period III Check-in 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
 
Period III Check-in 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
C 
Period III Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
C 
Period III Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
C 
Period III Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
C 
Period III 3.5 hr 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 46 of 49 
 
Intervals (msec) 
 
Subject 
No. 
Treatment Visit 
Time Point 
Date 
Time 
Vent. 
Rate 
(bpm) 
PR 
QRS 
QT 
QTc 
Result 
Clinical 
Significance 
(if abnormal) 
xxxx 
C 
Period III Release 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Abnormal Not Clinically 
Significant 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx 
 
Screening  
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
xxxx 
B 
Period I 
Pre-dose 
dd/Mmm/yyyy hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
Normal 
 
… 
 
… 
… 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 47 of 49 
Listing 16.2.8.6 Physical Examination Results 
Subject 
No. 
Treatment 
Visit 
Time Point Category 
Result 
Description (if abnormal/changed) 
xxxx 
 
  
 
General Appearance 
  
 
xxxx 
 
Screening 
 
Skin 
Abnormal 
 
xxxx 
 
Screening 
 
EENT 
 
 
xxxx 
 
Screening 
 
Head 
 
 
xxxx 
 
Screening 
 
Neurological 
 
 
xxxx 
 
Screening 
 
Cardiovascular 
 
 
xxxx 
 
Screening 
 
Lungs/Thorax 
 
 
xxxx 
 
Screening 
 
Abdominal 
 
 
xxxx 
 
Screening 
 
Musculoskeletal 
 
 
xxxx 
 
Screening 
 
Extremities 
 
 
xxxx 
A 
Period I 
Check-in 
General Appearance 
No Change 
 
xxxx 
A 
Period I 
Check-in 
Cardiovascular 
Change 
 
xxxx 
A 
Period I 
Check-in 
Lungs/Thorax 
 
 
xxxx 
A 
Period I 
Check-in 
Abdominal 
 
 
xxxx 
A 
Period I 
Release 
General Appearance 
 
 
xxxx 
A 
Period I 
Release 
Cardiovascular 
 
 
xxxx 
A 
Period I 
Release 
Lungs/Thorax 
 
 
xxxx 
A 
Period I 
Release 
Abdominal 
 
 
xxxx 
B 
Period II 
Check-in 
General Appearance 
 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 48 of 49 
Listing 16.2.8.7 Genotyping Results (If Applicable) 
Subject No. 
CYP2D6 Metabolizer Status 
xxxx 
Extensive Metabolizer 
xxxx 
Intermediate Metabolizer 
xxxx 
Poor Metabolizer 
xxxx 
Ultrarapid Metabolizer 
… 
 
 
 
 
 
 
Created on: DDMMMYYYY 
Page 1 of N 
 
 


STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. USWM-LX2-1001 / 
 
LOFEXIDINE GRANULES FOR RECONSTITUTION (ORAL) FORMULATION, 90 µG/ML 
 
USWM-LX2-1001; SAP Ver.1.0  
  Page 49 of 49 
Figure 11.4.1.1 Mean Plasma Lofexidine Concentrations 
Figure 11.4.1.2 Mean Plasma Lofexidine Concentrations – Semi-logarithmic Scale 
 
Figure 14.2.1 Mean Plasma Lofexidine Concentrations (Including Error-bars) – Treatment A 
Figure 14.2.2 Mean Plasma Lofexidine Concentrations (Including Error-bars) – Treatment B 
Figure 14.2.3 Mean Plasma Lofexidine Concentrations (Including Error-bars) – Treatment C 
 
Appendix 16.1.9 Individual Plasma Lofexidine Concentrations by Subject 
Appendix 16.1.9 Individual Plasma Lofexidine Concentrations by Subject – Semi-logarithmic Scale 

Prot_001.pdf: 
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 
 
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; 25 Jan 2021 
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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 
 
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; 25 Jan 2021 
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  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 
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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 
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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 
 
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; 25 Jan 2021 
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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 
 
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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 
 
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; 25 Jan 2021 
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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 
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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 
 
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; 25 Jan 2021 
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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 
 
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; 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 
 
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. 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 
 
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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 
 
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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 
 
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; 25 Jan 2021 
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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 
 
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; 25 Jan 2021 
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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 
 
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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 
 
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; 25 Jan 2021 
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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 
 
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; 25 Jan 2021 
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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 
 
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; 25 Jan 2021 
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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 
 
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; 25 Jan 2021 
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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 
 
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; 25 Jan 2021 
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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 
 
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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 — 
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Administration, Center for Drug Evaluation and Research (CDER), February 2019. 
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Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) 
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2020, Updated December 4, 2020. 
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11. Guidance for Industry. Compliance Policy for the Quantity of Bioavailability and 
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